Title of Invention

GLUCOCORTICOID RECEPTOR MODULATORS

Abstract The present invention provides non-steroidal compounds of formula I which are selective modulators (i.e., agonists and antagonists) of a steroid receptor, specifically, the glucocorticoid receptor. The present invention also provides pharmaceutical compositions containing these compounds and methods for using these compounds to treat animals requiring glucocorticoid receptor agonist or antagonist therapy. Glucocorticoid receptor modulators are useful to treat diseases, such as obesity, diabetes, inflammation and others as described below. The present invention also provides intermediates and processes for preparing these compounds.
Full Text GLUCOCORTICOID RECEPTOR MODULATORS
FIELD OF THE INVENTION |
The present invention provides non-steroidal compounds which are selective
modulators (i.e., agonists and antagonists) of a steroid receptor, specifically, the
glucocorticoid receptor. The present invention also provides pharmaceutical
compositions containing these compounds and methods for using these compound$
to treat animals requiring glucocorticoid receptor agonist and/or antagonist therapy.:
Glucocorticoid receptor modulators are useful to treat diseases, such as obesity,
diabetes, inflammation and others as described below. The present invention also
provides intermediates and processes for preparing these compounds.
BACKGROUND OF THE INVENTION
Nuclear receptors are classically defined as a family of ligand dependent
transcription factors, that are activated in response to ligand binding (R.M. Evans,
240 Science, 889 (1988)). Members of this family include the following receptors:
glucocorticoid, mineralocorticoid, androgen, progesterone and estrogen. Naturally
occurring ligands to these receptors are low molecular weight molecules that play an
important role in health and in many diseases. Excesses or deficiencies of these
ligands can have profound physiological consequences. As an example,
glucocorticoid excess results in Cushing's Syndrome, while glucocorticoid
insufficiency results in Addison's Disease. j
The glucocorticoid receptor (GR) is present in glucocorticoid responsive cellsi
where it resides in the cytosol in an inactive state until it is stimulated by an agonist.
Upon stimulation the glucocorticoid receptor translocates to the cell nucleus where it
specifically interacts with DNA and/or protein(s) and regulates transcription in a
glucocorticoid responsive manner. Two examples of proteins that interact with the
glucocorticoid receptor are the transcription factors, API and NFK-B. Such
interactions result in inhibition of API- and NFic-B- mediated transcription and are
believed to be responsible for some of the anti-inflammatory activity of endogenously
administered glucocorticoids. In addition, glucocorticoids may also exert physiologic
effects independent of nuclear transcription. Biologically relevant glucocorticoid
receptor agonists include cortisol and corticosterone. Many synthetic glucocorticoid
receptor agonists exist including dexamethasone, prednisone and prednisilone. By
definition, glucocorticoid receptor antagonists bind to the receptor and prevent
glucocorticoid receptor agonists from binding and eliciting GR mediated events,
including transcription. RU486 is an example of a non-selective glucocorticoid
receptor antagonist.
U.S. Patent No. 3,683,091 discloses phenanthrene compounds, specifically
certain di-7-hydroxy or methyl-2,3,4,4a,9,10-hexahydrophenanthren-2-one and 4aalkyl
derivatives, hydrogenated derivatives, functional derivatives and optically active
isomers thereof useful as specific anti-acne agents.
Japanese Patent Application, Publication No. 45014056, published 20 May
1970, discloses the manufacture of 1,2,3,4,9,10,11a,12-octahydro-7-methoxy-12(3-
butylphenanthren-2(3-ol and certain of its derivatives useful as antiandrogenic and i
antianabolic drugs.
Japanese Patent Application, Publication No. 6-263688, published 20
September 1994, discloses certain phenanthrene derivatives which are interleukin-1
(IL-1) inhibitors. It also discloses their preparation and certain intermediates thereto,
International Patent Application Publication No. WO 95/10266, published 20 April
1995, discloses the preparation and formulation of certain phenanthrene derivatives
as nitrogen monoxide synthesis inhibitors.
Japanese Patent Application, Publication No. 45-36500, published 20
November 1970, discloses a method of making certain optically active phenanthrene
derivatives which are useful as antiandrogenic agents.
European Patent Application, Publication No. 0 188 396, published 23 July
1986, discloses certain substituted steroid compounds, certain processes and
intermediates for preparing them, their use and pharmaceutical compositions
containing them. These compounds are disclosed to possess antiglucocorticoid
activity, and some of them have glucocorticoid activity.
C.F. Bigge et al., J. Med. Chem. 1993, 36, 1977-1995, discloses the synthesis
and pharmacolgical evaluation of a series of octahydrophenanthrenamines and
certain of their heterocyclic analogues as potential noncompetitive antagonists of th0
AAmethyl-D-aspartate receptor complex. |
i
P.P. Kanjilal et al., J. Org. Chem. 1985, 50, 857-863, discloses synthetic
studies toward the preparation of certain complex diterpenoids.
G, Sinha et al., J. Chem. Soc., Perkin Trans. I (1983), (10), 2519-2528,
discloses the synthesis of the isomeric bridged diketones c/s-3,4,4a,9,10,10a-
hexahydro-1,4a-ethanophenanthren-2(1 /-0,12-dione and frans-3,4,4a,9,10,10ahexahydro-
3,4a-ethanophenanthren-2(1/-/),12-dione by highly regioselective
intramolecular aldol condensations through the stereochemically defined cis- and
frans-2,2-ethylenedioxy-1,2,3,4,4a,9,10,10a-octahydrophenanthren-4aylacetaldehydes.
U.R. Ghatak, M. Sarkar and S.K. Patra, Tetrahedron Letters No. 32, pp.
2929-2931, 1978, discloses a simple stereospecific route to certain polycyclic
bridged-ring intermediates useful in preparing some complex diterpenoids.
P.N. Chakrabortty et al., Indian J. Chem. (1974), 12(9), 948-55, discloses the
synthesis of 1a-methyl-1p,4a(3-dicarboxy-1,2,3,4,4a,9,10,10a3-octahyditophenanthrene,
an intermediate in the synthesis of certain diterpenoids and diterpene
alkaloids, and of 1p,4ap-dicarboxy-1,2,3,4,4a,9,10,10aa-octahydrophenanthrene. i
E. Fujita et al., J. Chem. Soc., Perkin Trans. I (1974), (1), 165-77, discloses
the preparation of enmein from 5-methoxy-2-tetralone via ent-3-p\2-epoxy-i3-
methoxy-17-norkaurane-6a,16a-diol.
H. Sdassi et al., Synthetic Communications, 25(17), 2569-2573 (1995)
discloses the enantioselective synthesis of (R)-(+)-4a-cyanomethyl-6-methoXy-
3,4,9,10-tetrahydrophenanthren-2-one, which is a key intermediate in morphinin
synthesis.
T. Ibuka et al., Yakugaku Zasshi (1967), 87(8), 1014-17, discloses certalin
alkaloids of menispermaceous plants.
Japanese Patent 09052899, dated 25 February 1997, discloses certain
diterpene or triterpene derivatives which are leukotriene antagonists obtained by
extraction from Tripterygium wilfordii for therapeutic use.
U.S. Patent No. 5,696,127 discloses certain nonsteroidal compounds, such $s
5H-chromeno[3,4-f]quinolines, which are selective modulators of steroid receptors.
U.S. Patent No. 5,767, 113 discloses certain synthetic steroid compounds
useful for concurrently activating glucocorticoid-induced response and reducing
multidrug resistance.
Published European Patent Application 0 683 172, published 11 November
1995, discloses certain 11,21-bisphenyl-19-norpregnane derivatives having antiglucocorticoid
activity and which can be used to treat or prevent glucocorticoiddependent
diseases.
D. Bonnet-Delpon et al., Tetrahedron (1996), 52(1), 59-70, discloses certain
CF3-substituted alkenes as good partners in Diels-Alder reactions with Danishefsky's
diene and in 1,3-dipolar cycloadditions with certain nitrones and non-stabilized
azomethine ylides.
International Patent Application Publication No. WO 98/26783, published 25
June 1998, discloses the use of certain steroid compounds with anti-glucocorticoid
activity, with the exception of mifepristone, for preparing medicaments for the
prevention or treatment of psychoses or addictive behavior.
International Patent Application Publication No. WO 98/27986, published 2
July 1998, discloses methods for treating non-insulin dependent Diabetes Mellitus
(NIDDM), or Type II Diabetes, by administering a combination of treatment agents
exhibiting glucocorticoid receptor type I agonist activity and glucocorticoid receptor
type II antagonist activity. Treatment agents such as certain steroid compounds
having both glucocorticoid receptor type I agonist activity and glucocorticoid receptor
type II antagonist activity are also disclosed.
International Patent Application Publication No. WO 98/31702, published 23
July 1998, discloses certain 16-hydroxy-11 -(substituted phenyl)-estra-4,9-diene
derivatives useful in the treatment or prophylaxis of glucocorticoid dependent
diseases or symptoms.
Published European Patent Application 0 903 146, published 24 March 1999,
discloses that the steroid 21-hydroxy-6,19-oxidoprogesterone (21 OH- 6OP) has been
found to be a selective antiglucocorticoid and is used for the treatment of diseases
associated with an excess of glucocorticoids in the body, such as the Cushing's
syndrome or depression.
All of the above cited patents and published patent applications are hereby
incorporated by reference herein in their entirety.
J. A. Findlay et al, Tetrahedron Letters No. 19, pp. 869-872, 1962, discloses
certain intermediates in the synthesis of diterpene alkaloids.
Although there are glucocorticoid receptor therapies in the art, there is a
continuing need for and a continuing search in this field of art for selective
glucocorticoid receptor therapies. Thus, the identification of non-steroidal
compounds which have specificity for one or more steroid receptors, but which have
reduced or no cross-reactivity for other steroid or intracellular receptors, is of
significant value in this field.
SUMMARY OF THE INVENTION
The present invention particularly provides:
compounds of formula I
isomers thereof, prodrugs of said compounds and isomers, and
pharrnaceutically acceptable salts of said compounds, isomers and prodrugs;
wherein m is 1 or 2;
— represents an optional bond;
A is selected from the group consisting of
(Figure Removed)
G, H and I together with 2 carbon atoms from the A-ring or 2 carbon atoms
from the B-ring form a 5-membered heterocyclic ring comprising one or more N, O
S atoms; provided that there is at most one of O and S per ring;
J, K, L and M together with 2 carbon atoms from the B-ring forms a 6-membered
heterocyclic ring comprising 1 or more N atoms;
or
X is a) absent, b) -CHr, c) -CH(OH)- or d) -C(O)-;
R, is a) -H, b) -Z-CF3, c) -(C1C6)alkyl, d) -(C2-C6)alkenyl, e) -(C2-C6)alkynylj
f) -CHO, g) -CH=N-OR12, h) -Z-C(O)OR12, i) -Z-C(0)-NR12R13, j) -Z-C(O)-NR12-Z-hek
k) -Z-NR12R13,1) -Z-NR12het, m) -Z-het, n) -Z-0-het, o) -Z-aryl', p) -Z-O-aryl', q)
-CHOH-aryl' or r) -C(O)-aryl'; wherein aryl1 in substituents o) to r) is substituted
independently with 0, 1 or 2 of the following: -Z-OH, -Z-NR12Ri3, -Z-NRi2-het,
-C(0)NR12R13, -0(0)0(C1C6)alkyl, -C(O)OH, -C(0)-het, -NR12-C(O)-(C1C6)alkyl,
-NR12-C(0)-(C2-C6)alkenyl, -NR12-C(0)-(C2-C6)alkynyl, -NR12-C(O)-Z-het, -ON,
-Z-het, -O-(C1-C3)alkyl-C(O)-NR12R13,-O-(C1-C3)alkyl-C(O)O(C1-C6)alkyll
-NR12-Z-C(O)0(C1C6))alkyll-N(Z-C(O)O(C1-C6)alkyl)2,-NR12-Z-C(O)-NR12R13)
-Z-NR12-S02-R13, -NR12-SO2-het, -C(0)H, -Z-NR12-Z-0(CrC6)alkyl,
-Z-NR12-Z-NR12R13, -Z-NR12-(C3-C6)cycloalkyl, -Z-N(Z-0((C1C6)alkyl)2, -SO2R12,
-SOR12, -SR12, -S02NR12R13, -O-C(O)-(CrC4)alkyl, -0-SO2-(C1-C4)alkyll -halo or
-CF3;
Z for each occurrence is independently a) -(C0-C6)alkyl, b) -(C2-C6)alkenyl ori
c) -(C2-C6)alkynyl;
R2 is a) -H, b) -halo, c) -OH, d) -(C1C6)alkyl substituted with 0 or 1 -OH, e)
-NR12R13, f) -Z-C(0)O(C1C6)alkyl, g) -Z-C(O)NR12R13, h) -©-(d-CeJalkyI, i)
-Z-O-C(0)-(C1C6)alkyl, j) -Z-O-(d-C3)alkyl-C(0)-NR12R13, k)
-Z-O-(Ci-C3)alkyl-C(O)-0(CrC6)alkyl, I) -O-(C2-C6)alkenyl, m) -O-(C2-C6)alkynyl, n)
-O-Z-het, o) -COOH, p) -C(OH)Ri2R13 or q) -Z-CN;
R3 is a) -H, b) -(C1C6))alkyl wherein 1 or 2 carbon atoms, other than the
connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms
independently selected from S, O and N and wherein each carbon atom is substituted
with 0,1 or 2 Ry c) -(C2-C10)alkenyl substituted with 0,1 or 2 Ry, d) -(C2-C10)alkynyl
wherein 1 carbon atom, other than the connecting carbon atom, may optionally be
replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0,1
or 2 Ry, e) -CH=C=CH2, f) -ON, g) -(C3-C6)cycloalkyl, h) -Z-aryl, i) -Z-het, j)
-C(O)O(C1-C6)alkyl, k) -O(C1C6)alkyl, I) -Z-S-R12, m) -Z-S(0)-R12, n) -Z-S(O)2-R12, o]
-CF3, p) -NR12O-(C1C6)alkyl or q) -CH2ORy.
provided that one of R2 and R3 is absent when there is a double bond
between CR2R3 (the 7 position) and the F moiety (the 8 position) of the C-ring;
Ry for each occurrence is independently a) -OH, b) -halo, c) -Z-CF3, d) -ZCF(
d-C3 alkyl)2, e) -CN, f) -NR,2R13. g) -(C3-C6)cycloalkyl, h) -(C3-C6)cycloalkenyl, i)
-(C0-C3)alkyl-aryl, j) -het or k) -N3;
or R2 and R3 are taken together to form a) =CHRn, b) =NORn, c) =O, d) |
=N-NR12, e) =N-NR12-C(O)-R12, f) oxiranyl or g) 1,3-dioxolan-4-yl;
R4 and R5 for each occurrence are independently a) -H, b) -CN, c)
-(d-C6)alkyl substituted with 0 to 3 halo, d) -(C2-C6)alkenyl substituted with 0 to 3
halo, e) -(C2-C6)alkynyl substituted with 0 to 3 halo, f) -0-(d-C6)alkyl substituted with
0 to 3 halo, g) -O-(C2-C6)alkenyl substituted with 0 to 3 halo, h) -O-(C2-C6)alkynyl
substituted with 0 to 3 halo, i) halo, j) -OH, k) (C3 -C6)cycloalkyl or I) (C3
-C6)cycloalkenyl;
or R4 and R5 are taken together to form =O;
R6 is a) -H, b) -CN, c) -(d-C6)alkyl substituted with 0 to 3 halo, d)
-(C2-C6)alkenyl substituted with 0 to 3 halo, e) -(C2-C6)alkynyl substituted with 0 to 3
halo or f) -OH;
R7 and R16 for each occurrence are independently a) -H, b) -halo, c) -CN, d)
-(d-C6)alkyl substituted with 0 to 3 halo, e) -(C2-C6)alkenyl substituted with 0 to 3
halo or f) -(C2-C6)alkynyl substituted with 0 to 3 halo; provided that R7 is other than
-CN or -halo when D is NR7;
or R7 and R16 are taken together to form =O;
Re, Rg, RU and R15 for each occurrence are independently a) -H, b) -halo, c)
(C1C6)alkyl substituted with 0 to 3 halo, d) -(C2-C6)alkenvl substituted with 0 to 3 halb,
e) -(C2-C6)alkynyl substituted with 0 to 3 halo, f) -CN. g) -{C3-C6)cycloalkyl, h)
-(C3-C6)cycloalkenyl, i) -OH, j) -O-(d-C6)alkyl, k) -O-(d-Ct)alkenyl, I)
-O-(d-C6)alkynyl, m) -NR12R13, n) -C(O)OR12 or o) -C(0)NR,2R13;
or R8 and R9 are taken together on the C-ring to form =O; provided that wherji
m is 2, only one set of R8 and R9 are taken together to form =O;
or R14 and Ri5 are taken together to form =0; provided that when R14 and R
are taken together to form =O, D is other than CR7 and E is other than C;
R10 is a) -(d-Cio)alkyl substituted with 0 to 3 substituents independently
selected from -halo, -OH and -N3) b) -(C2-C10)alkenyl substituted with 0 to 3
substituents independently selected from -halo, -OH and -N3, c) -(C2-C10)alkynyl
substituted with 0 to 3 substituents independently selected from -halo, -OH and -N3,
d) -halo, e) -Z-CN, f) -OH, g) -Z-het, h) -Z-NR12R13, i) -Z-C(O)-het, j)
-Z-CfOMd-QOalkyl, k) -Z-C(O)-NR12R13, I) -Z-C(O)-NR12-Z-CN, m)
-Z-C(O)-NR12-Z-het, n) -Z-C(O)-NR12-Z-aryl, o) -Z-C(O)-NR12-Z-NR12R13, p)
-Z-C(O)-NR12-Z-O(d-C6)alkyl, q) -(C0-C6)alkyl-C(O)OH, r) -Z-C(O)O(C1-C6)alkyl, s)
-Z-0-(C0-C6)alkyl-het, t) -Z-O-(C0-C6)alkyl-aryl, u) -Z-O-(d-C6)alkyl substituted with 0
to 2 Rx, v) -Z-0-(CrC6)alkyl-CH(O), w) -Z-O-(Ci-C6)alkyl-NR12-het, x)
-Z-O-Z-het-Z-het, y) -Z-O-Z-het-Z-NR12R13, z) -Z-O-Z-het-C(O)-het, a1)
-Z-O-Z-C(O)-het, b1) -Z-0-Z-C(O)-het-het, c1) -Z-O-Z-C(O)-(d-C6)alkyl, d1)
-Z-O-Z-C(S)-NR12R13, e1) -Z-O-Z-C(O)-NR12R13, f1)
-Z-O-Z-(CrC3)alkyl-C(O)-NR12R13, g1) -Z-O-Z-C(O)-O(CrC6)alkyl, hi)
-Z-O-Z-C(O)-OH, i1) -Z-0-Z-C(O)-NR12-O(CrC6)alkyl, J1) -Z-0-Z-C(O)-NR12-OH, k^
-Z-O-Z-C(O)-NR12-Z-NR12R13,11) -Z-O-Z-C(O)-NR12-Z-het, ml)
-Z-O-Z-C(O)-NR12-SO2-(CrC6)alkyl, n1) -Z-O-Z-C(=NR12)(NR12R13), o1)
-Z-O-Z-C(=NOR12)(NR12R13), p1) -Z-NR12-C(O)-O-Z-NR12R13) q1) -Z-S-C(O)-NR12R14,
r1) -Z-O-SO2-(Ci-C6)alkyl, s1) -Z-O-SO2-aryl, t1) -Z-0-SO2-NRi2R13l u1)
-Z-O-SO2-CF3, v1) -Z-NR12C(O)ORi3 or w1) -Z-NR12C(O)R13;
or R9 and Ri0 are taken together on the moiety of formula A-5 to form a) = O
or b) = NOR12;
Rn is a) -H, b) -(C1C6)alkyl, c) -(C3-C6)cycloalkyl or d) -(C0-C3)alkyl-aryl;
Ri2 and R13 for each occurrence are each independently a) -H, b)
-(C1C6)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom,
may optionally be replaced with 1 or 2 heteroatoms independently selected from S, (j)
and N and wherein each carbon atom is substituted with 0 to 6 halo, c)
-(C2-C6)alkenyl substituted with 0 to 6 halo, or d) (C1C6)alkynyl wherein 1 carbon
atom, other than the connecting carbon atom, may optionally be replaced with 1
oxygen atom and wherein each carbon atom is substituted with 0 to 6 halo;
or R12 and R,3 are taken together with N to form het;
or R6 and Ru or Ri5 are taken together to form 1,3-dioxolanyl;
aryl is a) phenyl substituted with 0 to 3 Rx, b) naphthyl substituted with 0 to 3
Rxor c) biphenyl substituted with 0 to 3 Rx;
het is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring
containing from one (1) to three (3) heteroatoms independently selected from the
group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in
which any of the above heterocyclic rings is fused to a benzene ring or another
heterocycle; and the nitrogen may be in the oxidized state giving the N-oxide form;
and substituted with 0 to 3 Rx;
Rx for each occurrence is independently a) -halo, b) -OH, c) -(C1C6)alkyl, d)
-(C2-C6)alkenyl, e) -(C2-C6)alkynyl, f) -O(C1C6)alkyl, g) -O(C2-C6)alkenyl, h)
-0(C2-C6)alkynyl, i) -(C0-C6)alkyl-NR12R13, j) -C(O)-NR12R13, k) -Z-SO2R12,1)-Z-SOR12,
m) -Z-SR12, n) -NR12-SO2Ri3, o) -NR12-C(O)-Ri3, p) -NR12-OR13, q) -SO2-NR12Ri3, r)
-CN, s) -CF3, t) -C(O)(CrC6)alkyl, u) =O, v) -Z-SO2-phenyl or w) -Z-SO2-het';
aryl' is phenyl, naphthyl or biphenyl;
net' is a 5-,6- or 7-membered saturated, partially saturated or unsaturated ring
containing from one (1) to three (3) heteroatoms independently selected from the
group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in
which any of the above heterocyclic rings is fused to a benzene ring or another
heterocycle;
provided that:
1) X-Ri is other than hydrogen or methyl;
2) when R9 and R10 are substituents on the A-ring, they are other than monpor
di-methoxy;
3) when R2and R3 are taken together to form =CHRn or =O wherein Rn is
-O(Ci-C6)alkyl, then -X-R, is other than (C1C6)alkyl;
4) when R2 and R3 are taken together to form =O and R9 is hydrogen on the;
A-ring; or when R2 is hydroxy, R3 is hydrogen and Rg is hydrogen on the A-ring, ther«
R10 is other than -O-(C1C6)alkyl or -O-CH2-phenyl at the 2-position of the A-ring;
5) when X-Ri is(C1C6)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl, R9 and R10 are
other than mono-hydroxy or =O, including the diol form thereof, when taken together1:
and
6) when X is absent, R! is other than a moiety containing a heteroatom
selected from N, O or S directly attached to the juncture of the B-ring and the C-ring.j
More particularly, the present invention provides:
compounds of formula I, isomers thereof, prodrugs of said compounds or isomers, or
pharmaceutically acceptable salts of said compounds, isomers or prodrugs;
wherein the A-ring is selected from the group consisting of:
(Figure Removed)
More particularly, the present invention provides:
compounds of formula I, isomers thereof, prodrugs of said compounds or isomers, dr
pharmaceutically acceptable salts of said compounds, isomers or prodrugs;
wherein D is CH2; E is CH; F is CH2; R8 is -H; R9 is -H on the C-ring; m is 2; R,4 is -Hi;
R15is -H; and the A-ring is the moiety of formula A-1a.
More particularly, the present invention provides:
compounds of formula II
isomers thereof, prodrugs of said compounds or isomers. or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R2 is a) -OH or b) -O-CH2-het;
R3 is a) -(CrC6)alkyl substituted with 0 or 1 of the following: -CF3, -CN,
-(C3-C6)cycloalkyl, -phenyl or -N3, b) -OC- substituted with 1 of the following:
-(Ci-C5)alkyl, -Cl, -CF3. -(C3-C6)cycloalkyl, -phenyl or -benzyl; c) -CH2OH, d)
-CH2O(d-C5)alkyl wherein 1 carbon atom may optionally be replaced with 1 oxygen
atom, e) -CH2O(C2-C5)alkenyl, f) -CH2O(C2-C5)alkynyl wherein 1 carbon atom may
optionally be replaced with 1 oxygen atom, g) -CH2ORy, h) -CN or i) -CF3;
Ry is a) -(d-C3)alkyl -CF3, b) -(C3-C6)cycloalkyl, c) -phenyl or d) -benzyl;
or R2 and R3 are taken together to form a) -1,3-dioxolan-4-yl or b) =NORn;
Rn is a) -H, b) -(C1C6)alkyl, c) -(C3-C6)cycloalkyl, d) -phenyl or e) -benzyl.
In addition, more particularly, the present invention provides:
compounds of formula II
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R, is a) -(C1C6)alkyl, b) -(C2-C4)alkenyl, c) -phenyl substituted with 0 or 1 of
the following: -OH, -NR12R13, -NR12-C(0)-(C1-C4)alkyl. -CM, -Z-het,
-O-(d-C3)alkyl-C(O)-NR12R13, -NR12-Z-C(O)-NR12R13, -Z-NR12-SO2-R13,
-NR12-SO2-het, -O-C(O)-(d-C4)alkyl or -O-SO2-(C1C6)alkyl; d) -O-phenyl substituted!
with 0 or 1 of the following: -Z-NR12R13 or -C(O)NR12R13, or e) -CH=CH-phenyl
wherein phenyl is substituted with 0 or 1 of the following: -Z-NR12Ri3 or -C(O)NR12Ri,i;
Z for each occurrence is independently -(C0-C2)alkyl;
R,o is a) -CH(OH)(C,-C5)alkyl, b) -CN, c) -OH, d) -het, e) -C(O)-(d-C4)alkyl, f)
-C(O)-NR12R13, g) -C(O)-NH-Z-het, h) -O-(C0-C2)alkyl-het, i) -O-Z-C(O)-NR12R13, j)
-O-Z-C(O)-NH-(C0-C3)alkyl-het or k) -O-Z-C(O)-NH-(C0-C3)alkyl-NR12R13;
R12 and R,3 are independently a) -H or b) -(C1C6)alkyl;
or R12 and Ri3 are taken together with N to form het.
Yet, even more particularly, the present invention provides:
compounds of formula II
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R, is a) -(C2-C4)alkyl, b) -CH2-CH=CH2 or c) -phenyl;
R3 is a) -(C1C6)alkyl substituted with 0 or 1 CF3, b) -C=C-CH3, c) -0=0-01, d)
3, e) -CH2O(C1C6)alkyl substituted with 0 or 1 CF3, or f) -CF3;
RIO is -OH.
Most particularly, the present invention provides:
compounds of formula III
(Figure Removed)
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or
prodrugs;
wherein R3 and RIO are as defined immediately above.
In addition, the present invention more particularly provides:
compounds of formula II
RIO
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R, is a) -(C2-C4)alkyl, b) -CH2-CH=CH2 or c) -phenyl;
R2 is -OH;
R3 is a) -(C1C6)alkyl substituted with 0 or 1 CF3, b) -C=C-CH3, c) -CsC-CI, d)
-CHC-CF3, e) -CH2O(C1C6)alkyl substituted with 0 or 1 CF3) or f) -CF3;
RIO is -ON.
Most particularly, the present invention provides:
compounds of formula III
(Figure Removed)
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or
prodrugs;
wherein R3 and RIO are as defined immediately above. Preferably, it provides a
compound of formula III wherein R3 is -OC-CH3 and R10 is -CN; a compound of
formula III wherein R3 is -(CH2)2-CH3 and R10 is -CN; a compound of formula III
wherein R3 is -CF3 and Ri0 is -CN; and a compound of formula III wherein R3 is -
CH2CH2CF3 and Ri0 is -CN; and pharmaceutically acceptable salts thereof.
In addition, the present invention more particularly provides:
compounds of formula II
RIO
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R! is a) -(C2-C4)alkyl, b) -CH2-CH=CH2 or c) -phenyl;
R2 is -OH;
R3 is a) -(C1C6)alkyl substituted with 0 or 1 CF3, b) -C=C-CH3, c) -C=C-CI, d)i
-C=C-CF3, e) -CH20(d-C3)alkyl substituted with 0 or 1 CF3, or f) -CF3;
R10 is -C(O)-NH-Z-het wherein het is selected from the group consisting of aj
pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, d) morpholinyl an

e) oxadiazolyl;
Z is -(C0-C2) alkyl.
Most particularly, the present invention provides:
compounds of formula III
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or
prodrugs;
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -CnC-CHg, e) -C=C-CI orf)
R10 is as defined immediately above. Preferably, it provides a compound ol
formula III or a pharmaceutically acceptable salt thereof as follows: a compound ol
formula III wherein R3 is -OC-CH3 and R10 is -C(O)-NH-CH2-(4-pyridinyl); a
compound of formula III wherein R3 is -C=C-CH3 and Ri0 is -
C(O)-NH-CH2-(2-pyridinyl); a compound of formula III wherein R3 is -C=C-CH3 and
R10 is -C(O)-NH-CH2-(3-pyridinyl); a compound of formula III wherein R3 is -C=C-Ch3
and R10 is -C(O)-NH-(2-pyrazinyl); a compound of formula III wherein R3 is -C=C-CH3
and R,o is -C(O)-NH-CH2-(2-methyl-3-pyridinyl); a compound of formula III wherein R^
is -(CH2)2-CH3 and R10 is -C(O)-NH-CH2-(2-methyl-3-pyridinyl); a compound of
formula III wherein R3 is -(CH2)2-CH3 and R,0 is -C(O)-NH-CH2-(2-pyridinyl); a
compound of formula III wherein R3 is -(CH2)2-CF3 and R10 is
-C(O)-NH-CH2-(2-methyl-3-pyridinyl); a compound of formula III wherein R3 is -CH3
and RIO is -C(O)-NH-CH2-(2-methyl-3-pyridinyl); a compound of formula III wherein R3
is -CH3 and RIO is -C(O)-NH-(3-pyridinyl); and a compound of formula III
wherein R3 is -CF3 and R10 is -C(0)-NH-CH2-(2-methyl-3-pyridinyl).
In addition, the present invention more particularly provides:
compounds of formula II
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R, is a) -(C2-C4)alkyl, b) -CH2-CH=CH2 or c) -phenyl;
R2 is -OH;
R3 is a) -(C,-C4)alkyl substituted with 0 or 1 CF3) b) -CHC-CH3, c) -OC-CI, d)
-C=C-CF3, e) -CH2O(C1C6)alkyl substituted with 0 or 1 CF3, or f) -CF3;
R10 is -O-(Ci-C2)alkyl-het wherein het is selected from the group consisting bf
a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, d) morpholinyj
and f) oxadiazolyl.
Most particularly, the present invention provides:
compounds of formula III
(Figure Removed)
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or
prodrugs;
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -OC-CH3, e) -C=C-CI or fj)
RIO is -O-(d-C2)alkyl-het wherein het is selected from the group consisting of
a) 2-pyridinyl, b) 3-pyridinyl, c) 4-pyridinyl, d) 2-methyl-3-pyridinyl and e) pyrazinyl.
Preferably, it provides a compound of formula III and pharmaceutically acceptable
salts thereof as follows: a compound of formula III wherein R3 is -CsC-CH3 and R10 |s
-O-CH2-(4-pyridinyl); a compound of formula III wherein R3 is -C=C-CH3 and R10 is
-O-CH2-(2-pyridinyl); a compound of formula III wherein R3 is -(CH2)2-CF3 and Ri0 isi
-O-CH2-(3-pyridinyl); a compound of formula III
wherein R3 is -(CH2)2-CF3 and RIO is -O-CH2-(2-methyl-3-pyridinyl); a compound of
formula III wherein R3 is -(CH2)2-CF3 and R10 is -O-CH2-(2-pyridinyl); and a compound
of formula III wherein R3 is -CF3 and R10 is -O-CH2-(2-methyl-3-pyridinyl).
In addition, the present invention more particularly provides:
compounds of formula II
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R, is a) -(C2-C4)alkyl, b) -CH2-CH=CH2 or c) -phenyl;
R2 is -OH;
R3 is a) (C1C6)alkyl substituted with 0 or 1 CF3, b) -C=C-CH3, c) -Cs(C1C6)
-OC-CF3, e) -CH2O(CrC3)alkyl substituted with 0 or 1 CF3,orf) -CF3;
R,o is a) -O-Z-C(O)-NH-(C0-C3)alkyl-N((C1-C2)alkyl)2, b) -O-Z-C(O)-NR12R13,
c) -O-Z-C(O)-NH-(C0-C3 )alkyl-het wherein het is selected from the group consisting
of 1) pyridinyl substituted with 0 or 1 methyl, 2) pyrimidinyl, 3) pyrazinyl, 4)
morpholinyl, 5) pyrrolidinyl, 6) imidazolyl and 7) oxadiazolyl;
R12 and R,3 are independently a) -H or b) -(d-C2)alkyl; or R12 and R,3 are
taken together with N to form pyrrolidinyl;
Zis-(C1C6)alkyl.
Most particularly, the present invention provides:
compounds of formula III
(Figure Removed)
prodrugs thereof, or pharmaceutically acceptable salts of said compounds or
prodrugs;
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3> d) -C^C-CHa, e) -CnC-CI or f)
-CF3;
R10 is a) -O-C(O)-NH-(Co-C3)alkyl-N((CrC2)alkyl)2l b) -O-C(O)-N(CH3)2 , c)
-O-C(O)-(1-pyrrolidinyl) or d) -O-C(O)-NH-(C0-C3)alkyl-het wherein het is selected
from the group consisting of 1) 2-pyridinyl, 2) 3-pyridinyl, 3) 4-pyridinyl, 4)
2-methyl-3-pyridinyl, 5) pyrazinyl, 6) morpholinyl, 7) pyrrolidinyl and 8) imidazolyl.
Preferably, it provides a compound of formula III wherein R3 is -OC-CH3 and R,0 is
-O-C(O)-NH-(CH2)2-(1-pyrrolidinyl); a compound of formula III wherein R3 is -OC-CN
and R10 is -O-C(O)-NH-(CH2)2- N(CH3)2; a compound of formula III wherein R3 is
-CsC-CH3 and R10 is -O-C(O)-NH-CH2-2-pyridyl; a compound of formula III wherein R3
is -C=C-CH3 and R10 is -O-C(O)-NH-CH2-4-pyridyl; and a compound of formula III
wherein R3 is -OC-CH3 and RIO is -0-C(O)-NH-CH2-3-pyridyl; and pharmaceutically
acceptable salts of the above compounds.
The present invention also provides:
compounds of formula IV
(Figure Removed)
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein the variables are as defined above for formula I.
More particularly, the present invention provides compounds of formula V,
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R8 is -H; R9 is -H on the C-ring; m is 2; R7 is -H; R14 is -H; Ri5 is -H; R16 is -H;
and the A-ring is the moiety of formula A-1a.
Even more particularly, the present invention provides compounds of formula)
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein X is -CH2-;
RI is a) -(C1C6)alkyl, b) -(C2-C4)alkenyl, c) -phenyl substituted with 0 or 1 o^
the following: -OH, -NR12R13, -NR12-C(O)-(d-C4)alkyl, -CN, -Z-het,
-(C1C6)-CaJalkyl-C-NR^R.-NR^-Z-O-NR,-Z-NR12-SO2-Ri3,
-NR12-S02-het, -O-C(O)-(d-C4)alkyl or -O-SO2-(d-C4)alkyl; d) -O-phenyl substituted
with 0 or 1 of the following: -Z-NR12R13 or -C(O)NR12R13; e) -CH=CH-phenyl wherein
phenyl is substituted with 0 or 1 of the following: -Z-NR12R13 or -C(O)NR12R13;
Z is for each occurrence independently -(C0-C2)alkyl;
R4 and R5 are each hydrogen or are taken together to form =O;
R10 is a) -CH(OH)(d-C5)alkyl, b) -CN, c) -OH, d) -het, e) -C(O)-(d-C4)alkyl, i)
-C(O)-NR12Ri3, 9) -C(O)-NH-Z-het, h) -O-(C0-C2)alkyl-het, i) -O-Z-C(O)-NR12R13 or jj
-O-Z-C(0)-NH-(C0-C3)alkyl-het;
R12 and R13 for each occurrence are independently a) -H or b) (C1C6)alkyl.
Most particularly, the present invention provides compounds of formula VI
'10 VI
isomers thereof, prodrugs of said compounds or isomers, or pharmaceutically
acceptable salts of said compounds, isomers or prodrugs;
wherein R2 is a) -C(O)OH, b) -C(O)OCH3, c) -C(O)OCH2CH3 or d) -CH2OH;
R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3 or d) -CF3;
R4 and R5 are each hydrogen or are taken together to form =O;
R10 is a) -OH, b) -O-(C0-C3)alkyl-phenyl or c) -0-(C0-C3)alkyl-het wherein het
is selected from the group consisting of a) 2-pyridinyl, b) 3-pyridyl, c) 4-pyridyl, d)
2-methyl-3-pyridyl and e) pyrazinyl.
The present invention also provides:
compounds of formula VII
and isomers thereof;
wherein is an optional bond;
X' is -CHr;
R'T is phenyl substituted with 0, 1 or 2 R'x;
R'2 is -OH;
R'3 is a) -(C1C6)alkyl substituted with 0 or 1 R'y or b) -(C2-C6)alkynyl
substituted with 0 or 1 R'y;
R'v is -CF3;
or R'2 and R'3 are taken together to form =O;
R'9 is -H;
R'10 is a) -halo, b) -C(O)OH, c) -C(O)O(CrC6)alkyl, d) -C(O)-NR'12R'13l e) -Clil,
f) -OH or g) -O-(C,-C3)alkyl;
R'x is a) -halo, b) -OH, c) -((C1C6)alkyl, d) -CN, e) -CF3, f)
-(C0-C6)alkyl-NR'2R'13, g) -C(O)-NR'12R'13, h) -NR'12-SO2R'13l i) -NR'12-C(0)-R'13, j)
-SO2R'12 or k) -S02-NR'12R'13;
R'i2 and R'i3 for each occurrence are each independently a) -H or b)
-(Ci-C6)alkyl. More particularly, the present invention provides the compound, 2(3H)f
phenanthrenone, 4,4a,9,10-tetrahydro-7-bromo-4a-(phenylmethyl-,(S)-.
The present invention also provides:
compounds of formula VIII
and isomers thereof;
wherein D' is C;
R'i is phenyl substituted with 0 to 2 R'x;
-20-
R's, R', R's. R'g, R'is and R'i6 for each occurrence are independently a) -H, b)
-O-(CrC6)alkyl, c) -(CrC6)alkyl or d) halo;
R'10 is a) -halo, b) -CN, c) -OH, d) -C(O)-NR'12R'13, e) -C(O)-NR'12-Z'-het
wherein het is substituted with 0 or 1 R'x, f)-C(O)-NR'12-Z'-aryl wherein aryl is
substituted with 0 or 1 R'x, g) -O-(C0-C6)alkyl-het wherein het is substituted with 0 or| 1
R'x, or h) -O-(C0-C6)alkyl-aryl wherein aryl is substituted with 0 or 1 R'x;
Z' is a) -(C0-C6)alkyl, b) -(C2-C6)alkenyl, or c) -(C2-C6)alkynyl;
R'x is a) -halo, b) -OH, c) -(C1C6)alkyl, d) -CN, e) -CF3, f)
-(C0-C6)alkyl-NR'12R'13> g) -C(O)-NR'12R'13, h) -NR'12-S02R',3, i) -NR'12-C(O)-R'13, \\)
-SO2R'12 or k) -SO2-NR'12R'13;
R'12 and R'13 for each occurrence are each independently a) -H or b)
-(C1C6))alkyl;
aryl is phenyl;
het is a 5-,6- or 7-membered saturated, partially saturated or unsaturated rin^j
containing from one (1) to three (3) heteroatoms independently selected from the
group consisting of nitrogen, oxygen and sulfur. More particularly, the present
invention provides the compound, 1(R)-benzyl-6-methoxy-1-(S)-(3-oxo-butyl)-3,4-
dihydro-1 H-naphthalen-2-one.
In addition, the present invention provides compounds of formula II
R2
an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug;
wherein R, is -phenyl;
R2 is -OH;
R3 is a) -(CrC6)alkyl substituted with 0 or 1 CF3, b) -C=C-CH3, c) -C=C-CI, d)
-C=C-CF3, e) -CH20(CrC3)alkyl substituted with 0 or 1 CF3, or f) -CF3;
R,o is -OH, -CN, -C(O)OH or-C(O)O(C1C6)alkyl.
More particularly, the present invention provides compounds of formula III
(Figure Removed)
a prodrug thereof, or a pharmaceutically acceptable salt of said compound or
prodrug;
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -C^C-CHa, e) -C=C-CI or f)
-CF3; and
R10 is as defined immediately above. Most particularly, it provides a
compound of formula III wherein R3 is -CsC-CH3 and R)0 is -OH; or a
pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is
-OC-CH3 and RIO is -CM; or a pharmaceutically acceptable salt thereof; a
compound of formula III wherein R3 is -OC-CH3 and R,0 is -COOH; or a
pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is
-(CH2)2-CH3 and R10 is -OH; or a pharmaceutically acceptable salt thereof; a
compound of formula III wherein R3 is -(CH2)2-CH3 and R,0 is -CN; or a
pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is
-(CH2)2-CH3 and RIO is -COOH; or a pharmaceutically acceptable salt thereof; a
compound of formula III wherein R3 is -(CH2)2-CF3 and R,0 is -OH; or a
pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is
-(CH2)2-CF3 and R10 is -CN; or a pharmaceutically acceptable salt thereof; a
compound of formula III wherein R3 is -(CH2)2-CF3 and R.0 is -COOH; or a
pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is
-CH3 and R10 is -OH; or a pharmaceutically acceptable satt thereof; a compound of
formula III wherein R3 is -CH3 and RIO is -CN; or a pharmaceutically acceptable salt
thereof; a compound of formula III wherein R3 is -CH3 and RIO is -COOH; or a
pharmaceutically acceptable salt thereof; a compound of formula III wherein R3 is
-CF3 and Ri0 is -OH; or a pharmaceutically acceptable salt thereof; a compound of
formula III wherein R3 is -CF3 and R is -CN; or a pharmaceutically acceptable salt
thereof; and a compound of formula III wherein R3 is -CF3 and R10 is -COOH; or a
pharmaceutically acceptable salt thereof.
The present invention provides methods of treating obesity in a mammal
comprising administering to said mammal a therapeutically effective amount of a
compound of formula I, an isomer thereof, a prodrug of said compound or isomer, oir
a pharmaceutically acceptable salt of said compound, isomer or prodrug. More
particularly, the present invention provides such methods wherein the mammal is a
female or male human.
The present invention also provides pharmaceutical compositions comprising
a therapeutically effective amount of a compound of formula I, an isomer thereof, a
prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said
compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or
diluent.
The present invention also provides pharmaceutical compositions for the
treatment of obesity comprising an obesity treating amount of a compound of formula
I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug; and a pharmaceutically
acceptable carrier, vehicle or diluent.
The present invention also provides pharmaceutical combination
compositions comprising: a therapeutically effective amount of a composition
comprising:
a first compound, said first compound being a compound of formula I, an
isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being a (33 agonist, a
thyromimetic agent, an eating behavior modifying agent or a NPY antagonist; and
a pharmaceutical carrier, vehicle or diluent. More particularly, it provides such
compositions wherein the second compound is orlistat or sibutramine.
In addition, the present invention provides methods of treating obesity
comprising administering to a mammal in need of such treatment
an amount of a first compound, said first compound being a compound of
formula I, an isomer thereof, a prodrug of said compound or isomer, or a
pharmaceutically acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being a p3 agonist, a
thyromimetic agent, an eating behavior modifying agent or a NPY antagonist; and
wherein the amounts of the first and second compounds result in a
therapeutic effect. More particularly, it provides such methods wherein the second
compound is orlistat or sibutramine.
The present invention also provides kits comprising:
a) a first compound, said first compound being a compound of formula I, ar)
isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug and a pharmaceutically
acceptable carrier, vehicle or diluent in a first unit dosage form;
b) a second compound, said second compound being a (33 agonist, a
thyromimetic agent, an eating behavior modifying agent or a NPY antagonist; and
a pharmaceutically acceptable carrier, vehicle or diluent in a second unit dosage
form;and
c) a container for containing said first and second dosage forms; wherein the
amounts of said first and second compounds result in a therapeutic effect.
In addition, the present invention provides methods of inducing weight loss irh
a mammal comprising administering to said mammal a therapeutically effective
amount of a compound of formula I, an isomer thereof, a prodrug of said compound
or isomer, or a pharmaceutically acceptable salt of said compound, isomer or
prodrug. The present invention also provides pharmaceutical compositions for
inducing weight loss comprising a weight loss-treating amount of a compound of
formula I, an isomer thereof, a prodrug of said compound or isomer, or a
pharmaceutically acceptable salt of said compound, isomer or prodrug; and a
pharmaceutically acceptable carrier, vehicle or diluent.
Another aspect of the present invention provides methods of treating diabete^
in a mammal comprising administering to said mammal a therapeutically effective
amount of a compound of formula I, an isomer thereof, a prodrug of said compound
or isomer, or a pharmaceutically acceptable salt of said compound, isomer or
prodrug.
The present invention also provides pharmaceutical compositions for the
treatment of diabetes comprising a diabetes-treating amount of a compound of
formula I, an isomer thereof, a prodrug of said compound or isomer, or a
pharmaceutically acceptable salt of said compound, isomer or prodrug; and a
pharmaceutically acceptable carrier, vehicle or diluent.
In addition, the present invention provides pharmaceutical combination
compositions comprising: a therapeutically effective amount of a composition
comprising:
a first compound, said first compound being a compound of formula I, an
isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being an aldose reductase
inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor,
insulin, troglitazone, suIfonylureas, glipizide, glyburide, or chlorpropamide; and
a pharmaceutical carrier, vehicle or diluent. More particularly, the present
invention provides such pharmaceutical combinationcompositions wherein the aldose
reductase inhbitior is 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-
trifluoromethyl)-2-benzothiazolyl]methyl]- or a pharmaceutically acceptable salt
thereof.
The present invention also provides methods of treating diabetes comprising
administering to a mammal in need of such treatment
an amount of a first compound, said first compound being a compound of
formula I, an isomer thereof, a prodrug of said compound or isomer, or a
pharmaceutically acceptable salt of said compound, isomer or prodrug;
a second compound, said second compound being an aldose reductase
inhibitor, a glycogen phosphorylase inhibitor, a sorbitol dehydrogenase inhibitor,
insulin, troglitazone, sulfonylureas, glipizide, glyburide. or chlorpropamide ; and
wherein the amounts of the first and second compounds result in a
therapeutic effect.
In another aspect, the present invention provides pharmaceutical combination
compositions comprising:
therapeutically effective amounts of a compound of formula I, an isomer
thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt!
of said compound, isomer or prodrug; and
a compound selected from the group consisting of a glucocorticoid receptor
agonist, a cholinomimetic drug, an anti-Parkinson's drug, an antianxiolytic drug, an
antidepressant drug and an antipsychotic drug; and
a pharmaceutical carrier, vehicle or diluent. More particularly, it provides such
compositions wherein the anti-Parkinson's drug is selected from the group consisting
of L-dopa, bromocriptine and selegiline. More particularly, it provides such
compositions wherein the antianxiolytic drug is selected from the group consisting of
benzodiazepine, valium and librium. More particularly, it provides such compositions
wherein the antidepressant drug is selected from the group consisting of
desipramine, sertraline hydrochloride and fluoxetine hydrochloride.
More particularly, it provides such compositions wherein the antipsychotic drug is
selected from the group consisting of haloperidol and clozapine.
The present invention also provides kits comprising:
a) a first compound, said first compound being a compound of formula I, an
isomer thereof, a prodrug said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug; and a pharmaceutically
acceptable carrier, vehicle or diluent in a first unit dosage form;
b) a second compound, said second compound being selected from the
group consisting of a glucocorticoid receptor agonist; a cholinomimetic drug; an anti-
Parkinson's drug; an antianxiolytic drug; an antidepressant drug; and an antipsychotip
drug; and a pharmaceutically acceptable carrier, vehicle or diluent in a second unit
dosage form; and
c) a container for containing said first and second dosage forms wherein the
amounts of said first and second compounds result in a therapeutic effect. More
particularly, it provides such kits wherein the anti-Parkinson's drug is selected from
the group consisting of L-dopa, bromocriptine and selegiline. More particularly, it
provides such kits wherein the antianxiolytic drug is selected from the group
consisting of benzodiazepine, valium and librium. More particularly, it provides such
kits wherein the antidepressant drug is selected from the group consisting of
desipramine, sertraline hydrochloride and fluoxetine hydrochloride. More particularly
it provides such kits wherein the antipsychotic drug is selected from the group
consisting of haloperidol and clozapine.
In another aspect, the present invention provides methods of treating anxiety
in a mammal comprising administering to said mammal a therapeutically effective
amount of a compound of formula I, an isomer thereof, a prodrug of said compound
or isomer, or a pharmaceutically acceptable salt of said compound, isomer or
prodrug. It also provides pharmaceutical compositions for the treatment of anxiety
comprising an anxiety-treating amount of a compound of formula I, an isomer thereof
a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said
compound, isomer or prodrug; and a pharmaceutically acceptable carrier, vehicle or
diluent.
In another aspect, the present invention provides methods of treating
depression in a mammal comprising administering to said mammal a therapeutical^
effective amount of a compound of formula I, an isomer thereof, a prodrug of said
compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer
or prodrug. It also provides pharmaceutical compositions for the treatment of
depression comprising a depression-treating amount of a compound of formula I, arl
isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug; and a pharmaceutically
acceptable carrier, vehicle or diluent.
In another aspect, the present invention provides methods of treating
neurodegeneration in a mammal comprising administering to said mammal a
therapeutically effective amount of a compound of formula I, an isomer thereof, a
prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said
compound, isomer or prodrug. It also provides pharmaceutical compositions for the
treatment of neurodegeneration comprising a neurodegeneration-treating amount of
a compound of formula I, an isomer thereof, a prodrug of said compound or isomer,
or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a
pharmaceutically acceptable carrier, vehicle or diluent.
In other aspects, the present invention provides the following methods:
methods of affecting glucocorticoid receptor activity comprising administering to a
mammal in need thereof a therapeutically effective amount of a compound of formul£
I, an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug; methods of modulating a
process mediated by glucocorticoid receptor comprising administering to a mammal
in need thereof a therapeutically effective amount of a compound of formula I, an
isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug; methods of treating a mammal|
requiring glucocorticoid receptor therapy comprising administering to said mammal a
therapeutically effective amount of a glucocorticoid receptor modulator compound of
formula I, an isomer thereof, a prodrug of said compound or isomer, or a
pharmaceutically acceptable salt of said compound, isomer or prodrug.
In another aspect, the present invention provides methods of treating an
inflammatory disease in a mammal comprising administering to said mammal a
therapeutically effective amount of a compound of formula I, an isomer thereof, a
prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said
compound, isomer or prodrug. More particularly, it provides such methods wherein!
the mammal is a female or male human.
The present invention also provides pharmaceutical compositions for the
treatment of an inflammatory disease comprising an inflammatory-treating amount df
a compound of formula I, an isomer thereof, a prodrug of said compound or isomer,;
or a pharmaceutically acceptable salt of said compound, isomer or prodrug; and a
pharmaceutically acceptable carrier.
In another aspect, the present invention provides methods for the treatment DT
an inflammatory disease in a mammal which comprises: administering to said mammal
therapeutically effective amounts of a glucocorticoid receptor modulator and a
glucocorticoid receptor agonist. More particularly, it provides such methods which
further comprise reducing the undesirable side effects of said treatment. Also, it
provides such methods wherein the inflammatory disease is selected from the groub
consisting of arthritis, asthma, rhinitis and immunomodulation. More particularly, it
provides such methods wherein the glucocorticoid receptor modulator is a compounq
of formula I, an isomer thereof, a prodrug of said compound or isomer, or a
pharmaceutically acceptable salt of said compound, isomer or prodrug. Also, more
particularly, it provides such methods wherein the glucocorticoid receptor agonist is a
compound selected from the group consisting of prednisone, prednylidene,
prednisolone, cortisone, dexamethasone and hydrocortisone.
The present invention also provides a process for preparing a compound of
formula III
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -C=C-CH3, e) -C=C
Cl or f) -CF3; and RIO is -O-CH2-het wherein het is pyridinyl substituted with 0 or
methyl;
which comprises reacting a compound of formula III-A
(Figure Removed)
wherein R3 is as defined above, with a base in an aprotic solvent at room
temperature to 200°C; and then with a compound of formula RIO-XT wherein R,0 is ajs
defined above and -X, is halo, mesylate or tosylate. More particularly, it provides th s
process wherein the base is NaH, f-butoxide or Et3N; and the solvent is DMF or THI:.
The present invention also provides a process for the preparing a compound
of formula III
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -OC-CH3, e) -Of -
Cl or f) -CF3; R10 is -C(O)-NH-Z-het wherein het is selected from the group consisting
of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl,
morpholinyl and e) oxadiazolyl; and Z is -(Co-C^) alkyl;
which comprises reacting a compound of formula III-B
(Figure Removed)
wherein R3 is as defined above, with a coupling reagent and a compound of
formula NH2-Z-het or a salt thereof wherein -Z and -het are as defined above in an
aprotic solvent at 0 °C to 1 00° C. More particularly, it provides this process wherein
the coupling reagent is selected from the group consisting of 1 -(3-
dimethylaminopropyl-3-ethylcarbodiimide (EDC), dicyclohexyl carbodiimide (DCC)
and hydroxybenzotriazole hydrate (HOBt).
In addition, the present invention provides a process for preparing a
compound of formula III
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -OC-CH3, e) -C*CCl
or f) -CF3; RIO is -C(O)-NH-Z-het wherein het is selected from the group consisting
of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, I d)
morpholinyl and e) oxadiazolyl; and Z is -(C1C6) alkyl;
which comprises reacting a compound of formula III-C
(Figure Removed)
wherein R3 is as defined above, with a tri(C1C6)alkyl-aluminum compound
and a compound of formula NH2-Z-het wherein -Z and -het are as defined above in
solvent at 0 °C to 40 °C. More particularly, it provides this process wherein the tri(C
C4)alkyl-aluminum compound is AI(CH3)3 and the solvent is methylene chloride.
Further, the present invention provides a process for preparing a compound)
of formula III
wherein R3 is a) -(CH2)2-CF3) b) -(CH2)2-CH3, c) -CH3, d) -CHC-CH3, e)
-CiiC-CI or f) -CF3; R10 is a) -O-C(O)-N(CH3)2, b) -O-C(O)-(1-pyrrolidinyl) or c)
-O-C(O)-NH-(Co-C3)alkyl-het wherein het is selected from the group consisting of 1]
2-pyridinyl, 2) 3-pyridinyl, 3) 4-pyridinyl, 4) 2-methyl-3-pyridinyl, 5) pyrazinyl, 6)
morpholinyl, 7) pyrrolidinyl and 8) imidazolyl;
which comprises reacting a compound of formula III-A
wherein R3 is as defined above, with phosgene or triphosgene in an aprotjc
solvent and then with a compound selected from the group consisting of NH(C1C6)2,
1-pyrrolidinyl and NH2-(C0-C3)alkyl-het wherein het is as defined above at 0° C to
room temperature. More particularly, it provides this process wherein the solvent is
toluene.
In addition, the present invention provides a process for preparing a
compound of formula III
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -OC-CH3, e) -
Cl or f) -CF3; and RIO is -O-(d-C2)alkyl-het wherein het is pyridinyl substituted with 0
or 1 methyl;
which comprises reacting a compound of formula III-D
wherein R10 is as defined above, with R3-metal selected from the group
consisting of R3Li, R3MgBr and R3MgCI wherein R3 is as defined above in an aprc|tic
solvent at -78 °C to room temperature.
Further, the present invention provides a process for preparing a compound
of formula III
(Figure Removed)
wherein R3 is -CF3 and R10 is -O-(CrC2)alkyl-het wherein het is pyridiifiyl
substituted with 0 or 1 methyl;
which comprises a) reacting a compound of formula III-D
(Figure Removed)
wherein R10 is as defined above, with trimethylsilyl-CF3 in the presence of terjtbutylammonium
fluoride or cesium fluoride in a protic solvent; and b) hydrolyzing the}
resulting intermediate with tert-butylammonium fluoride or hydrochloric acid.
The present invention also provides process for preparing a compound of
formula III
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3) c) -CH3, d) -C=C-CH3, e) -0=0-
Cl or f) -CF3; R10 is -C(O)-NH-Z-het wherein het is selected from the group consisting
of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, cl)
morpholinyl and e) oxadiazolyl; and Z for each occurrence is independently -(C0-C;.)
alkyl;
which comprises reacting a compound of formula III-D
RIO
III-D
wherein R10 is as defined above, with R3-metal selected from the group
consisting of R3Li, R3MgBr and R3MgCI wherein R3 is as defined above in an aprotic
solvent at -78 °C to room temperature.
Finally, the present invention provides a process for preparing a compound of!
formula III
wherein R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -C=C-CH3l e) -C=CCl
or f) -CF3; R10 is -C(O)-NH-Z-het wherein het is selected from the group consisting
of a) pyridinyl substituted with 0 or 1 methyl, b) pyrimidinyl, c) pyrazinyl, j)
morpholinyl and e) oxadiazolyl; and Z for each occurrence is independently -(C0-C2)
alkyl;
which comprises a) reacting a compound of formula III-D
III-D
wherein R10 is as defined above, with trimethylsilyl-CF3 in the presence of ter
butylammonium fluoride or cesium fluoride in a protic solvent; and b) hydrolyzing the
resulting intermediate with tert-butylammonium fluoride or hydrochloric acid.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are named according to the IUPAC;
or CAS nomenclature system.
In one way of naming the compounds of the present invention, the carbon
atoms in the ring may be numbered as shown in the following simplified structure:
Alternatively, another way of naming the compounds of the present inventionl,
the carbon atoms in the ring may be numbered as shown in the following simplified
structure:
(Figure Removed)
The carbon atom content of various hydrocarbon-containing moieties is
indicated by a prefix designating the minimum and maximum number of carbon
atoms in the moiety, i.e., the prefix d-Cj indicates a moiety of the integer "i" to the
integer "j" carbon atoms, inclusive. Thus, for example, Ci-Ca alkyl refers to alkyl of
one to three carbon atoms, inclusive, or methyl, ethyl, propyl and isopropyl, and all
isomeric forms and straight and branched forms thereof.
Examples of alkyl of one to nine carbon atoms, inclusive, are methyl, ethyl,
propyl, butyl, pentyl, hexyl, heptyl, octyl, and nonyl, and all isomeric forms and
straight and branched thereof.
Examples of alkenyl of two to five carbon atoms, inclusive, are ethenyl,
propenyl, butenyl, pentenyl, and all isomeric forms and straight and branched forms
thereof.
Examples of alkynyl of two to five carbon atoms, inclusive, are ethynyl,
propynyl, butynyl, pentynyl and all isomeric forms and straight and branched forms
thereof.
The terms cycloalkyl, cycloalkenyl and cycloalkynyl refer to cyclic forms of
alkyl, alkenyl and alkynyl, respectively. Exemplary (C3-C8)cycloalkyl groups are
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term halo includes chloro, bromo, iodo and fluoro.
The term aryl refers to an optionally substituted six-membered aromatic rind,
including polyaromatic rings. Examples of aryl include phenyl, naphthyl an|d
biphenyl.
The term het refers to an optionally substituted 5-, 6- or 7-membereld
saturated, partially saturated or unsaturated heterocyclic ring containing from 1 to 3
heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and
including any bicyclic group in which any of the above heterocyclic rings is fused to a
benzene ring or another heterocyclic ring; and the nitrogen atom may be in the
oxidized state giving the N-oxide form; and substituted by 0 to 3 independent
substituents.
The following paragraphs describe exemplary ring(s) for the generic ring
descriptions contained herein.
Exemplary five-membered rings are furyl, thienyl, 2H-pyrrolyl, 3H-pyrrolyl,
pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl,
imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2-pyrazolinyl,
pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl,
1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-
triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatrizaolyl, 3HJ-
1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 5H-1,2,5-
oxathiazolyl and 1,3-oxathiolyl.
Exemplary six-membered rings are 2H-pyranyl, 4H-pyranyl, pyridinyl,
piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,
thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-
triazinyl, 1,2,3-trizainyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1.3-
oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1,2,5-
oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-
oxathiazinyl, 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl.
Exemplary seven-membered rings are azepinyl, oxepinyl, thiepinyl and 1,2,4-
diazepinyl.
Exemplary eight membered rings are cyclooctyl, cyclooctenyl and
cyclooctadienyl.
Exemplary bicyclic rings consisting of combinations of two fused partially
saturated, fully saturated or fully unsaturated five or six membered rings, taken
independently, optionally having one to four heteroatoms selected independently from
nitrogen, sulfur and oxygen are indolizinyl, indolyl, isoindolyl, 3H-indolyl, 1H-isoindolyl,
indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl, benzofuryl, isobenzofuryl,
benzo(b)thienyl, benzo(c)thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyli
benzimidazolyl, benzthiazolyl, purinyl, 4Hquinolizinyl, quinolinyl, isoquinolinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl,
indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido(3,4-b)-
pyridinyl, pyrido(3,2-b)-pyridinyl, pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-
benzoxazinyl, 1 H-2,3-benzoxazinyl, 4H-3,1-benzoxazmyl, 2H-1,2-benzoxazinyl and
4H-1,4-benzoxazinyl.
As used herein the term "mammals" is meant to refer to all mammais,
including, for example, primates such as humans and monkeys. Examples of othjer
mammals included herein are rabbits, dogs, cats, cattle, goats, sheep and horses.
The term "treating", "treat" or "treatment" as used herein includes preventative
(e.g., prophylactic) and palliative treatment.
By "pharmaceutically acceptable" it is meant the carrier, vehicle, diluent,
excipient and/or salt must be compatible with the other ingredients of the formulation,
and not deleterious to the recipient thereof.
The expression "prodrug" refers to compounds that are drug precursors whicth
following administration, release the drug in vivo via some chemical or physiological
process (e.g., a prodrug on being brought to the physiological pH or through enzym$
action is converted to the desired drug form). Exemplary prodrugs upon cleavage
release the corresponding free acid, and such hydrolyzable ester-forming residues o|f
the Formula I compounds include but are not limited to those having a carboxyl
moiety wherein the free hydrogen is replaced by (d-C4)alkyl, (C2-
C7)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1 -
methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -
(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-
(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-
(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-
(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-
crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1C6)alkylamino(C2-C3)alkyl (suoh
as p-dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di(C1C6)alkylcarbamoyl-((C1C6)
alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl.
The compounds of formula I of the present invention are prepared as
described in the Schemes, Preparations and Examples below, or are prepared by
methods analogous thereto, which are readily known and available to one of ordinarjy
skill in light of this disclosure. In each of the Schemes, the R groups (e.g., RI, R2,
etc...) correspond to those noted in the Summary above. In addition, the variable h
is defined as 0 to 6. However, it will be understood by those skilled in the art that
other functionalities disclosed herein at the indicated positions of compounds of
Formula I also comprise potential substituents for the analogous positions on the
structures within the Schemes.
(Figure Removed)
Schemes A-1, A-2 and A-3
The compound of formula A-1 (prepared as described in Org. Syn. 1971, 51,
109-112) (wherein D is methylene, substituted carbon, oxygen, sulfur or optionally
protected nitrogen, R10 is halogen, hydrogen, methyl ether, or benzyl ether or is as
described in the Summary above, and the other variables are as defined in the
Summary above) is reacted with a nitrogen-containing base, such as pyrrolidine,
piperidine or morpholine, at a refluxing temperature in an aprotic solvent such as
toluene, benzene, dichloromethane or dioxane, and then reacted with the alkylatirjig
agent of formula R,X-X! wherein R,X- is (C2-C4)a!kyl straight chain or an isopropyl,itbutyl
or benzyl group or is as described in the Summary above, and X, is a leaving
group (see Francis A. Carey, in Advanced Organic Chemistry, Part A, Chapter 5.6 for
examples) in dioxane, methanol, ethanol, isopropanol, DMF, DMSO or THF to give
the compound of formula A-2. Typical alkylating agents are primary, secondary,
benzylic or allylic halides and are preferably alkyl bromides or alkyl iodides.
Alternatively, the compound of formula A-1 is converted to its anion with a
strong base, such as sodium hydride, sodium methoxide, lithium diisopropylamidp,
lithium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium
butoxide or others, in an aprotic solvent, such as dimethylformamide (DMF) 0r
tetrahydrofuran (THF). This reaction is conducted at -78 °C to room temperature
depending on the nature of the base used. The resulting anion is alkylated with the
appropriate alkylating agent of formula RiX-X, as defined previously to give th|e
compound of formula A-2.
Alternatively, the compound of formula A-1 is reacted with R^-CHO and a
base, such as pyrrolidine or an acid, such as acetic acid or hydrochloric acid, in a
solvent such as toluene, benzene, methanol or ethanol. The intermediate this
obtained is then hydrogenated using a palladium on carbon catalyst or numerous
other reagents such as platinum oxide or rhodium on aluminum oxide (see P.M.
Rylander in Hvdrogenation Methods. Academic Press, New York, 1985; Herbert C).
House in Modern Synthetic Reactions. Chapter 1, pp. 1-45; and John Fried and John
A. Edwards in Organic Reactions in Steroid Chemistry. Chapter 3, pp. 111-145) 1o
give the compound of formula A-2. Alternatively, the intermediate is reacted with a
reducing metal reagent, such as an alkali (group IA in the periodic table) or alkaline
metal (group MA in the periodic table), including Li, Na, or Ca, and an amine, such as
NH3 or ethylene diamine, in an aprotic solvent, such as THF or dioxane, at -78 °Q to
room temperature to give the compound of formula A-2.
The compound of formula A-2 is reacted with (R)-(+)-a-methylbenzylam|ne
(as shown in Scheme A-2) or (S)-(-)-cx-methylbenzylamine (as shown in Scheme A-1)
and an electrophile of formula A-6 (to form a 6-membered ring) or an electrophile of
formula A-7 (to form a 5-membered ring) wherein R5, R8 and R9 are as defined above
in the Summary and X2 is a leaving group that is typically a halogen such as bromide
(see Francis A. Carey, in Advanced Organic Chemistry. Part A, Chapter 5.6 for
examples), in an aprotic solvent such as toluene to give the C2-S or C2-R substituted
intermediates of formula A-2a (which will form a six-membered ring) and of formula
A-2b (which will form a five-membered ring), as shown in Schemes A-1 and A-J*.
These intermediates of formula A-2a and A-2b may be ring closed or ring opened |as
illustrated in the schemes.
Alternatively, the compound of formula A-2 is reacted with an electrophile of
formula A-6 (to form a 6-membered ring) or with an electrophile of formula A-7 (to
form a 5-membered ring) and a base, such as sodium methoxide or KOH, in a
solvent, such as methanol, to give a racemic mixture of the intermediates of formila
A-2a of Schemes A-1 and A-2 (which will form a six-membered ring) or to give a
racemic mixture of the intermediates of formula A-2b of Schemes A-1 and A-2 (which
will form a five-membered ring). This reaction may also give directly a racerric
mixture of the products A-3a of Schemes A-1 and A-2 (which have a six-memberod
ring) or give directly a racemic mixture of the products A-3b of Schemes A-1 and A 2
(which have a five-membered ring), which mixtures may be resolved by chiral HPUC
or by other literature methods.
The resulting intermediate of formula A-2a or A-2b is reacted with a base,
such as sodium methoxide or KOH, in a solvent, such as methanol, or is reacted wi h
an acid such as p-toluenesulfonic acid in a solvent such as toluene to give tre
compound of formula A-3a or A-3b, respectively, wherein the variables are as defined
in the Summary above and wherein Ri0 is halogen, hydrogen, methyl ether, or benz/l
ether or is as described in the Summary above.
Alternatively, the compounds of formula A-3a or A-3b are prepared from the
compound of formula A-2a or A-2b, respectively, by other reported, annulatio|n
methods, some of which are described in M.E. Jung, Tetrahedron, 1976, 32, pp.
31.
The compound of formula A-3a or A-3b wherein R10 is, for example, metnoxy
is reacted with BBr3 or BCI3and tetrabutylammonium iodide or dimethylboron bromicjle
in an aprotic solvent, such as dichloromethane or toluene at -78 °C to room
temperature to give the compound of formula A-3a or A-3b wherein R10 is, for
example, hydroxy.
Alternatively, the compound of formula A-3a or A-3b wherein R10 is, fbr
example, methoxy is reacted with sodium ethanethiol in DMF or is reacted with
methionine in methanesulfonic acid to give the compound of formula A-3a or A-3b
wherein R10 is, for example, hydroxy.
Also, the compound of formula A-3a or A-3b wherein R10 is, for example,
hydroxy may be prepared by other literature methods as described in Protecting
Groups in Organic Synthesis. Second Edition, T. W. Greene and P. G. M. Wuts,
John Wiley and Sons, Inc. (1991) or as illustrated in Comprehesive Organic
Transformation. R.C. Larock, VCH Publishers Inc. (1989), pp. 501-527.
The compound of formula A-3a or A-3b wherein R10 is halogen, hydrogeh,
methyl ether, or hydroxy or is as described in the Summary above is hydrogenated
with a palladium on carbon catalyst or other reagents such as platinum oxide or
rhodium on aluminum oxide (see P.N. Rylander in Hvdrogenation Methods.
Academic Press, New York, 1985; Herbert O. House in Modern Synthetic Reactions.
Chapter 1, pp. 1 -45; and John Fried and John A. Edwards in Organic Reactions
Steroid Chemistry. Chapter 3, pp. 111-145) in a variety of solvents including
methanol, ethanol, and THF to yield the compound of formula A-4a or A-4b or A-E
or A-5b wherein the variables are as described in the Summary above and where
the cis compounds are the major products.
The compound of formula A-3a or A-3b wherein R10 is hydrogen, methU
ether, hydroxy or is as described in the Summary above is reacted with a reducing
metal reagent, such as an alkali (group IA in the periodic table) or alkaline metil
(group IIA in the periodic table), including Li, Na, or Ca, and an amine, such as NH3
or ethylene diamine, in an aprotic solvent, such as THF or dioxane, at -78 °C to room
temperature to give the compound of formula A-5a or A-5b or A-4a or A-4b wherein
the variables are as described in the Summary above and wherein the trans
compounds are the major products.
Alternatively, as shown in Scheme A-3, for example, the compound of formula
A-3a or A-3b of Scheme A-1 wherein R10 is halogen, hydrogen, methyl ether,
hydroxy, carboxyl or is as described in the Summary above is treated with an alcohol
or diol, such as methanol or ethylene glycol, and a strong acid, such as ptoluenesulfonic
acid, in an aprotic solvent, such as toluene or benzene, to form a
ketal intermediate of formula A-6 wherein m is one or two, Ra is lower alkyl or wherein
the Ra's taken together with the two oxygen atoms form, for example, 1,3-dioxolarjie
and wherein the other variables are as defined in the Summary above. Alternative
this ketal intermediate may be prepared by other literature methods such as thoj
described in Protecting Groups in Organic Synthesis. Second Edition, T. W. Greer
and P. G. M. Wuts, John Wiley and Sons, Inc. (1991). The ketal intermediate
hydrogenated using Pd(OH)2 on carbon or other reagents, such as platinum oxide
rhodium on aluminum oxide (see P.M. Rylander in Hydrogenation Methoc
Academic Press, New York, 1985; Herbert O. House in Modern Synthetic Reaction
Chapter 1, pp. 1 -45; and John Fried and John A. Edwards in Organic Reactions
Steroid Chemistry. Chapter 3, pp. 111-145) in a solvent such as toluene from 1
2000 psi (which is about 1 to about 133 atm) H2 at room temperature to 1009C.
resultant intermediate of formula A-7 is then reacted with an acid, such as
toluenesulfonic acid, in acetone or is reacted using various literature methods, sucfi
as those described in Protecting Groups in Organic Synthesis. Second Edition, T.
Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991), to yield the compoun)d
of formula A-5a of Scheme A-1 or the compound of formula A5-b of Scheme A
wherein R10 is halogen, hydrogen, methyl ether, hydroxy or is as described in th
Summary above, and the other variables are as defined in the Summary above. Th
corresponding stereoisomers of these compounds are prepared by procedure
analogous to those described above.
Alternatively, as shown in Scheme A-3, for example, the compound of fomu
A-3a or A-3b of Scheme A-1, wherein R10 is halogen, hydrogen, methyl ethe
hydroxy or is as described in the Summary above, is reacted with triethylorthoforma
and p-toluenesulfonic acid in ethanol or toluene to form an enol ether intermediate i
formula A-8 wherein m is one or two, Rai is ethyl or other acyclic or cyclic lower alk
or acyl, depending on the reagent used, and the other variables are as defined in th
Summary above. Alternatively, this enol ether intermediate may be prepared by othe
literature methods such as those described in Protecting Groups in Organ
Synthesis. Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons]
other reagents, such as platinum oxide or rhodium on aluminum oxide (see P.M.
Rylander in Hydrogenation Methods. Academic Press, New York, 1985, Herbert Q.
House in Modern Synthetic Reactions. Chapter 1 pp. 1-45, and John Fried and John
A. Edwards in "Organic Reactions in Steroid Chemistry," Chapter 3 pp. 111-145) in a
variety of solvents including ethanol, methanol, and THF at 15-60 psi H2 pressure.
The resulting intermediate of formula A-9 is then reacted with an acid such $s
aqueous HCI, in a protic solvent, such as ethanol, or is reacted under other literature
conditions, such as those described in Protecting Groups in Organic Synthesis.
Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (199
to yield the compound of formula A-5a of Scheme A-1 (which has a six-membere|d
ring) or the compound of formula A-5b of Scheme A-1 (which has a five-member* d
ring) wherein Ri0 is halogen, hydrogen, methyl ether, hydroxy or is as described
the Summary above, and the other variables are as defined in the Summary abov
The corresponding stereoisomers of these compounds are prepared by procedure|s
analogous to those described above.
Alternatively, the resulting intermediate of formula A-3a or A-3b of Scheme A-
1 is hydrogenated using Pd/BaSO4 in a solvent such as ethanol at 15 to 200 psi H2
pressure to yield the compound of formula A-5a of Scheme A-1 (which has a sixmembered
ring) or the compound of formula A-5b of Scheme A-1 (which has a fivemembered
ring) wherein R5 is COOR^ and wherein R is, for example,(C1C6)alkyl
Other reagents which may be used in the above hydrogenation reactions ars
described in P.N. Rylander in Hvdrogenation Methods. Academic Press, New York,
1985.
Alternatively, in Schemes A-1 and A-2, the compounds of formula A-5a or A-
5b are prepared from the compounds of formula A-3a or A-3b, respectively, by other
reported reduction methods, some of which are described in P. Jankowski, S.
Marczak, J. Wicha, Tetrahedron, 1998,12071-12150.
(Figure Removed)
The compound of formula B-1, which is obtained as described in Scheme AM|
and Scheme H, is reacted with a base, such as NaH, f-butoxide or Et3N, in an aprojic
solvent, such as DMF or CH3CN, at a temperature which is between room
temperature and 200°C depending on the nature of the solvent used, and is then
reacted with an alkylating agent of formula Rb-X1 wherein X, is a leaving group, to
give the compound of formula of B-2 wherein Rb is, for example, alkyl or alkylheterocycle
and is further illustrated by a variety of different groups within the
definition of R10 in the Summary above. To obtain compounds of formula B-2 which
are carbamates wherein Rb is, for example, -C(O)NR12R3 and wherein R,2 and R13
are as defined in the Summary above, the compound of formula B-1 is reacted with a
compound of formula R2R3-NC(O)CI. Alternatively, to obtain compounds of formula
B-2, which are carbamates wherein Rb is, for example, C(O)NR12R3, the compound
of formula B-1 is reacted with phosgene or triphosgene in an aprotic solvent such a 5
toluene and then with an amine of the formula R12R13NH. To obtain compounds of
formula B-2 which are thiocarbamates wherein Rb is, for example, -C(S)NR12R13and
R12 and R13 are defined in the Summary above, the compound of formula B-1 is
reacted with a compound of the formula R12R13NC(S)Cl. Throughout this scheme,
the other variables are as defined in the Summary above.
The compound of formula B-3 wherein n is, for example, one to six (prepared
by the procedures for the formula B-2 compound) is reacted with a base such as
Na2CO3with or without sodium iodide in an aprotic solvent, such as DMF, at a
temperature which is between room temperature and 200~C, depending on the
nature of the solvent used, and is then reacted with an amine of formula R12R-,3NH tb
obtain the compound of formula B-4 wherein n is, for example one to six and R 2 anq
R13 are as defined in the Summary above.
The compound of formula B-5 wherein n is, for example, one to six, (prepared
by the procedures for the formula B-2 compound) is reacted with OsO4, Nmethylmorpholine-
N-oxide or K2MnO4to give the corresponding diol. The diol is
oxidatively cleaved with NalO4 or Pb(OAc)4 to give the compound of formula B-6
wherein n is one to six, for example. Alternatively, the compound of formula B-5 is
reacted with ozone and quenched with dimethyl sulfite, triphenylphosphine or other
known reagent to give the compound of formula B-6. Alternatively, the compound ojf
formula B-6 is obtained from the compound of formula B-5 by the methods illustratejj
in Comprehensive Organic Transformation. R.C. Larock, VCH Publisher, Inc. (1989)
pp. 595-596, pp. 615-616.
Alternatively, the compound of formula B-4 wherein n is, for example, one to
six, and R12 and R13 are as defined in the Summary above, is obtained from the
compound of formula B-6 wherein n is one to six, for example, by reductive
amination. The reductive amination is typically carried out with a reducing agent,
such as sodium cyanoborohydride or sodium triacetoxyborohydride, preferably at a
pH of between 6 and 8. The reaction is normally performed in a protic solvent, such
as methanol or ethanol, or in a mixture of solvents, such as dichloroethane/methanoi,
at temperature of about -78°C to about 40°C. (See A. Abdel-Magid, C. Maryanoff, K.
Carson, Tetrahedron Lett. Vol. 34, Issue 31, 5595-98,1990). Other conditions involve
the use of titanium isopropoxide and sodium cyanoborohydride (R.J.Mattson et al.,
J.Org.Chem. 1990, 55, 2552-4) or involve the formation of the imine under
dehydrating conditions followed by reduction (Comprehensive Organic
Transformation. R.C. Larock, VCH Publisher, Inc (1989) pp. 421-425).
The compound of formula B-7 wherein n is, for example, one to six (prepared
by the procedures for the formula B-2 compound) is reacted with a hydroxyamine or
its HCI salt in a protic solvent, such as ethanol or methanol, and a base such as
K2CO3 at a temperature between room temperature and 150 °C, depending on the
nature of the solvent used, to give the compound of formula B-8 wherein n is one to
six, for example.
To obtain compounds of formula B-9 wherein, for example, Rbi is alkyl, and n
is one to six, the compound of formula B-8 wherein n is one to six, for example, is
reacted with a base, such as NaH and Rbi-CH2CO2Et in an aprotic solvent such as
THF at a temperature between room temperature to 140°C, depending on the nature
of the solvent used. To obtain compounds of formula B-9 wherein Rb1 is =O and n is.
for example one to six, the compound of formula B-8 wherein n is one to six, for
example, is reacted with a base, such as pyridine and 2-ethylhexylchloro-formate in
an aprotic solvent, such as DMF. The intermediate thus obtained is refluxed in xylenfe
or other high boiling point aromatic solvent to give the compound of formula B-9
wherein Rb1 is =0. To obtain compounds of formula B-9 wherein Rb1 is =S and n is,
for example, one to six, the compound of formula B-8 wherein n is one to six, for
example, is reacted with a base such as DBU in an aprotic solvent, such as CH3CN
and TCDI (1,1-thiocarbonyldiimidazole).
The compound of formula B-7 wherein n is, for example, one to six, is reactejd
with TMSN3 and AIMe3 in an aprotic solvent such as toluene at between 40°C to 20C
°C, depending on the nature of the solvent used, to give the compound of formula B-
10 wherein n is one to six, for example. Alternatively, the compound of formula B-1Q
is obtained by reacting the above compound of formula B-7 with NaN3 and
triethylamine or ammonium chloride in an aprotic solvent, such as DMF, at elevated
temperatures.
The compound of formula B-7 wherein n is, for example, one to six, is reacteM
with an amine and AI(Me)3 in an aprotic solvent, such as toluene, at a temperature
between room temperature and 180°C, depending on the nature of the solvent used)
to give the compound of formula B-11 wherein n is, for example, one to six and R12
and R13 are as defined in the Summary above. Alternatively, this compound of
formula B-11 is obtained by reacting the above compound of formula B-7 with an
amine in the presence of a Lewis acid, such as AICI3 or ZnCI2 at 150 ° C to 200 °C, Or
in the presence of an organometallic reagent, such as CuCI, CuBr or lanthanide (III)
triflate. (See Tetrahedron Lett. 1993, Vol. 34, Issue 40, 6395-6398.)
The compound of formula B-12 wherein n is, for example, one to six
(prepared by the procedures for the formula B-2 compound) is reacted with an amine^
or its salt and AI(Me)a in an aprotic solvent, such as dichloromethane, to give the
compound of formula B-13 wherein n is, for example, one to six and R12 and R13 are
independently hydrogen, alkyl, hydroxy or methoxy, for example or as defined in the
Summary above. Alternatively, the compound of formula B-12 is hydrolyzed by the
methods mentioned in Greene and Wuts, Protecting Groups in Organic Synthesis.
Wiley, New York (1981) to give the corresponding free acid. The free acid thus
obtained is reacted with an amine and a coupling reagent, such as DCC or EDCI, to
give the above compound of formula B-13 (as illustrated in Comprehensive Organic
Transformation. R.C. Larock, VCH Publisher, Inc. (1989) pp. 972-976).
To obtain compounds of formula B-14 wherein, for example, n is one to six, 2
is O and Rb2 is alkyl or halo, the compound of formula B-12 wherein n is one to six,
for example, is reacted with a base, such as NaH, in an aprotic solvent, such as THF
and NH2C(=N-OH)Rb2 wherein R, is alkyl at refluxing temperatures. To obtain
compounds of formula B-14 wherein, for example, n is one to six, Z is N and Rb2 is
alkyl or halo, the compound of formula B-12 wherein n is one to six, for example, is
reacted with a base, such as NaOMe, in a protic solvent, such as MeOH, and
aminoguanidine nitrate.
The compound of formula B-15 wherein R12 and Ri3 are as defined in |he
Summary above (prepared by the procedures for the formula B-2 compound) is
dissolved in an aprotic solvent such as toluene and refluxed to give the compound of
formula B-16 wherein R12 and R13 are as defined in the Summary above.
(Figure Removed)
The compound of formula C-1 (which is the same as the compound of
formula B-1, see Scheme B) is treated with an acid scavenger, such as 2,6-lutidine
diisopropylethylamine, or potassium carbonate, with a trifluoromethylsulfonylation
reagent, such as trifluoromethylsulfonic anhydride, N-phenyltrifluoromethanesulfonamide,
or 4-nitrophenyltrifluoromethanesulfonate, with or without a catalyst,
such as 4-dimethylaminopyridine (DMAP), in a solvent, such as dichloromethane,
DMF or methyl-2-pyrrolidinone (NMP), from -78 °C to room temperature to obtain the
compound of formula C-2 wherein R10 is -OS(O)2CF3. Throughout this scheme, the
other variables are as defined in the Summary above. Alternatively, the above
compounds of formula C-2 are prepared from the compound of formula C-1 by othe^
reported fluoroalkylsulfonylation methods, some of which are described in K. Ritter,
Synthesis, 1993, pp. 735-762.
The compound of formula C-2 wherein the group at the RIO position is -
OS(O)2CF3 or a halogen is reacted with metalcyanide, preferably zinc(ll)cyanide
(Zn(CN)2), and with a palladium source, such as tetrakis(triphenylphosphine)
palladium(O) (Pd(PPh3)4), palladium(ll)acetate, or tris(dibenzylidenacetone)
dipalladium(O), in a solvent such as N-methyl-2-pyrrolidinone (NMP), DMF or
acetonitrile, at room temperature to 120 °C to give the cyano-substituted compound
of formula C-3.
To obtain the compound of formula C-4 wherein, for example, Met is
tetrazolyl, the compound of formula C-3 is reacted with dibutyltin oxide (Bu2SnO) and
trimethylsilylazide (TMSN3) in toluene from room temperature to reflux. Alternatively
the compounds of formula C-4 wherein, for example, Met is tetrazolyl are prepared
from the compound of formula C-3 by other reported methods, some of which are
described in S J. Wittenberger, Organic Preparations and Procedures Int. 1994,
26(5), pp. 499-531. Alternatively, the compound of formula C-4 wherein Met is, for
example, 2-pyridyl or 3-pyridyl, is obtained by reacting the compound of formula C-2
with a heterocycle-metal, such as bromo-2-pyridyl zinc or diethyl-(3-pyridyl)borane,
and a catalyst, such as Pd(PPh3)2CI2, tetrakis(triphenylphosphine)palladium(0)
(Pd(PPh3)4), or palladium acetate, and 1,1 '-bis(diphenylphosphino)ferrocene, in an
organic solvent, such as THF, DMF, or NMP at room temperature to 150 °C,
depending on the nature of the solvent used.
The compound of formula C-2 is reacted under CO 1-3 atm, with a catalyst
such as palladium acetate (Pd(OAc)2) and 1,1'-bis(diphenylphospino)ferrocene
(DPPF) or bis(diphenylphosphino)propane (DPPP), tetrakis(triphenylphosphine)
palladium(O) (Pd(PPh3)4), or tris(dibenzylidenacetone) dipalladium(O), and a base,
such as triethylamine or potassium carbonate, with an alcohol, such as methanol,
ethanol, or benzyl alcohol, in a solvent, such as DMF, NMP, or DMSO, at room
temperature to 150 °C, depending on the nature of the solvent used, to give the ester
of formula C-5, wherein Rc is, for example, alkyl or aryl.
An aqueous base, such as KOH, in a solvent, such as THF, is added to a
solution of the compound of formula C-5 in a solvent, such as THF. The resulting
solution is stirred at room temperature to reflux to give the acid of formula C-6.
A solution of the compound of formula C-6, diphenylphosphoryl azide (DPPAJ),
triethylamine, and an alcohol of the formula RCOH, such as t-butanol, is stirred at
room temperature to reflux to give the carbamate of formula C-7, wherein, for
example, Rc is t-butyl.
The compound of formula C-6 is treated with a coupling reagent, such as 1,3ldimethylaminopropyl-
3-ethylcarbodiimide (EDC) or dicyclohexyl carbodiimide (DCC)
and hydroxybenzotriazole hydrate (HOBt), with or without a catalyst, such as 4-
dimethylaminopyridine (DMAP), and an amine, Ri2Ri3NH, in an aprotic solvent, such|
as dichloromethane or DMF, at 0 °C to room temperature to give the amide of
formula C-8 wherein R12 and Ri3 are defined in the Summary above. Also, the
compounds of formula C-8 can be prepared from the compound of formula C-6 by
other reported, coupling methods, such as those described in Comprehensive
Organic Transformation. R.C. Larock, VCH Publishers Inc. (1989), p 972-988.
Alternatively, the ester of formula C-5 is added to a mixture of
trimethylaluminum (AI(CH3)3) and R12R3NH, such as 1-(3-aminopropyl)imidazole, in a
solvent, such as dichloromethane, dichloroethane (DCE), or toluene at 0 °C to room
temperature. The resulting mixture is stirred at room temperature to reflux to obtain
the amide of formula C-8 wherein, for example, Ri2 is hydrogen and R13 is propylimidazol-
1-yl, and are further defined in the Summary above.
The ester of formula C-5 is reacted with a reducing agent, such as sodium
borohydride or diisobutylaluminum hydride, in an organic solvent, such as methanol,
THF or hexane depending on the nature of the reducing agent used, at -78 °C to
room temperature, to obtain the alcohol of formula C-9 wherein R^ is H. To obtain
other compounds of formula C-9, wherein, for example, R i s methyl, the compound
of formula C-5 is reacted with RC1-metal, such as methylmagnesium bromide, in an
organic solvent, such as THF or toluene, at -78 °C to room temperature.
The carbamate of formula C-7, wherein Rc is, for example, f-butyl, is reacted
with an acid, such as trifluoroacetic acid (TFA), in a solvent, such as
dichloromethane, at -78 °C to room temperature to give the amine of formula C-10.
Also, the compound of formula C-10 may be prepared from the compound of formula
C-7, wherein Rc is f-butyl, benzyl, or other protecting groups, by other literature
methods, some of which are described in Protecting Groups in Organic Synthesis.
Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991)
To obtain the compound of formula C-11 wherein Rca is -OS02-methyl, the
compound of formula C-9 wherein RC1 is hydrogen or alkyl is reacted with a
methylsulfonating reagent, such as methanesulfonyl chloride (MsCI), and an acid
scavenger, such as diisopropylethylamine, in an organic solvent, such as THF or
toluene at -78 °C to room temperature. To obtain the compound of formula C-11
wherein R is Cl, the compound of formula C-9 wherein RC1 is hydrogen or alkyl is
reacted with a chlorinating reagent, such as thionyl chloride, an acid scavenger, such
as pyridine, in an organic solvent, such as methylene chloride, at -78 °C to room
temperature.
The amine of formula C-10 is reacted with an acylating reagent, such as
CH3COCI and an acid scavenger, such as triethylamine or pyridine, in a solvent, such
as methylene chloride or THF, at -78 °C to room temperature to give the amide of
formula C-12 wherein R12 is as defined in the Summary above.
The compound of formula C-13 (which is obtained from the compound of
formula C-6 by reacting it with N,O-dimethylhydroxylamine hydrochloride, 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, HOBt and DMAP) is reacted
with Rc3-Metal, such as ethylmagnesium bromide, in a solvent, such as THF or
toluene, at -78 °C to room temperature to give the compound of formula C-14,
wherein R& is, for example, ethyl.
The compound of formula C-11 and an amination reagent, such as sodium
azide, in a solvent, such as DMF, NMP, or DMSO, are stirred at room temperature to
150 °C, depending on the nature of the solvent used, to give the compound of
formula C-15 wherein RC1 is hydrogen or alkyl and R& is N3. The resulting azide is
-57-
treated with a reducing reagent, such as triphenylphosphine (PPh3), in a solvent or
mixture of solvents, such as THF, methanol and water, at -20 °C to reflux, to give
compound of formula C-15 wherein R^ is NH2.
The aldehyde of formula C-14 wherein R& is hydrogen or the ketone of
formula C-14 wherein R^ is alkyl is treated with a reducing agent such as sodium
borohydride or diisobutylaluminum hydride, in an organic solvent, such as methanol,
THF, or hexane depending on the nature of the reducing agent used, at -78°C to
room temperature, to obtain the alcohol of formula C-1 6 wherein R& is, for example^
ethyl.
The amine of formula C-15 wherein Rci is hydrogen or alkyl and RCA is -NH2 s
reacted with an acylating reagent, such as CH3COCI and an acid scavenger, such as
triethylamine or pyridine, in a solvent, such as methylene chloride or THF, at -78 °C
room temperature to give the amide of formula C-1 7 wherein R12 and Ri3 are as
defined in the Summary above.
(Figure Removed)
The compound of formula D-1 is prepared from commercially available
cyclohexane-1,3-dione by literature procedures described in Chem. Ber., 85, 1031
(1952); Org. Syn., Coll. Vol. V, page 486; and S. Ramachandran and M.S. Newman,
Org. Syn. 41, 38 (1961). It is reacted with triethylorthoformate, p-toluenesulfonic acid
and ethanol in toluene to obtain the dienol ether of formula D-2. Throughout this
scheme, the other variables are as defined in the Summary above.
The compound of formula D-2 in ethanol or methanol is hydrogenated usincj 1
atm of H2 over Pd/CaCO3 or strontium carbonate to obtain the compound of formijila
D-3. The compound of formula D-3 is reacted with lithium diisopropylamide (prepared
from diisopropylamine and n-butyllithium) and n-bromo-succinimide in THF to obtain
the brominated compound of formula D-4. The compound of formula D-3 is react 3d
with ethyl formate in THF and potassium t-butoxide to obtain the carboxaldehyde of
formula D-5.
The compound of formula D-4 is hydrolyzed with an aqueous acid, such las
sulfuric acid, to obtain the compound of formula D-6. Likewise, once the compounds
of formula D-8 and D-9 are obtained, as described below, they are hydrolyzed with
aqueous acid to obtain the compounds of formula D-10 and D-11, respectively.
The compound of formula D-6 is reacted with thiourea in acetonitrile and thfen
heated to reflux to obtain the amine-substituted thiazole compound of formula D-'
The carboxaldehyde of formula D-5 is reacted with hydrazine in ethanol/water to
of
te
obtain the pyrazole compound of formula D-8. The carboxaldehyde compound
formula D-5 is reacted with a refluxing solution of sodium metal and guanidine sulfc
in isopropyl alcohol to obtain the amino-substituted pyrimidine compound of formijila
D-9.
The compound of formula D-7 is reacted with an organometallic compourld,
R3-Metal, such as R3Li, R3MgBr or R3MgCI, (for example, lithio-2-chloroethyne), in an
aprotic solvent such as THF at -78 °C to room temperature to obtain the compound
formula D-12 wherein R2 and R3 are, for example, hydroxy and chloroethyn/l,
respectively, and are further defined in the Summary above. Likewise, tlie
compounds of formula D-13 and D-14 are obtained from the compounds of formula
D-10 and D-11, respectively, by analogous procedures.
(Figure Removed)
Scheme E
The compound of formula E-1 (which is the same as the compound of
formula A-3a (see Scheme A) wherein R10 is methoxy and the other variables are a|s
defined in the Summary above) is treated with a reducing metal reagent, such as an
alkali (group IA in the periodic table) or alkaline metal (group IIA in the periodic table),
including Li, Na, or Ca, an amine, such as NH3 or ethylene diamine, and a proton
source, such as f-butyl alcohol or ethanol, in an aprotic solvent, such as THF or
dioxane, at -78 °C to room temperature to give the compound of formula E-2, wherein
the variables are as described in the Summary above.
The compound of formula E-2 wherein the variables are as described in the
Summary above is reacted with R3-Metal, such as R3Li, R3MgBr or R3MgCI, whereirji
R3 is, for example, alkynyl, in an aprotic solvent such as THF at low temperature to
give the compound of formula of E-3 wherein the variables are as described in the
Summary above.
The compound of formula E-3 is treated with an aqueous acid, such as HCI,
acetic acid, or oxalic acid, in a solvent, such as THF or dioxane, at -20 °C to reflux to
give the compounds of formula E-4 and E-5 wherein the variables are as defined in
the Summary above in various ratios depending on the nature of the aqueous acid
and the solvent used. Also, the compounds of formula E-4 and E-5 may be prepared
by other literature methods as described in Protecting Groups in Organic Synthesis.
Second Edition, T. W. Greene and P. G. M. Wuts, John Wiley and Sons, Inc. (1991
(Figure Removed)
The compound of formula F-1 (prepared as described in Schemes A, B, C,
and H) wherein the variables are as described in the Summary above is treated with
an oxidizing agent, such as osmium tetroxide in f-butanol, with or without an agent to
regenerate the oxidizing agent, such as N-methylmorpholine-N-oxide, with or withoujt
a catalyst, such as pyridine, in a solvent, such as methylene chloride, at 0 °C to room
temperature to obtain the diol compound of formula F-2 wherein the variables are as|
described in the Summary above.
The compound of formula F-2 wherein the variables are as described in the
Summary above is reacted with a carbonylation reagent, such as
carbonyldiimidazole, diphosgene or phosgene, in a solvent, such as THF or
methylene chloride, at 0 °C to reflux to obtain the (2-oxo-1,3-dioxolan-4-yl)methyl
compound of formula F-3 wherein all the variables are as described in the Summary
above.
The diol compound of formula F-2 wherein the variables are as described in
the Summary above is oxidatively cleaved with an oxidation reagent, such as sodiurr
periodate (NalO4), with or without an acid scavenger, such as sodium bicarbonate, in
a solvent, such as methylene chloride, at 0 °C to room temperature to obtain the
aldehyde of formula F-4 wherein the variables are as described in the Summary
above.
Alternatively, the compound of formula F-1 wherein the variables are as
described in the Summary above is treated concomitantly with an oxidation reagent,
such as osmium tetroxide in f-butanol, and an oxidative cleavage reagent, such as
sodium periodate (NalO4), with or without an agent to regenerate the oxidizing agent,
such as N-methylmorpholine-N-oxide, with or without a catalyst, such as pyridine, in a1
solvent mixture, such as dioxane and water, at 0 °C to room temperature to obtain
the aldehyde of formula F-4 wherein the variables are as described in the Summary
above.
Alternatively, the compound of formula F-1 wherein the variables are as
described in the Summary above is treated with ozone in a solvent, such as THF, at
78°C to 0°C followed by treatment with a reducing agent, such as dimethyl sulfide, at
-78°C to room temperature to obtain the aldehyde of formula F-4 wherein the
variables are as described in the Summary above.
The aldehyde of formula F-4 wherein the variables are as described in the
Summary above is treated with an amine, (NHR12Ri3, for example, piperidine), withjor
without a drying agent, such as molecular sieves or magnesium sulfate, with a
reducing agent, such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium
cyanoborohydride (NaCNBH3), in a solvent or a mixture of solvents, such as acetic
acid and/or dichoromethane, at 0 °C to room temperature to obtain the compound
formula F-5, wherein, for example, R 2 and R13 taken together are piperidinyl and
wherein the other variables are as described in the Summary above.
The oxime-containing compound of formula F-6 wherein R12 is hydroxy or
alkoxy and wherein the other variables are as described in the Summary above, is
prepared by reacting the formula F-4 compound wherein the variables are as
described in the Summary above with hydroxylamine or an alkoxyamine or an HCI
salt, with or without a base, such as KHCO3 or pyridine, in a solvent, such as
methanol, ethanol or pyridine, at 0 °C to reflux.
An olefination reagent, such as PO(ORi)2CH2R1, is treated with a base, suctli
as lithium diisopropyl amine (LDA) or n-butyl lithium, and is reacted with the aldehyde
of formula F-4 wherein the variables are as described in the Summary above in a
solvent, such as THF at -78 °C to room temperature to obtain the alkenyl compound
of formula F-7 wherein the variables are as described in the Summary above.
The aldehyde of formula F-4 wherein the variables are as described in the
Summary above is treated with a reducing agent, such as diisobutylaluminum hydricjle
(DiBAI) in hexane or sodium borohydride (NaBH4), in a solvent, such as THF or
methanol, at -78 °C to room temperature to obtain the alcohol of formula F-8 whereih
the variables are as described in the Summary above.
The alkenyl compound of formula F-7 wherein the variables are as described!
in the Summary above is hydrogenated using hydrogen with a palladium on carbon
catalyst or other reagents such as platinum oxide or rhodium on aluminum oxide (sele
P.N. Rylander in Hvdrogenation Methods. Academic Press, New York, 1985; Herbeit
O. House in Modern Synthetic Reactions. Chapter 1, pp. 1-45; and John Fried and
John A. Edwards in Organic Reactions in Steroid Chemistry. Chapter 3, pp. 111-145)
in a variety of solvents including methanol, ethanol and THF to obtain the compound
of formula F-9 wherein the variables are as described in the Summary above.
The alcohol of formula F-8 is coupled with RpArylOH, utilizing an
azocarboxylate such as diethylazodicarboxylate (DEAD), a trialkyl phosphine such ds
triphenylphosphine (PPh3) in a solvent, such as methylene chloride, to obtain the
compound of formula F-10 wherein R( is formyl and other aromatic substituents as
described in the Summary above and the other variables are as defined in the
Summary above. Alternatively, formula F-10 compounds are prepared by reacting
the compound of formula F-8 with p-toluenesulfonyl chloride. The resulting
intermediate in DMF is reacted with an alkali metal salt of RpArylOH to give the
compound of formula F-10.
The ester of formula F-11 (prepared from the aldehyde of formula F-4 by an
olefination procedure described above) wherein R(1 is, for example, methyl, and the
other variables are as described in the Summary above is reacted with an aqueous
base, such as KOH, in a solvent, such as THF, and the resulting solution is heated
and stirred at room temperature to reflux to obtain the acid of formula F-11 wherein
RM is hydrogen and all the additional variables are as described in the Summary
above.
The compound of formula F-11 wherein Rf1 is hydrogen and the other
variables are as described in the Summary above is treated with a coupling reagent,
such as 1,3-dimethylaminopropyl-3-ethylcarbodiimide (EDC) or dicyclohexyl
carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt), with or without a
catalyst, such as 4-dimethylaminopyridine (DMAP), and an amine (RiaRiaNH, such a$
pyrrolidine), in an aprotic solvent, such as dichloromethane or DMF, at 0 °C to room
temperature to obtain the compound of formula F-12 wherein, for example R12 and
R13 taken together are pyrrolidinyl, and the other variables are as described in the
Summary above. Also, the compounds of formula F-12 are prepared from the
compounds of formula F-11 by other reported, coupling methods, some of which are
described in Comprehensive Organic Transformation. R.C. Larock, VCH Publishers
Inc. (1989), pp. 972-988.
The compound of formula F-13 wherein Rn is COOR^, wherein R0 is, for
example, methyl, and wherein the other variables are as defined in the Summary
above (prepared from the aldehyde of formula F-4 by an olefination procedure
described above) is hydrolyzed with an aqueous base, such as KOH, in a solvent,
such as THF, and the resulting solution is stirred at room temperature to reflux to give
the compound of formula F-13 wherein RK is COOH and the other variables are as
described in the Summary above.
-66-
The compound of formula F-13 wherein R(2 is COOH is treated with a
coupling reagent, such as 1 -(3-dimethy!aminopropyl)-3-ethylcarbodiimide (EDC) or
dicyclohexyl carbodiimide (DCC) and hydroxybenzotriazole hydrate (HOBt), with or
without a catalyst, such as 4-dimethylaminopyridine (DMAP), and an amine
(R12Ri3NH, such as pyrrolidine), in an aprotic solvent, such as dichloromethane or
DMF, at 0 °C to room temperature to obtain the compound of formula F-14 wherein,
for example Ri2 and Ri3 taken together are pyrrolidinyl, R' and R' are taken together
to form =O, and the other variables are as described in the Summary above. Also,
the compounds of formula F-14 are prepared from the compounds of formula F-13 bv
other reported, coupling methods, some of which are described in Comprehensive
Organic Transformation. R.C. Larock, VCH Publishers Inc. (1989), pp. 972-988.
The compound of formula F-13 wherein Rf2 is CHO and the other variables
are as described in the Summary above (which is prepared analogously to the
compound of formula F-7) is treated with an amine, (NHR,2R13, for example,
piperidine), with or without a drying agent, such as molecular sieves or magnesium
sulfate, and with a reducing agent, such as sodium tnacetoxyborohydride
(NaBH(OAc)3) or sodium cyanoborohydride (NaCNBHj). in a solvent or a mixture of
solvents, such as acetic acid and/or dichoromethane, at 0 ;C to room temperature tcji
obtain the compound of formula F-14, wherein, for example, R12 and R13 taken
together with the nitrogen atom are piperidinyl, each R' is H, and wherein the other
variables are as described in the Summary above.
The protected compound of formula F-13 wherein R^ is, for example, -
CH2OTBDMS is prepared from the aldehyde of formula F-4 by Wittig coupling as
described above. This compound is deprotected to the alcohol by using
tetabutylammonium fluoride in a solvent, such as tetrahydrofuran. This alcohol
wherein R^ is CH2OH is reacted with methanesulfonyl chloride, diisopropylethylamin^
and a primary or secondary amine, such as morpholine, to give the compound of
formula F-14 wherein R12and R13 taken together are, for example, morpholinyl, each|
R1 is H and the other variables are as described in the Summary above.
The compound of formula F-10 wherein Rf is CHO and the other variables arfe
as described in the Summary above (which is prepared as described above) is
treated with an amine, (NHRi2Ri3, for example, piperidine), with or without a drying
agent, such as molecular sieves or magnesium sulfate, and with a reducing agent,
such as sodium triacetoxyborohydride (NaBH(OAc)3) or sodium cyanoborohydride
(NaCNBH3). in a solvent or a mixture of solvents, such as acetic acid and/or
dichoromethane, at 0 °C to room temperature to obtain the compound of formula F-
15. wherein, for example, R,2 and R13 taKen together with N are pipendinyl, R' is H
and the other variables are as described in the Summary above The compounds of
formula F-15. wherein R' and R1 taken together to form =O, may be prepared by
procedures analogous to those described above.
Scheme G
Scheme G
The compound of formula G-i wherein 2 is NH2 and the other variables are
as defined in the Summary above (which is prepared according to the procedures in
Schemes A and H) is reacted with an aldehyde or ketone such as R12C(O)R^ and
with sodium tnacetoxyborohydride (Na(OAc)3BH) or sodium cyanoborohydnae
(NaCNBHs) as reducing agents to give the reductive ammation product of formula G-
2 wherein Z, is N and the other variables are as defined in the Summary above
Alternatively, the compound of formula G-2 is prepared from the compound of
formula G-1 by other reductive amination methods known in the art. sucn as those
disclosed for the preparation of the compound of formula B-4 in Scheme B above
The compound of formula G-1 wherein Z, is Nhk or OH is reacted with a
coupling reagent, such as 1.3-dimethylaminopropyh3-ethylcarbodiimide (EDC) or
diCyciohexyl carbodiimide (DCC) and nydraxybenzotriazoie hydrate (HOBt). and a
base, such as 4-dimethylaminopyndine (DMAP) or tnethyiamme. m an aprotic solvent,
such as methylene chloride, and an acid to give the compound of formula G-3
wherein Z, is O or NR12, Rg is for example, alkyl and the other variables are as
defmea in the Summary above. Alternatively, the compound of formula G-3 is
obtained from the compound of formula G-1 by standard acylation, such as treating
the compound of formula G-1 with a base, such as pyndine, and an acyi halide or
acid anhydride in an aprotic solvent to give the compound of formula G-3
The compound of formula G-4 wherein Z, is O or NR12 and the other variables
are as defined in the Summary above is obtained from the compound of formula G-1
according to the procedures described in Scheme B, such as the preparation of the
carbamate of formula B-2 wherein RD is -C(O)NRl2Ri3 Alternatively, the compound
of formula G-4 wherem Z, is NHBoc is reacted with a base, such as n-BuUi, in an
aprotic solvent and an amine to give the compound of formula G-4 wherein Z, is NM.
The compound of tne formula G-1 is reacted witn the compound of formula
RgiSO2Ci and a base, such as tnethyiamme, in an aprotic solvent, such as THF, to
give the compound of formula G-5 wherein Z, is O or NR,a, Rgi is, for example, alkyl
and the other variables are as defined in the Summary above.
The compound of formula G-i wherein Z, is -NH2 and the other variables are
as defined in the Summary above is reacted with (Me2NCH=N}2 in an aprotic solvent
such as toluene and with an acid, such as p-toiuenesulfonic acid, to give the
compound of formula G-6 wherem the variables are as defined in the Summary
above
Scheme H
Scheme H
The compound of formula H-1 wherein the variables are as described in the
Summary above (which is prepared by the procedures in Scheme A above) is
reacted with reagents such as P(Rh2)3CH2Ri2 or PO(ORh2)2CH2Ri2 wherein R^ is
lower alkyl or aryl and the other variables are as defined in the Summary above and a
base such as lithium diisopropylamide (LDA) or sodium hydride (NaH) in an apro'ic
solvent, such as THF or DMF, to give the compound of formula H-2 wherein Z is CH,
and Ri2 and the other variables are as defined in the Summary above.
The compound of formula H-1 is reacted with the compound of formula
H2NORi2 or its hydrochloride salt in ethanol or methanol, with or without sodium
acetate (NaOAc), at room temperature or at the refluxing temperature of the solvent,
to give the compound of formula H-2 wherein Z is N, and Ri2 and the other variables
are as defined in the Summary above.
The compound of formula H-1 is reacted with RhOH wherein Rh is, or
example, lower alkyl or ethylene glycol, and an acid such as p-toluenesulfonic acid in
an aprotic solvent such as toluene at reflux temperature under Dean-Stark trap to
remove water to give the compound of the formula H-3 wherein Rh is, for exampe,
lower alkyl or wherein Rh's taken together with the two oxygen atoms form, 'or
example, 1,3-dioxolane, and the other variables are as defined in the Summary
above.
The compound of the formula H-2 wherein Z is CH, R12 is, for example, alKyi
and the other variables are as defined in the Summary above is reacted with H2, a id
Pd/C or other reagents as described by P. N. Rylander in Hvdrogenation Methods.
Academic Press, New York, 1985 in a solvent, such as methanol, to give tie
compound of formula H-4 wherein Z is CH, Ri2 is, for example, alkyl, and the other
variables are as defined in the Summary above.
The compound of the formula H-2 wherein Z is N, Ri2 is, for example, alkyl
and the other variables are as defined in the Summary above is reacted with
hydrochloric acid in methanol and borane-trimethyl-amine complex (Me3N BH3) or
other reducing reagents to give the compound of formula H-4 wherein Z is NH, R12 is
alkyl and the other variables are as defined in the Summary above.
Alternatively, the compound of formula H-4 is obtained from the compound PT
formula H-2 by other hydrogenation procedures which are known and available in tf(ie
art.
The compound of formula H-1 is reacted with trimethylsulfonium iodide
((CH3)3ST) or trimethylsulfoxonium iodide ((CH3)3S+->OI') and a base, such as
potassium t-butoxide, in an aprotic solvent such as DMF to give the compound of
formula H-5 wherein the variables are as defined in the Summary above.
Alternatively, the compound of formula H-5 is obtained from the compound of formula
H-1 by an analogous method to that illustrated in Comprehensive Organic
Transformation. R.C. Larock, VCH Publishers Inc. (1989), pp. 468-470.
The compound of formula H-1 is reacted with R3-Metal, such as R3Li, R3Mgfer
or R3MgCI, wherein R3 is, for example, alkynyl or alkyl in an aprotic solvent such £is
THF at low temperature to give the compound of formula H-6 wherein R3 is alkynyl or
alkyl and the other variables are as defined in the Summary above.
The compound of formula H-1 is reacted with TMSCF3 and TBAF a^s
described in G.A. Olah et al., J.Am.Chem.Soc. (1989) 111, 393, to give the
compound of formula H-6 wherein R3 is -CF3 and the other variables are as definec in
the Summary above. Alternatively, the compound of formula H-1 is treated with other
-CF3 nucleophiles which are known and available in the literature including, but rpot
limited to, that disclosed by J. Russell, N. Roques, Tetrahedron, 1998, 54, 137
13782.
Alternatively, the compound of formula H-5, wherein the variables are
defined in the Summary above, is reacted with R3-Metal such as R3Li, R3MgBr,
R3MgCI wherein R3 is, for example, alkyl in an aprotic solvent such as THF at I
temperature to give the compound of formula H-6 wherein R3 is, for example, -CH2-
alkyl, and the other variables are as defined in the Summary above. Alternatively, tie
compound of formula H-5 wherein the variables are as defined in the Summjiry
above is reacted with R3-X-Metal, such as R3ONa, R3SNa, R3OK, R3OLi or R Li
wherein R3 is, for example, alkynyl and X is O or S in an aprotic solvent such as TH
at room temperature to the refluxing temperature of the solvent used, to give the
compound of the formula H-6 wherein R3 is, for example, -O-CH2-alkynyl or -S-CH2
alkynyl and the other variables are as defined in the Summary above. Alternative y,
the compound of formula H-5 wherein the variables are as defined in the Summary
above is reacted with an amine in an aprotic solvent such as THF, at room
temperature to the refluxing temperature of the solvent used, to give the compound of
the formula H-6 wherein R3 is -CH2-NR12R13 and the other variables are as defined
the Summary above.
The compound of formula H-6 wherein R3 is alkynyl and the other variables
are as defined in the Summary above is reacted with H2, Pd/C, or PtO2 to give the
corresponding saturated alkyl product. The compound of formula H-6 wherein R3
alkynyl and the other variables are as defined in the Summary above is reacted wi
LiAIH4 in an aprotic solvent such as THF to give the corresponding trans-alken^l
product. The compound of formula H-6 wherein R3 is alkynyl and the other variabl
are defined in the Summary above is reacted with H2 and Lindlar catalyst to give trie
corresponding cis-alkenyl product. Alternatively, these compounds are obtained
using other conditions as described in Modern Synthetic Reactions. Herbert CJ).
House, Ed., Chapters 1 & 2.
The compound of formula H-6 wherein R3 is hydroxyalkyl and the oth^r
variables are as defined in the Summary above is reacted with an acid such as ptoluenesulfonic
acid in an aprotic solvent such as toluene at reflux temperature to
give the compound of formula H-7 wherein n is 1 or 2 and the other variables are as
defined in the Summary above. Alternatively, the compound of formula H-6 wherein
R3 contains a leaving group such as halogen, mesylate, tosylate or triflate and the
other variables are as defined in the Summary above is reacted with a base such s
NaH in an aprotic solvent such as THF to give the compound with the formula H-7
wherein n is 1 or 2 and the other variables are as defined in the Summary above.
The compound of formula H-6 wherein the variables are as defined in the
Summary above is reacted with a base such as Et3N or NaH and Rh1X wherein, far
example, RM is methyl and X is halogen or other leaving group in an aprotic solvent
such as THF or methylene chloride to give the compound of formula H-8 wherein, for
example, Rhi is methyl and the other variables are as defined in the Summary above.
Alternatively, the compound of formula H-6 wherein the variables are as defined in
the Summary above is reacted with N2CHRhi, wherein, for example, R is methyl,
and Rh(OAc)3, in an aprotic solvent such as methylene chloride to give the compound
of formula H-8 wherein, for example, RM is methyl and the other variables are as
defined in the Summary above.
(Figure Removed)
The compound of formula 1-1 wherein R1 is, for example, benzyl, and whorein
m is one, is prepared as described in L.M. Fuentes, G.L. Larson, Tetrahedron Lett.
1982, 23 (3), pp. 271-274. The compound of formula 1-1 wherein RI is, for example,
benzyl, and wherein m is two, is prepared as described in A. Ijima, K. Takashi, Chem
Pharm. Bull. 1973, 21(1), pp. 215-219. The compound of formula 1-1 and the
compound of formula I-2 (which is commercially available) (or a salt of the compound
of formula I-2, such as the hydrobromide or hydrochloride salt) are reacted in a
solvent, such as isopropanol, at between 200°C and 300 °C to obtain the compound
of formula 1-3 wherein RIO is hydroxy and the other variables are as described in tho
Summary above.
The compound of formula I-3 wherein R10 is hydroxy and the other variables;
are as described in the Summary above, which is in a solvent, such as DMF, is
reacted with a base, such as potassium t-butoxide in t-butanol, and an electrophile,
such as benzyl bromide, at 0°C to 100°C to obtain the compound of formula I-3
wherein Ri0 is, for example, -O-benzyl.
The compound of formula I-3 wherein R 0 is, for example, -O-benzyl, and t t e
other variables are as defined in the Summary above, which is in a solvent, such as
THF, is treated with 2 eq. of a strong base, such as lithium diisopropylamide in THF
at -78°C to 0°C, and is then treated with an electrophile, such as methylchloroforma
(CICOOMe), at -78° to 0° C. A second electrophile, such as propyl iodide, is added
and the resulting mixture heated to between 0°C to 55°C to give the compound of
formula I-4 wherein, for example, R10 is -O-benzyl, R3 is propyl, RM is methoxy and
the other variables are as defined in the Summary above.
The compound of formula I-4 wherein, for example, R10 is -O-benzyl, R3 is
propyl, RM is methoxy and the other variables are as defined in the Summary above is
hydrogenated to obtain the compound of formula I-4 wherein, for example, R10 is
hydroxy, R3 is propyl, R:1 is methoxy and the other variables are as defined in the
Summary above, using ammonium formate(NhVHCOO-) in methanol and a
palladium on carbon catalyst at refluxing temperatures. The compound of f o r m u l
which is prepared below, wherein, for example, R 0 is -O-benzyl or -O-methyl, R3 is
propyl and the other variables are as defined in the Summary above, is treated with
boron tribromide (BBr3) in methylene chloride at -78 °C to room temperature to obta fi
the corresponding compound wherein R 0 is hydroxy. Likewise, the compound of
formula I-6, which is prepared below, wherein, for example, RIO is -O-benzyl, R3 is
propyl and the other variables are as defined above, is cleaved under similar
conditions. A variety of other hydrogenating agents and conditions are known and
available in the art, such as using H2 on a palladium on carbon catalyst in methanol.
The compound of formula I-4 wherein, for example, R10 is -O-benzyl, R3 is
propyl, Rn is methoxy and the other variables are as defined in the Summary above,
is reacted with a reducing agent, such as lithium aluminum hydride (LiAIH4), in a
solvent, such as THF, at 0 °C to refluxing temperatures to obtain the compound of
formula 1-5 wherein, for example, R10 is -O-benzyl, R3 is propyl and the other
variables are as defined in the Summary above.
The compound of formula I-4 wherein, for example, R10 is -O-benzyl, R3 is
propyl, RM is methoxy and the other variables are as defined in the Summary above,
is reacted with a reducing agent, such as lithium borohydride (LiBH4), in a solvent,
such as THF, at 0°C to room temperature to obtain the compound of formula I-6
wherein, for example, RIO is -O-benzyl, R3 is propyl and the other variables are as
defined in the Summary above. A variety of other esterifying conditions are known
and available in the art.
The compound of formula I-7 (which is prepared by procedures described ir
Scheme A) is reacted with thallium trinitrite.3H2O in a solvent, such as methylene
chloride to obtain the acid of formula I-8 wherein R^ is H and wherein, for example,
RrX- is benzyl and RIO is CH3-C(O)-O-, and wherein these variables are further
defined in the Summary above.
The acid of formula I-8 wherein R,2 is H and wherein, for example, RrX- is
benzyl and R10 is CH3-C(O)-O-, and wherein these variables are further defined in tlfie
Summary above, is reacted with an alcohol, such as methanol, and catalytic acid,
such as sulfuric acid, at 0 °C to reflux to obtain the ester of formula I-8 wherein Ri2 i
methyl and wherein, for example, RrX- is benzyl and RIO is hydroxy, and wherein
these variables are further defined in the Summary above.
(Figure Removed)
The compound of formula J-1 wherein the variables correspond to those in
the Summary above (see scheme A for its preparation) is reacted with a base such
as sodium methoxide, in a protic solvent such as methanol, and methyl acrylate to
give the compound of formula of J-2 wherein the variables correspond to those in the
Summary above. Alternatively, the compound of formula of J-1 is prepared using the
conditions described in Scheme A for the preparation of the compound of formula A-2
from the compound of formula A-1.
The compound of formula of J-2 wherein the variables correspond to those in
the Summary above is reacted with a base such as sodium carbonate in a prctic
solvent or mixed solvents such as methanol/water at 90°C to yield the compound of
formula J-3 wherein the variables correspond to those in the Summary abovo.
Alternatively, the compound of formula J-2 is hydrolyzed by the methods mention 3d
in Protecting Groups in Organic Synthesis. Second Edition, T.W. Greene and P.G.M.
Wuts, John Wiley and Sons, Inc. (1991) to give the corresponding free acic of
formula J-3 wherein the variables correspond with those in the Summary above.
The compound of formula J-3 wherein the variables correspond with thoso in
the Summary above is reacted with a reducing agent, such as sodium borohydride in
a protic solvent such as ethanol to give the compound of the formula J-4 wherein the
variables are as defined in the Summary above. Alternatively, the compound of the
formula J-4 is prepared from the compound of formula J-3 according to other
reducing methods described in Modern Synthetic Reactions. Chapters 2-3, pp. 45-
227, Herbert 0. House, ed., Academic Press, New York (1985).
The compound of formula J-5 wherein the variables are as defined in the
Summary above is prepared from the compound of formula J-4 using BBr3 or BCI3
and tetrabutylammonium iodide or dimethylboron bromide in an aprotic solvent, such
as dichloromethane or toluene, at -78 °C to room temperature.
The compound of formula J-6 is prepared from the compound of J-5 using
conditions described in Scheme H for the preparation of the compound of formula
6 from the compound of formula H-1.
(Figure Removed)
All compounds in this Scheme can serve as intermediates for Schemes At3,
B, C, F, G, or H.
The compound of formula K-1 (prepared as described in Scheme A-J3),
wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is as
described in the Summary above, Rk is, for example, lower alkyl or wherein Rk's
taken together are cyclic lower alkyl, and all other variables are as described in the
Summary above, is treated with a hydroboration reagent, such as BH3 in THF, in an
aprotic solvent, such as THF or dioxane, from 0°C to 60°C and then treated with an
oxidizing agent, such as hydrogen peroxide and aqueous sodium hydroxide, from
0°C to 60°C to give the compound of formula K-2. Alternatively, the compound of
formula K-2 is prepared from the compound of formula K-1 by other methods known
in the art, as exemplified in Comprehensive Organic Transformations. R.C. Laro k,
VCH Publishers Inc. (1989), pp. 497-498.
The compound of formula K-2, wherein R10 is halogen, hydrogen, carboxy
methyl ether, or benzyl ether or is as described in the Summary above, RK is,
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and
other variables are as described in the Summary above, is treated with a fluorinating
agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such as
diglyme, from 0°C to 60°C, depending on the nature of the solvent used, to give the
compound in formula K-5. Alternatively, the compound of formula K-5 is prepared
from the compound of formula K-2 by other halogenation methods known in the cirt,
as exemplified in Comprehensive Organic Transformations. R.C. Larock, VCH
Publishers Inc. (1989), pp. 353-363.
The compound of formula K-2, wherein R10 is halogen, hydrogen, carboxyla
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and all
other variables are as described in the Summary above, is treated with an oxidizi
agent, such as (nPr)3NRuO4 and N-methylmorpholine-N-oxide, in a solvent, such as
dichloromethane, from 0°C to 60°C, depending on the nature of the solvent used,
give the compound in formula K-3. Alternatively, the compound of formula K-3 is
prepared from the compound of formula K-2 by other oxidation methods known in the
art, as exemplified in Comprehensive Organic Transformations. R.C. Larock,
Publishers Inc. (1989), pp. 604-614.
The compound of formula K-3, wherein R10 is halogen, hydrogen, carboxyla e,
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, lor
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and all
other variables are as described in the Summary above, is treated with a fluorinatipg
agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such ^s
diglyme, from 0°C to 60°C, depending on the nature of the solvent used, to give the
compound in formula K-6. Alternatively, the compound of formula K-6 is prepared
from the compound of formula K-3 by other halogenation methods known in the art,
as exemplified in Comprehensive Organic Transformations. R.C. Larock, VCH
Publishers Inc. (1989), pp. 353-363.
The compound of formula K-1, wherein R10 is halogen, hydrogen, carboxylale,
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and all
other variables are as described in the Summary above, is treated with an oxidizing
agent capable of allylic oxidation, such as selenium dioxide (SeO2) and/or f-buyl
hydrogen peroxide or chromium trioxide, in a solvent, such as dichloromethane, from
0°C to 60°C, depending on the nature of the solvent used, to give the compound of
formula K-4. Alternatively, the compound of formula K-4 is prepared from the
compound of formula K-2 by other oxidation methods known in the art, as exemplified
in Comprehensive Organic Transformations. R.C. Larock, VCH Publishers Inc.
(1989), pp. 592-593.
The compound of formula K-4, wherein R. is. for example, lower alkyl Dr
wherein Rk's taken together are cyclic lower alkyl, and the other variables are as
described in the Summary above, is reduced using Pd(OH)2 on carbon or other
reagents, such as platinum oxide or rhodium on aluminum oxide (see P.N. Rylander
in Hydrogenation Methods. Academic Press, New York, 1985; Herbert O. House in
Modern Synthetic Reactions. Chapter 1, pp. 1-45; and John Fried and John A.
Edwards in Organic Reactions in Steroid Chemistry. Chapter 3, pp. 111-145) under
15 to 1000 p.s.i (which is about 1 to about 133 atm) H2 pressure in a solvent, such cis
toluene, f-butyl methyl ether, or ethanol, from 0°C to 60°C, depending on the nature
of the solvent used, to give the compound in formula K-7.
The compound of formula K-7, wherein R10 is halogen, hydrogen, carboxylato,
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, fr
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and eill
other variables are as described in the Summary above, is treated with a reducing
agent, such as sodium borohydride or lithium aluminum hydride, in a solvent, such £
methanol or THF, from -78°C to 60°C, depending on the nature of the reductait
and/or solvent used, to give the compound in formula K-9, wherein R7 is hydroger
Alternatively, the compound of formula K-9 is prepared from the compound of formula
K-4 by other reduction methods known in the art, as exemplified in Comprehensive
Organic Transformations. R.C. Larock, VCH Publishers Inc. (1989), pp. 527-547.
Alternatively, the compound of formula K-7, wherein R10 is halogen, hydrogen,
carboxylate, methyl ether, or benzyl ether, or is as described in the Summary above,
Rk is, for example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl,
and all other variables are as described in the Summary above, is treated with
metal, such as R7Li, R7MgBr, or R7MgCI, wherein R7 is, for example, alkyl, in an
aprotic solvent, such as THF or diethyl ether from -78 °C to 60 °C, depending on the
nature of R7-metal and/or solvent used, to give the compound in formula K-9, wher in
R7 is, for example, alkyl.
The compound of formula K-3, wherein R10 is halogen, hydrogen, carboxyla
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for
example, lower alkyl or wherein RK's taken together are cyclic lower alkyl, and all
other variables are as described in the Summary above, is treated with a reduci
agent, such as sodium borohydride or lithium aluminum hydride, in a solvent, such as
methanol or THF, from -78°C to 60°C, depending on the nature of the reductant
and/or solvent used, to give the compound in formula K-8, wherein Ri5 is hydroge n.
Alternatively, the compound of formula K-8 is prepared from the compound of formuli
K-3 by other reduction methods known in the art, as exemplified in Comprehens
Organic Transformations. R.C. Larock, VCH Publishers Inc. (1989), pp. 527-547.
Alternatively, the compound of formula K-3, wherein R0 is halogen, hydrogen,
carboxylate, methyl ether, or benzyl ether or is as described in the Summary above,
Rk is, for example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl,
and all other variables are as described in the Summary above, is treated with R
metal, such as RisLi, R15MgBr, or R15MgCI, wherein R15 is, for example, alkyl, in an
aprotic solvent, such as THF or diethyl ether from -78°C to 60°C, depending on tie
nature of R5-metal and/or solvent used, to give the compound in formula K-8,
wherein R15 is, for example, alkyl.
The compound of formula K-7, wherein R10 is halogen, hydrogen, carboxylaje,
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, for
example, lower alkyl or wherein Rk's taken together are lower alkyl, and all other
variables are as described in the Summary above, is converted to its anion with a
base, such as sodium hydride, sodium methoxide, or lithium diisopropylamide, in a
solvent, such as THF or DMF from -78°C to 60°C, depending on the nature of the
base and solvent used. The reaction mixture is treated with an alkylating agent of
formula Ru-X, wherein R14 is, for example, alkyl and X is a leaving group (sse
Francis A. Carey, in Advanced Organic Chemistry. Part A, Chapter 5.6 for examples)
to give the compound of formula K-10, wherein Ru and Ri5 are, for example, alkyl or
hydrogen or mixtures thereof.
The compound of formula K-3, wherein R10 is halogen, hydrogen, carboxyla :e,
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, lor
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and all
other variables are as described in the Summary above, is converted to its anion with
a base, such as sodium hydride, sodium methoxide, or lithium diisopropylamide, ir a
solvent, such as THF or DMF from -78°C to 60°C, depending on the nature of tie
base and solvent used. The reaction mixture is treated with an alkylating agent of
formula R7-X, wherein R7 is, for example, alkyl and X is a leaving group (see Francis
A. Carey, in Advanced Organic Chemistry. Part A, Chapter 5.6 for examples) to give
the compound of formula K-11, wherein R7 and Ri6 are, for example, alkyl or
hydrogen or mixtures thereof.
The compound of formula K-10, wherein R10 is halogen, hydrogen,
carboxylate, methyl ether, or benzyl ether or is as described in the Summary above,
Rk is, for example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl,
and all other variables are as described in the Summary above, is treated with a
reducing agent, such as sodium borohydride or lithium aluminum hydride, in a
solvent, such as methanol or THF, from -78°C to 60°C, depending on the nature of
the reductant and/or solvent used, to give the compound of formula K-12, wherein R7
is hydrogen. Alternatively, the compound of formula K-12 is prepared from tie
compound of formula K-10 by other reduction methods known in the art, as
exemplified in Comprehensive Organic Transformations. R.C. Larock, VCH
Publishers Inc. (1989), pp. 527-547. Alternatively, the compound of formula K-10,
wherein R10 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is 0s
15
e
described in the Summary above, Rk is, for example, lower alkyl or wherein Rjs
taken together are cyclic lower alkyl, and all other variables are as described in the
Summary above, is treated with R7-metal, such as R7Li, R7MgBr, or R7MgCI, where n
R7 is, for example, alkyl, in an aprotic solvent, such as THF or diethyl ether from -78
°C to 60 °C, depending on the nature of R7-metal and/or solvent used, to give trje
compound of formula K-12, wherein R7 is, for example, alkyl.
The compound of formula K-11, wherein R10 is halogen, hydrogep,
carboxylate, methyl ether, or benzyl ether or is as described in the Summary abo
Rk is, for example, lower alkyl or wherein Rk's taken together are cyclic lower alk
and all other variables are as described in the Summary above, is treated with
reducing agent, such as sodium borohydride or lithium aluminum hydride, in a
solvent, such as methanol or THF, from -78°C to 60°C, depending on the nature of
the reductant and/or solvent used, to give the compound of formula K-13, wherein F
is hydrogen. Alternatively, the compound of formula K-13 is prepared from t
compound of formula K-11 by other reduction methods known in the art,
exemplified in Comprehensive Organic Transformations. R.C. Larock, VC|H
Publishers Inc. (1989), pp. 527-547. Alternatively, the compound of formula K-11,
wherein Ri0 is halogen, hydrogen, carboxylate, methyl ether, or benzyl ether or is
described in the Summary above, Rk is, for example, lower alkyl or wherein R
taken together are cyclic lower alkyl, and all other variables are as described in t e
Summary above, is treated with Ri5-metal, such as R5Li, R15MgBr, or R15Mg
wherein R15 is, for example, alkyl, in an aprotic solvent, such as THF or diethyl ethfer
from -78°C to 60°C, depending on the nature of R15-metal and/or solvent used,
give the compound of formula K-13, wherein R15 is, for example, alkyl.
The compound of formula K-7, wherein Ri0 is halogen, hydrogen, carboxyla
methyl ether, or benzyl ether or is as described in the Summary above, Rk is,
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and
other variables are as described in the Summary above, is treated with a fluorinati
agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such
diglyme, from 0°C to 60°C, depending on the nature of the solvent used, to give t
compound in formula K-14. Alternatively, the compound of formula K-14 is prepar
from the compound of formula K-7 by other halogenation methods known in the a
as exemplified in Comprehensive Organic Transformations. R.C. Larock, VCH
Publishers Inc. (1989), pp. 353-363.
The compound of formula K-9, wherein R10 is halogen, hydrogen, carboxyla:e,
methyl ether, or benzyl ether or is as described in the Summary above, Rk is, lor
example, lower alkyl or wherein Rk's taken together are cyclic lower alkyl, and all
other variables are as described in the Summary above, is treated with a fluorinatihg
agent, such as diethylaminosulfur trifluoride (DAST), in an aprotic solvent, such jas
diglyme, from 0°C to 60°C, depending on the nature of the solvent used, to give tie
compound in formula K-15. Alternatively, the compound of formula K-15 is prepared
from the compound of formula K-9 by other halogenation methods known in the a rt,
as exemplified in Comprehensive Organic Transformations. R.C. Larock, VCH
Publishers Inc. (1989), pp. 353-363.
Some of the preparation methods useful for the preparation of the
compounds described herein may require protection of remote functionality (e.g.,
primary amine, secondary amine, carboxyl in Formula I precursors). The need for
such protection will vary depending on the nature of the remote functionality and the
conditions of the preparation methods. The need for such protection is readily
determined by one skilled in the art. The use of such protection/deprotection methods
is also within the skill in the art. For a general description of protecting groups and
their use, see T.W. Greene, Protective Groups in Organic Synthesis. John Wiley &
Sons, New York, 1991.
The subject invention also includes isotopically-labelled compounds, which
are identical to those recited in Formula I, but for the fact that one or more atoms ar|e
replaced by an atom having an atomic mass or mass number different from the
atomic mass or mass number usually found in nature. Examples of isotopes that c4r
be incorporated into compounds of the invention include isotopes of hydrogen,
carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C,
14C, 15N, 180,170,31P,P, XS, 18F, and "Cl, respectively. Compounds of the present
invention, prodrugs thereof, and pharmaceutically acceptable salts of said
compounds and of said prodrugs which contain the aforementioned isotopes and/or
other isotopes of other atoms are within the scope of this invention. Certain
isotopically-labelled compounds of the present invention, for example those into
which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug
and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14(
isotopes are particularly preferred for their ease of preparation and detectability.
Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford
certain therapeutic advantages resulting from greater metabolic stability, for example
increased in vivo half-life or reduced dosage requirements and, hence, may be
preferred in some circumstances. Isotopically labelled compounds of Formula I of
this invention and prodrugs thereof can generally be prepared by carrying out the
procedures disclosed in the Schemes and/or in the Examples below, by substituting a
readily available isotopically labelled reagent for a non-isotopically labelled reagent.
Any of the compounds and prodrugs of the present invention can be
synthesized as pharmaceutically acceptable salts for incorporation into various
pharmaceutical compositions. As used herein, pharmaceutically acceptable salts
include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, hydrofluoric,
sulfuric, sulfonic, citric, camphoric, maleic, acetic, lactic, nicotinic, nitric, succinic,
phosphoric, malonic, malic, salicyclic, phenylacetic, stearic, palmitic, pyridine,
ammonium, piperazine, diethylamine, nicotinamide, formic, fumaric, urea, sodium,
potassium, calcium, magnesium, zinc, lithium, cinnamic, methylamino,
methanesulfonic, picric, p-toluenesulfonic, naphthalenesulfonic, tartaric, triethylaminb,
dimethylamino, and tris(hydroxymethyl)aminomethane. Additional pharmaceutically
acceptable salts would be apparent to one of ordinary skill in the art. Where more
than one basic moiety exists, the expression includes multiple salts (e.g., di-salt).
Some of the compounds of this invention are acidic and they form a salt with
a pharmaceutically acceptable cation. Some of the compounds of this invention are
basic and they form a salt with a pharmaceutically acceptable anion. All such salts,
including di-salts, are within the scope of this invention and they can be prepared by
conventional methods. They can be prepared simply by contacting the acidic and
basic entities, in either an aqueous, non-aqueous or partially aqueous medium. For
example, the mesylate salt is prepared by reacting the free base form of the
compound of Formula I with methanesulfonic acid under standard conditions.
Likewise, the hydrochloride salt is prepared by reacting the free base form of the
compound of Formula I with hydrochloric acid under standard conditions. The salts
are recovered either by filtration, by precipitation with a non-solvent followed by
filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by
lyophilization, as appropriate.
In addition, when the compounds and prodrugs of the present invention form
hydrates or solvates, they are also within the scope of the present invention.
The compounds and prodrugs of the present invention also includes
racemates, stereoisomers and mixtures of these compounds, including isotopicallylabeled
and radio-labeled compounds. Such isomers can be isolated by standard
resolution techniques, including fractional crystallization and chiral column
chromatography.
For instance, the compounds of the present invention have asymmetric
carbon atoms and are therefore enantiomers or diastereomers. Diasteromeric
mixtures can be separated into their individual diastereomers on the basis of their
physical/chemical differences by methods known in the art, for example, by
chromatography and/or fractional crystallization. Enantiomers can be separated by
converting the enantiomeric mixture into a diasteromeric mixture by reaction with an
appropriate optically active compound (e.g., alcohol), separating the diastereomers
and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding
pure enantiomers. All such isomers, including diastereomers, enantiomers and
mixtures thereof are considered as part of this invention.
The following configurations of the compounds of the present invention (as
represented by simplified structures) are preferred, with the first configuration being
more preferred:
Also, the compounds and prodrugs of the present invention can exist in
several tautomeric forms, including the enol form, the keto form and mixtures therecjf.
All such tautomeric forms are included within the scope of the present invention.
The GR agonists, partial agonists and antagonists of the present invention
can be used to influence the basic, life sustaining systems of the body, including
carbohydrate, protein and lipid metabolism, electrolyte and water balance, and the
functions of the cardiovascular, kidney, central nervous, immune, skeletal muscle arjd
other organ and tissue systems. In this regard, GR modulators are used for the
treatment of diseases associated with an excess or a deficiency of glucocorticoids in
the body. As such, they may be used to treat the following: obesity, diabetes,
cardiovascular disease, hypertension, Syndrome X, depression, anxiety, glaucoma,
human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome
(AIDS), neurodegeneration (for example, Alzheimer's and Parkinson's), cognition
enhancement, Cushing's Syndrome, Addison's Disease, osteoporosis, frailty,
inflammatory diseases (such as osteoarthritis, rheumatoid arthritis, asthma and
rhinitis), tests of adrenal function, viral infection, immunodeficiency,
immunomodulation, autoimmune diseases, allergies, wound healing, compulsive
behavior, multi-drug resistance, addiction, psychosis, anorexia, cachexia, posttraumatic
stress syndrome, post-surgical bone fracture, medical catabolism and
prevention of muscle frailty.
The compounds of the present invention, isomers, prodrugs and
pharmaceutically acceptable salts thereof are useful to induce weight loss in
mammals needing or desiring to lose weight. While not intending to limit the preserit
invention to a specific mechanism of action, the compounds of the present invention,
isomers, prodrugs and salts thereof are able to induce weight loss by a variety of
mechanisms, such as appetite suppression, decreasing food intake, and stimulation
of the metabolic rate in peripheral tissue, thereby increasing energy expenditure. In
addition, the compounds of the present invention, isomers, prodrugs and salts thereof
are useful to induce a more favorable partitioning of nutrients from fat to muscle
tissue in mammals. Thus, while not necessarily resulting in weight loss, this increasb
in muscle mass may be useful in preventing or treating diseases, such as obesity and
frailty.
In addition, the compounds of the present invention, isomers, prodrugs and
pharmaceutically acceptable salts thereof may also be useful to increase lean meat
deposition, improve lean meat to fat ratio, and trim unwanted fat from non-human
animals, as described further below.
It will be understood by those skilled in the art that while the compounds,
isomers, prodrugs and pharmaceutically acceptable salts thereof of the present
invention will typically be employed as selective agonists, partial agonists or
antagonists, there may be instances where a compound with a mixed steroid receptor
profile is preferred.
Furthermore, it will be understood by those skilled in the art that the
compounds, isomers, prodrugs and pharmaceutically acceptable salts thereof of the
present invention, including pharmaceutical compositions and formulations containing
these compounds, isomers, prodrugs and salts can be used in a wide variety of
combination therapies to treat the conditions and diseases described above. Thus,
the compounds, isomers, prodrugs and pharmaceutically acceptable salts thereof of
the present invention can be used in conjunction with other pharmaceutical agents for
the treatment of the disease/conditions described herein. For example, they may be
used in combination with pharmaceutical agents that treat obesity, diabetes,
inflammatory disease, immunodefficiency, hypertension, cardiovascular disease, vir^l
infection, HIV, Alzheimers's disease, Parkinson's disease, anxiety, depression, or
psychosis. In combination therapy treatment, both the compounds, isomers, prodrugs
and pharmaceutically acceptable salts thereof of this invention and the other drug
therapies are administered to mammals (e.g., humans, male or female) by
conventional methods.
For instance, glucocorticoid receptor agonists are efficacious agents for the
treatment of various inflammatory diseases; however, treatment is often
accompanied by undesirable side effects. These side effects include, but are not
limited to, the following examples: metabolic effects, weight gain, muscle wasting,
decalcification of the skeleton, osteoporosis, thinning of the skin and thinning of the
skeleton. However, according to the present invention, glucocorticoid receptor
modulators may be used in combination with glucocorticoid receptor agonists to blo some of these side effects, without inhibiting the efficacy of the treatment. Thus, any
glucocorticoid receptor agonist may be used as the second compound in the
combination aspect of the present invention. This combination includes the treatment
of various inflammatory diseases, such as arthritis (osteo and rheumatiod), asthma,
rhinitis, or immunomodulation. Examples of glucocorticoid receptor modulators
include those known in the art (many of which are described above) as well as the
novel compounds of formula I of the present invention. More particularly, examples
of glucocorticoid receptor modulators known in the art include, but are not limited to,
certain nonsteroidal compounds, such as 5H-chromeno[3,4-f]quinolines, which are
selective modulators of steroid receptors, as disclosed in U.S. Patent No. 5,696,127;
and certain steroid compounds substituted at position 10, which possess
antiglucocorticoid activity, and some of which have glucocorticoid activity, as
disclosed in Published European Patent Application 0 188 396, published 23 July
1986. Examples of glucocorticoid receptor agonists include those known in the art,
such as prednisone (17,21-dihydroxypregnane-1,4-diene-3,11,20-trione),
I
prednylidene ((11 P)-11,17,21-trihydroxy-16-methylenepregna-1,4-diene-3, 20-dionej,
prednisolone ((11(3)-11,17,21 -trihydroxypregna-1,4-diene-3, 20-dione), cortisone
(17a,21-dihydroxy-4-pregnene-3,11,20-trione), dexamethasone ((11(3, 16a)-9-fluoro-
11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione), and hydrocortisone
(11(3,17a,21-trihydroxypregn-4-ene-3, 20-dione). These compounds, which are
glucocorticoid receptor agonists, will generally be administered in the form of a
dosage unit at a therapeutically effective amount of such compound. For example,
prednisone or an equivalent drug may be administered from about 5 to about 80 mg
depending on the condition; hydrocortisone may be administered from about 100 to
about 400 mg, depending on the condition; and dexamethasone may be
administered from about 4 to about 16 mg, depending on the condition. These dos^s
are typically administered once to twice daily, and for maintenance purposes,
sometimes on alternate days.
For the treatment of Alzheimer's disease, any cholinomimetic drug, such as
donepizil, may be used as the second compound in the combination aspect of this
invention.
For the treatment of Parkinson's disease, any anti-Parkinson's drug, such a
L-dopa, bromocriptine, or selegiline, may be used as the second compound in the
combination aspect of this invention.
For the treatment of anxiety, any antianxiolytic drug, such as benzodiazepin
valium, or librium, may be used as the second compound in the combination aspect
of this invention.
For the treatment of depression, any tricyclic antidepressant such as,
desipramine, or any selective serotonin reuptake inhibitor (SSRI's), such as sertralir
hydrochloride and fluoxetine hydrochloride, may be used as the second compound
the combination aspect of this invention.
For the treatment of psychosis, any typical or atypical antipsychotic drug, su
as haloperidol or clozapine may be used as the second compound in the combination
aspect of this invention.
Any aldose reductase inhibitor may be used as the second compound in the
combination aspect of this invention. The term aldose reductase inhibitor refers to a
compound which inhibits the bioconversion of glucose to sorbitol catalyzed by the
enzyme aldose reductase. Such inhibition is readily determined by those skilled in
the art according to standard assays (J. Malone, Diabetes, 29:861-864,1980, "Red
Cell Sorbitol, an Indicator of Diabetic Control"). A variety of aldose reductase
inhibitors are described and referenced below; however other aldose reductase
inhibitors will be known to those skilled in the art. Examples of aldose reductase
inhibitors useful in the compositions and methods of this invention include, for
example, zopolrestat, and other such compounds as disclosed and described in
PCT/IB99/00206, filed 5 February 1999 (the disclosure of which is hereby
incorporated by reference), and assigned to the assignee hereof.
Any glycogen phosphorylase inhibitor may be used as the second compounp
in the combination aspect of this invention. The term glycogen phosphorylase
inhibitor refers to any substance or agent or any combination of substances and/or
agents which reduces, retards or eliminates the enzymatic action of glycogen
phosphorylase. The currently known enzymatic action of glycogen phosphorylase
the degradation of glycogen by catalysis of the reversible reaction of a glycogen
macromolecule and inorganic phosphate to glucose-1-phosphate and a glycogen
macromolecule which is one glucosyl residue shorter than the original glycogen
macromolecule (forward direction of glycogenolysis). Such actions are readily
determined by those skilled in the art according to standard assays (e.g., as
described in PCT/IB99/00206, filed 5 February 1999). A variety of these compouncjs
are described in the following published international patent applications: WO
96/39384, published 12 December 1996, and WO 96/39385, published 12
December 1996; and in the following filed international patent application:
PCT/IB99/00206, filed 5 February 1999; the disclosures of all of these applications
are hereby incorporated by reference herein.
Any sorbitol dehydrogenase inhibitor may be used as the second compounc
in the combination aspect of this invention. The term sorbitol dehydrogenase inhibitor
refers to a compound which inhibits the enzyme sorbitol dehydrogenase, which
catalyzes the oxidation of sorbitol to fructose. Such inhibition is readily determined
those skilled in the art according to standard assays (as described in U.S. Patent N 5,728,704 and references cited therein). A variety of these compounds are described
and referenced below; however other sorbitol dehydrogenase inhibitors will be known
to those skilled in the art. U.S. Pat. No. 5,728,704 (the disclosure of which is hereb;
incorporated by reference) discloses substituted pyrimidines which inhibit sorbitol
dehydrogenase, lower fructose levels, and/or treat or prevent diabetic complications^
-91-
such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic
microangiopathy and diabetic macroangiopathy.
Any known, commercially marketed antidiabetic compound may be used as
the second compound in the combination aspect of this invention. A variety of such
compounds are described and referenced below; however other such compounds \jvill
be known to those skilled in the art. Examples of such compounds useful in the
compositions and methods of this invention include, for example, insulin, metformin
troglitazone (REZULIN®) and sulfonylureas, such as glipizide (GLUCOTROL®),
glyburide (GLYNASE®, MICRONASE®) and chlorpropamide (DIABINASE®).
Any p-adrenergic agonist may be used as the second compound in the
combination aspect of this invention. (3-Adrenergic agents have been categorized
into p,, p2, and p3 subtypes. Agonists of p-receptors promote the activation of aderjyl
cyclase. Activation of Pi receptors invokes increases in heart rate. Activation of (
receptors induces relaxation of smooth muscle tissue which produces a drop in bloc-d
pressure and the onset of skeletal muscle tremors. Activation of p3 receptors is
known to stimulate lipolysis, which is the breakdown of adipose tissue triglycerides tb
glycerol and fatty acids. Activation of p3 receptors also stimulates the metabolic rato,
thereby increasing energy expenditure. Accordingly, activation of p3 receptors
promotes the loss of fat mass. Compounds that stimulate P receptors are therefore
useful as anti-obesity agents. Compounds which are p3-receptors agonists have
hypoglycemic and/or anti-diabetic activity. Such activity is readily determined by
those skilled in the art according to standard assays (International Patent Applicatiorfi,
Publication No. WO 96/35671). Several compounds are described and referenced
below; however, other p-adrenergic agonists will be known to those skilled in the art.
International Patent Application, Publication No. WO 96/35671 (the disclosure of
which is incorporated herein by reference) discloses compounds, such as substitute^
aminopyridines, which are p-adrenergic agonists. International Patent Application,
Publication No. 93/16189 (the disclosure of which is incorporated herein by
reference) discloses the use of selective Pa receptor agonists in combination with
compounds which modify eating behavior for the treatment of obestiy.
Any thyromimetic antiobesity agent may be used as the second compound in
the combination aspect of this invention. These compounds are tissue selective
thyroid hormone agonists. These compounds are able to induce weight loss by
mechanisms other than appetite suppression, e.g., through stimulation OT tne
metabolic rate in peripheral tissue, which, in turn, produces weight loss. Such
metabolic effect is readily measured by those skilled in the art according to standard
assays. A variety of these compounds are described and referenced below; howevei
other thyromimetic antiobesity agents will be known to those skilled in the art. It is
well known to one of ordinary skill in the art that selectivity of thermogenic effect is a
important requirement for a useful therapeutic agent in the treatment of, for example,
obesity and related conditions.
Any eating behavior modifying compound may be used as the second
compound of this invention. Compounds which modify eating behavior include
anorectic agents, which are compounds which diminish the appetite. Such classes
anorectic agents are well known to one of ordinary skill in the art. A variety of these
compounds are described in and referenced below; however, other anorectic agents
will be known to those skilled in the art. Also, the following are antiobesity agents:
phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a Neuropeptide Y
(hereinafter also referred to as "NPY") antagonist, a cholecystokinin-A (hereinafter
referred to as CCK-A) agonist, a monoamine reuptake inhibitor (such as
sibutramine), a sympathomimetic agent, a serotoninergic agent (such as
dexfenfluramine or fenfluramine), a dopamine agonist (such as bromocriptine), a
melanocyte-stimulating hormone receptor agonist or mimetic, a melanocytestimulating
hormone analog, a cannabinoid receptor antagonist, a melanin
concentrating hormone antagonist, the OB protein (hereinafter referred to as "leptin
a leptin analog, a galanin antagonist or a Gl lipase inhibitor or decreaser (such as
orlistat). Other antiobesity agents include phosphatase 1B inhibitors, bombesin
agonists, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor
modulators, orexin receptor antagonists, urocortin binding protein antagonists or
glucagon-like peptide-1 (insulinotropin) agonists. A particularly preferred monoamine
reuptake inhibitor is sibutramine, which can be prepared as disclosed in U.S. Patent
No. 4,929,629, the disclosure of which is incorporated herein by reference. Preferred
serotoninergic agents include fenfluramine and dexfenfluramine, which can be
prepared as disclosed in U.S. Patent No. 3,198,834, the disclosure of which is
incorporated herein by reference. A particularly preferred dopamine agonist is
bromocriptine, which can be prepared as disclosed in U.S. Patent Nos. 3,752,814
and 3,752,888, the disclosures of which are incorporated herein by reference.
Another preferred anorectic agent is phentermine, which can be prepared as
disclosed in U.S. Patent No. 2,408,345, the disclosure of which is incorporated herein
by reference.
Any NPY receptor antagonist may be used as the second component in the
combination aspect of this invention. The term NPY receptor antagonist refers to
compounds which interact with NPY receptors and inhibit the activity of neuropeptid
Y at those receptors and thus are useful in treating disorders associated with
neuropeptide Y, such as feeding disorders, including obesity. Such inhibition is
readily determined by those skilled in the art according to standard assays (such as
those described in International Patent Application, Publication No. WO 99/07703).
In addition, the compounds described and referenced below are NPY receptor
antagonists; however, other NPY receptor antagonists will also be known to those
skilled in the art. International Patent Application, Publication No. WO 99/07703 (th
disclosure of which is hereby incorporated by reference) discloses certain 4-
aminopyrrole (3,2-d) pyrimidines as neuropeptide Y receptor antagonists.
International patent application, Publication No. WO 96/14307, published 17 May
1996; International patent application, Publication No. WO 96/40660, published 19
December 1996; International patent application, Publication No. WO 98/03492;
International patent application, Publication No. WO 98/03494; International patent
application, Publication No. WO 98/03493; International patent application,
Publication No. WO 96/14307, published 17 May 1996; International patent
application, Publication No. WO 96/40660, published 19 December 1996; (the
disclosures of which are hereby incorporated by reference) disclose additional
compounds, such as substituted benzylamine derivatives, which are useful as
neuropeptide Y specific ligands.
In combination therapy treatment, both the compounds of this invention and
the other drug therapies are administered to mammals (e.g., humans, male or
female) by conventional methods. As recognized by those skilled in the art, the
therapeutically effective amounts of the compounds of this invention and the other
drug therapies to be administered to a patient in combination therapy treatment will
depend upon a number of factors, including, without limitation, the biological activity
desired, the condition of the patient, and tolerance for the drug.
For example, the second compound of this invention, when administered to a
mammal, is dosed at a range between about 0.01 to about 50 mg/kg/day body
weight, preferably about 0.1 mg/kg/day to about 10 mg/kg/day body weight,
administered singly or as a divided dose. Particularly, when the second compound f
i
this invention is (1) sibutramine, the dosage of sibutramine is about 0.01 mg/kg/day b
about 30 mg/kg/day body weight, preferably about 0.1 mg/kg/day to about 1
mg/kg/day body weight; (2) dexfenfluramine, the dosage of dexfenfluramine is about
0.01 mg/kg/day to about 30 mg/kg/day body weight, preferably about 0.1 mg/kg/day
to about 1 mg/kg/day body weight; (3) bromocriptine, the dosage of bromocriptine is
about 0.01 to about 10 mg/kg/day body weight, preferably 0.1 mg/kg/day to about 10
mg/kg/day body weight; (4) phentermine, the dosage of phentermine is about 0.01
mg/kg/day to about 10 mg/kg/day, preferably about 0.1 mg/kg/day to about 1
mg/kg/day body weight. Also, for example, as noted above, an amount of an aldoso
reductase inhibitor that is effective for the activities of this invention may be used as
the second compound of this invention. Typically, an effective dosage for aldose
reductase inhibitors for this invention is in the range of about 0.1 mg/kg/day to abou'
100 mg/kg/day in single or divided doses, preferably about 0.1 mg/kg/day to about 2:0
mg/kg/day in single or divided doses.
As noted above, the compounds, isomers, prodrugs and pharmaceutically
acceptable salts of the present invention can be combined in a mixture with a
pharmaceutically acceptable carrier, vehicle or diluent to provide pharmaceutical
compositions useful for treating the biological conditions or disorders noted herein in
mammalian, and more preferably, in human, patients The particular carrier, vehicle
or diluent employed in these pharmaceutical compositions may take a wide variety of
forms depending upon the type of administration desired, for example, intravenous,
oral, topical, suppository or parenteral. Also, the compounds, isomers, prodrugs and
salts thereof of this invention can be administered individually or together in any
conventional dosage form, such as an oral, parenteral, rectal or transdermal dosage
form.
For oral administration a pharmaceutical composition can take the form of
solutions, suspensions, tablets, pills, capsules, powders, and the like. Tablets
containing various excipients such as sodium citrate, calcium carbonate and calciurtu
phosphate are employed along with various disintegrants such as starch and
preferably potato or tapioca starch and certain complex silicates, together with
binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additional y,
lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are
often very useful for tabletting purposes. Solid compositions of a similar type are also
employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this
connection also include lactose or milk sugar as well as high molecular weight
polyethylene glycols. When aqueous suspensions and/or elixirs are desired for
administration, the compounds, prodrugs and pharmaceutically acceptable salts
thereof of this invention can be combined with various sweetening agents, flavorin
agents, coloring agents, emulsifying agents and/or suspending agents, as well as
such diluents as water, ethanol, propylene glycol, glycerin and various like
combinations thereof.
Due to their ease of administration, tablets and capsules represent the mo^t
advantageous oral dosage form for the pharmaceutical compositions of the presert
invention.
For purposes of parenteral administration, solutions in sesame or peanut 01
or in aqueous propylene glycol can be employed, as well as sterile aqueous solutions
of the corresponding water-soluble salts. Such aqueous solutions may be suitably
buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient
saline or glucose. These aqueous solutions are especially suitable for intravenous,
intramuscular, subcutaneous and intraperitoneal injection purposes. In this
connection, the sterile aqueous media employed are all readily obtainable by
standard techniques well-known to those skilled in the art.
For purposes of transdermal (e.g.,topical) administration, dilute sterile,
aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration)^
otherwise similar to the above parenteral solutions, are prepared.
For topical administration, the compounds of the present invention may be
formulated using bland, moisturizing bases, such as ointments or creams. Examples
of suitable ointment bases are petrolatum, petrolatum plus volatile silicones, lanolin
and water in oil emulsions.
Methods of preparing various pharmaceutical compositions with a certain
amount of active ingredient are known, or will be apparent in light of this disclosure,
those skilled in this art. For examples of methods of preparing pharmaceutical
compositions, see Remington's Pharmaceutical Sciences. Mack Publishing
Company, Easter, Pa., 15th Edition (1975).
The pharmaceutical compositions and compounds, isomers, prodrugs and
pharmaceutically acceptable salts thereof of the present invention will generally be
administered in the form of a dosage unit (e.g., tablet, capsule, etc.) at a
therapeutically effective amount of such compound, prodrug or salt thereof from
about 0.1 ng/kg of body weight to about 500 mg/kg of body weight, more particularly
from about 1 ng/kg to about 250 mg/kg, and most particularly from about 2 ng/kg 1o
about 100 mg/kg. More preferably, a compound of the present invention will be
administered at an amount of about 0.1 mg/kg to about 500 mg/kg of body weight]
and most preferably from about 0.1 mg/kg to about 50 mg/kg of body weight. As
recognized by those skilled in the art, the particular quantity of pharmaceutical
composition according to the present invention administered to a patient will deperd
upon a number of factors, including, without limitation, the biological activity desired,
the condition of the patient, and tolerance for the drug.
Since the present invention has an aspect that relates to the treatment of the
disease/conditions described herein with a combination of active ingredients which
may be administered separately, the invention also relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two separate
pharmaceutical compositions: a compound of formula I, an isomer thereof, a prodn
thereof or a salt of such compound, isomer or prodrug and a second compound as
described above. The kit comprises a container, such as a divided bottle or a divided
foil packet. Typically the kit comprises directions for the administration of the separate
components. The kit form is particularly advantageous when the separate
components are preferably administered in different dosage forms (e.g., oral and
parenteral), are administered at different dosage intervals, or when titration of the
individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well
known in the packaging industry and are being widely used for the packaging of
pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs
generally consist of a sheet of relatively stiff material covered with a foil of a
preferably transparent plastic material. During the packaging process, recesses
formed in the plastic foil. The recesses have the size and shape of the tablets or
capsules to be packed. Next, the tablets or capsules are placed in the recesses and
the sheet of relatively stiff material is sealed against the plastic foil at the face of the
foil which is opposite from the direction in which the recesses were formed. As a
result, the tablets or capsules are sealed in the recesses between the plastic foil andI
the sheet. Preferably, the strength of the sheet is such that the tablets or capsules
can be removed from the blister pack by manually applying pressure on the recesses
whereby an opening is formed in the sheet at the place of the recess. The tablet qr
capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of
numbers next to the tablets or capsules whereby the numbers correspond with the
days of the regimen which the tablets or capsules so specified should be ingested.
Another example of such a memory aid is a calendar printed on the card, e.g., as
follows "First Week, Monday, Tuesday, ...etc.... Second Week, Monday, Tuesday,,
etc. Other variations of memory aids will be readily apparent. A "daily dose" can bp
a single tablet or capsule or several pills or capsules to be taken on a given day.
Also, a daily dose of formula I compound (or an isomer, prodrug or pharmaceutical
acceptable salt thereof) can consist of one tablet or capsule while a daily dose of th«
second compound can consist of several tablets or capsules and vice versa. The
memory aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to
dispense the daily doses one at a time in the order of their intended use is provided.
Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate
compliance with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been dispensed. Anothar
example of such a memory-aid is a battery-powered micro-chip memory coupled wit
a liquid crystal readout, or audible reminder signal which, for example, reads out the
date that the last daily dose has been taken and/or reminds one when the next dose;
is to be taken.
The following paragraphs describe exemplary formulations, dosages etc.
useful for non-human animals. The administration of compounds of this invention cdn
be effected orally or non-orally, for example by injection. An amount of a compounc
of formula I, an isomer, prodrug or pharmaceutically acceptable salt thereof, is
administered such that a therapeutically effective dose is received, generally a daily
dose which, when administered orally to an animal is usually between 0.01 and 500
mg/kg of body weight, preferably between 0.1 and 50 mg/kg of body weight.
Conveniently, the medication can be carried in the drinking water so that a
therapeutic dosage of the agent is ingested with the daily water supply. The agent
can be directly metered into drinking water, preferably in the form of a liquid, watersoluble
concentrate (such as an aqueous solution of a water soluble salt).
Conveniently, the active ingredient can also be added directly to the feed, as si
in the form of an animal feed supplement, also referred to as a premix or conce
A premix or concentrate of therapeutic agent in a carrier is more commonly
employed for the inclusion of the agent in the feed. Suitable carriers are liquid
solid, as desired, such as water, various meals such as alfalfa meal, soybean rr
cottonseed oil meal, linseed oil meal, corncob meal and corn meal, molasses, u
bone meal, and mineral mixes such as are commonly employed in poultry feeds
particularly effective carrier is the respective animal feed itself; that is, a small p
of such feed. The carrier facilitates uniform distribution of the active materials ir
finished feed with which the premix is blended. It is important that the compoun
thoroughly blended into the premix and, subsequently, the feed. In this respect,
agent may be dispersed or dissolved in a suitable oily vehicle such as soybean
corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then bier
with the carrier. It will be appreciated that the proportions of active material in th
concentrate are capable of wide variation since the amount of agent in the finish
feed may be adjusted by blending the appropriate proportion of premix with the f
to obtain a desired level of therapeutic agent.
High potency concentrates may be blended by the feed manufacturer wil
proteinaceous carrier such as soybean oil meal and other meals, as described a
to produce concentrated supplements which are suitable for direct feeding to ani
In such instances, the animals are permitted to consume the usual diet.
Alternatively, such concentrated supplements may be added directly to the feed 1
produce a nutritionally balanced, finished feed containing a therapeutically effect!
level of a compound according to the invention. The mixtures are thoroughly blei
by standard procedures, such as in a twin shell blender, to ensure homogeneity.
If the supplement is used as a top dressing for the feed, it likewise hel|
ensure uniformity of distribution of the active material across the top of the dre
feed.
The present invention has several advantagous veterinary features. For t
pet owner or veterinarian who wishes to increase leanness and trim unwanted fat
from pet animals, the present invention provides the means by which this can be
accomplished. For poultry and swine raisers, using the method of the present
invention yields leaner animals which command higher prices from the meat industry.
Drinking water and feed effective for increasing lean meat deposition and or
improving lean meat to fat ratio are generally prepared by mixing a compound of the
invention with a sufficient amount of animal feed to provide from about 10~3 to 500
ppm of the compound in the feed or water.
The preferred medicated swine, cattle, sheep and goat feed generally contain
from 1 to 400 grams of active ingredient per ton of feed, the optimum amount or
these animals usually being about 50 to 300 grams per ton of feed.
j T h e preferred feed o about 1 to 400 grams and preferably 10 to 400 grams of active ingredient per ton of
feed.
For parenteral administration in animals, the compounds of the present
invention may be prepared in the form of a paste or a pellet and administered as an
implant, usually under the skin of the head or ear of the animal in which increase in
lean meat deposition and improvement in lean mean to fat ratio is sought.
In general, parenteral administration involves injection of a sufficient amoiint
of a compound of the present invention to provide the animal with 0.01 to 500
mg/kg/day of body weight of the active ingredient. The preferred dosage for poultry,
swine, cattle, sheep, goats and domestic pets is in the range of from 0.1 to i50
mg/kg/day of body weight of active ingredient.
Paste formulations can be prepared by dispersing the active compound in
pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.
Pellets containing an effective amount of a compound of the present invention
can be prepared by admixing a compound of the present invention with a diluent such
as carbowax, carnuba wax, and the like, and a lubricant, such as magnesium Or
calcium stearate, can be added to improve the pelleting process.
It is, of course, recognized that more than one pellet may be administered
an animal to achieve the desired dose level which will provide the increase in lean
meat deposition and improvement in lean meat to fat ratio desired. Moreover, it has
been found that implants may also be made periodically during the animal treatment
period in order to maintain the proper drug level in the animal's body.
The activity of the compounds of the present invention are demonstrated by
one or more of the assays described below:
The following is a description of an assay for the identification bf
glucocorticoid receptor antagonists/agonists: HeLa cells containing endogenous
to
human glucocorticoid receptors are transfected with a SxGRE-luciferase plasrriid
generated by standard procedures and a plasmid conferring neomycin resistance.
Novel glucocorticoid responsive cell lines are generated and characterized. One
such cell line designated HeLa-GRE9 is used for determining the activity of
compounds at the glucocorticoid receptor. Cells are maintained in charcoal-strippod
serum and transferred to 96-well microtiter plates one day prior to treatment with
various concentrations (10"12 to 10"5) of test compounds in the absence and presence
of known glucocorticoid receptor agonists (i.e., dexamethasone, hydrocortisone) for
up to 24 hours. Treatments are performed in triplicate. Cell lysates are prepared ariid
luciferase activity is determined using a luminometer. Agonist activity is assessed by
comparing the luciferase activity from cells treated with test compound to cells treated
with the agonist dexamethasone. Antagonist activity is assessed by comparing the
luciferase activity of an ECso concentration of dexamethasone in the absence arid
presence of test compound. The ECso (concentration that produced 50% of the
maximal response) for dexamethasone is calculated from dose response curves.
The following is a description of an assay for determining the competitive
inhibition binding of the Human Type II Glucocorticoid receptor expressed in Sf9 cell
Binding protocol: Compounds are tested in a binding displacement assay
using human glucocorticoid receptor expressed in Sf9 cells with 3H-dexamethasone
as the ligand. Human glucorticoid receptor is expressed in Sf9 cells as described in
Mol. Endocrinology 4:209,1990. Pellets containing Sf9 cells expressing the human
GR receptor from 1L vats are lysed with 40 ul of 20mM AEBSF stock (Calbiochem,
LaJolla, CA) containing 50 mg/ml leupeptin and 40 ml of homogenization buffer is
added. The assay is carried out in 96-well polypropylene plates in a final volume of
130 ul containing 200 ug Sf9 lysate protein, 6.9 nM 3H-dexamethasone (Amersham,
Arlington Heights, IL) in presence of test compounds, test compound vehicle (for total
counts) or excess dexamethasone (7 uM non-radioactive, to determine non-specific
binding) in an appropriate volume of assay buffer. All compounds are tested at 6
concentrations in duplicate (concentration range 0.1-30 nM or 3-1000 nM). Test
compounds are diluted from a 25 mM stock in 100% DMSO with 70%EtOH and
added in a volume of 2 //I. Once all additions are made the plates are shaken,
sealed with sealing tape and incubated at 4 °C overnight.
After the overnight incubation, unbound counts are removed with dextran
coated charcoal as follows: 75 //I of dextran coated charcoal (5.0 g activated
charcoal, 0.5 g dextran adjusted to volume of 100 ml with assay buffer) is added,
plates are shaken and incubated for five minutes at 4 °C. Plates are then centrifuged
in a refrigerated benchtop centrifuge at top speed for 15 minutes. 100 /;! of the
supernatant from each well is placed into a 96-well PET plate with 200 p\ of
scintillation cocktail and counted on a beta counter (1450 MicroBetaTrilux, from
Wallac, Turku, Finland).
Data analysis: After subtracting non-specific binding, counts bound are
expressed as % of total counts. The concentration response for test compounds are
fitted to a sigmoidal curve to determine the IC50 (concentration of compound that
displaces 50% of the bound counts).
Reagents: Assay Buffer: 2.0 ml 1M Tris, 0.2 ml 0.5mM EDTA, 77.1 mg DTT
0.243 g sodium molybdate in a volume of 100 ml water; Homogenization buffer: 2.0
ml 0.5 M K2HPO4 (pH 7.6), 20 fj\ 0.5 M EDTA ( pH 8.0), 77.1 mg DTT, 0.486 g
sodium molybdate in a volume of 100 ml water.
The following is a description of an assay for determining receptor selectivity:
T47D cells from ATCC containing endogenous human progesterone and
mineralocorticoid receptors are transiently transfected with a SxGRE-luciferase using
Lipofectamine Plus (GIBCO-DRL, Gaithersburg, MD). Twenty-four hours posttransfection
cells are maintained in charcoal-stripped serum and transferred to 96-
well microtiter plates. The next day cells are treated with various concentrations (10'1Z
to 10'5) of test compounds in the absence and presence of a known progesterone
receptor agonist (progesterone) and a known mineralocorticoid receptor agonist
(aldosterone) for up to 24 hours. Treatments are performed in triplicate. Cell lysates
are prepared and luciferase activity is determined using a luminometer. Agonist
activity is assessed by comparing the luciferase activity from cells treated with
compound alone to cells treated with either the agonist progesterone or aldosterone.
Antagonist activity is assessed by comparing the luciferase activity of an EC^
concentration of progesterone or aldosterone in the absence and presence of
compound. The ECso (concentration that produced 50% of maximal response) for
progesterone and aldosterone is calculated from dose response curves.
The following is a description of an assay for determining anti-diabetes and
anti-obesity activity: The obese, diabetic ob/ob mouse is used to assess the antidiabetes
and anti-obesity activity of the compounds. Six to 10 week old ob/ob male
mice (Jackson Labs, Bar Harbor, Maine) are dosed with test compound for 2 to 10
days. Plasma glucose levels are determined by measuring glucose from samples
obtained by orbital bleeding. Glucose is quantitated using an Abbott Autoanalyzer
(Abbott, Inc., Abbott Park, IL). Food intake is monitored on a daily basis by
differential weighing.
The following is a description of an assay for determining the ability of a
compound to inhibit glucocorticoid agonist induction of liver tyrosine amino
transferase (TAT) activity in conscious rats:
Animals: Male Sprague Dawley rats (from Charles River, Wilimington MA)
(adrenal-intact or adrenalectomized at least one week prior to the screen) b.w. 90<_> are used. The rats are housed under standard conditions for 7-1 Od prior to use in trie
screen.
Experimental protocol: Rats (usually 3 per treatment group) are dosed with
test compound, vehicle or positive control (Ru486) either i.p., P.O., s.c. or i.v. (tail
vein). The dosing vehicle for the test compounds is typically one of the following:
100% PEG 400, 0.25% methyl cellulose in water, 70% ethanol or 0.1 N HCI and the
compounds are tested at doses ranging from 10 to 125 mg/kg. The compounds are
dosed in a volume of 1.0 ml/100 g body weight (for p.o.) or 0.1 ml/100g body weigh
for other routes of administration . Ten minutes after the administration of the test
compound, the rats are injected with dexamethasone (0.03 mg/kg i.p. in a volume of
0.1 ml/ 100g) or vehicle. To prepare the dexamethasone dosing solution,
dexamethasone (from Sigma, St. Louis, MO) is dissolved in 100% ethanol and diluted
with water (final: 10% ethanol:90% water, vol:vol). Groups treated with vehiclevehicle,
vehicle-dexamethasone, and Ru486-dexamethasone are included in each
screen. The compounds are tested vs. dexamethasone only. Three hours after the
injection of dexamethasone the rats are sacrificed by decapitation. A sample of liver
(0.3 g) is excised and placed in 2.7 ml of ice cold buffer and homogenized with a
polytron. To obtain cytosol the liver homogenate is centrifuged at 105,000g for 60
min and the supernatant is stored at -80 °C until analysis. TAT is assayed on 100 ul
of a 1:20 dilution of the 105,000g supernatant using the method of Granner and
Tomkins (Methods in Enzymology 17A: 633-637,1970) and a reaction time of 8-10
minutes. TAT activity is expressed as umol product/min/g liver.
Interpretation: Treatment data are analyzed by using analysis of variance
(ANOVA) with protected least significant difference (PLSD) post-hoc analysis.
Compounds are considered active in this test if the TAT activity in the group
pretreated with compound prior to dexamethasone administration is significantly (P
0.05) decreased relative to the TAT activity in the vehicle-dexamethasone treated
group.
The following is a description of an assay for determining the effect of a
compound on two typical genes that are upregulated during an inflammatory
response. This assay, the glucocorticoid inhibition of IL-1 (lnterleukin-1) induced
MMP-1 (Matrix Metalloproteinase-1) and IL-8 (lnterleukin-8) production in human
chondrosarcoma cells, is conducted as follows: SW1353 human chondrosarcoma
cells (obtained from ATCC) from passage 12 through passage 19 are used in a 96
well format assay. Cells are plated at confluence into 96 well plates in DMEM
(Dulbecco's Modified Eagle Medium) with 10% fetal bovine serum and incubated at
37 °C, 5% CO2. After 24 hours, serum containing media is removed and replaced
with 200 ul/well DMEM containing 1 mg/L insulin, 2 g/L lactalbumin hydrosylate, anc
0.5 mg/L ascorbic acid and returned to incubation at 37 °C, 5% CO2. The following
morning, the serum free media is removed and replaced with 150 ul/well fresh serurfi
free media containing +/- 20 ng/ml IL-1 beta, +/- 5 nM dexamethasone, +/-
compound. All conditions are completed in triplicate using only the inner 60 wells of
the 96 well plate. Outside surrounding wells of plate contain 200 ul of serum free
DMEM. Plates are incubated at 37 °C, 5% C02. At 24 hours after addition of IL-1,;
ul of sample from each well is removed under aseptic conditions for IL-8 production
analysis. Samples are stored at -20 °C until time of analysis. IL-8 production is
assessed using the Quantikine human IL-8 ELISA kit from R&D Systems (D8050) 0(1
samples diluted 60-fold in RD5P Calibrator Diluent, following the manufacturer's
protocol. The percent of the average IL-1 control is determined for the average of
each of the triplicate samples following subtraction of the average signal from
untreated cells. IC50s are determined from log linear plots of the percent of control
versus the concentration of inhibitor. At 72 hours after IL-1 addition, the remaining
media is removed and stored at -20 °C until time of MMP-1 production analysis.
MMP-1 production is assessed via the Bio-Trak MMP-1 ELISA kit from Amersham
(RPN2610) on 100 ul of neat sample following the manufacturer's protocol.
The percent of the average IL-1 control is determined for the average of eacn
of the triplicate samples following subtraction of the average signal from untreated
cells. IC50's are determined from log linear plots of the percent of control versus the
concentration of inhibitor. Dexamethasone has proven to be a good positive contrql
inhibitor of both IL-8 and MMP1 expression (ICso=5nM).
The following compounds of the present invention are preferred:
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-AA(4-pyridinylmethyl)-, [4bS-(4bct,7a,8ap)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-/V-(2-pyridinylmethyl)-, [4bS-(4ba,7a,8ap)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-/V-(3-pyridinylmethyl)-, [4bS-(4bcc,7a,8ap)]-;
carbamic acid, [2-(dimethylamino)ethyl]-, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl ester,[4bS-(4ba,7a,8ap)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-A/-pyrazinyl-, [4bS(4ba,7a,8ap)]-;
2-phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-(1-
propynyl)-7-(4-pyridinylmethoxy)-, [2f?-(2a,4aa,1 Oap)];
2-phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(1-
propynyl)-7-(2-pyridinylmethoxy)-, [2f?-(2a,4aa,1 Oap)];
2-phenanthrenecarbonitrile, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-, [4bS-(4ba,7a,8ap)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-/V-[(2-
methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(1-propynyl)-, [4bS-(4ba,7a,8ap)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-/V-[(2-
methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-propyl-t [4bS-(4ba,7a,8ap)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-AA(2-pyridinylmethyl)-, [4bS-(4ba,7a,8ap)]-;
2-phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-2-(3,3,3-trifluoropropyl)-, [2S-(2a,4aa, 10ap)]-;
2-phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(2-methyl-3-
pyridinyl)methoxy]-4a-(phenylmethyl)-2-(3,3,3-trifluoropropyl)-,[2S-(2a,4aa,10ap)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-A/-[(2-
methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(3,3,3-trifluoropropyl)-, (4bS,7S,8af?j;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-
methyl-/V-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-, (4bS,7R,8aR)-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9, 1 0-octahydro-7-hydroxy-7-
methyl-4b-(phenylmethyl)-A/-3-pyridinyl-, (4bS,7 R,8aR)-;
2-phenanthrenol, 1 ,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-(trifluoromethyl)-, (2fl,4aS,10aR)-; and
2-phenanthrenecarboxamide, 4b, 5, 6, 7, 8, 8a, 9, 10-octahydro-7-hydroxy-Nl-
[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(trifluoromethyl)-, (4bS, 7R, 8aR)
EXAMPLES
Preparation 1 1-Benzyl-6-methoxy-3,4-dihydro-1H-naphthalen-2-one
A solution of 51 g (0.289 mol) of 6-methoxy-2-tetralone of formula A
wherein D is C, R10 is methoxy; R14l R15 and R16 are each H, and 24.2 mL (0.289 mol)
of pyrrolidine in 1.5 L of toluene was heated to reflux, over a Dean-Stark trap,
overnight. After removal of the azeotroped water, the reaction mixture was cooled to
RT, concentrated to an oil, and dissolved in 725 mL of dioxane. To this solution was
added 52 mL (0.434 mol) of benzyl bromide and the resulting solution was heated to
reflux overnight. Water (100 mL) was added to the solution the resultant mixture was
heated to reflux for an additional 2 h. The mixture was cooled to room temperature
and poured into a solution of 1 N HCI and extracted 3 times with EtOAc. The organic
layers were washed with H2O and saturated NaHCO3, then dried over Na2S04,
filtered, and evaporated to dryness. The crude product was purified by flash
chromatography over SiO2 using 10% EtOAc to 15°o EtOAc in hexanes as the
gradient eluant to give 65.2 g of the title product of this preparation as a yellow oil
(85%). IR (neat) 2937, 1712, 1500 cm'1; 1H NMR (400 MHz. CDCI3) 8 2.41-2.59 (m,
3H), 2.76 (dt, 1H, J = 5.4, 15.5), 3.15-3.70 (m, 2H). 367 (t. 1H, J = 6.3), 3.77 (s, 3H),
6.67-6.70 (m, 2H), 6.81 (d, 1H, J = 8.1), 6.87-6.89 (m, 2H), 7.13-7.17 (m, 3H); 13C
NMR (100 MHz, CDCI3) 6 27.44, 38.19, 39.19, 54.13. 55.14, 112.11, 112.96, 126.30,
128.07, 128.26, 129.35, 129.53, 138.05, 138.20, 158.30, 212.41; MS m/z 267
Preparation 2 1 (F?)-Benzyl-6-methoxy-1 (S)-(3-oxo-butyl)-3,4-dihydro-1 Hnaphthelen-
2-one
A solution of 62 g (0.23 mol) of the title product of Preparation 1 and 28 mL ,
(0.23 mol) of freshly distilled (S)-(-)-alpha-methyl benzylamine in 100 mL of toluenu
was heated to reflux, over a Dean-Stark trap, overnight. After removal of tho
azeotroped water, the imine solution was cooled to 0 °C and 21 mL (0.26 mol) of
freshly distilled methylvinylketone was added dropwise to the solution. The solution
was stirred at 0 °C for 30 min then heated to 40 °C overnight. The reaction solut on
was cooled to 0° C and 17 ml of acetic acid and 14 ml of H20 were added and 1he
resultant solution was allow to warm to RT for 2 h. The solution was poured into H2O
and extracted three times with EtOAc. The combined organic layers were washed
with 1 N HCI, H2O, saturated NaHCO3, then dried over Na2SO4, filtered, and
evaporated to dryness. The crude product was purified by chromatography over Si02
using 15% EtOAc to 35% EtOAc in hexanes as the gradient eluant to give 48 g of tne
title product of this preparation as a yellow solid. 1HNMR (400 MHz, CDCL3) 6 1.J38
(s, 3H), 1.40-1.51 (m, 2H), 1.64 (ddd, 1H, J = 2.1, 4.5, 13), 1.97 (broad s, 1H), 2.;>0
(dt, 1H, J = 4.5, 13), 2.59 (d, 1H, J = 6.6), 3.08 (d, 1H, J = 18), 3.16 (d, 1H, J = 1(5),
3.33 (dd, 1H, J = 6.6, 18), 3.62 (d, 1H, J = 16), 3.72 (s, 3H), 6.57 (d, 1H, J = 2.J5),
6.67 (dd, 1H, J = 2.5, 8.8), 7.00-7.23 (m, 6H); 13C NMR (100 MHz, CDCI3) 5 27.90,
32.79, 34.40, 38.43, 41.49, 53.51, 55.12, 58.47, 79.06, 112.05, 113.09, 125.3
127.63, 127.69, 130.27, 132.21, 135.45, 138.65, 157.88, 213.49; MS m/z 3,
(M+H)+, 319(M-OH)+.
Preparation 3 f(S)-Benzyl-6-methoxy-1 (fl)-(3-oxo-butyl)-3,4-dihydro-1 Hnaphthelen-
2-one
The title product of this preparation was prepared using a method analogous
to Preparation 2, using (f?)-(+)-alphamethyl benzylamine in the initial imine formation.
Starting with 4.64 g 1-benzyl-6-methoxy-3,4-dihydro-1H-naphthalen-2-one produced
3.58 g of the title product of this preparation as a yellow solid. 1HNMR (400 MH
CDCL3) 8 1.38 (s, 3H), 1.40-1.51 (m, 2H), 1.64 (ddd, 1H, J = 2.1, 4.5, 13), 1.97
(broad s, 1H), 2.20 (dt, 1H, J = 4.5, 13), 2.59 (d, 1H, J = 6.6), 3.08 (d, 1H, J = 18),
3.16 (d, 1H, J = 16), 3.33 (dd, 1H, J = 6.6, 18), 3.62 (d, 1H, J = 16), 3.72 (s, 3H), 6.5J7
(d, 1H, J = 2.5), 6.67 (dd, 1H, J = 2.5, 8.8), 7.00-7.23 (m, 6H); 13C NMR (100 MH
CDCI3) 5 27.90, 32.79, 34.40, 38.43, 41.49, 53.51, 55.12, 58.47, 79.06, 112.0
113.09, 125.37, 127.63, 127.69, 130.27, 132.21, 135.45, 138.65, 157.88, 213.49; MS
m/z 337 (M+H)+, 319 (M-OH)+.
Preparation 4 2(3/-/)-Phenanthrenone, 4a-[(4-isopropylaminophenyl)methyl]-
4,4a,9,10-tetrahydro-7-hydroxy-, (S)-
To a stirring solution of 200 mg of the title product of Preparation 18 in 0.21
mL of AcOH , 3 mL of acetone and 3 mL of dichloroethane under N2 atmosphere wa
added 373 mg of NaBH(OAc)3 at RT. The reaction mixture was stirred at RT for 2 h,
then quenched with NaHCO3 (sat). The mixture was extracted with EtOAc (X3),
washed with brine, dried over Na2SO4, filtered and concentrated to dryness.
Purification by flash chromatography over SiO2 using 30% EtOAc in hexanes as the
eluant afforded 108 mg of the title product of this preparation as white powder (47%).
MSm/z362(M+H)+.
Preparation 5 2(1 H)-Phenanthrenone, 4a-[[3-(dimethylamino)phenyl]methyl]-
3,4,4a,9,10,10a-hexahydro-7-hydroxy-, (4aS-cis)-
A solution of 255 mg of the title product of Preparation 19 in 0.11 mL of
formaldehyde (37% w/w), 255 mg of 5% Pd(OH)2/C and 10 mL of EtOH was shaken
under 50 psi (which is about 3.3 atm.) H2 pressure for 2 days. The mixture was
filtered and concentrated to dryness. Purification by flash chromatography SiO2 usirjg
2% EtOAc in hexanes to 40% EtOAc in hexanes as the gradient elutant afforded 1G
mg (48%) of the title product of this example as white fluffy powder. MS m/z450
(M+H)+.
Preparation 6 1 -Naphthalenepropanoic acid, 1,2,3,4-tetrahydro-6-methoxy-;
oxo-1 -(phenylmethyl)-, methyl ester
To a solution of 3.18 g of the title compound of Preparation 1 in 30 mL
anhydrous MeOH was added 31 mL of 0.5 M NaOMe/MeOH at -15 °C under nitrogejn
atmosphere. This solution was stirred vigorously while 1.5 mL of fresh distilled methyl
acrylate was added dropwise at -15 °C. The mixture was stirred for 1 h at 0 °C and
then allowed to settle for 5 min. The precipitate was collected by filtration and the filter
cake was washed with MeOH to yield 2 g (52%) of the title product of this preparation
as white solid. MS m/z353 (M+H)+.
Preparation 7 1 -Naphthalenepropanoic acid, 1,2,3,4-tetrahydro-6-methoxyoxo-
1 -(phenylmethyl)-
A solution of 200 mg of the title product of Preparation 6 and 92 mg cjrf
Na2CO3 in 8 mL of MeOH and 10 mL of water was heated to reflux for 30 min. The
mixture was cooled and adjusted to pH around 5 with 1 N HCI solution. NaCI was
added to make a saturated solution. The solution was extracted with EtOAc (X3
washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The titlle
product of this preparation was obtained in 98% yield as white solid. MS m/z 339
(M+H)+.
Preparation 8 3H-Naphtho[2,1 -b]pyran-3-one, 1,2,4a,5,6,1 Ob-hexahydro-8-
methoxy-1 Ob-(phenylmethyl)-
To a solution of 199 mg of the title product of Preparation 7 in 5 ml_ of etharjol
was added 67 mg of sodium borohydride at 0 °C under N2 atmosphere. The mixture
was then allowed to stirred overnight at room temperature. The solution was th^n
acidified to pH 1 with 1 N HCI solution and extracted with EtOAc (X3), dried ovsr
Na2SO4, filtered and concentrated to dryness. Purification by preparative TLC SiC2
using 35% EtOAc in hexanes as the elutant afforded 73 mg (37%) of the title product
of this preparation as white fluffy powder. MS m/z323 (M+H)+.
Preparation 9 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[3-[4-(f-butyldimethylsiloxymethyl)phenyl]-2-
propenyl]-, [2f?-[2a,4aa(E),10a(3]]-
The title compound of this preparation was prepared by procedures
analogous to those described below in Example 35.
Preparation 9a Carbamic acid, dimethyl-, 4b-[2-acetaldehydro]-
4b,5,6,7I8,8a,9,10-octahydro-7-hydroxy-7-(1 -propynyl)-2-
phenanthrenyl ester, [4bS-(4bu,7u,8a3)]-
To a stirred solution of 4a(2H)-phenanthreneacetaldehyde, 2-(1-propynyl)-
1,3,4,9,10,10a-hexahydro-2,7-dihydroxy-, [2f?-(2a,4au.lOap)]- (1.5g) in THF were
added sequentially 4-dimethylaminopyridine (0.12g), tnethylamine (1.8g) and
dimethylcarbamyl chloride (1.6g). After 18 h, the heterogeneous mixture was
quenched with saturated aqueous ammonium chlonde, extracted with ethyl acetate
the organic layer was dried over sodium sulfate and concentrated in vacuo. The
resulting oil was purified by flash chromatography on silica gel (30-50% ethyl
acetate/hexanes) to afford the title compound of this preparation as a colorless solid,
2.3g.
Preparation 10 Carbamic acid, dimethyl-, 4b-[2-hydroxyethyl]
4bl5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8a(3)]-
To a cooled (-78 °C), stirred solution of the title product of Preparation 9a (2.C
g) in tetrahydrofuran (60 mL) was added a 1 M solution of diisobutylaluminum hydride
in cyclohexane (8 mL). After 2.5 h, the reaction was quenched with 0.5 M sodium
potassium tartrate and the resulting mixture was stirred overnight at room
temperature. The two-phase mixture was extracted with ethyl acetate (3x), the
combined extracts washed with brine, dried over sodium sulfate and concentrated in
vacuo to afford a colorless foam. Flash chromatography on silica gel (50-75% ethyl
acetate/hexanes) afforded the title product of this preparation a colorless foam, 1.9
Preparation 11 8-R,Sa-Benzyl-6-ethoxy-3,7,8,8a-tetrahydro-2H-naphthalenone
A solution of 8-R,Sa-benzyl-3,4,8,8a-tetrahydro-2H,7H-naphthalene-1,6-dioifie
(5.0 g), triethylorthoformate (13 ml_), p-toluenesulfonic acid (200 mg), ethanol (1.5
mL) in toluene (100 ml) was heated at 80 °C for 1.5 h. The reaction solution was
cooled, diluted into ethyl ether, washed with 1N NaOH, water, brine, dried over
sodium sulfate and concentrated in vacuo to afford a red oil. Filtration (20% ethyl
ether/hexanes) through a pad of Florisil® provided the title product of this preparation
as a red solid, 5.7 g.
Preparation 12 (cis/trans)-8-R,Sa-Benzyl-6-ethoxy-3,4,4a,5,8,8a-hexahydro-
2H-naphthalen-1 -one
A solution of the title product of Preparation 11 (2 g) in ethanol (56 mL) was
hydrogenated at 1 atm of hydrogen pressure over 2% strontium carbonate (0.2 g) for
4.5 h. After removal of catalyst by filtration and concentration of the filtrate in vacuo,
the trans and cis isomers of the title product of this preparation were separated by
chromatography on silica gel (0-2% ethyl acetate/hexanes). The cis isomer (0.1 g)
eluted first with the trans isomer (1.2 g) predominating.
Preparation 13 (trans)-8-R,Sa-Benzyl-2-bromo-6-ethoxy-3,4,4a,5,8,8ahexahydro-
2H-naphthalen-1 -one
To a cooled (0 °C), stirred solution of lithium diisopropyamide (prepared from
diisopropylamine (0.17 mL) and n-butyllithium (0.42 mL, 2.5 M in hexanes)) in
tetrahydrofuran (9 mL) was added a solution of (trans)-8-R,Sa-benzyl-6-ethoxy-
3,4,4a,5,8,8a-hexahydro-2H-naphthalen-1-one (0.25 g) in tetrahydrofuran (4 mL).
After 30 min, the solution was cooled to -78 °C and a solution of n-bromosuccinimid^
(0.2 g) in tetrahydrofuran (9 mL) was added. After 1 h, the reaction was quenched
with saturated aqueous sodium bicarbonate, extracted with ethyl ether, the organic
layers were combined, dried over sodium sulfate and concentrated in vacuo. The
resulting oil was purified by flash chromatography on silica gel (0-1% ethyl
acetate/hexanes) to afforded the title compound of this preparation as an oil (200
mg). The cis-isomer of the title product of Preparation 12 can be analogously
reacted.
Preparation 14 (trans)-8a-Benzyl-2-bromo-hexahydro-naphthalene-1,6-dione
A solution of the title product of Preparation 13 (0.15 g) in a solution of
ethanol (8 mL) containing 2.5% concentrated sulfuric acid and 1 % water was stirred
for 2 h. The reaction was diluted with ethyl ether, washed with sat. sodium
bicarbonate, brine, dried over sodium sulfate and concentrated in vacuo to afford an
oil. Flash chromatography on silics gel (15% ethyl scetate/hexanes) afforded the titl^
compound of this preparation as a colorless solid, 53 mg. The cis-isomer can be
similarly reacted.
Prepsration 15 (tr3ns)-8-R,S3-Benzyl-6-ethoxy-1 -oxo-1,2,3,4,43,5,8,83-
octahydro-n3phth3lene-2-carbaldehyde
To a cooled (0 °C), stirred solution of the trans isomer of the title product of
Preparation 12 (2.1 g) and ethyl formate (2.2 g) in tetrahydrofuran (8 ml) was added
potsssium t-butoxide (15.6 ml_, 1 M in THF). The resction solution wss maintained 3
0 °C for 0.5 h snd 3t room temperature for 6 h, quenched with sat. aqueous
smmonium chloride and extracted with ethyl scetste. The combined organic extracts
were washed with brine, dried over sodium sulfate and concentrated in vscuo to
afford the title compound of this preparation as 3 red oil, 2.3 g.
Prepsration 16 Phenol, 4-[4-(chloroethynyl)-4-hydroxy-1-
(phenylmethyl)cyclohexyl]-
The title compound of this prepsration wss prepared by procedures
analogous to those described below in Exsmple 8. MS: 342 (M+1)+.
Preparation 17 2(1 H)-Phenanthrenone, 3,4,4a,9,10,103-hex3hydro-7-hydroxy
4a-[(4-hydroxyphenyl)methyl]-, (4aSc/s)
The title compound of this preparation was prepared by procedures
analogous to those described below in Example 7. MS: 323 (M+1)+
Preparation 18 2(3H)-Phenanthrenone, 43-[(4-3minophenyl)methyl]-4,4a,9,10-
tetrahydro-7-hydroxy-, (S)-
The title compound of this preparation was prepared by procedures
analogous to those described below in Example 3. MS: 321 (M+1)+
Preparation 19 2(1/-/)-Phenanthrenone, 4a-[(3-aminophenyl)methyl]-
3,4,4a,9,10,103-hexahydro-7-hydroxy-, (4aS-c/s)-
The title compound of this prepsration was prepared by procedures
anslogous to those described below in Prepsration 5. MS: 322 (M+1)+
Preparation 20 Pyridine, 3-[[[(2R,4'aS,10'aR)-3'l4',4'a,9',10l,10'a-hexahydro
4'a-(phenylmethyl)spiro[oxirane-2,2'(1'H)-phenanthren]-7'-
yl]oxy]methyl]-
The title compound of this preparation was prepared by procedures
analogous to those described below in Example 76. MS: 413 (M+1)+.
Preparation 21 Pyridine, 3-[[[(2R,4'aS,10'aR)-3',4',4'a,9',10'a-hexahydro-4'a-
(phenylmethyl)spiro[oxirane-2,2'(1'H)-phenanthren]-7'-
yl]oxy]methyl]-2-methyl-
The title compound of this preparation was prepared by procedures
analogous to those described below in Example 76. MS: 427 (M+1)+.
Preparation 22 Pyridine, 2-[[[(2R, 4'aS, lO'aRJ-S'a.g'.IO'.IO'i
4'a-(phenylmethyl)spiro[oxirane-2,2'(1'H)-phenanthren]-7'-
yl]oxy]methyl]-
The title compound of this preparation was prepared by procedures
analogous to those described below in Example 76. MS: 413 (M+1)*
Example 1 2(3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-methoxy-4a-
(phenylmethyl)-, (S)-
A solution of 48 g (143 mmol) of the title product of Preparation 2 and 71
of 1 M sodium methoxide in 100 ml_ of methanol was stirred at room temperature for
15 min, then heated to 75 °C for 3 h. The solution was cooled to 0 °C, 8.2 ml of
acetic acid was added dropwise, and the solution was concentrated to an oil. The oil
was dissolved in EtOAc, washed with saturated NaHCO3 and brine, dried over
Na2SO4, filtered, and evaporated to dryness. The crude product was purified by
chromatography over SiO2 using 15% EtOAc to 35% EtOAc in hexanes as the
gradient eluant to give 44 g 2(3H)-phenanthrenone, 4,4a,9,10-tetrahydro-7-metho
4a-(phenylmethyl)-, (S)- as an off-white powder (60% from 1 -benzyl-6-methoxy-3,4-
dihydro-1 H-naphthalen-2-one). Recrystallization from EtOAc/hexane afforded 35 g of
the title product of this example as a white crystalline solid, mp 101-102 °C;
(neat) 1667, 1500 cm-1; 1HNMR (CDCL3) 1.83-1.90 (m, 1H), 2.02 (dt, 1H, J = 5.5
14), 2.27 (dt, 1H, J = 4.3, 14) 2.44-2.51 (m, 2H), 2.64-2.79 (m, 3H), 3.14 (d, 1H,,
13), 3.21 (d, 1H, J = 13), 3.78 (s 3H), 5.96 (s, 1H), 6.54 (d, 1H, J = 2.6), 6.71 (d, 2H,
J = 7.1), 6.77 (dd, 1H, J = 2.6, 8.7), 7.06-7.23 (m, 4H)); 13C NMR (100 MHz, CDCI3
30.71, 32.10, 34.62, 36.09, 43.62, 46.36, 55.20, 112.78, 112.84, 125.53, 126.^8,
127.96, 128.12, 130.08, 133.01, 137.24, 137.28, 157.75, 169.16, 198.81; MS
(M+H)+. Anal. Calcd. for C22H2202: C, 82.99; H, 6.96; N, 0. Found: C, 83.21; H,
7.08;N, 0.10.
Example 2 2(3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-methoxy-4a-
(phenylmethyl)-, (R)-
The title product of this preparation was prepared using a method analogous
to Example 1. Starting with 3.53 g of the title product of Preparation 3 produced 2.78
g of the title product of this example as an off-white powder (51 % from 1 -benzyl-6-
methoxy-3,4-dihydro-1 H-naphthalen-2-one. Recrystallization from EtOAc/hexane
afforded 2.15 g of the title product of this example as a white crystalline solid. All
physical constants are the same as reported for the title product of Example 1. Anal.
Calcd. for C^H^: C, 82.99; H, 6.96; N, 0. Found: C, 83.17; H, 7.13; N, Example 3 2(3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-hydroxy-4a-
(phenylmethyl)-, (S)-
To a stirring solution of 40 g (0.126 mol) of the title product of Example 1
(which was made by procedures described in Example 1) and 46.5 g (0.126 mol) of
tetrabutylammonium iodide in 630 ml of dichloromethane at -78 °C under N2
atmosphere was added 300 mL of 1 M boron trichloride in methylene chloride. The
resultant solution was allowed to warm to RT for 1.5 h, then poured into excess iGe
and stirred rapidly, overnight. The mixture was extracted with dichloromethane, dried
over Na2SO4l filtered, and concentrated to dryness. Purification by flash
chromatography over Si02 using 20%EtOAc to 60%EtOAc in hexanes as the
gradient eluant afforded 33.3 g of the title product of this example as an off-whiie
powder (87%). 1H NMR (400 MHz, CD3OD) 5 1.81-2.00 (m, 2H), 2.26 (dt, 1H, J =
4.2, 13), 2.40 (dd, 1H, J = 4.5, 18), 2.53 (ddd, 1H, J = 1.7, 5.6, 14), 2.58-2.80 (m,
3H), 3.20 (d, 1H, J=13), 3.26 (d, 1H, J = 13), 5.92 (s, 1H), 6.45 (d, 1H, J = 2.5), 6.67
(dd, 1H, J = 2.5, 8.5), 6.76 (d, 2H, J = 6.6), 7.05-7.14 (m, 4H); 13C NMR (100 MHZ,
CD3OD) 6 30.22, 32.03, 34.08, 36.04, 43.73, 45.97, 113.76, 113.91, 124.50, 126.25,
127.49, 127.94, 129.84, 131.86, 137.0, 137.71, 155.34, 171.73, 200.33; MS m/2305
(M+H)+.
Example 4 2(3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-hydroxy-4a-
(phenylmethyl)-, (R)-
The title product of this example was prepared using a method analogous to
Example 3. Starting with 1.8 g of the title product of Example 2 produced 1.3 g of the
title product of this example as a white solid (75%). All physical constants are the
same as reported for the title product of Example 3.
Example 5 2,7-Phenanthrenediol, 2,3,4,4a,9,10-hexahydro-4a-
(phenylmethyl)-2-(1-propynyl)-, (2f?-c/s)- and 2,7-
Phenanthrenediol, 2,3,4,4a,9,10-hexahydro-4a-
(phenylmethyl)-2-(1-propynyl)-, (2S-trans)-
To a stirring solution of 5 ml_ of THF saturated with propyne gas at 0 °C was
added 4 mL of 0.5 M lithium diisopropylamide in THF and the resultant mixture stirred
under nitrogen atomosphere for 20 min. A solution of 50 mg (0.16 mmol) of the title
product of Example 3 in 2 ml of THF was added dropwise, and the reaction mixture
was warmed to RT and stirred for 16 h. Saturated, aqueous ammonium chloride was
added, and the mixture was extracted with EtOAc, dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 2%
acetone in dichloromethane to 4% acetone in dichloromethane with 0.5%
triethylamine as the gradient eluant afforded 25 mg (45%) of the first listed title
product of this example (higher Rf) and 5 mg (9%) of the second listed title product of
this example.
The physical properties of the first listed title product of this example are as
follows: 1H NMR (400 MHz, d6acetone) 5 1.67 (s, 3H), 1.67-1.80 (m, 2H), 2.00-
2.22 (m, 2H + d6acetone), 2.26 (ddd, 1H, J = 2.9, 4.2, 7.0), 2.60-2.78 (m, 3H),
3.01, (d, 1H, J = 13), 3.05 (d, 1H, J =13), 4.30 (s, 1H), 5.52 (s, 1H), 6.49, (d, 1H,
J = 2.6), 6.55 (dd, 1 H, J = 2.6, 8.5), 6.67 (d, 1 H, J = 8.5), 6.76-6.80 (m, 2H),
7.08-7.13 (m, 3H), 8.06, (s, 1H); 13C NMR (100 MHz, d6acetone) 5 2.5, 31.4,
33.3, 35.6, 41.8, 46.8, 54.8, 65.8, 77.8, 83.9,113.1, 114.4, 126.0, 127.4, 127.7,
128.4, 130.6, 134.0, 137.2, 138.7, 141.1, 155.1; MS m/z327 (M-OH)+.
The physical properties of the second listed title product of this example are
as follows: 1H NMR (400 MHz, deacetone) 6 1.77 (s, 3H), 1.77-2.30 (m, 5H +
d6acetone), 2.58-2.78 (m, 3H), 2.96, (d, 1H, J = 13), 3.02 (d, 1H, J =13), 4.06 (s
1 H), 5.60 (s, 1 H), 6.47 (d, 1 H, J = 2.3), 6.56 (dd, 1 H, J = 2.3, 8.3), 6.78-6.82 (rh,
3H), 7.10-7.14 (m, 3H), 8.03 (s, 1H); 13C NMR (100 MHz, d6acetone) 6 2.5, 30.9,
31.6, 35.3 , 41.9, 46.3, 54.6, 63.1, 76.8, 84.7, 113.1, 114.3, 126.0, 126.7, 127.4,
128.4, 130.5, 134.0, 137.3,138.7, 142.3,155.1; MS z327 (M-OH)+.
Example 6 2(1H)-Phenanthrenone, 3,4,43,9,10,1 Oa-hexahydro-7-hydroxy-
4a- (phenylmethyl)-, (4aS-trans)-
Ammonia (1.5 L) was condensed into a round bottom flask at -78 °C equipped
with a dry ice reflux condenser at -78 °C and a mechanical stirrer. To this flask was
added 0.7 g (99 mmol) of lithium wire and the solution turned dark blue. A solution of
10 g (32.8 mmol) of the title product of Example 3 in 400 ml of 1:1 dioxane:ether was
added to the mixture slowly in order to keep the reaction a dark blue. As the blue
color dissipated, a small amount of lithium wire was added to the mixture to
regenerate the blue color. The total amount of lithium added to the reaction mixture
did not exceed 3.5 g (495 mmol). After the complete addition of 10 g of the title
product of Example 3, the reaction was stirred an additional 30 min, then 14 g of solid
ammonium chloride was added and immediate dissipation of the blue color was
observed. H2O was added to the mixture and it was extracted with EtOAc, dried over
Na2SO4, filtered, and concentrated to dryness. The crude product was purified by
flash chromatography over SiO2 using 15% EtOAc to 20% EtOAc in hexanes as the
gradient eluant to afford 8.16 g of the title product of this example as a white sofid
(81%). 1H NMR (400 MHz, CD3OD) 6 1.52 (dt, 1H, J = 4.5, 13), 1.64-1.71 (m, 1H),
1.90-2.15 (m, 2H), 2.27 (ddd, 1H, J = 2.5, 3.7, 15), 2.39 (dm, 1H, J = 15), 2.48 (ddd,
1H, J = 2.0, 6.5, 13), 2.72 (t, 1H, J = 14), 2.84 (d, 1H, J = 13), 2.89-3.01 (m, 3H), 3.22
(d, 1H, J = 13), 6.17 (d, 1H, J = 8.5), 6.24 (dd, 1H, J = 2.5, 8.5), 6.53 (d, 1H, J = 2.5),
6.65-6.68 (m, 1H), 7.04-7.13, (m, 3H); 13C NMR (100 MHz, CD3OD) 8; 27.9, 33.7,
34.8, 36.0, 37.6, 39.4, 43.6, 44.0, 111.3, 114.6, 125.7, 127.0, 127.9, 130.5, 133.4,
136.8, 138.0, 155.1, 212.7; MS ^307 (M+H)+.
Example 7 2(1/-/)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a- (phenylmethyl)-, (4aS-c/s)-
To a solution of 1 g (3.6 mmol) of the title product of Example 3 in 75 mL of
ethanol and 0.27 mL of 2M KOH was added 0.15 g of 10% Pd/C. The reaction
mixture was shaken under 45 p.s.i. (which is about 3 atm) of H2 gas for 4 h. Acetic
acid (0.035 mL) was added then the mixture was filtered through Celite®, washing
the Celite® with ethanol, and then the ethanol was removed under reduced pressure.
The resultant residue was partitioned between EtOAc and sat. NaHCOa, extracted
with EtOAc, dried over Na2SO4, filtered, and concentrated to dryness. The crude
product was purified by flash chromatography over Si02 using 25% EtOAc in
hexanes as the eluant to afford 947 mg of the title product of this example as a white
solid (86%). 1H NMR (400 MHz, CD3OD) 5 1.52-1.60 (m, 1H), 1.87 (ddd, 1H, J = 4.8,
11, 14), 2.00-2.35 (m, 6H), 2.39 (dt, 1H, J = 5.2, 14), 2.69-2.92 (m, 2H), 2.96 (d, 1H,
J = 13), 3.00 (d, 1H, J = 13), 6.56-6.58 (m, 2H), 6.88-6.92 (m, 3H), 7.13-7.15, (m,
3H); 13C NMR (100 MHz, CD3OD) 5 23.7, 25.3, 34.7, 37.2, 39.6, 40.3, 42.8, 47.7,
113.1, 115.1, 127.3, 128.0, 130.5, 137.2, 137.8,155.2,213.9; MS m/z 307 (M+H)+.
Example 8 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2F-(2a,4aa,10ap)]- and 2,7-
Phenanthrenediol,2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2S-(2a,4apMOacc)]-
To a stirring solution of 95 mg of cis-dichloroethylene (0.98 mM) in 5 mL of
THF at 0 °C was added 2.5 mL of 0.5 M lithium diisopropylamide in THF and the
resultant mixture was allowed to warm to RT for 30 min under nitrogen atomosphere.
A solution of 30 mg (0.098 mmol) of the title product of Example 6 in 0.65 mL of THF
was added dropwise, and the reaction mixture was stirred an additional 2 h.
Saturated, aqueous ammonium chloride was added, and the mixture was extracted
with EtOAc, dried over Na2SO4, filtered, and concentrated to dryness. Initial
purification by flash chromatography over Si02 using 20% EtOAc in hexanes as the
eluant afforded 30 mg of a light brown solid. Further purification by flash
chromatography over SiO2 using 2% acetone in dichloromethane to 4% acetone in
dichloromethane as a gradient eluant afforded 20 mg (56%) of the first listed title
product of this example (higher Rf) and 7.0 mg (19%) of the second listed title
product of this example (lower Rf) as white solids. The physical characteristics of the
first listed title product of this example are as follows: mp 230-232 °C (decomp.); 1H
NMR (300 MHz, CD3OD) 5 1.40 (mt, 1H, J = 14), 1.64-1.70.(m, 1H), 1.80-2.13 (m,
7H), 2.59 (d, 1H, J = 13), 2.93-2.97 (m, 3H), 6.13 (d, 1H, J = 8.5), 6.25 (dd, 1H, J =
2.6, 8.5), 6.54-6.57 (m, 3H), 7.00-7.07 (m, 3H); 13C NMR (75 MHz, CD3OD) 6 25.5,
28.7, 31.8, 37.2, 40.52, 41.71, 43.43, 63.1, 70.7, 74.1, 112.4, 116.1, 126.8, 128.3,
138.9, 132.1,136.2,138.3,139.5, 156.3; MS An/2366 (M+H)+, 349 (M-OHf.
The physical characteristics of the second listed title product of this example
are as follows: mp 216-219 °C (decomp.) 1H NMR (400 MHz, CD3OD) 5 1.47 (mt,
1H, J =14), 1.56-1.62 (m, 1H), 1.80-2.00 (m, 5H), 2.08 (mt, 1H, J = 13), 2.23 (dt, 1H,
J = 3.8, 14), 2.59 (d, 1H, J = 13), 2.82-2.93 (m) and 2.95 (d, 1H, J = 13), 6.08 (d, 1H,
-116-
J = 8.6), 6.20 (dd, 1H, J = 2.2, 8.6), 6.50 (d, 1H, J = 2.2), 6.54-6.56 (m, 2H), 7.03-
7.06 (m, 3H); 13C NMR (75 MHz, CD3OD) S 25.4,28.8, 28.9, 36.0, 36.7, 40.4, 42.5,
65.1, 67.3, 75.9, 112.3, 116.1, 126.8, 128.2, 128.8, 132.2, 136.3, 138.3, 139.7, 156.2;
MS m/z366 (M+H)+, 349 (M-OH)*.
Example 9 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-, [2fl-(2a,4acx,10ap)]- and 2,7^
Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-, [2S-(2a,4ap,10aa)]-
To a stirring solution of 183 ml of THF saturated with propyne gas at 0 °C was
added 143 ml of 1 M lithium diisopropylamide in THF and the resultant mixture was
stirred under nitrogen atomosphere for 20 min. A solution of 7.3 g (23.8 mmol) of the
title product of Example 6 in 250 mL of THF was added dropwise, and the reaction
mixture was warmed to RT and stirred overnight. Saturated, aqueous ammonium
chloride was added, and the mixture was extracted with EtOAc, dried over Na2SO4,
filtered, and concentrated to dryness. Purification by flash chromatography over SiO2
using 2% acetone in dichloromethane to 4% acetone as the eluant afforded 4.0 g (49
%) of the first listed title product of this example (higher Rf) and 2.4 g (29 %) of the
second listed title product of this example as white solids.
Physical characteristics of the first listed title product of this example are as
follows: mp 227-229 °C (decomp.), 1H NMR (400 MHz, CD3OD) 8 1.42 (mt, 1H, J =
14), 1.61.(ddd, 1H, J = 3.4, 4.1, 8.8), 1.72 (s, 3H), 1.73-1.82 (m, 2H), 1.84-2.10 (m,
5H), 2.55 (d, 1H, J = 13), 2.83-2.93 (m) and 2.94 (d, 3H, J = 13), 6.10 (d, 1H..J =
8.3), 6.23 (dd, 1H, J = 2.5, 8.4), 6.52-6.55 (m, 3H), 7.00-7.05 (m, 3H); 13C NMR (62
MHz, CD3OD) 8 2.5, 24.1, 27.3, 30.5, 35.8, 36.1, 39.1, 40.2, 42.4, 68.9, 79.5, 82.3,
110.9, 114.7, 125.4, 126.8, 127.5, 130.7, 135.1, 136.9, 138.3, 154.8; MS m/z 346
(M+H)+, 329 (M-OH)+.
Physical characteristics of the second listed title product of this example are as
follows: mp 222-223 °C (decomp.); 1H NMR (400 MHz, CD3OD) 8 1.46 (mt, 1H, J =
14), 1.54-1.60.(m, 1H), 1.83 (s) overlap with 1.75-1.94 (m, 8H), 2.08 (mt, 1H, J = 13),
2.20 (dt, 1H, J = 4, 14), 2.57 (d, 1H, J = 13), 2.88 (t, 2H, J =8.7), 2.94 (d, 1H, J = 13),
6.08 (d, 1H, J = 8.3), 6.20 (dd, 1H, J = 2.4, 8.3), 6.50 (d, 1H, J » 24), 6.53-6.56 (m,
2H), 7.01-7.06 (m, 3H); 13C NMR (62 MHz, CD3OD) 8 1.7, 24.1, 27.4, 27.6, 35.0,
-117-
35.2, 36.4, 39.0, 41.6, 65.5, 76.9, 84.5, 110.8, 114.6, 125.3, 126.8, 127.4, 130.7,
135.0, 136.9, 138.4, 154.7; MS m/z346 (M+H)+, 329 (M-OH)+.
Example 10 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-[2f?-(2a,4aa, 10a(3)j-
A mixture of 975 mg of the first listed title product of Example 9, 195 mg of 10
% Pd/C, and 100 mg K2CO3 in MeOH was shaken under 40 p.s.i. (which is about 2.6
atm) of H2 gas for 16 h. The mixture was filtered through Celite® and concentrated
to afford 945 mg of the title product of this example as a white solid. MS: 368
(M+18)*.
Example 11 Pentanal, 5-[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-2-phenanthrenyl]oxy]-, [4bS-
(4bct,7a,8af3)]-
To a stirring solution of 157 mg of the title compound of Example 314, below,
in 4.8 mL of dioxane and 1.2 ml_ of H20 was added 72 mg of 4-methylmorpholine-Noxide,
0.003 mL of pyridine, and 0.18 ml of 2.5 wt. % OsO4 in f-butanol and the
reaction mixture was stirred for 4 h. To this mixture was added 776 mg of Nal04 and
the resultant mixture was stirred overnight. The reaction mixture was poured into
H2O and extracted with EtOAc. The organic layer was dried over Na2S04, filtered,
and concentrated to dryness. Purification by flash chromatography over SiO2 using
25 % EtOAc in hexanes to 10 % EtOAc in hexanes as the gradient eluant afforded
141 mg of the title product of this example as colorless oil. MS: 417 (M-17)+.
Example 12 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[[5-(4-
morpholinyl)pentyl]oxy]-4a-(phenylmethyl)-2-propyl-, [2R-
(2a,4aa,10ap)]-
To a stirring solution of 34.6 mg of the title product of Example 11 in 1 mL of
AcOH was added 0.014 mL of morpholine and 109 mg of Na2SO4 and the resultant
mixture was stirred for 15 min. To this mixture was added 24 mg of NaHB(OAc)3 and
the resultant mixture was stirred for 1.5 h. The mixture was cooled to 0 °C and sat.
Na2CO3 added until the pH of the mixture was approximately 8 to 9. The reaction
mixture was extracted with EtOAc, dried over Na2S04, filtered, and concentrated to
dryness. Purification by flash chromatography over Si02 using 5 % MeOH in
dichloromethane to MeOH as the eluant afforded 26.6 mg of the title product of this
example as a white solid. MS: 506 (M+1 )*.
Example13 Methanesulfonic acid, trifluoro, 4b, 5, 6, 7, 8, 8a, 9, 10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4bcc, 7a, 8a(3)]-
To a stirring solution of 4.14 g of the first listed title compound of Example 9
(which was prepared by procedures described in Example 9), 1.95 mL of 2,6-lutidine,
and 292 mg of 4-dimethylaminopyridine in 150 mL of dichloromethane at -40 °C
under nitrogen was added 2.6 mL of trifluoromethylsulfonic anhydride. The resultant
mixture was stirred for 0.5 h at -40 °C, 0.5 h at 0 °C, then 1.5 h at RT. The reaction
mixture was poured into 1 N HCL and extracted with dichloromethane. The organic
layer was washed with water, sat. NaHCO3, and brine, dried over Na2S04, filtered,
and concentrated to dryness. Purification by flash chromatography over SiO2 using
15% EtOAc in hexanes to 20% EtOAc in hexane as the gradient eluant afforded 4.4 g
(77%) of the title product of this example as a white solid. 1H NMR (400 MHz, C6D6) 8
6.07 (d, 1 H, J = 8.4), 6.63 (d, 1 H, J = 2.5).
Example 14 2-Phenanthrenecarboxylic acid, 4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-, methyl ester,
[4bS-(4ba,7a,8ap)]-
A mixture of 1.18 g of the title product of Example 13, 0.27 g of 1,3-
bis(diphenylphosphino)-propanol, 2.54 mL of triethylamine, and 0.1 g of palladium
acetate in 40 mL of 1:1 DMF / MeOH was shaken under 60 p.s.i. (which is about 4
atm) carbon monoxide at 70 °C for 4 h. The reaction mixture was concentrated to
remove MeOH. The mixture was poured into 1:1 hexane / EtOAc, washed with 50 %
brine, dried over Na2SO4, filtered, and concentrated to dryness. Purification by flash
chromatography over SiO2 using 23 % EtOAc in hexanes to 28 % EtOAc in hexane
as the gradient eluant afforded 0.79 g (82 %) of the title product of this example as a
white solid. MS: 371 (M-17)+.
Example 15 2-Phenanthrenecarbonitrile, 4b,5,6>7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4ba,7cc,8ap)]-
A stirring mixture of 1.0 g of the title product of Example 13, 0.4 g of
tetrakis(triphenylphosphine)palladium(0), and 0.17 g of zinc(ll)cyanide in 9.5 mL of 1-
methyl-2-pyrrolidinone (NMP) under nitrogen was heated to 90 °C for 4 h. The
reaction mixture was poured into sat. NaHCO3, filtered through Celite®, and
extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography over Si02 using 20%
EtOAc in hexanes to 30 % EtOAc in nexanes as the gradient eluant afforded 0.64 g
(86 %) of the title product of this example as a white solid. MS: 338 (M-17)+.
Example 16 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-7-(2-pyridinyl)-, [2R-
(2a,4aa,10ap)]-
Nitrogen gas was bubbled through a solution 300 mg of the title product of
Example 13, 70 mg of 1,1'-bis(diphenylphosphino)ferrocene, and 28 mg of palladium
acetate in THF for 5 min. Under nitrogen atmosphere, the solution was cooled to -78
°C and 3.78 ml of 0.5 M bromo-2-pyridyl zinc in THF was added. The solution was
warmed to RT then heated to 70 °C overnight. After cooling to RT, sat. NH4CI was
added and the resultant mixture was extracted with EtOAc, dried over Na2S04,
filtered, and concentrated to dryness. Purification by flash chromatography over SiO2
using 20% EtOAc in hexanes as the eluant afforded 173 mg (67 %) of the title
product of this example as a white solid. MS: 408 (M+1)".
Example 17 2-Phenanthrenecarboxylic acid, 4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4ba,7x,8ap)]-
To a stirring solution of 170 mg of the title product of Example 14 in 4 ml of
THF was added 0.26 ml of 2 N KOH and the resultant solution was heated to reflux
for 3 days. An additional 0.75 ml_ of 2 N KOH was added and the mixture was
heated to reflux overnight. The reaction mixture was cooled to RT, diluted with a
small amount of water, and washed with diethyl ether. The aqueous layer was
acidified with 2N HCI and extracted with EtOAc. The organic layer was dried over
Na2SO4, filtered, and concentrated to dryness to yield 155 mg of the title product of
this example as an off-white solid. MS: 357 (M-17)*.
Example 18 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-yV-[3-(1 H-imidazol-1 -yl)propyl]-4b-(phenylmethyl)-7-(1 -
propynyl)-,[4bS-(4ba,7a,8a|3)]-
To a stirring solution of 1 -(3-aminopropyl)imidazole in 1 ml_ of
dichloromethane at 0 °C under N2 was added 0.1 ml_ of 2.0 M trimethylaluminum in
hexane. The mixture was stirred at 0 °C for 20 min. then at RT for 1 h. To this
mixture was added 20 mg of the title compound of Example 14 in 1 ml of
dichloromethane. The mixture was heated to reflux for 6 h then removed from the
heat and stirred at RT for 3 days. To the reaction mixture was added 1 N HCI
dropwise until the aqueous layer was approximately pH 4. The resultant mixture was
extracted with EtOAc, dried over Na2S04, filtered, and concentrated to dryness.
Purification by flash chromatography over Si02 using 5% MeOH in dichloromethane
to 10% MeOH in dichloromethane as the gradient eluant afforded 22 mg (88 %) of
the title product of this example as a white solid. MS: 483 (M+1)+.
Example 19 2-Phenanthrenemethanol, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-a,a-dimethyl-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4ba,7a,8ap)]-
To a stirring solution of 100 mg of the title compound of Example 14 in 2 mL
of THF at 0 °C under N2 was added 0.77 ml of 1 M methyl magnesium bromide in
butyl ether. The mixture was stirred at 0 °C for 2 h, warmed to RT and stirred an
additional 1 h. To the reaction mixture was added 1.2 mL of 1 M methyl magnesium
bromide in butyl ether and the resultant mixture was stirred at RT for 1 h. Sat. NH4CI
was added and the resultant mixture was extracted with EtOAc, dried over Na2SO4,
filtered, and concentrated to dryness. Purification by flash chromatography over SiO2
using 20% EtOAc in hexanes to 30 % EtOAc in hexanes as the gradient eluant
afforded 80.5 mg of the title product of this example as a white solid. MS: 371 (M-
17).
Example 20 2-Phenanthrenemethanol, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4ba,7a,8ap)]-
To a stirring solution of 50 mg of the title compound of Example 14 in 2 mL of
dichoromethane at -78 °C under N2 was added 0.39 mL of 1 M diisobutylaluminum
hydride in hexane and the resultant mixture was stirred for 35 min. Methanol (10
drops) was added dropwise to the reaction mixture followed by 2 mL of sat.
Rochelle's salt. The mixture was extracted with dichoromethane. The organic layer
was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated to
dryness. The resultant solid was washed with a small amount of EtOAc to afford 18
mg of the title product of this example as a white solid. MS: 343 (M-17)+.
Example 21 2-Phenanthrenemethanol, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-, amethanesulfonate,
[4bS-(4ba,7a,8ap)j-
To a stirring solution of 20 mg of the title product of Example 20 (which was
prepared by procedures described in Example 20) in 0.5 ml_ of THF at 0 °C under N2
was added 0.017 ml_ of methanesulfonyl chloride and 0.02 ml of
diisopropylethylamine. After 3 h, the reaction mixture was diluted with EtOAc, washed
with H2O and brine, dried over Na2SO4, filtered, and concentrated to give 18 mg of
the title product of this example as a yellow solid. 1H NMR (400 MHz, C6D6) 6 4.79
Example 22 2-Phenanthrenol, 7-(azidomethyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2a,4acc,10ap)]-
The title product of Example 21 (18 mg) and 20 mg of sodium azide in 0.5 mL
of DMF were heated to 100 °C under N2 for 3 h. The reaction mixture was cooled to
RT, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 20%
EtOAc in hexanes as the eluant afforded 18 mg of the title product of this example as
a white solid. IR (neat) 2098 cm'1; 1H NMR (400 MHz, C6D6) 5 4.24 (s, 2H).
Example 23 2-Phenanthrenol, 7-(aminomethyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2 To a stirring solution of 18 mg of the title product of Example 22 in 1 mL of 2 :
1 :1 THF : MeOH : H2O was added 25 mg of triphenylphosphine and the resultant
mixture stirred at RT for 1.5 h. The reaction mixture was concentrated to a white
residue. To this residue was added diethyl ether and the resultant mixture was
extracted with 1 N HCI. The aqueous layer was taken to pH greater than 10 by the
addition of 15% NaOH, extracted with EtOAc, dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography over Si02 using 5%
MeOH in dichloromethane to 50 % MeOH in dichloromethane with 1 % triethylamine
as the gradient eluant afforded 10 mg of the title product of this example as a white
solid. MS:360(M+ir.
Example24 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(1 H-tetrazol-5-yl)-, [2R-
(2a,4aa,10a(3)]-
To a stirring solution of 42 mg of the title compound of Example 15 in 1 ml of
toluene under N2 was added 4.7 g of dibutyltin oxide and 0.032 ml of
trimethylsilylazide. The resultant mixture was stirred at 90 °C for 7 days then at RT
for 7 additional days. The reaction mixture was concentrated in vacua, dissolved in
MeOH, and concentrated in vacua. The residue was dissolved in EtOAc, washed
with sat. NaHCO3, dried over Na2SO4, filtered, and concentrated to dryness.
Purification by flash chromatography over SiO2 using 10% MeOH in dichloromethane
as the eluant afforded 4 mg of the title product of this example as a white solid. MS:
399 (M+1)+.
Example 25 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-AAmethoxy-AAmethyl-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4ba,7a,8ap)]-
To a stirring solution of 168 mg of the title compound of Example 17 (which
was prepared by procedures described in Example 17) dichloromethane was added
sequentially 53 mg of N,O-dimethylhydroxylamine hydrochloride, 172 mg of 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochlonde, 121 mg of
hydroxybenzotriazole hydrate, and 110 mg of 4-dimethylaminopyridine at RT under
N2. The resultant mixture was stirred at RT overnight, poured into 2 N HCI, and
extracted with EtOAc. The organic layer was washed sequentially with 2 N HCI, H2O,
and sat. NaHCO3, dried over Na2SO4, filtered, and concentrated to dryness.
Purification by flash chromatography over SiO2 using 3% MeOH in dichloromethane
as the eluant afforded 134 mg (71 %) of the title product of this example as a
colorless oil. MS: 418 (M+1)+.
Example 26 1 -Propanone, 1 -[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]-, [4bS-
(4ba,7a,8ap)]-
To a stirring solution of 119 mg of the title product of Example 25 in 1.5 ml_ of
THF at -78 °C under N2 was added 0.86 ml of 1 M ethyl magnesium bromide in THF.
The reaction mixture was stirred at -78 °C for 1 h, 0 °C for 2 h, then RT for 2 h. The
reaction mixture was poured into 5% HCI in EtOH and stirred for 5 min. The resultant
mixture was poured into brine, and extracted with EtOAc. The organic layer was dried
over Na2SO4, filtered, and concentrated to dryness. Purification by flash
chromatography over SiO2 using 15% EtOAc in hexanes to 20% EtOAc in hexane as
the gradient eluant afforded 49.5 mg (48%) the title product of this example as a
white solid. MS: 387 (M+1)+.
Example 27 2-Phenanthrenemethanol, a-ethyl-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-, [4bS*
(4ba,7a,8ap)]-
To a stirring solution of 32.3 mg of the title product of Example 26 in 0.8 ml of
MeOH was added 3.2 mg of NaBH4 and the resultant mixture stirred at RT for 2 days.
An additional 2 mg of NaBH4 was added and the reaction mixture was heated to
reflux for 2 h. After cooling to RT, H2O was added and the mixture concentrated in
vacua to remove MeOH. The resultant mixture was extracted with EtOAc, dried over
Na2SO4, filtered, and concentrated to dryness. Purification by flash chromatography
over SiO2 using 15% EtOAc in hexanes as the eluant afforded 24 mg of the title
product of this example as a colorless oil. MS: 371 (M-17)+.
Example 28 Carbamic acid, [4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]-, 1,1-
dimethylethyl ester, [4bS-(4ba,7a,8a|3)]-
A solution of 124 mg of the title compound of Example 17, 91 mg of
diphenylphosphoryl azide, and 0.046 mL of triethylamine in 1ml_ of f-butanol was
heated to reflux for 16 h. The solution was concentrated in vacua and the resultant
residue was dissolved in EtOAc. The EtOAc solution was washed with 5% citric acid,
H2O, sat. NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated to
dryness. Purification by flash chromatography over SiO2 using 30% EtOAc in
hexanes to 50% EtOAc in hexanes as the gradient eluant afforded 34.1 mg of the title
product of this example as a white solid. MS: 328 (M-17)+.
Example 29 2-Phenanthrenol, 7-amino-1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-, [2ft-(2a,4aa,1 Oap1)]-
To a stirring solution of 20 mg of the title product of Example 28 in 0.5 ml of
dichloromethane was added 0.07 mL of trifluoroacetic acid. The solution was stirred
at RT for approximately 1.5 h. Sat. NaHCO3 was added to the solution. The
resultant mixture was extracted with EtOAc, washed with brine, dried over Na2SO4,
filtered, and concentrated to dryness. Purification by flash chromatography over SiO2
using 20% EtOAc in hexanes as the eluant afforded 7.5 mg of the title product of this
example as a white solid. MS: 328 (M+1)+.
Example 30 2-Phenanthrenecarboxamide, 4b-(2,3-dihydroxypropyl)-
4b,5,6,7,8,8a,9l10-octahydro-7-hydroxy-7-(1-propynyl)-> [4bS-
(4ba,7a,8a(3)j-
To a stirring suspension of 303 mg of 2-phenanthrenecarboxamide,
4b,5,6,7>8,8a,9,10-octahydro-7-hydroxy-4b-(2-propenyl)-7-(1-propynyl)-, [4bS-
(4ba,7a,8ap)]- in 13.5 mL of dioxane and 3.3 ml of H2O was added 186 mg of 4-
methylmorpholine-N-oxide, 0.008 mL of pyridine, and 0.47 mL of 2.5 wt. % OsO4 in fbutanol
and the mixture was stirred at RT overnight. To this mixture was added 1:1
sat. NaHCO3 and sat. NaHSO3. The resultant mixture was extracted with EtOAc,
dried over Na2SO4, filtered, and concentrated to afforded 292 mg of the title product
of this example as a white solid. MS: 358 (M+1)+.
Example 31 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-[(2-oxo-1,3-dioxolan-4-yl)methyl]-7-(1 -propynyl)-,
[4bS-(4ba,7a,8ap)]-
To a stirring solution of 90 mg the title product of Example 30 in
dichloromethane at 0 °C under N2 was added 45 mg of carbonyldiimidazole. The
reaction mixture was warmed to RT and stirred for 3 h. The mixture was
concentrated to dryness and purified by flash chromatography over SiO2 using 3 %
MeOH in dichloromethane to 5% MeOH in dichloromethane as the gradient eluant to
afford 46 mg of the title product of this example as a white solid. MS: 384 (M+1)+.
Example 32 4a(2H)-Phenanthreneacetaldehyde, 2-(chloroethynyl)-
1,3,4,9,10,10a-hexahydro-2,7-dihydroxy-, [2R-(2a,4aa,10ap)]-
To a stirring solution of 1.77 g of the title compound of Example 172, below, in
100 mL of dioxane and 25 mL of H2O was added 1.11 g of 4-methylmorpholine-Noxide,
0.045 mL pyridine, and 2.8 mL of 2.5 wt. % OsO4 in f-butanol and the reaction
mixture stirred for 6 h. To this mixture was added 12 g of NalO4 and the resultant
mixture was stirred overnight. The reaction mixture was poured into H2O and
extracted with EtOAc. The organic layer was dried over Na2S04, filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 30%
EtOAc in hexanes as the eluant afforded 1.04 g of the title product of this example as
a white solid. 1H NMR (400 MHz, D6-acetone) 5 4.8 (s, 2H).
Example 33 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[2-(1-piperidinyl)ethyl]-, [2fr(2a,4aa,10a(3)]-
To a stirring solution of 100 mg of the title product of Example 32 in 1.5 mL of
AcOH was added 0.062 ml of piperidine and 446 mg of Na2SO4 and the resultant
mixture was stirred for 15 min. To this mixture was added 100 mg of NaHB(OAc)3 in
two portions and the resultant mixture was stirred for 1.5 h. The mixture was cooled
to 0 °C and sat. Na2COs added until the pH of the mixture was approximately 8 to 9.
The reaction mixture was extracted with EtOAc, dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 5%
MeOH in dichloromethane to MeOH as the gradient eluant afforded 95 mg of the title
product of this example as a white solid. MS: 388 (M+1)+.
Example 34 4a(2H)-Phenanthreneacetaldehyde, 2-(chloroethynyl)-
1,3,4,9,10,10a-hexahydro-2,7-dihydroxy-, oxime, [2R-
[2a,4aa,10ap]]-
To a stirring solution of 150 mg of the title product of Example 32 in 6 ml of
MeOH was added 147 mg of KHC03 and 141 mg of hydroxylamine hydrochloride.
The reaction mixture was heated to reflux for 3 h then cooled to RT and concentrated
to dryness. Purification by flash chromatography over SiO2 using 5% MeOH in
dichloromethane to 8% MeOH in dichloromethane as the gradient eluant afforded 64
mg of the title product of this example as a white solid. MS: 316 (M-17)+.
Example 35 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(3-phenyl-2-propenyl)-, [2/?-[2a,4aa(E),10ap]]-
To a stirring solution of 410 mg of diethyl benzylphosphonate in 5 mL of THF
at -78 °C under N2 was added 0.65 mL of 2.5 M butyl lithium in hexane. The reaction
mixture was warmed to 0 °C and stirred for 1 h. To the reaction mixture was added
104 mg of the title product of Example 32 in 2 mL of THF and the mixture was stirred
an additional 3.5 h. The reaction mixture was poured into sat. NH4CI, extracted with
EtOAc, dried over Na2SO4> filtered, and concentrated to dryness. Purification by flash
chromatography over SiO2 using 10 % EtOAc in hexanes to 20% EtOAc in hexane as
the gradient eluant afforded 60 mg of the title product of this example as a white
solid. MS:375(M-17)+.
-126-
Example 36 2-Butenoic acid, 4-[2-(chloroethynyl)-1,3,4,9,10,10ahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-, [2ft-
[2a,4aa(E),10ap]]-
To a stirring solution of 2.2 g of the title compound of Example 183, below, in
40 mL of THF was added 11 ml of 2 N KOH and the resultant solution was heated to
reflux for 4 h. The reaction mixture was cooled to RT, diluted with a small amount of
water, and washed with diethyl ether. The aqueous layer was acidified with 2N HCI
and extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to dryness to
yield 1.55 g of the title product of this example as an off-white solid. 1H NMR (400
MHz, CD3OD) 65.66 (d, 1H, J = 15), 6.67-6.80 (m, 1H).
Example 37 Pyrrolidine, 1-[4-[2-(chloroethyny!)-1,3,4,9,10,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1 -oxo-2-butenyl]-, [2ft-
[2a,4aa(E),10ap]]- (Formula F-12: R2 is OH, R3 is
chloroethynyl, R5 is H, R8 is H, R9 is H, R10 is OH, R7, RU, Ris,
R16 are each H, m is 2, R,2 and Ri3 taken together with N are
pyrrolidinyl) Refer to Scheme F.
To a stirring solution of 168 mg of the title product of Example 36 in
dichloromethane was added sequentially 0.67 mL of pyrrolidine, 140 mg of
dicyclohexylcarbodiimide, 91 mg of hydroxybenzotriazole hydrate, and 10 mg of 4-
dimethylaminopyridine at RT under N2. The resultant mixture was stirred at RT
overnight. The mixture was diluted with MeOH, filter through Celite®, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 90%
acetonitrile and 10% dichloromethane with 0.5% to 1 % H2O as the gradient eluant
afforded 90 mg of the title product of this example as a white solid. MS: 414 (M+1)+.
Example 38 4H-Benzo[a]quinolizin-4-one, 1,2,3,6,7,11 b-hexahydro-9-
hydroxy-11 b-(phenylmethyl)-
A solution of 973 mg of 2-(3-hydroxyphenyl)ethylamine hydrobromide and 920
mg of 5-oxo-6-phenyl-hexanoic acid in 3 mL of isopropanol was heated to 210 °C
open to the air for 5 h. The resultant residue was purified by flash chromatography
over SiO2 using 5% MeOH in dichloromethane to 20% MeOH in dichloromethane as
the gradient eluant to afford 774 mg (56%) of the title product of this example as an
off-white solid. MS: 307 (M+1)+.
Example 39 4H-Benzo[a]quinolizin-4-one, 1,2,3,6,7,11 b-hexahydro-9-
(phenylmethoxy)-l 1 b-(phenylmethyl)-
To a stirring solution of 770 mg of the title product of Example 38 in DMF was
added sequentially 3 ml of 1 M potassium f-butoxide in f-butanol followed by 0.35
ml of benzyl bromide. The reaction mixture was heated to 60 °C for 2 h. The mixture
was cooled to room temperature and 1 N HCI was added. The resultant mixture was
extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to dryness.
Purification by flash chromatography over SiO2 using 60% EtOAc in hexanes to
100% EtOAc as the gradient eluant afforded 797 mg (80%) of the title product of this
example as an off-white solid. MS: 398 (M+1)+.
Example 40 2H-Benzo[a]quinolizine-3-carboxylic acid, 1,3,4,6,7,11bhexahydro-
4-oxo-9-(phenylmethoxy)-11 b-(phenylmethyl)-3-
propyl-, methyl ester, (3-cis)-
To a stirring solution of 0.61 ml_ of diisopropylamine in 9 ml_ of THF at 0 °C
under N2 was added 1.75 mL of 2.5 M n-butyl lithium in hexane. The resultant
solution was stirred for 10 min. at 0 °C then cooled to -78 °C. To this solution was
added 790 mg of the title product of Example 39 in 10 mL of THF dropwise over 30
min. The resultant solution was stirred at -78 °C for 30 min., warmed to 0 °C for 2 h,
then cooled to -78 °C. To this solution was added 0.17 ml of methyl chloroformate.
The resultant mixture was stirred for 30 min at -78 °C then warmed to RT and stirred
for 1 h. To the reaction mixture was added 0.42 mL of propyl iodide and the resultant
mixture was stirred at 0 °C for 1 h then warmed to RT for 14 h. To the reaction
mixture was added an additional 0.5 mL of propyl iodide and the resultant mixture
heated to 55 °C for 4 h. The mixture was poured into EtOAc and washed with 1 N
HCI, H2O, sat NaHCO3, and brine. The organic solution was dried over Na2SO^,
filtered, and concentrated to dryness. Purification by flash chromatography over Si02
using 40% EtOAc in hexanes as the eluant afforded 768 mg (78%) of the title product
of this example as an off-white solid. MS: 498 (M+1 )*.
Example 41 2H-Benzo[a]quinolizine-3-methanol, 1,3,4,6,7,11 b-hexahydro-
9-(phenylmethoxy)-11 b-(phenylmethyl)-3-propyl-, (3-c/s)-
To a stirring solution of 50 mg of the title product of Example 40 in 1 mL of
THF was added 3 mL of 1.0 M lithium aluminum hydride in THF. The reaction
mixture was heated to reflux under N2 overnight. The mixture was cooled to 0 °C and
0.12 ml H2O, 0.12 ml 15% NaOH, and 0.36 ml H2O was added slowly and
sequentially with stirring to the reaction mixture. After 5 min of rapid stirring, the
mixture was filtered through Celite® and concentrated to dryness. Purification by
flash chromatography over Si02 using 3% MeOH in dichloromethane to 10% MeOH
in dichloromethane as the gradient eluant afforded 36 mg (79%) of the title product of
this example as a white solid. MS: 456 (M+1)+.
Example 42 2H-Benzo[a]quinolizine-3-methanol, 1,3,4,6,7,11 b-hexahydro-
9-hydroxy-11 b-(phenylmethyl)-3-propyl-, (3-c/s)-
To a stirring solution of 31 mg of the title product of Example 41 in
dichloromethane at -78 °C under N2 was added 0.05 ml of BBr3 and the reaction
mixture allowed to warm to RT. The reaction mixture was cooled to -78 °C and
MeOH was added dropwise to quench the reaction. The mixture was concentrated to
dryness, dissolved in MeOH and concentrated to dryness. Purification by flash
chromatography over SiO2 using 5% MeOH in dichloromethane with 0.1%
triethylamine to 10 % MeOH in dichloromethane with 0.1% triethylamine as the
gradient eluant afforded a white solid. This solid was partitioned between EtOAc and
sat. NaHCO3. The EtOAc layer was dried over Na2SO4, filtered, and concentrated to
afford 10 mg of the title product of this example as a white solid. 1H NMR (400 MHz,
CD3OD) 5 2.45 (d, 1H, J = 12), 2.66 (d, 1H, J = 12).
Example 43 2H-Benzo[a]quinolizine-3-carboxylic acid, 1,3,4,6,7,11 bhexahydro-
9-hydroxy-4-oxo-11 b-(phenylmethyl)-3-propyl-,
methyl ester, (3-ds)-
A mixture of 50 mg of the title product of Example 40, 63 mg of ammonium
formate, and 20 mg of 20% palladium hydroxide on carbon in 5 ml_ of MeOH was
heated to reflux for 3 h. The mixture was cooled to RT, filtered through Celite®, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 50%
EtOAc in hexanes as the eluant afforded 41 mg of the title product of this example as
a white solid. MS: 408 (M+1)+.
Example 44 4H-Benzo[a]quinolizin-4-one, 1,2,3,6,7,11 b-hexahydro-3-
(hydroxymethyl)-9-(phenylmethoxy)-11 b-(phenylmethyl)-3-
propyl-, (3-cis)-
To a stirring solution of 50 mg of the title product of Example 40 in 5 mL of
THF under N2 was added 10 mg of lithium borohydride. The resultant mixture was
stirred for 2 h at RT then warmed to 40 °C and stirred an additional 2 h. After cooling
to RT, sat. ammonium chloride was added and the mixture was extracted with EtOAc.
The EtOAc solution was dried over Na2SCO4, filtered, and concentrated to dryness.
Purification by flash chromatography over SiO2 using 40% EtOAc in hexanes to 80%
EtOAc in hexanes as the gradient eluant afforded 17 mg of the title product of this
example as a white solid. MS: 470 (M+1)+.
Example 45 2(1 H)-Phenanthrenone, 7-(acetyloxy)-3,4,4a,9,10,10ahexahydro-
4a-(phenylmethyl)-, (4aS-frans)-
To a stirring solution of 54 mg of the title compound of Example 6 in 2 ml of
dichloromethane was added 0.037 ml of triethylamine and 0.015 mL of acetyl
chloride and the resultant mixture was stirred overnight. The mixture was poured into
1 N HCI and extracted with dichloromethane. The dichloromethane solution was dried
over Na2SO4, filtered, and concentrated to dryness. Purification by flash
chromatography over SiO2 using 20% EtOAc in hexanes as the eluant afforded 55
mg of the title product of this example. 1H NMR (400 MHz, CDCI3) 5 2.27 (s, 3H)
Example 46 1 H-Benz[e]indene-2-carboxylic acid, 7-(acetyloxy)-
2,3,3a,4,5,9b-hexahydro-9b-(phenylmethyl)-, [2R-
(2a,3acc,9bp)]-
To a stirring solution of 50 mg of the title product of Example 45 in 1 mL of
dichloromethane was added 75 mg of thallium trinitrate • 3H2O under N2 and the
mixture stirred overnight. To the reaction mixture was added an additional 75 mg of
thallium trinitrate • 3H2O and the mixture was again stirred overnight. The mixture
was filtered through Celite® and concentrated to afford the title product of this
example as an off-white solid. MS: 363 (M-1)+.
Example 47 1 H-Benz[e]indene-2-carboxylic acid, 2,3,3a,4,5,9b-hexahydro-
7-hydroxy-9b-(phenylmethyl)-, methyl ester, [2R-
(2a,3acc,9bp)]-
Continuing the procedure began in Example 46, a solution of the title product
of Example 46 in methanol and catalytic sulfuric acid was heated to reflux under a
soxlet extractor filled with 3 angstroms molecular sieves for 4 h. After cooling to RT,
a small amount of solid NaHCO3 was added to the solution, and it was concentrated
to dryness. Purification by flash chromatography over SiO2 using 20% EtOAc in
hexanes as the eluant afforded 28 mg of the title product of this example. MS: 335
(M-1)+.
Example 48 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 H--\ ,2,4-triazol-1-ylmethyl)-, [2R-
(2a,4aa,10ap)]-
A solution of 50 mg of the title compound of Example 79 below (which was
prepared by procedures described in Example 79), 54 mg of 1,2,4-triazole, and 108
mg of potassium carbonate in 4 mL of DMF was heated to 90 °C for 2 h. After
cooling to RT, sat. ammonium chloride was added and the resultant mixture was
extracted with EtOAc. The EtOAc solution was dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 5%
MeOH in dichloromethane as the eluant afforded 50 mg of the title product of this
example as a white solid. MS: 391 (M+1)+.
Example 49 2(1 H)-Phenanthrenone, 4a-(2-butenyl)-3,4,4a,5,8,9,10,10aoctahydro-
7-methoxy-,[4aS-[4aa(E),10a3]]-
Ammonia (200 mL) was condensed into a round bottom flask at -78 °C
equipped with a dry ice reflux condenser at -78 °C and a mechanical stirrer. To this
flask was added 80 mL of f-butanol followed by lithium wire until the solution turned
dark blue. A solution of 5 g of 2(3H)-phenanthrenone, 4a-(2-butenyl)-4,4a,9,1Qtetrahydro-
7-methoxy-, [S-(E)]- in 80 mL of THF was added to the mixture slowly in
order to keep the reaction a dark blue. As the blue color dissipated, a small amount
of lithium wire was added to the mixture to regenerate the blue color. The total
amount of lithium added to the reaction mixture did not exceed 4 g. After the
complete addition of the starting compound the reaction was stirred an additional 40
min, then 100 mL of sat. ammonium chloride was added and immediate dissipation of
the blue color was observed. H2O was added to the mixture and it was extracted with
EtOAc, dried over Na2SO4, filtered, and concentrated to dryness. The crude product
was purified by flash chromatography over SiO2 using 10% EtOAc to 25% EtOAc in
hexanes as the gradient eluant to afford 2.0 g of the title product of this example as a
white solid. MS: 287 (M+1)+.
Example 50 2-Phenanthrenol, 4a-(2-butenyl)-1,2,3,4,4al5,8,9,10,10adecahydro-
7-methoxy-2-(1 -propynyl)-, [2R-[2a,4aa(E),'\Gap1]]-
To a stirring solution of 200 ml of THF saturated with propyne gas at 0 °C
was added 16.4 ml of 2.5 M n-butyl lithium in hexane and the resultant mixture
stirred under nitrogen atomosphere for 20 min. A solution of 1.96 g of the title
product of Example 49 in 50 mL of THF was added dropwise, and the reaction
mixture was warmed to RT and stirred for 40 min. Saturated, aqueous ammonium
chloride was added, and the mixture was extracted with EtOAc, dried over Na2SO4,
filtered, and concentrated to dryness. Purification by flash chromatography over SiO2
using 10% EtOAc in hexanes to 15% EtOAc in hexanes as the eluant afforded 879
mg of the title product of this example as a white solid. MS: 327 (M+1 )*.
Example 51 2(3H)-Phenanthrenone, 4b-(2-butenyl)-
4,4a,4b,5,6)7,8,8a,9,10-decahydro-7-hydroxy-7-(1-propynyl)-,
[4af?-[4aa,4b(3(£),7p,8aa]]- and 2(1 H)-Phenanthrenone, 4b-(2-
butenyl)-3,4,4b,5,6,7,8,8a,9,10-decahydro-7-hydroxy-7-(1-
propynyl)-, [4bS-[4ba(E),7cc,8ap]]-
Continuing the procedures began in Example 50, to a stirring solution of the
title product of Example 50 in 20 mL of THF was added 1 ml of 2 N HCI. After 3 h at
RT, sat. NaHCO3 was added and the mixture was extracted with EtOAc. The organic
layer was dried over Na2SO4l filtered, and concentrated to dryness. Purification by
flash chromatography over SiO2 using 20% EtOAc in hexanes to 35% EtOAc in
hexanes as the gradient eluant afforded 154 mg of the second listed title product of
this example as a white solid. MS: 313 (M+1)+. Further purification of lower Rf
material by flash chromatography over SiO2 using 3% acetone in dichloromethane to
4% acetone in dichloromethane as the gradient eluant afforded 215 mg of the first
listed title product of this example as a white solid. MS: 313 (M+1)+.
Example 52 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-[[4-
[(methylsulfonyl)oxy]phenyl]methyl]-2-propyl-, 7-
methanesulfonate,(4aS,10aS)-; and 2,7-Phenanthrenediol,
1,2,3,4,43,9,10,1 Oa-octahydro-4a-[[4-[(methylsulf onyl)oxy]
phenyl]methyl]-2-propyl-, (4aS,10aS)-
To a stirring solution of 50 mg of 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,103-
octahydro-4a-[(4-hydroxyphenyl)methyl]-2-propyl-, (4aS,103S)- in 0.039 mL of
triethylamine and 3 mL of anhydrous THF was added slowly 0.011 mL of MeSO2CI 3t
0 °C under N2 atmosphere. The reaction was allowed to warm to RT for 2 h, then
quenched with wster. The mixture was extracted with EtOAc (X3), washed with brine,
dried over Na2S04, filtered and concentrated to dryness. Purification by flash
chromatography over SiO2 using 25% EtOAc in hexanes to 45% EtOAc in hexanes
as the gradient eluant afforded 18 mg of the second listed title product of this
example and 35 mg of the first listed title product of this example as white powder.
MSm/z540(M+NH4)+.
Example 53 1-Piperazinecarboxamide, A/-[4-[[1,3,4,9,10,1 Oa-hexahydro-
2,7-dihydroxy-2-(1-propynyl)-4a(2/-y)-phenanthrenyl]methyl]
phenyl]-4-methyl-,(4aS,10afl)-
To a stirring solution of 97 mg of carbamic acid, [4-[[1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-2-(1 -propynyl)-4a(2/-/)-phenanthrenyl]methyl]phenyl]-, 1,1-
dimethylethyl ester, [2/7-(2ct,4aa,10ap)]- in 0.078 ml_ of 1-methylpiperazine and 5 mL
of anhydrous THF under N2 atmosphere was added 0.56 ml of 2.5 M n-BuLi and the
mixture was heated to 65 °C. After 2 h, the reaction was quenched with NH4CI (sat),
extracted with EtOAc (X3), washed with brine, dried over Na2SO4, filtered and
concentrated to dryness. Purification by flash chromatography over SiO2 using 5%
MeOH in CH2CI2 as the elutant afforded 40 mg (40%) of the title product of this
example as white fluffy powder. MS m/z472 (M-Me)*.
Example 54 Acetic acid, [4-[[1,3,4,9,10,1 Oa-hexahydro-2-hydroxy-7-(2-
methoxy-2-oxoethoxy)-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenoxy]-, methyl ester,[2R-
(2a,4aa,10ap)]-
A solution of 50 mg of 2,7-phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-
4a-[(4-hydroxyphenyl)methyl]-2-(1-propynyl)-, [2R-(2a,4aa, 10ab)]- in 5 ml anhydrous
CH3CN, 109.5 mg of Cs2CO3 and 0.067 mL of methyl bromoacetate was stirred at RT
under N2 atmosphere overnight. The reaction was quenched with NH4CI (sat.),
extracted with EtOAc (X3), washed with brine, dried over Na2SO4, filtered and
concentrated to dryness. Purification by SiO2 preparative TLC using 45% EtOAc in
hexanes as the elutant afforded 20 mg (28%) of the title product of this example as
white fluffy powder. MS m/z489 (M-17)+.
Example 55 Acetamide, 2-[4-[[7-(2-amino-2-oxoethoxy)-1,3,4,9,10,10ahexahydro-
2-hydroxy-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenoxy]-, [2/?-(2a,4aa,1 Oaf3)]-
A solution of 17 mg of the title product of Example 54 in 2 mL of NH4OH (aq),
0.5 mL of toluene and 10 drops of MeOH was heated at 60 °C overnight. The
reaction was quenched with NH4CI (sat.), extracted with EtOAc (X3), washed with
brine, dried over Na2S04, filtered and concentrated to dryness. Purification by flash
chromatography SiO2 using 2% MeOH in CH2CI2 to 4% MeOH in CH2CI2 as the
elutant afforded 5 mg (30%) of the title product of this example as white fluffy powder.
MSm/z478(M+H)+.
Example 56 2(1 H)-Phenanthrenone, 4a-[[3-(dimethylamino)phenyl]methyli]-
3,4,4a,9,10,10a-hexahydro-7-hydroxy-, (4aS-c/s)-. See also
Preparation 5 above.
Example 57 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-(1-
propynyl)-4a-[[4-(4H-1,2,4-triazol-4-yl)phenyl]methyl]-, [2ft-
(2a,4aa,10ap)]-
A solution of 50 mg of the title product of Example 776, below, 20 mg of
dimethyl formamideazine and 3 mg of p-toluenesulfonic acid in 5 ml_ of toluene was
refluxed overnight. The reaction was quenched with NaHCO3(sat.), extracted with
EtOAc (X3), washed with brine, dried over Na2SO4, filtered and concentrated to
dryness. Purification by flash chromatography SiO2 using 1°o MeOH in CH2CI2 to 5%
MeOH in CH2CI2 as the elutant afforded 18 mg (31%) of the title product of this
example as white fluffy powder. MS m/z398 (M-Me)V
Example 58 4-Morpholinecarboxylic acid, 7-(chloroethynyl)-
4b,5f6,7,8,8a,9l10-octahydro-7-hydroxy-4b-(phenylmethyl)-2-
phenanthrenyl ester, (AbS.Baty-
To a solution of 50 mg of 2,7-phenanthrenediol. 2-(chloroethynyl)-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-. (2S(2u.4aa,10ap)]-, in 3 ml of
anhydrous THF was added 0.019 mL of triethylamine. 1.7 mg of DMAP and followed
by slow addition of 0.020 mL of 4- morpholinecarbonyl chloride at 0 °C under N2
atmosphere. The reaction was warmed up to RT for 4 h and then quenched with
NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over Na2S04,
filtered and concentrated to dryness. Purification by flash chromatography SiO2 using
2% EtOAc in hexanes to 30% EtOAc in hexanes as the gradient elutant afforded 57
mg (85%) of the title product of this example as white fluffy powder. MS m/z480 (M)*.
Example 59 Carbamic acid, [2-(dimethylamino)ethyl]-, 4b-[[3-
(dimethylamino)phenyl]methyl]-4b, 5, 6, 7, 8, 8a, 9,10-
octahydro-7-hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,
[4bS-(4ba,7a,8ap)]-
A solution of 68 mg of 2,7-phenanthrenediol, 4a-[[3-(dimethylamino)phenyl]
methyl]-1,2I3,4,4a,9,10l10a-octahydro-2-(1-propynyl)-l (4aS,10afl)- in 64 mg of
triphosgene, 0.03 ml of triethylamine and 2 ml of anhydrous dichloromethane was
stirred at RT for 1.5 h under N2 atmosphere. To the mixture, 0.099 ml of N, Ndimethyletnylenediamine
was added dropwise and stirred overnight under N2
atmosphere. The reaction was quenched with NH4CI (sat.), extracted with EtOAc
(X3), washed with brine, dried over Na2SO4, filtered and concentrated to dryness.
Purification by flash chromatography SiO2 using 100% CHCI3 and 0.1% of
triethylamine to 2% EtOH in CHCI3 and 0.1% of triethylamine as the gradient elutant
afforded 20 mg (23%) of the title product of this example as white fluffy powder. MS
m/z504(M+H)+.
Example 60 2-Phenanthrenol, 4a-[[3-(dimethylamino)phenyl]methyl]-
1,2,3,4,4a,9,10,1 Oa-octahydro-7-(2-hydroxyethoxy)-2-(1 -
propynyl)-, [2F?-(2a,4act,10ap)]-
To a solution of 76 mg of 2,7-phenanthrenediol, 4a-[[3-(dimethylamino)phenyl]
methyl]-1,2,3,4,4a,9,10,10a-octahydro-2-(1-propynyl)-, (4aS,10a/?)- in 3 ml_
anhydrous DMF was added 1.4 mg of TBAI and 17 mg of ethylene carbonate, and
the mixture was heated to 100 °C for 2 h. The reaction was quenched with water,
extracted with EtOAc (X3), washed with brine, dried over Na2SO4, filtered and
concentrated to dryness. Purification by flash chromatography Si02 using 5% EtOAc
in hexanes and 0.1% of triethylamine to 40% EtOAc in hexanes and 0.1% of
triethylamine as the gradient elutant afforded 30 mg (36%) of the title product of this
example as white fluffy powder. MS m/z435 (M+H)+.
Example 61 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-7-[(3-pyrazinyl-1,2,4-oxadiazol-
5-yl)methoxy]-, [2fl-(2a,4aa,10ap)]-
To a solution of 29 mg of acetic acid, [[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-, methyl ester, [4bS-
(4ba,7a,8ap)]- and 19.5 mg of pyrazine-2-carboxamide oxime in 3 ml. of anhydrous
THF was added 24 mg of NaH (60%) and refluxed overnight. The reaction was
cooled to RT, filtered and concentrated to dryness. Purification by preparative TLC
SiO2 using 5% MeOH in dichloromethane as the elutant afforded 7 mg (20%) of the
title product of this example . MS m/z 507 (M+H)+.
Example 62 2-Phenanthrenol, 7-[(5-amino-1 H-1,2,4-triazol-3-yl)methoxy]-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-(1-
propynyl)-,(4aS,10aR)-
To a cooled (0 °C) solution of NaOMe prepared from 7 mg of sodium and 1
mL of anhydrous MeOH was added 40 mg of amino guanidine nitrate. Then 30 mg
acetic acid, [[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-
propynyl)-2-phenanthrenyl]oxy]-, methyl ester, [4bS-(4ba,7a,8a(3)]-in 1 mL of
anhydrous MeOH was added dropwise to the resultant mixture and refluxed under N2
atmosphere overnight. The mixture was concentrated to dryness and purified with
preparative TLC using 10% MeOH in dichloromethane as the elutant to yield 11 mg
of the title product of this example (33%) as white fluffy powder. MS m/z443 (M+H)+.
Example 63 Acetic acid, [[4^5,6,7,8,83,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]oxy]-, [4bS-
(4ba,7a,8ap)]-
A solution of 20 mg of acetic acid, [[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-
4b-(phenylmethyl)-7-(1-propynyl)-2-phen3nthrenyl]oxy]-, methyl ester, [4bS-(4ba,
7a,8a3)]- and 5.36 mg of KOH in 3 mL of MeOH and 0.5 mL of H2O was heated at 80
°C for 4 h. The reaction was cooled to RT, extracted with EtOAc (X3), washed with
brine, dried over Na2SO4, filtered and concentrated to dryness. Purification by a plug
of SiO2 using 5% MeOH in CH2CI2 as the elutant afforded 18 mg (93%) of the title
product of this example as white fluffy powder. MS m/z387 (M-17)+.
Example 64 Acetonitrile, [[4b)5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]oxy]-, [4bS-
(4ba,7a,8a3)]-
To a solution of 54 mg of the first listed title product of Example 8 (which was
prepared by procedures analogous to those described in Example 8) and 8 mg of
60% NaH in 5 mL of anhydrous CH3CN was added 0.056 mL bromoacetonitrile under
N2 atmosphere. The reaction was heated to 85 °C overnight. The reaction was
quenched with NH4CI (sat), extracted with EtOAc (X3), washed with brine, dried over
Na2SO4, filtered and concentrated to dryness. Purification by flash chromatography
SiO2 using 0.5% acetone in CH2CI2 to 1% acetone in CH2CI2 as the gradient elutant
afforded 46 mg (76%) of the title product of this example as white fluffy powder. MS
m/z(M-17)+.
Example 65 2-Phenanthrenol, 7-(2-bromoethoxy)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2a,4aa,10ap)]-
To a solution of 5 mg of the first listed title product of Example 8 and 7 mg of
60% NaH in 5 ml_ of anhydrous CH3CN was added 0.125 ml 1,2-dibromoethane
under N2 atmosphere. The reaction was heated to 85 °C overnight. The reaction was
quenched with NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over
Na2SO4, filtered and concentrated to dryness. Purification by flash chromatography
SiO2 using 2% EtOAc in hexanes to 20% EtOAc in hexanes as the gradient elutant
afforded 29 mg (44%) of the title product of this example as white fluffy powder. MS
m/z453(M+H)+.
Example 66 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(1 /-f tetrazol-5-ylmethoxy)-,
[2fl-(2a,4aa,10ap)]- (Refer to Scheme B: B-7 -> B-10)
A solution of 0.019 ml of TMSN3 and 0.067 ml of MesAI in 5 ml of
anhydrous toluene was stirred at 0 °C under N2 atmosphere. To the resultant solution
was added 43 mg of the title product of Example 64 in 1 ml of toluene slowly to keep
the temperature below 5 °C. The reaction was then allowed to warm to RT and
heated to 80 °C overnight. The reaction was cooled to 0 °C and quench with 5 L of
10% HCI and 5 mL of EtOAc. The aqueous phase was acidified with 1 N HCI to pH
around 3 and extracted with EtOAc (X3), dned over Na2SO4, filtered and
concentrated to dryness. Purification by flash chromatography SiO2 using 1 % MeOH
in CH2CI2 and a couple of drops of AcOH to 10% MeOH in CH2CI2 and a couple of
drops of AcOH as the gradient elutant afforded 17 mg (36%) of the title product of
this example as white fluffy powder. MS m/z427 (M-H)*.
Example 67 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[2-(4-methyl
-1 -piperazinyl)ethoxy]-4a-(phenylmethyl)-2-(1 -propynyl)-, [2f?-
(2a,4aa,10ap)]-
To a solution of 30 mg of the title product of Example 65 (which was
prepared by procedures described in Example 65), 8 mg of anhydrous Na2CO3 and
12 mg of Nal in 2 ml of anhydrous DMF was added 0.015 mL of 1-methylpiperazine
under N2 atmosphere. The reaction was heated to 60 °C overnight. The reaction was
quenched with NaHCO3 (sat.), extracted with EtOAc (X3), washed with brine, dried
over Na2SO4, filtered and concentrated to dryness. Purification by preparative TLC on
SiO2 using 5% MeOH in methylene chloride as the elutant afforded 19 mg (60%) of
the title product of this example as white fluffy powder. MS m/z473 (M+H)+.
Example 68 Ethanimidamide, /V-hydroxy-2-[[4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyljoxy]-, [4bS-(4ba,7a,8a0)]-
To a solution of 30 mg of the title product of Example 64 and 22 mg of K2C03
in 2 ml of anhydrous EtOH was added 8 mg of NH2OH.HCI and heated to reflux for 6
h. The reaction was then concentrated to dryness and purified by preparative TLC
using 5% MeOH in CH2CI2 as the elutant to yield 11 mg of the title product of this
example as white powder (34%). MS m/z419 (M+H)+.
Example 69 2-Phenanthrenol, 7-[[5-[(dimethylamino)methyl]-1,2,4-
oxadiazol-3-yl]methoxy]-1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-,[2/:?-(2a,4aa,10ap)]-
A solution of 30 mg of the title product of Example 68 (which was prepared by
procedures described in Example 68) and 3 mg of 60% NaH in 3 ml_ of anhydrous
THF was heated to 60 °C for 20 min. The solution was cooled to RT and 0.02 mL of
ethyl-N, N-dimethyl glycine was added to the solution. The resultant mixture was
heated to reflux for 1 h then cooled to RT, filtered and concentrated to dryness.
Purification by preparative TLC using 10% acetone in CH2CI2 and 0.05% of NH4OH
as the elutant yielded 4 mg of the title product of this example (11%). MS m/z486
(M+H)*.
Example 70 1,2,4-Oxadiazol-5(2W)-one, 3-[[[4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]methylJ-,[4bS(4ba,7a,8ap)]-
To a solution of 30 mg of the title product of Example 68 (which was prepared
by procedures described in Example 68), 0.006 mL of pyridine a and 1 mL of
anhydrous DMF in 2 mL of xylene was slowly added 0.014 mL of 2-ethyl hexyl
chloroformate at 0 °C under N2 atmosphere. After the reaction was stirred for 30 min,
it was diluted with water, extracted with EtOAc (X3), washed with brine, dried over
Na2SO4, filtered and concentrated to dryness. The residue was dissolved in xylene
and refluxed for 2 days. The mixture was then concentrated to dryness and purified
by preparative TLC on SiO2 using 5% MeOH in methylene chloride as the elutant to
afford 6 mg (19%) of the title product of this example. MS m/z443 (M-H)+.
Example 71 1,2,4-Oxadiazole-5(2H)-thione, 3-[[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyl]oxy]rnethyl]-,[4bS-(4ba,7a,8a(3)]-
To a solution of 20 mg of the title product of Example 68 (which was prepared
by procedures described in Example 68) and 0.029 mL of DBU in 2 ml of anhydrous
CH3CN was added 14 mg of 1,1 -thiocarbonyldiimidazole at RT and stirred for 1.5 h.
The solution was diluted with water, adjusted to pH around 4 with 10% HCI, extracted
with EtOAc (X3), washed with brine, dried over Na2SO4, filtered and concentrated to
dryness. Purification by preparative TLC on SiO2 using 5% MeOH in methylene
chloride as the elutant afforded 12 mg (54%) of the title product of this example as
white fluffy powder. MS m/z459 (M-H)*.
Example 72 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[[5-[2-(4-
morpholinyl)ethyl]-1,2,4-oxadiazol-3-yl]methoxy]-4a-
(phenylmethyl)-2-(1-propynyl)-,[2f?-(2a,4aa,10ap)]-
To a solution of 30 mg of the title product of Example 68 (which was prepared
by procedures described in Example 68) and 3 mg of 60% NaH in 3 mL of anhydrous
THF was added 0.023 mL of methyl 4-morpholine propionate and heated to reflux for
2 h. The solution was cooled, filtered, concentrated to dryness and purified by
preparative TLC using 20% acetone in CH2CI2 and a few drops of NH4OH as the
elutant to afford 14 mg of the title product of this example (36%) as white fluffy
powder. MS m/z542 (M+H)+.
Example 73 Carbamothioic acid, dimethyl-, S-[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl] ester, [4bS-(4ba,7a,8a(3)]-
A solution of 55 mg of carbamothioic acid, dimethyl-, O-[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl] ester, [4bS-
(4ba,7a,8ab)]- of in 2 mL of phenol ether was refluxed overnight under N2
atmosphere. The solution was concentrated to dryness and purified by preparative
TLC using 2% MeOH in CH2CI2 as the elutant to yield 5 mg of the title product of this
example. MS m/z434 (M+H)+.
Example 74 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(pyrazinyloxy)-, [2R-
(2a,4aa,10a3)]-
To a solution of 30 mg of the first listed title product of Example 8 (which was
prepared by procedures described in Example 8) and 4 mg of 60% NaH in 2 mL of
anhydrous DMF was added 0.01 ml of chloropyrazine at 0 °C under N2 atmosphere.
The reaction was then heated to 60 °C for 2 h. The reaction was quenched with
NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over Na2S04,
filtered and concentrated to dryness. Purification by flash chromatography SiO2 using
2% EtOAc in hexanes to 25% EtOAc in hexanes as the gradient elutant afforded 20
mg (54%) of the title product of this example as white fluffy powder. MS m/z 426
(M+2)+.
Example 75 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[[2-(4-
morpholinyl)-4-pyrimidinyl]oxy]-4a-(phenylmethyl)-2-(1-
propynyl)-, [2fl-(2a,4aa,10ap)]-
A solution of 12 mg of 2-phenanthrenol, 7-[(4-chloro-2-pyrimidinyl)oxy]-
1,2,3,4I4a,9,10)10a-octahydro-4a-(phenylmethyl)-2-(1-propynyl)-, [2R-
(2a,4aa,10a(3)]-and 0.011 mL of morpholine in 2 mL of anhydrous THF was heated at
65°C overnight under N2 atmosphere. The reaction was quenched with NH4CI (sat.),
extracted with EtOAc (X3), washed with brine, dried over Na2SO4, filtered and
concentrated to dryness. Purification by preparative TLC SiO2 using 50% EtOAc in
hexanes as the elutant afforded 10 mg (75%) of the title product of this example as
white fluffy powder. MS m/z 510 (M+H)+.
Example 76 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]-
To a solution of 30 mg of the first listed title product of Example 8 (which was
prepared by procedures described in Example 8) and 8 mg of 60% NaH in 2 mL of
anhydrous DMF was added 18 mg of 3-picolyl chloride hydrochloride at RT under N2
atmosphere overnight. The reaction was quenched with NH4CI (sat.), extracted with
EtOAc (X3), washed with brine, dried over Na2SO4, filtered and concentrated to
dryness. Purification by preparative TLC Si02 using 4% MeOH in CH2CI2 as the
elutant afforded 32 mg (80%) of the title product of this example as white fluffy
powder. MS m/z 438 (M+H)+.
Example 77 2(1 H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-(phenylmethyl)-, Oethyloxime
To a solution of 150 mg of the first listed title product of Example 8 (which was
prepared by procedures described in Example 8) and 80 mg of sodium acetate in 5
mL of EtOH was added 96 mg of O-ethylhydroxylamine hydrochloride and heated to
70 °C for 30 min. The solution was concentrated to dryness and purified by flash
chromatography SiO2 using 5% EtOAc in hexanes with 0.1% of Et3N to 7% EtOAc in
hexanes with 0.1% of Et3N as the gradient elutant afforded 148 mg (86%) of the title
product of this example as white fluffy powder. MS m/z350 (M+H)+.
Example 78 2-Phenanthrenol, 4b,5,6,7,8,8a,9,10-octahydro-4b-[(4-
hydroxyphenyl)methyl]-7-propylidene-, [4bS-(4ba,7Z,8aa)]-
A solution of 170 mg of propyltriphenylphosphonium bromide in 3 ml of
anhydrous DMSO was added dropwise 0.44 mL of 1M sodium
bis(trimethylsilane)amide in ether at RT under N2 atmosphere for 10 min. To the
resultant solution was added 35 mg of the title product of Preparation 17 in 1.5 mL
DMSO dropwise and the mixture was heated at 70 °C overnight. The reaction was
quenched with NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over
Na2SO4, filtered and concentrated to dryness. Purification by flash chromatography
SiO2 using 10% EtOAc in hexanes to 25% EtOAc in hexanes as the gradient elutant
afforded 34 mg (89%) of the title product of this example as white fluffy powder. MS
m/z349(M+H)*.
Example 79 Spiro[oxirane-2,2'(1 'H)-phenanthren]-7'-ol, 3',4I,4laI9I,10l,10Iahexahydro-
4'a-(phenylmethyl)-, [2'ff-(2'a,4'acx, 10'ap1 )]-
To a solution of 91 mg of trimethyl sulfonium iodide in 1 mL of anhydrous
DMF was added 55 mg of t-BuOK at 0 °C under N2 atmosphere and the mixture was
stirred for 5 min. To the resultant solution was added 20 mg of the title product of
Example 6 in 1 mL of DMF slowly and stirred for another 1 h at 0 °C. The reaction
was quenched with NH4CI (sat), extracted with EtOAc (X3), washed with brine, dried
over Na2S04, filtered and concentrated to dryness. Purification by flash
chromatography SiO2 using 100% CH2CI2 to 2% acetone in CH2CI2 as the gradient
elutant afforded 13 mg (70%) of the title product of this example as white fluffy
powder. MS m/z303 (M-17)+.
Example 80 2-Phenanthreneacetonitrile, 1,2,3,4,4a,9,10,1 Oa-octahydro-
2,7-dihydroxy-4a-(phenylmethyl)-, (AaSOaR)-, -2R-,
A solution of 9 mg of the title product of Example 79 and 22 mg of potassium
cyanide in 1 mL of ethylene glycol was heated at 100 °C for 2 h. The reaction was
cooled and diluted with water, extracted with EtOAc (X3), washed with brine, dried
over Na2SO4, filtered and concentrated to dryness. Purification by preparative TLC
SiO2 using 35% EtOAc in hexanes as the elutant afforded 5 mg (51%) of the title
product of this example as white fluffy powder. MS m/z330 (M-17)*.
Example 81 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
(methoxymethyl)-4a-(phenylmethyl)-, [2R-(2a,4acc,10ap)]-
A solution of 20 mg of the title product of Example 79 (which was prepared by
procedures described in Example 79) and 0.071 ml of 25% (w/w) sodium methoxide
in 5 ml of anhydrous MeOH was heated to reflux for 3 h. The reaction was cooled
and quenched with NH4CI(sat.), extracted with EtOAc (X3), washed with brine, dried
over Na2SO4, filtered and concentrated to dryness. Purification by preparative TLC
SiO2 using 30% EtOAc in hexanes as the elutant afforded 15 mg (69%) of the title
product of this example as white fluffy powder. MS m/z335 (M-17)+.
Example 82 2,7-Phenanthrenediol, 2-(azidomethyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2F?-(2a,4aa,1 Oa[3)]-
A solution of 20 mg of the title product of Example 79 (which was prepared by
procedures described in Example 79), 20 mg of sodium azide and 17 mg of NH4CI in
0.8 mL of MeOH and 0.1 mL of water was heated to reflux for 3 h. The reaction was
cooled and diluted with NH4CI (sat.), extracted with EtOAc (X3), washed with brine,
dried over Na2SO4, filtered and concentrated to dryness. Purification by preparative
TLC SiO2 using 27% EtOAc in hexanes as the elutant afforded 15 mg (66%) of the
title product of this example as white fluffy powder. MS m/z348 (M-17)+.
Example 83 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-(4-
morpholinylmethyl)-4a-(phenylmethyl)-, [2fl-(2a,4aa,1 Oap)]-
A solution of 20 mg of the title product of Example 79 (which was prepared by
procedures described in Example 79) and 0.055 mL of morphiline in 1 mL of
anhydrous MeOH was heated to reflux for 2 h. The reaction was cooled and diluted
with NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over Na2S04,
filtered and concentrated to dryness. Purification by preparative TLC Si02 using 5%
MeOH in methylene chloride as the elutant afforded 14 mg (55%) of the title product
of this example as white fluffy powder. MS m/z408 (M+H)+.
The following compounds were prepared by using methods analogous to
those described in Example 8 above.
Example 84 Piperidine, 4-[[2-(chloroethynyl)-1,3,4,9,10,1 Oa-hexahydro-2,7-
dihydroxy-4a(2H)-phenanthrenyl]methyl]-1-(methylsulfonyl)-,
[2fl-(2a,4acc,10a|3)]-, m.p. = 124-127°C.
Example 85 Piperidine, 4-[[2-(chloroethynyl)-1,3,4,9,10,10a-hexahydro-2,7-
dihydroxy-4a(2H)-phenanthrenyl]methyl]-1-(ethylsulfonyl)-,
[2fl-(2a,4aa,10ap)]-, m.p. = 174-176°C.
Example 86 Piperidine, 4-[[2-(chloroethynyl)-1,3,4,9,10,10a-hexahydro-2,7-
dihydroxy-4a(2H)-phenanthrenyl]methyl]-1-(2-thienylsulfonyl)-,
[2fl-(2a,4aa,10ap)]-, m.p. = 145-148°C.
Examples 87-90
The following compounds were prepared by using methods analogous to
those described in Example 35 above.
Example 87 Benzoic acid, 4-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2/-/)-phenanthrenyl]-1-propenyl]-,
methyl ester, [2f?-[2a,4aa(£),10a(3]]-, m.p. = 199-208°C (dec).
Example 88 Benzoic acid, 3-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-propenyl]-,
methyl ester, [2fl-[2a,4aa(E),10ap]]-, m.p. = 93-95 °C.
Example 89 4-Thiazolecarboxylic acid, 2-[3-[2-(chloroethynyl)-
1,3,4,9,10>10a-hexahydro-2,7-dihydroxy-4a(2H)-
phenanthrenyl]-1-propenyl]-, ethyl ester, [2R-
[2a,4aa(£),10ap]]-, MS: 472.
Example 90 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[3-[4-(hydroxymethyl)phenyl]-2-propenyl]-, [2R-
[2a,4aa(£),10ap]]-, MS: 405 (M-18)+
Example 91 Benzoic acid, 4-[3-[2-(chloroethynyl)-1,3,4,9,10,10ahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-propenyl]-,
[2R-[2a,4aa(£),10a|3]]-
To a stirred solution of the title compound of Example 87 in methanol (9 ml)
was added a solution of potassium hydroxide (250mg) in water (0.6mL) and the
resulting solution was refluxed for 3 h. The reaction was allowed to cool to room
temperature, saturated aqueous ammonium chloride was added and the mixture was
extracted with ethyl acetate (3x). The combined organic layers were dried over
magnesium sulfate and concentrated in vacuo to afford the title compound of this
example as an off-white solid, 381 mg. mp 145-146 °C (dec).
Example 92 Morpholine, 4-[4-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-
propenyl]benzoyl]-, [2ft-[2a,4aa(E),10ap]]-
To a stirred solution of the title product of Example 91 (100 mg) and Nhydroxysuccinimide
(26 mg) in dioxane (2.3 ml) at 0 °C was 1,3-
dicyclohexylcarbodiimide (47 mg) and the resulting solution was allowed to warm to
room temperature and stirred for 3 h. Acetonitrile (10 mL) was added and the
resulting slurry was filtered through Celite®. Concentration of the filtrate afforded an
oil (170 mg), which slowly crystallized upon standing. The solid residue and
morpholine (0.08ml) were suspended in acetonitrile (3.5 mL) and heated at 50 °C for
3 h. Saturated aqueous ammonium chloride was added, extracted with ethyl acetate
(3x), the organic layers combined, dried over sodium sulfate and concentrated in
vacuo to afford a foam. Flash chromatography on silica gel (1:1 to 3:1 ethyl
acetate:hexanes) afforded the title compound of this example as an off-white foam,
60mg. m.p. = 129-136 °C, MS: 506.
Examples 93-100
The following styryl amide compounds were prepared using procedures
analogous to those described above in Examples 91 and 92.
Example 93 Piperazine, 1 -[4-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-
propenyl]benzoyl]-4-methyl-, [2fl-[2a,4aa(E),10ap]]-MS: 519
Example 94 4-Piperidinol, 1-[4-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-
propenyl]benzoyl]-, [2/^[2a,4aa(E),10ap]]-MS: 520
Example 95 Benzamide, 4-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1 -propenyl]-, [2R-
[2 Example 96 Benzoic acid, 3-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1 -propenyl]-,
[2fl-[2a,4aa(E),10ap]]-m.p. = 101-105°C
Example 97 Morpholine, 4-[3-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-
propenyljbenzoyl]-, [2f?-[2a,4aa(H),10a(3]]-m.p. = 135-141 °C
Example 98 Piperazine, 1-[3-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-
propenyl]benzoyl]-4-methyl-, [2fH[2a,4aa(E),10a|3]]- MS: 519
Example 99 4-Piperidinol, 1-[3-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenylJ-1-
propenyl]benzoyl]-, [2fl-[2a,4aa(E),10a|3]]-MS: 520
Example 100 Morpholine, 4-[[2-[3-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2/H)-phenanthrenyl]-1-propenyl]-4-
thiazolyl]carbonyl]-, [2fl-[2a,4aa(E),10ap]]-MS: 513
Example 101 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[3-[4-(hydroxymethyl)phenyl]-2-propenyl]-, 7-
acetate, [2ff-[2a,4acc(E),10ap]]-
To a stirred solution of 2,7-Phenanthrenediol, 2-(chloroethynyl)-
1,2,3,4,4a,9,10,10a-octahydro-4a-[3-[4-(Nbutyldimethylsiloxymethyl)phenyl]-2-
propenyl]-, [2/?-[2a,4a and sodium hydroxide (60 mg) in dioxane (1 ml_) at 5 °C was added dropwise a
solution of acetyl chloride (57 mg) in dioxane (1 mL). The reaction was allowed to
warm to room temperature and stirred for 2 h. An additional portion of acetyl chloride
(57 mg) was added and stirring was continued an additional 2 h. The reaction was
quenced with aqueous ammonium chloride, extracted with ethyl acetate, the organic
phase dried over sodium sulfate and the filtrate concentrated in vacuo. Flash
chromatography on silica gel (10 to 20% ethyl acetate/hexanes) afforded an oil, 91
mg. To a cooled (0 °C), stirred solution of this oil in tetrahydrofuran (1.6 mL) was
added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.23 mL).
After 2 h, the reaction was quenched with saturated aqueous ammonium chloride,
extracted with ethyl acetate, the organic layer dried over sodium sulfate, concentrated
and flash chromatographed on silica gel (10-50% ethyl acetate/hexanes) to afford the
title compound of this example, 22 mg. mp 73-77 °C.
Example 102 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[3-[4-(4-morpholinylmethyl)phenyl]-2-propenyl]-,
7-acetate, [2f?-[2a,4aa(E),10a(3]]-
To a cooled (0 °C), stirred solution of the title product of Example 101 (40 mg)
(which was prepared by procedures described in Example 101) in tetrahydrofuran
(0.9 mL) were added sequentially methanesulfonyl chloride (39 mg) and
diisopropylethylamine (33 mg). After 2 h, the reaction was cooled to -78 °C,
morpholine (0.12ml_) was added and the reaction solution was allowed to warm to 0
°C. After 4 h, the reaction was quenched with aqueous ammonium chloride,
extracted with ethyl ether, dried over sodium sulfate and concentrated in vacuo to
afford a gum. Flash chromatography on silica gel (40-75% ethyl acetate/hexanes)
afforded the title compound of this example as a colorless gum, 35 mg: MS: 534
Example 103 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,10aoctahydro-
4a-[3-[4-(4-morpholinylmethyl)phenyl]-2-propenyl]-,
[2fl-[2a,4aa(E),10a3]]-
To a suspension of the title product of Example 102 (25 mg) in methanol (0.5
ml) and water (0.25 mL) was added saturated aqueous sodium bicarbonate (0.25
mL) and the reaction mixture was allowed to stir at room temperature for 2 h. The
reaction was quenched with saturated aqueous ammonium chloride, extracted with
ethyl acetate, the organic phase was dried over sodium sulfate and concentrated in
vacuo to afford a colorless solid. Flash chromatography on silica gel (50-100% ethyl
acetate/hexanes) afforded the title compound of this example as a colorless solid, 15
mg: MS: 492
Examples 104-106
The following aminomethyl substituted styryl compounds were prepared using
procedures analogous to those described above in Examples 101-103.
Example 104 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[3-[4-[(4-hydroxy-1-piperidinyl)methyl]phenyl]-2-
propenyl]-, 7-acetate,[2ff-[2a,4aa(H),10ap]]-MS: 548
Example 105 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,103-
octahydro-43-[3-[4-[(4-hydroxy-1-piperidinyl)methyl]phenyl]-2-
propenyl]-,[2fl-[2a,4aa(E),1 Oap"]]-MS: 506
Example 106 2,7-Phenanthrenediol, 2-(chloroethynyl)-4a-[3-[4-
[(dimethyl3mino)methyl]phenyl]-2-propenyl]-
1,2,3,4,4a,9,10,1 Oa-octahydro-, [2R-[2a,4aa(£),10a(3]]-MS:
450.
Example 107 Carbamic acid, dimethyl-, 4b-[2-(4-formylphenoxy)ethyl]-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8a[3)]-
To a stirred solution of the title product of Preparation 10 (1.9 g) in pyridine
(50 ml_) was added p-toluenesulfonyl chloride (2.0 g). After 18 h at room
temperature, the reaction solution was partitioned between ethyl ether and 0.5 N
aqueous sodium hydrogensulfate, the aqueous phase extracted with additional ethyl
ether (2x), the combined organic layers dried over sodium sulfate, concentrated in
vacuo and flash chromatographed on silica gel (50-60% ethyl acetate/hexanes) to
afford a colorless foam, 1.5 g. To a solution of this oil in dimethylformamide (9 ml_)
was added a solution of p-hydroxybenzaldehyde (0.44 g) and potassium t-butoxide (1
M in tetrahydrofuran, 3.3 ml) in dimethylformamide (5 ml, stirred at ambient
temperature for 0.5 h) and the resulting solution was heated at 80 °C for 4 h. The
reaction was cooled, diluted into ethyl ether, washed with water, brine, dried over
sodium sulfate and concentrated in vacuo. The resulting oil was flash
chromatographed to afford the title compound of this example as a colorless foam,
1.3g. MS:476(M+1)+.
Example 108 Carbamic acid, dimethyl-, 4b,5l6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-[2-[4-(4-moipholinylmethyl)phenoxy]ethyl]-7-(1-
propynyl)-2-phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, HCI salt
A solution of the title product of Example 107 (50 mg), acetic acid (7 mg),
morpholine (18 mg) and sodium triacetoxyborohydride (33 mg) in 1,2-dichloroethane
(2 mL) was stirred at room temperature for 3 h. The reaction was quenched with
saturated aqueous sodium bicarbonate, extracted with dichloromethane, the organic
phase was dried over sodium sulfate and concentrated in vacuo to afford an oil.
Flash chromatography on silica gel (ethyl acetate) afforded the title compound of this
example as colorless foam, 50 mg. MS: 547.
Examples 109-129
The following examples were prepared using procedures analogous to those
described above in Examples 107 and 108.
Example 109 Carbamic acid, dimethyl-, 4b-[2-[4-
[(dimethylamino)methyl]phenoxy]ethyl]-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-7-(1-propynyl)-2-phenanthrenyl
ester,[4bS-(4ba,7a,8ap)]-, HCI salt, MS: 505
Example 110 Carbamic acid, dimethyl-, 4b-[2-[4-
[(ethylamino)methyl]phenoxy]ethyl]-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-7-(1-propynyl)-2-phenanthrenyl
ester,[4bS-(4ba,7a,8ap)]-, HCI salt, MS: 505
Example 111 Carbamic acid, dimethyl-, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-[2-[4-[(methylamino)methyl]phenoxy]ethyl]-7-(1-
propynyl)-2-phenanthrenylester, [4bS-(4ba,7a,8ap)]-, HCI salt,
MS: 491
Example 112 Carbamic acid, dimethyl-, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-[2-[4-[[methyl(methylsulfonyl)amino]methyl]
phenoxy]ethyl]-7-(1-propynyl)-2-phenanthrenyl ester, [4bS-
(4ba,7a,8ap)]-, m.p. 82-85 °C
Example 113 Carbamic acid, dimethyl-, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-7-(1 -propynyl)-4b-[2-[4-(1 -
pyrrolidinylmethyl)phenoxy]ethyl]-2-phenanthrenyl ester, [4bS-
(4bcc,7a,8ap)]-, HCI salt, MS: 531
Example 114 Carbamic acid, dimethyl-, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-[2-[4-[(4-methyl-1 -
piperazinyl)methyl]phenoxy]ethyl]-7-(1 -propynyl)- 2-
phenanthrenyl ester, [4bS(4ba,7a,8ap)J-, HCI salt, MS: 560
Example 115 Carbamic acid, dimethyl-, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-[2-[4-[[methyl(1-methyl-4-
piperidinyl)amino]methyl]phenoxy]ethyl]-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS(4ba,7a,8ap)]-, HCI salt, MS: 588
Example 116 Carbamic acid, dimethyl-, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-[2-[4-[[(2-
methoxyethyl)amino]methyl]phenoxy]ethyl]-7-( 1 -propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, HCI salt, MS: 535
Example 117 Carbamic acid, dimethyl-, 4b-[2-[4-[[[2-
(dimethylamino)ethyl]amino]methyl]phenoxy]ethyl]-
Example 118
Example 119
Example 120
Example 121
Example 122
Example 123
Example 124
Example 125
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, HCI salt, MS: 548
Carbamic acid, dimethyl-, 4b-[2-[4-[[[2-
(dimethylamino)ethyl]methylamino]methyl]phenoxy]ethylj-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, HCI salt, MS: 562
Carbamic acid, dimethyl-, 4b-[2-[4-
[(diethylamino)methyl]phenoxy]ethyl]-4b,5,6,7,8,8a,9,10-
octahydrc~7-hydroxy-7-(1-propynyl)-2-phenanthrenyl
ester,[4bS-(4ba,7a,8ap)]-, HCI salt, MS: 533
Carbamic acid, dimethyl-, 4b-[2-[4-
[(cyclopropylamino)methyl]phenoxy]ethyl]-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-7-( 1 -propynyl)-2-phenanthrenyl
ester,[4bS-(4ba,7a,8ap)]-, HCI salt, MS: 517
Carbamic acid, dimethyl-, 4b-[2-[4-[[bis(2-
methoxyethyl)3mino]methyl]phenoxy]ethyl]-4b,5,6,7,8,83,9,10-
octahydro-7-hydroxy-7-(1-propynyl)-2-phenanthrenyl
ester,[4bS(4ba,7a,8ap)]-, HCI salt, MS: 593
2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,103-
cx;tahydro-4a-[2-[4-(4-morpholinylmethyl)phenoxy]ethyl]-, [2ft-
(2a,4aa,10ap)]-,MS:496
Carbamic acid, dimethyl-, 7-(chloroethynyl)-4b,5,6,7,8,8a,9,10-
cctahydro-7-hydroxy-4b-[2-[4-(4-
morpholinylmethyl)phenoxy]ethyl]-2-phenanthrenylester,[4bS
(4ba,7a,83p)]-, HCI sslt, MS: 567
2,7-Phen3nthrenediol, 2-(chloroethynyl)-4a-[2-[4-
[(dimethyl3mino)methyl]phenoxy]ethyl]-1,2,3,4,4a,9,10,10aoctahydro-,[
2f?-(2a,43a,103p)]-, MS: 454
Csrbamic acid, dimethyl-, 7-(chloroethynyl)-4b-[2-[4-
[(dimethylamino)methyl]phenoxy]ethyl]-4b,5,6)7,8,8a,9,10-
octahydro-7-hydroxy-2-phenanthrenyl ester, [4bS-
(4ba,7a,83p)]-, HCI S3lt, MS: 525
Example 126 Sulfamic acid, dimethyl-, 7-(chloroethynyl)-4b-[2-[4-
[(dimethylamino)methyl]phenoxy]ethyl]-4b, 5, 6,7,8, 8a, 9,10-
octahydro-7-hydroxy-2-phenanthrenyl ester, [4bS-
(4ba,7a,8a(3)]-, HCI salt, MS: 561
2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[2-[4-(hydroxymethyl)phenoxy]ethyl]-, [2R-
(2a,4aa,10ap)]-, m.p. = 179-1 86 °C
Benzaldehyde, 4-[2-[2-(chloroethynyl)-1 ,3,4,9, 10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]ethoxy]-, [2R-
(2a,4aa,10a(3)]-, MS: 407 (M-18)+
2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(2-phenoxyethyl)-, [2fl-(2a,4aa,10a|})]-, MS: 379
Example 127
Example 128
Example 129
Example 1 30 Naphtho[1 ,2-d]thiazol-7-ol, 2-amino-7-(chloroethynyl)-
4,5)5aI617,8,9,9a-octahydro-9a-(phenylmethyl)-1 [5aR,S-
(5aa,7p,9ap)]-
A solution of the title product of Preparation 14 (46 mg) and thiourea (22 mg)
in acetonitrile (2 ml) were heated at reflux for 8 h. The reaction was concentrated in
vacuo, partitioned between sat. aqueous sodium bicarbonate and chloroform, the
organic layer dried over sodium sulfate, concentrated in vacuo and flash
chromatographed on silica gel (40% ethyl acetate/hexanes) to afford a colorless
solid, 25 mg. Addition of lithio-2-chloroethyne was carried out using the general
procedure described above in Example 8 to afford the title compound of this example
as a tan solid, 7 mg. MS: 373
Example 1 31 Formamide, A/-[7-(chloroethynyl)-4,5,5a,6,7,8,9,9a-octahydro-
7-hydroxy-9a-(phenylmethyl)naphtho[1,2-d]thiazol-2-yl]-,
[5aft,S-(5aa,7p,9ap)]-
Using procedures analogous to those described in Preparations 11-14 and
Example 1 30 above, except dimethylformamide was substituted in the thiourea
cyclization reaction to afford the corresponding N-formyl derivative, which is the title
product of this example. MS: 401
Example 132 2H-Benz[g]indazol-7-ol, 7-(chloroethynyl)-4,5,5a,6,7>8,9>9aoctahydro-
9a-(phenylmethyl)-, [5aR,S-(5aa,7p\9a|3)]-
A solution of the title product of Preparation 15 (244 mg) and hydrazine (75
mg) in ethanol (7 mL)/water (1 ml) was stirred at room temperature for 16 h. The
reaction was diluted into ethyl acetate, washed with water, brine, dried over sodium
sulfate and flash chromatographed to afford a colorless foam, 190 mg. To this foam
was added a solution of ethanol (10 ml), 20% sulfuric acid/water (v/v) and the
resulting solution was refluxed for 5 h. The reaction was diluted into ethyl ether,
washed with sat. aqueous sodium bicarbonate, brine, dried over sodium sulfate and
concentrated in vacuo to afford a golden oil. Addition of lithio-2-chloroethyne was
carried out using the general procedure described above in Example 8 to afford the
title compound of this example as a tan foam, 129 mg. MS: 341
Example 133 2H-Benz[g]indazol-7-ol, 7-(chloroethynyl)-4,5,5a,6,7,7,9,9aoctahydro-
9a-(phenylmethyl)-, [5aR,S-(5aa,7(3,9aa)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 132. MS: 341.
Example 134 Benzo[h]quinazolin-8-ol, 2-amino-8-(chloroethynyl)-
5,6,6a,7,8I9,10,10a-octahydro-10a-(phenylmethyl)- [6aR,S-
(6aa,8(3,10ap)]-
A solution of sodium metal (25 mg) in isopropyl alcohol (1.5 ml_) and
quanidine sulfate (107 mg) were refluxed for 1 h, then the title product of Preparation
15 (154 mg) was added and refluxing was continued for 24 h. Work-up and
subsequent elaboration according to procedures analogous to those described in
Example 132 afforded the title compound of this example as a colorless foam, 43
Example 135 2-Phenanthrenol, 2-(chloroethynyl)-2,3,4,4a,9,10-hexahydro-7-
methoxy-4a-(phenylmethyl)-, (2R-cis)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 8. MS: 361 (M-17)+.
Example 136 2-Phenanthrenol, 2,3,4,43,9,10-hexahydro-7-methoxy-2-
phenyl-4a-(phenylmethyl)-, (2f?-c/s)-
To a flame dried flask, 5 ml of THF and 1.3 ml of phenylmagnesium chloride
were added. The title product of Example 3 (200 mg) in 5 ml THF was added
dropwise to the solution (sat.) at 0 °C. The reaction was stirred at 0 °C for an hour
and quenched with Nh^CI extracted with EtOAc, dried over Na2SO4 and filtered. The
mixture was purified with flash chromatography (25% EtOAc in hexane) on silica gel
to afford the title product of this example as light yellow solid, 245 mg, yield 98%, MS:
379(M-17)+.
Example 137 2,7-Phenanthrenediol, 2,3,4,4a,9,10-hexahydro-2,4abis(
phenylmethyl)-, (2S-cis)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. MS: 379 (M-17)+.
Example 138 2,7-Phenanthrenediol, 2,3,4,4a,9,10-hexahydro-4a-
(phenylmethyl)-2-(2-pyridinyl)-, (2R-cis)~
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 383 (M+1)+.
Example 139 2(3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-(4-
nitrophenoxy)-4a-(phenylmethyl)-, (R)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. MS: 426 (M+1)+.
Examples 140-143
The title compounds of Examples 140-143 were prepared by procedures
analogous to those described above in Example 136.
Example 140 2,7-Phenanthrenediol,(C1C6)a.g.lO.IOa-octahydro^a-
(phenylmethyl)-2-(1,2-propadienyl)-, (4aS,10afl)-, MS: 329 (M-
17)*.
Example 141 2,7-Phenanthrenediol, 2,3,4,43,9,10-hexahydro-2-(2-
naphthalenylmethyl)-4a-(phenylmethyl)-, (4aS)-, MS: 429 (M-
17)+.
Example 142 2,7-Phenanthrenediol, 2,3,4,4a,9,10-hexahydro-2-(2-
naphthalenylmethyl)- 4a-(phenylmethyl)-, (4aS)-, MS: 429 (M-
17)+.
Example 143 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2,4abis(
phenylmethyl)-, (4aS)-, MS: 416 (M+18)+.
Example 144 2,7-Phenanthrenediol, 2-(chloroethynyl)-2,3,4,4a,9,10-
hexahydro-4a-(phenylmethyl)-, (2R-cis)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 8. MS: 347 (M-17)+.
-152-
Example 145 2,7-Phenanthrenediol, 2-ethynyl-2,3,4,4a,9,10-hexahydro-4a-
(phenylmethyl)-, (2R-cis)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 5. MS: 313 (M-17)+.
Examples 146-147
The title compounds of Examples 146-147 were prepared by procedures
analogous to those described above in Example 136.
Example 146 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
phenyl-4a-(phenylmethyl)-, (4aS,10af)-, MS: 367 (M-17)+.
Example 147 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
phenyl-4a-(phenylmethyl)-, (4aS,10afl)-, MS: 367 (M-17)+.
Example 148 2,7-Phenanthrenediol, 2-ethynyl-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2fl-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 350 (M+18)+.
Example 149 2,7-Phenanthrenediol, 2-cyclopropyl-1,2,3,4,43,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2f-(2a,4aa,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above Example 136. MS: 331 (M-17)*.
Example 150 2,7-Phenanthrenediol, 2-(cyclopropylethynyl)-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above Example 9. MS: 355 (M-17)*.
Example 151 2,7-Phenanthrenediol, 2-butyl-1,2,3,4,4a,9,10,10a-octahydro-
4a-(phenylmethyl)-, (4aS,10af?)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. MS: 382 (M+18)+.
Examples 152-153
The title compounds of Examples 152-153 were prepared by procedures
analogous to those described above in Example 9.
Example 152 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(2-thienyl)-, (4aS,10afl)-, MS: 373 (
Example 153 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(2-pyridinyl)-, [2f-(2a,4aa,10ap)]-, MS: 386
Example 154 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-, [2ft-(2a,4aa,10a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 6. MS: 309 (M+1)+.
Example 155 2,7-Phenanthrenediol, 2-(chloroethynyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2S-(2a,4aa,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 8. MS: 349 (M-17)+.
Example 156 2,7-Phenanthrenediol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(3,3,3-trif luoro-1 -propynyl)-, [2R-
(2a,4aa,10ap)]-
A 5-L three-necked, round-bottom flask was equipped with a dry ice
condenser and a dropping funnel. The flask was charged with 1 000 ml_ anhydrous
THF, and 3,3,3-trifluoropropyne gas was bubbled through for 10 mins. About 100 g
(-15 eqs) of the gas was condensed during this period. Solution was then cooled to -
78 °C and 200 ml of n-BuLi (2.5 M solution in hexanes, -8 eqs) was added slowly via
the dropping funnel. The resultant mixture was stirred under -78 °C for 1 hour. Then
300 mL of anhydrous THF was added to the reaction flask. A solution of 20 g of the
starting compound, 2(1H)-phenanthrenone, 4a-(benzyl)-3,4,4a,5,8l9,10,10aoctahydro-
7-hydroxy-, [4aS-[4aa[E], 10af3]]- in 200 mL of THF was added dropwise,
followed by the addition of another 500 mL anhydrous THF, and the reaction mixture
was stirred at -78 °C for another hour. Saturated, aqueous ammonium chloride
solution was added and the mixture was extracted with EtOAc three times, dried and
concentrated. Purification by flash chromatography over SiO2 using 2% Ethyl Acetate
in Methylene Chloride to 5% Ethyl Acetate in Methylene Chloride as the eluant
afforded 20.8 g of the title product of this example as a yellow-white solid. MS : 399
(M-1)+.
Example 157 2(1 H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-(phenylmethyl)-, (4aR-cis)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 7. MS: 307 (M+1 )".
Examples 158-159
The title compounds of Examples 158-159 were prepared by procedures
analogous to those described above in Example 8.
Example 158 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2S-(2a,4aa,10aa)]-, MS: 349
Example 159 2,7-Phenanthrenediol, 2-(chloroethynyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2fl-(2a,4a3,10ap)]-, MS: 349
(M-17)+.
Example 160 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(2-thiazolyl)-, (4aS,1 Oafl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 392 (M+1 )*.
Example 161 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2fl-(2a,4ap,1 Oaa)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 8. MS: 349 (M-17)*.
Example 162 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-, [2S-(2a,4apM Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 349 (M-1 7)+.
Examples 163-164
The title compounds of Examples 163-164 were prepared by procedures
analogous to those described above in Example 8.
Example 163 2,7-Phenanthrenediol, 2-(chloroethynyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2fl-(2a,4aa,10aa)]-, MS: 349
Example 164 2,7-Phenanthrenediol, 2-(chloroethynyl)-1 ,2,3,4,43,9,1 0,1 Oaoctahydro-
4a-(phenylmethyl)-, [2S-(2a,4ap,10ap)]-, MS: 349
Example 165 2-Phenanthrenecarbonitrile, 1,2,3,4,4a,9,10,10a-octahydro-
2,7-dihydroxy-4a-(phenylmethyl)-, [2f-(2a,4aa,10a(3)]-
At room temperature and under nitrogen atmosphere, 159 mg of KCN was
added into 75 mg of the title product of example 6 in methanol (4 ml) and followed by
0.070 ml of HOAc. The mixture was stirred overnight at room temperature,
quenched with NaHCOa (sat.), extracted with EtOAc, dried over Na2SO4, filtered and
concentrated to dryness. The crude product was purified with column
chromatography with 0.5% acetone in CH2CI2 as the eluant to yield 20.4 mg of the
title product of this example as white solid. MS: 322 (M+1) +13C NMR (100 MHz,
CD3OD) 8; 24.8, 27.8, 33.6, 36.0, 37.6, 39.3, 43.6, 44.0, 74.6, 111.3, 114.6, 125.6,
126.8, 127.0, 127.9, 130.7, 133.8, 136.8, 138.0, 155.1.
Example 166 2-Phenanthrenecarbonitrile, 1,2,3,4,4a,9,10,10a-octahydro-
2,7-dihydroxy-4a-(phenylmethyl)-, (4aS,1 OaR)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 165. 13C NMR (100 MHz, CD3OD) 5; 26.2, 29.3,
35.1,37.4,39.1,41.6,45.1,45.5,71.5, 112.7, 116.0, 127.1, 128.3, 128.4, 129.4,
132.1,134.9,138.6,139.5,156.5.
Example 167 2-Phenanthrenecarbonitrile, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-
[[(4-methylphenyl)sulfonyl]oxy]-4a-(phenylmethyl)-,
(4aS,10afl)-
Tosyl cloride (0.13 mL) was added slowly to a stirring solution of 106 mg of
the corresponding phenol in 0.1 ml of triethylamine and 1 mL of anhydrous CH2CI at
0 °C under nitrogen atmosphere. The reaction was allowed to warm to room
temperature for 4 h, then 40 °C overnight. It is quenched with water. The mixture was
extracted with CH2CI2 (X3), washed with brine, dried over Na2SO4, filtered and
concentrated to dryness. Purification with flash chromatography over SiO2 using 20%
EtOAc in hexanes as the eluant afforded 63 mg of pure title product of this example
as white crystalline solid. MS: 489 (M+18)+.
Example 168 2,7-Phenanthrenediol, 4a-(2,3-dihydroxypropyl)-
1,2,3,4,4a,9,10,1 Oa-octahydro-,[2fl-(2a,4aa,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 6. IR (neat) 3380, 2929,1612 cm'1.
Example 169 Acetamide, /V-[5-[3-(3,4,9,10-tetrahydro-7-methoxy-2-oxo-
4a(2H)-phenanthrenyl)-1 -propenyl]-2-pyridinyl]-, [S-(E)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 35. MS: 403 (M+1)+.
Example 170 2-Phenanthrenecarbonitrile, 1,2,3,4,4a,9,10,10a-octahydro-7-
hydroxy-4a-(phenylmethyl)-, (4aS,1 Oaff)-
The title product of Example 167 (20 mg) and KOH (38 mg) in EtOH (0.7 ml)
and water (0.7 ml) were mixed. The mixture was refluxed overnight, then neutralized
with HOAc, extracted with EtOAc, dried and concentrated to dryness. The crude
mixture was purified with column chromatography with 5% isopropanol in hexane as
the eluant to yield 1.2 mg of the pure title product of this example as the white solid.
MS:318(M+1)+
The title compounds of Examples 171-174 were prepared by procedures
analogous to those described above in Example 8.
Example 171
Example 172
Example 173
Example 174
Example 175
Acetamide, A/-[5-[3-[2-(chloroethynyl)-3,4,9,10-tetrahydro-2,7-
dihydroxy-4a(2/-/)-phenanthrenyl]-1-propenyl]-2-pyridinyl]-,
[2fl,4a(£)]-, MS:449(M+1)+.
2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,103-
oct3hydro-43-(2-propenyl)-, [2ff-(2a,4aa,10ap)]-, 1H NMR (400
MHz, CD3OD) 8 4.90-4.97 (m, 2H), 5.45-5.61 (m, 1H), 6.51-
6.53 (m, 2H), 6.95 (d, 1H,J = 9).
2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,103-
oct3hydro-4a-(2-propenyl)-, [2S-(2a,4apM03a)]-, 1H NMR (400
MHz, CD3OD) 6 4.90-4.96 (m, 2H), 5.53-5.60 (m, 1H), 6.48-
6.51 (m, 2H), 6.93 (d, 1H, J = 9)
2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,103-
oct3hydro-4a-(2-propenyl)-, [2S(2a,43pM03p)]-, 1H NMR (400
MHz, CD3OD) 6 4.87-5.46 (m, 2H), 5.70-5.80 (m, 1H), 6.50 (d,
1 H, J = 2.7), 6 57 (dd, 1 H, J = 2.7, 8.5), 7.04 (d, 1 H, J = 8.5).
2(3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-hydroxy-4a-(2-
propenyl)-, (S)-, 1H NMR (400 MHz, CD3OD) 54.95-5.01 (m,
2H), 5.60-5.75 (m, 2H),5.95 (s, 1H), 6.58 (d, 1H, J = 2.6), 6 73
(dd, 1 H, J = 2.6, 8.5), 7.12 (d, 1 H, J = 8.5).
The title compound of this example was prepared by procedures analogous to
those described above in Example 3.
Example 176 2(1H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-(2-propenyl)-,(4aS-frans)-
The title compound of this example was prepared by procedures analogous to
those described above or below in Example 6. MS: 357 (M+1)+.
Example 177 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,10aoctahydro-
4a-[2-(4-morpholinyl)ethyl]-, (4aS,10afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 33. MS: 390 (M+1 )*.
Example 178 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,103-
octahydro-4a-(2-propenyl)-, [2R-(2a,4aa,103a)]-
The title compound of this exsmple was prepared by procedures analogous to
those described above for the preparation of the title compound of Example 8. 1H
NMR (400 MHz, CD3OD) 5 4.95-4.99 (m, 2H), 5.60-5.80 (m, 2H), 6.50 (d, 1H, J =
2.4), 6 57 (dd, 1H, J = 2.4, 8.5), 7.03 (d, 1H, J = 8.5).
Examples 179-181
The title compounds of Examples 179-181 were prepared by procedures
analogous to those described above in Example 33.
Example 179 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[2-(4-hydroxy-1 -piperidinyl)ethyl]-, [2R-
(2a,4aa,10ap)]-, MS: 404 (M+1)+.
Example 180 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[2-(4-methyl-1 -piperazinyl)ethyl]-, [2ft-
(2a,4aa,10ap)]-, MS: 403 (M+1)+.
Example 181 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,43,9,10,103-
octahydro-4a-[2-[4-[2-(2-hydroxyethoxy)ethyl]-1-
piperazinyl]ethyl]-, [2ft-(2a,4acc,10ap)]-, MS: 477 (M).
Example 182 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,103-
octahydro-4a-(2-hydroxy-2-phenylethyl)-, [2ft-(2a,43a,1 Qa$)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. MS: 396 (M).
Example 183 2-Butenoic acid, 4-[2-(chloroethynyl)-1,3,4,9,10,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-, ethyl ester,
[2fl-[2a,4aa(E),10a3]]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 35. MS: 406 (M+18)*.
Example 184 4a(2H)-Phenanthreneacetaldehyde, 2-(chloroethynyl)-
1,3,4,9,10,10a-hexahydro-2,7-dihydroxy-, O-methyloxime, [2R-
[2a,4acx,10ap]]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 34. 1H NMR (400 MHz, CD3OD) 5 3.70 (s) and
3.74 (s, 3H).
Example 185 2(1 /-/)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-propyl-, (4aR-cis)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 7. 1H NMR (400 MHz, CD3OD) 6 0.826 (t, 3H, J =
7). MS:276(M+18r.
Example 186 2-Phenanthrenol, 4b,5,6,7,8,8a,9,10-octahydro-4b-propyl-7-
propylidene-,[4bf-(4ba,7Z,8aa)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 78. MS: 285 (M+1)+.
Example 187 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(2-
propenyl)-2-(1 -propynyl)-, [2fl-(2a,4aa,1 Oap1)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 279 (M-17)+.
Examples 188-189
The title compounds of Examples 188-189 were prepared by procedures
analogous to those described above in Example 7.
Example 188 2(1H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-propyl-, (4aR-trans)-, MS: 259 (M+1)+.
Example 189 2,7-Phenanthrenediol, I^.S^^a.g.lO.IO
dipropyl-, [2f?-(2a,4aa,10ap)]-, MS: 285 (M-17)+.
Example 190 Piperazine, 1-[4-[2-(chloroethynyl)-1,3,4,9,10,1 Oa-hexahydro-
2,7-dihydroxy-4a(H)-phenanthrenyl]-1-oxo-2-butenyl]-4-[2-(2-
hydroxyethoxy)ethyl]-, [2fl-[2a,4aa(E),1 Oap1]]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 37. MS: 517 (M).
Example 191 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4apropyl-,
[2S-(2a,4apMOap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 7. MS: 243 (M-17)+.
Examples 192-193
The title compounds of Examples 192-193 were prepared by procedures
analogous to those described above in Example 136.
Example 192 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2,4adipropyl-,
[2f?-(2a,4aa,10aa)]-, MS: 285 (M-17)+.
Example 193 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2,4adipropyl-,
[2S-(2a,4ap,10ap)]-, MS: 285 (M-17)+.
Example 194 Piperazine, 1-[4-[2-(chloroethynyl)-1,3,4,9,10,10a-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-oxo-2-butenyl]-4-
methyl-, [2fl-[2a,4aa(£),10a(3]]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 37. MS: 443 (M+1)+.
Example 195 2,7-Phenanthrenediol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[3-(2-thienyl)-2-propenyl]-, [4aS(E)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 35. MS: 382 (M-18)+.
Example 196 2-Phenanthrenol, 4b,5,6,7,8,8a,9,10-octahydro-4b,7-dipropyl-I
(4bfl,8aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 287 (M+1)+.
Examples 197-202
The title compounds of Examples 197-202 were prepared by procedures
analogous to those described above in Example 37.
Example 197
Example 198
4-Piperidinol, 1-[4-[2-(chloroethynyl)-1, 3,4,9,1 0,1 Oahexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-1-oxo-2-
butenyl]-, [2R-[2a,4aa(E),10ap]]-, MS: 426 (M-17)+.
2-Butenamide, 4-[2-(ch!oroethynyt)-1 ,3,4,9, 10,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-A/-[3-
(dimethylamino)propyl]-, [2R-[2a,4aa(£),10ap]]-, MS: 446
Example 199 2-Butenamide, 4-[2-(chloroethynyi)-1 , 3,4,9, 10,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-/V,A/-diethyl-, [2R-
[2a,4aa(£),10a(33]-, MS: 416 (M+1)+.
Example 200 2-Butenamide, 4-[2-(chloroethynyl)-1 ,3,4,9, 10,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-/V-[3-(4-
morpholinyl)propyl]-, [2fl-[2ct,4aa(E),10ap]]-, MS: 487 (M).
Example 201 2-Butenamide, 4-[2-(chloroethyny)- 1,3,4,9, 10,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-/\/-(2-pyridinylmethyl)-1
[2f?-[2a,4aa(E),10ap]]-, MS: 452 (M+1)+.
Example 202 2-Butenamide, 4-[2-(chloroethynyl)-1 ,3,4,9,1 0,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-A/-{4-pyridinylmethyl)-,
[2fl-[2a,4aa(£),10ap]]-, MS: 451 (M+1)+.
Example 203 2,7-Phenanthrenedtol, 2-(chloroethyny!)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-[3-(2-pyridinyl)-2-propenyl]-, [2/7-
[2a,4aa(E),10ap]]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 35. MS: 394 (M+1)*.
Example 204 2-Butenamide, 4-[2-{chloroethynyl)-1 ,3,4,9, 10,1 Oa-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-W-[2-(4-pyridinyl)ethyl]-,
[2fl-[2cc,4aa(E),10ap]]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 37. MS: 465 (M+1 )+.
Example 205 2,7-Phenanthrenediol, 2-(chloroethynyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-[3-(5-isoxazolyl)-2-propenyf]-, [4aS(£),10afIThe
title compound of this example was prepared by procedures analogous to
those described above in Example 35. MS: 366 (M-1 7)+.
Example 206 2-Butenamide, 4-[2-(chloroethynyl)-1 ,3,4, 9,10, 10a-hexahydro-
2,7-dihydroxy-4a(2H)-phenanthrenyl]-/V-ethyl-, [2R-
[2a,4aa(f),10ap]]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 37. MS: 370 (M-17)+.
Example 207 2-Phenanthrenecarboxylic acid, 4b,5,6,7,8,8a>9, 1 0-octahydro-
7-hydroxy-4b-(2-propenyl)-7-(1 -propynyl)-, [4bS-(4ba,7a,8ap)]-
, 13C NMR (1 00 MHz, CDCI3) 5 1 1 6.6, 1 68.5
The title compound of this example was prepared by procedures analogous to
those described above in Example 9.
Examples 208-209
The title compounds of Examples 208-209 were prepared by procedures
analogous to those described above in Example 8.
Example 208 2,7-Phenanthrenediol, 2-(chloroethynyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-(3-phenylpropyl)-, (4aR)-, MS: 377 (M-17)+.
Example 209 2,7-Phenanthrenediol, 2-(chloroethynyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-(3-phenylpropyl)-, [2S-(2a,4ap,10aa)]-, MS: 377
Examples 2 10-2 12
The title compounds of Examples 210-212 were prepared by procedures
analogous to those described above in Example 1 8.
Example 21 0 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9>1 0-octahydro-7-
hydroxy-4b-(2-propenyl)-7-(1 -propynyl)-, [4bS-(4bcc,7a,8ap)]-,
MS:324(M+1)+.
Example 21 1 2-Phenanthrenecarboxamide, 4b, 5,6,7,8,83,9, 1 0-octahydro-7-
hydroxy-/V,A/-dimethyl-4b-(2-propenyl)-7-(1 -propynyl)-, [4bS-
(4ba,7a,8ap)]-, MS: 353 (M+1)+.
Example 212 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4ba,7a,8ap)]-, MS: 374 (M+1)+.
Examples 2 13-2 14
The title compounds of Examples 213-214 were prepared by procedures
analogous to those described above in Example 9.
Example 213 2-Phenanthrenol, 1 ,2,3,4,43,9,1 0,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-, [2fl-(2a,4aa,10a(3)]-, MS: 313
Example 214 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-, [2S-(2a,4ap,10aa)]-, MS: 313
Examples 2 15-2 16
The title compounds of Examples 215-216 were prepared by procedures
analogous to those described above in Example 1 0.
Example 215 2-Phenanthrenol, 7-fluoro-1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-, (4aS,10aS)-, MS: 352 (M).
Example 216 2-Phenanthrenol, 7-fluoro-1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-, (4aS,10aS)-, MS: 352 (M).
Example 217 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-methyl-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 18. MS: 388 (M+1)+.
Examples 21 8-21 9
The title compounds of Examples 218-219 were prepared by procedures
analogous to those described above in Example 9.
Example 218 2-Phenanthrenol, 7-fluoro-1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-, [2S-(2a,4ap,10aa)]-, MS: 331
Example 219 2-Phenanthrenol, 7-fluoro-1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-, [2ft-(2a,4acc,10ap)]-, MS: 331
Example 220 2-Phenanthrenecarboxamide, 4b-[(2,2-dimethyl-1 ,3-dioxolan-
4-yl)methyl]-4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-(1-
propynyl)-, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 18. MS: 398 (M+1)+.
Example 221 2-Phenanthrenecarboxylic acid, 45,5,6,7,8,83,9,10-octahydro-
7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-, methyl ester,
[4bS(4ba,7p,8a(3)JThe
title compound of this example was prepared by procedures analogous to
those described above in Example 14. MS: 371 (M-17)+.
Example 222 2-Phenanthrenemethanol, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-a,a-dimethyl-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4ba,7a,8a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 19. MS: 371 (M-17)+.
Example 223 Carbamic acid, [4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]-, 2-
(dimethylamino)ethyl ester,[4bS-(4ba,7a,8a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 28. MS: 461 (M+1)+.
Example 224 2-Phenanthrenol, 7-(chloromethyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 361 (M-17)+.
Examples 225-231
The title compounds of Examples 225-231 were prepared by procedures
analogous to those described above in Example 18.
Example 225 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a>9,10-octahydro-7-
hydroxy-4b-(3-phenyl-2-propenyl)-7-(1 -propynyl)-, [4bS-
(4ba,7a,8ap)]-, MS: 400 (M+1)+.
Example 226 2-Phenanthrenecarboxamide, /V-[2-(dimethylamino)ethyl]-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 445 (M+1)+.
Example 227 2-Phenanthrenecarboxamide, AA[6-(dimethylamino)hexyl]-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8a(3)]-, MS: 501 (M+1)+.
Example 228
Example 229
2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-[2-(1 -
pyrrolidinyl)ethyl]-,[4bS-(4ba,7a,8a(3)]-, MS: 471 (M+1)+.
2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9, 1 0-octahydro-7-
hydroxy-AA[3-(4-methyl-1-piperazinyl)propyl]-4b-
(phenylmethyl)-7-(1-propynyl)-,[4bS-(4ba,7a,8ap)]-, MS: 514
Example 230 2-Phenanthrenecarboxamide, AA[3-(dimethylamino)propyl]-
4b,5,6,7l8l8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 459 (M+1)+.
Example 231 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/\A[2-(4-morpholinyl)ethyl]-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 487 (M+1)+.
Example 232 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-AA[2-(4-morpholinyl)ethyl]-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4ba,7cc,8a(3)]- HCI salt
The title compound of this example is the HCI salt of the title compound of
Example 231 . MS: 487 (M+1 )+.
Examples 233-237
The title compounds of Examples 233-237 were prepared by procedures
analogous to those described above in Example 1 8.
Example 233
Example 234
Example 235
Example 236
2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-, [4bS-
(4bcc,7p,8ap)]-, MS: 374 (M+1)+.
2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-A/-[3-(1 /-/-imidazol-1 -yl)propyl]-4b-(phenylmethyl)-7-(1 -
propynyl)-,[4bS-(4ba,7a,8ap)]-HCI salt, MS: 483 (M+1)+.
2-Phenanthrenecarboxamide, /V-[4-(dimethylamino)butyl]-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap>)]-1 MS: 473 (M+1)+.
2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-A/-[3-(4-morpholinyl)propyl]-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 501 (M+1)+.
Example 237 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-[3-(4-morpholinyl)propyl]-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4bcx,7a,8ap)]-HCI salt, MS: 501 (M+1)+.
Example 238 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4apropyl-
2-(1-propynyl)-,[2f?-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 281 (M-17)+.
Examples 239-240
The title compounds of Examples 239-240 were prepared by procedures
analogous to those described above in Example 18.
Example 239 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-A/-(3-methoxypropyl)-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4bcc,7a,8ap)]-, MS: 446 (M+1)+
Example 240 2-Phenanthrenecarboxamide, 4b,5,617,8,8a,9,10-octahydro-7-
hydroxy-AA[3-(2-methoxyethoxy)propyl]-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4bcc,7a,8ap)]-, MS: 490 (M+1)+
Example 241 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-A/-(4-
pyridinylmethyl)-, [4bS-(4ba,7a,8ap)JTo
a stirring solution of 779 mg of 4-aminomethylpyridine in 10 ml of
dichloromethane at 0 °C under N2 was added 3.6 ml_ of 2.0 M trimethylaluminum in
toluene. The mixture was stirred at 0 °C for 20 min. then at RT for 1 h. To this
mixture was added 350 mg of the title compound of Example 14 in 5 ml of
dichloromethane. The mixture was heated to reflux overnight. To the reaction
mixture was added 1 N HCI dropwise until the aqueous layer was approximately pH
4. The resultant mixture was extracted with EtOAc, dried over Na2SO4l filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 5%
MeOH in dichloromethane to 10% MeOH in dichloromethane as the gradient eluant
afforded 362 mg (87 %) of the title product of this example as a white solid. MS: 465
(M+1)+.
Example 242 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9)10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-/V-(4-
pyridinylmethyl)-, [4bS-(4ba,7cc,8ap)]-, HCI salt
The title compound of this example is the HCI salt of the title compound of
Example 241. MS: 465 (M+1)+.
Example 243 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-AA[2-(4-
pyridinyl)ethyl]-, [4bS-(4ba,7cc,8ap)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 241. MS: 479 (M+1 )*.
Example 244 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7*
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-/V-(2-
pyridinylmethyl)-, [4bS(4ba,7a,8a|3)]-
To a stirring solution of 6.2 g of 2-aminomethylpyridine in 80 ml of
dichloromethane at 0 °C under N2 was added 26 ml_ of 2.0 M trimethylaluminum in
toluene. The mixture was stirred at 0 °C for 20 min. then at RT for 1 h. To this
mixture was added 2.2 g of the title compound of Example 14 (which was made by
procedures described in Example 14) in 50 ml_ of dichloromethane. The mixture was
heated to reflux overnight. To the reaction mixture was added 1 N HCI dropwise until
the aqueous layer was approximately pH 4. The resultant mixture was extracted with
EtOAc, dried over Na2SO4, filtered, and concentrated to dryness. Purification by flash
chromatography over SiO2 using 5% MeOH in dichloromethane to 10% MeOH in
dichloromethane as the gradient eluant afforded 1.4 g (53 %) of the title product of
this example as a white solid. MS: 465 (M+1)+.
Examples 245-247
The compounds of Examples 245-247 were prepared by procedures
analogous to those described above in Example 244.
Example 245 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-/S/-(2-
pyridinylmethyl)-, [4bS-(4ba,7a,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
244. MS: 465 (M+1)+.
Example 246 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9110-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-/V-[2-(2-
pyridinyl)ethyl]-, [4bS-(4ba,7a,8a|3)]-, MS: 479
Example 247 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,1O-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-/\A[(tetrahydro-2-
furanyl)methyl]-,[4bS-(4ba,7a,8ap)]-, MS: 458 (M+1)+.
Example 248 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)- N-(3-
pyridinylmethyl)-, [4bS-(4ba,7a,8a(3)]-
To a stirring solution of 0.21 ml_ of 3-aminomethylpyridine in 1 mL of
dichloromethane at 0 °C under N2 was added 0.1 mL of 2.0 M trimethylaluminum in
hexane. The mixture was stirred at 0 °C for 20 min. then at RT for 1 h. To this
mixture was added 20 mg of the title compound of Example 14 in 1 mL of
dichloromethane. The mixture was heated to reflux overnight. To the reaction
mixture was added 1 N HCI dropwise until the aqueous layer was approximately pH
4. The resultant mixture was extracted with EtOAc, dried over Na2S04, filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 5%
MeOH in dichloromethane to 10% MeOH in dichloromethane as the gradient eluant
afforded 18 mg (75 %) of the title product of this example as a white solid. MS: 465
(M+1)+.
Example 249 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)- N-(3-
pyridinylmethyl)-, [4bS-(4ba,7a,8a3)]-HCI-salt
The title product of this example is the HCI salt of the title product of Example
248. MS: 465 (M+1)+
Example 250 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-AA[2-(1-methyl-2-pyrrolidinyl)ethyl]-4b-(phenylmethyl)-
7-(1-propynyl)-,[4bS-(4bct,7a,8apv)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 248. MS: 485 (M+1)+.
Example 251 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-AA[2-(1-methyl-2-pyrrolidinyl)ethyl]-4b-(phenylmethyl)-
7-(1 -propynyl)-,[4bS-(4ba,7a,8a3)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
251. MS: 485 (M+1)+.
Examples 252-253
The title compounds of Examples 252-253 were prepared by procedures
analogous to those described above in Example 9.
Example 252 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4apentyl-
2-(1-propynyl)-,[2fl-(2a,4aa, 103(3)]-, MS: 309 (M-17)+.
Example 253 2,7-Phenanthrenediol, 4a-butyl-1,2,3,4,43,9,10,10a-octahydro-
2-(1-propynyl)-,[2f?-(2a,4aa,10ap)]-, MS: 295 (M-17)+.
Example 254 2-Phenanthrenecarboxsmide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-[3-(1 -
pyrrolidinyl)propyl]-, [4bS-(4ba,7a,8a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 248. MS: 485 (M+1)+.
Example 255 2-Phenanthrenecarboxamide, 4b,5,6,7,8,83,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-AA[3-(1 -
pyrrolidinyl)propyl]-,[4bS-(4ba,7a,83p)]-HCIs3lt
The title product of this example is the HCI salt of the title product of Example
254. MS: 485 (M+1)+.
Example 256 2-Phen3nthrenec3rboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-[3-(1 H-1,2,4-
triazol-1-yl)propyl]-,[4bS(4ba,7a,8ap)]-
The title compound of this example wss prepared by procedures analogous to
those described above in Example 248. MS: 483 (M+1)+.
Example 257 2-Phenanthrenec3rbox3mide, 4b>5,6,7,8,83,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-[3-(1 H-1,2,4-
triazol-1 -yl)propyl]-,[4bS-(4ba,7a,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
256. MS: 483 (M+1)+.
Example 258 2,7-Phenanthrenediol, 4a-(3-butenyl)-1,2,3,4,4a,9,10,10aoctahydro-
2-(1-propynyl)-, [2ff-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 293 (M-17)*.
Example 259 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-A/-[5-(4-morpholinyl)pentyl]-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4ba,7a,8a3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 248. MS: 529 (M+1)+.
Example 260 2-Phenanthrenecarboxamide, 4^5,6,7,8,83,9,10-octahydro-7-
hydroxy-/V-[5-(4-morpholinyl)pentyl]-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4ba,7a,8a|3)]- HCI salt
The title compound of this example is the HCI salt of the title compound of
Example 259. MS: 529 (M+1)+.
Example 261 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-pentyl-7-(1 -propynyl)-AA[3-(1 H-~\ ,2,4-triazol-1 -
yl)propyl]-,[4bfl-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 248. MS: 463 (M+1)+.
Example 262 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-pentyl-7-(1 -propynyl)-/V-[3-(1 H-1,2,4-triazol-1 -
yl)propyl]-,[4b/?-(4ba,7a,8a|3)]-HCIsalt
The title product of this example is the HCI salt of the title product of Example
261. MS: 463 (M+1)+.
Examples 263-265
The title compounds of Examples 263-265 were prepared by procedures
analogous to those described above for the preparation of the title compound of
Example 59.
Example 263 Carbamic acid, dimethyl-, 7-(chloroethynyl)-4b,5,6,7,8,8a,9,10-
octahydro-7-methoxy-4b-(2-methoxyethyl)-2-phenanthrenyl
ester, [4bS-(4ba,7a,8ap)]-, MS: 420 (M+1)+.
Example 264 Carbamic acid, dimethyl-, 7-(chloroethynyl)-4b)5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(2-methoxyethyl)-2-phenanthrenyl
ester, [4bS-(4ba,7a,8ap)]-, MS: 406 (M+1)+.
Example 265 Carbamic acid, dimethyl-, 7-(chloroethynyl)-4b-[2-[2-
(dimethylamino)-2-oxoethoxy]ethyl]-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-2-phenanthrenyl ester,[4bS-
(4ba,7a,8ap)]-, 1H NMR (400 MHz, CDCI3) 5 2.94 (s 3H), 2.96
(S, 3H), 3.06 (s, 3H), 3.09 (s, 3H), 4.34 (s, 2H).
Example 266-267
The title compounds of Examples 266-267 were prepared by procedures
analogous to those described above in Example 248.
Example 266 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,1O-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-AA2-pyridinyl-, [4bS-
(4ba,7a,8ap)]-, MS: 451 (M+1)+.
Example 267 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-2-pyridinyl-, [4bS-
(4ba,7a,8ap)]-HCI salt, MS: 451 (M+1)+.
Example 268 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-pyrazinyl-, [4bS-
(4bcc,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. MS: 452 (M+1 )*.
Examples 269-270
The title products of Examples 269-270 are the HCI salt and the pmethanesulfonic
acid salt, respectively, of the title product of Example 268.
Example 269 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-pyrazinyl-, [4bS-
(4ba,7a,8ap)]-HCI salt, MS: 452 (M+1)+.
Example 270 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-pyrazinyl-, [4bS-
(4ba,7a,8ap)]-p-methanesulfonic acid salt, MS: 452 (M+1)+.
Example 271 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-A/-3-pyridinyl-, [4bS-
(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 248. MS: 450 (M).
Example 272 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8aI9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-3-pyridinyl-, [4bS-
(4ba,7cc,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
271. MS: 451 (M+1)+.
Examples 273-274
The title compounds of Examples 273-274 were prepared by procedures
analogous to those described above in Example 248.
Example 273 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,1O-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-/V-4-pyrimidinyl-,
[4bS-(4ba,7a,8ap)]-, MS: 452 (M+1)+.
Example 274 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-propyl-7-(1 -propynyl)-/V-(4-pyridinylmethyl)-, [4bf-
(4ba,7cx,8ap)]-, MS: 417 (M+1)+.
Example 275 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-propyl-7-(1 -propynyl)-/v-(4-pyridinylmethyl)-, [4bR-
(4ba,7cx,8ap)]- HCI salt
The title compound of this example is the HCI salt of the title compound of
Example 274. MS: 417 (M+1)+.
Example 276 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-1,3,4-thiadiazol-2-
yl-, [4bS(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 248. MS: 458 (M+1 )+.
Example 277 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-AA1,3,4-thiadiazol-2-
yl-, [4bS-(4ba,7a,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
276. MS: 458 (M+1 )+.
Example 278 2-Phenanthrenecarboxamide, 4b,5,6,7,8I8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-A/-2-pyrimidinyl-,
[4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 248. MS: 452 (M+1 )+.
Example 279 2-Phenanthrenecarboxamide, 4b,5,6,7)8)8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-/V-2-pyrimidinyl-,
[4bS-(4ba,7a,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
278. MS: 452 (M+1)+.
Examples 280-283
The title compounds of Examples 280-283 were prepared by procedures
analogous to those described above in Example 248.
Example 280 2-Phenanthrenecarboxamide, A/-(cyanomethyl)-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8a(3)]-, MS: 413 (M+1)+.
Example 281 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-AA(1 H-tetrazol-5-
ylmethyl)-, [4bS-(4ba,7a,8a(3)]-, MS: 454 (M-1)+.
Example 282 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-AM ,2,4-triazin-3-yl-,
[4bS-(4ba,7a,8a|3)]-, MS: 453 (M+1)+.
Example 283 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
methoxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-pyrazinyl-, [4bS-
(4ba,7a,8a3)]-, MS: 466 (M+1)+.
Example 284 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
methoxy-4b-(phenylmethyl)-7-(1 -propynyl)-/V-pyrazinyl-, [4bS
(4ba,7a,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
283. MS:466(M+1)+.
Example 285 2-Phenanthrenol, 1,2,3,4,4a,9F10,1 Oa-octahydro-4a-propyl-2-
(1 -propynyl)-7-(2-thiazolyl)-, [2fl-(2a,4aa,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 16. MS: 366 (M+1)+.
Examples 286-287
The title compounds of Examples 286-287 were prepared by procedures
analogous to those described above in Example 248.
Example 286 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-(5-methyl-1 W-pyrazol-3-yl)-4b-(phenylmethyl)-7-(1 -
propynyl)-,[4bS-(4bx,7a,8a|3)]-1 MS: 454 (M+1)+.
Example 287 1 ffPyrazol-3-amine, 5-methyl-1 -[[4^5,6,7,8,83,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]carbonyl]-, [4bS-(4ba,7a,8a(3)j-, MS: 454
Example 288 2-Phenanthrenol, 1 ,2,3,4,4a,9, 1 0, 1 Oa-octahydro-4a-propyl-2-
(1 -propynyl)-7-(3-pyridinyl)-, [2-(2a,4aa, 1 Oa(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 1 6. MS: 360 (M+1 )+.
Example 289 2-Phenanthrenol, 1 ,2,3,4,4a,9, 1 0, 1 Oa-octahydro-4a-propyl-2-
(1-propynyl)-7-(3-pyridinyl)-, [2f-(2a,4aa,10ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
288. MS: 360 (M+1 )*.
Example 290 Carbamic acid, [2-(4-morpholinyl)ethyl]-, 4b-butyl-
4bI5,6I7,8,8a,9l10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4b/-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. MS: 469 (M+1 )+.
Example 291 Carbamic acid, [2-(4-morpholinyl)ethyl]-, 4b-butyl-
4b,5,6,7,8,8a,9)10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4bfl-(4ba,7a,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
290. MS: 469 (M+1 )*.
Example 292 Carbamic acid, [2-(1 -pyrrolidinyl)ethyl]-, 4b-butyl-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4bf?-(4ba,7a,8a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. MS: 453 (M+1)+.
Example 293 2(3H)-Phenanthrenone, 7-f luoro-4,4a,9, 1 0-tetrahydro-4a-
(phenylmethyl)-, (S)-, 1H NMR (400 MHz, CDCI3) 8 5.99 (s,
1H), 6.88-6.93 (m,1H).
The title compound of this example was prepared by procedures analogous to
those described above in Example 1 .
Example 294 Carbamic acid, [2-(dimethylamino)ethyl]-, 4b-butyl-
4b)5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-(1-propynyl)-2-
phenanthrenyl ester, [4bfl-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. MS: 427 (M+1)+
Examples 295-296
The title compounds of Examples 295-296 were prepared by procedures
analogous to those described above in Example 16.
Example 295 2-Phenanthrenol, 1,2,3,4,43,9,10,10a-octahydro-7-(5-methyl-
1H-1 )2>4-triazol-3-yl)-4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2ct,4aa,10ap)]- and 2-Phenanthrenol, 1,2,3,4,4a,9,10,10aoctahydro-
7-(5-methyl-11,2,4-triazol-3-yl)-4a-(phenylmethyl)-
2-propyl-, [2f?-(2a,4acx,10ap)]-, MS: 413 (M+2)+
Example 296 2-Phenanthrenecarbonitrile, 4b,5,6,7,8,83,9,10-octahydro-7-
hydroxy-4b-propyl-7-(1-propynyl)-, [4bR-(4ba,7a,8a(3)]-, MS:
290(M-17)+.
Example 297 2-Phenanthrenol, 4a-butyl-1,2,3,4,4a,9,10,10a-octahydro-2-(1-
propynyl)-7-(pyrazinyloxy)-, [2R(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. MS: 391 (M+1 +.
Examples 298-299
The title compounds of Examples 298-299 were prepared by procedures
analogous to those described above in Example 16.
Example 298 2-Phenanthrenol, 4a-butyl-1 )2,3,4l4a,9,10,10a-octahydro-2-(1-
propynyl)-7-(2-thiazolyl)-, [2fl-(2a,4aa,10ap)]-, MS: 380
(M+1)+.
Example 299 2-Phenanthrenol, 4a-butyl-1,2,3,4,4a,9,10,10a-octahydro-2-(1-
propynyl)-7-(2-pyridinyl)-, [2f?-(2a,4aa,10ap)]-, MS: 3374
(M+1)+.
Example 300 2-Phenanthrenol, 4a-butyl-1,2,3,4,43,9,10,1 Oa-octahydro-2-(1-
propynyl)-7-(2-pyridinyl)-, [2ff-(2a,4aa,10ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
299. MS: 3374 (M+1)+.
Example 301 2-Phenanthrenol, 4a-butyl-1,2,3,4,4a,9,10,10a-octahydro-2-(1-
propynyl)-7-(2-pyrimidinyloxy)-, [2R-(2a,4aa, 10a3)]-
-175-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. MS: 391 (M+1)+.
Example 302 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propyny!)-7-(2-thiazolyl)-, [2ft-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 16. MS: 414 (M+1)+.
Example 303 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(2-pyridinyl)-, [2ft-
(2a,4aa,10ap)]-HCIsalt
The title product of this example is the HCI salt of the title product of Example
16. MS: 408 (M+1)+.
Example 304 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(3-pyridinyl)-, [2ft-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 16. MS: 408 (M+1)+.
Example 305 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(3-pyridinyl)-, [2ft-
(2a,4acc,10ap)]-HCIsalt
The title product of this example is the HCI salt of the title product of Example
304. MS: 408 (M+1 T.
Example 306 2-Phenanthrenol, 4a-butyl-1,2,3,4,4a,9,10l10a-octahydro-2-(1-
propynyl)-7-(pyrazinylmethoxy)-, [2ft-(2a,4aa,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 405 (M+1)+.
Example 307 2-Phenanthrenol, 4a-butyl-1,2,3,4,43,9,10,10a-octahydro-2-(1-
propynyl)-7-(pyrazinylmethoxy)-, [2ft-(2a,4aa,10ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
306. MS: 405 (M+1)+.
Example 308 4H-Benzo[a]quinolizin-4-one, 1,2,3,6,7,11 b-hexahydro-9-
hydroxy-11 b-(phenylmethyl)-3-propyl-
The title compound of this example was prepared by procedures analogous to
those described above in Example 40. MS: 350 (M+1)+.
Examples 309-311
The title compounds of Examples 309-311 were prepared by procedures
analogous to those described above in Example 15.
Example 309 2-Phenanthrenecarbonitrile, 4b-butyl-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-7-(1-propynyl)-, [4bfi-(4ba,7a,8ap)]-, MS:
322 (M+1)+.
Example 310 2-Phenanthrenecarbonitrile, 4b,5,6,7,8,8a,9,10-octahydro-7-(2-
propenyloxy)-4b-propyl-7-(1 -propynyl)-, [4bfl-(4ba,7a,8ap)]-,
1H NMR (400 MHz, CD3OD) 6 5.88-5.97 (m, 1H)
Example 311 Acetic acid, [[7-cyano-1,2,3,4,4a,9,10,10a-octahydro-4apropyl-
2-(1-propynyl)-2-phenanthrenyl]oxy]-, ethyl ester, [2R-
(2a,4aa,10ap)]-, 1H NMR (400 MHz, CD3OD) 8 4.25 (s, 1H).
Example 312 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-(4-pyridinylmethoxy)-, [2R-
(2a,4acc,10ap)]-
The title compound was obtained as described in Example 627, below, except
4-picolyl chloride hydrochloride was used instead of 2-picolyl chloride hydrochloride.
Mass: 442 (M+1 )*
Example 313 2-Phenanthrenecarbonitrile, 4b,5,6,7>8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-, [4bS(4ba,7a,8ap)]-, 1H
NMR (400 MHz, CD3OD) 5 0.88 (t, 3H, J = 7.3), 6.43 (d, 1H, J
= 8.3)
The title compound of this example was prepared by procedures analogous to
those described above in Example 15.
Example 314 2-Phenanthrenol, 7-(5-hexenyloxy)-1,2,3,4,43,9,10,103-
oct3hydro-4a-(phenylmethyl)-2-propyl-, [2ff-(2a,43a,1 Oap)]-
The title compound of this example was prepared by procedures snslogous to
those described above in Example 63. MS: 415 (M-17)+.
Example 315 2-Phenanthrenol, 7-[(4-ethenylphenyl)methoxy]-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-propyl-,
The title compound of this example was prepared by procedures analogous to
those described above in Example 39. MS: 449 (M-17)+.
Example 316 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-(6-methyl-2-pyridinyl)-4b-(phenylmethyl)-7-propyl-,
[4bS-(4ba,7a,8a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. MS: 469 (M+1)+.
Example 317 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-(6-methy!-2-pyridinyl)-4b-(phenylmethyl)-7-propyl-,
[4bS-(4ba,7a,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
316. MS:534(M+1)+.
Example 318 2-Phenanthrenol, 7-[[5-(2,6-dimethyl-4-morpholinyl)pentyl]oxy]-
1,2,3,4,43,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-propyl-
,[2fl-(2a,4aa,10a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 12. MS: 469 (M+1)+.
Examples 319-320
The title compounds of Examples 319-320 were prepared by procedures
analogous to those described above in Example 136.
Example 319 2,7-Phenanthrenediol, 2-(4-fluorophenyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, (4aS,10afl)-, MS: 385 (M-17)+.
Example 320 2,7-Phenanthrenediol, 2-(4-fluorophenyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, (4aS,10afl)-, MS: 385 (M-17)+.
Example 321 2-Phenanthrenol, 4b,5,6,7,8,8a,9,10-octahydro-7-phenyl-4b-
(phenylmethyl)-,(4bS,8afl)-, 1H NMR (400 MHz, CDCI3) 5 6.58-
6.63 (m 2H)
The title compound of this example was prepared by procedures analogous to
those described above in Example 10.
Examples 322-323
The title compounds of Examples 322-323 were prepared by procedures
analogous to those described above in Example 12.
Example322 2-Phenanthrenol, I . S a . Q J
(phenylmethyl)-7-[[5-(1 -piperidinyl)pentyl]oxy]-2-propyl-, [2R-
(2a,4aa,10ap)]-, MS: 504 (M+1)+.
Example 323 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-[[5-(1 -pyrrolidinyl)pentyl]oxy]-, (2R-
(2a,4aa,10ap)]-, MS: 490 (M+1)+.
Example 324 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/\A[(6-methyl-2-pyridinyl)methyl]-4b-(phenylmethyl)-7-
propyl-, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described below in Example 332. MS: 483 (M-17)+.
Example 325 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-A/-[(6-methyl-2-pyridinyl)methyl]-4b-(phenylmethyl)-7-
propyl-, [4bS(4ba,7a,8ap)]- HCI salt
The title compound of this example is the HCI salt of the title compound of
Example 324. MS: 483 (M-17)*.
Example 326 2-Phenanthrenecarboxamide, 7-(4,6-dimethyl-2-pyridinyl)-
4b,5,6,7,8,8a)9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
propyl-, [4bS-(4ba,7a,8ap)j-
The title compound of this example was prepared by procedures analogous to
those described below in Example 332. MS: 483 (M-17)+.
Example 327 2-Phenanthrenecarboxamide, AA(4,6-dimethyl-2-pyridinyl)-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
propyl-, [4bS-(4ba,7a,8a3)]- HCI salt
The title compound of this example is the HCI salt of the title compound of
Example 326. MS: 483 (M-17)+.
Examples 328-331
The title compounds of Examples 328-331 were prepared by procedures
analogous to those described below in Example 332.
Example 328 2-Phenanthrenecarboxamide, 7-(4,6-dimethyl-2-pyridinyl)-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 479 (M+1)+.
Example 329 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-(6-methyl-2-pyridinyl)-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 465 (M+1)+.
Example 330 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-AA[(6-methyl-2-pyridinyl)methyl]-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 479 (M+1)+.
Example 331 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/v4(6-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 479 (M+1)+.
Example 332 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-AA[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
(1 -propynyl)-, [4bS-(4ba,7a,8ap)]-
To a stirring solution of 250 mg of 2-methyl-3-aminomethylpyridine in 5 mL of
dichloromethane at 0 °C under N2 was added 1.02 mL of 2.0 M trimethylaluminum in
toluene. The mixture was stirred at 0 °C for 20 min. then at RT for 1 h. To this
mixture was added 100 mg of the title compound of Example 14 in 5 mL of
dichloromethane. The mixture was heated to reflux overnight. To the reaction
mixture was added 1 N HCI dropwise until the aqueous layer was approximately pH
4. The resultant mixture was extracted with EtOAc, dried over Na2SO4, filtered, and
concentrated to dryness. Purification by flash chromatography over SiO2 using 90%
EtOAc in hexanes as the eluant afforded 99 mg (80 %) of the title product of this
example as a white solid. MS: 479 (M+1)+.
Examples 333-336
The compounds of Examples 333-336 were prepared by procedures
analogous to those described above in Example 244.
Example 333 2-Phenanthrenecarboxamide, A/-(4,6-dimethyl-2-pyrimidinyl)-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 480 (M+1)+.
Example 334 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a)9,10-octahydro-7-
hydroxy-AA(4-methyl-2-pyrimidinyl)-4b-(phenylmethyl)-7-(1-
propynyl)-, [4bS(4ba,7a,8ap)]-, MS: 466 (M+1)+.
Example 335 2-Phenanthrenecarboxamide, /V-(2,6-dimethyl-4-pyrimidinyl)-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-, [4bS-(4ba,7a,8ap)]-, MS: 480 (M+1)+.
Example 336 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propenyl)-, [2R-[2a,2(E),4aa,10ap]]-, MS:
347(M-1)+.
Example 337 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-A/-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
(1 -propynyl)-, [4bS-(4ba,7a,8a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 332. MS: 479 (M+1)+.
Example 338 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,1O-octahydro-7-
hydroxy-A/-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
propyl-, [4bS-(4ba,7a,8ap)]-
To a stirring solution of 232 mg of 2-methyl-3-aminomethylpyridine in 10 ml
of dichloromethane at 0 °C under N2 was added 0.95 mlL of 2.0 M trimethylaluminum
in toluene. The mixture was stirred at 0 °C for 20 min. then at RT for 1 h. To this
mixture was added 300 mg of 2-phenanthrenecarboxylic acid, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propyl)-, methyl ester, [4bS-
(4ba,7a,8a3)]- in 10 mL of dichloromethane. The mixture was heated to reflux
overnight. To the reaction mixture was added 1 N HCI dropwise until the aqueous
layer was approximately pH 4. The resultant mixture was extracted with EtOAc, dried
over Na2SO4, filtered, and concentrated to dryness. Purification by flash
chromatography over SiOg using 10 % isopropanol and 1 % acetone in hexanes to 30
% isopropanol and 5 % acetone in hexanes as the gradient eluant afforded 303 mg
(80 %) of the title product of this example as a white solid. 1H NMR (400 MHz, CDCI3)
5 2.56 (s, 2H), MS: 483 (M+1)+.
Example 339 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8at9,10-octahydro-7-
hydroxy-A/-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
propyl-, [4bS-(4ba,7cc,8ap)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
338. 1H NMR (400 MHz, CD3OD) 8 2.56 (s, 2H), MS: 483 (M+1)+.
Examples 340-342
The title compounds of Examples 340-342 were prepared by procedures
analogous to those described above in Example 338.
Example 340 2-Phenanthrenecarboxamide, /V-[(2-chloro-6-methyl-4-
pyridinyl)methyl]-4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-,[4bS-(4ba,7a,8ap)]-, MS: 517 (M).
Example 341 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9>10-octahydro-7-
hydroxy-/V-[(2-methyl-4-pyridinyl)methyl]-4b-(phenylmethyl)-7-
propyl-, [4bS(4ba,7a,8ap)]-, MS: 483 (M+1)+.
Example 342 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-/V-(2-pyridinylmethyl)-,
[4bS-(4ba,7a,8a3)]-, MS: 469 (M+1)+.
Example 343 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-/V-(2-pyridinylmethyl)-,
[4bS-(4ba,7a,8a3)]-HCI salt
The title product of this example is the HCI salt of the title product of Example
342. MS: 469 (M+1)+.
Examples 344-345
The title compounds of Examples 344-345 were prepared by procedures
analogous to those described above in Example 338.
Example 344 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-AA(4-pyridinylmethyl)-,
[4bS-(4ba,7a,8ap)]-, MS: 469 (M+1)+.
Example 345 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-A/-(3-pyridinylmethyl)-,
[4bS-(4ba,7a,8ap)]-, MS: 469 (M+1)+.
Examples 346-347
The title compounds of Examples 346-347 were prepared by procedures
analogous to those described above in Example 9.
Example 346 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-(4-
methyl-1-pentynyl)-4a-(phenylmethyl)-, [2/-(2a>4aal10ap)]-,
MS: 371 (M-17)+.
Example 347 2,7-Phenanthrenediol, 1, 2,3, 4,4a, 9,10, 10a-octahydro-2-(3-
methyl-1-butynyl)-4a-(phenylmethyl)-, [2fl-(2a,4aa,10a|3)]-,
MS:357(M-17)+.
Example 348 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(3,3,3-trif luoropropyl)-, [2S-(2a,4aa, 1 0ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 487 (M-17)+.
Examples 349-350
The title compounds of Examples 349-350 were prepared by procedures
analogous to those described above in Example 338.
Example 349 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-/V-pyrazinyl-, [4bS-
(4ba,7a,8a(3)]-, MS: 456 (M+1 )+.
Example 350 2-Phenanthrenecarboxamide, 4b)5,6,7,8,8a,9, 1 O-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-/V-2-pyridinyl-, [4bS-
(4ba,7a,8ap)]-, 1H NMR (400 MHz, CD3OD) 8 7.22 (d, 1 H, J =
1).
Examples 351 -353
The title compounds of Examples 351 -353 were prepared by procedures
analogous to those described above in Example 1 0.
Example 351 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-2-(2-
methylpropyl)-4a-(phenylmethyl)-, [2R-(2a,4a(3,10aa)]-, MS:
347(M-17)+.
Example 352 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-2-(2-
methylpropyl)-4a-(phenylmethyl)-, [2R-(2a,4aa,10a(3)]-, MS:
347(M-17)+.
Example 353 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-2-(3-
methylbutyl)-4a-(phenylmethyl)-, [2R-(2a,4aa,10a3)]-, MS: 361
Examples 354-355
The title compounds of Examples 354-355 were prepared by procedures
analogous to those described above in Example 74.
Example 354 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-2-(3-methyl-
1 -butynyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, MS: 448 (M-17)+.
Example 355 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-7-(3-pyridinylmethoxy)-2-(3,3,3-trifluoropropyl)-,
[2S-(2a,43a, 103(3)]-, MS: 496 (M+1)+.
Example 356 4W-Benzo[a]quinolizin-4-one, 1,2,3,6,7,11 b-hexahydro-9-
hydroxy-3-(hydroxymethyl)-11 b-(phenylmethyl)-3-propyl-, (3Scis)-,
1H NMR (400 MHz, CD3OD) 6 4.53 (dm, 1H, J = 13).
The title compound of this example was prepared by procedures analogous to
those described above in Example 42.
Examples 357-358
The title compounds of Examples 357-358 were prepared by procedures
analogous to those described above in Example 9.
Example 357 2-Phenanthreneacetonitrile, 1,2,3,4,4a,9,10,10a-octahydro-
2,7-dihydroxy-4a-(phenylmethyl)-, (4aS,10afl)-, MS: 346 (MD*
Example 358 2-Phenanthreneacetonitrile, 1,2,3,4,4a,9,10,10a-octahydro-
2,7-dihydroxy-4a-(phenylmethyl)-, (435,103/7)-, MS: 346 (MD+.
Examples 359-360
The title compounds of Examples 359-360 were prepared by procedures
analogous to those described above in Example 136.
Example 359 2,7-Phenanthrenediol, 2-cyclopentyl-1,2,3,4,4a,9,10,103-
octahydro-4a-(phenylmethyl)-, (43S,10afl)-, MS: 359 (M-17)+.
Example 360 2,7-Phenanthrenediol, 2-cyclohexyl-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, (4aS,103fl)-, MS: 389 (M-1)+.
Examples 361 -363
The title compounds of Examples 361-363 were prepared by procedures
analogous to those described above in Example 332.
Example 361 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-A/-4-pyridinyl-, [4bS-
(4ba,7a,8ap)]-, MS: 455 (M+1)+.
Example 362 2-Phenanthrenecarboxamide, /V-(2,6-dichloro-4-pyridinyl)-
4b,5,6,718,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
propyl-, [4bS-(4ba,7a,8ap)]-, MS: 523 (M).
Example 363 2-Phenanthrenecarboxamide, 4b,5>6,7)8,8a>9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-A/-3-pyridinyl-, [4bS-
(4ba,7a,8ap)]-, MS: 455 (M+1)+.
Examples 364-365
The title compounds of Examples 364-365 were prepared by procedures
analogous to those described above in Example 76.
Example 364 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-2-(2-
methylpropyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2S-
(2a,4aa,10ap)]-, MS: 456 (M+1)+.
Example 365 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-2-(3-
methylbutyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, MS: 370 (M+1)+.
Examples 366-368
The title compounds of Examples 366-368 were prepared by procedures
analogous to those described above in Example 10.
Example 366 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-(4-
methylpentyl)-4a-(phenylmethyl)-, [2f?-(2a,4aa,10ap)]-, MS:
391 (M-1)+.
Example 367 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-(4-
methylpentyl)-4a-(phenylmethyl)-, [2S-(2a,4ap,10aa)]-, MS:
391 (M-1)+.
Example 368 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-(3-
hydroxy-3-methylbutyl)-4a-(phenylmethyl)-, [2S-
(2a,4act,10ap)]-, MS: 393 (M-1)+.
Examples 369-370
The title compounds of Examples 369-370 were prepared by procedures
analogous to those described above in Example 76.
Example 369 2-Phenanthrenepropanol, 1,2,3,4,43,9,10,1 Oa-octahydro-2-
hydroxy-a,a-dimethyl-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2S-(2a,4aa,10a3)]-, MS: 486 (M+1)+.
Example 370 2-Phenanthrenol, 1,2,3,4,4a,9,10,1Oa-octahydro-2-(4-
methylpentyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,10a(3)]-, MS: 484 (M+1)+.
Examples 371 -372
The title compounds of Examples 371-372 were prepared by procedures
analogous to those described above in Example 9.
Example 371 2,7-Phenanthrenediol, 2-(cyclopropylmethyl)-
1,2,3,4,43,9,10,10a-octahydro-4a-(phenylmethyl)-, [25-
(2a,4aa,10a3)]-, MS: 363 (M+1)+.
Example 372 2,7-Phenanthrenediol, 2-(cyclopropylmethyl)-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-, [2R-
(2a,4ap,10aa)]-, MS: 363 (M+1)+.
Example 373 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-(3-
hydroxypropyl)-4a-(phenylmethyl)-, (4aS,1 OaR}-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 365 (M-1 )*.
Examples 374-375
The title compounds of Examples 374-375 were prepared by procedures
analogous to those described above in Example 9.
Example 374 2,7-Phenanthrenediol, 2-(3,3-dimethyl-1 -butynyl)-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-, [2R-
(2a,4aa,103p)]-, MS: 387 (M-1)*.
Example 375 2,7-Phenanthrenediol, 2-(3,3-dimethyl-1 -butynyl)-
1,2,3,4,4a,9,10,10a-octahydrc~4a-(phenylmethyl)-, [2S-
(2a,4ap,10aa)]-, MS: 387 (M-1)+.
Example 376 2-Phenanthrenol, 2-(cyclopropylethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 464 (M+1)+.
Example 377 2,7-Phenanthrenediol, 2-(2-cyclopropylethyl)-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 361 (M-17)+.
Examples 378-379
The title compounds of Examples 378-379 were prepared by procedures
analogous to those described above in Example 76.
Example 378 2-Phenanthrenol, 2-(3,3-dimethyl-1-butynyl)-
1,2,3,4,43,9,10,10a-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2fl-(2a,4aa,10ap)]-, 1H NMR (400 MHz,
CD3OD)68.61 (s, 1H).
Example 379 2-Phenanthrenepropanol, 1,2,3,4,4a,9,10,10a-octahydro-2-
hydroxy-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2S-
(2a,4aa,10a3)]-, MS: 458 (M+1)+.
Examples 380-381
The title compounds of Examples 380-381 were prepared by procedures
analogous to those described above in Example 9.
Example 380 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
(phenylethynyl)-4a-(phenylmethyl)-, [2fl-(2a,4aa,10a|3)]-, MS:
407(M-1)+.
Example 381 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
(phenylethynyl)-4a-(phenylmethyl)-, [2S-(2a,4a(3,10aa)]-, MS:
407(M-1)+.
Example 382 2,7-Phenanthrenediol, 2-(3,3-dimethylbutyl)-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 391 (M-1 )*.
Example 383 2-Phenanthrenol, 2-(2-cyclopropylethyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,10a3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 450 (M-17)+.
Example 384 2(3/-/)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-, (5)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 3. Mass: 321 (M+1)+
Example 385 (3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-4a-[(4-
hydroxyphenyl)methyl]-7-methoxy-, (S)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 1. Mass: 335 (M+1)+
Examples 386-387
The title compounds of Examples 386-387 were prepared by procedures
analogous to those described above in Example 6.
Example 386 2(1 H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-[(4-hydroxyphenyl)methyl]-, (4aS)-, Mass:321 (M-1)+.
Example 387 2(1 /-y)-Phenanthrenone, 3,4,43,9,10,1 Oa-hexahydro-4a-[(4-
hydroxyphenyl)methyl]-7-methoxy-, (4aS)-, Mass:335 (M-1)+.
Example 388 2,7-Phenanthrenediol, 2-(chloroethynyl)-2,3,4,4a,9,10-
hexahydro-4a-[(4-hydroxyphenyl)methyl]-, (2R-cis)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 8. Mass: 363 (M-17)+.
Example 389 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-, (4aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 6. Mass: 325 (M+1)+.
Examples 390-391
The title compounds of Examples 390-391 were prepared by procedures
analogous to those described above in Example 8.
Example 390 2-Phenanthrenol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[(4-hydroxyphenyl)methyl]-7-methoxy-, Mass:
397(M+1)+.
Example 391 2-Phenanthrenol, 2-(chloroethynyl)-1,2,3,4,4a,9,10,10aoctahydro-
4a-[(4-hydroxyphenyl)methyl]-7-methoxy-, Mass:
397(M+1)+.
Examples 392-393
The title compounds of Examples 392-393 were prepared by procedures
analogous to those described above in Example 10.
Example 392
Example 393
2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-propyl-, (4aS)-, Mass: 366 (M), 384
2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-propyl-, (4aS)-, Mass: 366 (M), 384
Examples 394-406
The title compounds of Examples 394-406 were prepared by procedures
analogous to those described above in Example 77.
2( 1 /-/)-Phenanthrenone, 3,4,4a,9, 1 0, 1 Oa-hexahydro-7-hydroxy-
4a-(phenylmethyl)-,oxime, (4aS)-, Mass: 322 (M+1)+.
2(1H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-(phenylmethyl)-,O-(phenylmethyl)oxime, (4aS)-, Mass: 412
(M+1)*.
2(1AV)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-(phenylmethyl)-, O-[(4-nitrophenyl)methyl]oxime, (4aS)-,
Mass: 457 (M+1)+.
2(3H)-Phenanthrenone, 4,4a,9, 1 0-tetrahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-, O-ethyloxime, (S), Mass: 364 (M+1)+.
2(1H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-1,7,10atrihydroxy-
4a-[(4-hydroxyphenyl)methyl]-, O-ethyloxime, Mass:
398(M+1)+.
2(1 H)-Phenanthrenone, 3,4,4a,9,10,1 Oa-hexahydro- 1,7,1 Oatrihydroxy-
4a-[(4-hydroxyphenyl)methyl]-, O-ethyloxime, Mass:
398(M+1)+.
Benzoic acid, [3,4,4a,9,10,10a-hexahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-2(1H)-phenanthrenylidene]hydrazide,
(4aS-trans)-, Mass: 441 (M+1)+.
2(1 /-/)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-[(4-hydroxyphenyl)methyl]-, O-2-propenyloxime, (4aS
trans)-, Mass: 378 (M+1)+.
Acetic acid, [[[3,4,4a,9,10,10a-hexahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-2(1W)-phenanthreny1idene]amino]oxy]-,
(4aSf/-ans)-, Mass: 396 (M+1)+.
Example 394
Example 395
Example 396
Example 397
Example 398
Example 399
Example 400
Example 401
Example 402
Example 403 Hydrazinecarboxylic acid, [3,4,4a,9,10,1 Oa-hexahydro-7-
hydroxy-4a-[(4-hydroxyphenyl)methyl]-2(1H)-
phenanthrenylidene]-, ethyl ester,(4aS-frans)-, Mass: 409
(M+1)+.
Example 404 Acetic acid, [[[3,4,4a,9,10,1 Oa-hexahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-2(1H-phenanthrenylidene]arnino]oxy]-,
methyl ester, (4aS-trans)-, Mass: 410 (M+1)+.
Example 405 2(3H)-Phenanthrenone, 4,4a,9,10-tetrahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-, O-methyloxime, Mass: 350 (M+1)+.
Example 406 3-Pyridinecarboxylic acid, [3,4,4a,9,10,10a-hexahydro-7-
hydroxy-4a-[(4-hydroxyphenyl)methyl]-2(1/-/)-
phenanthrenylidene]hydrazide,(4aSfrans)-, Mass: 442 (M+1)+.
Example 407 Acetic acid, [4,4a,9,10-tetrahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-2(3H)-phenanthrenylidene]-, ethyl
ester, [S-(E)]~
The title compound of this example was prepared by procedures analogous to
those described above in Example 78. Mass: 391 (M+1)+.
Example 408 Acetic acid, cyano-, [3,4,4a,9,10,1 Oa-hexahydro-7-hydroxy-4a-
[(4-hydroxyphenyl)methyl]-2(1 H)-
phenanthrenylidene]hydrazide,(4aS-frans)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 77. Mass: 404 (M+1)+.
Example 409 2,7-Phenanthrenediol, 4a-[(4-aminophenyl)methyl]-
1,2,3,4,4a,9,10,10a-octahydro-[2ft-(2a,4aa, 10a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 6. Mass: 322 (M-1)+.
Examples 410-411
The title compounds of Examples 410-411 were prepared by procedures
analogous to those described above in Example 77.
Example 410 Hydrazinecarboxylic acid, [4,4a,9,10-tetrahydro-7-hydroxy-4a-
[(4-hydroxyphenyl)methyl]-2(3W)-phenanthrenylidene]-, ethyl
ester, (S)-, Mass: 407 (M+1)+.
Example 41 1 2(1 AV)-Phenanthrenone, 4a-[(4-aminophenyl)methyl]-
3,4,43,9, 10,10a-hexahydro-7-hydroxy-, Oethyloxime, Mass:
365(M+1)+.
Examples 41 2-41 3
The title compounds of Examples 412-413 were prepared by procedures
analogous to those described above in Example 1 0.
Example 412 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[[4-
[(1-methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,10afl-,
Mass: 408 (M+1)+.
Example 41 3 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9, 1 0, 1 0a-octahydro-4a-[[4-
[(1-methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,10af?)-,
Mass: 408 (M+1)+.
Examples 41 4-41 5
The title compounds of Examples 414-415 were prepared by procedures
analogous to those described above in Example 77.
Example 414 2(1 W)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-[[4-[(1 -methylethyl)amino]phenyl]methylj-, O-ethyloxime,
(4aS-trans)-, Mass: 407 (M+1)+.
Example 415 2(1 H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-[[4-[(1 -methylethyl)amino]phenyl]methyl]-, O-methyloxime,
(4aS-trans)-, Mass: 393 (M+1)+.
Examples 41 6-41 8
The title compounds of Examples 416-418 were prepared by procedures
analogous to those described above in Example 78.
Example 416 2-Phenanthrenol, 4b,5l6,7,8,8a,9,10-octahydro-4b-[(4-
hydroxyphenyl)methyl]-7-propylidene-, (4bS,72)-, Mass: 349
Example 417 2-Phenanthrenol, 7-butylidene-4b,5,6,7,8,8a,9,10-octahydro-
4b-[(4-hydroxyphenyl)methyl]-, (4bS,72)-, Mass: 363 (M+1)+.
Example 418 Acetonitrile, [3,4,4a,9,10,10a-hexahydro-7-hydroxy-4a-[(4-
hydroxyphenyl)methyl]-2(1 H-phenanthrenylidene]-, [4aS
(2Z,4aa,10ap)]-, Mass: 363 (M+18)+.
Examples 41 9-421
The title compounds of Examples 419-421 were prepared by procedures
analogous to those described above in Example 1 36.
Example 419 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[[4-
[(tetrahydro-2/-Apyran-4-yl)amino]phenyl]methyl]-2-propyl-,
(4aS,10afl)-, Mass: 450 (M+1)+.
Example 420 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[[4-
[(tetrahydro-2H-pyran-4-yl)amino]phenyl]methyl]-2-propyl-,
{4aS,10afl)-, Mass: 450 (M+1)+.
Example 421 2,7-Phenanthrenediol, 1 ,2,3,4 ,4a,9,10,10a-octahydro-4a-[[4-
[(1 -methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,1 Oafl)-,
Mass: 409 (M+1)+.
Example 422 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-(1 -hydroxypropyl)-, (4aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 30. Mass: 400 (M+18)*.
Examples 423-426
The title compounds of Examples 423-426 were prepared by procedures
analogous to those described above in Example 1 36.
Example 423 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-propyl-, (4aS,10a/7)-, Mass: 349
Example 424 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-propyl-, (4aS,10afl)-, Mass: 349
Example 425 2,7-Phenanthrenediol, 1 ,2,3,4,43,9,1 0,1 Oa-octahydro-4a-[[4-
[[1-(1-methylethyl)-4-piperidinyl]amino]phenyl]methyl]-2-propyl-
,(4aS,10afl)-, Mass: 491 (M+1)+.
Example 426 2,7-Phenanthrenediol, 1 ,2,3,4,43,9,10, 1 0a-octahydro-4a-[[3-
[(1-methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,10afl)-,
Mass: 408 (M+1)+.
Example 427 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9, 1 0, 1 0a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-(1 -hydroxypropyl)-, (4aS, 1 0aS}-
The title compound of this example was prepared by procedures analogous to
those described above in Example 30. Mass: 382 (M).
Examples 428-429
The title compounds of Examples 428-429 were prepared by procedures
analogous to those described above in Example 78.
Example 428 2-Phenanthrenol, 7-butylidene-4b,516,7,8,8a,9, 10-octahydro-
4b-[(4-hydroxyphenyl)methyl]-, [4bS-(4ba,7Z,8aa)]-, Mass: 363
(M+1)+.
Example 429 2-Phenanthrenol, 4b,5,6I7,8,8a,9>10-octahydro-4b-[(4-
hydroxyphenyl)methyl]-7-pentylidene-, [4bS-(4ba,7Z,8aa)]-,
Mass: 377 (M+1)+.
Examples 430-432
The title compounds of Examples 430-432 were prepared by procedures
analogous to those described above in Example 77.
Example 430 2(1 /-^-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-[(4-hydroxyphenyl)methyl]-, O-(phenylmethyl)oxime, (4aScis)-,
Mass: 428 (M+1)+.
Example 431 2(1 /-/)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-[(4-hydroxyphenyl)methyl]-, O-2-propenyloxime, (4aS-c/s)-,
Mass: 378 (M+1)+.
Example 432 2(1 H)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-[(4-hydroxyphenyl)methyl]-, Oethyloxime, (4aS-c/s)-, Mass:
366(M+1)+.
Example 433 2,7-Phenanthrenediol, 4a-[(3-aminophenyl)methyl]-
1,2,3,4,43,9,10,10a-octahydro-2-propyl-, (4aS,10aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. Mass: 366 (M+1)+.
Examples 434-435
The title compounds of Examples 434-435 were prepared by procedures
analogous to those described above in Example 9.
Example 434 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-1-
propynyl]-, (4aS,10aS)-, Mass: 481 (M+18)*.
Example 435 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-[(4-
hydroxyphenyl)methyl]- 2-[3-[(tetrahydro-2H-pyran-2-yl)oxy]-1 -
propynyl]-, (4aS,10aS)-, Mass: 481 (M+18)+.
Examples 436-438
The title compounds of Examples 436-438 were prepared by procedures
analogous to those described above in Example 136.
Example 436 2,7-Phenanthrenediol, 2-butyl-1,2,3,4,4a,9,10,10a-octahydro-
4a-[(4-hydroxyphenyl)methyl]-, (4aS,10aS)-, Mass: 380 (M).
Example 437 2,7-Phenanthrenediol, 2-butyl-1,2,3,4,4a,9,10,10a-octahydro-
4a-[(4-hydroxyphenyl)methyl]-, (4aS,10aS)-, Mass: 381
Example 438 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[[3-
[(1-methyl-4-piperidinyl)amino]phenyl]methyl]-2-propyl-,
(4aS,10af?)-, Mass: 463 (M+1)+.
Example 439 2,7-Phenanthrenediol, 4a-[(3-aminophenyl)methyl]-
1 ,2,3,4,43,9, 10,1 Oa-octahydro-2-( 1 -propynyl)-, (4aS, 1 QaFT)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 362 (M+1 )+.
Examples 440-442
The title compounds of Examples 440-442 were prepared by procedures
analogous to those described above in Example 1 36.
Example 440 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-[[3-
(methylamino)phenyl]methyl]-2-propyl-, (4aS,10aS)-, Mass:
380 (M+1 )+.
Example 441 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-4a-[[3-
[(1 -methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,1 Oaf?)-,
Mass: 408 (M+1 T.
Example 442 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-[[3-
[(1 -methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,1 Oafl)-,
Mass: 408 (M+1 )+.
Examples 443-444
The title compounds of Examples 443-444 were prepared by procedures
analogous to those described above in Example 9.
Example 443 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-[[3-
[(1 -methylethyl)amino]phenyl]methyl]-2-(1 -propynyl)-,
(4aS,10aS)-, Mass: 404 (M+1)+.
Example 444 2,7-Phenanthrenediol, 2-ethynyl-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-[[3-[(1-methylethyl)amino]phenyl]methyl]-,
(4aS,10aS)-, Mass: 390 (M+1)+.
Example 445 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[[4-
[(methylsulfonyl)oxy]phenyl]methyl]-2-propyl-, (4aS,1 OaS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. Mass: 462 (M+14)+.
Examples 446-447
The title compounds of Examples 446-447 were prepared by procedures
analogous to those described above in Example 77.
Example 446 2(1H)-Phenanthrenone, 3,4,43,9, 10,1 Oa-hexahydro-7-hydroxy-
4a-(phenylmethyl)-,O-ethyloxime, (4aS-trans)-, Mass: 350
(M+1)+.
Example 447 2(1/^)-Phenanthrenone, 3,4,4a,9,10,10a-hexahydro-7-hydroxy-
4a-(phenylmethyl)-,O-ethyloxime, (4aS-trans)-, Mass: 350
Examples 448-449
The title compounds of Examples 448-449 were prepared by procedures
analogous to those described above in Example 9.
Example 448 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(2-pyridinylethynyl)-, (4aS,10afl)-, Mass: 410
(M+1)+.
Example 449 2,7-Phenanthrenediol, 4a-[[3-(dimethylamino)phenyl]methyl]-
1 ,2,3,4,4a,9, 10,10a-octahydro-2-(1-propynyl)-, (4aS,10afl)-,
Mass: 390 (M+1)+.
Example 450 2-Phenanthrenol, 4b-[[3-(dimethylamino)phenyl]methyl]-7,7-
diethoxy-4b,5,6,7,8,8a,9,1 0-octahydro-, (4bS-trans)-
The title compound of this example was prepared by procedures analogous to
those described above Preparation 5. Mass: 424 (M+1 )+.
Example 451 2-Phenanthrenol, 7I7-diethoxy-4b,5,6,7,8,8a,9,10-octahydro-
4b-(phenylmethyl)-, (4bS-trans)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 77. Mass: 335 (M-45)+.
Example 452 2,7-Phenanthrenediol, 2-[3-(dimethylamino)-1-propynyl]-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-,
(4aS,10afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 390 (M+1)+.
Example 453 2(1 H)-Phenanthrenone, 4a-[[3-(dimethylamino)phenyl]methyl]-
3,4,4a,9,10,10a-hexahydro-7-hydroxy-, O-ethyloxime, (4aStrans)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 77. Mass: 393 (M+1)+.
Examples 454-456
The title compounds of Examples 454-456 were prepared by procedures
analogous to those described above in Example 136.
Example 454 2,7-Phenanthrenediol, 4a-[(4-aminophenyl)methyl]-
1,2,3,4,43,9,10,10a-octahydro-2-propyl-, (4aS,10aS)-, Mass:
348(M-17)+.
Example 455 Acetamide, AA[4-[(1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
propyl-4a(2H)-phenanthrenyl)methyl]phenyl]-, (4aS,1 OsS)-,
Mass: 407 (M).
Exsmple 456 Acetsmide, A/-[3-[[2-(acetyloxy)-1,3,4,9,10,1 Oa-hexahydro-7-
hydroxy-2-propyl-4a(2H)-phenanthrenyl)methyl]phenyl]-,
(4aS,10aS)-, Mass: 450 (M+1)+.
Exsmple 457 2,7-Phenanthrenediol, 4a-[[4-(dimethylamino)phenyl]methyl]-
1,2,3,4,4a,9,10,10a-octahydro-2-(1-propynyl)-, (4aS,10a/:?)-
The title compound of this example was prepared by procedures analogous to
those described above Example 9. Mass: 390 (M+1)+.
Example 458 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[[4-
[(1 -methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,1 OsS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. Mass: 408 (M+1)+.
Example 459 Carbamic acid, dimethyl-, 7-(chloroethynyl)-4b,5,6,7)8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-2-phenanthrenyl ester,
(4bS,8afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 58. Mass: 438 (M+1)+.
Example 460 Acetamide, /V-[3-[[1,3,4,9,10,10a-hexahydro-2,7-dihydroxy-2-
(1-propynyl)-4a(2/-/)-phenanthrenyl]methyl]phenyl]-, [2R-
(2a,4aa,10a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 386 (M-17)+.
Example 461 1 -Pyrrolidinecarboxylic acid, 7-(chloroethynyl)-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-2-
phenanthrenyl ester, (4bS,8a/?)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 58. Mass: 464 (M).
Examples 462-465
The title compounds of Examples 462-465 were prepared by procedures
analogous to those described above in Example 136.
Example 462 Cyanamide, [3-[(1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
propyl-4a(2/-/)-phenanthrenyl)methyl]phenyl]-, (4aS,1 OaS)-,
Mass: 389 (M-1)+
Example 463 Cyanamide, [3-[(1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
propyl-4a(2H)-phenanthrenyl)methyl]phenyl]-, (4aS, 10aS)-,
Mass: 389 (M-1)+
Example 464 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-propyl-
4a-[[3-[(tetrahydro-2/-/-pyran-4-yl)amino]phenyl]methyl]-,
(4aS,10aS)-, Mass: 450 (M+1)+
Example 465 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-propyl-
4a-[[3-[(tetrahydro-2/-/-pyran-4-yl)amino]phenyl]methyl]-,
(4aS,10aS)-, Mass: 450 (M+1)+
Example 466 Carbamic acid, dimethyl-, 4-[[7-[[(dimethylamino)carbonyl]oxy]-
1,3,4,9,10,1Oa-hexahydro-2-hydroxy-2-propyl-4a(2H)-
phenanthrenyl]methyl]phenyl ester,(4aS, 10aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 58. Mass: 526 (M+18)+.
Example 467 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-[[4-
[(1 -methylethyl)amino]phenyl]methyl]-2-propyl-, (4aS,1 OaS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. Mass: 408 (M+1)+.
Example 468 2( 1 H)-Phenanthrenone, 4a-[(3-aminophenyl)methyl]-
3,4,4a,9,10,10a-hexahydro-7-hydroxy-, O-ethyloxime, (4aStrans)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 77. Mass: 365 (M+1)+.
Example 469 Carbamic acid, dimethyl-, 4b,5,6,7,8,8a,9,1O-octahydro-7-
hydroxy-4b-[[4-[(1-methylethyl)amino]phenyl]methyl]-7-propyl-
2-phenanthrenyl ester,(4bS,8aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 58. Mass: 479 (M+1)+.
Example 470 2-Phenanthrenol, 4b-[(3-aminophenyl)methyl]-7-
(ethoxyamino)-4b,5,6,7,8,8a,9,10-octahydro-, (4bS,8afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. Mass: 367 (M+1)+.
Examples 471 -472
The title compounds of Examples 471-472 were prepared by procedures
analogous to those described above in Examples 58.
Example 471 Carbamic acid, dimethyl-, 4b-[(3-aminophenyl)methyl]-7-
(ethoxyimino)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl
ester, (4aS-trans)-, Mass: 436 (M+1)+.
Example 472 Carbamic acid, dimethyl-, 4b-[[3-
[[(dimethylamino)carbonyl]amino]phenyl]methyl]-7-
(ethoxyimino)-4b,5,6,7,8,8a,9,10-octahydro-2-phenanthrenyl
ester, (4aS-frans)-, Mass: 407 (M+1)+.
Example 473 2,7-Phenanthrenediol, 4a-[[4-(dimethylamino)phenyl]methyl]-
1,2,3,4,4a,9,10,1 Oa-octahydro-2-(1 -propynyl)-, (4aS,1 OaS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 390 (M+1)+.
Example 474 Carbamic acid, dimethyl-, 4b-[[4-
(dimethylamino)phenyl]methyl]-4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,(4bS,8aR)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 58. Mass: 461 (M+1)+.
Example 475 2-Phenanthrenol, 4b-[[3-(dimethylamino)phenyl]methyl]-7-
(ethylamino)-4b,5,6,7>8,8a,9,10-octahydro-, (4bS,8aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Preparation 4. Mass: 379 (M+1)+.
Example 476 Acetamide, /V-[4a-[[3-(dimethylamino)phenyl]methylJ-
1,2,3,4,4a,9,10,1 Oa-octahydro-7-hydroxy-3-phenanthrenyl]-/Vethyl-,
(4aft,10aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 47. Mass: 421 (M+1)+.
Example 477 Acetamide, A/-[4-[[1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
(1-propynyl)-4a(2H)-phenanthrenyl]methyl]phenyl]-,
(4aS,10afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 404 (M+1)+.
Examples 478-479
The title compounds of Examples 478-479 were prepared by procedures
analogous to those described above in Example 58.
Example 478 1 -Piperazinecarboxylic acid, 4-methyl-, 4b-[[3-
(dimethylamino)phenyl]methyl]-4b,5,6,7,8,8a,9, 10-octahydro-
7-hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,(4bS,8a/r?)-1
Mass: 516 (M+1)+
Example 479 2,7-Phenanthrenediol, 4a-[[3-(dimethylamino)phenyl]methyl]-
1,2,3,4,43,9,10,1 Oa-octahydro-2-(1-propynyl)-, 7-carbamate,
(4aS,10afl)-, Mass: 433 (M+1)+
Example 480 4-Morpholinecarboxamide, A/-[4-[[1,3,4,9,10,10a-hexahydro-
2,7-dihydroxy-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-, [2f?-(2a,4aa, 10afi)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 476 (M+2)+.
Example 481 Carbamic acid, [3-(dimethylamino)propyl]-, 4b-[[3-
(dimethylamino)phenyl]methyl]-4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,(4bS,8R)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 518 (M+1)+.
Example 482 Acetamide, /V-[4-[[7-[(aminocarbonyl)oxy]-1,3,4,9,10,10ahexahydro-
2-hydroxy-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-, (4aS,10aR)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 55. Mass: 447 (M+1)+.
Example 483 Benzonitrile, 4-[[1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
propyl-4a(2H)-phenanthrenyl]methyl]-, (4aS,10aS)-
The title compound of this example was prepared by procedures analogous to
those described above or below in Example 136. Mass: 375 (M).
Examples 484-487
The title compounds of Examples 484-487 were prepared by procedures
analogous to those described above in Example 59.
Example 484 Carbamic acid, [2-(1 -pyrrolidinyl)ethyl]-, 4b-[[3-
(dimethylamino)phenyl]methyl]-4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,[4bS-
(4bcc,7cx,8ap)]-, Mass: 530 (M+1)+.
Example 485 1 -Piperidinecarboxylic acid, 4-(dimethylamino)-,4b-[[3-
(dimethylamino)phenyl]methyl]-4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-7-(1-propynyl)-2-phenanthrenyl ester, [4bS-
(4ba,7a,8ap)]-, Mass: 544 (M+1)+
Example 486 1 -Piperazinecarboxylic acid, 4-acetyl-, 4b-[[3-
(dimethylamino)phenyl]methyl]-4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,[4bS-
(4ba,7a,8ap)]-, Mass: 544 (M+1)+.
Example 487 2,7-Phenanthrenediol, 4a-[[3-(dimethylamino)phenyl]methyl]-
1,2,3,4,4a,9,10)10a-octahydro-2-(1 -propynyl)-, 7-
(methylcarbamate), [2fl-(2a,4aa,10ap)]-, Mass: 447 (M+1)+.
Examples 488-489
The title compounds of Examples 488-489 were prepared by procedures
analogous to those described above in Example 6.
Example 488 2(1 H)-Phenanthrenone, 4a-[[3-(dimethylamino)phenyl]methyl]-
3,4,4a,9,10,10a-hexahydro-7-hydroxy-, (4aS-trans)-, Mass:
350(M+1)+.
Example 489 Carbamic acid, [4-[(1,3,4,9,10,1 Oa-hexahydro-7-hydroxy-2-
oxo-4a(2/-/)-phenanthrenyl)methyl]phenyl]-, 1,1-dimethylethyl
ester, (4aS-trans)-, Mass: 423 (M+2)+.
Example 490 Carbamic acid, 1H-1,2,4-triazol-3-yl-, 4b-[[3-
(dimethylamino)phenyl]methyl]-4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,(4bS,8a/:?)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 500 (M+1)+.
Example 491 2,7-Phenanthrenediol, 4a-[[3-(dimethylamino)phenyl]methyl]-
1,2,3,4,43,9,10,10a-octahydro-2-propyl-, [2ft-(2a,4aa,10aa)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 136. Mass: 395 (M+2)+.
Examples 492-495
The title compounds of Examples 492-495 were prepared by procedures
analogous to those described above in Example 9.
Example 492 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-[(4-
hydroxyphenyl)methyl]-2-(1-propynyl)-, [2R-(2a,4aa,10ap)]-I
Mass: 362 (M).
Example 493 Glycine, /V-[3-[[1,3,4,9,10,1 Oa-hexahydro-2-hydroxy-7-(2-
methoxy-2-oxoethoxy)-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-/V-methyl-, methyl ester, [2R-
(2a,4aa,10ap)]-, Mass: 521 (M+2)+.
Example 494 Glycine, A/-[3-[[1,3,4,9,10,10a-hexahydro-2-hydroxy-7-(2-
methoxy-2-oxoethoxy)-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-/V-(2-methoxy-2-oxoethyl)-
,methyl ester, [2/?-(2cc,4aa,10ap)]-, Mass: 579 (M+2)+.
Example 495 Urea, /V-[4-[[1,3,4)9,10,10a-hexahydro-2,7-dihydroxy-2-(1-
propynyl)-4a(2/-/)-phenanthrenyl]methyl]phenyl]-/V,/V-dimethyl-,
[2f?-(2a,4aa,10a(3)]-, Mass: 435 (M+2)+.
Example 496 Acetamide, 2-[[3-[[7-(2-amino-2-oxoethoxy)-1,3,4,9,10,10ahexahydro-
2-hydroxy-2-(1-propynyl)-4a(2H)-
phenanthrenyljmethyljphenyljmethylamino]--
(2a,4aa,10a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 55. Mass: 491 (M+2)+.
Examples 497-499
The title compounds of Examples 497-499 were prepared by procedures
analogous to those described above in Example 9.
Example 497 Methanesulfonamide, AA[4-[[1,3,4,9,10,1 Oa-hexahydro-2,7-
dihydroxy-2-(1 -propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-, [2/7-(2a,4aa,10ap)]-, Mass:
442 (M+3)+.
Example 498 Acetamide, AA[4-[[1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
(1 -propynyl)-4a(2H)-phenanthrenyl]methyl]phenyl]-, [2/7-
(2a,4aa,10ap)]-, Mass: 404 (M+1)+.
Example 499 Acetamide, /V-[4-[[1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
(1 -propynyl)-4a(2H)-phenanthrenyl]methyl]phenyl]-, [2R-
(2a,4aa,10ap)]-, Mass: 404 (M+1)+.
Example 500 Carbamic acid, [2-(1 -pyrrolidinyl)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 470 (M-16)+.
Example 501 2-Pyridinecarboxamide, AA[4-[[1,3,4,9,10,1 Oa-hexahydro-2,7-
dihydroxy-2-(1 -propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-, [2ff-(2a,4aa, 10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 434 (M-32)+.
Example 502 Carbamic acid, [2-(1-pyrrolidinyl)ethyl]-, 4b,5,6,7,8,8a,9l10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyl ester.monohydrochloride, [4bS-(4bcc,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 506 (M-17)+.
Example 503 5-lsoxazolecarboxamide, /V-[4-[[1,3,4,9,10,1Oa-hexahydro-2,7-
dihydroxy-2-(1 -propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-, [2f?-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 459 (M+3)+.
Example 504 Acetamide, 2-[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]oxy]-, [4bS-
(4ba,7a,8a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 55. Mass: 404 (M+1 )+.
Example 505 1(2H)-Pyrimidineacetamide, A/-[4-[[1,3,4,9,10,10a-hexahydro-
2,7-dihydroxy-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-3,4-dihydro-5-methyl-2,4-dioxo-,
[2fl-(2a,4acc,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 546 (M+18+
Example 506 Carbamic acid, dimethyl-, 2-[[7-[[(dimethylamino)carbonyl]oxy]-
4b-[[3-(dimethylamino)phenyl]methyl]-4b,5,6>7,8,8a,9,10-
octahydro-7-(1 -propynyl)-2-phenanthrenyl]oxy]ethyl ester,
[4bS-(4bcc,7a,8apv)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 576 (M+1 )+.
Example 507 Acetamide, N-[2-(dimethylamino)ethyl]-2-[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]-,[4bS-(4ba,7cc,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. Mass: 476 (M+2)+.
Examples 508-511
The title compounds of Examples 508-511 were prepared by procedures
analogous to those described above in Example 59.
Example 508 Carbamic acid, [3-(dimethylamino)propyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester,[4bS-(4ba,7a,8a[3)]-, Mass: 457 (M-17)+.
Example 509 Carbamic acid, dimethyl-, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-2,7-phenanthrenediyl ester, [2R-
(2a,4aa,10ap)]-, Mass: 489 (M+1)+.
Example 510 Carbamic acid, [2-(4-morpholinyl)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester,[4bS-(4ba,7a,8a[3)]-, Mass: 485 (M-17)+.
Example 511 Carbamic acid, [3-(1 H-imidazol-1 -yl)propyl]-,
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-2-phenanthrenyl ester,[4bS-(4ba,7a,8a3)]-, Mass:
498 (M+1)*.
Example 512 Acetic acid, [[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]oxy]-, methyl
ester, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 54. Mass: 418 (M).
Example 513 1 H-lmidazole-4-sulfonamide, /V-[4-[[1,3,4,9,10,1 Oa-hexahydro-
2,7-dihydroxy-2-(1-propynyl)-4a(2H)-
phenanthrenyl]methyl]phenyl]-1 -methyl-, [2fl-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 523 (M+18)+.
Example 514 Acetamide, A/-[2-(4-morpholinyl)ethyl]-2-[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]-,[4bS-(4bcc,7a,8a3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. Mass: 517 (M+1 )+
Example 515 Acetamide, 2,2'-[[1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-2,7-
phenanthrenediyl]bis(oxy)]bis-, [2f?-(2a,4ace,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 55. Mass: 459 (M-1)+.
Example 516 Acetamide, A/-[3-(1 H-imidazol-1-yl)propyl]-2-
[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-2-phenanthrenyl]oxy]-,[4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. Mass: 512 (M+1)+.
Example 517 Carbamic acid, [2-(dimethylamino)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenylester,[4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 461 (M+1)+.
Example 518 Carbamic acid, [2-(dimethylamino)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenylester,[4bS-(4ba,7a,8a|3)]-HCI
The title product of this example is the HCI salt of the title product of Example
517. Mass: 498 (M+1)+.
Examples 519-523
The title compounds of Examples 519-523 were prepared by procedures
analogous to those described above in Example 244.
Example 519 Acetamide, 2-[[4b,516,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-/V-[2-(3-
pyridinyl)ethyl]-,[4bS-(4ba,7cx>8ap)]-, Mass: 509 (M+1)+.
Example 520 Piperazine, 1 -methyl-4-[[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyl]oxy]acetyl]-,[4bS-(4ba,7a,8ap)]-, Mass: 487
Example 521 Acetamide, A/-[3-(4-methyl-1-piperazinyl)propyl]-2-
[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1 -propynyl)-2-phenanthrenyl]oxy]-,[4bS(4ba,7a,8ap)]-, Mass:
544 (M+1)+.
Example 522 Piperidine, 1-[[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]acetyl]-4-
(1-pyrrolidinyl)-,[4bS(4ba,7a,8a3)]-> Mass: 541 (M+1)+.
Example 523 Acetamide, A/-methoxy-2-[[4b,5,6,7,8,8a,9.,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 432 (M-1)+.
Example 524 2-Phenanthrenol, 7-[(4,5-dihydro-1 H-imidazol-2-yl)methoxy]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(1-
propynyl)-,[2R-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 429 (M+1)+.
Examples 525-526
The title compounds of Examples 525-526 were prepared by procedures
analogous to those described above in Example 59.
Example 525 Carbamic acid, [3-(1-pyrrolidinyl)propyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester,[4bS-(4ba,7a,8ap)]-, Mass: 501 (M+1)+.
Example 526 Acetamide, /V-hydroxy-2-[[4b,5,6,7,8,8a,9,1O-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 418 (M-1)+.
Examples 527-528
The title compounds of Examples 527-528 were prepared by procedures
analogous to those described above in Example 67.
Example 527 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[2-(1 -pyrrolidinyl)ethoxy]-,
Mass: 444 (M+1)+; isomer of title compound of Example 528.
Example 528 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[2-(1 -pyrrolidinyl)ethoxy]-,
Mass: 444 (M+1)+; isomer of title compound of Example 527.
Examples 529-535
The title compounds of Examples 529-535- were prepared by procedures
analogous to those described above in Example 244.
Example 529 Acetamide, A/-(methylsulfonyl)-2-[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyljoxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 480 (M-1)+.
Example 530 Acetamide, 2-[[4b,5,Q,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-/V-(2-
pyridinylmethyl)-, [4bS-(4ba,7cc,8ap)]-, Mass: 495 (M+1)+.
Example 531 Acetamide, 2-[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-AA(3-
pyridinylmethyl)-, [4bS-(4ba,7 Example 532 Acetamide, 2-[[4b,5,6,7,8)8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-A/-3-
pyridinyl-, [4bS-(4ba,7a,8ap)]-, Mass: 481 (M+1)+.
Example 533 Acetamide, 2-[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-/Vpyrazinyl-,
[4bS-(4bcc,7a,8ap)]-, Mass: 482 (M+1)+.
Example 534 Ethanimidamide, 2-[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-
4b-(phenylmethyl)-7-(1 -propynyl)-2-phenanthrenyl]oxy]-, [4bS-
(4ba,7a,8ap)]-, Mass: 403 (M+1)+.
Example 535 Carbamic acid, [2-(1 -pyrrolidinyl)ethyl]-, 4b-[[4-
(acetylamino)phenyl]methyl]-4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-7-(1 -propynyl)-2-phenanthrenyl ester,[4bS-
(4ba,7a,8ap)]-, Mass: 544 (M+1)+.
Example 536 Carbamothioic acid, dimethyl-, O[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl] ester, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 434 (M+1)+.
Examples 537-538
The title compounds of Examples 537-538 were prepared by procedures
analogous to those described in Example 74.
Example 537
Example 538
2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(2-pyrimidinyloxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 425 (M+1)+.
2-Phenanthrenol, 7-[(2-amino-6-methyl-4-pyrimidinyl)oxy]-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-(1 -
propynyl)-,[2/?-(2a,4aa,10ap)]-, Mass: 454 (M+1)+.
Example539 Acetamide, /V-[2-(1-methyl-2-pyrrolidinyl)ethyl]-2-
[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1-propynyl)-2-phenanthrenyl]oxy]-,[4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. Mass: 515 (M+1)+.
Example 540 Carbamic acid, [2-(1 -methyl-2-pyrrolidinyl)ethyl]-,
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-
(1 -propynyl)-2-phenanthrenyl ester, [4bS-(4ba,7a,8a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 501 (M+1)+.
Example 541 3-Pyridinecarboxamide, 6-[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyljoxy]-, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 467 (M+1 )*.
Example 542 Carbamic acid, [2-(1 -pyrrolidinyl)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(2-propenyl)-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 437 (M+1)+.
Examples 543-544
The title compounds of Examples 543-544 were prepared by procedures
analogous to those described above in Example 69.
Example 543 2-Phenanthrenol, 7-[[5-[2-(dimethylamino)ethyl]-1,2,4-
oxadiazol-3-yl]methoxy]-1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-, [2/?-(2a,4aa,10ap)]-, Mass:
500 (M+1)+.
Example 544 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-7-[[5-(1 -piperidinylmethyl)-1,2,4-oxadiazol-3-
yl]methoxy]-2-(1-propynyl)-, [2ft-(2a,4aa,10a|3)]-, Mass: 526
Example 545 2-Phenanthrenol, 7-[(4,6-dimethoxy-1 ,3,5-triazin-2-yl)oxy]-
1 ,2,3,4,43,9, 10,1 Oa-octahydro-4a-(phenylmethyl)-2-(1 -
propynyl)-, [2f?-(2a,4aa,10a3)JThe
title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 486 (M+1 )+.
Examples 546-547
The title compounds of Examples 546-547 were prepared by procedures
analogous to those described above in Example 72.
Example 546 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-7-[[3-(1 -piperidinylmethyl)-1 ,2,4-oxadiazol-5-
yl]methoxy]-2-(1-propynyl)-,[2/?-(2a,4aa,10ap)]-, Mass: 526
(M+1)+.
Example 547 2-Phenanthrenol, 1 ,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[[3-(2-pyridinyl)-1 ,2,4-
oxadia2ol-5-yl]methoxy]-,[2fl-(2a,4aa,10ap)]-l Mass: 506
Examples 548-550
The title compounds of Examples 548-550 were prepared by procedures
analogous to those described above in Example 59.
. Example 548 Carbamic acid, [2-(3-pyridinyl)ethyl]-, 4b,5,6,7,8,8a,9, 1 0-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, Mass: 495 (M+1)+.
Example 549 Carbamic acid, (2-pyridinylmethyl)-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, Mass: 481 (M+1)+.
Example 550 Carbamic acid, [2-(2-pyridinyl)ethyl]-, 4b,5,6,7,8,8a,9,1 0-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, Mass: 495 (M+1)+.
Example 551 2-Phenanthrenol, 4b,5,6,7,8,8a,9,10-octahydro-4b-pentyl-7-
propyl-,(4bf?,8afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. Mass: 313 (M-1)+.
Examples 552-553
The title compounds of Examples 552-553 were prepared by procedures
analogous to those described above in Example 59.
Example 552 Carbamic acid, [2-(1-pyrrolidinyl)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-propyl-7-(1-propynyl)-2-phenanthrenyl
ester, [4b/?-(4bcc,7a,8ap)]-, Mass: 439 (M+1)+.
Example 553 Carbamic acid, [2-(dimethylamino)ethyl]-, 4b,5,6,7,8,8a,9)10-
octahydro-7-hydroxy-4b-propyl-7-(1-propynyl)-2-phenanthrenyl
ester, [4bfl-(4ba,7a,8ap)]-, Mass: 413 (M+1)+.
Example 554 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-propyl-2-
(1 -propynyl)-7-(pyrazinyloxy)-, [2fl-(2a,4aa,1 Oa|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 377 (M+1)+.
Example 555 Carbamic acid, (1 H-tetrazol-5-ylmethyl)-, 4b,5)6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyl ester,[4bS-(4ba,7a,8a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 470 (M-1)+.
Example 556 2-Phenanthrenol, 7-[(4-chloro-2-pyrimidinyl)oxy]-
1,2,3,4,43,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-(1 -
propynyl)-, [2ff-(2a,4acc,10a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 460 (M+1)+.
Examples 557-558
The title compounds of Examples 557-558 were prepared by procedures
analogous to those described above in Example 72.
Example 557 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[[3-(1 -
piperidinylmethyl)-1,2,4-oxadiazol-5-yl]methoxy]-4a-propyl-2-
(1-propynyl)-, [2ff-(2a,4aa,10ap>)]-> Mass: 478 (M+1)+.
Example 558 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-propyl-2-
(1 -propynyl)-7-[[3-(2-pyridinyl)-1 ,2,4-oxadiazol-5-yl]iTiethoxy]-,
[2fr(2a,4aa,10ap)]-, Mass: 458 (M+1)+.
Examples 559-561
The title compounds of Examples 559-561 were prepared by procedures
analogous to those described above in Example 59.
Example 559 Carbamic acid, (4-pyridinylmethyl)-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap>)]-> Mass: 481 (M+1)+.
Example 560 Carbamic acid, (3-pyridinylmethyl)-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-, Mass: 481 (M+1)+.
Example 561 Carbamic acid, (3-pyridinylmethyl)-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-propyl-7-(1-propynyl)-2-phenanthrenyl
ester, [4bf?-(4ba,7a,8ap)]-, Mass: 433 (M+1)+.
Example 562 2-Phenanthrenol, 1,2,3,4,43,9,10,1Oa-octahydro-7-[(5-
methoxy-2-pyrimidinyl)oxy]-4a-(phenylmethyl)-2-(1-propynyl)-,
[2fl-(2a,4acc,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 455 (M+1)+.
Example 563 Morpholine, 4-[[6-[[4b,5,6,7>8,8aI9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-3-
pyridinyljcarbonyl]-, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. Mass: 537 (M+1)+.
Examples 564-565
The title compounds of Examples 564-565 were prepared by procedures
analogous to those described above in Example 59.
Example 564 Carbamic acid, (2-pyridinylmethyl)-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-propyl-7-( 1 -propynyl)-2-phenanthrenyl
ester, [4bfl-(4ba,7a,8ap)]-, Mass: 433 (M+1)+.
Example 565 Carbamic acid, (4-pyridinylmethyl)-, 4b,5,6,7,8,8a>9,10-
octahydro-7-hydroxy-4b-propyl-7-(1 -propynyl)-2-phenanthrenyl
ester, [4bfl-(4ba,7a,8ap)]-, Mass: 433 (M+1)+.
Example 566 2-Phenanthrenol, 7-[(5-amino-1 H-1,2,4-triazol-3-yl)methoxy]-
1,2,3,4,4a,9,10,10a-octahydro-4a-propyl-2-(1-propynyl)-> [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 62.
Examples 567-568
The title compounds of Examples 567-568 were prepared by procedures
analogous to those described above in Example 76. Mass: 395 (M+1)+.
Example 567 Pyridine, 3,3'-[[1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-2,7-
phenanthrenediyl]bis(oxymethylene)]bis-, [2/?-(2a,4aa,1 Oa|3)]-,
Mass: 529 (M+1)+.
Example 568 Pyridine, 4,4'-[[1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-2,7-
phenanthrenediyl]bis(oxymethylene)]bis-, [2/7-(2a,4a Mass: 529 (M+1)+.
Example 569 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(4-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]
The title compound was obtained as described in Example 76, except 4-
picolyl chloride hydrochloride was used instead of 3-picolyl chloride hydrochloride. MS
m/z438 (M+H)+.
Example 570 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4apentyl-
2-propyl-,[2f?-(2cc,4aa, 10aa)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. Mass: 313 (M-17)+.
Example 571 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-pentyl-2-
(1-propynyl)-7-(pyrazinyloxy)-, [2/?-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 405 (M+1)+.
Example 572 Carbamic acid, [2-(1 -pyrrolidinyl)ethyl]-, 4b,5,6,7,8,8a,9l10-
octahydro-7-hydroxy-4b-pentyl-7-( 1-propynyl)-2-phenanthrenyl
ester, [4bfl-(4ba,7cx,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 467 (M+1)+.
Example 573 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-propyl-2-
(1-propynyl)-7-(4-pyridinylmethoxy)-, [2ff-(2a,4aa,10a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 390 (M+1)+.
Example 574 Carbamic acid, [2-(4-pyridinyl)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl ester, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 59. Mass: 495 (M+1)+.
Example 575 2-Phenanthrenol, 1,2,3,4,43,9,10,1Oa-octahydro-4a-pentyl-2-
(1-propynyl)-7-(2-pyridinylmethoxy)-, [2/?-(2a,4acx,10ap)]-
To a solution of 50 mg of the title compound of Example 252 and 9.2 mg of
60% NaH in 2 ml_ of anhydrous DMF was added 30 mg of 2-picolyl chloride
hydrochloride at RT under N2 atmosphere overnight. The reaction was quenched with
NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over Na2SO4,
filtered and concentrated to dryness. Purification by preparative TLC SiO2 using 4%
MeOH in CH2CI2 as the elutant afforded 40 mg (65%) of the title product of this
example as white fluffy powder. Mass: 419 (M+2)+.
Examples 576-577
The title compounds of Examples 576-577 were prepared by procedures
analogous to those described above in Example 244.
Example 576 Acetamide, 2-[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-( 1 -propynyl)-2-phenanthrenyl]oxy]- N-[2-(4-
pyridinyl)ethyl]-, [4bS-(4ba,7a,8ap)]-, Mass: 509 (M+1)+.
Example 577 Acetamide, 2-[[4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(1-propynyl)-2-phenanthrenyl]oxy]-/V-[2-(2-
pyridinyl)ethyl]-, [4bS-(4ba,7a,8ap)]-, Mass: 509 (M+1)+.
Example 578 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(2-pyridinylmethoxy)-, [2R-
(2a,4acc,10ap)]
The title compound was obtained as described in Example 76, except 2-
picolyl chloride hydrochloride was used instead of 3-picolyl chloride hydrochloride.
Examples 579-580
The title compounds of Examples 579-580 were prepared by procedures
analogous to those described above in Example 59.
Example 579 Carbamic acid, [2-(2-pyridinyl)ethyl]-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-pentyl-7-( 1 -propynyl)-2-phenanthrenyl
ester, [4bft-(4ba,7a,8ap)]-, Mass: 476 (M+2)+.
Example 580 Carbamic acid, [2-(4-morpholinyl)ethyl]-, 4b,5,6,7>8,8a,9,10-
octahydro-7-hydroxy-4b-pentyl-7-(1-propynyl)-2-phenanthrenyl
ester, [4bft-(4bcc,7a,8ap)]-, Mass: 483 (M+1)+.
Example 581 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[2-(4-
morpholinyl)ethoxy]-4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2a,4aa,10ap)JThe
title compound of this example was prepared by procedures analogous to
those described above in Example 67. Mass: 460 (M+1)+.
Example 582 2-Phenanthrenol, 7-[(2,6-dimethoxy-4-pyrimidinyl)oxy]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(1-
propynyl)-, [2f?-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 485 (M+1)+.
Examples 583-584
The title compounds of Examples 583-584 were prepared by procedures
analogous to those described above in Example 59.
Example 583 Carbamic acid, (4-pyridinylmethyl)-, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-pentyl-7-(1-propynyl)-2-phenanthrenyl
ester, [4bfl-(4ba,7a,8ap)]-, Mass: 461 (M+1)+.
Example 584 Carbamic acid, (3-pyridinylmethyl)-, 4b,5,6>7,8,8a,9,10-
octahydro-7-hydroxy-4b-pentyl-7-(1-propynyl)-2-phenanthrenyl
ester, [4bfr(4ba,7a,8ap)]-, Mass: 461 (M+1)+.
Examples 585-588
The title compounds of Examples 585-586 were prepared by procedures
analogous to those described above in Example 75.
Example 585 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[[3-(1 -
Example 586
Example 587
Example 588
pyrrolidinyl)pyrazinyl]oxy]-, [2/=(2a,4aa,10ap)]-( Mass: 494
(M+1)+.
2-Phenanthrenol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[[6-(1 -pyrrolidinyl)-4-
pyrimidinyljoxy]-, [2/?-(2a,4aa, 1 030)]-, Mass: 494 (M+1 )+.
2-Phenanthrenol, 1,2,3,4,43,9, 10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[[6-(1 -pyrrolidinyl)-2-
pyridinyl]oxy]-, [2fl-(2a,4aa,10ap)]-, Mass: 493 (M+1)+.
2-Phenanthrenol, 1 ,2,3,4,43,9,1 0,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[[6-(1 -
pyrrolidinyl)pyrazinyl]oxy]-, [2fl-(2a,4aa,10ap)]-, Mass: 494
Example 589 2-Phen3nthrenol, 1 ,2,3,4,43,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(pyrazinylmethoxy)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 439 (M+1 )+.
Examples 590-591
The title compounds of Examples 590-591 were prepared by procedures
analogous to those described above in Example 67.
Example 590
Example 591
2-Phenanthrenol, 1, 2,3,4,43,9,10, 1 0a-octahydro-4a-
(phenylmethyl)-7-[2-(1 -piperazinyl)ethoxy]-2-(1 -propynyl)-, [2R-
(2a,4aa, 1 Gap)]-, Mass: 459 (M+1 )+.
Piperazine, 1 -acety\-4-[2-[[4b,5,6,7, 8,^,9,1 0-octshydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]ethyl]-,[4bS-(4ba,7cx,8ap)]-l Mass: 501
Example 592 2-Phenanthrenol, 1 ,2,3,4,43,9,1 0,1 Oa-oct3hydro-43-pentyl-2-
(1 -propynyl)-7-(2-pyrimidinyloxy)-, [2fl-(2a,4aa, 1 0ap)]-
The title compound of this exsmple was prepared by procedures analogous to
those described above in Example 74. Mass: 405 (M+1 )+.
Example 593 2-Phenanthrenol, 1 ,2,3,4,4a,9, 1 0,1 Oa-octahydro-4a-pentyl-2-
(1 -propynyl)-7-(pyrazinylmethoxy)-, [2/?-(2a,4aa, 1 0ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 419 (M+1)+.
Example 594 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-pentyl-2-
(1 -propynyl)-7-(3-pyridinylmethoxy)-, [2/=?-(2 The title compound was obtained as described in Example 575, except 3-
picolyl chloride hydrochloride was used instead of 2-picolyl chloride hydrochloride.
Mass: 418 (M+1)+
Example 595 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-pentyl-2-
(1-propynyl)-7-(4-pyridinylmethoxy)-, [2/=?-(2a,4aa,10ap)]
The title compound was obtained as described in Example 575, except 4-
picolyl chloride hydrochloride was used instead of 2-picolyl chloride hydrochloride.
Mass: 418 (M+1)+.
Examples 596-599
The title compounds of Examples 596-599 were prepared by procedures
analogous to those described above in Example 67.
Example 596 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[2-[4-(2-pyrimidinyl)-1 -
piperazinyl]ethoxy]-, [2F?-(2a,4aa,10a|3)]-, Mass: 537 (M+1)+.
Example 597 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-7-[2-(4-pyridinylamino)ethoxy]-,
Mass: 467 (M+1)+; isomer of title compound of Example 598.
Example 598 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-7-[2-(4-pyridinylamino)ethoxy]-,
Mass: 467 (M+1)+; isomer of title compound of Example 597.
Example 599 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[2-(4-
morpholinyl)ethoxy]-4a-pentyl-2-(1 -propynyl)-, [2R-
(2a,4aa,10ap)]-, Mass: 441 (M+2)+.
Examples 600-601
The title compounds of Examples 600-601 were prepared by procedures
analogous to those described above in Example 76.
Example 600 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-pentyl-2-
(1 -propynyl)-7-(5-pyrimidinylmethoxy)-, [2R-(2a,4aa, 1Oa(3)]-,
Mass: 419 (M+1)+.
Example 601 2-Phenanthrenol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(4-pyrimidinylmethoxy)-, [2ft-
(2a,4act,10ap)]-, Mass: 439 (M+1)+.
Examples 602-603
The title compounds of Examples 602-603 were prepared by procedures
analogous to those described above in Example 75.
Example 602 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-[[2-(1 -pyrrolidinyl)-4-
pyridinyl]methoxy]-, [2ft-(2a,4aa,10a|3)]-, Mass: 507(M+1)+.
Example 603 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-pentyl-2-
(1-propynyl)-7-[[6-(1 -pyrrolidinyl)-3-pyridinyl]methoxy]-, [2ft-
(2a,4aa,10ap)]-, Mass: 487 (M+1)+.
Example 604 2-Phenanthrenecarbonitrile, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-pentyl-7-(1 -propynyl)-, [4bft-(4ba,7cx,8af3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 15. Mass: 335 (M).
Example 605 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-7-[2-(4-
morpholinyl)ethoxy]-4a-(phenylmethyl)-2-propyl-, [2ft-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 67. Mass: 464 (M+1)+.
Example 606 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[2-(4-
morpholinyl)ethoxy]-4a-(phenylmethyl)-2-propyl-, [2ft-
(2a,4acc,10ap)]-HCI
The title product of this example is the HCI salt of the title product of Example
605. Mass: 464 (M+1-HCI)+.
Example 607 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[2-(4-
morpholinyl)ethoxy]-2,4a-dipropyl-, [2ft-(2a,4aa,1 Oa{3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 67. Mass: 416 (M+1)+.
Examples 608-609
The title compounds of Examples 608-609 were prepared by procedures
analogous to those described above in Example 76.
Example 608 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-pentyl-7-
(2-piperidinylmethoxy)-2-propyl-, [2/7-(2a,4aa,10a3)]-, Mass:
428 (M+1 )+
Example 609 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-[1 -(4-pyridinyl)ethoxy]-, [2R-
(2a,4aa,10ap)]-, Mass: 456 (M+1)+.
Example 610 2-Phenanthrenol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-7-[2-(4-
morpholinyl)ethoxy]-4a-pentyl-2-propyl-, [2fl-(2a,4aoc,1 Oa(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 67. Mass: 444 (M+1 )+.
Example 61 1 Acetamide, A/-[2-(4-morpholinyl)ethyl]-2-[[4b,5,6,7l8,8a,9,1 0-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-2-
phensnthrenyl]oxy]-, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described sbove in Exsmple 244. Msss: 521 (M+1)+.
Example 61 2 2-Phenanthrenol, 1 ,2,3,4,4a,9, 10,1 Oa-octahydro-43-pentyl-2-
propyl-7-(4-pyridinylmethoxy)-, [2fl-(2a,43a,1 03^)]-
The title compound of this exsmple was prepared by procedures anslogous to
those described above in Example 76. Mass: 422 (M+1 )+.
Examples 61 3-61 4
The title compounds of Exsmples 613-614 were prepsred by procedures
snslogous to those described sbove in Example 1 5.
Example 61 3 2-Phenanthrenecarbonitrile, 4b,5,6,7,8I8a,9, 1 0-octahydro-7-
methoxy-4b-pentyl-7-(1-propynyl)-, [4bR-(4ba,7a,8ap)]-> Msss:
367(M+18)+.
Example 614 2-Phenanthrenecarbonitrile, 4b,5,6,7,8,8a,9I10-octahydro-7-
methoxy-4b-pentyl-7-propyl-, [4b/:?-(4ba,7a,8ap)]-, Mass: 371
Examples 61 5-61 9
The title compounds of Examples 615-619 were prepared by procedures
analogous to those described above in Example 74.
Example 61 5 2-Ph snanthrenol, 1 ,2,3,4,4a,9, 10,1 Oa-octahydro-4a-
(phenylmethyl)-2-propyl-7-(pyrazinyloxy)-, [2f?-(2a,4aa, 1 Oa|3)]-
, Mass: 429 (M+1 )+.
Example 616 2-Phenanthrenol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-4a-
(phenylmethyl)-2-propyl-7-(2-pyrimidinyloxy)-, [2R-
(2a,4aa,1 Oa|3)]-, Mass: 429 (M+1 )+.
Example 617 2-Phenanthrenol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-7-[(3-
methylpyrazinyl)oxy]-4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2a,4aa,10ap)]-, Mass: 439 (M+1)+.
Example 61 8 2-Phenanthrenol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-7-[(3-methyl-
2-quinoxalinyl)oxy]-4a-(phenylmethyl)-2-(1 -propynyl)-, (2R-
(2a,4aa,10ap)]-, Mass: 489 (M+1)+.
Example 619 2-Phenanthrenol, 7-[(3,6-dimethylpyrazinyl)oxy]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(1-
propynyl)-, [2fl-(2a,4aa,10ap)]-, Mass: 453 (M+1)+.
Example 620 2-Phenanthrenol, 1 ,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 452 (M+1 )+.
Example 621 2-Phenanthrenol, 1 ,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-propyl-, [2R-
(2o,4aa,10ap)]
The title compound was obtained as described in Example 627, below, except
2-methyl-3-picolyl chloride hydrochloride was used instead of 2-picolyl chloride
hydrochloride. Mass: 456 (M+1 )+.
Example 622 2-Phenanthrenol, 7-[(2-amino-6-methyl-4-pyrimidinyl)oxy]-
1 ,2,3,4,43,9,1 0,1 Oa-octahydro-4a-(phenylmethyl)-2-propyl-,
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 458 (M+1 )+.
Example 623 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(6-methyl-
2-pyridinyl)methoxy]-4a-(phenylmethyl)-2-propyl-, [2ft-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 456 (M+1)+.
Example 624 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(6-methyl-
2-pyridinyl)methoxy]-4a-(phenylmethyl)-2-(1 -propynyl)-, [2ft-
(2ct,4aa,10ap)]
The title compound was obtained as described in Example 76, except 3-
methyl-2-picolyl chloride hydrochloride was used instead of 3-picolyl chloride
hydrochloride, yield 90%. MS m/z452 (M+H)+.
Examples 625-626
The title compounds of Examples 625-626 were prepared by procedures
analogous to those described above in Example 74.
Example 625 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-[[4-(trifluoromethyl)-2-
pyrimidinyl]oxy]-, [2ft-(2a,4aa,10ap)]-, Mass: 479 (M-17)+.
Example 626 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-7-[[4-(trifluoromethyl)-2-
pyrimidinyl]oxy]-, [2ft-(2a,4aa,10ap)]-, Mass: 493 (M+1)+.
Example 627 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-propyl-7-(2-pyridinylmethoxy)-, [2ft-
(2a,4aa,10ap)]
To a solution of 30 mg of the title compound of Example 10 and 8 mg of 60%
NaH in 2 mL of anhydrous DMF was added 17 mg of 2-picolyl chloride hydrochloride
at RT under N2 atmosphere overnight. The reaction was quenched with NH4CI (sat.),
extracted with EtOAc (X3), washed with brine, dried over Na2SO4, filtered and
concentrated to dryness. Purification by preparative TLC SiO2 using 30% EtOAc in
hexanes as the elutant afforded 32 mg (84%) of the title product of this example as
white fluffy powder. Mass: 442 (M+1)+.
Example 628 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-propyl-7-(3-pyridinylmethoxy)-, [2ft-
(2a,4aa,10ap)]
The title compound was obtained as described in Example 627, except the 3-
picolyl chloride hydrochloride was used instead of 2-picolyl chloride hydrochloride.
Mass: 442 (M+1)+.
Examples 629-633
The title compounds of Examples 629-633 were prepared by procedures
analogous to those described above in Example 76.
Example 629
Example 630
Example 631
Example 632
2-Phenanthrenol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-7-[(6-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-propyl-, [2R-
(2a,4acc,10ap)]-, Mass: 456 (M+1)+.
2-Phenanthrenol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-7-[(6-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-(1 -propynyl)-, [2R-
(2a,4aa,10ap)]-, Mass: 452 (M+1)+.
Pyridine, 3,3'-[[1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1-propynyl)-2,7-
phenanthrenediyl]bis(oxymethylene)]bis[6-methyl-, [2ft-
(2a,4a 2-Pyridinecarbonitrile, 6-[[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-2-
phenanthrenyl]oxy]methyl]-, [4bS-(4ba,7a,8ap)]-( Mass: 467
Example 633 2-Pyridinecarbonitrile, 6-[[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1 -propynyl)-2-
phenanthrenyl]oxy]methyl]-, [4bS-(4ba,7a,8ap)]-, Mass: 481
Examples 634-646
The title compounds of Examples 634-646 were prepared by procedures
analogous to those described above in Example 74.
Example 634
Example 635
2-Phenanthrenol, 7-[(3-amino-4-methyl-2-pyridinyl)oxy]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-propyl-,
[2ft-(2a,4aa,10ap)]-, Mass: 457 (M+1f.
2-Phenanthrenol, 7-[(3-amino-2-pyridinyl)oxy]-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-propyl-,
[2ff-(2a,4aa,10ap)]-, Mass: 443 (M+1)+.
Example 636
Example 637
Example 638
Example 639
Example 640
Exampel 641
Example 642
Example 643
Example 644
Example 645
Example 646
3-Pyridinecarbonitrile, e-methyl^-f^b.S.ej.S.Sa.S.10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 463 (M+1)+.
3-Pyridinecarbonitrile, 6-methy\-2-[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 467 (M+1)+.
3-Pyridinecarbonitrile, 2-[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-2-phenanthrenyl]oxy]-,
[4bS-(4ba,7a,8ap)]-, Mass: 453 (M+1)+.
2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-propyl-7-[2-(trifluoromethyl)phenoxy]-, [2R-
(2a,4aa,10ap)]-, Mass: 496 (M+1)+
2-Pyridinecarbonitrile, 6-[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-( 1 -propynyl)-2-
phenanthrenyljoxy]-, Mass: 449 (M+1)+.
2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-( 1 -propynyl)-7-[[6-(trif luoromethyl)-2-
pyridinyl]oxy]-, Mass: 492 (M+1)+.
2-Pyridinecarbonitrile, 6-[[4b,5,6,7,8,8a,9^ O-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-2-phenanthrenyl]oxy]-,
[4bS-(4ba,7a,8ap)]-, Mass: 471 (M+18)+.
3-Pyridinecarbonitrile, 4,6-dimethyl-2-[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyljoxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 477 (M+1)+.
3-Pyridinecarbonitrile, 6-[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 449 (M+1)+.
3-Pyridinecarbonitrile, 6-[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-2-phenanthrenyl]oxy]-,
[4bS-(4ba,7a,8ap)]-, Mass: 453 (M+1)+.
3-Pyridinecarbonitrile, 4,6-dimethyl-2-[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7a,8ap)]-, Mass: 481 (M+1)+.
Examples 647-649
The title compounds of Examples 647-649 were prepared by procedures
analogous to those described above in Example 76.
Example 647 2-Phenanthrenol, 7-[(2,6-dichloro-4-pyrimidinyl)methoxy]-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-2-propyl-,
[2f?-(2a,4aa,10ap)]-, Mass: 511 (M).
Example 648 2-Phenanthrenol, 7-[(2,6-dimethoxy-4-pyrimidinyl)methoxy]-
1,2,3,4,43,9,10,10a-octahydro-4a-(phenylmethyl)-2-propyl-,
[2/?-(2a,4aa,10ap)]-, Mass: 503 (M+1)+.
Example 649 2-Phenanthrenol, 7-[(2-chloro-6-methyl-4-pyridinyl)methoxyj-
1,2,3,4,4a,9,10,10a-oct3hydro-43-(phenylmethyl)-2-propyl-,
[2fl-(2a,4aa,10ap)]-, Mass: 490 (M).
Example 650 2-Phenanthrenol, 7-[(6-chloro-2-pyridinyl)oxy]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-propyl-,
[2ff-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 444 (M-18)+.
Example 651 2-Pyridinecarbonitrile, 3-[[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(1-propynyl)-2-
phenanthrenyl]oxy]methyl]-, [4bS-(4ba,7cx,8ap)]
The title compound was obtained as described in Example 76, except 2-
cyano-3-picolyl chloride hydrochloride was used instead of 3-picolyl chloride
hydrochloride, yield 90%. MS m/z463 (M+H)+.
Example 652 2-Pyridinecarbonitrile, 3-[[[4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-propyl-2-
phenanthrenyl]oxy]methyl]-, [4bS-(4ba,7a,8ap)]
The title compound was obtained as described in Example 627, except 2-
cyano-3-picolyl chloride hydrochloride was used instead of 2-picolyl chloride
hydrochloride. Mass: 449 (M-17)+.
Examples 653-660
The title compounds of Examples 653-660 were prepared by procedures
analogous to those described above in Example 76.
Example 653 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-7-[(2-
methoxy-6-methyl-4-pyridinyl)methoxy]-4a-(phenylmethyl)-2-
propyl-, [2fl-(2a,4aa,10ap)]-, Mass: 486 (M+1)+.
Example 654 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl*
4-pyridinyl)methoxy]-4a-(phenylmethyl)-2-propyl-, [2R-
(2a,4aa,10ap)]-, Mass: 456 (M+1)+.
Example 655 2-Phenanthrenol, 1,2,3,4,43,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(1 -propynyl)-7-(2-quinolinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 488 (M+1)+.
Example 656 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-(2-quinolinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 492 (M+1)+.
Example 657 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(2-
methoxy-3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-propyl-,
[2f?-(2a,4aa,1 Oap)]-, Mass: 472 (M+1)+.
Example 658 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-(pyrazinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 443 (M+1)+.
Example 659 2(1 H)-Pyridinone, 3-[[[4b,5,6,7,8,8a,9,W-octahydro-7-hydroxy-'
4b-(phenylmethyl)-7-propyl-2-phenanthrenyl]oxy]methyl]-,
[4bS-(4ba,7a,8ap)]-> Mass: 458 (M+1)+.
Example 660 2-Phenanthrenol, 1,2,3,4,43,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-(4-pyrimidinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 443 (M+1)+.
Example 661 2,7-Phenanthrenediol, 1,2,3,4,43,9,10,10a-octahydro-2-(3-
methoxy-1-propynyl)- 4a-(phenylmethyl)-, [2H-(2a,4aa,10ap)JThe
title compound of this example was prepared by procedures analogous to
those described above in Example 9. Mass: 359 (M-17)+.
Example 662 3-Pyridinecarboxamide, 6-methyl-2-[[4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7o,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 485 (M+1)+.
Examples 663-665
The title compounds of Examples 663-665 were prepared by procedures
analogous to those described above in Example 76.
Example 663 2-Phenanthrenol, 7-[(4,6-dimethyl-2-pyrimidinyl)methoxy]-
1,2,3,4,43,9,10,10a-octahydro-4a-(phenylmethyl)-2-propyl-,
[2ff-(2a,43a, 103(3)]-, Mass: 471 (M+1)+.
Example 664 2-Phenanthrenol, 1,2,3,4,43,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-7-(3-quinolinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 492 (M+1)+.
Example 665 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-propyl-7-(4-quinolinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 492 (M+1)+.
Example 666 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(3-methyl-
2-quinoxalinyl)oxy]-4a-(phenylmethyl)-2-propyl-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. Mass: 493 (M+1)+.
Example 667 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(5-methyl-
3-isoxazolyl)methoxyJ-4a-(phenylmethyl)-2-propyl-, [2R-
(2a,4acc,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 428 (M-17)+.
Example 668 2,7-Phenanthrenediol, 1,2,3,4,43,9,10,10a-oct3hydro-2-(3-
methoxypropyl)-4a-(phenylmethyl)-, [2S-(2a,4aa, 10a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. Mass: 363 (M-17)+.
Example 669 2,7-Phenanthrenediol, 2-(ethoxyethynyl)-1,2,3,4,43,9,10,1 Oaoctahydro-
43-(phenylmethyl)-, [2R-(2a,43a,1 Qa$)]-
The title compound of this exsmple wss prepsred by procedures analogous to
those described above in Example 9. Mass: 359 (M-17f.
Examples 670-671
The title compounds of Examples 670-671 were prepared by procedures
anslogous to those described above in Example 10.
Example 670 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(3-phenyl-2-propynyl)-, [2f?-(2a,4aa, 1 Oaf} )]-t
Mass:405(M-17)+.
Example 671 2,7-Phenanthrenediol, 2-(2-ethoxyethyl)-1 ,2(3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-, [2/7-(2a,4aa,10a3)]-, Mass: 363
Example 672 3-Pyridinecarbonitrile, e-t
hydroxy-4b-(phenylmethyl)-7-propyl-2-
phenanthrenyl]oxy]methyl]-, [4bS-(4ba,7a,8a|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 467 (M+1 )+.
Example 673 2-Phenanthrenol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-2-(3-
methoxypropyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-,
[2S-(2a,4aa,10ap)]
To a solution of 28 mg of the title compound of Example 668 and 7 mg of
60% NaH in 2 mL of anhydrous DMF was added 15 mg of 3-picolyl chloride
hydrochloride at RT under N2 atmosphere overnight. The reaction was quenched with
NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over Na2SO4,
filtered and concentrated to dryness. Purification by preparative TLC SiO2 using 35%
EtOAc in hexanes as the eluant afforded 30 mg (87%) of the title product of this
example as white fluffy powder. Mass: 472 (M+1 )+.
Example 674 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(6-
methoxy-2-pyridinyl)methoxy]-4a-(phenylmethyl)-2-propyl-,
[2fl-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 472 (M+1 )+.
Examples 675-677
The title compounds of Examples 675-677 were prepared by procedures
analogous to those described above in Example 81 .
Example 675 2,7-Phenanthrenediol, 2-[(cyclopropylmethoxy)methyl]-
1 ,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-, [2R-
(2a,4aa,10a3)]-, Mass: 375 (M-17)+.
Example 676 2,7-Phenanthrenediol, 2-(ethoxymethyl)-1 ,2,3,4,4a,9,10,10aoct3hydro-
43-(phenylmethyl)-, [2R-(2a,4aa,10a3)]-, Mass: 349
Example 677 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-[(2,2,2-trifluoroethoxy)methyl]-, [2R-
(2a,4aa,10ap)]-, Mass: 403 (M-17)+.
Example 678 2,7-Phenanthrenediol, 1 ,2,3,4,43,9, 10,1 Oa-octahydro-2-(1-
piperidinylmethyl)-4a-(phenylmethyl)-, [2ff-(2a,4acc,1 Oa|3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 83. Mass: 406 (M+1 )+.
Examples 679-682
The title compounds of Examples 679-682 were prepared by procedures
analogous to those described above in Example 81 .
Example 679 2,7-Phen3nthrenediol, ITREa.gjO.IOa-octahydroY5-Omethylethoxy)
ethoxy]methyl]-43-(phenylmethyl)-, [2R-
(2a,4aa,10ap)]-, Mass: 423 (M+1)+.
Example 680 2-Phenanthrenol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-2-
(methoxymethyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-,
[2fr(2a,4aa,1 Oap)]-, Mass: 444 (M+1 )+.
Example 681 2-Phenanthrenol, 2-(ethoxymethyl)-1 ,2,3,4,4a,9,1 0,1 Oaoctahydro-
4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]-, Mass: 458 (M+1)+.
Example 682 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9, 1 0,1 Oa-octahydro-2-[(2-
methoxyethoxy)methyl]-4a-(phenylmethyl)-, (4aS,1 Oafl)-,
Mass: 397 (M+1 )+.
Example 683 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-
5-thiazolyl)methoxy]-4a-(phenylmethyl)-2-propyl-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. Mass: 462 (M+1 )+.
Examples 684-685
The title compounds of Examples 684-685 were prepared by procedures
analogous to those described above in Example 72.
Example 684 2-Phenanthrenol, 7-[[5-(1 ,1 -dimethylethyl)-1 ,2,4-oxadiazol-3-
yl]methoxy]-1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-4a-(phenylmethyl)+
2-propyl-, [2/?-(2cc,4aa, 1 Oap)]-, Mass: 489 (M+1 )+.
Example 685 2-Phenanthrenol, 7-[[5-(3,5-dimethyl-4-isoxazolyl)-1 ,2,4-
oxadiazol-3-yl]methoxy]-1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-propyl-, [2f?-(2a,4aa,10ap)]-, Mass: 510 (MExample
686 2-Phenanthrenol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-2-(3-methoxy-
1 -propynyl)-4a-(phenylmethyl)-7-(2-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above for the preparation of the title compound of Example 76.
Mass: 468 (M+1 )+.
Example 687 2-Phenanthrenol, 4b,5,6,10-tetrahydro-7-phenyl-4b-
(phenylmethyl)-, (S)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 1 36. MS: 364 (M+1 )+.
Examples 688-691
The title compounds of Examples 688-691 were prepared by procedures
analogous to those described above in Example 51 .
Example 688 2(1 H)-Phenanthrenone, 4b-(2-butenyl)-3,4,4b,5,6,7,8,8a,9,1 0-
decahydro-7-hydroxy-7-(1 -propynyl)-, [4bS-[4ba(E),7a,8ap]]-;
See also Example 51 .
Example 689 2(3H)-Phenanthrenone, 4b-(2-butenyl)-
4,4a,4b,5>6,7,8,8a,9,1 0-decahydro-7-hydroxy-7-(1 -propynyl)-,
[4bS(£),7S,8aff|-, MS: 312 (M+1)+.
Example 690 2(3AV)-Phenanthrenone, 4b-(2-butenyl)-
4,4a,4b,5,6,7,8,8a,9,1 0-decahydro-7-hydroxy-7-(1 -propynyl)-,
[4afl-[4aa,4bp(E),7p,8aa]]-; See also Example 51 .
Example 691 2(1 H)-Phenanthrenone, 4b-(2-butenyl)-3I4,4b,5)6,7,8,8a,9,1 0-
decahydro-7-hydroxy-7-(1 -propynyl)-, [4bS-[4ba(£),7p,8ap]]-,
MS: 31 3 (M+1 )+.
Example 692 2(3W)-Phenanthrenone, 4b-(2-butenyl)-
4,4a,4b,5,6,7,8,8a,9,10-decahydro-7-hydroxy-7-(1 -propynyl)-,
oxime, [4bS(E),7R,8aR\-
The title compound of this example was prepared by procedures analogous to
those described above in Example 77. MS: 328 (M+1)+.
Examples 693-695
The title compounds of Examples 693-695 were prepared by procedures
analogous to those described above in Example 136.
Example 693 2-Phenanthrenol, 4b,5,6l8aI9I10-hexahydro-4b-[(4-
hydroxyphenyl)methyl]-7-propyl-, (4bS-c/s), MS: 349 (M+1)+.
Example 694 2,7-Phenanthrenediol, 4a-[[4-(dimethylamino)phenyl]methyl]-
1,2,3,4,43,9,10,10a-octahydro-2-propyl-, (4aS,10aS)-, MS: 370
(M+1)+; isomer of the title product of Example 695.
Example 695 2,7-Phenanthrenediol, 4a-[[4-(dimethylamino)phenyl]methyl]-
1,2,3,4,4a,9,10,10a-octahydro-2-propyl-, (4aS,10aS)-, MS: 370
(M+1)+; isomer of the title product of Example 694.
Example 696 2-Phenanthrenol, 4a-[[3-(dimethylamino)phenyl]methyl]-
1,2,3,4,43,9,10,10a-octahydro-7-(2-hydroxyethoxy)-2-( 1 -
propynyl)-, [2H-(2a,4aa,10a3)]-; See also Example 60.
Examples 697-699
The title compounds of Examples 697-699 were prepared by procedures
analogous to those described above in Example 9.
Example 697 2,7-Phenanthrenediol, 1,2,3,4,43,9,10,1 Oa-octahydro-1,1,4atrimethyl-
2-(1-propynyl)-, MS: 299 (M+1)+.
Example 698 2,7-Phenanthrenediol, 2-(3-fluoro-3-methyl-1 -butynyl)-
1,2,3,4,4al9,10,10a-octahydro-4a-(phenylmethyl)-> [2ft-
(2a,4aa,10a|3)]-, MS: 394 (M+1)+.
Example 699 2,7-Phenanthrenediol, 2-(3-fluoro-3-methyl-1 -butynyl)-
1,2,3,4,43,9,10,10a-octahydro-4a-(phenylmethyl)-,[2S-
(2a.4ap.103a)]-, MS: 394 (M+1)+.
Example 700 2-Phen3nthrenol, 2-(3,3-dimethylbutyl)-1,2,3,4,4a,9,10,10aoct3hydro-
43-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,103p)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 485 (M+1)+.
Example 701 2,7-Phenanthrenediol, 1,2,3,4,43,9,10,10a-octahydro-2-(2-
phenylethyl)-4a-(phenylmethyl)-, [2f?-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 414 (M+1)+
Example 702 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
[(methylthio)methyl]-4a-(phenylmethyl)-, [2fl-(2a,4aa, 1Oap1)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 81. MS: 370 (M+1)+.
Examples 703-705
The title compounds of Examples 703-705 were prepared by procedures
analogous to those described above in Example 76.
Example 703 2-Phenanthrenol, 1,2,3,4,43,9,10,10a-octahydro-2-(2-
phenylethyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-, [2R-
(2a,4aa,1 Oap)]-, MS: 505 (M+1)+.
Example 704 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(2-methyl-
5-thiazolyl)methoxy]-4a-(phenylmethyl)-2-propyl-, [2R-
(2a,4aa,10ap)]-, MS: 463 (M+1)+.
Example 705 2-Phenanthrenol, 7-[[5-(1,1 -dimethylethyl)-1,2,4-oxadiazol-3-
yl]methoxy]-1,2,3,4,43,9,10,1 Oa-octahydro-4a-(phenylmethyl)-
2-propyl-, [2fl-(2a,4aa,103p)]-, MS: 490 (M+1)+.
Example 706 2-Phen3nthrenol, 7-[[5-(3,5-dimethyl-4-isoxazolyl)-1,2,4-
oxadiazol-3-yl]methoxy]-1,2,3,4,4a,9,10,103-oct3hydro-4a-
(phenylmethyl)-2-propyl-, [2/?-(2a,4aa,1030)]-
The title compound of this example wss prepsred by procedures snslogous to
those described above in Example 69. MS: 529 (M+1)+.
Example 707 2-Phenanthrenol, 1,2,3,4,4a,9,10,103-oct3hydro-2-(3-methoxy-
1 -propynyl)-43-(phenylmethyl)-7-(2-pyridinylmethoxy)-, [2R-
(2a,43a,103p)]-
The title compound of this example was prepared by procedures anslogous to
those described above in Example 76. MS: 469 (M+1)+.
Examples 708-710
The title compounds of Examples 708-710 were prepared by procedures
analogous to those described above in Example 81 .
Example 708 2-Phenanthrenol, 2-[(cyclopropylmethoxy)methyl]-
1 ,2,3,4,43,9,1 0,1 Oa-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2fl-(2a,4aa,10ap)]-, MS: 485 (M+1)+
Example 709 2-Phenanthrenol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-7-(3-pyridinylmethoxy)-2-[(2,2,2-
trifluoroethoxy)methyl]-, [2fl-(2a,4aa,10ap)]-, MS: 513
Example 710 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-2-[(1-
methylethoxy)methyl]-4a-(phenylmethyl)-7-(2-
pyridinylmethoxy)-, [2fl-(2a,4aa,10ap)]-, MS: 458 (M+1)+.
Example 71 1 2-Phenanthrenol, 2-(azidomethyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
4a-(phenylmethyl)-7-(2-pyridinylmethoxy)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 82. MS: 473 (M+1 )+.
Examples 71 2-71 7
The title compounds of Examples 712-717 were prepared by procedures
analogous to those described above in Example 81 .
Example 712 2-Phenanthrenol, 1 ,2,3,4,4a,9, 10,1 Oa-octahydro-4a-
(phenylmethyl)-7-(3-pyridinylmethoxy)-2-[(2-
pyridinylmethoxy)methyl]-, [2fl-(2a,4aa,10ap)]-, MS: 522
Example 71 3 Propanenitrile, 3-[[1 ,2,3,4,43,9,1 0,1 Oa-octahydro-2-hydroxy-
4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-2-
phenanthrenyl]methoxy]-, [2/=?-(2a,4aa,10ap)]-, MS: 484
Example 714 2-Phenanthrenol, 2-[(cyclopentyloxy)methyl]-
1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2/?-(2a,4aa,10ap)]-, MS: 499 (M+1)+.
Example 71 5 2-Phenanthrenol, 1 ,2,3,4,4a,9,1 0,1 Oa-octahydro-2-[[(3-methyl-
3-oxetanyl)methoxy]methyl]-4a-(phenylmethyl)-7-(3-
Example716 2-Phenanthrenol, 2-[(1,1-dimethylethoxy)methyl]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2fl-(2a,4aa,10ap)]-, MS: 487 (M+1)+.
Example 717 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-2-
(phenoxymethyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-,
[2fl-(2a,4aa,10ap)]-, MS: 507 (M+1)+.
Example 718 1 H-Benz[e]indene-2-carboxylic acid, 2,3,3a,4,5,9b-hexahydro-
9b-(phenylmethyl)-7-(3-pyridiny!methoxy)-, methyl ester, [2R-
(2a,3aa,9b(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 429 (M+1 )+.
Example 719 Spiro[1,3-dioxolane-2,2'(1 'H)-phenanthren]-7'-ol,
S'^'^'a.g'.IO'.IO'a-hexahydro^'a-tphenylmethyl)-, (4'aStrans)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 7. MS: 351 (M+1+.
Example 720 2,7-Phenanthrenediol, 1,2,3,4,4a,9.10,10a-octahydro-2-(1 Himidazol-
1-ylmethyl)-4a-(phenylmethyl)-, [2/?-(2a,4aa,10a3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 48. MS: 390 (M+1 )+.
Example 721 2,7-Phenanthrenediol, 1,2,3.4.4a.9,10.1 Oa-octahydro-4a-
(phenylmethyl)-2-(1 H-1,2,4-tna2Ol-1 -ylmethyl)-, [2ft-
(2a,4aa,10ap)]-; See also Example 48.
Example 722 2,7-Phenanthrenediol, 1,2,3t4,4a,9.10,10a-octahydro-4a-
(phenylmethyl)-2-[2-(2-pyridinyl)ethyl]-, [2S-(2a,4aa,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 415 (M+1)+.
Examples 723-724
The title compounds of Examples 723-724 were prepared by procedures
analogous to those described above in Example 76. MS: 506 (M+1)+.
Example 723 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-[2-(2-pyridinyl)ethyl]-7-(3-pyridinylmethoxy)-,
[2S-(2a,4aa,10ap)]-
Example 724 2-Phenanthrenol, 1,2.3,4,43,9,10,1 Oa-octahydro-2-
[{methylthio)methyl]-4a-(phenylmethyl)-7-(3-pyridinylmetho)(y)-1
[2ff-(2a,4aa,10ap)]-, MS: 461 (M+1)+.
Example 725 2-Phenanthrenol, 2-[(cyclobutyloxy)methyl]-
1,2,3,4,43,9,10,1 Oa-octahydro-4a-(phenylmethyl)-7-{3-
pyridinylmethoxy)-, [2ff-(2cc,4aa,1 O + ) ] -
To a solution of 20 mg of the title compound of Preparation 20 and 6 mg of
Na in 1 mL of anhydrous DMF was added 0.019 mL of cyclobutanol at 85 °C under
N2 atmosphere overnight. The reaction was quenched with NH4CI (sat.), extracted
with EtOAc (X3), washed with brine, dried over Na2SO4, filtered and concentrated to
dryness. Purification by preparative TLC SiO2 using 8% acetone in methylene
chloride as the eluant afforded 18 mg (76%) of the title product of this example as
white fluffy powder. Mass: 4 8 4 { M + 1 ) + E x a m p l e s 726-734
The title compounds of Examples 726-734 were prepared by procedures
analogous to those described above in Example 725.
Example 726 2-Phenanthrenol, 2-{(2-fluoroethoxy)methyl]-
1,2,3,4,4a,9,10,1 Oa-octahydro-4a-(phenylmethyl)-7-{3-
pyridinylmethoxy)-, [2fl-(2a,4aa,10a3)K MS: 477 (M+1)+.
Example 727 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-2-[[2-
(methylthio)ethoxy]methyi]-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2R-{2ot,4aa,1 Dap")]-, MS: 505 (M+1)+.
Example 728 2-Phenanthrenol, 2-[(2,2-dimethylpropoxy)methyl]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2ff-(2a,4aa,10ap)]-, MS: 501 (M+1)+. ;
Example 729 2-Phenanthrenol, 2-[(2-ethylbutoxy)methyl]-
1,2,3l4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy}-, [2fl-{2a,4aa,10ap)]-( MS: 515 (M+1)*
Example 730 2-Phenanthrenol, 2-[(2-butynyloxy)methyl]-
1,2,3,4,43,9,10,1 Oa-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2f-(2a,4aa, 1 Dap")]-, MS: 483 (M-t-1)+.
Example 731 2-Phenanthrenol, 2-[(cyclohexylmethoxy)methyl]-
1,2,3,4,43,9,10,10a-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2fl-(2a,4aa,1 Oap)]-, MS: 527 (M+1)+.
Example 732 2-Phenanthrenol, 2-[(cyclopentylmethoxy)methyl]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2fl-(2a,4aa,10ap)]-, MS: 513 (M+1)+.
Example 733 2-Phenanthrenol, 2-[(cyclobutylmethoxy)methyl]-
1,2,3,4,43,9,10,103-oct3hydro-4a-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2fl-(2a,4aa,10a(5)]-, MS: 499 (M+1)+.
Example 734 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-[[(3-phenyl-1-propynyl)oxy]methyl]-7-(3-
pyridinylmethoxy)-, [2fl-(2a,4aa,10ap)]-, MS: 545 (M+1)+.
Example 735 2-Phenanthrenol, 2-(3-fluoro-3-methyl-1-butynyl)-
1,2,3,4,4a,9,10,1Oa-octahydro-43-(phenylmethyl)-7-(3-
pyridinylmethoxy)-, [2ft-(2a,43a,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 485 (M+1 )*.
Examples 736-738
The title compounds of Examples 736-738 were prepared by procedures
anslogous to those described above in Example 76.
Example 736
Example 737
Exsmple 738
Example 739
2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-2-(1 Himidazol-
1-ylmethyl)-4a-(phenylmethyl)-7-(3-pyridinylmethoxy)-
, [2f?-(2a,4aa,10a3)]-F MS: 481 (M+1)+.
2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-7-(3-pyridinylmethoxy)-2-(1 H-1,2,4-triazol-1 -
ylmethyl)-, [2f?-(2a,4aa,10ap)]-, MS: 482 (M+1)+.
Pyridine, 3-[[[3',4',4'a,9',10',10'a-hexahydro-4'a-
(phenylmethyl)spiro[1,3-dioxolane-2,2'(1 'H)-phenanthren]-7'-
yl]oxy]methyl]-, (4'aS-trans)-, MS: 443 (M+1)+.
2-Phenanthrenol, 2-(ethoxymethyl)-1,2,3,4,43,9,10,103-
octahydro-4a-(phenylmethyl)-7-(2-pyridinylmethoxy)-, [2R-
(2a,43a,10ap)]-
To a solution of 20 mg of the title compound of Example 676 and 5 mg of
60% NaH in 2 ml_ of anhydrous DMF was added 11 mg of 2-picolyl chloride
hydrochloride at RT under N2 atmosphere overnight. The reaction was quenched with
NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over Na2SO4,
filtered and concentrated to dryness. Purification by preparative TLC (SiO2) using
45% EtOAc in hexanes as the eluant afforded 24 mg (96%) of the title product of this
example as white fluffy powder. Mass: 458 (M+1)+.
Example 740 2-Phenanthrenol, 2-(ethoxymethyl)-1,2,3,4,43,9,10,103-
oct3hydro-7-[(5-methyl-3-isox3zolyl)methoxy]-43-
(phenylmethyl)-, [2f?-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures anslogous to
those described sbove in Example 81. MS: 463 (M+1)+.
Exsmple 741 2-Phenanthrenol, 2-(ethoxymethyl)-1,2,3,4,4a,9,10,10aoctahydro-
7-[2-(4-morpholinyl)ethoxy]-4a-(phenylmethyl)-, [2R-
(2a.4aa.10ap1)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 67. MS: 481 (M+1)+.
Examples 742-744
The title compounds of Examples 742-744 were prepared by procedures
analogous to those described above in Example 74.
Example 742 2-Phenanthrenol, 2-(ethoxymethyl)-1,2,3,4,4a,9,10,1 Oaoctahydro-
4a-(phenylmethyl)-7-(pyrazinyloxy)-, [2R-
(2a.4aa.10ap1)]-, MS: 446 (M+1)+.
Example 743 2-Phenanthrenol, 7-[(2-amino-6-methyl-4-pyrimidinyl)oxy]-
1,2,3,4,4a,9,10,10a-oct3hydro-4a-(phenylmethyl)-, [2F?-
(2a.4aa.10ap1)]-, MS: 475 (M+1)+.
Example 744 3-Pyridinecarboxamide, 6-[[7-(ethoxymethyl)-
4b,5,6,7,8,8a,9,10-oct3hydro-7-hydroxy-4b-(phenylmethyl)-2-
phenanthrenyl]oxy]-, [4bS-(4ba,7a,83p)]-, MS: 488 (M+1)+.
Exsmple 745 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
[(methylsulfonyl)methyl]-43-(phenylmethyl)-, [2R-
(2a,4aa,103p)]-
At room temperature, under nitrogen, meta-chloroperoxybenzoic acid (58 mg)
was added to the title product of Example 702 (20 mg) in CH2CI2 and monitored by
TLC. When no starting material remained, the reaction was quenched with 1 0%
sodium bissulfite solution and extracted with CH2Cl2 (3X). The organics were
combined and dried with NagSO^ filtered and concentrated. Purification by flash
chromotography with 10% MeOH in CH2CI2 yielded 15 mg of white solid. Mass: 402
Example 746 2-Phenanthrenol, 2-(cyclopropylethynyl)-1 ,2,3,4,4a,9,10,10aoctahydro-
7-[(2-methyl-3-pyridinyl)methoxy]-4a-
(phenylmethyl)-, [2ft-(2a,4aa, 1 Oap)]-
The title compound was obtained as described in Example 764 except the title
compound of Example 150 was used as starting material. Mass: 478 (M+1 )+.
Examples 747-748
The title compounds of Examples 747-748 were prepared by procedures
analogous to those described above in Example 76.
Example 747 2-Phenanthrenol, 2-(cyclopropylethynyl)-1 ,2,3,4,4a,9,1 0,1 Oaoctahydro-
4a-(phenylmethyl)-7-(2-pyridinylmethoxy)-, [2ft-
(2a,4aa, 1 0ap)]-, MS: 465 (M+1 )+.
Example 748 2-Phenanthrenol, 2-(2-cyclopropylethyl)-1 ,2,3,4,4a,9,10,1 Oaoctahydro-
4a-(phenylmethyl)-7-(2-pyridinylmethoxy)-, [2ft-
(2a,4aa,10ap)]-, MS: 469 (M+1)+.
Example 749 2-Phenanthrenol, 2-(2-cyclopropylethyl)-1,2,3,4,4a,9,10,10aoctahydro-
7-[(2-methyl-3-pyridinyl)methoxy]-4a-
(phenylmethyl)-, [2ft-(2a,4aa, 1 Oa0)]-
The title compound was obtained as described in Example 764 except the title
product of Example 377 was used as starting material. MS: 482 (M+1 )+.
Example 749a 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-(trifluoromethyl)-,
(2ft,4aS,10aft)-
The title compound was obtained as described in Example 764 except the title
product of Example 799 was used as starting material. MS: 482 (M+1 )+.
Example 749b 2-Pyridinecarbonitrile, 3-[[[(4bS,7ft,8aft)-4b,5,6,7,8,8a,9, 1 0-
octahydro-7-hydroxy-7-methyl-4b-(phenylmethyl)-2-
phenanthrenyljoxyjmethyl]-
To a solution of 222 mg of the title compound of Example 750 and 55 mg of
60% NaH in 5 mL of anhydrous DMF was added 400 mg of 2-cyanol-3-picolyl
chloride hydrochloride at RT under N2 atmosphere overnight. The reaction was
quenched with NH4CI (sat.), extracted with EtOAc (X3), washed with brine, dried over
Na2S04, filtered and concentrated to dryness. Purification by column chromatography
using 35% EtOAc in hexanes as the eluant afforded 220 mg (74%) of the title
product of this example as white fluffy powder. MS: 439 (M+1)+.
Example 750 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
methyl-4a-(phenylmethyl)-,[2fl-(2a,4aa>10a(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 323 (M+1)+.
Example 751 2-Phenanthrenol, 2-[(cyclobutyloxy)methyl]-
1,2,3,4,43,9,10,10a-octahydro-7-[(1-oxido-3-
pyridinyl)methoxy]-4a-(phenylmethyl)-, [2ff-(2a,4aa,10ap)JThe
title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 503 (M+1)+.
Example 752 Carbamic acid, dimethyl-, 7-(ethoxymethyl)-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-2-phenanthrenyl ester,
[4bS-(4ba,7a,8a3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 58. MS: 439 (M+1)+.
Example 753 2-Phenanthrenol, 1,2,3,4,4a.9,10,1 Oa-octahydro-7-(1 -
methylethoxy)-4a-(phenylmethyl)-2-[(2-
pyridinylmethoxy)methyl]-, [2f?-(2a,4aa,10a3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 81. MS: 473 (M+1)+.
Example 754 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-2-[[2-(1 H-pyrazol-1 -yl)ethoxy]methyl]-7-(3-
pyridinylmethoxy)-, [2 fl-(2a,4aa, 10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 725. MS: 525 (M+1)+.
Example 755 2-Phenanthrenecarboxylic acid, 7-(cyclopropylethynyl)-
4b,5,6,7,8,8a,9l10-octahydro-7-hydroxy-4b-(phenylmethyl)-
methyl ester, [4bS-(4ba,7a,8ap))-
The title compound of this example was prepared by procedures analogous to
those described above in Example 14. MS: 416 (M+1)+.
Example 756 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-7-[(2-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-(3,3,3-
trifluoropropyl)-, [2S-(2a,4aa, 10ap)]-
The title compound was obtained as described in Example 764 except the title
product of Example 348 was used as starting material. MS: 510 (M+1)+.
Example 757 2-Phenanthrenol, 1,2,3,4,4a,9,10,1 Oa-octahydro-4a-
(phenylmethyl)-7-(2-pyridinylmethoxy)-2-(3,3,3-trifluoropropyl)-,
[2S-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 497 (M+1 )+.
Example 758 2-Phenanthrenemethanol, 7-(cyclopropylethynyl)-
4b,5,6,7,8,8a,9,10-octanydro-7-hydroxy-a,a-dimethyl-4b-
(phenylmethyl)-, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 19. MS: 415 (M+1)+.
Examples 759-760
The title compounds of Examples 759-760 were prepared by procedures
analogous to those described above in Example 725.
Example 759 2-Phenanthrenol, 2-[(cyclopropylmethoxy)methyl]-
1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(2-methyl-4-
thiazolyl)methoxy]-4a-(phenylmethyl)-, [2fr(2a,4aa,1 Oaf})]-,
MS: 505 (M+1)+.
Example 760 2-Phenanthrenol, 2-[(cyclopropylmethoxy)methyl]-
1,2,3,4,4a,9,10,1 Oa-octahydro-7-[(5-methyl-3-
isoxazolyl)methoxy]-4a-(phenylmethyl)-, [2f?-(2a,4aa,10ap)]-,
MS: 489 (M+1)+.
Example 761 2-Phenanthrenol, 2-(ethoxymethyl)-1,2,3,4,43,9,10,1 Oaoctahydro-
7-[(2-methyl-4-thiazolyl)methoxy]-4a-
(phenylmethyl)-, [2fl-(2a,4aa,1 Oap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 81. MS: 479 (M+1)+.
Example 762 2-Phenanthrenol, 2-[(cyclopropylmethoxy)methyl]-
1,2,3,4,43,9,10,1 Oa-octahydro-4a-(phenylmethyl)-7-(2-
pyridinylmethoxy)-, [2/z?-(2a,4aa,10ap)j-
The title compound of this example was prepared by procedures analogous to
those described above in Example 725. MS: 485 (M+1 )+.
Example 763 2-Phenanthrenol, 2-[(cyclopropylmethoxy)methyl]-
1,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-3-
pyridinyl)methoxy]-4a-(phenylmethyl)-, [2fl-(2cc,4aa,1 Oa|3)]-
The title compound was obtained as described in Example 764 except the title
product of Example 675 was used as starting material. MS: 498 (M+1)+
Example 764 2-Phenanthrenol, 2-(ethoxymethyl)-1,2,3,4,43,9,10,103-
octahydro-7-[(2-methyl-3-pyridinyl)methoxy]-4a-
(phenylmethyl)-, [2fl-(2a,4aa,1 Oap)]-
To a solution of 20 mg of the title compound of Example 676 and 3 mg of
60% NaH in 2 mL of anhydrous DMF was added 9 mg of 2-methyl-3-picolyl chloride
hydrochloride at RT under N2 atmosphere with stirring overnight. The reaction was
quenched with NH4CI(sat.), extracted with EtOAc (X3), washed with brine, dried over
NazSOA, filtered and concentrated to dryness. Purification by preparative TLC (SiOa)
using 55% EtOAc in hexanes as the eluant afforded 21 mg (81%) of the title product
of this example as white fluffy powder. MS: 472 (M+1)+.
Example 765 2-Phenanthrenecarboxamide, 7-(ethoxymethyl)-
4b,5,6,7,8,8a,9,10-octahydrc-7-hydroxy-4b-(phenylmethyl)-/\/-
3-pyridinyl-, [4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. MS: 472 (M+1)+.
Example 766 2-Phenanthrenol, 2-(2-cyclopropylethyl)-1,2,3,4,43,9,10,10aoctahydro-
7-[(2-methylphenyl)methoxy]-4a-(phenylmethyl)-,
[2«-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 482 (M+1 )+.
Example 767 2-Phenanthrenol, 2-(2-cyclopropylethyl)-1,2,3,4,43,9,10,10.3-
oct3hydro-7-(phenylmethoxy)-43-(phenylmethyl)-, [2R-
(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 10. MS: 468 (M+1)+.
Example 768 2-Phenanthrenecarbonitrile, 7-(ethoxymethyl)-
4b,5,6,7,8l83,9,10-oct3hydro-7-hydroxy-4b-(phenylmethyl)-,
[4bS-(4ba,7a,8ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 81. MS: 377 (M+1 ).
Examples 769-770
The title compounds of Examples 769-770 were prepared by procedures
anslogous to those described above in Example 725.
Example 769 2-Phenanthrenec3rbonitrile, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-[(2,2,2-trifluoroethoxy)methyl]-,
[4bS-(4ba,7a,8ap)]-, MS: 430 (M+1)+.
Example 770 2-Phenanthrenecarbonitrile, 7-[(cyclopropylmethoxy)methyl]-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-,
[4bS-(4ba,7a,8ap)]-, MS: 403 (M+1)+.
Example 771 2-Phenanthrenecarboxamide, 7-(2-pentyl)-4b,5,6>7,8l83,9,10-
octahydro-7-hydroxy-A/-[(2-methyl-3-pyridinyl)methyl]-4b-
(phenylmethyl)-, [4bS-(4ba,7a,8ap)]-
To a stirring solution of 150 mg of 2-phenanthrenecarboxylic acid,
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(pentyl)-, methyl ester,
[4bS-(4ba,7a,8ap)]- in 7 mL of dichloromethane was added 2 mL of 0.5 M 2-methyl-
3-aminomethylpyridine aluminum amide solution prepared as in Example 772. The
mixture was heated to reflux for 3 h. An additional 1 mL of 0.5 M 2-methyl-3-
aminomethylpyridine aluminum amide solution was added and the mixture was
heated to reflux for an additional 2 h. The mixture was cooled to 0 °C. To the
reaction mixture was added 1 N HCI dropwise until the aqueous layer was
approximately pH 4. The resultant mixture was extracted with EtOAc, dried over
Na2SO4, filtered, and concentrated to dryness. Purification by flash chromatography
over SiO2 using 10% MeOH in dichloromethane as the eluant afforded 172 mg (94
%) of the title product of this example as a white solid. MS: 511 (M+1)+.
Example 771A-1 2 (2-Phenanthrenecarboxylic acid, 4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-4b-(phenylmethyl)-7-(butyl)-, methyl
ester, [4bS-(4ba,7a,8a(3)]-;
The title compound of this example was prepared by procedures analogous to
those described above in Example 14. MS: 421 (M+1)+.
Example 771A-2 2-Phenanthrenecarboxamide, 7-butyl-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-AA[(2-methyl-3-pyridinyl)methyl]-4b-
(phenylmethyl)-, (4bS,7f,8afl)-
To a stirring solution of 210 mg of the title compound of Example 771 A-1 in
10 mL of dichloromethane was added 3 ml_ of 0.5 M 2-methyl-3-aminomethylpyridine
aluminum amide solution prepared as in Example 772. The mixture was heated to
reflux overnight. The mixture was cooled to 0 °C. To the reaction mixture was added
1 N HCI dropwise until the aqueous layer was approximately pH 4. The resultant
mixture was extracted with EtOAc, dried over Na2SO4l filtered, and concentrated to
dryness. Purification by flash chromatography over SiO2 using 40% acetone in
hexanes to 50% acetone in hexanes as the gradient eluant afforded 163 mg (63%) of
the title product of this example as a white solid. MS: 497 (M+1)+.
Example 771B 2-Phenanthrenecarboxamide, 7-(cyclopropylethynyl)-
4b,5,6,7,8,8a,9,1O-octahydro-7-hydroxy-A/-[(2-methyl-3-
pyridinyl)methyl]-4b-(phenylmethyl)-, (4bS,7f?,8af?)- (Refer to
Scheme C: C-5-»C-8)
To a stirring solution of 200 mg of 2-phenanthrenecarboxylic acid,
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-( cyclopropyl- ethynyl)-,
methyl ester, [4bS-(4ba,7a,8a(3)]-) in 10 mL of dichloromethane was added 3 mL of
0.5 M 2-methyl-3-aminomethylpyridine aluminum amide solution prepared as in
Example 772. The mixture was heated to reflux overnight. The mixture was cooled
to 0 °C. To the reaction mixture was added 1 N HCI dropwise until the aqueous layer
was approximately pH 4. The resultant mixture was extracted with EtOAc, dried over
Na2SO4, filtered, and concentrated to dryness. Purification by flash chromatography
over SiO2 using 40% acetone in hexanes to 50% acetone in hexanes as the gradient
eluant afforded 196 mg (81 %) of the title product of this example as a white solid.
MS:505(M+1)+.
Example 771C-1 Methanesulfonic acid, trifluoro, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(3,3,3-trifluoropropyl)-2-
phenanthrenylester, [4bS, 7S, 8aR]-
The title compound of this example was prepared by procedures analogous to
those described above for the preparation of the title compound of Example 13. MS:
537 (M+1)+;1H NMR (400MHz, d6-acetone) 6 7.18 (d, 1H, J =2.9) 6.83 (dd, 1H, J =
2.9, 8.7), 6.43 (d,1H,J = 8.7).
Example 771C-2 2-Phenanthrenecarboxylic acid, 4b,5,6,7,8,8a,9,10- octahydro-
7-hydroxy-4b-(phenylmethyl)-7-(3,3,3-trifluoropropyl)-, methyl
ester, [4bS, 7S, 8aR]-
The title compound of this example was prepared by procedures analogous to
those described above for the preparation of the title compound of Example 14. MS:
447 ((M+1 )VH NMR (400 Mhz, CDOD3) 5 7.75 (d, 1H, J = 1.7), 7.40 (dd, 1H, J = 1.7,
8.2), 6.39 (d,1H,J = 8.2).
Example 771C-3 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-AA[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
(3,3,3-trifluoropropyl)-, (4bS,7S,8afl)-
To a stirring solution of 286 mg of the title compound of Example 771 C-2 in
12 mL of dichloromethane was added 4 mL of 0.5 M 2-methyl-3-aminomethylpyridine
aluminum amide solution prepared as in Example 772. The mixture was heated to
reflux overnight. The mixture was cooled to 0°C. To the reaction mixture was added
1 N HCI dropwise until the aqueous layer was approximately pH 4. The resultant
mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to
dryness. Purification by flash chromatography over SiO2 using 40% acetone in
hexanes to 50% acetone in hexanes as the gradient eluant afforded 272 mg (79%) of
the title product of this example as a white solid. MS: 537 (M+1)+.
Example 771D 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-4b-(phenylmethyl)-7-(propoxymethyl)-A/-3-pyridinyl-,
(4bS,7R,8aR)-
To a stirring solution of 50 mg of 2-phenanthrenecarboxylic acid,
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-( propoxymethyl)-,
methyl ester, [4bS-(4ba,7ex,8ap)]- in 5 mL of dichloromethane was added 4 mL of 0.5
M 3-aminopyridine aluminum amide solution prepared as in Example 772. The
mixture was heated to reflux overnight. The mixture was cooled to 0 °C. To the
reaction mixture was added 1 N HCI dropwise until the aqueous layer was
approximately pH 4. The resultant mixture was extracted with EtOAc, dried over
Na2SO4, filtered, and concentrated to dryness. Purification by preparative TLC (Si02)
with 3 % MeOH in dichloromethane afforded 9 mg (16%) of the title product of this
example as a white solid. MS: 485 (M+1 )+.
Example 771E-1 (2-Phenanthrenecarboxylic acid, 4b,5,6,7,8,8a,9,10-octahydro-
7-hydroxy-4b-(phenylmethyl)-7-(methyl}-, methyl ester, [4bS-
(4ba,7a,8a(3)]-)
The title compound of this example was prepared by procedures analogous to
those described above in Example 14. 1HNMR (400MHz, CD3OD) 8 7.81 (S,1H), 3.90
(s, 1H), 1,29 (s, 1H); MS: 365 (M+1)+.
Example 771E-2 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-7-methyl-rV"[(2-methyl-3-pyridinyl)methyl]-4b-
(phenylmethyl)-, (4bS,7fl,8aR)-
To a stirring solution of 300 mg of the title compound of Example 771 E-1 in
16 ml of dichloromethane was added 8.2 mL of 0.5 M 2-methyl-3-
aminomethylpyridine aluminum amide solution prepared as in Example 772. The
mixture was heated to reflux overnight. The mixture was cooled to 0 °C. To the
reaction mixture was added 1 N HCI dropwise until the aqueous layer was
approximately pH 4. The resultant mixture was extracted wrth EtOAc, dried over
NaaSO*, filtered, and concentrated to dryness. Purification by flash chromatography
over Si02 using 40% acetone in hexanes to 50% acetone in hexanes as the gradient
eluant afforded 344 mg (92%) of the title product of this example as a white solid.
MS: 455 (M+1 )*.
Example 772 2-Phenanthrenecarboxamide, 7-(ethoxymethyl)-
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-8a-methyl-/V-[(2-
methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-,[4bS-
(4ba,7cc,8ap)]-
To a stirring solution of 31 mL of of 2.0 M trimethylaluminum in toluene and 24
mL of dichloromethane was added 8.25 g of 2-methyl-3-aminomethylpyridine in 80
mL of dichloromethane at 0 °C under N2. The mixture was stirred at 0 °C for 20 min.
then at RT for 1 h to give 2-methyl-3-aminomethylpyridine aluminum amide solution.
A separate flask was charged with 1.68 g of 2-phenanthrenecarboxylic acid,
4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(ethoxymethyl)-, methyl
ester, [4bS-(4ba,7a,8a|3)]- in 80 ml_ of dichloromethane. To this solution was added
32 ml of 2-methyl-3-aminomethylpyridine aluminum amide solution, prepared as
described above. The mixture was heated to reflux overnight. The mixture was
cooled to 0 °C. To the reaction mixture was added 1N HCI dropwise until the
aqueous layer was approximately pH 4. The resultant mixture was extracted with
dichloromethane, dried over Na2SO4, filtered, and concentrated to dryness.
Purification by flash chromatography over SiO2 using 40% acetone in hexanes to
50% acetone in hexanes as the gradient eluant afforded 1.9 g (96 %) of the title
product of this example as a white solid. MS: 499 (M+1)+.
Example773 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-2-[(1-
methylethoxy)methyl]-7-[(2-methyl-3-pyridinyl)methoxy]-4a-
(phenylmethyl)-, [2f?-(2a,4aa,10ap)]-
To a solution of 500 mg of the title product of Preparation 21 and 135 mg of
Na in 5 ml_ of anhydrous DMF was added 10 ml of isopropanol at 85 °C under N2
atmosphere overnight. The reaction was quenched with NH4CI (sat.), extracted with
EtOAc (X3), washed with brine, dried over Na2SCO4, filtered and concentrated to
dryness. Purification by column chromatography using 1.5% methanol in methylene
chloride as the eluant afforded 528 mg (93%) of the title product of this example as
white fluffy powder. MS: 486 (M+1 )*
Example 774 2-Phenanthrenol, 1,2,3,4,4a,9,10,10a-octahydro-7-[(2-methyl-
3-pyridinyl)methoxy]-4a-(phenylmethyl)-2-[(2,2,2-
trifluoroethoxy)methyl]-, [2R-(2a,4aa,1 Oa(3)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 773. MS: 525.6 (M+1 )*.
Example 775 2(3H)-Phenanthrenone, 4a-[(4-isopropylaminophenyl)methyl]-
4,4a,9,10-tetrahydro-7-hydroxy-, (S)-; MS: 362 (M+H)+; see
also Preparation 4.
Example 776 2,7-Phenanthrenediol, 4a-[(4-aminophenyl)methyl]-
1.Sa.g.lO.IOa-octahydro^-O -propynyl)-, [2R-
(2a,4aa,10ap)]-;
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 462 (M+1)+.
Example 777 2-Phenanthrenol, 7-[(2-chloro-4-pyrimidinyl)oxy]-
1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(1-
propynyl)-, [2f?-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 74. MS: 460 (M+1)+.
Example 778 3/-/-Naphtho[2,1 -b]pyran-3-one, 1,2,4a,5,6,10b-hexahydro-8-
hydroxy-1 Ob-(phenylmethyl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 3. MS: 309 (M+1)+.
Example 779 1H-Naphtho[2,1-b]pyran-3,8-diol, 2,3,43,5,6,10b-hexahydro-
10b-(phenylmethyl)-3-(1 -propynyl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 349 (M+1)+.
Example 780 1 H-Naphtho[2,1-d]pyran-8-ol, 2,3,4a,5,6,10b-hexahydro-10b-
(phenylmethyl)-3-[(phenylmethyl)imino]-, (4aS,10bfl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 77. MS: 397 (M+1)+.
Example 781 2,7-Phenanthrenediol, 1,2,3,4,43,9,10,1 Oa-octahydro-2-
(methoxymethyl)-4a-(phenylmethyl)-, (2S,4aS,1 Oafl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 81. MS: 353 (M+1)+.
Example 782 Benzonitrile, 4-[[(2fl,4aS)-3,4,9110-tetrahydro-2,7-dihydroxy-2-
(1 -propynyl)-4a(2 H)-phenanthrenyl]methyl]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 5. MS: 370 (M+1)+.
Example 783 2-Phenanthrenecarbonitrile, 4b-[(4-cyanophenyl)methyl]-
4b,5,6I7,8,8a,9,10-octahydro-7-hydroxy-7-(1 -propynyl)-,
(4bS,7R,8aR)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 381 (M+1)+.
Example 784 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
(propoxymethyl)-, (4bS,7R,8aR)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. MS: 514 (M+1)+.
Example 785 2-Phenanthrenol, 1 ,2,3,4,4a,9,10)10a-octahydro-7-[(2-methyl-
3-pyridinyl)methoxy]-2-(1-pentynyl)-4a-(phenylmethyl)-,
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 481 (M+1 )+
Examples 786-793
The title compounds of Examples 786-793 were prepared by procedures
analogous to those described above in Example 244.
Example 786
Example 787
Example 788
Example 789
Example 790
2-Phenanthrenecarboxamide, 7-(1-butynyl)-4b,5,6,7,8,8a,9,10-
octahydro-7-hydroxy-/V-[(2-methyl-3-pyridinyl)methyl]-4b-
(phenylmethyl)-, (4bS,7fl,8afl)-; MS: 494 (M+1)+.
2-Phenanthrenecarboxamide, 4b.5.6,7,8,8a,9,10-octahydro-7-
hydroxy-/V-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-
[(2,2,2-trifluoroethoxy)methyl]-,(4bS.7/:?,8afl)-; MS: 554
(M+1)*.
2-Phenanthrenecarboxamide. 7-[(cyclopropylmethoxy)methyl]
4b)5,6,7,8,8a,9, 1 O-octahydro-7-hydroxy- A/-[(2-methyl-3-
pyridinyl)methyl]-4b-(phenylmethy1)-.(4bS,7fl,8afl)-; MS: 526
2-Phenanthrenecarboxamide, 7-[(cyclopropylmethoxy)methyl]-
4b,5l6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-A/-
3-pyridinyl-, (4bS,7f?,8af?)-; MS: 498 (M+1)+.
2-Phenanthrenecarboxamide, 4b)5,6,7,8,8a,9, 1 0-octahydro-7-
hydroxy-7-[( 1 -methylethoxy)methyl]-/S/-[(2-methyl-3-
pyridinyl)methyl]-4b-(phenylmethyl)-,(4bS,7/:?,8af-; MS: 514
Example 791 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9, 1 0-octahydro-7-
hydroxy-7-methyl-4b-(phenylmethyl)-A/-3-pyridinyl-,
(4bS,7R,8aR)- MS: 428 (M+1)+.
Example 792 2-Phenanthrenecarboxamide, 4b,5,6,7,8l8a)9I10-octahydro-7-
hydroxy-7-(3-methylbutyl)-A/-[(2-methyl-3-pyridinyl)methyl]-4b-
(phenylmethyl)-,(4bS,7f?,8afl)-; MS: 512 (M+1)+.
Example 793 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-7-(3-methyl-1 -butynyl)-AA[(2-methyl-3-
pyridinyl)methyl]-4b-(phenylmethyl)-, (4bS,7 R,8aR)-; MS: 508
(M+1)*.
Example 794 2-Phenanthrenol, 2-(1-butynyl)-1,2,3,4,4a,9,10,10a-octahydro-
7-[(2-methyl-3-pyridinyl)methoxy]-4a-(phenylmethyl)-,
(2fl,4aS,10afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 467 (M+1)+.
Example 795 2-Phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-
hydroxy-7-[(2-methylpropoxy)methyl]-AA[(2-methyl-3-
pyridinyl)methyl]-4b-(phenylmethyl)-,(4bS,7/:?l8aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 81. MS: 528 (M+1 )+.
Examples 796-798
The title compounds of Examples 796-798 were prepared by procedures
analogous to those described above in Example 9.
Example 796 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,1 Oa-octahydro-2-
methyl-4a-(phenylmethyl)-,(2fl,4aS,10aS)-; MS: 323 (M+1)+.
Example 797 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,1Oa-octahydro-2-
methyl-4a-(phenylmethyl)-,(2S,4aS,10aS)-; MS: 323 (M+1)+.
Example 798 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-
methyl-4a-propyl-,(2fl,4a/:?,10aS)-; MS: 275 (M+1)+.
Example 799 2,7-Phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(trifluoromethyl)-, (2fl,4aS, 10aR)-;
To a solution of 455 mg of the title product of Example 6 in 20 mL of
anhydrous THF and 15 mL of 1 M trifluoromethyl trimethylsilane was added 194 mg
of TBAF at 0 °C under nitrogen atmosphere for 10 min. The mixture was then stirred
at RT for 3 hr. Two equivalents of TBAF were added and stirred for 1 hr at RT. The
mixture was concentrated and purification by flash chromatography SiO2 using 100%
hexanes to 20% ethyl acetate in hexanes as the gradient eluant afforded 518 mg
(93%) of the title product as white fluffy powder. MS m/z375 (M-1 )+.
Example 800 2,7-Phenanthrenediol, 1 ,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-2-(trifluoromethyl)-, (4aS,1 OaS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 799. MS: 377 (M+1 )*.
Example 801 2-Phenanthrenol, 1,2,3,4,43,9,10,1 Oa-octahydro-2-methyl-7-
[(2-methyl-3-pyridinyl)methoxy]-4a-(phenylmethyl)-,
(2ft,4aS,10aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 76. MS: 429 (M+1 )*.
Example 802 2-Phenanthrenecarboxamide, 7-(ethoxyimino)-
4b,5,6,7,8,8a,9,10-octahydro-/V-[(2-methyl-3-pyridinyl)methyl]-
4b-(phenylmethyl)-, (4bS,7Z,8afl)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. MS: 483 (M+1)+.
Example 803A Methanesulfonic acid, trifluoro, 4b,5,6,7,8,8a,9,1O-octahydro-7-
hydroxy-4b (phenylmethyl)-7-(trifluoromethyl)-2-phenathrenyl
ester [(4ba, 7a, 8a|3)]
A solution of 50 mg of the title compound of Example 799, 55 mg of K2CO3,
43 mg of 4-nitrophenyltriflate in 5 ml_ of anhydrous DMF was stirred under N2 at room
temperature overnight. The reaction mixture was quenched with NaHCO3 (sat.),
extracted with EtOAc, dried over MgSO4, filtered and concentrated to dryness.
Purification by preparative TLC using 25% EtOAc in hexanes as the eluant yielded 45
mg (66%) of the title product of this example as a white solid. MS: 509 (M+1)+
Example 803B 2-Phenanthrene carboxylic acid, 4b,5)6,7,8,8a,9,10-octahydro*
7-hydroxy-4b(phenylrnethyl)-7-(trifluoromethyl)-, methyl ester,
[4bS-(4ba, 7a, 8ap)]
Starting with the title product of Example 803A and utilizing procedures
analogous to those described in Example 14, the title product of this example was
obtained. MS: 419((M+1).+
Example 803C 2-Phenanthrenecarboxamide, 4b, 5, 6, 7, 8, 8a, 9,10-
octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-
(phenylmethyl)-7-(trifluoromethyl)-, (4bS, 7R, 8aR)-
To a stirring solution of 300 mg of the title compound of Example 803B in 12
mL of dichloromethane was added 4 ml_ of 0.5 M 2-methyl-3-aminornethylpyridine
aluminum amide solution prepared as in Example 772. The mixture was heated to
reflux overnight. The mixture was cooled to 0 °C. To the reaction mixture was added
1 N HCI dropwise until the aqueous layer was approximately pH 4. The resultant
mixture was extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to
dryness. Purification by flash chromatography over SiO2 using 40% acetone in
hexanes to 50% acetone in hexanes as the gradient eluant afforded 290 mg (80%) of
the title product of this example as a white solid. MS: 509 (M+1 )+.
Example 804 2-Phenanthrenecarboxamide, 4b, 5, 6, 7, 8, 8a, 9,10-
octahydro-7-hydroxy-7-methyl-N-[(2-methyl-3-pyridinyl)methyl]*
4b-propyl-, (4bR, 7R, 8aS)-
The title compound of this example was prepared by procedures analogous to
those described above in Example 244. MS: 408 (M+1)+.
Example 805 2(3H)-Phenanthrenone, 4a-(2-butenyl)-4,4a,9,1O-tetrahydro-7-
methoxy-, [&(£)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 1. MS: 283 (M+1)+.
Example 806 Carbamic acid, [4-[[1,3,4,9,10,1 Oa-hexahydro-2,7-dihydroxy-2-
(1-propynyl)-4a(2/-/)-phenanthrenyl]methyl]phenyl]-, 1,1-
dimethylethyl ester, [2ff-(2a,4aa,10ap)]-
The title compound of this example was prepared by procedures analogous to
those described above in Example 9. MS: 463 (M+1 )+
The compounds of this invention either alone or in combination with each
other or other compounds generally will be administered in a convenient formulation.
The following formulation examples only are illustrative and are not intended to limit
the scope of the present invention.
In the formulations which follow, "active ingredient" means a compound of this
invention.
Formulation 1: Gelatin Capsules
Hard gelatin capsules are prepared using the following:
Ingredient Quantity (mg/capsule)
Active ingredient 0.25-100
Starch, NF 0-650
Starch flowable powder 0-50
Silicone fluid 350 centistokes 0-15
A tablet formulation is prepared using the ingredients below:
Formulation 2: Tablets
Ingredient Quantity (mg/tablet)
Active ingredient 0.25-100
Cellulose, microcrystalline 200-650
Silicon dioxide, fumed 10-650
Stearicacid 5-15
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 0.25-100 mg of active ingredients are
made up as follows:
Formulation 3: Tablets
Ingredient Quantity (mg/tablet)
Active ingredient 0.25-100
Starch 45
Cellulose, microcrystalline 35
Polyvinylpyrrolidone (as 10% solution in water) 4
Sodium carboxymethyl cellulose 4.5
Magnesium stearate 0.5
Talc 1
The active ingredient, starch, and cellulose are passed through a No. 45
mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed
with the resultant powders which are then passed through a No. 14 mesh U.S. sieve.
The granules so produced are dried at 50° - 60°C and passed through a No. 18 mesh
U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc,
previously passed through a No. 60 U.S. sieve, are then added to the granules which,
after mixing, are compressed on a tablet machine to yield tablets.
Suspensions each containing 0.25-100 mg of active ingredient per 5 ml dose
are made as follows:
Formulation 4: Suspensions
Ingredient Quantity (mg/5 ml)
Active ingredient 0.25-100 mg
Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 mg
Benzoic acid solution 0.10 ml_
Flavor q.v.
Color q.v.
Purified Water to 5 ml_
The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed
with the sodium carboxymethyl cellulose and syrup to form smooth paste. The
benzoic acid solution, flavor, and color are diluted with some of the water and added,
with stirring. Sufficient water is then added to produce the required volume. An
aerosol solution is prepared containing the following ingredients:
Formulation 5: Aerosol
Ingredient Quantity (% by weight)
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (Chlorodifluoromethane) 70.00
The active ingredient is mixed with ethanol and the mixture added to a portion
of the propellant 22, cooled to 30°C, and transferred to a filling device. The required
amount is then fed to a stainless steel container and diluted with the remaining
propellant. The valve units are then fitted to the container.
Suppositories are prepared as follows:
Formulation 6: Suppositories
Ingredient Quantity (mg/suppository)
Active ingredient 250
Saturated fatty acid glycerides 2,000
The active ingredient is passed through a No. 60 mesh U.S. sieve and
suspended in the saturated fatty acid glycerides previously melted using the minimum
necessary heat. The mixture is then poured into a suppository mold of nominal 2 g
capacity and allowed to cool.
An intravenous formulation is prepared as follows:
Formulation 7: Intravenous Solution
Ingredient
Active ingredient
Isotonic saline
Quantity
20 mg
1 ,000 mL
The solution of the above ingredients is intravenously administered to a
patient at a rate of about 1 mL per minute.
The active ingredient in any of the formulations above may also be a
combination of agents.



















we claim:
A compound of formula I (Formula removed)


an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically
acceptable salt of said compound, isomer or prodrug;
wherein m is 1 or 2;
— represents an optional bond;
D is CR7 or CR7R16;
E is C or CR6;
F is CR4 or CR4R5;
R1 is is aryl', wherein aryl' is substituted independently with 0, 1 or 2 of the following:
-Z-OH, -Z-NR12R13, -Z-NR12-het, -C(O)NR12R13,
-C(O)O(C1-C6)alkyl, -C(O)OH, -C(O)-het, -NR12-C(O)-(C1-C6)alkyl,
-NR,2-C(O)-(C2-C6)alkenyl, -NR12-C(O)-(C2-C6)alkynyl, -NR12-C(O)-Z-het, -CN,
-Z-het, -O-(C1-C3)alkyl-C(O)-NR12R13, -O-(C1-C3)alkyl-C(O)O(C1-C6)alkyl,
-NR12-Z-C(O)O(C1-C6)alkyl, -N(Z-C(O)O(C1-C6)alkyl)2, -NR12-Z-C(O)-NR12R13,
-Z-NR12-SO2-R13, -NR12-SO2-het, -C(O)H, -Z-NR12-Z-O(C1-C6)alkyl,
-Z-NR12-Z-NR12R13, -Z-NR12-(C3-C6)cycloalkyl, -Z-N(Z-O(C1-C6)alkyl)2, -SO2R12,
-SOR12, -SR12, -SO2NR12R13, -O-C(O)-(C1-C4)alkyl, -O-SO2-(C1-C4)alkyl, -halo or -CF3;
Z for each occurrence is independently -(Co-C6)alkyl,
-(C2-C6)alkenyl or -(C2-C6)alkynyl;
R2 is -H, -halo, -OH, -(C1-C6)alkyl substituted with 0 or 1 -OH, -NR12R13,
-Z-C(O)O(C1-C6)alkyl, -Z-C(O)NR12R13, -0-(C1-C6)alkyl, -Z-O-C(O)-(C1-C6)alkyl,
-Z-O-(C1-C3)alkyl-C(O)-NR12R13, -Z-O-(C1-C3)alkyl-C(O)-O(C1-C6)alkyl,
-O-(C2-C6)alkenyl, -O-(C2-C6)alkynyl, -O-Z-het, -COOH, -C(OH)R12R13 or-Z-CN;

R3 is -H, -(C1-C10)alkyl, wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom is substituted with 0, 1 or 2 Ry, -(C2-C10)alkenyl substituted with 0, 1 or 2 Ry, -(C2-C10)alkynyl, wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0,1 or 2 Ry, -CH=C=CH2, -CN, -(C3-C6)cycloalkyl, -Z-aryl, -Z-het, -C(O)O(C1-C6)alkyl, -O(C1-C6)alkyl, -Z-S-R12, -Z-S(O)-R12, -Z-S(O)2-R12, -CF3, -NR12O-(C1-C6)alkyl or -CH2ORy,
provided that one of R2 and R3 is absent when there is a double bond between CR2R3 (the 7 position) and the F moiety (the 8 position) of the C-ring;
Ry for each occurrence is independently -OH, -halo, -Z-CF3, -Z-CF(C1-C3alkyl)2, -CN, -NR12R13, -(C3-C6)cycloalkyl, -(C3-C6)cycloalkenyl, -(C0-C3)alkyl-aryl, -het or -N3;
R4 and R5 for each occurrence are independently -H, -CN, -(C1-C6)alkyl substituted with 0 to 3 halo, -(C2-C6)alkenyl substituted with 0 to 3 halo, -(C2-C6)alkynyl substituted with 0 to 3 halo, -O-(C1-C6)alkyl substituted with 0 to 3 halo, -O-(C2-C6)alkenyl substituted with 0 to 3 halo, -O-(C2-C6)alkynyl substituted with 0 to 3 halo, halo, -OH, (C3-C6)cycloalkyl or (C3-C6)cycloalkenyl;
or R4 and R5 are taken together to form =0;
R6 is -H, -CN, -(C1-C6)alkyl substituted with 0 to 3 halo, -(C2-C6)alkenyl substituted with 0 to 3 halo, -(C2-C6)alkynyl substituted with 0 to 3 halo or-OH;
R7 and R16 for each occurrence are independently -H, -halo, -CN, -(C1-C6)alkyl substituted with 0 to 3 halo, -(C2-C6)alkenyl substituted with 0 to 3 halo, or -(C2-C6)alkynyl substituted with 0 to 3 halo;
or R7 and R16 are taken together to form =0;

R8, R9, R14 and Rl5 for each occurrence are independently -H, -halo, (C1-C6)alkyl substituted with 0 to 3 halo, -(C2-C6)alkenyl substituted with 0 to 3 halo, -(C2-C6)alkynyl substituted with 0 to 3 halo, -CN, -(C3-C6)cycloalkyl, -(C3-C6)cycloalkenyl, -OH, -O-(C1-C6)alkyl, -O-(C1-C6)alkenyl, -O-(C1-C6)alkynyl, -NR12R13, -C(O)OR12 or -C(O)NR12R13; or R8 and R9 are taken together on the C-ring to form =O; provided that only one set of R8 and R9 are taken together to form =O;
or R14 and R15 are taken together to form =0; provided that when R14 and R15 are taken together to form =0, D is other than CR7, and E is other than C;
R10 is -(C1-C10)alkyl substituted with 0 to 3 substituents independently selected from -
halo, -OH and -N3, -(C2-C10)alkenyl -halo, -OH and -N3, -(C2-C10)alkynyl substituted
with 0 to 3 substituents independently selected from -halo, -OH and -N3, -halo, -Z-CN,
-OH, -Z-het, -Z-NR12R13, -Z-C(O)-het, -Z-C(O)-(C1C6)alkyl, -Z-C(O)-NR12R13,
-Z-C(O)-NR12-Z-CN, -Z-C(O)-NR12-Z-het, -Z-C(0)-NR12-Z-aryl,
-Z-C(O)-NR12-Z-NR12R13, -Z-C(O)-NR12-Z-O(C1-C6)alkyl, -(C0-C6)alkyl-C(O)OH,
-Z-C(O)O(C,-C6)alkyl, -Z-O-(C0-C6)alkyl-het, -Z-O-(C0-C6)alkyl-aryl, -Z-0-(C1-C6)alkyl
substituted with 0-2 Rx, -Z-0-(C1-C6)alkyl-CH(O), -Z-O-(C1-C6)alkyl-NR12-het,
-Z-O-Z-het-Z-het, -Z-0-Z-het-Z-NR12R13, -Z-O-Z-het-C(O)-het, -Z-O-Z-C(O)-het,
-Z-O-Z-C(O)-het-het, -Z-O-Z-C(O)-(C1-C6)alkyl, -Z-O-Z-C(S)-NR12R13,
-Z-O-Z-C(O)-NR12R13, -Z-O-Z-(C1-C3)alkyl-C(O)NR12R13, -Z-O-Z-C(O)-O(C1-C6)alkyl,
-Z-O-Z-C(O)-OH, -Z-O-Z-C(O)-NR12-O(C1-C6)alkyl, -Z-O-Z-C(O)-NR12-OH,
-Z-O-Z-C(O)-NR12-Z-NR12R13, -Z-O-Z-C(O)-NR12-Z-het,
-Z-O-Z-C(O)-NR12-SO2-(C1-C6)alkyl, -Z-O-Z-C(=NR12)(NR12R13),
-Z-O-Z-C(=NOR12)(NR12R13), -Z-NR12-C(O)-0-Z-NR12R13, -Z-S-C(O)-NR12R13, -Z-O-SO2-(C1-C6)alkyl, -Z-O-SO2-aryl, -Z-O-SO2-NR12R13, -Z-O-S02-CF3, -Z-NR12C(O)OR13 or -Z-NR12C(O)R13;
R11 is -H, -(C1-C5)alkyl, -(C3-C6)cycloalkyl or -(C1C3)alkyl-aryl;
R12 and R13 for each occurrence are each independently -H, -(C1-C6)alkyl wherein 1 or 2 carbon atoms, other than the connecting carbon atom, may optionally be replaced with 1 or 2 heteroatoms independently selected from S, O and N and wherein each carbon atom
is substituted with 0 to 6 halo, -(C2-C6)alkenyl substituted with 0 to 6 halo or -(C1-C6)alkynyl wherein 1 carbon atom, other than the connecting carbon atom, may optionally be replaced with 1 oxygen atom and wherein each carbon atom is substituted with 0 to 6 halo;
or R12 and R13 are taken together with N to form het;
aryl is phenyl substituted with 0 to 3 Rx, naphthyl substituted with 0 to 3 Rx or biphenyl
substituted with 0 to 3 Rx;
het is 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; and the nitrogen may be in the oxidized state giving the N-oxide form; and substituted with 0 to 3 Rx;
Rx for each occurrence is independently -halo, -OH, -(C1-C6)alkyl, (C2-C6)alkenyl,
-(C2-C6)alkynyl, -O(C1-C6)alkyl, -O(C2-C6)alkenyl, -O(C2-C6)alkynyl,
-(C0-C6)alkyl-NR12R13, -C(O)-NR12R13, -Z-SO2R12, -Z-SOR12, -Z-SR12, -NR12-SO2R13, -NR12-C(O)-R13, -NR12-OR13, -SO2-NR12R13, -CN, -CF3, -C(O)(C1-C6)alkyl, =0, -Z-SO2-phenyl or-Z-SO2-het;
het' is 5-, 6- or 7-membered saturated, partially saturated or unsaturated ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle; provided that:
1) when R9 and R10 are substituents on the A-ring, they are other than mono or di-methoxy; and
2) when R2 and R3 taken together are C=0 and R9 is hydrogen on the A-ring; or when R2 is hydroxy, R3 is hydrogen and R9 is hydrogen on the A-ring, then R10 is other than -O-(C1 -C6)alkyl or -O-CH2-phenyl at the 2-position of the A-ring.
2. A compound as claimed in claim 1, or a pharmaceutically acceptable salt thereof; wherein D is CH2; E is CH; F is CH2; R8 is -H; R9 is -H; R14 is -H; and R15 is -H.
3. A compound as claimed in claim 2 of formula II (Formula removed)


an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein
R2 is a) -OH or b) -O-CH2-het;
R3 is a) -(C1-C4)alkyl substituted with 0 or 1 of the following: -CF3, -CN, -(C3-C6)cycloalkyl, -phenyl or -N3, b) -C≡C- substituted with 1 of the following: -(C1-C5)alkyl, -C1, -CF3, -(C3-C6)cycloalkyl, -phenyl or -benzyl; c) -CH2OH, d) -CH2O(C1-C5)alkyl wherein 1 carbon atom may optionally be replaced with 1 oxygen atom, e) -CH2O(C2-C5)alkenyl, f) -CH2O(C2-C5)alkynyl wherein 1 carbon atom may optionally be replaced with 1 oxygen atom, g) -CH2ORy, h) -CN or i) -CF3;
Ry is a) -(C1C3)alkyl -CF3, b) -(C3-C6)cycloalkyl, c) -phenyl or d) -benzyl;
or R2 and R3 are taken together to form a) -l,3-dioxolan-4-yl or b) =NORn;
R11 is a) -H, b) -(C1-C5)alkyl, c) -(C3-C6)cycloalkyl, d) -phenyl or e) -benzyl.
A compound as claimed in claim 3 of formula II (Formula removed)


an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein wherein:
R1 is -(C1-C4)alkyl, -(C2-C4)alkenyl, -phenyl substituted with zero or one of the
following: -OH, -NR12R13, -NR12-C(O)-(C1-C4)alkyl, -CN, -Z-het,
-O-(C1-C3)alkyl-C(O)-NR12R13, -NR12-Z-C(O)-NR12R13, -Z-NR12-SO2-R13,
-NR12-SO2-het, -O-C(O)-(C1-C4)alkyl or -O-SO2-(C1-C4)alkyl; -O-phenyl substituted with 0 or 1 of the following: -Z-NR12R13 or -C(O)NR12R13, or -CH=CH-phenyl wherein phenyl is substituted with 0 or 1 of the following: -Z-NR12R13 or -C(0)NR12R13;
Z for each occurrence is independently -(Co-C2)alkyl;
R10 is -CH(OH)(C1-C5)alkyl, -CN, -OH, -het, -C(O)-(C1-C4)alkyl, -C(O)-NR12R13,
-C(O)-NH-Z-het, -O-(C0-C2)alkyl-het, -O-Z-C(O)-NR12R13,
-O-Z-C(O)-NH-(C0-C3)alkyl-hetor-O-Z-C(O)-NH-(Co-C3)alkyl-NR12R13;
R12 and R13 are independently -H or -(C1-C4)alkyl;
or R12 and R13 are taken together with N to form het.
5. A compound as claimed in claim 4 of formula II (Formula removed)


an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein
R1 is a) -(C2-C4)alkyl, b) -CH2-CH=CH2 or c) -phenyl;
R2 is -OH;
R3 is a) -(C1-C6)alkyl substituted with 0 or 1 CF3, b) -OC-CH3, c) -OC-C1, d) -OC-CF3, e) -CH20(C1-C3)alkyl substituted with 0 or 1 CF3, or f) -CF3; R10 is -OH.
6. A compound as claimed in claim 5 of formula III
(Formula removed)
a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug; wherein
R3 and R10 are as defined in claim 5.
7. A compound as claimed in claim 6 selected from the group consisting of:
2,7-phenanthrenediol,2-(chloroethynyl)-1,2,3,4,4a,9,10,10a-octahydro-4a-
(phenylmethyl)-, [2R-(2α,4aα,10aß)]-;
2,7-phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-propyl-[2R-(2a,4aa,10aß)]-;
2,7-phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-( 1 -propynyl)-, [2R-(2α,4aα,10aß)]-;
2,7-phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(3,3,3-trifluoro-l-propynyl)-, [2R-(2α,4aα,10aß)]-;
2,7-phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(3,3,3-trifluoropropyl)-, [2S-(2α,4aα, 1 0aß)]-;
2,7-phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-2-methyl-4a-(phenylmethyl)-,[2R-(2α,4aα, 10aß)]-; and
2,7-phenanthrenediol, 1,2,3,4,4a,9,10,10a-octahydro-4a-(phenylmethyl)-2-(trifluoromethyl)-, (2R,4aS',10aR)-;
or a pharmaceutically acceptable salt thereof.
8. A compound as claimed in claim 4 of formula II
(Formula removed)
an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; wherein
R1 is a) -(C2-C4)alkyl, b) -CH2-CH=CH2 or c) -phenyl;
R2 is -OH;
R3 is a) -(C1-C5)alkyl substituted with 0 or 1 CF3, b) -C≡C-CH3, c) -OC-C1, d) -C=C-CF3, e) -CH2O(C1-C3)alkyl substituted with 0 or l CF3, or f) -CF3;
R10 is -CN. 9. A compound as claimed in claim 6 of formula III
(Formula removed)

a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug; wherein:
R3 and R10 are as defined in claim 7.
10. A compound as claimed in claim 9 selected from the group consisting of:
2-phenanthrenecarbonitrile, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(l-propynyl)-, [4bS-(4bα,7α,8aß)]; and
2-phenanthrenecarbonitrile, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-propyl-, [4bS-(4bα,7a,8aß)]-;
or a pharmaceutically acceptable salt thereof.
11. A compound as claimed in claim 4 of formula III

a prodrug thereof, or a pharmaceutically acceptable salt of said compound or prodrug; wherein:
R3 is a) -(CH2)2-CF3, b) -(CH2)2-CH3, c) -CH3, d) -C≡C-CH3, e) -C≡C-C1 or f) -CF3; R10 is as defined in claim 4.
12. A compound as claimed in claim 11 selected from the group consisting of:
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(l-propynyl)-7V-(4-pyridinylmethyl)-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(l-propynyl)-7V-(2-pyridinylmethyl)-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-(phenylmethyl)-7-(l-propynyl)-7V-(3-pyridinylmethyl)-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-( 1 -propynyl)-N-2-pyridinyl-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-( 1 -propynyl)-N-pyrazinyl-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-(l-propynyl)-N:-3-pyridinyl-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-( 1 -propynyl)-, [4bS-(4bα,7a,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-N[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-propyl-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-N-(2-pyridinylmethyl)-, [4bS-(4ba,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-N-(4-pyridinylmethyl)-, [4b.S-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-N-(3-pyridinylmethyl)-, [4bS'-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-N-2-pyridinyl-, [4bS"-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-N-4-pyridinyl-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-4b-
(phenylmethyl)-7-propyl-N-3-pyridinyl-, [4bS-(4bα,7α,8aß)]-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(3,3,3-trifluoropropyl)-, (4bS,7S,8aR)-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-methyl-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-, (4bS,7R,8aR)-;
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-7-methyl-4b-
(phenylmethyl)-N-3-pyridinyl-, (4bS,7R,8aR)-; and
2-phenanthrenecarboxamide, 4b,5,6,7,8,8a,9,10-octahydro-7-hydroxy-N-[(2-methyl-3-pyridinyl)methyl]-4b-(phenylmethyl)-7-(trifluoromethyl)-, (4bS, 7R, 8aR)-;
or a pharmaceutically acceptable salt thereof.
13. A compound as claimed in claim 2 selected from the group consisting of:
a compound of formula III wherein R3 is -C≡C-CH3 and R10 is -OH; or a pharmaceutically acceptable salt thereof;
a compound of formula III wherein R3 is -C≡CH3 and R10 is -CN; or a pharmaceutically acceptable salt thereof;
a compound of formula III wherein R3 is - C≡CH3 and R10 is -COOH; or a pharmaceutically acceptable salt thereof.

Documents:

456-DEL-2000-Abstract-(16-06-2010).pdf

456-del-2000-abstract.pdf

456-del-2000-Claims-(05-04-2011).pdf

456-DEL-2000-Claims-(16-06-2010).pdf

456-del-2000-claims.pdf

456-del-2000-Correspondence Others-(05-04-2011).pdf

456-DEL-2000-Correspondence-Others-(16-06-2010).pdf

456-DEL-2000-Correspondence-Others-(29-07-2009).pdf

456-del-2000-correspondence-others.pdf

456-del-2000-description (complete).pdf

456-del-2000-form-1.pdf

456-del-2000-form-18.pdf

456-del-2000-form-2.pdf

456-del-2000-form-3.pdf

456-del-2000-form-5.pdf

456-DEL-2000-GPA-(16-06-2010).pdf

456-DEL-2000-GPA-(29-07-2009).pdf

456-DEL-2010-Correspondence-Others-(02-07-2010).pdf

456-DEL-2010-Form-3-(02-07-2010).pdf

456-DEL-2010-Petition 137-(02-07-2010).pdf


Patent Number 248090
Indian Patent Application Number 456/DEL/2000
PG Journal Number 24/2011
Publication Date 17-Jun-2011
Grant Date 16-Jun-2011
Date of Filing 25-Apr-2000
Name of Patentee PFIZER PRODUCTS INC.
Applicant Address EASTERN POINT ROAD,GROTON,CONNECTICUT 06340,U.S.A.
Inventors:
# Inventor's Name Inventor's Address
1 ROBERT LEE DOW 132 SHORE ROAD,WATERFORD,CONNECTICUT 06385,U.S.A.
2 KEVIN KUN-CHIN LIU 5 GOLDFINCH TERRACE,EAST LYME,CONNECTICUT 06333,U.S.A.
3 BRADLEY PAUL MORGAN 84 KEENEY ROAD,LYME,CONNECTICUT 06371, U.S.A.
4 ANDREW GORDEN SWICK 19 SPRING ROCK ROAD, EAST LYME,CONNECTICUT 06333, U.S.A.
PCT International Classification Number C07C 311/30
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/132,130 1999-04-30 U.S.A.