Title of Invention

ISOCHROMAN COMPOUNDS

Abstract This invention relates to compounds of formula (I) where R1 to R12, -W-V-, -X-Y-, p and n have the values defined in claim 1, their preparation and use as pharmaceuticals.
Full Text FIELD OF THE INVENTION
This invention relates to novel isochroman compounds, their preparation and use as
Pharmaceuticals.
Certain isochroman compounds useful as antipsychotics and in the treatment of
disorders of the central nervous system, are disclosed in WO 95/18118 and WO
97/02259.
The compounds of the invention are of the following general formula:
in which
R1 is any one of
-CN, -CONR13R14, -(CH2)t-R21
where R13, R14, R22 and R23 are each hydrogen or C1-6
alkyl, or R13 and R14 taken together with the nitrogen
atom to which they are attached form a morpholino,
pyrrolidino or piperidinyl ring optionally substituted
with one or two C1-6 alkyl groups.
R13'and R24 are each independently selected from
hydrogen, C1-6 alkyl, C1-6 alkoxy, carboxy, hydroxy,
cyano, halo, trifluoromethyl, nitro, amino, C1-6
acylamino, C1-6 alkylthio, phenyl or phenoxy.
A is 0 or S
t is 0, 1 or 2,
r is 0, 1, 2 or 3,
v is 0,1 or 2;
r2 is hydrogen, C1-6 alkyl, C1-6 alkoxy or halo;
r3, r4, r5, r6, r7# and r8 are each hydrogen or C1-6
alkyl,-
r9, Rl0, r11 and r12 are each hydrogen, C1-6 alkyl or
-(CH2)q-OR20, wherein R20 is C1-6 alkyl;
n is 1 or 2;
p is 0, 1 or 2;
q is 1 or 2;
in which -T- is -CH2-, -O-, -S-, -C(O)- or -CH=CH-,
m and s are each 0 or 1,
r15, r16 and r19 are each hydrogen, halo, C1-5
alkyl or C1-6 alkoxy, carboxy-C1-6 alkyl, cyano,
halogen, trifluoromethyl, trifluoromethoxy, nitro,
amino, C1-C6 acylamino or C1-C6 alkylthio and
R17 and R18 are each hydrogen or C1-6 alkyl,
Q is hydrogen, halo, nitrile, carboxy-C1-6 alkyl,
hydroxy, C1-6 alkyl or C1-6 alkoxy; and pharmaceutically
acceptable salts thereof; provided that:
a) when -T- is -CH2-/ -0-, -S- or -C(O)-, then (m+s) is
1 or 2, and
b) when Z is (i)a, (ii)a, (iii)a, (iv), (v)a, (vi),
(vii), (viii)a, (x)a, (xi)a, (xii)a, (x)b, (xi)b or
(xiii), then R1 is -(CH2)t-R21•
The compounds of the invention and their
pharmaceutically acceptable salts are indicated for use
as a pharmaceutical. Particularly the compounds of the
invention and their pharmaceutically acceptable salts
are indicated for use in the treatment of disorders of
the central nervous system.
Accordingly the present invention also includes the
use of a compound of formula I or a pharmaceutically
acceptable salt thereof in the manufacture of a
medicament for the treatment of a disorder of the
central nervous system in mammals. The present invention
also includes a method of treating an animal, including
a human, suffering from or susceptible to a disorder of
the central nervous system, which comprises
administering a therapeutically effective amount of a
compound of formula I or a pharmaceutically acceptable
salt thereof.
In the above formula (I), a C1-6 alkyl group can be
branched or unbranched and, for example, includes
methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
t-butyl, pentyl and hexyl, and is preferably methyl or
ethyl, and especially methyl. A C1-6 alkoxy group is
one such alkyl group linked to a ring through an oxygen
atom, and is preferably methoxy or ethoxy, and
especially methoxy. A halo group is fluoro, chloro or
bromo, and especially fluoro. A (C1-C6)alkylthio is an
alkyl group linked to a sulphur atom, where the alkyl
group is as defined above. A (C1-C6) alkylthio group
includes for example thiomethyl or thioethyl. A C1-C6
acylamino group is an alkyl group linked to an amide
group, where the alkyl is as defined above, and is
preferably of the formula RIV-NH-CO- where R1V is C1-C5
alkyl. A C1-C6 acylamino group includes for example
acetamide.
Particular embodiments of the present invention include
the following-groups of compounds of formula (I)
wherein:
1. R1 is -CONR13R14 and Z is independently selected
from (xxi), (xxi), (xxiv) or (xxv);
2. 2 is (xxi), T is -CH2- and (m+s) is 1;
3. Z is (xxi), T is -o- and m is 1 and s is 1;
4. Z is (xxi), T is -S- and m is 1 and s is 1;
5. Z is (xxi), T is -CH=CH- and both m and s are 0;
6. Z is (xxi), T is -C(O)- and both m and s are 0;
7. R3 to R8 are each C1-6 alkyl;
8. n is 1 or 2, preferably n is 2 ;
9. n is 1;
10. p is 1;
11. p is 2;
12. each of R13 and R14 is hydrogen; or
13. one of R9, R10, Rll and R12 is C1-6 alkyl,
preferably methyl or ethyl, and each of the remainder of
R9, R10, R11 or R12 is hydrogen.
When n is 2 it will be appreciated that the values
of R3 and R4 in the repeated units can be different.
In a particular embodiment of the present
invention, R1 is -{CH2)t-R21.
In another particular embodiment of the present
invention, Z is (xxi) , (xxii), (xxiii), (xxiv) or (xxv) .
In a further embodiment of the present invention,
R1 is -CCH2)t -R21 and Z is (xxi), (xxii), (xxiii) or
(xxv).
Any of the groups of compounds of formula (I) above
may be combined with any other group or groups to define
further particular embodiments of the present invention.
In a preferred embodiment, R1 is CONR13R14 and Z is
(xxi). In said embodiment:
— when -T- is -O-, preferably m is 1 and s is 1;
— when -T- is -S-, preferably m is 1 and s is 1;
— when -T- is -CH2-, (m+s) is preferably 1;
— when -T- is -C(O)-, (m+s) is preferably 1; and
— when -T- is -CH=CH-, (m+s) is preferably 0;
In another preferred embodiment, R1 is -(CH2)t-R21
and Z is any one of (xxi), (i)a and (xii)a, especially
(xxi) or (i)a.
In a preferred group of compounds of formula (I)
according to the present invention, R1 is -CONr13r14.
More preferably, Rl is -CONR13R14 where R13 and R14 are
each hydrogen or C1-6 alkyl, especially hydrogen.
In another preferred group of compounds of formula
(I) according to the present invention, R1 is
-(CH2)t -R21- More preferably, R1 is -(CH2)t-R21 where
t is 0 or 1. In the group -(CH2)t-R21, -R21 may be any
of the values defined above and:
r13 is preferably hydrogen or C1-C6 alkyl,
especially hydrogen;
r14 is preferably hydrogen or C1-C6 alkyl,
especially hydrogen;
R24 is preferably hydrogen or C1-C6 alkyl,
especially hydrogen; or methyl;
r22 is preferably hydrogen or C1-C6 alkyl,
especially hydrogen; or methyl;
Preferred groups of compounds of formula (I) according
to the present invention, where R1 is -(CH2)t-R21,
include the following:
t is 0 and R24 is hydrogen.
In the compounds of the present invention, R2 is
preferably hydrogen or C1-6 alkyl, especially hydrogen.
Each of R3, R4, R5, R6, R7 and R8 is preferably
hydrogen.
When one or each of R11 and R12 is C1-C6 alkyl or
-(CH2)q-OR20, R9 and R10 are both preferably hydrogen.
When one or each of R9 and R10 is C1-C6 alkyl or
-(CH2)q-0R20, R11 and R12 are both preferably hydrogen.
In a preferred embodiment, R9, R10, R11 and R12 are
each hydrogen. In another preferred embodiment, one of
R11 and R12 is methyl and the other is hydrogen, and R^
and RlO are both hydrogen.
In the compounds of the present invention, p is
preferably 1 or 2.
In a preferred embodiment of the present invention,
In said invention Q is preferably hydrogen and more
preferably R9, R11, r11 and R12 are hydrogen.
In further preferred embodiments, Z is (xxi); Z is
(xxii); Z is (xxiii); Z is (xxiv) , Z is (xxv) ; Z is
(i)a; Z is (xii)a. Especially preferred compounds are
those in which Z is (xxi); Z is (i)a; Z is (xii)a. When
Z is (i)a' preferably one of R15 and R16 is -cn and the
other is hydrogen. When Z is (xii)a, preferably one of
r15 and r16 is -F or -CN, and the other is hydrogen, and
R19 is hydrogen.
When Z is (xxi), preferably m+s is 1 or 2.
R25 is hydrogen.
In another preferred embodiment of the present
invention, -X-Y- is
In a preferred embodiment of the present invention,
r1 is -{CH2)t-R21- and 2 is (xii)a, wherein preferably
one of R15 and R16 is -F or -CN and the other is
hydrogen, and preferably R19 is hydrogen.
In another preferred embodiment of the present
invention, R1 is -(CH2)t-R21 and Z is (xxi), wherein -T-
is preferably -CH2- and (m+s) is preferably 1.
In yet another preferred embodiment of the present
invention, R1 is -{CH2)t-R21 and z is (i)a, wherein
preferably one of R^-5 and R16 is -CN, and the other is
hydrogen.
Any of the preferred groups herein may be combined
with any other preferred group or groups to define
further preferred compounds.
Preferred compounds of formula (I) of the present
invention include compounds of formulae:
wherein R1, r2, r5 to R10 and Z have the values defined
for formula I above, with the provisos for formula I;
Particularly preferred compounds of formula (I'}
include groups of compounds wherein R5 to R8 are
hydrogen; or wherein R2 is hydrogen; or wherein R1 is -
CONR13r14/ wherein preferably R13 and R14 are hydrogen;
or wherein Z is (xxi) wherein preferably -T- is -CH2-
and (m+s) is 1; or wherein one of R9, r10, r11 and R12
is C1-6 alkyl, preferably methyl or ethyl and each of
the remainder R9, R10, R11 and R12 is hydrogen.
Particularly preferred compounds of the invention
include compounds of formula (I') above wherein R5 to
r8 are hydrogen, R2 is hydrogen, R1 is -CONr13r14
wherein preferably R13 and R14 are hydrogen, Z is (xxi),
wherein preferably -T- is -CH2- and (m+s) is 1 and one
of R9, R10, R11 and r12 is C1-6 alkyl, preferably methyl
or ethyl and each of the remainder R9, R10, R11 and R12
is hydrogen;
wherein R1, R2, R5 to R10 and Z have the values defined
for formula I above, with the provisos for formula I;
Particularly preferred compounds of formula (I'')
include groups of compounds wherein R5 to R8 are
hydrogen; or wherein R2 is hydrogen; or wherein R1 is -
CONR13r14, wherein preferably R13 and R14 and hydrogen;
or wherein Z is (xxi) wherein preferably -T- is -CH2-
and (m+s) is 1; or wherein one of R9, R10, R11 and R12
is C1-6 alkyl, preferably methyl or ethyl and each of
the remainder R9, R10, r11 and R12 is hydrogen.
Particularly preferred compounds of the invention
include compounds of formula (I'') above wherein R5 to
r8 are hydrogen, R2 is hydrogen, R1 is -CONR13R14,
wherein preferably R13 and R14 are hydrogen, Z is (xxi),
wherein preferably -T- is -CH2- and (m+s) is 1 and one
of R9, R10, R11 and R12 is C1-6 alkyl, preferably methyl
or ethyl and each of the remainder R9, R10, r11 and R12
is hydrogen; and
wherein R1, R2, r5 to R10, Q and Z have the values
defined for formula I above, with the provisos for
formula I; Particularly preferred compounds of formula
(Iiv) include groups of compounds wherein R5 to R8 are
hydrogen; or wherein R2 is hydrogen; or wherein Q is
hydrogen; or wherein one of R9, R10, R11 and R12 is C1-6
alkyl, preferably methyl or ethyl and each of the
remainder R9, R10, R11 and R12 is hydrogen. Particularly
preferred compounds of the invention include compounds
of formula (I**) above wherein R5 to R8 are hydrogen, R2
is hydrogen, Q is hydrogen and one of R9, R10, R11 and
R12 is C1-6 alkyl, preferably methyl or ethyl and each
of the remainder R9, R10, R11 and R12 is hydrogen.
Particularly preferred compounds of the present
invention of formula (I' ) :
wherein
Each of R13 and R14 is H or C1-C6 alkyl, preferably
hydrogen;
Each of R5, R6, R7 and R8 is H or C1-C6 alkyl,
preferably hydrogen;
One or both of R11 and R12 is C1-C6 alkyl,
preferably methyl or ethyl and especially methyl;
preferably one of R11 and R12 is C1-C6 alkyl, preferably
methyl or ethyl and especially methyl and the other is
hydrogen;
Each of R9 and R10 is hydrogen, C1-C6 alkyl,
preferably methyl or hydrogen and especially hydrogen.
-X- is -CH- or -N-, especially -N-;
T is -CH2-, -O-, -S-, -C(O)- or -CH=CH-, especially
-CH2- provided that when T is -CH2-, -O-, -S- or -C(O)-,
m+s is 1 or 2, and each of m and s is 0 or 1; and when T
is -CH2-. m+s is especially 1.
Particularly preferred embodiment of the invention
includes compounds of formula (I) selected from:
(lS)-l-{2-[(2R)-4-(l,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyll ethyl} -3,4-dihydro-lH-2-benzopyran-6-
carboxamide,
(IS) -l-{2- [(2R) -4-(l,2-Dihydro-5-acenaphthylenyl) -2-
ethylpiperazinyl]ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
carboxamide,
(1S) -l-{2- [(2S) -4-(l,2-Dihydro-5-acenaphthylenyl)-2-
ethylpiperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
carboxamide,
(1S) -l-{2- [4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-
lH-1,4-diazepin-l-yl]ethyl}-3, 4-dihydro-lH-2-benzopyran-
6-carboxamide,
(1S)-l-{2~{(2R)-4-(5-Acenaphthylenyl)-2-
methylpiperazinyl] ethyl} -3,4-dihydro-lH-2-benzopyran-6-
carboxamide,
(1S) -1-{2-[{2R) -2-Methyl-4-(1H, 3H-naphtho[l,8-cd]pyran-
6-yl) piperazinyl] ethyl} -3,4-dihydro-lH-2-benzopyran-6-
carboxamide,
(lS)-l-{2-t(2R)-2-Methyl-4-(lH,3H-naphtho[l,8-
cd] thiopyran-6-yl)piperazinyl] ethyl} -3,4-dihydro-lH-2-
benzopyran-6-carboxamide,
(lS)-l-{2-[4-(l,2-Dihydro-5-acenaphthylenyl)-l-
piperidinyl] ethyl} -3,4-dihydro-lH-2-benzopyran-6-
carboxamide,
(lS)-l-{2-[(2R)-4-{l,2-Dihydro-5-acenaphthylenyl}-2-
methylpiperazinyl 1 ethyl} -1,3-dihydro-2-benzofuran-5-
carboxamide,
(ls)-l-{2-l (2R)-4-(l,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl] ethyl} -1,3-dihydro-2-benzofuran-5-
carboxamide,
l-{2- {4- (1,2-Dihydro-5-acenaphthylenyl)hexahydro-lH-l, 4-
diazepin-l-yl]ethyl}-l,3-dihydro-2-benzofuran-5-
carboxamide,
1-({2-[(2J?)-4-(6-Fluoro-l-naphthyl)-2-
methylpiperazinyl] ethyl} -3, 4-dihydro-lH-2-benzopyran-6-
yl)methanamine,
1-({2-[{2R)-4-(6-Fluoro-l-naphthyl)-2-methyl-
piperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
y1)methylformamide,
N-[({1S)-l-{2-[(2R)-4-(6-Fluoro-l-naphthyl)-2-
methylpiperazinyl] ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
yl)methyl]acetamide,
N-[((15)-l-{2-[(2R)-4-(6-Fluoro-l-naphthyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
yl)methyl]methanesulfonamide,
5-[(3R)-3-Methyl-4-(2-{ (1S)-6-[(2-oxo-1,3-oxazolidin-3-
yl)methyl]-3,4-dihydro-1H-2-benzopyran-l-
yl}ethyl)piperazinyl]-2-naphthonitrile,
3-[((1S)-l-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl] ethyl} -3,4-dihydro-1H-2-benzopyran-6-
yl)methyl]-1,3-oxazolidin-2-one,
3-[(3R)-3-Methyl-4-(2-{(1S)-6- t (2-oxo-l, 3-oxazolidin-3-
yl)methyl] -3, 4-dihydro-lH-2-benzopyran-l-yl}ethyl)-
piperazinyl]-l-benzothiophene-6-carbonitrile,
1-[((1S)-l-{2-[(2R)-4-(1, 2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl] ethyl} -3, 4-dihydro-lH-2-benzopyran-6-
yl)methyl]-2-pyrrolidinone,
3- t (3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-l-
pyrrolidinyl)methyl] -3, 4-dihydro-lH-2-benzopyran-l-
yl}ethyl )piperazinyl] -l-benzothiophene-6-carbonitrile,
(2R)-4-(l,2-Dihydro-5-acenaphthylenyl)-l-{2-[(lS)-6-(lH-
imidazol-1 -ylmethy 1)-3, 4-dihydro-1H-2-benzopyran-1 -
y1]ethyl}-2-methylpiperazine,
3-((3R)-4-(2-[(1S)-6-(lH-Imidazol-1-ylmethyl)-3 , 4-
dihydro-lH-2-benzopyran-1-yl] ethyl} -3-methyl-
piperazinyl)-l-benzothiophene-6-carbonitrile,
3-((3R)-3-Methyl-4-{2-[(1S)-6-(lH-pyrazol-1-ylmethyl)-
3,4-dihydro-lH-2-benzopyran-l-yl]ethyl}piperazinyl)-l-
benzothiophene-6-carbonitrile,
(lS)-l-{2-[(2R)-4-(6-Fluoro-l-naphthyl)-2-
methylpiperazinyl] ethyl} -3, 4-dihydro-lH-2-benzopyran-6-
amine,
3-((1S)-1-{2-[(2R)-4-(6-Cyano-l-naphthyl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
yl)-l,3-oxazolidin-2-one,
3-((1S)-l-{2-((2R)-4-(1.2-dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
yl)-1,3-oxazolidin-2-one,
3-((lS)-l-{2-t (2l?)-4-{6-Cyano-l-benzothien-3-yl)-2-
methylpiperazinyl] ethyl}-3,4-dihydro-lH-2-benzopyran-6-
yl)-l,3-oxazolidin-2-one,
l-((lS)-l-{2-[(2R)-4-(6-fluoro-l-naphthyl)-2-
methylpiperazinyl] ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
yl)-2-pyrrolidinone,
1-((1S)-l-{2-[(2R)-4-(6-Cyano-l-naphthyl)-2-
methylpiperazinyl] ethy 1} -3, 4-dihydro-1H-2-benzopyran-6-
yl)-2-pyrrolidinone,
1-((1S)-1- {2-[{2R)-4-(6-cyano-l-benzothien-3-yl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
yl)-2-pyrrolidinone,
1-( (1S)-1- {2-[(2R)-4-(6-f luoro-1-naphthyl)-2-
methylpiperazinyllethyl}-3,4-dihydro-lH-2-benzopyran-6-
yl)-2-azetidinone,
1-((1S)-l-{2-( (2R)-4-(6-cyano-l-naphthyl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
yl)-2-azetidinone,
(2K)-4-(l,2-Dihydro-5-acenaphthylenyl)-l-{2-[(lS)-6-
(1, l-dioxido-2-isothiazolidinyl)-3, 4-dihydro-lH-2-
benzopyran-1-yl] ethyl}-2-methylpiperazine,
1-((15)-1- {2- {{2R)-4-(6-Cyano-l-benzothien-3-yl)-2-
methylpiperazinyl] ethyl} -3, 4-dihydro-lH-2-benzopyran-6-
yl)-2-imidazolidinone,
l-( (lS)-l-{2-[(2R)-4-(6-Fluoro-l-naphthyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
yl)-2-imidazolidinone,
l-( (lS)-l-{2-[(2R)-4-(6-Cyano-l-benzothien-3-yl)-2-
methylpiperazinyl] ethyl} -3, 4-dihydro-lH-2-benzopyran-6-
yl)-3-methyl-2-imidazolidinone,
3-( (3R)-3-Methyl-4- {2-[(1S)-6-(4-thiomorpholinyl)-3, 4-
dihydro-lH-2-benzopyran-l-yl] ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile,
3-( (3R)-3-Methyl-4-(2-[(1S)-6-(4-morpholinyl)-3, 4-
dihydro-lH-2-benzopyran-l-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile,
(2R)-4-(1, 2-Dihydro-5-acenaphthylenyl)-2-methyl-l-{2-
(lS)-6-(lH-pyrazol-l-yl)-3,4-dihydro-lH-2-benzopyran-l-
yl] ethyl}piperazine,
3-( (3R)-3-Methyl-4-{2-[(lS)-6-(lH-pyrazol-l-yl)-3, 4-
dihydro-lH-2-benzopyran-l-yl] ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile,
(2R)-4-(l,2-Dihydro-5-acenaphthylenyl)-l-{2-[(lS)-6-(lH-
imi dazol-1-yl)-3,4-dihydro-lH-2-benzopyran-l-yl] ethyl}-
2-methylpiperazine,
3-((3i?)-4-{2-[(1S)-6-(lH-Imidazol-1-yl)-3, 4-dihydro-lH-
2-benzopyran-l-yl]ethyl}-3-methylpiperazinyl)-1-
benzothiophene-6-carbonitrile,
(2R)-4-(1, 2-Dihydro-5-acenaphthylenyl)-2-methyl-l-{2-
(lS)-6-(2H-l,2,3-triazol-2-yl)-3,4-dihydro-lH-2-
benzopyran-1-yl]ethyl}piperazine,
(2R)-4-(l,2-Dihydro-5-acenaphthylenyl)-2-methyl-l-{2-
[(lS)-6-(lH-l,2,3-triazol-l-yl)-3,4-dihydro-lH-2-
benzopyran-1-yl]ethyl}piperazine,
3-((3R)-3-Methyl-4-{2-[ (1S)-6-(2H-1,2,3-triazol-2-yl)-
3,4-dihydro-lH-2~benzopyran~l-yl] ethyl}piperazinyl} -1-
benzothiophene-6-carbonitrile,
3-{(3R)-3-Methyl-4-{2-1(1S)-6-(lH-1,2,3-triazbl-1-yl)-
3,4-dihydro-lH-2-benzopyran-1-yl] ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile,
(2R)-4-(l,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-
[(1S)-6-(1H-l,2,4-triazol-1-yl)-3,4-dihydro-lH-2-
benzopyran-1-yl] ethyl}piperazine,
3-((3R)-3-Methyl-4-{2- {(1S)-6- (1H-1,2,4-triazol-1-yl)-
3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile,
1-((1S)-1-{2-1 (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl ] ethyl} -3,4-dihydro-1H-2-benzopyran-6-
yl)-2 (1H)-pyridinone, and
3~((3R)-3-Methyl-4-{2-[(1S)-6-(2-oxo-1(2H)-pyridinyl-
3,4-dihydro-lH-2-benzopyran-1-yl] ethyl Jpiperazinyl)-1-
benzothiophene-6-carbonitrile and pharmaceutically
acceptable salts thereof.
An especially preferred compound of formula (I) is
(1S)-1-{2-{(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl J ethyl} -3,4-dihydro-lH-2-benzopyran-6-
carboxamide and pharmaceutically acceptable salts
thereof.
As indicated above, it is, of course, possible to
prepare salts of the compounds of the invention and such
salts are included in the invention. Acid addition
salts are preferably the pharmaceutieally acceptable,
non-toxic addition salts with suitable acids, such as
those with inorganic acids, for example hydrochloric,
hydrobromic, nitric, sulphuric or phosphoric acids, or
with organic acids, such as organic carboxylic acids,
for example glycollic, maleic, hydroxymaleic, fumaric,
malic, tartaric, citric, salicyclic, o-acetoxybenzoic.
or organic sulphonic, 2-hydroxyethane sulphonic,
toluene-p-sulphonic, naphthalene-2-sulphonie or
bisethane sulphenic acids. The fumarate is a most
preferred salt.
In addition to the pharmaceutically acceptable
salts, other salts are included in the invention. They
may serve as intermediates in the purification of
compounds or in the preparation of compounds or in the
preparation of other, for example pharmaceutieally
acceptable acid addition salts, or are useful for
identification, characterisation or purification.
It will be appreciated that the compounds of the
invention can contain one or more asymmetric carbon
atoms which gives rise to isomers. The compounds are
normally prepared as racemie mixtures, but individual
isomers can be isolated by conventional techniques if so
desired. Such racemic mixtures and individual optical
isomers form part of the present invention the
compounds being employed as racemates or in
enantiomerically pure form.
Preferred compounds of the invention are those of
formula:
-X-Y-, R1 to R12, n and p have the values defined
for formula I above, and -W- is -CH2-, -O-, or -S-, with
the proviso's as for formula I above.
Compounds of formula Ia can contain more asymmetric
carbons. For example when the R11 and R12 groups are
different, this gives rise to further isomers, such as
compounds of formula (Ib) and (Ic) :
wherein all of the values -X-Y-, R1 to R12, n and p
are as defined in formula (I) above, and -W- is -CH2-, -
O- or -S-, with the proviso's therein. Said isomers are
also an aspect of the present invention.
Compounds of formula (Ib) above, wherein the group
r11 takes priority over R12 according to the Cahn-
Ingold-Prelog sequence rules as described in J. March,
Fourth Edition, Chapter 4, page 109, and wherein
therefore the configuration of the carbon to which R11
and R12 are attached is R, are preferred. Particularly
preferred compounds are those of formula (Ib) wherein
R9, R10 and R12 are hydrogen and R11 is C1-6 alkyl.
In the same way, when the R9 and R10 groups are
different in compounds of formula Ia, this also gives
rise to isomers, such as compounds of formula (Id) and
(Ie):
wherein all of the values -X-Y-,R1 to R12, n and p
have the values defined for formula I above, and -W- is
-CH2-, -O-, or -S- with the proviso's as for formula I.
Said isomers are also an aspect of the invention.
Compounds of formula (Id) above, wherein the
group R9 takes priority over R10 according to the Cahn-
Ingold-Prelog sequence rules as described in J. March,
Fourth Edition, Chapter 4, page 109, and wherein
therefore the configuration of the carbon to which r9
and R10 are attached is R, are preferred. Particularly
preferred compounds are those of formula (Id) wherein R9
is C1-6 alkyl and R10, R11 and R12 are hydrogen.
The preferred stereochemistry detailed above
applies also the compounds of the present invention of
formulae (I'), (I"). (I'') and (Iiv) .
The compounds of the invention can be produced by
reacting a compound having the formula:
where the substituents have the values defined for
formula (I) above.
The reaction is preferably carried out in the
presence of a base such as potassium carbonate, in an
organic solvent such as a polar aprotic solvent, for
example, acetonitrile, at a temperature of from 20°C to
100°C. Examples of suitable leaving groups are mesylate,
tosylate, triflate, chloride, bromide and iodide,
especially bromide and iodide.
Intermediate compounds of formula (III) can, for
example, be prepared from the corresponding alcohols of
the formula:
using standard methods known in the literature such as
the ones shown in March, Advanced Organic Chemistry,
Fourth Edition, for example the methods mentioned on
pages 353 and 354.
Compounds of formula (IV) can be prepared by a
variety of methods well known in the art. Substituted 3-
(1,2,3,6-tetrahydro-4-pyridinyl)-11H-indoles, fluoro
substituted -3-(4-piperidinyl)-IH-indoles and (31?)-6-
fluoro-3-(3-pyrrolidinyl)-lH-indole may be prepared
using methods described in European patent application
EP-A 0897921 and WO patent applications WO 99/58525 and
WO 00/02341. Substituted and unsubstituted 4-(l-
naphthyl)-1,2,3,6-tetrahydropyridines and 4-(1-
naphthyDpiperidines may be prepared using methods
described in USA patents 5,472,966, 5,250,544, and
5,292,711. Substituted and unsubstituted 1-(1-
naphthyDpiperazines may be prepared using methods
described in USA patent 5,166,156. (2R,4S)-2-methyl-4-
2-naphthyl)piperidine was prepared using methods
referred to in Med.Chem. Res. (1997), 7(4), 207-218.
Substituted and unsubstituted 4-(l-benzopyran-3-yl)-
1, 2, 3, 6-tetrahydropyridines and 4-(l-benzopyran-3-
yDpiperidines may be prepared using methods described
in EP-A 0466585 or in Japanese patent JP 2000086603. 6-
fluoro-3-(1, 2,3, 6-tetrahydro-4-pyridinyl)-1, 2-
benzisoxazole may be prepared by methods based on USA
patent US 3,678,062. Substituted and unsubstituted 6-
fluoro-1-3-(1,2, 3, 6-tetrahydro-4-pyridinyl)-lH-indazoles
may be prepared by methods described in EP-A 0135781.
4-(Thieno [3, 2-b]pyrrol-6-yl)-1, 2, 3, 6-tetrahydropyridine
may be prepared by methods found in Heterocycl. Commun.
(1999), 5(4) 305-310. Substituted and unsubstituted 4-
l-benzothieny-7-yl)-1,2,3,6-tetrahydropyridines and 4-
(4-fluoro-1-benzopyran-7-yl)-1,2,3, 6-tetrahydro-pyridine
may be prepared using methods described in WO 00/00198.
6-Substituted 2-[3, 4-dihydro-lH-2-benzopyran-1-yl] ethyl
methanesulfonates may be made by procedures described in
WO 95/18118. 5-Methoxy-3-(1,2,3,6-tetrahydro-4-
pyridinyl)-lH-indole may be obtained from Tocris
Cookson. 3-[2-(4-piperidinyl)ethyl]-lH-indoles may be
prepared using methods described in J. Med. Chem. 1993,
36(15), 2242 and J. Med. Chem, 36(9) 1194.
Compounds of formula (IV) wherein R10 is -CH2-Or20
and X-Y- is can be prepared as described in the
synthetic scheme below:
In the above scheme, the nitrogen atoms are
protected with a suitable protecting group such as N-
tert-butoxycarbonyl (BOC) or any other suitable group
using methods described in Greene and Wuts, Protecting
Groups in Organic Synthesis, 3rd. Ed., John Wiley &
Sons, followed by reduction of the acid moiety to the
alcohol, alkylation of said alcohol and deprotection of
the nitrogen atoms.
The unprotected piperidine is then reacted with a
compound of formula Z-Liii in the presence of a palladium
catalyst such as palladium acetate, BINAP ((R)-2,2'-
bis(diphenylphosphino)-1,1'-binaphthyl) and a base such
as Caesium carbonate.
The nitrogen groups can for example be protected
with a BOC group using di-tert-butyl dicarbonate in the
presence of a base such as sodium hydroxide in an
organic solvent such as ethanol.
The reduction is preferably carried out in the
presence of a reducing agent such as borane dimethyl
sulfide in a organic solvent such as THF at a
temperature ranging from 0°C to room temperature.
The alkylation reaction is preferably carried out
in an organic solvent such as DMF, in the presence of a
base such as sodium hydride and an alkylating agent such
as iodomethane (for compounds where r20 is methyl).
Compounds of formula (V) wherein R7 and R8 are
hydrogen can, for example, be prepared from the
appropriate esters of the formula:
where R is C1-6 alkyl. Such esters can be reduced in the
presence of a reducing agent such as lithium borohydride
or lithium aluminium hydride in a suitable organic
solvent such as tetrahydrofuran (THF).
Compounds of formula (V) wherein R1 is -CONR13R14
can be prepared from the appropriate halo-substituted
alcohols of the formula:
where R' is a halo group, such as chloro, bromo or iodo.
Such alcohols are prepared using the same conditions as
shown above. Then the alcohol is protected using a
suitable protecting group as shown in Greene and Wuts,
Protecting Groups in Organic Synthesis, 3rd. Ed., John
Wiley & Sons. Preferred protecting groups are silyloxy
protecting groups such as for example
tertbutyldimethylsilyl group.
The halogen is then converted to the corresponding
carboxamido group {-C0NR13r14)/ via formation of the
corresponding carboxy group and then condensation with
the appropriate amine of formula HNR13R14 . The carboxy
group is formed by reaction of the intermediate
organolithium reagent with carbon dioxide in a suitable
organic solvent such as THF. The subsequent condensation
reaction with the appropriate amine of formula HNr13r14
is preferably carried out in the presence of a coupling
reagent such as carbonyldiimidazole (CDI) in a suitable
solvent such as dioxan.
Similarly the halogen can be converted in one step
to the corresponding carboxamido group by reaction of
the organolithium reagent described above with
trimethylsilyl isocyanate.
Alternatively the halogen can be converted to the
corresponding carboxamido group by initial reaction with
an inorganic cyanide, such as zinc cyanide, in the
presence of a palladium catalyst, such as
tris(dibenzylideneacetone) dipalladium, and a phosphine
ligand, such as tri-tert-butylphosphine. The reaction is
carried out in a suitable solvent such as dioxan,
usually at reflux. The resultant nitrile is then
hydrolysed to the carboxamide under basic conditions,
such as hydrogen peroxide with potassium carbonate. The
reaction is carried out in a suitable solvent such as
DMSO in methanol. In this conversion there is no
necessity to protect the alcohol function.
Then the alcohols are deprotected using standard
methods known in the literature, such as Greene and
Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed.,
John Wiley & Sons.
Compounds of the formula (VI) wherein -
and r5 and R6 are hydrogen can be prepared from the
appropriate ketones of formula (VII) as shown in Scheme
1 below.
Such ketones react with activated ylides such as
for example a phosphonate of the formula
(RiiO)2P(O)CH2CO2Riii, wherein R11 and Riii are each
C1-6 alkyl, in the presence of a base such as sodium
hydride in a suitable solvent such as for example THF to
form the corresponding unsaturated ester (VIII) . The
alkene is reduced for example via hydrogenation in the
presence of a catalyst such as Pd on charcoal in a
suitable solvent such as ethanol or methanol.
Unsaturated esters of formula (IX) can be prepared
via isomerisation of the corresponding unsaturated ester
of formula (VIII) as shown in scheme 1 above. This
reaction is carried out in the presence of a suitable
base such as sodium methanide in a suitable solvent such
as THF.
Compounds of the formula (VI) wherein ¦ -
can be prepared as shown in scheme 2 from the
appropriate lactones of formula (X).
Such lactones are converted to the corresponding
hemiacetals via reduction of the lactone using a
reducing agent such as diisobutylaluminium hydride
(DIBAL) in the presence of a suitable solvent such as
dichloromethane, followed by the protection of the
intermediate hemiacetal with a suitable protecting group
such as acetate. The protected hemiacetal is reacted
with an appropriate organozincate derived from the
corresponding haloacetal of formula Li-CH2-CO2R wherein
Li is a halogen group such as bromo or iodo and R has
the value defined above, in the presence of a Lewis acid
such as trimethylsilyltriflate to form esters of the
formula (VI)ii.
Alternatively the hemiacetal is reacted directly
with an activated ylid such as for example a phosphonate
of the formula (RiiO)2P(O)CH2CO2Riii, wherein Rii and Riii
are each C1-6 alkyl, in the presence of a base such as
caesium carbonate in a suitable solvent such as for
example THF, to form the corresponding ester (VI)11.
Such esters can be converted to the corresponding
alcohols using the method mentioned above. Alternatively
they can be hydrolysed in acidic conditions to the acid,
followed by formation of the mixed anhydride and final
reduction of such a mixed anhydride to the corresponding
alcohol of formula (V)ii.
Alternatively compounds above wherein n is 2 can be
synthesised via standard acid catalysed cyclisation of
the corresponding phenyl alcohol of formula (XII) with
an appropriate aldehyde of the formula CHO-CH2-COOR or
its corresponding acetal of the formula
(RVO)2CH-CH2-COOR , wherein Riv and RV are each
independently a C1-C6 alkyl group, in the presence of a
Lewis acid such as titanium tetrachloride in a suitable
solvent such as dichloromethane, see Scheme 3 below.
Compounds of the formula (V) wherein —w—V— is --CH2—N--
can be prepared as shown in scheme 4 from the
appropriate quinolines of formula (XIII).
Such quinolines are converted to the corresponding
1,2,3,4 tetrahydroquinolines by reduction, for example
by hydrogenation in the presence of ammonium formate anc
a suitable catalyst such as Palladium on charcoal in a
suitable solvent such as methanol. The
tetrahydroquinoline is then alkylated with allyl halide
for example allyl bromide in the presence of a suitable
base such as sodium hydride in a suitable solvent such
as dimethylformamide (DMF) . The double bond of the ally]
group is then cleaved for example via ozonolysis. The
intermediate ozonide formed is reduced with a suitable
reducing agent such as sodium borohydride to give the
corresponding alcohol. Alternatively such a double bond
can be cleaved for example with osmium tetroxide and
sodium periodate in the presence of a suitable reducing
agent such as sodium borohydride.
Compounds of the formula (V) wherein
can be prepared as shown in scheme 5 from the
appropriate 2-oxo-l,2,3,4-tetrahydroquinoline of formula
(XVI) .
Scheme 5
Such 2-oxo-l,2, 3,4-tetrahydroquinolines can be
alkylated with an allyl halide for example allyl bromide
in the presence of a suitable base such as sodium
hydride in a suitable solvent such as dimethylformamide
(DMF) . The allyl group can be converted to the
corresponding alcohol using the method shown above.
Compounds of the invention can also be synthesised
via reaction of the corresponding amine of the formula
(XIX) with a compound of the formula Z-L wherein L
is a leaving group such as triflate or a halide such as
bromide or iodide.
Scheme 6
Such reactions are usually carried out in the
presence of a palladium catalyst such as palladium
acetate and a base such as potassium tertbutoxide.
Some intermediates of the general formula Z-Liii
wherein L is a halogen group such as bromo are
commercially available. Alternatively, they can be
synthesised from known literature routes, such as by
brominating the corresponding aromatic group with NBS.
Intermediates wherein L is a triflate can be prepared
using methods known in the art such as from the
corresponding ketones in the presence of triflic
anhydride. Such intermediates are illustrated in scheme
7 for compound wherein Z is (i) and (xii) , but it will
be appreciated that such method can be used for any
values of Z. It will also be appreciated that for
compounds wherein Z is (xxi) to (xxv) the linker -T-
might have to be protected during any of these
processes, especially for compounds wherein -T- is -
C(O)- or -CH=CH-.
Compounds of formula (I) wherein H1 is
synthesised from the corresponding amide intermediates
of formula (V)v wherein the alcohol moiety is protected
with an appropriate alcohol protecting group P, such as
those shown in Greene and Wuts, Protecting Groups in
Organic Synthesis, 3rd. Ed., John Wiley & Sons.
Such intermediates are cyclised via reaction with
dimethylformamide dimethylacetal in a suitable solvent
such as toluene, followed by reaction with the
corresponding hydrazine of the formula R13-NH-NH2 in a
suitable solvent such as for example methanol. Then the
alcohols are deprotected using methods known in the art
such as those shown in Greene and Wuts, Protecting
Groups in Organic Synthesis, 3rd. Ed., John Wiley &
Sons.
Scheme 8
As described above the compounds of the invention
can have an asymmetric centre, said compounds, for
example compounds of formula Ia, can be prepared in a
similar way as those compounds of general formula I, by
reacting a compound of formula:
where n and R1 to R8 have the values defined for formula
I above, -W- is -CH2-, -O-, or -S-, and Liv is a leaving
group, with a compound of formula (IV) .
The reaction is preferably carried out using the
same conditions as described above, such as in the
presence of a base such as potassium carbonate, in an
organic solvent such as a polar aprotic solvent, for
example, acetonitrile, at a temperature of from 20°C to
100°C. Examples of suitable leaving groups are mesylate,
tosylate, triflate, chloride, bromide and iodide.
Intermediate compounds of formula (IIIa) can, for
example, be prepared from the corresponding alcohols of
the formula:
where the substituents have the values defined for
formula (IIIa) above, using standard methods known in
the literature such as the ones shown in March, Advanced
Organic Chemistry, Fourth Edition, for example the
methods mentioned on pages 353 and 354.
Said alcohols of formula (Va) can be prepared via
methods known in the literature such as for example the
procedure described in TenBrink et al., J. Wed. Chem.,
1996, 39, 2435-2437.
In the same way compounds of the invention having
two asymmetric carbon atoms such as compounds of formula
(Ib) , can be prepared by reacting the corresponding
chiral intermediates such as a compound of formula
(IIIa) with a compound of the formula:
For compounds of formula (Ic), by reacting a
compound of formula (IIIa) with a compound of the
formula:
where the substituents have the values defined for
formulae (Ib) and (Ic) above.
The reaction is preferably carried out in the
presence of a base such as potassium carbonate, in an
organic solvent such as a polar aprotic solvent, for
example, acetonitrile, at a temperature of from 20°C to
100°C. Examples of suitable leaving groups are mesylate,
tosylate, triflate, chloride, bromide and iodide.
It will be appreciated that compounds of formulae
(Ib) and (Ic) can also be produced by the preparation of
compounds of formula (Ia) as the racemic mixture,
followed by the separation of the corresponding isomers.
Intermediates of formula (IVa) wherein -X-Y- is
-N(Z)-CH2- can be synthesised via reaction of the
unprotected piperazine of the formula
with a compound of formula Z- Liii.
Such reactions are usually carried out in the
presence of a palladium catalyst such as palladium
acetate, BINAP ((R)-2,2'-bis(diphenylphosphino)-1,1'-
binaphthyl) and a base such as Caesium carbonate.
In the same way intermediates of formula (IVb)
wherein -X-Y- is -N(Z)-CH2~ can be synthesised via
reaction of the unprotected piperazine of the formula
with a compound of formula Z-Liii, using the same
reaction conditions as described above.
Methods for the preparation of intermediates of
formula (IVa) are further illustrated below. Said
methods refer to compounds wherein -X-Y- is -N(Z)-CH2-
for methods (a) to (1) or -C(Q)(Z)-CH2- for method (m),
and wherein Z has different values and several
substitution patterns. Additionally methods (n) to (s)
illustrate methods for the preparation of intermediates
of formula (IIIa) with different values of R1. Any of
variety of intermediates of formula (IVa) can be used
for the preparation of the starting materials and can
equally be used to obtain the corresponding
intermediates of formula (IVb). They all use the common
step of reaction of the unprotected piperazine with a
compound of formula Z- Liii using the conditions
described above, unless stated otherwise.
method a)
Intermediates of formula (IVa) wherein Z is (xii)a and
R16 is CN can be prepared as shown in the scheme below:
via conversion of the naphthoic acid into the
corresponding naphthonitrile, followed by reaction with
the unprotected piperazine as described above. The last
reaction is preferably carried out in a solvent such as
toluene and in the presence of a Palladium catalyst such
as tris(dibenzylideneacetone)dipalladium(0), (R)-2,2'-
bis {diphenylphosphino)-1,1' -binaphthy 1 {BINAP) , and a
base such as sodium tert-butoxide.
The acid moiety is converted to the nitrile using
general methods known in the art, for example the
reaction can be carried out in the presence of an
activating reagent such as methanesulfonyl chloride and
reacting the reactive intermediate with ammonia in an
organic solvent such as pyridine. Further addition of
methanesulfonyl chloride dehydrates the intermediate
carboxamide to the nitrile.
method b)
Intermediates of formula (IVa) wherein Z is (xii)a and
R19 is cl can be prepared as shown in the scheme below:
via conversion of the alcohol into a suitable leaving
group Liii, followed by reaction with the unprotected
piperazine, as described above. When the Liii group is a
triflate, reaction of the alcohol can, for example, be
carried out in an organic solvent such as THF, in the
presence of a base such as sodium tert-butoxide and a
triflating agent such as, for example,
N-phenyltrifluoromethanesulfonimide.
method c)
Intermediates of formula (IVa) wherein Z is (xii)a and

r19 is CN can also be prepared as shown in the scheme
below:
via conversion of the amino group of the corresponding
aminonaphthonitrile into a suitable leaving group Liii,
followed by reaction with the unprotected piperazine, as
described above. When the Liii group is a halide, the
reaction can, for example, be carried out in the
presence of copper(I)halide and nitrous acid, formed
from a mixture of aqueous sodium nitrite and an acid
such as hydrochloric acid.
method d)
i Intermediates of formula (IVa) wherein Z is (xii)a and
r16 and R19 are both F can be prepared as shown in the
scheme below:
An iodo group is introduced into the napthalene
ring, followed by protection of the nitrogen atom with a
suitable protecting group P, conversion of the iodo
group to a fluoro group and final deprotection.
The introduction of the iodo group is preferably
carried out using general iodination conditions, such as
in the presence of a mixture of bis (pyridine) iodonium(I)
tetrafluoroborate and tetrafluoroboric acid, in an
organic solvent such as dichloromethane.
The nitrogen atom can be protected using general
conditions as described in Greene and Wuts, Protecting
Groups in Organic Synthesis, 3rd. Ed. , John Wiley &
Sons. A suitable protecting group is for example CBZ.
Said protecting groups can be cleaved following the
procedures also described in Greene and Wuts, Protecting
Groups in Organic Synthesis, 3rd. Ed., John Wiley &
Sons.
The iodo group is converted to a fluoro group in
the presence of N-fluorobenzenesulfonimide and a base
such as tert-butillithium, in an organic solvent such as
tetrahydrofuran.
Intermediates of formula (IVa) wherein Z is (xii)a
and r16 is F and R19 is CN can be prepared as shown in
the scheme below:
via conversion of the iodo group into the corresponding
nitrile group.
The reaction is preferably carried out in the
presence of a cyanide such as potassium cyanide', a
catalyst such as copper (I) iodide and a palladium
catalyst such as tetrakis(triphenylphosphine)palladium
(O), in an organic solvent such as tetrahydrofuran. The
reaction mixture is preferably heated, for example, at a
temperature around 100o C.
method e)
Intermediates of formula (IVa) wherein Z is (xii)a and
r16 and r19 are both methyl can be prepared as shown in
the scheme below:
wherein the 1H, 3H-naphtho[1,8-cd]pyran-l,3-dione is
reduced to the corresponding 1H, 3H-naphtho[l, 8-cd]pyran.
Then the pyran ring of the 1H, 3H-naphtho[l,8-cd]pyran is
then opened to give the corresponding
bis (bromomethyl)naphthalene derivative, which is
subsequently converted to the dimethyl compound.
Reaction with the corresponding unprotected piperazine
is performed as described above.
The reduction is preferably carried out in the
presence of a reducing agent such as sodium borohydride,
in an organic solvent such as ethanol, followed by
reaction with an acid such as trifluoroacetic acid, in
an organic solvent such as dichloromethane and in the
presence of a reducing agent such as triethylsilane.
The pyran ring is preferably opened in the presence
of a reagent such as boron tribromide, in an organic
solvent such as dichloromethane at reflux.
The dimethyl compound is preferably prepared in the
presence of a reducing agent such as sodium borohydride.
in the presence of an activating agent such as silver
nitrate, in an organic solvent such as
dimethylf onnamide.
method f)
Intermediates of formula (IVa) wherein Z is (xii)a and
R16 is F can be prepared as shown in the scheme below:
wherein the naphthol compound is protected with a
suitable alcohol protecting group P', as described in
Greene and Wuts, Protecting Groups in Organic Synthesis,
3rd. Ed., John Wiley & Sons, followed by conversion of
the bromo group into a fluoro group. The alcohol is
deprotected and converted into a suitable leaving group
Liii, then reacted with the corresponding unprotected
piperazine, as described above.
The alcohol can be protected using general
conditions, as described in Greene and Wuts, Protecting
Groups in Organic Synthesis, 3rd. Ed., John Wiley &
Sons, a suitable protecting group is, for example, tert-
butyldimethylsilane. Said protecting groups can be
cleaved following the procedures also described in
Greene and Wuts, Protecting Groups in Organic Synthesis,
3rd. Ed., John Wiley & Sons.
The bromo group is converted to a fluoro group in
the presence of N-fluorobenzenesulfonimide and a base
such as tert-butillithium, in an organic solvent such as
tetrahydrofuran.
The conversion of the alcohol into a suitable
leaving group such as a triflate can be carried out in
an organic solvent such as THF in the presence of a base
such as sodium tert-butoxide and a triflating agent such
as, for example, N-phenyltrifluoromethanesulfonimide.
method g)
Intermediates of formula (IVa) wherein Z is (xii)a and
r16 is cl can also be prepared as shown in the scheme
below:
via conversion of the alcohol into a suitable leaving
group Liii , the amino group into a chloro group, followed
by reaction with the unprotected piperazine, as
described above. When the Liii group is a triflate, the
first reaction can, for example, be carried out in an
organic solvent such as THF, in the presence of a base
such as sodium tert-butoxide and a triflating agent such
as, for example, N-phenyltrifluoromethanesulfonimide.
The amino group is preferably reacted with
copper(I)chloride and nitrous acid, prepared from a
mixture of aqueous sodium nitrite and an acid such as
hydrochloric acid.
method h)
Intermediates of formula (IVa) wherein Z is (xii)a and
r16 is cn can also be prepared as shown in the scheme
below:
via conversion of the alcohol into a suitable leaving
group Lv , deprotection of the ether to give an alcohol,
displacement of Lv with a nitrile group, conversion of
the alcohol into a suitable leaving group Liii, followed
by reaction with the unprotected piperazine, as
described above.
The conversions of the alcohol into suitable
leaving groups Liii and Lv, when the Liii and Lv groups are
triflates can, for example, be carried out in an organic
solvent such as THF, in the presence of a base such as
sodium tert-butoxide and a triflating agent such as, for
example, N-phenyltrifluoromethanesulfonimide.
The methyl ether is deprotected with boron
tribromide in a suitable organic solvent such as
dichloromethane.
The displacement of Lv with a nitrile group is
preferably carried out by heating the compound in a
suitable organic solvent such as DMF, in the presence of
a cyanide such as, for example, zinc cyanide and a
palladium catalyst such as tetrakis triphenylphosphine
palladium (O).
method i)
Intermediates of formula (IVa) wherein Z is (xxi), m and
s are both 1 and -T- is -O-, can be prepared as shown in
the scheme below:
wherein the 1H, 3H-naphtho[l,8-cd]pyran-l, 3-dione is
reduced to the corresponding 1H, 3H-naphtho [1,8-cd]pyran,
followed by reaction with the corresponding unprotected
piperazine, as described above.
The reduction is preferably carried out in the
presence of a reducing agent such as sodium borohydride
in an organic solvent such as ethanol, followed by
reaction with an acid such as trifluoroacetic acid in an
organic solvent such as dichloromethane and in the
presence of an ionic reducing agent such as
triethylsilane.
method j)
Intermediates of formula (IVa) wherein Z is (xxi), and -
T- is -CH2-, can be prepared as illustrated in the
scheme below for compounds wherein in is 1, s is 0 and
Liii is a suitable leaving group, such as bromide:
via reaction of the corresponding 5-bromo-l, 2-
dihydroacenaphthylene with the corresponding unprotected
piperazine as described above.
method k)
Intermediates of formula (IVa) wherein Z is (xxi), both
m and s are 0, and -T- is -CH=CH- can be prepared from
the corresponding 1,2-dihydroacenaphthylene as shown in
the scheme below:
via aromatisation in the presence of a suitable reagent
such as DDQ, and in a suitable solvent such as
dichloromethane, followed by reaction with the
corresponding unprotected piperazine, as described
above.
method 1)
Intermediates of formula (IVa) wherein Z is (xxi), m and
s are both 1 and -T- is -S-, can be prepared as shown in
the scheme below:
wherein the bis(bromomethyl)naphthalene intermediate
(described above) is cyclised to give the thiopyran
ring, followed by reaction with the corresponding
unprotected piperazine, as described above.
The cyclisation is preferably carried out with a
sulfide such sodium sulfide nonahydrate, in an organic
solvent such as dimethylformamide.
Compounds of formula I wherein Z is (xxi), m is 0,
s is 1, and -T- is -C(O)- can be prepared from the
corresponding 1,2-dihydroacenaphth-1-ol, as shown in the
scheme below:
method m)
Intermediates of formula (IVa) wherein -X-Y- is
Q is hydrogen and for example Z is (xii)a can be
prepared as shown in the scheme below:
via reaction of the Z-Lvi compound, wherein Lv1 is a
suitable leaving group such as triflate, with a N-
protected 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-
yl)-3, 6-dihydro-l (2H)-pyridine, (which can be
synthesised according to the procedure described by Paul
R. Eastwood in Tetrahedron Letters, 2000, 41, 3705-
3708) . The reaction is carried out in the presence of a
base such as potassium carbonate and a palladium
catalyst such as bis(diphenylphosphino)-
ferrocenedichloropalladium(II) in a suitable solvent
such as DMF, to give the corresponding protected 3,6-
dihydro-l(2H)-pyridine, which is reduced to the
corresponding protected piperidine, and then
deprotected.
The piperidine compound can be prepared by
reduction with hydrogen in the presence of a palladium
catalyst, such as palladium on carbon in a suitable
solvent such as methanol.
The deprotection of the piperidine can be carried
out according to the nitrogen-protecting group (P) used.
Suitable protecting groups are described in Greene and
Wuts, Protecting Groups in Organic Synthesis, 3rd. Ed.,
John Wiley & Sons and include tert-butylcarboxynyl
(BOC), which can be deprotected, for example, in a
suitable solvent such as dichloromethane and in the
presence of trifluoroacetic acid.
method n)
Intermediates of formula (IIIa) wherein R1 is
can be prepared from the corresponding protected
alcohols of formula (Va) via deprotection following
suitable conditions described in Greene and Wuts,
Protecting Groups in Organic Synthesis, 3rd. Ed., John
Wiley & Sons. Suitable protecting groups (F') are also
described in the above reference and include the
tertbutyldimethylsilyl group. Said alcohols of formula
(Va) can be prepared as shown in the scheme below:
wherein LVii is a suitable leaving group such as
bromide, via reaction with the corresponding
dioxaborinanyl pyridine. This reaction is preferably
carried out in the presence of a suitable solvent such
as toluene and in the presence of a palladium catalyst
such as tetrakis(triphenylphosphine) palladium and a
suitable base such as potassium hydroxide.
method o)
Intermediates of formula (IIIa) wherein R1 is SO2NR13R14
can be prepared from the corresponding protected
alcohols of formula (Va)" via deprotection following
suitable conditions described in Greene and Wuts,
Protecting Groups in Organic Synthesis, 3rd. Ed., John
Wiley & Sons. Suitable protecting groups (P') are also
described in the above reference and include
tertbutyldimethylsilyl groups. Said alcohols of formula
(Va)" can be prepared as shown in the scheme below:
wherein Lvii is a suitable leaving group such as
bromide, via formation of the corresponding sulfonamide.
This reaction is preferably carried out in a suitable
solvent such as tetrahydrofuran and in the presence of
sulphur dioxide and a suitable base such as n-
butyllithium, followed by reaction in a suitable solvent
such as dichloromethane in the presence of N-
chlorosuccinimide and the corresponding amine
(HNR13R14).
method p)
Intermediates of formula (IIIa) wherein R1-is -(CH2)t-
R21', t is 0 and R21'is a protected amino group can be
prepared from the corresponding protected alcohols of
formula (Vb), as shown in scheme below:
wherein Lvii is a suitable leaving group such as
bromide, via reaction with a suitable imine, such as for
example benzophenone imine. Suitable protecting groups
(P') are described in Greene and Wuts, Protecting Groups
in Organic Synthesis, 3rd. Ed., John Wiley & Sons, and
include tertbutyldimethylsilyl groups. Said protected
alcohols are deprotected following suitable conditions
as also described in the above reference, and are
subsequently converted to intermediates of formula
{IIIa}1.
Said intermediates of formula (IIIa)1 are reacted
with the corresponding unprotected piperazine using
standard conditions described above. The last step is
the deprotection of the protected amino group to give
the corresponding free amino compound of formula (If).
The displacement of the Lvii group is preferably
carried out in a suitable solvent such as toluene, in
the presence of a catalyst such as tris(dibenzylidene-
acetone) dipalladium, a suitable ligand such as BINAP
and a suitable base such as sodium tert-butoxide.
The amino group is preferably deprotected in basic
mild conditions such as in the presence of hydroxylamine
hydrochloride and sodium acetate, in a suitable solvent
such as methanol.
Compounds of formula (If) can be used as
intermediates for the synthesis of compounds of formula
I wherein R1 is -(CH2)t-R21, wherein t is 0 and R21 is
via reaction with Lviii-CH2-(CH2)v-CH2-O-CO-Lix, wherein
both Lviii and Lix are suitable leaving groups such as
for example chloride, in the presence of a suitable base
such as pyridine, in a suitable solvent such as DMF, as
shown in the scheme below:
method q)
Intermediates of formula (IIIa) wherein R1 is -CH2-R21
can be prepared from the corresponding protected
alcohols of formula (Vb), as shown in scheme below:
wherein Lvii and Lx are suitable leaving groups, and p'
is a suitable alcohol protecting group such as described
in Greene and Wuts, Protecting Groups in Organic
Synthesis, 3rd. Ed., John Wiley & Sons, for example a
tertbutyldimethylsilyl group.
Intermediate (Vb) is converted to the corresponding
carboxaldehyde via reaction with dimethyl formamide in
the presence of a suitable base such as tert-
butyllithium and in a suitable solvent such as THF. Said
aldehyde is reduced to the corresponding alcohol using
standard reducing agents, such as for example sodium
borohydride in a suitable solvent such as ethanol. The
resulting primary alcohol is converted into a suitable
leaving group Lx» such as for example raesylate, in the
presence of mesyl chloride and a suitable base such as
triethylamine. Said mesylate is subsequently displaced
with the corresponding nitrogen containing compound HR21
in the presence of a suitable base, such as for example
sodium hydride, and in a suitable solvent such as DMF.
method r)
Intermediates of formula (IIIa) wherein R1 is
-(CH2)t-R21, t is 0 and R21 is
can be prepared from the corresponding protected
alcohols of formula (Vb), as shown in scheme below:
wherein Lvii is a suitable leaving group, such as for
example bromide, chloride, iodide or mesylate. P' is a
suitable alcohol protecting group such as described in
Greene and Wuts, Protecting Groups in Organic Synthesis,
3rd. Ed., John Wiley & Sons, for example a
tertbutyldimethylsilyl group.
Lvii of intermediate (Vb) is displaced via reaction
with the corresponding triazole, in a suitable solvent
such as DMF and in the presence of a catalytic amount of
copper iodide and a suitable base such as potassium
carbonate.
It will be appreciated that the above reaction
scheme is illustrated for compounds wherein the alcohol
is protected but it can equally be carried out for the
corresponding unprotected alcohols wherein P' is
hydrogen.
method s)
Intermediates of formula (IIIa) wherein R1 is
-CCH2)t--R21, t is 0 and R21 is

can be prepared from the corresponding protected
alcohols of formula (Vb), as illustrated in the scheme
below, for compounds wherein R21 is 2-imidazolidinone:
wherein Lvii is a suitable leaving group such as for
example bromide, chloride, iodide or mesylate. P' is a
suitable alcohol protecting group such as described in
Greene and Wuts, Protecting Groups in Organic Synthesis,
3rd. Ed., John Wiley & Sons, for example a
tertbutyldimethylsilyl group.
Lvii of intermediate (Vb) is displaced via reaction
with the corresponding imidazolidinone, in a suitable
solvent such as DMF and in the presence of a catalytic
amount of copper iodide and a suitable base such as
potassium carbonate.
It will be appreciated above reaction scheme is
illustrated for compounds wherein the alcohol is
protected but it can equally be carried out for the
corresponding unprotected alcohols wherein P' is
hydrogen.
Alternatively, compounds of formula I wherein R1 is
-(CH2)t-R21 and t is 0, can be prepared from the
reaction of compounds of formula (IIIa)ii as shown in
scheme below:
wherein Lxi and Lxii are suitable leaving groups.
Intermediate (IIIa)ii is reacted with a compound of
formula (IVa), following standard procedures described
above, to give a compound of formula (Ig) . Lxi of
intermediate (Ig) is converted to R2* via reaction with
HR21, in the presence of a suitable catalyst such as
tris(dibenzylideneacetone) dipalladium, a suitable
ligand such as BINAP, a suitable base such as Caesium
Carbonate and in a suitable solvent such as toluene.
In the same way compounds of formula I wherein R1
is -(CH2)t-R21 and t is 1, can be prepared from the
corresponding nitriles as shown in scheme below:
wherein Lxiii is a suitable leaving group such as for
example bromide, chloride, iodide or mesylate. Said
leaving group is converted to the nitrile using standard
methods described above. The free alcohol can be
converted to a suitable leaving group which can be
displaced with a compound of formula (IVa).
Alternatively said alcohol can be oxidised to the
corresponding aldehyde using standard oxidating
procedures known in the literature, followed by
reductive amination in the presence of the unprotected
piperazine using the standard conditions described
above. The nitrile is then reduced to the corresponding
amine in the presence of a suitable reducing agent such
as for example lithium aluminium hydride. Said amine can
be converted to several of the R21 substituents, such as
for example,
via cyclisation in the presence of Lviii-CH2-{CH2)V-CH2-
O-CO-Lix as illustrated in method {p} above.
As shown above substituents in any of the aromatic
rings, such as R1 and R2, may be present in the starting
materials or introduced at an appropriate point in the
manufacture of the product compound. If necessary said
substituents may be protected during the reaction
procedure.
Compounds of the invention have been demonstrated
to be active at the serotonin, 5-HT 1D receptor. Their
binding activity has been demonstrated in a test
described by Pullar I. A. et al, European Journal of
Pharmacology, 407 (2000), 39-40.
As mentioned above, the compounds of the invention
and their pharmaceutically acceptable salts have useful
central nervous system activity. They have been shown
to increase release of tritiated-5HT from guinea pig
cortical slices in a test with the following procedure.
Cortical slices from the brains of male guinea pigs
were incubated with 50 nM [3H]-5-HT for 30 minutes at
37oC. The slices were washed in basal buffer containing
1 nM paroxetine and then transferred to baskets. The
baskets were used to transfer the tissue between the
washing and release buffers, all of which contained 1 MM
paroxetine.
In order to obtain a stable baseline release, the
slices were incubated for 11 minutes in buffer and then
transferred for 4 minutes to a second tube containing
buffer. Following incubation they were again
transferred, for a further 4 minutes, to a buffer in
which NaCl had been substituted, on an equimolar basis,
to give a KC1 concentration of 30 mM (release sample) .
The tritium in the tissue samples and in the
buffers from the three incubation periods was estimated
by liquid scintillation spectroscopy. Test compound was
present throughout the three incubation periods. The
compounds of the invention enhanced release of 5-HT.
The compounds of the invention are serotonin
reuptake inhibitors, and possess excellent activity as,
for example, in the test described by Carroll et al. ,
J. Med. Chem. (1993), 36, 2886-2890, in which the
intrinsic activity of the compound to competitively
inhibit the binding of selective serotonin reuptake
inhibitors to the serotonin transporter is measured.
These results were also confirmed by in vivo tests in
which the effect of the compound on a behavioural
syndrome in mice dosed with 5-HTP and a monoamine
oxidase inhibitor (MAOI) such as pargyline, is measured,
see Christensen, A. V., et al. , Eur. J. Pharmacol. 41,
153-162 (1977).
In view of the selective affinity of the compounds
of the invention for the serotonin receptors, they are
indicated for use in treating a variety of conditions
associated with serotonin dysfunction in mammals
including disorders of the central nervous system such
as depression, bipolar disorder, anxiety, obesity,
eating disorders such as anorexia and bulimia,
alcoholism, pain, hypertension, ageing, memory loss,
sexual dysfunction, psychotic disorders, schizophrenia,
gastrointestinal disorders, headache, cardiovascular
disorders, smoking cessation, epilepsy, drug abuse and
addiction, emesis, Alzheimer's disease and sleep
disorders. The compounds of the invention are
principally intended for the treatment of depression or
anxiety, or disorders with depressive or anxiety
symptoms.
Accordingly the present invention includes the use
of a compound of formula I or a pharmaceutically
acceptable salt thereof in the manufacture of a
medicament for the treatment of a disorder associated
with serotonin dysfunction in mammals, including any of
the disorders mentioned above.
The compounds of the invention are effective over a
wide dosage range, the actual dose administered being
dependent on such factors as the particular compound
being used, the condition being treated and the type and
size of animal being treated. However, the dosage
required will normally fall within the range of 0.001 to
20, such as 0.01 to 20 mg/kg per day, for example in the
treatment of adult humans, dosages of from 0.5 to 100 or
200 mg per day may be used.
The compounds of the invention will normally be
administered orally or by injection and, for this
purpose, the compounds will usually be utilised in the
form of a pharmaceutical composition. Such compositions
are prepared in a manner well known in the
pharmaceutical art and comprise at least one active
compound.
Accordingly the invention includes a pharmaceutical
composition comprising as active ingredient a compound
of formula (I) or a pharmaceutically acceptable salt
thereof, associated with a pharmaceutically acceptable
diluent or carrier. In making the compositions of the
invention, the active ingredient will usually be mixed
with a carrier, or diluted by a carrier, or enclosed
within a carrier which may be in the form of a capsule,
sachet, paper or other container. More than one active
ingredient or excipient may, of course, be employed.
The excipient may be a solid, semi-solid or liquid
material which acts as a vehicle, excipient or medium
for the active ingredient. Some examples of suitable
excipients are lactose, dextrose, sucrose, sorbitol,
mannitol, starches, gum acacia, calcium phosphate,
alginates, tragacanth, gelatin, syrup, methyl cellulose,
methyl- and propyl-hydroxybenzoate, talc, magnesium
stearate or oil. The compositions of the invention may,
if desired, be formulated so as to provide quick,
sustained or delayed release of the active ingredient
after administration to the patient.
Depending on the route of administration, the
foregoing compositions may be formulated as tablets,
capsules or suspensions for oral use and injection
solutions or suspensions for parenteral use or as
suppositories. Preferably the compositions are
formulated in a dosage unit form, each dosage containing
from 0.5 to 100 mg, more usually 1 to 100 mg, of the
active ingredient.
The following Preparations and Examples illustrate
routes to the synthesis of the compounds of the
invention.
Preparation
(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-lH-2-benzopyran~6-
carboxamide
Method A
a) 2-(6-Bromo-3,4-dihydro-lH-2-benzopyran-1-yl) acetic
acid ethyl ester
A solution of 3-bromophenethyl alcohol {15 g, 74.6
mmol) and ethyl-3~3-diethoxypropionate (17.1 g, 89.9
mmol) in dichloromethane (60 mL) under an atmosphere of
nitrogen was cooled to -1G°C and treated with a 4N
solution of titanium tetrachloride in dichloromethane
(61.5 ml, 3.3 eguiv.) over a period of 15 minutes. The
reaction mixture was then allowed to warm to room
temperature. Analysis of an aliquot by HPLC indicated
that the reaction was complete after 3 h at ambient
temperature. The reaction mixture was then cooled to 0
°C and water slowly added (over 15 minutes) maintaining
the temperature between 0 and 10°C. The mixture was
agitated for an additional period of 15 minutes and
layers were separated. After washing with water (60 mL),
0.5N NaOH (80 mL), then brine (80 mL), the organic layer
was concentrated in vacuo to give the title compound as
an oil.
b) 2-(6-Bromo-3,4-dihydro-lH-2-benzopyran-1-yl)acetic
acid
2-(6-Bromo-3,4-dihydro-lH-2-benzopyran~l-yl)acetic
acid ethyl ester (20 g, 66.9 mmol) was dissolved in
absolute ethanol (40 mL) . The mixture was cooled to 0°C
and 4N NaOH (22 mL) was added over five minutes. The
reaction mixture was then stirred for 1.5 h at room
temperature. Water {22 ml} was added, and the solution
washed with dichloromethane {70 mk). The aqueous layer
was collected and acidified with 6N HC1 {17 mL) and
extracted with dichloromethane {70 mL) . The organic
layer was concentrated in vacuo to give an off-white
solid. This solid was suspended in toluene (66 mL) and
heated to 100°C. The resulting solution was cooled to
80°C and cyclohexane {66 mL) added, The resulting
suspension was cooled to room ternperature and stirred
for an hour. The solid was then filtered off, washed
with cyclohexane {20 mL), and dried at 40°C in vacuo to
give the title compound as a white solid.
c) 2-{{1S)-6-Bromo-3,4-dihydro-lH-2-benzopyran~l~
yl)acetic acid
To a suspension of 2-{6-bromo-3,4-dihydro-lH-2-
benzopyran-1-yl)acetic acid {55 g, 203 mmol) in
acetonitrile {375 mL) and water {40 mL) was added a
solution of {H}-1-{4-methylphenyl)ethylamine {27,45 g»
203 mmol) in acetonitrile {370 mL). The mixture was
heated to reflux and the resulting solution cooled to
room temperature. A precipitate appeared upon cooling.
After stirring for 2 h the salt was filtered off, washed
with 95/5 acetonitrile/water {80 mL), and dried in
vacuo. The salt was recrystallized in 95/5
acetonitrile/water to give a solid which was suspended
in water {390 mL) and treated with 6N HC1 {17 mL) . After
stirring for 1.5 h, filtration, washing, and drying gave
the title compound {98% e.e.) as a white solid.
d) 2-({1S)-6~Bromo-3,4-dihydro-lH-2-benzopyran-1-
yl)ethanol
To a solution of 2-({lS)-6-bromo-3,4-dihydro-lH-2-
benzopyran-1-yl) acetic acid {21.3 g, 78,6 mmol) in
anhydrous THF (65 ml) under an atmosphere of nitrogen
and cooled to 0°C, was added dropwise borane. THF complex
in THF {1M} C94 mL, 94 mmol). After stirring for 111
between 0 and 10oC the reaction mixture was treated
with aqtieotis sodium carbonate then extracted into
toluene. The organic layer was washed with dilute
aqueous hydrochloric acid, then concentrated in vacuo to
give the title compound as a white solid.
e) (1S)-1-(2-Hydroxyethyl)-3,4-dihydro-lH-2-benzopyran-6-
carbonitrile
A suspension of 2-((lS)-6-bromo-3,4-dihydro-1H-2-
betuzopyran-1-yl)ethanol (300 g. 1.17 mol), copper (I)
cyanide (209 g, 2.34 nol)r and copper (I) iodide (33.3
g, 0.18 mol) in dry EMP {1.16 L), under an atmosphere of
nitrogen was heated to 140°C. After 8h at this
temperature, HPLC analysis of an aliquot indicatad that
the reaction was complete. The reaction mixture was
cooled to room temperature and poured into/ an aqueous
solution of ethylenediaroine 13 L, v/v 3/1} then
extracted into toluene. The combined organic layers were
washed with water and concentrated in vacua to give the
crude title confound. This material is used without
further purification in the subsequent step,
f) (1S)-1- 12-Hydroxyethyl)-3,4-dihydro-lH-2-benzopyran-6-
carboxantide f'
To a solution of crude (1S)-1-{2-byhydroxyethyl)-3,4-
dihydro-lH-2-benzopyran-6-carbonitrile {178 g, 0.88 mol
in methanol {460 mL) and DMSO (125 ML) was add.
potassium carbonate (13 g, 94 mmol) . 35% hydrogen
peroxide (102 mL) was then added dropwise while
maintaining the temperature of the mixture below 50°C.
The reaction mixture was then allowed to stir for 1 h at
ambient temperature. Analysis of an aliquot by silica
TLC (ethyl acetate) indicated that the reaction was
complete. Water (130 mL) was added and methanol removed
in vacuo. Water (800 mL) and IN HCl (100 mL) were added
and the mixture allowed to stir overnight. The solid was
filtered, washed with water, and dried.
Recrystallization from methyl(i-butyl)ketone gave the
title compound.
Method B
a) 2-((15)-6-Bromo-3,4-dihydro-lH-2-benzopyran-1-
yDethyl tert-butyl (dimethyl)silyl ether
A 1M solution of tert-butyldimethylsilyl chloride in
dichloromethane (30mL, 30mmol) was added dropwise under
nitrogen to an ice/water-cooled solution of 2-((1S)-6-
bromo-3, 4-dihydro-lH-2-benzopyran-1-yl) ethanol (6. 7g,
24.4mmol), diisopropylethylamine (6.7g. 51.8mmol) and
dimethylaminopyridine (0.32g, 2.5mmol) in dry
dimethylformamide (70mL). After stirring overnight at
room temperature, the mixture was quenched with
ice/water and extracted with ether (2x). The combined
organic extracts were washed with water (5x), dried
(MgSO4) and evaporated in vacuo to give an oil. This
was purified by flash chromatography on silica, eluting
with ethyl acetate/hexane (0:100 to 10:90), to give the
title compound as oil.
b) (1S)-1-(2-{[tert-Butyl (dimethyl)silyl]oxy}ethyl)-3,4-
dihydro-lH-2-benzopyran-6-carboxylic acid
A 1.7M solution of tert-butyl lithium in pentane
(1.75mL, 2.97mmol) was added under nitrogen to a
solution of 2-((15)-6-bromo-3, 4-dihydro-lH-2-benzopyran-
1-yl) ethyl tert-butyl (dimethyl) silyl ether (0.5g,
1.35mmol) in tetrahydrofuran (l0mL), maintained at -
70°C. After stirring for 30min, carbon dioxide was
bubbled through the reaction mixture for 30min. After
stirring at room temperature overnight, saturated
ammonium chloride in water was added and the product
extracted into ethyl acetate. The organic extracts were
dried (MgSO4) and evaporated in vacuo to give an oil
(0.57g). This was purified by flash chromatography on
silica, eluting with ethyl acetate/hexane (0:100 to
25:75) to give the title compound as a white solid.
c) (1S)-1-(2-{[ tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,4-
dihydro-lH-2-benzopyran-6-carboxamide
A solution of (1S)-1-(2-{[tert-
butyl (dimethyl) silyl]oxy}ethyl)-3, 4-dihydro-1H-2-
benzopyran-6-carboxylic acid (20.7g, 61.2mmol) and 1,1'-
cabonyldiimidazole (20g, 123mmol) in dry tetrahydrofuran
(450mL) was stirred under nitrogen at room temperature
for 16h. A 0.5M solution of ammonia in dioxane (620mL,
310mmol) was added and the mixture stirred at room
temperature for 1 day. Water (1L) was added and the
product extracted into dichloromethane (2x 1L) . The
combined organic extracts were washed with saturated
aqueous sodium bicarbonate (2x 500mL) and brine (2x
500mL) , dried (MgSO4) and evaporated in vacuo to give a
solid (21g). This was purified by flash chromatography
on silica , eluting with hexane/ethyl acetate (1:1) then
ethyl acetate to give the title compound.
d) {1S)-1-(2-Hydroxyethyl)-3,4-dihydro-lH-2-benzopyran~
6 - carboxami de
(1S)-1-(2-{[tert-Butyl (dimethyl) silyl]oxy}ethyl)-3,4-
dihydro-lH-2-benzopyran~6-carboxamide (1g, 2.98mmol) was
dissolved in a mixture of acetic acid (l0mL) and water
{5 mL), then stirred for 2h. The solution was
evaporated to give a residue that was dried in vacuo at
55°C to give the title compound as a white solid.
2-[(1S)-6-(Aminocarbonyl)-3,4-dihydro-lH-2-benzopyran-l-
yl]ethyl methanesulfonate
(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-lH-2-benzopyran-
6-carboxamide (5g, 22.6mmol) was dissolved in a mixture
of dry tetrahydrofuran (375mL) and dry dimethylformamide
(15mL) with the aid of gentle heating. Triethylamine
(4.6g, 45.5mmol) was added, followed by methanesulfonyl
chloride (2.72g, 23.8mmol). The mixture was stirred
under nitrogen at room temperature for 1 day. The
reaction mixture was quenched with water (l000mL) and
the product extracted into ethyl acetate (2x 500mL).
The combined organic extracts were washed with brine (2x
500mL), dried (MgSO4) , and evaporated in vacuo to give
the crude product as a white solid (6.5g, 97%). The
solid was triturated with ether (300mL) to give 2-(1S)-
6-(aminocarbonyl)-3, 4-dihydro-lH-2-benzopyran-1-yl]ethyl
methanesulfonate as a white solid.
(3R)-1-(6-Fluoro-1-naphthyl)-3-methylpiperazine
a) 6-Fluoro-3,4-dihydro-1-naphthalenyl trifluoromethane-
sulfonate
To a stirred solution of 6-fluoro-3,4-dihydro-
l(2ff)-naphthalenone (0.50g, 3mmol) in dry THF (25mL) at
-78°C under nitrogen was added lithium
bis(trimethylsilyl)amide (1M in THF) (3.6mL, 3.6mmol)
over 5 min. The solution was stirred for lh, then N-
phenyltrifluoromethanesulfoninu.de {1.3g, 3.6mmol) was
added in one portion and the reaction mixture allowed to
warm to room temperature. Stirring was continued for 2h,
then the solvent was removed in vacuo. The residue was
dissolved in ethyl acetate and washed with 2M sodium
hydroxide, water, and then brine. The organic extracts
were dried (MgSO4), and concentrated in vacuo. The
resultant red oil was purified by column chromatography
on silica, eluting with ethyl acetate/hexane (1:9), to
yield 6-fluoro-3,4-dihydro-1-naphthalenyl
trifluoromethane sulfonate as a colourless oil.
b) 6-Fluoro-1-naphthyl trifluoromethanesulfonate
To a solution of 6-fluoro-3,4-dihydro-1-
naphthalenyl trifluoromethane sulfonate (0.77g, 2.8mmol)
in dioxan (15mL) was added 2,3-dichloro-5,6-dicyano-l,4-
benzoquinone (0.95g, 4.2mmol) and the reaction mixture
heated under reflux for 18h. The solvent was removed in
vacuo and the crude product purified by column
chromatography on silica, eluting with hexane, to yield
6-fluoro-1-naphthyl trifluoromethanesulfonate as a white
solid.
c) (3R)-1-(6-Fluoro-1-naphthyl)-3-methylpiperazine
To a solution of 6-fluoro-1-naphthyl trifluoro-
methanesulfonate (0.29g, lmmol) in toluene (2mL) under
nitrogen was added (2R)-methylpiperazine (0.l0g,
1. 2mmol), (R)-2,2' -bis (diphenylphosphino)-1,1'-
binaphthyl (47mg, 0.075mmol), palladium (II) acetate
(llmg, 0.05mmol) and caesium carbonate (0.46g, 1.4mmol).
The resulting suspension was heated at 110oC for 16 h.
Upon cooling, the mixture was filtered through a short
celite pad (washing with ethyl acetate), the filtrate
concentrated in vacuo and the crude product purified by
flash column chromatography on silica gel, eluting with
dichloromethane/methanol (7:3), to yield (3R)-1-(6-
fluoro-1-naphthyl)-3-methylpiperazine as a brown oil.
(3R)-1-(6-Cyano-1-naphthyl)-3-methylpiperazine
a) 5-Bromo-2-naphthonitrile
To a solution of 5-bromo-2-naphthoic acid (4.3g,
17mmol)) in dry pyridine (75mL) at 0°C was added
methanesulfonyl chloride (1.4mL, 18mmol) . After
stirring at 0°C for lh, ammonia gas was bubbled through
the solution for 10 min, whilst maintaining the
temperature below 5°C. During the gas addition the
solution became viscous, so additional dry pyridine
(~30mL) was added. Excess ammonia was removed in vacuo,
the solution again cooled to 0°C, then treated with
additional methanesulfonyl chloride (12.5mL) and allowed
to warm to room temperature overnight. The solution was
poured onto ice cold water, the mixture stirred for 30
min and the brown precipitate collected by filtration,
washed on the sinter with ice cold water, then dried in
vacuo. The crude product was dissolved in hot
chloroform {~35mL} and insoluble material filtered off.
The chloroform was removed and the residue dissolved in
a minimum volume of ether at reflux, Hexane was added
until the solution remained turbid at reflux, the
solution filtered rapidly into a pre-heated flask, and
allowed to cool slowly to room temperature. The
precipitate was collected by filtration, washed with
hexane, and dried in vacuo, to yield 5-bromo~2-
naphthonitrile. Further crops were obtained by cooling
the filtrate at -18°C overnight.
b) {3R)-1-(6-Cyano-1-naphthyl)-3-methylpiperazine
To a solution of 5-bromo-2-naphthonitrile (0.4?g,
2«anol} in dry toluene (30mL) was added
tris 2,2' -bis (diphenylphosphino} -1,1' -binaphthyl {82mg),
(2R)-methylpiperazine (0.24g, 2.4mmol) and sodium tert-
butoxide {0.27g, 2.8mmol). The solution was evacuated
until bubbling started, then the atmosphere replaced
with nitrogen. This purging and evacuation procedure
was repeated for 15 min, then the mixture heated under
reflux for 8 h. The reaction mixture was cooled to room
temperature, diluted with ethyl acetate and filtered
through celite. The filtrate was washed with aqueous
ammonia, dried CMgSO4), filtered and evaporated in
vacuo. The residue was dissolved in methanol (l0mL) and
applied to an activated SCX cartridge (10g). The
cartridge was washed with methanol (l00mL), then the
product isolated by elution with 2M ammonia in methanol
(50mL). The solvent was removed in vacuo and further
purified by flash chromatography on silica, eluting with
acetone, to yield (3R)-1-{6-cyana-l-naphthyl)-3-
methylpiperazine.
(3R)-1-(6-Cyano-1-benzothien-3-yl)-3-methylpiperazine
a) 3-Bromo-1-benzothiophene-6-carbonitrile
To a solution of l-benzothiophene-6-carbonitrile
(2.13g, 13.4mmol) in dry DMF (20mL) at -10cC was added
freshly recrystallised N-bromosuccinimide (2.38g,
13.4mmol). The solution was allowed to warm to room
temperature and stirred over the weekend. The mixture
was diluted with water and extracted into diethyl ether,
and the organic extract washed with water, then brine.
The extracts were dried (MgSO4), filtered and evaporated
in vacuo. The crude product was purified by flash
chromatography on silica, eluting with ethyl
acetate/hexane (1:9), to yield the title compound as a
white solid.
b) (3R)-1-(6-Cyano-1-benzothien-3-yl)-3-methylpiperazine
3-Bromo-1-benzothiophene-6-carbonitrile was coupled
with (2R)-methylpiperazine, as described above for (3R)-
1-(6-cyano-1-naphthyl)-3-methylpiperazine, to yield
[3R)-1-(6-cyano-1-benzothien-3-yl)-3-methylpiperazine.
Example 1
(1S)-1-{2-[(2R)-4-(1, 2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
carboxamide
a) (3R)-1-(1,2-Dihydro-5-acenaphthylenyl)-3-
methylpiperazine
A mixture of 2-(R)-methylpiperazine (0.124g,
l.lmmol), tris(dibenzylideneacetone)dipalladiuin (O)
(49mg, 0.05mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-
binaphthyl (69mg, 0.l0mmol) and sodium tert-butoxide
(0.148g, 1.5mmol) were stirred in toluene (50mL) under
nitrogen for 15 min to give a blood red solution. 5-
Bromo-l,2-dihydroacenaphthylene (0.256g, l.lmmol) was
added, the solution stirred under nitrogen and heated at
reflux for 3h. The mixture was cooled, diluted with
dichloromethane and filtered through celite. The organic
phase was washed with water, dried (MgSO4) , filtered and
evaporated in vacuo. The crude product was taken forward
to the next step without further purification.
b) (1S)-1-{2-[(2R)-4-(1, 2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl] ethyl}-3,4-dihydro-lH-2-benzopyran-
6-carboxamide
(3R)-1-(1,2-Dihydro-5-acenaphthylenyl)-3-
methylpiperazine (0.138g, 0.55mmol), 2-[(lS)-6-
aminocarbonyl)-3,4-dihydro-lH-2-benzopyran-1-yl]ethyl
methanesulfonate (0.15g, 0.50mmol), potassium carbonate
(0.138g, l.0mmol), potassium iodide (0.083g, l.Ommol)
and acetonitrile (50mL) were heated under reflux for 1
day with stirring under nitrogen. After cooling to room
temperature, the inorganics were filtered off and the
solvent evaporated in vacuo. The crude product was
purified by preparative LC-MS to give the title
compound. M+H = 456.
The following Examples were prepared by
substituting the (2R)-methylpiperazine in the above
Example with alternative piperazines or homopiperazine,
as indicated below:
Example 2
(1S)-1-{2-[(2.R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
ethylpiperazinyl] ethyl)-3, 4-dihydro-1H-2-benzopyran-6-
carboxamide
Prepared from 5-bromo-1,2-dihydro-acenaphthylene
and (2R)-ethylpiperazine. M+H = 470.
Example 3
(1S)-1-(2-[(2S)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
ethylpiperazinyl] ethyl}-3,4-dihydro-lH-2-benzopyran-6-
carboxamide
Prepared from 5-bromo-l, 2-dihydro-acenaphthylene
and (2S)-ethylpiperazine. M+H = 470.
Example 4
(lS)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-
lH-l,4-diazepin-1-yl]ethyl}-3,4-dihydro-lH-2-benzopyran-
6-carboxamide
Prepared from 5-bromo-l, 2-dihydro-acenaphthylene
and homopiperazine. M+H = 456.
Example 5
(1S)-1-{2-[(2R)-4-(5-Acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
carboxamide
5 a) 5-Bromoacenaphthylene
To 5-bromo-l,2-dihydroacenaphthalene (O.lOg,
0.43mmol) in dichloromethane (l0mL) was added 2,3-
dichloro-5,6-dicyano-l,4-benzoquinone (0.117g,
0.515mmol)and stirred at room temperature for 1 day. An
additional portion of DDQ (0.l0g) was added and the
reaction stirred for a further 1 day. The mixture was
washed with water and the organic phase dried (MgSO4),
filtered and evaporated in vacuo. The crude product was
purified by flash chromatography on silica, eluting with
ethyl acetate/heptane (0:10 to 1:9), to yield the title
compound.
b) (3R)-1-(5-Acenaphthylenyl)-3-methylpiperazine
5-Bromoacenaphthylene was coupled with (2R)-
methylpiperazine, as described for Example l a).
c) (lS)-1-{2-[(2R)-4-(5-Acenaphthylenyl)-2-
methylpiperazinyl}ethyl}-3,4-dihydro-lH-2-
benzopyran-6-carboxamide
(3R)-1-(5-Acenaphthylenyl)-3-methylpiperazine was
condensed with 2-((1S)-6-(aminocarbonyl)-3,4-dihydro-lH-
2-benzopyran-1-yl] ethyl methanesulfonate, as described
for Example 1 b), to yield the title compound. M+H =
454.
Example 6
(15)-1-{2-[(2R-4-(1-Oxo-l,2-dihydro-5-acenaphthylenyl)-
2-methylpiperazinyl] ethyl} -3, 4-dihydro-1H-2-benzopyran-
6-carboxamide
a) 5-Bromo-1,2-dihydro-1-acenaphthylenol
To 1,2-dihydro-1-acenaphthylenol (0.34g, 2mmol) in
dry DMF (l0mL) was added recrystallised W-bromo-
succinimide (0.39g, 2.2mmol), and the mixture stirred
for 3 h under nitrogen. The solution was poured onto
water (500mL) and the precipitate filtered off. The
resultant solid was redissolved in methanol, filtered
and evaporated in vacuo to yield the title compound as a
brown solid.
b) [(5-Bromo-l,2-dihydro-1-acenaphthylenyl)oxy](tert-
butyl)diphenylsilane
To 5-bromo-l,2-dihydro-1-acenaphthylenol (0.25g,
lmmol) in dry THF (30mL) was added chloro(tert-
butyl)diphenylsilane (0.275g, lmmol) and imidazole
(0.34g, 5mmol), and the reaction stirred at room
temperature under nitrogen for 18 h. The mixture was
diluted with diethyl ether, filtered through a pad of
silica, and evaporated in vacuo. Purification by flash
chromatography on silica, eluting with ethyl
acetate/hexane (1:9 to 1:1), yielded the title compound
as a colourless oil.
c) (3R)-1-(l-{ [tert-Butyl (diphenyl)silyl]oxy}-l,2-
dihydro-5-acenaphthylenyl)-3-methylpiperazine
[(5-Bromo-l,2-dihydro-1-acenaphthylenyl)oxy] (tert-
butyl)diphenylsilane was coupled with {2R)-
methylpiperazine, as described for Example l a).
d) (1S)-1-{2-[{2R)-4-(l-{tert-Butyl(diphenyl)silyl]-
oxy} -1,2-dihydro-5-acenaphthylenyl)-2-methyl-
piperazinyl] ethyl}-3,4-dihydro-lH-2-benzopyran-6-
carboxamide
(3R)-1-(l-{ [tert-Butyl (diphenyl) silyl]oxy}-1,2-
dihydro-5-acenaphthylenyl)-3-methylpiperazine was
condensed with 2-[(1S)-6-(aminocarbony 1)-3,4-dihydro-lH-
2-benzopyran-1-yl]ethyl methanesulfonate, as described
for Example 1 b).
e) (lS)-1-{2-[(2R)-4-(l-Hydroxy-l,2-dihydro-5-
acenaphthylenyl)-2-methylpiperazinyl] ethyl} -3, 4-
dihydro-1 if- 2 -benzopyran-6-carboxamide
To a solution of (1S)-1-{2-[(2R)-4-(l-{[tert-
butyl(diphenyl)silyl]oxy}-l, 2-dihydro-5-
acenaphthylenyl)-2-methylpiperazinyl] ethyl}-3, 4-dihydro-
lH-2-benzopyran-6-carboxamide (1.72g, 2.43mmol) in dry
THF (70mL) was slowly added tetrabutylammonium fluoride
(1M solution in THF) (2.9mL, 2.92mmol), and the mixture
stirred for 18 h at room temperature. Dichloromethane
was added to the reaction, which was then washed with
water. The combined organic phases were dried (MgSO4) ,
filtered and evaporated in vacuo to yield a brown oil.
The residue was dissolved in methanol and applied to an
activated SCX-2 ion exchange cartridge. The cartridge
was washed with methanol, then the product isolated by
elution with 2M ammonia in methanol. The solvent was
removed in vacuo and the crude product further purified
by preparative LC-MS, to yield the title compound.
f) (1S) -l-{2-[(2R)-2-Methyl-4-(1-oxo-l,2-dihydro-5-
acenaphthylenyl}piperazinyl]ethyl}-3,4-dihydro-lH-2-
benzopyran-6-carboxamide
To a solution of (1S)-1-{2-[(2i?)-4-{l-hydroxy-l,2-
dihydro-5-acenaphthylenyl)-2-methylpiperazinyl]ethyl}-
3,4-dihydro-lH-2-benzopyran-6-carboxamide (0. l0g,
0.21mmol) in dry DMF (2mL), cooled to 0°C under
nitrogen, was added pyridinium dichromate (0.08g,
0.21mmol}, and the mixture stirred for 4 h, allowing the
reaction to warm to room temperature. A further
equivalent of pyridinium dichromate was added and the
reaction stirred for a further 1 h. The mixture was
poured onto water and the resultant precipitate filtered
off. Purification by preparative LC-MS yielded (1S)-1-
{2-[(2R)-2-methyl-4-(l-oxo-l,2-dihydro-5-
acenaphthylenyl) piperazinyl} ethyl} -3,4-dihydro-lH-2~
benzopyran-6-carboxamide. M+H = 470.
Example 7
(1S)-1-{2- [(2R)-2-Methyl-4-(lH, 3H-naphtho[1,8-cd]pyran-
6-yl)piperazinyl) ethyl} -3, 4-dihydro-1H-2~benzopyran-6-
carboxamide
a} 6-Bromo- 1H, 3H-naphtho 11, 8-cd]pyran
To 6-bromo-lH, 3H-naphtho [1,8-cd] pyran-1, 3-dione
(1.5g, 5.4mmol) in ethanol (10 mL) was added sodium
borohydride (0.41g, 10.8 mmol) and the mixture stirred
at room temperature for 1 h- The reaction was quenched
with 3M hydrochloric acid and extracted into
dichloromethane. The combined organic extracts were
dried (Na2SO4) and concentrated in vacuo. The residue was
dissolved in dichloromethane and trifluoroacetic acid
(1.05mL, 13.53 mmol) and triethylsilane (4.3mL, 27mmol)
added. After stirring for 5min at room temperature, the
solvent was removed in vacuo and the residue purified by
column chromatography on silica gel, eluting with
dichloromethane, to yield 6-bromo-lH, 3H-naphtho[l, 8-
cd]pyran as a white solid.
b) (31?)-3-Methyl-1-(1H,3H-naphtho [1, 8-cd] pyran-6-
yl)piperazine
A mixture of 6-bromo-lH, 3H-naphtho[l, 8-cd]pyran
(0.30g, 1.2mmol), 2-(R)-methylpiperazine (0.145g,
1.44mmol), tris(dibenzylideneacetone)dipalladium (O)
(55mg, 0.06mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-
binaphthyl (56mg, 0.09mmol) and sodium tert-butoxide
(0.162g, 1.68 mmol) in toluene (5mL) was heated under
reflux for 2h. The solvent was evaporated in vacuo and
the crude mixture purified by column chromatography on
silica gel, eluting with dichloromethane/methanol (9:1),
to yield (31?)-3-methyl-1-{1H, 3H-naphtho[l, 8-cd]pyran-6-
yl)piperazine as an orange solid.
c) (1S)-1-{2-[(21?)-2-Methyl-4-(1H, 3H-naphtho[l, 8-
cd]pyran-6-yl)piperazinyl] ethyl} -3, 4-dihydro-lH-2-
benzopyran-6-carboxamide
(3R)-3-Methyl-1-(lH, 3H-naphtho[l, 8-cd]pyran-6-
yl)piperazine was coupled with 2-[(1S)-6-aminocarbonyl)-
3,4-dihydro-lH-2-benzopyran-1-yl]ethyl methanesulfonate
as described for Example 1 b) , to yield (1S)-1-{2-[(21?)-
2-methyl-4-(lH,3H-naphtho[l,8-cd]pyran-6-
yl) piperazinyl ] ethyl} -3,4-dihydro-lH-2-benzopyran-6-
carboxamide. M+H = 472.
Example 8
(1S)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-
cd] thiopyran-6-yl)piperazinyl] ethyl}-3, 4-dihydro-lH-2-
benzopyran-6-carboxamide
a) 6-Bromo-lH, 3H-naphtho[1, 8-cd] thiopyran
A mixture of l-bromo-4,5-bis(bromomethyl)-
naphthalene (0.38g, 0.97mmol) and sodium sulfide
nonahydrate (0.25g, 1.04mmol) in dimethylformamide
(13xnL) was stirred at room temperature for 5 h, in the
presence of sodium sulfate as scavenger for the water.
The reaction mixture was poured into water and extracted
into diethyl ether. The combined organic extracts were
washed with water, dried (Na2SO4) and concentrated to
dryness, to yield 6-bromo-lH, 3H-naphthotl,8-cd]thiopyran
as a pale yellow solid.
b) (3R)-3-Methyl-1-(1H, 3H-naphtho[l,8-cd] thiopyran-6-
yDpiperazine
The procedure used for the synthesis of (3.R)-3-
methyl-1-(lH, 3H-naphtho [ 1, 8-cd]pyran-6-yl)piperazine
(Example 5 b)) was followed, using 6-bromo-lH, 3H-
naphtho[l,8-cd] thiopyran as starting material and making
non-critical variations, to obtain the title compound
{3R)-3-methyl-1-(1H, 3H-naphtho[l, 8-cd] thiopyran-6-
yDpiperazine as brown solid.
c) (lS)-1-{2-[(2R)-2-Methyl-4-(1H,3H-naphtho[1,8-
cd) thiopyran-6-yl)piperazinyl] ethyl}-3,4-dihydro-1H-2-
benzopyran- 6 - carboxamide
(3R)-3-Methyl-1-(1H, 3H-naphtho [1,8-cd] thiopyran-6-
yl)piperazine was coupled with 2-[(1S)-6-aminocarbonyl)-
3, 4-dihydro-1H-2-benzopyran-1-yl] ethyl methanesulfonate
as described for Example 1 b), to yield (1S)-1-{2-[(2R)-
2-methyl-4-(1H, 3ff-naphtho [1, 8-cd]thiopyran-6-
yl)piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
carboxamide. M+H = 488.
Example 9
(lS)-1-{2-[4-l,2-Dihydro-5-acenaphthylenyl)-1-
piperidinyl]ethyl)-3, 4-dihydro-lH-2-benzopyran-6-
carboxamide
a) tert-Butyl 4-(1,2-dihydro-5-acenaphthylenyl)-4-
hydroxy-1-piperidinecarboxylate
To a solution of 5-bromoacenaphthylene (l.00g,
4.29mmol) in dry THF (20mL), under nitrogen at -78oC,
was added a solution of n-butyllithium (2.5M in hexanes)
(1.89mL, 4.72mmol) over a period of 30min. The resulting
deep red solution was left to stir for a further 30
minutes at -78oC. A solution of tert-butyl 4-oxo-1-
piperidinecarboxylate (0.94g, 4.72mmol) in dry THF
(l0mL) was then added over 30min. After 2.5h a cooled
solution of saturated ammonium chloride (30mL) was
added, the reaction mixture allowed to warm to room
temperature and then extracted with diethyl ether. The
combined organic extracts were dried (Na2SO4) and
concentrated in vacuo to yield a thick, yellowish tan
oil. This oil was purified by flash chromatography on
silica, eluting with a methanol/dichloromethane
gradient, to yield tert-butyl 4-(1,2-dihydro-5-
acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate as a
sticky yellow residue.
b) 4-(1,2-Dihydro-5-acenaphthylenyl)piperidine
To a solution of tert-butyl 4-(1,2-dihydro-5-
acenaphthylenyl)-4-hydroxy-1-piperidinecarboxylate
(0.44g, 1.24mmol) in dichloromethane (4mL) was added
triethylsilane (l.l0mL, 6.22mmol) under nitrogen. The
mixture was cooled to -30oC then trifluoroacetic acid
(0.48mL, 6.22mmol) added dropwise, maintaining the
temperature below -25oC. After 2.5h, the reaction
mixture was allowed to warm to 0oC and additional
trifluoroacetic acid (0.48mL, 6.22mmol) added over 5
min. The reaction mixture was allowed to warm to room
temperature and left to stir for 3 days. Ice was then
added to the reaction mixture, followed by potassium
hydroxide to a pH of 14, and the resultant slurry
extracted with dichloromethane. The combined organic
extracts were dried (Na2SO4) and concentrated in vacuo to
yield a yellow oil. The oil was dissolved in methanol
and loaded onto an SCX-2 column. The column was washed
with methanol, then a 2N solution of ammonia in
methanol. Concentration in vacuo of the ammonia solution
yielded 4-(1,2-dihydro-5-acenaphthylenyl)piperidine as a
pale yellow oil.
c) (lS)-1-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)-l-
piperidinyl] ethyl}-3 , 4-dihydro-lH-2-benzopyran-6-
carboxamide
4- (1,2-Dihydro-5-acenaphthylenyl)piperidine was
coupled with 2-[(1S)-6-aminocarbonyl)-3,4-dihydrro-1H-2-
benzopyran-1-yl]ethyl methanesulfonate, as described for
Example 1 b), to yield (1S)-1-{2-[4-{1,2-dihydro-5-
acenaphthylenyl) -1-piperidinyll ethyl)-3,4-dihydro-1H-2-
benzopyran-6-carboxamide as a pale yellow oil. M+H=
441.
Example 10
(1S)-1-(2- ( (2R)-4-(1,2-Dihydro--5-acenaphthylenyl)-2-
methylpiperazinyl)ethyl)-1,3-dihydro-2-benzofuran-5-
carboxamide
a) 5-Chloro-1,3-dihydro-2-benzofuran-1-ol
To a solution of 5-chlrophthalide 0.64g,
21.6mmol) in dichloromethane (10mL) at -78oC was added
di-isobutylaluminium hydride (1M in toluene) (23.8mL,
23.8mmol) dropwise. After 1h the reaction mixture was
quenched with a saturated solution of sodium tartrate
(250ml), allowed to warm to room temperature and stirred
for 1h. The layers were separated and the aqueous layer
extracted with dichloromethane. The combined organic
layers were dried (MgSO4), filtered and concentrated in
vacua to yield the title compound as a white solid.
b)Ethyl (5-chloro-1,3-dihydro-2-benzofuran-1-yl)acetate
5-Chloro-l, 3-dihydro-2-benzofuran-1-ol (2.95g,
l?.3mmol} was dissolved in THF (60mt) and cooled to 0oC.
Triethyl phosphonoacetate (ll.7g,52.1mmol) and caesium
carbonate {17g, 52.1 mmol) were added. After 20min the
cold bath was removed and the reaction mixture allowed
to stir at room temperature for 3h, then quenched with a
saturated solution of ammonium chloride and extracted
with ethyl acetate. The combined organic layers were
washed with brine, dried (MgSO4), filtered and
evaporated in vacuo. Purification by column
chromatography, eluting with ethyl acetate/hexane (1:4),
yielded the title compound as a colourless oil.
c) 2-(5-Chloro-l,3-dihydro-2-benzofuran-1-yl)ethanol
Ethyl (5-chloro-l,3-dihydro-2-benzofuran-1-yl)-
acetate (2.79g, 11.6mmol) in THF (60mL) was cooled to -
78OC and di-isobutylaluminium hydride (1M in toluene)
(12.7mL, 12.7mmol) was added dropwise. After lh, the
reaction mixture was quenched with a saturated solution
of sodium tartrate (150mL), allowed to warm to room
temperature and stirred for lh. The layers were
separated and the aqueous layer extracted with ethyl
acetate. The combined organic layers were dried (MgSO4),
filtered and evaporated in vacuo. The resultant crude
intermediate was dissolved in methanol (50mL), cooled to
0oC, and sodium borohydride (0.48g, 12.7mmol) added in
portions. The reaction was quenched with saturated
sodium hydrogen carbonate and extracted with ethyl
acetate. The combined organic layers were washed with
brine, dried (MgSO4), filtered and evaporated in vacuo.
The crude product was purified by column chromatography,
eluting with ethyl acetate/hexane (1:2), to yield the
title compound as a white solid.
d) tert-Butyl-[2-(5-chloro-l, 3-dihydro-2-benzofuran-1-
yl)ethoxy]dimethylsilane
Prepared from 2- {5-chloro-l, 3-dihydro-2-benzofuran-
l-yl)ethanol, as described for the preparation of 2-
((1S)-6-bromo-3, 4-dihydro-lH-2-benzopyran-1-yl) ethyl
tert-butyl{dimethyl)silyl ether, to yield tert-butyl-[2-
(5-chloro-l, 3-dihydro-2-benzofuran-1-yl)ethoxy] -
dimethylsilane.
e) 1-[2-(tert-Butyldimethylsilanoxy)-ethyl] -1, 3-dihydro-
2 -benzofuran-5-carboxaxnide
A solution of tert-butyl-[2-(5-chloro-l,3-dihydro-
2-benzofuran-1-yl)-ethoxy]dimethylsilane (0.94g,
1.48mmol) in dioxan (2mL) and a solution of tri-tert-
butylphosphine (89mg, 0.44mmol) in dioxan (0.7mL) were
added dropwise to a round bottom flask charged with
tris (dibenzylideneacetone) dipalladium (136mg,
0.148mmol) and zinc cyanide (0.208g, 1.78mmol). The
flask was fitted with a reflux condenser and the
resulting red-purple suspension heated at 120oC under
nitrogen. After 16 h the reaction mixture was cooled to
room temperature and diluted with ethyl acetate,
filtered through a pad of celite and concentrated in
vacuo. The crude product was purified by chromatography
on silica, eluting with hexane/ethyl acetate (10:1), to
yield the title compound contaminated with
dibenzylideneacetone. This crude mixture was dissolved
in dichloromethane (3mL) , and tetrabutylammonium
hydrogen sulfate (0.29mmol) was added in one portion.
Hydrogen peroxide (30% w/v aqueous solution) (5.75mmol)
and sodium hydroxide (2N aqueous solution) (1.15mL,
2.3mmol) were added dropwise. The resulting reaction
mixture was sonicated for lh, then quenched with
potassium hydrogen sulfate (4mL), diluted with
dichloromethane, and the layers separated. The organic
layer was washed with an aqueous solution of sodium
sulfite, dried (MgSO4) , filtered and evaporated in
vacuo. The crude product was purified by chromatography
on silica, eluting with ethyl acetate/hexane (1:1), to
yield the title compound as a white solid.
f) 1-(2-Hydroxyethyl)-1,3-dihydro-2-benzofuran-5-
carboxamide
Prepared from 1-[2-(tert-butyldimethylsilanoxy)-
ethyl]-1,3-dihydro-2-benzofuran-5-carboxamide, as
described for the preparation of (15)-1-(2-
hydroxyethyl)-3, 4-dihydro-lH-2-benzopyran-6-carboxamide.
g) (lS)l-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-l,3-dihydro-2-benzofuran-5-
carboxamide
The title compound was prepared from l-(2-
hydroxyethyl)-1, 3-dihydro-2-benzofuran-5-carboxamide by
initial formation of the methanesulfonate as described
for the preparation of 2-[(15)-6-(aminocarbonyl)-3,4-
dihydro-lH-2-benzopyran-1-yl]ethyl methanesulfonate, and
condensation of this sulfonate with (3R)-1-(1,2-dihydro-
5-acenaphthylenyl)-3-methylpiperazine, as described for
Example 1 b). The mixture of diastereomers was separated
by chiral HPLC using a Chiracel OJ column, eluting with
hexane/ethanol (1:1) with 0.2% dimethylethylamine. M+H =
442.
Example 11
l-{2-[4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-lH-1,4-
diazepin-1-yl]ethyl}-1,3-dihydro-2-benzofuran-5-
carboxamide
a) (-)-(5-Chloro-l,3-dihydro-2-benzofuran-1-yl)acetic
acid
(+/-)-Ethyl (5-chloro-l,3-dihydro-2-benzofuran-1-
yl)acetate (6.1g, 25.3mmol) and Amano Lipase P30 (3.8g)
were suspended in pH 7.0 buffer solution (150mL) and the
mixture was vigorously stirred for 24 h. The suspension
was then filtered through a pad of celite, and the
filter pad washed with water, hydrochloric acid (1M) and
several times with ethyl acetate. The aqueous layer was
separated and washed twice with ethyl acetate. The
combined organic phase was then extracted with saturated
aqueous sodium bicarbonate (3 x 150mL), dried over
magnesium sulphate, filtered and evaporated under
reduced pressure to give a pale yellow oil, ( + )-ethyl
(5-chloro-l,3-dihydro-2-benzofuran-1-yl)acetate (95%ee
by chiral HPLC)- this could be recycled by base
catalysed racemisation, as described below.
The aqueous bicarbonate layer was then acidified
with hydrochloric acid (1N), extracted with
dichloromethane (3x) , dried (MgSO4) , filtered and
evaporated in vacuo to give a white crystalline solid.
(95% ee by chiral HPLC). The solid was recrystallized
from hexane-ether to provide the title acid (>98% ee).
b) (-)-2-(5-Chloro-l,3-dihydro-2-benzofuran-1-yl)ethanol
(5-Chloro-l,3-dihydro-2-benzofuran-1-yl)acetic acid
(1.91g, 9.0mmol) was dissolved in dry THF (8 mL) under
nitrogen and cooled to 0oC. Borane-dimethylsulfide
complex (0.155mL, 1.64mmol) was added by syringe, After
lh the cooling bath was removed and the solution was
stirred at room temperature for 2h. The solution was
partitioned between saturated aqueous sodium hydrogen
carbonate and diethyl ether. The aqueous layer was
further extracted with ether, and the combined organic
layers washed with brine, dried {MgSO4), filtered and
concentrated in vacuo. This yielded the title compound
as a white solid (>98% ee by chiral HPLC).
c) (±)-Ethyl {5-chloro-l,3-dihydro-2-benzofuran-1-
yl)acetate
(+)-Ethyl (5~chloro-l,3-dihydro-2-benzofuran-1-
yl)acetate (95% ee} (185mg, 0.77mmol) was dissolved in
dry ethanol (8mL) under nitrogen- Sodium ethoxide (5mg,
0.07mmol) was added in one portion and the reaction
stirred at room temperature overnight. The solvent was
removed in vacua and the residue partitioned between
water and dichloromethane. The organic layer was washed
with brine, dried {MgSO4), filtered and concentrated in
vacuo to provide the title compound as a yellow oil.
3j {-)-2-[(5-Aminocarbonyl)-1,3-dihydro-2-benzofuran-1-
yl]ethyl methanesulfonate
Prepared from {-)-2-(5-chloro-l,3-dihydro-2-benzo-
furan-1-yl)ethanol, as described in Example 10 with the
corresponding racemic alcohol.
e) (-}-1-{2-{4-(1,2-Dihydro-5-acenaphthylenyl)hexahydro-
1H-1,4-diazepin-1-yl]ethyl}-1,3-dihydro-2-benzofuran-
5-carboxamide
Prepared from l-(1,2-dihydro-5-acenaphthylenyl)-
hexahydro-lH-l,4-diazepine and (-)-2-[(5-aminocarbonyl)-
l,3-dihydro-2-benzofuran-1-yl]ethyl methanesulfonate, as
described for Example 8. M+H = 442.
Example 12
l-({2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-
methylpiperazinyl) ethyl} - 3, 4-dihydro- 1H-2-benzopyran-6-
yl)methanamine
a) 1-(2-Hydroxyethyl)-3,4-dihydro-lH-2-benzopyran-6-
carbonitrile
2-(6-Bromo-3,4-dihydro-lH-2-benzopyran-1-yl)ethanol
(1.3g, 5.1mmol), zinc cyanide (0.36g, 3mmol) and
tetralris(triphenylphosphine) palladium (O) (0.23g,
0.20mmol) were stirred in degassed DMF (20mL) under
nitrogen at reflux for 9 h. The reaction mixture was
diluted with toluene and washed with 2M aqueous ammonia,
the aqueous layer further extracted with ethyl acetate,
then the combined organic extracts washed with brine.
The organic extracts were dried (MgSO4), filtered and
evaporated in vacuo. Purification by flash
chromatography on silica, eluting with ethyl acetate /
hexane (30:70 to 0:100), yielded the title compound as a
light brown oil.
b) 2-(6-Cyano-3, 4-dihydro-lH-2-benzopyran-1-yl)ethyl
methanesulfonate
Prepared from 1-(2-hydroxyethyl)-3,4-dihydro-lH-2-
benzopyran-6-carbonitrile, as described for the
preparation of 2-[(1S)-6-(aminocarbonyl)-3, 4-dihydro-lH-
2-benzopyran-1-y 1 ] ethyl methanesulfonate.
c) l-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methyl-
piperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
carbonitrile
Prepared by condensation of 2-{6-cyano-3,4-dihydro-
lH-2-benzopyran-1-yl)ethyl methanesulfonate with (3R)-1-
(6-Fluoro-1-naphthyl)-3-methylpiperazine, as described
for Example 1 b).
d) l-{2-{(2R)-4-(6-Fluoro-1-naphthyl)-2-methyl -
piperazinyl]ethyl}-3,4 -dihydro-1H-2-benzopyran-6-
yl)methanamine
To a stirred solution of l-{2-[(2R)-4-(6-fluoro-1-
naphthyl)-2-methyl-piperazinyl]ethyl}-3, 4-dihydro-1H-2-
benzopyran-6-carbonitrile (0.50g, 1.2mmol) in dry THF
(4mL) was added lithium aluminium hydride (1M solution
in THF) (1.4mL, 1.4mmol) and the mixture stirred
overnight at room temperature. The reaction was quenched
by cautious addition of 2M sodium hydroxide, then
extracted into chloroform. The combined organic extracts
were dried (MgSO4), filtered and evaporated in vacuo.
The crude product was purified by preparative LC-MS to
yield the title compound as a yellow oil. M+H - 480.
Example 13
1-((2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methyl-
piperazinyl} ethyl}-3, 4-dihydro-1H-2-benzopyran-6-
yl)methylformamide
To a stirred solution of l-{2-[(2R)-4-(6-£luoro-1-
naphthyl) ~2-methylpiperazinyl J ethyl}-3,4-dihydro-lH-2-
benzopyran-6-yl)methanamine (0.234g, 0.53mmol) in dry
DMF (10mL) was added formic acid (27mg, 0.59mmol), and
the reaction mixture heated at reflux for 1 h under
nitrogen. The mixture was diluted with dichloromethane
and washed three times with water, then aqueous sodium
hydrogen carbonate, dried (MgSO4) filtered and
evaporated in vacuo. The crude product was purified by
preparative LC-MS to yield the title compound as a beige
solid. M+H =508.
Example 14
H-[((1S)-1-(2-1 (2R)-4- (6-Fluoro-1-naphthyl) -2-
methylpiperazinyl) ethyl)-3,4 -dihydro-lH- 2-benzopyran~6-
yl) methyl]acetamide
a}1-{2-Oxoethyl)-3,4-dihydro-1H-2-benzopyran-6-
carbonitrile
Dimethylsulfoxide (0.35ml, 5mmol) and oxalyl
chloride (2M in dichloromethane) (2.2mL, 4.4mmol) were
stirred in dichloromethane {30mL) under nitrogen at-
78°C. After 10 man, 1-(2-hydroxyethyl)-3,4-dihydro-1H-2-
benzopyran-6-carbonitrile (0.48g, 2.4mmol) in
dichloromethane (50mL) was added dropwise and the
solution stirred at -?8°C for 1 h, before triethylamine
(2.5mL, 18mmol) was added slowly. The reaction was
allowed to warm to room temperature and after 2 h the
reaction was quenched by addition of water. Removal of
the solvent in vacuo yielded the title compound, which
was used in the next step without further purification.
b) l-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methyl-
piperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
carbonitri1e
To a stirred solution of 1-(2-oxoethyl)-3, 4-
dihydro-lH-2-benzopyran-6-carbonitrile (0.454g,
2.26mmol) in methanol (30mL) was added (3R)-1-(6-f luoro-
l-naphthyl)-3-methylpiperazine (0.61g, 2.49mmol), and
the mixture stirred for 10 min. Sodium cyanoborohydride
(0.157g, 2.49mmol) and acetic acid (0.25mL) were added
and the mixture stirred for 18 h. A further portion of
sodium cyanoborohydride (0.20g) was added and the
reaction stirred for 6 h. The mixture was quenched with
water, and the solvent removed in vacuo. Water was added
and the mixture extracted with chloroform, the organic
extracts dried (MgSO4) , filtered and evaporated in
vacuo. The crude product was purified by preparative LC-
MS to yield the title compound as a yellow oil.
c) l-{2- t (2R)-4-(6-Fluoro-1-naphthyl)-2-methyl-
piperazinyl) ethyl} -3,4-dihydro- 1H-2-benzopyran-6-
yl) methanamine
1-{2-[(2.R)-4-(6-Fluoro-1-naphthyl)-2-methyl-
piperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
carbonitrile was reduced with lithium aluminium hydride,
as described for Example 12 d).
d) N-[((1S)-1-{2-[{2R)-4-(6-Fluoro-1-naphthyl)-2-
methylpiperazinyl] ethyl} -3, 4-dihydro-lH-2-benzopyran-
6-yl)methyl]acetamide
To a solution of l-{2-[(2R)-4-(6-fluoro-1-
naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-lH-2-
benzopyran-6-yl)methanamine (O.llg, 0.25mmol) in dry
dichloromethane (l0mL) under nitrogen was added
triethylamine (0.3mL), then acetyl chloride (0.5mL,
0.5mmol), and the mixture stirred at room temperature
for 1 h. The reaction was quenched with water and the
organic layer dried (MgSO4) filtered and evaporated in
vacuo. The crude product was purified by preparative LC-
MS to yield the title compound as a white solid. M+H =
522.
Example 15
N-[((15)-1-{2-[(2.R)-4-(6-Fluoro-1-naphthyl)-2-
methylpiperazinyl] ethyl} -3, 4-dihydro-lH-2-benzopyran-6-
yl)methyl] methanesulfonamide
l-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-methyl-
piperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
y1)methanamine was acylated with methanesulfonyl
chloride as described for Example 14 d), to yield the
title compound. M+H = 512.
Example 16
5-[(3R)-3-Methyl-4-(2-{(15)-6-[(2-oxo-l,3-oxazolidin-3-
yl)methyl]-3,4-dihydro-lH-2-benzopyran-1-
yl}ethyl)piperazinyl]-2-naphthonitrile
a) 2-((15)-6-Bromo-3,4-dihydro-lH-2-benzopyran-1-
yl)ethyl tert-butyl(diphenyl)silyl ether
To a solution of 2-((15)-6-bromo-3,4-dihydro-lH-2-
benzopyran-1-yl)ethanol (3.0g, 11.7mmol) in dry THF
(l00mL) was added imidazole (3.97g, 58.4mmol) and
chloro-tert-butyl(diphenyl)silane (6.42g, 23.4mmol), and
the mixture stirred under nitrogen at room temperature
for 20 h. Diethyl ether was added and the mixture
filtered through a pad of silica. The filtrate was
evaporated in vacuo and the crude product purified by
flash chromatography on silica, eluting with ethyl
acetate / heptane (0:10 to 2:8), to yield the title
compound.
b) (15)-1-(2-{[tert-Butyl (diphenyl) silyl]oxy} ethyl)-3, 4-
dihydro- 1H- 2 -benz opyran- 6-carbaldehyde
To a stirred solution of 2-((15)-6-bromo-3,4-
dihydro-lH-2-benzopyran-1-yl) ethyl tert-
butyl (diphenyl) silyl ether (2.5g, 5.05mmol) in dry THF
(60mL), cooled to -78°C under nitrogen, was slowly added
n-butyllithium (2.5M in THF) (5.4mL, 13.5mmol). After 30
min stirring at -78°C, dry dimethylformamide (3.5mL,
45mmol) was added and the reaction allowed to warm to
room temperature overnight. The reaction was quenched by
addition of water and extracted into ethyl acetate. The
combined organic extracts were washed with brine, dried
(MgSO4) , filtered and evaporated in vacuo. The resultant
yellow oil was purified by flash chromatography on
silica, eluting with ethyl acetate / hexane (0:4 to
1:3), to yield the title compound as a colourless oil.
c) ((15)-1-(2- {[ tert-Butyl (diphenyl) silyl]oxy}ethyl)-
3,4-dihydro-lH-2-benzopyran-6-yl]methanol
To a stirred solution of (15)-1-(2-{[tert-
butyl (diphenyl) silyl]oxy}ethyl)-3, 4-dihydro-lH-2-
benzopyran-6-carbaldehyde (0.97g, 2.18mmol) in ethanol
(30mL) was added sodium borohydride (0.116g, 3.06mmol)
and the mixture stirred for 1.5 h at room temperature.
The reaction was extracted from water into ethyl
acetate, the combined organic extracts dried (MgSO4) ,
filtered and evaporated in vacuo, to yield the title
compound as a colourless oil.
d)3-{[(1S)-1-(2-{[tert-Butyl (diphenyl) silyl]oxy}ethyl)-
3,4-dihydro-lH-2-benzopyran-6-yl]methyl}-l, 3-
oxazolidin-2-one
To a stirred solution of [(1S)-1-(2-{[tert-
butyl (diphenyl) silyl]oxy}ethyl)-3 , 4-dihydro-lH-2-
benzopyran-6-yl]methanol (0.30g, 0.67mmol) in dry
diethyl ether (5mL) and triethylamine (O.llmL, 0.80mmol)
was added methanesulfonyl chloride (0.057mL, 0.74mmol),
and the mixture stirred for 2 h under nitrogen. In a
separate flask, sodium hydride (60% suspension in oil)
(0.107g, 2.68mmol) was added to a stirred solution of
1,3-oxazolidin-2-one (0.175g, 2.1mmol) and the mixture
heated at 50°C for 2 h. To this solution was added the
filtered solution of the mesylate and the mixture heated
at 50°C with stirring for a further 1.5 h, then stirred
at room temperature overnight. Ethyl acetate and water
were added to the reaction, the organic layer washed
with brine, dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by flash
chromatography on silica, eluting with ethyl acetate /
hexane (1:99 to 60:40), to yield the title compound.
e) 3-{( (lS)-1-(2-Hydroxyethyl)-3,4-dihydro-lH-2-
benzopyran-6-yl]methyl} -1, 3-oxazolidin-2-one
To a stirred solution of 3-{[(1S)-1-(2-{[tert-
butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-lH-2-
benzopyran-6-yl]methyl}-l,3-oxazolidin-2-one (0.22g,
0.43mmol) in dry THF (30ml) was added tetrabutylammonium
fluoride (1M solution in THF) (0.51mL, 0.51mmol) and the
reaction stirred at room temperature under nitrogen over
the weekend. The reaction was quenched by addition of
water and extracted with dichloromethane. The combined
organic extracts were dried (MgSO4) , filtered and
evaporated in vacuo. The crude product was purified by
flash chromatography on silica, eluting with methanol /
dichloromethane (1:9), to yield the title compound as a
colourless oil.
f) 5-[(3R)-3-Methyl-4-(2-{(lS)-6-[(2-oxo-l,3-oxazolidin-
3 -yl)methyl ]-3,4-dihydro-1H-2-benzopyran-1 -
yl}ethyl)piperazinyl]-2-naphthonitrile
3-{[(1S)-1-(2-Hydroxyethyl)-3, 4-dihydro-lH-2-
benzopyran-6-yl]methyl}-l,3-oxazolidin-2-one was reacted
with methanesulfonyl chloride, as described for the
preparation of 2-1 (1S)-6-(aminocarbonyl)-3,4-dihydro-1H-
2-benzopyran-1-yl]ethyl methanesulfonate. The resultant
crude mesylate was then condensed with (3R)-1-(6-cyano-
1-naphthyl)-3-methylpiperazine, as described for Example
1 b), to yield the title compound. M+H = 511.
The following Examples were similarly prepared,
replacing the l,3-oxazolidin-2-one in Example 16 d) with
the appropriate heterocycle and increasing the reaction
time with the mesylate from 1.5 h to 3 h at 50°C:
Example 17
3-[( (1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
yl)methyl]-1,3-oxazolidin-2-one
Prepared from l,3-oxazolidin-2-one. M+H = 512.
Example 18
3-[(3R)-3-Methyl-4-(2-{(15)-6-[(2-oxo-1,3-oxazolidin-3-
yl) methyl 1 -3,4-dihydro-1H-2-benzopyran-1-yl} ethyl)-
piperazinyl]-1-benzothiophene-6-carbonitrile
Prepared from 1,3-oxazolidin-2-one. M+H = 517.
Example 19
1-[((1S)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-1H-2-benzopyran-6-
yl) methyl 3 -2-pyrrolidinone
Prepared from 2-pyrrolidinone. M+H = 510.
Example 20
3-[(3R)-3-Methyl-4-(2-{(1S)-6-[(2-oxo-1-
pyrrolidinyl)methyl]-3, 4-dihydro-1H-2-benzopyran-1-
yl}ethyl)piperazinyl]-1-benzothiophene-6-carbonitrile
Prepared from 2-pyrrolidinone. M+H = 515.
Example 21
{2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(lS)-6-(1H-
imidazol-1-ylmethyl)-3,4-dihydro-1H-2-benzopyran-1-
yl]ethyl8}-2-methylpiperazine
Prepared from imidazole. M+H = 493.
Example 22
3-((3H)-4-{2-[(1S)-6-(lH-lmidazol-1-ylmethyl)-3,4-
dihydro-1H-2-benzopyran-1-yl]ethyl)-3-methyl-
piperazinyl?-1-benzothiophene-6-carbonitrile
Prepared from imidazole. M+H = 498.
Example 23
3-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-pyrazol-1-ylmethyl)-
3, 4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared from pyrazole. M+H = 498.
Example 24
(1S)-1- {2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-
methylpiperazinyl]ethyl} -3,4-dihydro-1H-2-benzopyran-6-
amine
a) (lS)-1-(2~{ [tert-Butyl(dimethyl)silyl]oxy)ethyl)-N-
(diphenylmethylene)-3,4-dihydro-1H-2-benzopyran-6-
amine
{2-[(lS)-6-Bromo-3,4-dihydro-1H-2-benzopyran-1-
yl]ethoxy)(tert-butyl)dimethylsilane (1.86g, mmol) was
dissolved in dry toluene (25mL),
tris(dibenzylideneacetone) dipalladium (0.234g, mmol)
added and the mixture degassed by alternate evacuation
and flushing with nitrogen. BINAP (0.495g, mmol), sodium
tert-butoxide (0.769g, mmol) and benzophenone imine
(lmL) were added with stirring and the reaction heated
at 90°C under nitrogen for 18h. The mixture was cooled,
diluted with diethyl ether and filtered through celite.
The crude product was evaporated in vacuo and used in
the next step without further purification.
b) 2-{ (lS)-6-[(Diphenylmethylene)amino]-3,4-dihydro-1H-
2-benzopyran-1-yl}ethanol
(1S)-1-(2-{[tert-Butyl (dimethyl) silyl]oxy}ethyl)-N-
(diphenylmethylene)-3,4-dihydro-1H-2-benzopyran-6-amine
was deprotected with aqueous acetic acid, as described
for the preparation of (1S)-1-(2-hydroxyethyl)-3,4-
dihydro-1H-2-benzopyran-6-carboxamide, to yield 2-{{lS)-
6-[(diphenylmethylene) amino]-3, 4-dihydro-1H-2-
benzopyran-1-yl}ethanol.
c) 2-{ (lS)-6-[(Diphenylmethylene)amino]-3,4 -dihydro-1H-
2-benzopyran-1-yl}ethyl methanesulfonate
2-{ (1S)-6-[(Diphenylmethylene)amino]-3, 4-dihydro-
lH-2-benzopyran-1-yl}ethanol was reacted with
methanesulfonyl chloride, as described for the
preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-
2-benzopyran-1-yl]ethyl methanesulfonate, to yield 2-
{ (lS)-6-[(diphenylmethylene)amino]-3,4-dihydro-1H-2-
benzopyran-1-yl)ethyl methanesulfonate.
d) (1S)-N-(Diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-
naphthyl)-2-methylpiperazinyl ]ethyl}-3,4-dihydro-1H-
2-benzopyran-6-amine
2-{(1S)-6-[(Diphenylmethylene)amino]-3,4-dihydro-
lH-2-benzopyran-1-yl}ethyl methanesulfonate was coupled
with (3R)-1-(6-fluoro-l~naphthyl)-3-methylpiperazine, as
described for Example 1 b) , to yield (1S)-W-
(diphenylmethylene)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-
2-methylpiperazinyl]ethyl}-3, 4-dihydro-1H-2-benzopyran-
6-amine.
e) (1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-
methylpiperazinyl]ethyl} -3, 4-dihydro-1H-2-benzopyran-
6-amine
To a solution of (1S)-N-(diphenylmethylene)-1-{2-[
(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]-
ethyl}-3, 4-dihydro-1H-2-benzopyran-6-amine (1.46g,
2.5mmol) in methanol (25mL) was added sodium acetate
(0.28g, 2.65mmol) and hydroxylamine hydrochloride
(0.194g, 2.8mmol), and the mixture stirred at room
temperature under nitrogen for 18h. Water was added and
extracted with dichloromethane. The combined organic
extracts were dried (MgSO4), filtered and evaporated in
vacuo. The crude product was purified by flash
chromatography on silica, eluting with methanol/ethyl
acetate (0:100 to 15:85), to yield (1S)-1-{2-[(2R)-4-(6-
f luoro-1-naphthyl)-2-methylpiperazinyl]ethyl} -3,4-
dihydro-1H-2-benzopyran-6-amine. M+H = 420.
The following amines were similarly prepared from
2-{ (1S)-6-[(diphenylmethylene) amino]-3 , 4-dihydro-1H-2-
benzopyran-1-yl}ethyl methanesulfonate and the
appropriate aryl piperazine, and subsequently further
derivativatised as described below:
(lS)-1-{2-[(2R)-4-(6-Cyano-1-naphthyl)-2-
methylpiperazinyl ]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
amine
(lS)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
amine
(1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
amine
Example 25
3-((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-
methylpiperazinyl ]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
yl)-1,3-oxazolidin-2-one
To a solution of (1S)-1-{2-[(2S)-4-(6-fluoro-1-
naphthyl)-2-methyl-piperazinyl]ethyl}-3, 4-dihydro-1H-2-
benzopyran-6-amine (0.217g, mmol) in dry DMF (5mL) was
added pyridine (0.05mL, mmol) and 2-chloroethyl
chloroformate (0.055mL, mmol), and the reaction stirred
at room temperature under nitrogen for 2h. The reaction
was quenched by addition of 2M sodium hydroxide (3mL),
diluted with water and extracted into dichloromethane.
The combined organic extracts were dried (MgSO4) ,
filtered and evaporated in vacuo. The crude product was
purified by prep LCMS to yield 3-((1S)-1-{2-[(2R)-4-(6-
fluoro-1-naphthyl)-2-methylpiperazinyl]-ethyl}-3, 4-
dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one. M+H
= 490.
Example 26
3-((1S)-1-(2-[(2R)-4-(6-Cyano-1-naphthyl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
yl)-1,3-oxazolidin-2-one
Prepared from (1S)-1-{2-[(2R)-4-(6-cyano-1-
naphthyl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-
benzopyran-6-amine, as described for Example 25. M+H =
497.
Example 27
3-((1S)-1-(2-[(2R)-4-(1,2-dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-1H-2-benzopyran-6-
yl)-1,3-oxazolidin-2-one
Prepared from (lS)-1-{2-[(2R)-4-(1,2-dihydro-5-
acenaphthylenyl)-2-methylpiperazinyl]ethyl}-3, 4-dihydro-
lH-2-benzopyran-6-amine, as described for Example 25.
M+H = 498.
Example 28
3-( (1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-1H-2-benzopyran-6-
yl)-1,3-oxazolidin-2-one
Prepared from (1S)-1-{2-[{2R)-4-(6-cyano-1-
benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3 , 4-dihydro-
lif-2-benzopyran-6-amine, as described for Example 25.
M+H = 503.
Example 29
1-((1S)-1-{2-[{2R)-4-(6-fluoro-1-naphthyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
yl)-2-pyrrolidinone
The title compound was prepared as described for
Example 25, substituting 4-bromobutyryl chloride for 2-
chloroethyl chloroformate. M+H = 488.
Example 30
l-((15)-1-{2-[(2R)-4-(6-Cyano-1-naphthyl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-lH-2-benzopyran-6-
yl)-2-pyrrolidinone
Prepared from (1S)-1-{2-[(2R)-4-(6-cyano-1-
naphthyl)-2-methylpiperazinyl]ethyl}-3, 4-dihydro-1H-2-
benzopyran-6-amine, as described for Example 29. M+H =
495.
Example 31
1-((1S)-1-{2-[(2R)-4-(6-cyano-1-benzothien-3-yl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-1H-2-benzopyran-6-
yl)-2-pyrrolidinone
Prepared from (1S)-1-{2-[(2R)-4-(6-cyano-1-
benzothien-3-yl)-2-methylpiperazinyl]ethyl}-3,4-dihydro-
1H-2-benzopyran-6-amine, as described for Example 29.
M+H = 501.
Example 32
1-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2~benzopyran-6-
yl)-2-azetidinone
The title compound was prepared as described for
Example 25, substituting 3-brompropionyl chloride for 2-
chloroethyl chloroformate and maintaining the reaction
for 3 days. M+H =474.
Example 33
1-((1S)-1-{2-[(2R)-4-(6-cyano-1-naphthyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran~6-
yl)-2-azetidinone
Prepared from (1S)-1-{2-[(2R)-4-(6-cyano-1-
naphthyl)-2-methylpiperazinyl]ethyl)-3,4-dihydro-1H-2-
benzopyran-6-amine, as described for Example 32. M+H =
481.
Example 34
(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-[(lS)-6-(1,1-dioxido-2-isothiazolidinyl)-3,4-dihydro-1H-2-
ben2opyran-1-yl]ethyl)-2-methylpiperazine
a) N-[(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy)ethyl)-
3,4-dihydro-1H-2-benzopyran~6-yl]-3-chloro-1-
propanesulfonamide
To a stirred solution of (1S)-1-(2-{[tert-
butyl (dimethyl) silyl}oxy}ethyl)-3,4-dihydro-1H-2-
benzopyran-6-amine (0.15g, 0.49mmol) in ethyl acetate
(18mL), cooled to 0°C, was added triethylamine (Q.274mL,
1.37mmol) then 3-chloro-1-propanesulfonyl chloride
(0.070mL,0.576mmol), and the reaction mixture allowed to
warm to room temperature. After stirring for lh, the
reaction was basified with IN sodium hydroxide (2.5mL),
and extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried (MgSO4) , filtered
and evaporated in vacuo to yield the title compound as
an oil. This crude product was used in the next step
without further purification.
b) 2-[(1S)-1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-
3 , 4-dihydro-1H-2-benzopyran~6-yll isothiazolidine 1,1-
dioxide
To a stirred solution of N-[(lS)-1-(2-{[tert-
butyl (dimethyl) silyl]oxy}ethyl)-3,4-dihydro-1H-2-
benzopyran-6-yl]-3-chloro-1-propanesulfonamide (0.367g,
0.82mmol) in DMF (8mL), cooled to 0°C, was added sodium
hydride (60% dispersion in oil) (0.036g, 0.9mmol) and
the mixture allowed to warm to room temperature. After
30 min, the reaction was quenched by addition of water
and extracted with ethyl acetate. The combined organic
extracts were washed with brine, dried (MgSO4), filtered
and evaporated in vacuo. The title compound, as an oil,
was used in the next step without further purification.
c) 2-t (lS)-6-(l,l-Dioxido-2-isothiazolidinyl)-3,4-
dihydro-1H-2-benzopyran-1-yl]ethanol
Prepared from 2-[(1S)-1-(2-{[tert-butyl(dimethyl)-
silyljoxy}ethyl)-3, 4-dihydro-1H-2-benzopyran-6-
yl]isothiazolidine 1,1-dioxide, as described for the
preparation of (1S)-1-(2-hydroxyethyl)-3, 4-dihydro-1H-2-
benzopyran-6-carboxamide.
d) (2R)-4-(1, 2-Dihydro-5-acenaphthylenyl)-1- {2-[(1S)-6-
(1, l-dioxido-2-isothiazolidinyl)-3, 4-dihydro-1H-2-
benzopyran-1-yl]ethyl} -2-me thy lpiperazine
2-[(1S)-6-(1,l-Dioxido-2-isothiazolidinyl)-3,4-
dihydro-1H-2-benzopyran-1-yl]ethanol was reacted with
methanesulfonyl chloride, as described for the
preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-
2-benzopyran-1-yl]ethyl methanesulfonate. The resultant
crude mesylate was then condensed with (3R)-1-(1, 2-
dihydro-5-acenaphthylenyl)-3-me thy lpiperazine, as
described for Example 1 b) , to yield the title compound.
M+H = 532.
Example 35
1-((1S)-1-{2-[{2R)-4-(6-Cyano-1-benzothien-3-yl)-2-
methylpiperaziny 1]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
yl)-2-imidazolidinone
Method A
a) 2-((lS)-6-Bromo-3, 4-dihydro-1H-2-benzopyran-1-
yl)ethyl methanesulfonate
The title compound was prepared from 2-((lS)-6-
bromo-3, 4-dihydro-1H-2-benzopyran-1-yl) ethanol and
methanesulfonyl chloride, as described for the
preparation of 2-[(lS)-6-(aminocarbonyl)-3,4-dihydro-1H-
2-benzopyran-1-yl]ethyl methanesulfonate.
b) 3-((3R)-4-{2-[(lS)-6-Bromo-3,4-dihydro-1H-2-
benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-
benzothiophene-6-carbonitrile
The title compound was prepared from 2-((lS)-6-
bromo-3,4-dihydro-1H-2-benzopyran-1-yl) ethyl
methanesulfonate and{3J?)-1-(6-cyano-1-benzothien-3-yl)-
3-methylpiperazine, as described for Example 1 b) .
c) l-((lS)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-
methylpiperazinyl]ethyl} -3,4-dihydro-1H-2-benzopyran-
6-yl)-2-imidazolidinone
3-((3R)-4- {2-((1S)-6-Bromo-3 , 4-dihydro-1H-2-
benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-
benzothiophene-6-carbonitrile (0.36g, 0.73mmol)was
dissolved in dry toluene (15mL) and degassed. 2-
Imidazolidinone (0.071g, 0.82mmol),
tris(dibenzylideneacetone) dipalladium (34mg), (+/-)-
2, 2'-bis(diphenylphosphino)-1,l'-binaphthyl (47mg) and
caesium carbonate (0.34g, 1.05mmol)were added and the
mixture heated under reflux with stirring, under a
nitrogen atmosphere, for 2 days. The reaction was cooled
to room temperature, diluted with dichloromethane,
filtered through celite and washed with water. The
organic extracts were dried (MgSO4) , filtered and
evaporated in vacuo. Purification by LC-MS yielded the
title compound as the free base. M+H = 502.
Method B
a) 3-[(lS)-1-(2-Hydroxyethyl)-3, 4-dihydro-1H-2-
benzopyran-6-yl]-1,3-oxazolidin-2-one
To a stirred solution of 2-{(1S)-6-bromo-3,4-
dihydro-1H-2-benzopyran-1-yl)ethanol (0.815g, 3.17mmol)
in dry dioxan (5mL) was added 1,3-oxazolidin-2-one
(0.26g, 2.95mmol), trans-1,2-cyclohexanediamine (0.05mL,
0.42mmol), copper (I) iodide (0.040g, 0.21mmol) and
potassium carbonate (1.02g, 7.36mmol), and the mixture
heated at reflux under nitrogen overnight. 2M Ammonia
was added and the mixture extracted into
dichloromethane. The combined organic extracts were
dried (MgSO4), filtered and evaporated in vacuo. The
crude product was purified by flash chromatography on
silica to yield the title compound.
b) 2-{ (lS)-6-(2-Oxo-imidazolidin-1-yl)-3,4-dihydro-1H-2-
benzopyran-1-yl)ethyl methanesulfonate
Prepared from 3-[(1S)-1-(2-hydroxyethyl)-3,4-
dihydro-lH-2-benzopyran-6-yl]-1,3-oxazolidin-2-one and
methanesulfonyl chloride, as described for the
preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-
2-benzopyran-1-yl]ethyl methanesulf onate
c) 1-((1S)-1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-
methylpiperazinyl]ethyl}-3, 4-dihydro-lH-2-benzopyran-
6-yl)-2-imidazolidinone
The title compound was prepared by condensation of
2-((1S)-6-(2-oxo-imidazolidin-1-yl)-3,4-dihydro-1H-2-
benzopyran-1-yl)ethyl methanesulfonate and (3R)-1-(6-
cyano-1-benzothien-3-yl)-3-methylpiperazine, as
described for Example 1 b) . M+H = 502.
Example 36
1-((1S)-1-{2-[(2R)-4-(6-Fluoro-1-naphthyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-
yl)-2-imidazolidinone
Prepared from (3R)-1-(6-cyano-1-naphthyl)-3-
methylpiperazine, as described for Example 35, Method A.
M+H = 489.
Example 37
1-((1S) -1-{2-[(2R)-4-(6-Cyano-1-benzothien-3-yl)-2-
methylpiperazinyl]ethyl)-3,4-dihydro-1H-2-benzopyran-6-
yl)-3-methyl-2-imidazolidinone
Prepared as described for Example 35, Method B,
substituting l-methyl-2-imidazolidinone for 2-
imidazolidinone. M+H = 516.
Example 38
3-((3R)-3-Methyl-4-{2-[(1S)-6-(4-thiomorpholinyl)-3,4-
dihydro-1H-2-benzopyran-1-yl] ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
a) 2-[(1S)-6-(4-Thiomorpholinyl)-3,4-dihydro-1H-2-
benzopyran-1-yl]ethanol
2-((1S)-6-Bromo-3, 4-dihydro-1H-2-benzopyran-1-
yl)ethanol (0.26g, 0.99mmol) was dissolved in dry
toluene (10mL) and degassed. Thiomorpholine (0.14mL,
1.48mmol), tris(dibenzylideneacetone) dipalladium
(51mg), {+/-)-2,2'-bis(diphenylphosphino)-1,l'-
binaphthyl (77mg) and sodium tert-butoxide (0.126g,
1. 3mmol)were added and the mixture heated tinder reflux
with stirring, under a nitrogen atmosphere, for 24 h.
The reaction was cooled to room temperature, diluted
with dichloromethane, filtered through celite and washed
with water, The organic extracts were dried (MgSO4),
filtered and evaporated in vacuo. The crude product was
purified by flash chromatography on silica, to yield the
title compound.
b) 2-[(1S)-6-(4-Thiomorpholinyl)-3,4-dihydro-1H-2-
benzopyran-1-yl]ethyl methanesulfonate
Prepared from 2-[(lS)-6-(4-thiomorpholinyl)-3,4-
dihydro-1H-2-benzopyran-1-yl]ethanol and methanesulfonyl
chloride, as described for the preparation of 2-[[lS)-6-
(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl
methanesulfonate.
c) 3-({3R)-3-Methyl-4-{2-[(15)-6-(4-thiomorpholinyl)-
3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-
l-benzothiophene-6-carbonitrile
Prepared by condensation of 2-[(lS)-6-{4-
thiomorpholinyl)-3,4-dihydro-1H-2-benzopyran-1-yl J ethyl
methanesulfonate with (3R)-1-{6-cyano-1-benzothien-3-
yl)-3-methylpiperazine, as described for Example 1 b).
M+H = 519.
Example 39
3-((3R)-3-Methyl-4-{2-[(1S)-6-(4-morpholinyl)-3,4-
dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared as described for Example 38, substituting
thiomorpholine with morpholine. M+H = 503.
Example 40
(2R)-4-(1,2~Dihydro-5-acenaphthylenyl) -2-methyl-1-{2-
[(1S)-6-(1H-pyrazol-1-yl)-3,4-dihydro-1H-2-benzopyran-l~
yl]ethyl}piperazine
a) 2-1 (1S)-6-(1H-Pyrazol-1-yl)-3,4-dihydro-lff~2-
benzopyran-1-yl]ethanol
2- {(1S)-6-Bromo-3,4-dihydro-Hf~2-benzopyran-1-
yDethanol (0.54g, 2.1mmol), pyrazole (0.29g, 4.3mmol),
copper (I) iodide (0.062g, 0.33mmol) and potassium
carbonate (0.30g, 2.2mmol) were stirred in dry DMF (3mL)
under nitrogen and heated at 150°C for 18 h. The
reaction mixture was cooled and extracted from water
into dichloromethane. The combined organic extracts were
dried (MgSO4), filtered and evaporated in vacuo. The
crude product was used in the next step without further
purification.
b)2-{(1S)-6-(lH-Pyrazol-1-yl)-3,4-dihydro-1H-2-
benzopyran-1-yl]ethyl methanesulfonate
Prepared from 2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-
dihydro-1H-2-benzopyran-1-yl)ethanol and methanesulfonyl
chloride, as described for the preparation of 2-[(lS)-6-
(aminocarbony1)-3,4-dihydro-1H- 2-benzopyran-1-y1]ethy1
methanesulfonate.
c) (2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-
[(lS)-6-(lH-pyrazol-1-yl)-3,4-dihydro-1H-2-
benzopyran-1-yl]ethyl}piperazine
Prepared by condensation of 2-[(1S)-6-(1H-pyrazol-
1-yl)-3, 4-dihydro-lH-2-benzopyran-1-yl]ethyl me thane-
sulfonate with (31?)-1-(1,2-dihydro-5-acenaphthylenyl)-3-
methylpiperazine, as described for Example 1 b). M+H =
479.
The following Examples were similarly prepared,
reacting 2- {(1S)-6-bromo-3,4-dihydro-1H-2-benzopyran-1-
yl)ethanol with the appropriate heterocycle, then
condensation of the subsequent mesylate with the
appropriate aryl piperazine:
Example 41
3-((3R)-3-Methyl-4-{2-[(1S)-6-(1H-pyrazol-1-yl)-3,4-
dihydro-1H-2-benzopyran-1-y1]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared from pyrazole. M+H = 484.
Example 42
(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-1-{2-{(1S)-6-(1H-
imidazol-1-yl)-3,4-dihydro-1H-2-benzopyran-1-y1]ethyl)-
2-methylpiperazine
Prepared from imidazole. M+H = 479.
Example 43
3-((3R)-4-{2-[(15)-6-(lH-Imidazol-1-yl)-3, 4-dihydro-1H-
2-benzopyran-1-yl]ethyl}-3-methylpiperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared from imidazole. M+H = 484.
Example 44
(2R)-4-(1, 2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-
l(1S)-6-(2H-1,2,3-triazol-2-yl)-3,4-dihydro-1H-2-
benzopyran-1-yl]ethyl}piperazine
Prepared from 1,2,3-triazole, to give a mixture
with the 6-(triazol-1-yl)benzopyran, which was separated
by preparative LC-MS. M+H = 480.
Example 45
(2R)-4-(l, 2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-
[(lS)-6-(lH-1,2,3-tria2ol-1-yl)-3,4-dihvdro-1H-2-
benzopyran-1-yl]ethyl}piperazine
Prepared from 1,2, 3-triazole, to give a mixture
with the 6-(triazol-2-yl)benzopyran, which was separated
by preparative LC-MS. M+H = 480.
Example 46
3-((3R)-3-Methyl-4-{2-[(15)-6-(2H-1,2,3-triazol-2-yl)-
3, 4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared from 1,2,3-triazole, to give a mixture
with the 6-(triazol-1-yl)benzopyran, which was separated
by preparative LC-MS. M+H = 485.
Example 47
3-((3R)-3-Methyl-4-(2-[(15)-6-(lH-1, 2, 3-triazol-1-yl)-
3, 4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared from 1,2,3-triazole, to give a mixture
with the 6-(triazol-2-yl)benzopyran, which was separated
by preparative LC-MS. M+H = 485.
Example 48
(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-methyl-1-{2-
[(15)-6-(1H-1,2,4-triazol-1-yl)-3,4-dihydro-1H-2-
benzopyran-1-yl]ethyl)piperazine
Prepared from 1,2,4-triazole. M+H = 480.
Example 49
3-((3R)-3-Methyl-4-{2-[(15)-6-(1H-1,2,4-triazol-1-yl)-
3,4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared from 1,2,4-triazole. M+H = 485.
Example 50
l-((lS)-1-{2-[(2R)-4-(l,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-lH-2-benzopyran-6-
yl)-2 (1H)-pyridinone
Prepared from 2-hydroxypyridine. M+H = 506.
Example 51
3-((3R)-3-Methyl-4-{2-[(1S)-6-(2-oxo-l(2H)-pyridinyl)-
3, 4-dihydro-1H-2-benzopyran-1-yl]ethyl}piperazinyl)-1-
benzothiophene-6-carbonitrile
Prepared from 2-hydroxypyridine. M+H = 511.
WE CLAIM:
1. A compound of formula (I)
where R13, R14, R22 and R23 are each hydrogen or C1-6 alkyl, or R13 and R14 taken
together with the nitrogen atom to which they are attached form a morpholino, pyrrolidino or
piperidinyl ring optionally substituted with one or two C1-6 alkyl groups;
R13' and R24 are each independently selected from hydrogen, C1-6 alkyl, C1-6 alkoxy,
carboxy, hydroxy, cyano, halo, trifluoromethyl, nitro, arnino, C1-6 acylamino, C1-6 alkylthio,
phenyl or phenoxy;
A is 0 or S;
t is 0,1 or 2;
r is 0, 1,2 or 3;
v is 0, 1 or 2;
R2 is hydrogen, C1-6 alkyl, C1-6 alkoxy or halo;
R3, R4, R5, R6, R7, and R8 are each hydrogen or C1-6 alkyl;
R9, R10, R11 and R12 are each hydrogen, C1-6 alkyl or -(CH2)q-OR20, wherein R20 is C1-6
alkyl;
n is 1 or 2;
p is 0, 1 or 2;
q is 1 or 2;
in which -T- is -CH2-, -O-, -S-, -C(O)- or -CH=CH-, and m and s are each 0 or 1;
R15 and R19 are each hydrogen, halo, C1-6 alkyl or C1-6 alkoxy, carboxy-C1-6 alkyl,
cyano, halogen, trifluoromethyl, trifluoromethoxy, nitro, amino, C1-C6 acylamino or
C1-C6 alkylthio;
R17 is hydrogen or C1-6 alkyl; and
Q is hydrogen, halo, nitrile, carboxy-C1-6 alkyl, hydroxy, C1-6 alkyl or C1-6 alkoxy;
and pharmaceutically acceptable salts thereof; provided that:
when -T- is -CH2-, -O-, -S- or -C(O)-, then (m+s) is 1 or 2.
2. A compound as claimed in claim 1 wherein
3. A compound as claimed in claims 1 or 2 wherein R25 is hydrogen.
4. A compound as claimed in any one of the preceding claims 1 to 3 wherein n is 2.
5. A compound as claimed in any one of the preceding claims 1 to 3 wherein n is 1.
6. A compound as claimed in any one of the preceding claims 1 to 5 wherein R2 is
hydrogen.
7. A compound as claimed in any one of the preceding claims 1 to 5 wherein each of R3,
R4, R5, R6, R7 and R8 is hydrogen.
8. A compound as claimed in any one of the preceding claims 1 to 7, wherein p is 1.
9. A compound as claimed in any one of the preceding claim 1 to 8 wherein
10. A compound as claimed in any one of the preceding claims 1 to 9 wherein one of R9,
R10, R11 and R12 is C1-6 alkyl and each of the remainder R9, R10, R11 and R12 is
hydrogen.
11. A compound as claimed in any one of the preceding claims 1 to 10 wherein R1 is -
CONR13R14.
12. A compound as claimed in claim 11, wherein each of R13 and R14 is hydrogen.
13. A compound as claimed in any one of the preceding claims 1 to 10 wherein R1 is -
R21.
14. A compound as claimed in any one of the preceding claims 1 to 10 wherein R1 is -
CONR13R14 and Z is (xxi).
15. A compound as claimed in any one of the preceding claims 1 to 10 wherein R1 is -(CH2)t-R21 and Z is (xxi).
16. A compound as claimed in claim 14 or 15 wherein -T- is -CH2- and (m+s) is 1.
17. A compound as claimed in claim 1 of formula (Id)
wherein all of the values -X-Y-, R1 to R12, n and p have the values defined for formula I in
claim 1, with the proviso as for formula I;
the values for R9 and R10 groups are different, R9 taking priority over R10 according to the
Cahn-Ingold-Prelog sequence rules, and
-W- is -CH2-, -O-, or -S-, or a pharmaceutically acceptable salt thereof.
18. A compound as claimed in claim 17 wherein R9 is C1-6 alkyl and R10, r11 and R12
are hydrogen.
19. The compound: (15)-1-{2-[(2R)-4-(1,2-Dihydro-5-acenaphthylenyl)-2-
methylpiperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-carboxamide or a
pharmaceutically acceptable salt thereof.
20. The compound as claimed in claim 19 wherein the pharmaceutically acceptable salt is
the fumarate salt.
This invention relates to compounds of formula (I) where R1 to R12, -W-V-, -X-Y-, p and n
have the values defined in claim 1, their preparation and use as pharmaceuticals.

Documents:

834-KOLNP-2004-CORRESPONDENCE 1.1.pdf

834-KOLNP-2004-CORRESPONDENCE.pdf

834-kolnp-2004-granted-abstract.pdf

834-kolnp-2004-granted-assignment.pdf

834-kolnp-2004-granted-claims.pdf

834-kolnp-2004-granted-correspondence.pdf

834-kolnp-2004-granted-description (complete).pdf

834-kolnp-2004-granted-examination report.pdf

834-kolnp-2004-granted-form 1.pdf

834-kolnp-2004-granted-form 13.pdf

834-kolnp-2004-granted-form 18.pdf

834-kolnp-2004-granted-form 2.pdf

834-kolnp-2004-granted-form 26.pdf

834-kolnp-2004-granted-form 3.pdf

834-kolnp-2004-granted-form 5.pdf

834-kolnp-2004-granted-reply to examination report.pdf

834-kolnp-2004-granted-specification.pdf

834-kolnp-2004-granted-translated copy of priority document.pdf

834-KOLNP-2004-OTHERS.pdf

834-KOLNP-2004-PA.pdf


Patent Number 223075
Indian Patent Application Number 834/KOLNP/2004
PG Journal Number 36/2008
Publication Date 05-Sep-2008
Grant Date 03-Sep-2008
Date of Filing 16-Jun-2004
Name of Patentee ELI LILLY AND COMPANY
Applicant Address LILLY CORPORATE CENTER, INDIANAPOLIS, INDIANA 46285
Inventors:
# Inventor's Name Inventor's Address
1 AGEJASCHICHARRO, JAVIER LILLY, S.A., AVENIDA DE LA INDUSTRIA 30, 28100 ALCOBENDAS
2 BUENO-MELENDO, ANA, BELEN LILLY, S.A. AVENIDA DE LA INDUSTRIA 30, 28100 ALCOBENDAS
3 GILMORE, JEREMY ELI LILLY AND COMPANY LIMITED, KINGSCLERE ROAD BASINGSTOKE, HAMPSHIRE RG21 2XA
4 LAMAS-PETEIRA, CARLOS LILLY, S.A., AVENIDA DE LA INDUSTRIA 30,28100 ALCOBENDAS
5 TIMMS, GRAHAM, HENRY ELI LILLY AND COMPANY LIMITED KINGSCLERE ROAD BASINGSTOKE, HAMPSHIRE RG21 2XA
6 WILLIAMS, ANDREW, CAERWYN ELI LILLY AND COMPANY LIMITED KINGSCLERE ROAD BASINGSTOKE, HAMPSHIRE RG21 2XA
7 CAMP, NICHOLAS, PAUL ELI LILLY AND COMPANY LIMITED, KINGSCLERE ROAD, BASINGSTOKE, HAMPSHIRE RG 21 2XA
PCT International Classification Number C07D 311/76
PCT International Application Number PCT/US02/36148
PCT International Filing date 2002-12-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 0130339.5 2001-12-19 U.K.