Title of Invention

ISOMERIC FUSED PYRROLOCARBAZOLES AND ISOINDOLONES.

Abstract The present invention is directed to novel fused pyrrofocarbazoles and isoindolones, including pharmaceutical compositions, diagnostic kits, assay standards or reagents containing the same, and methods of using the same as therapeutics. The invention is also directed to intermediates and processes for making these novel compounds.
Full Text ISOMERIC FUSED PYRROLOCARBAZOLES AND ISOINDOLONES
FIELD OF THE INVENTION
The present invention relates generally to isomeric fused pyrrolocarbazoles and
isoindolones, including pharmaceutical compositions, diagnostic kits, assay standards or
reagents containing the same, and methods of using the same as therapeutics. The invention is
also directed to intermediates and processes for making these novel compounds.
BACKGROUND OF THE INVENTION
The microbial-derived material referred to as "K-252a" is a unique compound which
has gained significant attention over the past several years due to the variety of functional
activities which it possesses. K-252a is an indolocarbazole alkaloid that was originally
isolated from a Nocardlosis sp. culture (Kasc, H et al. 39 J. Antibiotics 1059, 1986). K-252a
is an inhibitor of several enzymes, including protein kinase C (PKC) which plays a central role
in regulating cell functions, and trk tyrosine kinase. The reported functional activities of K-
252a and its derivatives are numerous and diverse: tumor inhibition (See U.S. Patent Nos.
4,877,776, 4,923,986, and 5,063330; European Publication 238,011 in the name of Nomato);
anti-insecticidal activity (See U.S. Patent No. 4,735,939); inhibition of inflammation (See U.S.
Patent No. 4,816,450); treatment of diseases associated with neuronal cells (See U.S. Patent
Nos. 5,461,146; 5,621,100; 5,621,101; and WIPO Publication WO 94/02488, published
February 3, 1994 in the names of Cephalon, Inc. and Kyowa Hakko Kogyo Co., Ltd.); and
treatment of prostate disease (See U.S. Patent Nos. 5,516,771; and 5,654,427). K-252a also
has been reported to inhibit IL-2 production (See Grove, O.S. et al., Experimental Cell
Research 193: 175-182,1991).
The reported indolocarbazoles share several common attributes. In particular, each
comprises three five member rings which all include a nitrogen moiety; staurosporinc (derived
from Streptomyces sp.) and K-252a each further comprise a sugar moiety linked via two N-
glycosidic bonds. Both K-252a and staurosporinc have been extensively studied with respect
to their utility as therapeutic agents. The indolocarbazoles are generally lypophilic, which
allows for their comparative ease in crossing biological membranes, and, unlike proteinaceous
materials, they manifest a longer in vivo half-life.
Although K-252a is normally derived from culture media via a fermentation process,
the total synthesis of the natural (+) isomer and the unnatural (-) isomer, in which the three
chiral carbons of the sugar have the opposite configurations, has been achieved (See Wood et
ah, J. Am. Chem. Soc. 117: 10413,1995, and WIPO Publication WO 97/07081). However,
this synthesis is not practical for commercial use.
In addition to the indoiocarbazole alkaloids represented by K-252a and siaurosporine.
synthetic small organic molecules which are biologically active and known as fused
pyrrolocarbazoles have been prepared (See U.S. Patent Nos. 5,475,110: 5,591.855; 5,594.009:
5,705,511; and 5,616,724).
Fused isoindolones which are non-indole-containing molecules that can be chemically
synthesized de novo are also known (See U.S. Patent No. 5,808,060 and WIPO Publication
WO 97/21677). Certain bis-indolylmaleimide macrocyciic derivatives have also been
reported (See for example U.S. Patent Nos. 5,710,145; 5,672,618; 5,552,396 and 5,545,636).
Sugar derivatives of indolopyrrolocarbazoles also have been reported (see WIPO Publication
WO98/07433). There remains a need for novel pyrrolocarbazole and isoindolone derivatives
that possess beneficial properties. This invention is directed to this, as well as other, important
ends.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel compounds which
are kinase inhibitors. Particularly, the compounds of the present invention are inhibitors of trk
kinase, platelet derived growth factor receptor (PDGFR) kinase, vascular endothelial growth
factor receptor (VEGFR) kinase, or NGF-stimulated trk phosphorylation. Another object of
the invention is to provide novel compounds which enhance the trophic factor-induced
activities of trophic factor responsive cells.
It is another object of the present invention to provide pharmaceutical compositions I
having activity toward trk kinase, platelet derived growth factor receptor (PDGFR) kinase,
vascular endothelial growth factor receptor (VEGFR) kinase, NGF-stimulated trk
phosphorylation, or tropic factor responsive cells wherein the composition comprises a
pharmaceutical ly acceptable carrier and a therapeutically effective amount of at least one of
the compounds of the present invention, or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method for treating or
preventing disorders associated with the aberrant activity of trk kinase, platelet derived growth
factor receptor (PDGFR) kinase, vascular endothclial growth factor receptor (VEGFR) kinase,
NGF-stimulated trk phosphorylation, or tropic factor responsive cells, wherein the method
comprises administering to a host in need of such treatment or prevention a therapeutically
effective amount of at least one of the compounds of the present invention.
It is another object of the present invention to provide a method for inhibiting trk
kinase, platelet derived growth factor receptor (PDGFR) kinase, vascular endothelial growth
factor receptor (VEGFR) kinase, NGF-stimulated trk phosphorylation, or enhancing tropic
factor responsive cell activity, in a body fluid sample wherein the method comprises treating
the body fluid sample with an effective amount of at least one of the compounds of the present
invention.
It is another object of the present invention to provide a kit or container containing at
least one of the compounds of the present invention in an amount effective for use as a
diagnostic, standard or reagent.
These and other objects, which will become apparent during the following detailed
description, have been achieved by the inventor's discovery that compounds of Formula I:
stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt
forms thereof, wherein A, B, C, D, E, F, G, Q, X, W, Y, R2, R\ R4, and R3 are defined below,
are effective kinase inhibitors.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Thus, in a first embodiment, the present invention provides a novel compound of
Formula I:
or a stereoisomer or pharmaceutkally acceptable salt form thereof, wherein:
ring D is selected from phcnyl and cyclohexene with double bond a-b;
ring B and ring F, independently, and each together with the carbon atoms to which
they are attached, are selected from:
a) a 6-membered carbocyclic ring in which from 1 to 3 carbon
atoms may be replaced by hetero atoms; and
b) a 5-membered carbocyclic ring in which either
1) one carbon atom may be replaced with an oxygen, nitrogen, or
sulfur atom;
2) two carbon atoms may be replaced with a sulfur and a nitrogen
atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or
3) three carbon atoms may be replaced with three nitrogen atoms, one
oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;
G-X-W is selected from:
a) -(A1A2-NC(R1)-CB1B2)-;
b) -CH(R1A)C(-O)-N(R1)and
c) -N(R1)-C(-O)CH(RIA)-;
R1 is selected from:
a) H, substituted or unsubstttuted alkyl of 1 to 6 carbons, substituted or
unsubsthuted aryl, substituted or unsubsthuted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted heteroaryialkyl;
b) -C(=O)R7, where R7 is selected from substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted carbocyclic
group, and substituted or unsubstituted heterocyclyl groups;
c) -OR2, where R2 is selected from H and alkyl having from 1 to 6 carbons;
-5-
d) -C(-O)NHR8 -NR9R . -(CH2)pNRV10. -CH2)POR8. -CKCH2)^OR* and
-O(CH2)pNR9R10. where p is from ! to 4: and where either
1) R9 and R10 are each independently selected from H. unsubstituted
alky I of I to 6 carbons, and substituted alky I: or
2) R9 and R10 together form a linking group of the formula
-O(CH2)pNR9R10. wherein X1 is selected from -O-. -S-. and
-CH2-;
R1A is the same as R1;
R2. R3. R4 and R5 are each independently selected from:
a) H. aryl, carbocyclyl. heterocyclyl. -CN. CF3. -NO2. -OH. -OR7. Br. I.
-CKCH:)pNR9Rlc. -OC(*=O)R\ -OC(=O)NR9R10. -CXCH^OR1. F. Cl.
-CHjOR1, -NRV0. -NRgS(-O)jR\ -NRaC(-O)R\ or-NR*C(=S)R7;
b) -CHjOR11, where R11 is the residue of an amino acid after the hydroxyl
group of the carboxyl group is removed;
c) -NR*C(«O)NRV°, -NRiC(=S)NR9R10, -CO2R12. -C(-O)R12.
-C(-O)NR*R10, -C(=S)NR9R1°. -CH-NOR12, -CH-NR7.
(CH2)pNR9R10. (CH2)pNHRn. or -CH-NNR12RI2A; where
R12 is selected from H, alkyl of 1 to 6 carbons, -OH, alkoxy of I to 6
carbons, -OC(«O)R7. -OC(-O)NR9R10. -OC(-S)NR9R10.
-©(CHzV^R^R10, -©(CHj^OR*. substituted or unsubstituted arylalkyl
having from 6 to 10 carbons, substituted or unsubstituted
heterocyclylaJkyl. and a substituted or unsubstituted carbocyclic group;
Rl2A is the same as R12;
d) -S(O),R12, -(CH)pOyR7. -CHjSCO^R11 where y is 0, 1 or 2;
e) alkyl of I to 8 carbons, alkenyl of 2 to 8 carbons, and alkynyl of 2 to 8
carbons, wherein:
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is substituted
with 1 to 3 groups selected from aryl of 6 to 10 carbons,
heterocyclyl, arylalkoxy, heterocycloalkoxy, hydroxylalkoxy,
alkyloxy-alkoxy, hydroxyalkylthio. alkoxy-alkyhhio. F, Cl, Br. I.
-CN. -NO2. -OH, -OR7.
-6-
-X2(CH3)pC(=O)NR9R10,-X2(CH2)pC(=S)NR9Ra0,
-X2(CH2)pOC(=O)NR9Rl0.-X2(CH2)pCO2R7,
-X2(CH2)pS(O)yR7,-X-(CH2)pNR8C(=O)NR9R10,
-OC(=O)R7, -OC(=O)NHR12. O-tetrahydropytanyl,
-NR9R10, -NR8CO2R7, -NR8C(=O)NR9R10.
-NRfC(«S)NR9R10, -NHC(=NH)NH2, -NR8C(=O)R7,
-NR8C(=S)R7, -NR8S(=OhR7, -S(O)yR7, -CO2R12,
-C(=O)NR9R10, -C(=S)NR9R10, -C(=O)R12, -CH2OR8,
-CH=NNRI2R12A, -CH=NOR12, -CH=NR7,
-CH=NNHCH(N=NH)NH2,-S(=O)2NR12R12A,
-P(=OXOR8)2, -OR", and a monosaccharide of 5 to 7 carbons
where each hydroxyl group of the monosaccharide is
independently either unsubstituted or is replaced by H, alkyl of 1 to
4 carbons, aikylcarbonyloxy of 2 to 5 carbons, or alkoxy of 1 to 4
carbons;
X2isO, S.orNR*;
Q is selected from -NR6, -O-, and -S-;
R6 is selected from H, -SO2R7, -CC^R7, -C(=O)R7, -C(=O)NR9R10, alkyl of 1-8
carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
1) each alkyl, alkenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl, or alkynyl group independently is
substituted, as defined for R2, R\ R4. and R5 in e) above;
Y is selected from:
a) an unsubstituted alkylene of 1-3 carbons;
b) an alkylene of 1 -3 carbons substituted with R13, where R13 is selected from
R12, thioalkyl of 1-4 carbons, halogen, alkyl of 1-8 carbons, alkenyl of 2-8
carbons, and alkynyl of 2-8 carbons, where
i) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8
carbons is unsubstituted; or
ii) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8
carbons, independently, is substituted, as defined for R2, R3, R4, and
R5 in e) above; and

c) a functional group selected from -CH=CH-. -CH(OH)-CH(OH)-. -O-. -S-.
-S(-OK -SC-Oh-, -C(R6)r, -OCfR1 V. -C(=O)-, -C(=NOR12K
-C(OR12)R12-.-C(=O)CH(R6)-, -CH(R6)C(=OK -C(=NORi:)CH(Rb)-.
-CHR*C(=NOR12)-, -C(=O)N(R8)-, -N(R8)C(-O)-, -CH2Z-. -ZCH;-. and
-CH2ZCH2-, where Z is selected from -C(RI2K -O-, -S-, -CO3Ri:.
-C(=NOR12)-,and -N(R12)-;
A1 and A2 are selected from H, H; H, OR12; H, -SR12; H, - N(R12)2; and a group where
A1 and A2 together form a moiety selected from =O, =S, and =NR:2; and,
B1 and B2 are selected from H, H; H, -OR12; H, -SR12; H, -N(R12)2; and a group where
B1 and B2 together form a moiety selected from =O, =S, and =NR12;
with the proviso that at least one of the pairs A1 and A% or B1 and B2. form =O.
In another embodiment, the present invention provides a novel compound of
Formula XXII
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
ring D is selected from phenyl and cyclohexene with double bond a-b;
ring B and ring F, independently, and each together with the carbon atoms to which
they are attached, are selected from:
a) a 6-membered carbocyclic ring in which from I to 3 carbon
atoms may be replaced by hetero atoms; and
b) a 5-mcmbcred carbocyclic ring in which either
1) one carbon atom may be replaced with an oxygen, nitrogen, or
sulfur atom;
2) two carbon atoms may be replaced with a sulfur and a nitrogen
atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or

3) three carbon atoms may be replaced with three nitrogen atoms, one
oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;
G-X-W is selected from:
a) -(A1A2)C-NCR1)CCB1B2)-;
b) -CH(RlA)-C(=O)-N(R1)-; and
c) -N(R1)-C(=O)-CH(R1A)-;
R1 is selected from:
a) H, substituted or unsubstituted alkyl of 1 to 6 carbons, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl. substituted or
unsubstituted hcteroaryl, or substituted or unsubstituted heteroarylalkyl;
b) -C(=O)R7, where R7 is selected from substituted or unsubstituted alkyl,
substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,
substituted or unsubstituted carbocyclic group, and substituted or
unsubstituted beterocyclyl groups;
c) -OR8, where R8 is selected from H and alkyl having from 1 to 6 carbons;
d) -C(=O)NHR1, -NR9R10, -(CH2)pNR9R10, -(CH2)pNROR8, -(CH2)pNR9R10 and
-O(CH2)pNR9R10, where p is from 1 to 4; and where either
1) R9 and R10 are each independently selected from H, unsubstituted
alkyl of 1 to 6 carbons, and substituted alkyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl; or
2} R9 and R10 together form a linking group of the formula
-(CH2)2Xl-(CH2)2-, wherein X1 is selected from -O-, -S-, and
-CH2
R1A is the same as R1;
R2, R3, R4 and R5 are each independently selected from:
a) H, aryl, carbocyclyl, heterocyciyl, -CN, CF3, -NO2, -OH, -OR7, Br, I,
-CKCH2)pNR*R10, -OC(=O)R7, -OC(=O)NR9R10, -OCCH^OR1, F, Cl,
-CH2OR", -NR9R10, -NR2S(=O)2R7, -NR8C(=O)R7 or -NR8C(=S)R7;
b) -CH2OR11, where R11 is the residue of an amino acid after the hydroxyl
group of the carboxyl group is removed;
c) -O(CH2)pNR9R10,, -NR8C(=S)NR9R10, -COjR12, -C(-O)R12,
-C(=O)NR9R10, -C(=S)NR9R10, -CH=NOR12, -CH-NR7,

-(CH2)pNR9R10. -(CH2)pNHR", or -CH=NNR12R12A; where
R12 is selected from H. alkyl of I to 6 carbons, -OH. alkoxy of 1 to 6
carbons, -OC(=O)R7, -OC(=O)NR9R10, -OC(=S)NR9R10,
-O(CH2)pNR9R10, -O(CH2)POR2. substituted or unsubstituted arylalkyl
having from 6 to 10 carbons, substituted or unsubstituted
heterocyclylaikyl, and a substituted or unsubscituted carbocyclic group;
RI2A is the same as R12;
d) -S(O)vR12, -(CHa)pS(O)YR7, -CH2S(O)yR11 where y is 0, 1 or 2;
e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, and alkyny! of 2 to 8
carbons, wherein:
1) each aikyl, alkenyl, or alkynyt group is unsubstituted: or
2) each aikyl, alkenyl or alkynyl group is substituted
with 1 to 3 groups selected from aryl of 6 to 10 carbons,
heterocyclyK arylalkoxy, heterocycloalkoxy, hydroxylaikoxy,
alkyloxy-alkoxy, hydroxyalkylthio. alkoxy-alkylthio, F, Cl, Br, I,
-CN, -NO2, -OH, -OR7,
-X2(CH2)PC(=O)NR*RU),-X2(CH2)PC(-S)NR9R10,
-X2(CH2)pOC(-O)NR9Rl0,-X2(CH2)pCO2Rt,
-X3(CH2)pS(O)vR7,-X2(CH2)pNR*C(=O)NR*R10,
-OC(=O)R7, -OC(=O)NHR12,0-tetrahydropyranyl,
-NR=R10, -NR=COjR7, -NR8C(=O)NR*R10,
-NR1CX=S)NR9R10, -NHC(=NH)NH2, -NR8C(*O)R7,
-NR*C(*S)R7, -NR1SC=O=R7, -S(O)yR\ -CCbR12,
-C(=O)NR9R10, -C(=S)NR*R10, -C(=O)R12, -CH2OR-CH*NNR12R12A, -CH=NOR12, -CH*NR7,
-CH-NNHCH(N=NH)NH2, -SC=O)cNR=R1",
-P(a=OXOR*)2, -OR", and a monosaccharide of 5 to 7 carbons
where each hydroxy) group of the monosaccharide is
independently either unsubstituted or is replaced by H, alkyl of 1 to
4 carbons, alkylcarbonyioxy of 2 to 5 carbons, or alkoxy of 1 to 4
carbons;
X2isO, S,orNR8;
-10-
Q is selected from -NR6, -O-, and -S-;
R6 is selected from H, -SO2R7, -COjR7, -C(-O)R\ -C(=O)NR9R10. alkyl of 1-8
carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons: and either
1) each alkyl. alkenyl, or alkynyl group is unsubstituted: or
2) each alkyl. alkenyl, or alkynyl group independently is
substituted, as defined for R2, R3, R4, and Rs in e) above:
Y is selected from:
a) an unsubstituted alkylene of 1 -3 carbons;
b) an alkylene of 1 -3 carbons substituted with R13, where R11 is selected from
R12, thioalkyl of 1-4 carbons, halogen, alkyl of 1-8 carbons, alkenyl of 2-8
carbons, and alkynyl of 2-8 carbons, where
i) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8
carbons is unsubstituted; or
ii) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8
carbons, independently, is substituted, as defined for R2, R3, R4, and
R5 in e) above; and
c) a functional group selected from -CH=CH-, -CH(OH)-CH(OH)-, -O-, -S-,
-S(=O)-, -S(=O)2-, -C(RV, -C=C(RlV, -C(=O>, -C=N(R13)-,
-C(=NOR12)-, -C(OR12)R12-, -C(=O)CH(R6)-, -CH(R6)C(=O)-, -
C(=NORI2)CH(R6K -CHR8C(=NOR12K -C(=O)N(R8)-, -N(R*)C(=O)-, -
CH2Z-, -ZCH2-, and -CH2ZCH2-, where Z is selected from -C(R12)-, -O-, -
S-, -COjR12, -C(=NOR12)-, and -N(R12)-;
A1 and A2 are selected from H, H; H, OR12; H, -SR12; H, - N(R12)2; and a group where
A1 and A2 together form a moiety selected from =O, =S, and =NR12; and,
B1 and B2 are selected from H. H; H, -OR12; H, -SR12; H, -N(RI2)2; and a group where
B1 and B2 together form a moiety selected from =O, =S, and =NR12;
with the proviso that at least one of the pairs A1 and A2, or B1 and B2, form =O.
In certain preferred embodiments of the compounds of Formula I, R1, R3, and Rs are
H. In certain further preferred embodiments, -G-X-Y- is CH2N(R1)C(=O), C(=O)N(R1)CH2,
orC(=O)N(R1)C(=O).
In other preferred embodiments, rings B and F, independently, are substituted or
unsubstituted phenyl or pyridyl. In other preferred embodiments, Q is —NR6, wherein the
referred values for R6 are H and substituted or unsubstituted lower alkyl. In certain further
preferred embodiments, Y is an unsubstituted alkylene of 1-3 carbons, -C(=O)-. -CHrO-. -S-,
-O-, or -CH=CH-.
In other preferred embodiments, the isomeric fused pyrrolocarbazoles are represented
by the formula:
In certain further preferred embodiments, the isomeric fused pyrrolocarbazoles are
represented by the formula:

In certain preferred embodiments of these formula, R1, R3 and R5 are H. In other
preferred embodiments. A1 and A2 are selected from H, H; H, OH; H, OCH3; H, -N(RI2)2;
or a group where A1 and A2 together form =O or =NR12; B1 and B2 are selected from H, H;
H, OH; H, OCH3; H, -N(RI2>2; or a group where B1 and B2 together form =O or -NR12;
and R13 is H, methyl, ethyl, propyl, -OH, or methoxy. In other preferred embodiments, the
referred values for R* are H or substituted or unsubstituted lower alkyl. In other preferred
embodiments, Y is an unsubstituted alkylene of 1-3 carbons, -C(=O)-, -CH2O-, -S-, -O-, or
-CH=CH-. Even further preferred embodiments are the compounds set forth in Tables 1 to 4.
In other embodiments, the present invention provides pharmaceutical compositions
comprising a compound of Formula I and a pharmaceutically acceptable carrier. In a
preferred composition, the compound of Formula I is one set forth in Table 1. 2, 3, or 4.
In certain preferred pharmaceutical compositions, the composition is for inhibiting one
or more of trk kinase activity, VEGFR kinase activity, or PDGFR activity wherein the
composition comprises a compound of Formula 1 and a pharmaceutically acceptable carrier.
In other preferred pharmaceutical compositions the composition is for enhancing tropic factor
or spinal chord ChAT activity wherein the composition comprises a compound of Formula 1
and a pharmaceutically acceptable carrier.
In other preferred pharmaceutical compositions, the composition is for treating or
preventing prostate disorders such as prostate cancer or benign prostate hyperplasia. In other
preferred pharmaceutical compositions, the composition is for treating or preventing
angiogenic disorders such as cancer of solid tumors, endometriosis, diabetic retinopathy,
psoriasis, hemangioblastoma, ocular disorders or macular degeneration. In other preferred
pharmaceutical compositions, the composition is for treating or preventing neoplasia,
rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing,
atherosclerosis, or restenosis. In other preferred pharmaceutical compositions, the
composition is for treating or preventing Alzheimer's disease, amyotrophic lateral sclerosis,
Parkinson's disease, stroke, ischaemia, Huntingdon's disease, AIDS dementia, epilepsy,
multiple sclerosis, peripheral neuropathy, or injuries of the brain or spinal chord.
In other embodiments, the present invention provides a method for inhibiting trk
kinase activity comprising providing a compound of Formula I in an amount sufficient to
result in effective inhibition. In a preferred embodiment, the compound of Formula I is
provided to treat inflammation. In another preferred embodiment, the trk kinase receptor is trk
A.
In other embodiments, the present invention provides a method for treatine-ar
preventing prostate disorders which comprises administering to a host in need of such
treatment or prevention a therapeutically effective amount of a compound of Formula I. In a
preferred embodiment, the prostate disorder is prostate cancer or benign prostate hyperplasia.
In other embodiments, the present invention provides a method for treating or
preventing angiogenic disorders where VEGFR kinase activity contributes to pathological
conditions, the method comprising providing a compound of Formula I in an amount sufficient
to result in the vascular endothelial growth factor receptor being contacted with an effective
inhibitory amount of the compound. In another embodiment, the present invention provides a
method for treating or preventing angiogenic disorders which comprises administering to a
host in need of such treatment or prevention a therapeutically effective amount of a compound
of Formula I. In a preferred embodiment, the angiogenic disorder is cancer of solid tumors,
ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or
hemangioblastoma.
In other embodiments, the present invention provides a method for treating or
preventing disorders where PDGFR activity contributes to pathological conditions, the method
comprising providing a compound of Formula I in an amount sufficient to result in the platelet
derived growth factor receptor being contacted with an effective inhibitory amount of the
compound. In another embodiment, the present invention provides a method for treating or
preventing pathological disorders which comprises administering to a host in need of such
treatment or prevention a therapeutically effective amount of a compound of Formula I. In
preferred embodiments, the pathological disorder is neoplasia, rheumatoid arthritis, pulmonary
fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.
In other embodiments, the present invention provides a method for treating disorders
characterized by the aberrant activity of trophic factor responsive cells, the method comprising
providing a compound of Formula I in an amount sufficient to result in the trophic factor cell
receptor being contacted with an effective activity inducing amount of the compound. In
preferred embodiments, the activity of the trophic factor responsive cells is ChAT activity. In
another embodiment, the present invention provides a method for treating or preventing
Alzheimer1s disease, amyotrophic lateral sclerosis, Parkinson1s disease, stroke, ischaemia,
Huntington1s disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, or
injuries of the brain or spinal chord which comprises administering to a host in need of such
treatment or prevention a therapeutically effective amount of a compound of Formula I. The
compounds represented by Formula I may also be referred to as Compound 1, and the same
applies to the compounds of other formula numbers.
Definitions
The following terms and expressions have the indicated meanings. As used herein
"stable compound" or "stable structure" is meant to indicate a compound that is sufficiently
robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably
capable of formulation into an efficacious therapeutic agent. The present invention is directed
only to stable compounds. As used herein, "substituted" is intended to indicate that one or
more hydrogen atoms on the indicated atom is replaced with a selected group referred to
herein as a "substituent", provided that the substituted atom1s valency is not exceeded, and that
the substitution results in a stable compound.
As used herein, the term "alkyl" means a straight-chain, cyclic, or branched alkyl
group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, penryl, isoamyl, neopentyl, 1 -ethylpropyl, hexyl, octyl, cyclopropyl. and
cyclopentyl. The alkyl moiety of alkyl-containing groups, such as alkoxy, alkoxycarbonyl,
and alkylaminocarbonyl groups, has the same meaning as alkyl defined above. Lower alkyl
groups, which are preferred, are alkyl groups as defined above which contain 1 to 4 carbons.
Alkyl groups and alkyl moieties contained within substituent groups such as aralkyl,
alkoxy, arylalkoxy, hydroxyalkoxy, alkoxy-alkoxy, hydroxy-alkylthio, alkoxy-alkylthio,
alkylcarbonyloxy, hydroxyalkyl and acyloxy groups may be substituted or unsubstituted. A
substituted alkyl group has 1 to 3 independently-selected substitutes, preferably hydroxy,
lower alkoxy, lower alkoxy-alkoxy, substituted or unsubstituted arylalkoxy-lower alkoxy,
substituted or unsubstituted heteroarylalkoxy-lower alkoxy, substituted or unsubstituted
arylalkoxy, substituted or unsubstituted heterocycloalkoxy, halogen, carboxyl, lower
alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, dioxolane, dioxane, dithiolane,
dithione, furan, lactone, or lactam.
As used herein, the term "alkenyl" is intended to include straight-chain, cyclic, or
branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of
alkenyl groups include ethenyl, propenyl, 3-methylbutenyl, and cyclohexenyl groups. As used
herein, the term "alkynyl" is intended to include straight-chain, cyclic, or branched
hydrocarbon chains having at least one carbon-carbon triple bond. Examples of alkynyl
groups include ethynyl, propynyl, 3-methylbutynyl, and cyclohexynyl groups.
As used herein, the "acyl" moiety of acyl-containing groups such as acyloxy groups is
intended to include a straight-chain, branched, or cyclic alkanoyl group having 1 to 6 carbon
1 atoms, such as formyl, acetyl, propanoyl, butyryl, valeryl, pivaloyl or hexanoyl.
As used herein, the term "carbocyclic" refers to cyclic groups in which the ring portion
is composed solely of carbon atoms. These include, but are not limited to, cyclopropyl,
cyclobutyl, cyciopentyl, cyclohexl, cycloheptyl. cyclooctyl. The terms "heterocyclo" and
"heterocyclic" refer to cyclic groups in which the ring portion includes at least one heteroatom
such as O, N, or S. Heterocyclyl groups include heteroaryl and hcteroalkyl groups.
As used herein the term "aryl" means an aromatic ring having 6 to 12 carbon atoms
such as phenyl, teiphenyl and naphthyl. Preferred aryl groups include unsubstituted or
substituted phenyl and naphthyl groups. The term "heteroaryl" as used herein denotes an aryl
group in which one or more ring carbon atoms is replaced by a hetero (i.e., non-carbon) atom
such as O, N or S. Preferred heteroaryl groups include pyridyl, pyrimidyl, pyrrolyl, furyl,
thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl. benzoimidazolyl. thiazolyl,
pyrazolyl, and benzothiazotyl groups. The term "heteroalkyl" denotes a cycioalkyl group in
which one or more ring carbon atoms is replaced by hetero atoms such as O, N. or S.
As used herein, the term =aralkyl" (or "arylalkyP) is intended to denote a group
having from 7 to IS carbons, consisting of an alkyl group that bears an aryl group. Examples
of aralky 1 groups include, but are not limited to, benzyl, phenethyl, benzhydryl and
naphthylmethyl groups. Substituted aryl, substituted heterocyclic and substituted aralky)
groups each have 1 to 3 independently selected substituents that are preferably lower alkyl,
hydroxy, lower alkoxy, carboxy, tower atkoxycarbonyl, nitro, amino, mono- or di-lower
alkylamino, and halogen.
Preferred heterocyclic groups formed with a nitrogen atom include pyrrolidinyl,
piperidinyl, piperidino, morpholinyi, morpholino, thiomorpholino, N-methylpiperazinyl,
indolyl, isoindolyl, imidazolc, imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole,
isothiazole, thiadiazoles, triazines, isoxazole, oxindole, indoxyl, pyrazoie, pyrazolone,
pyrimidine, pyrazine, quinoline, iosquinoline, and tetrazole groups. Preferred heterocyclic
groups formed with an oxygen atom include furan, tetrahydrofuran, pyran, benzofurans,
isobenzofurans, and tetrahydropyran groups. Preferred heterocyclic groups formed with a
sulfur atom include thiophene, thianaphthene, tetrahydrothiophene, tctrahydrothiapyran, and
benzothiophenes.
As used herein, "hydroxyalkyl" groups are alkyl groups that have a hydroxyl group
appended thereto. As used herein, "hydroxyalkoxy" groups are alkoxy groups that have a
hydroxyl group appended thereto. As used herein, "halogen" refers to fluorine, chlorine,
bromine and iodine.
As used herein, the term "heteroarylalkyl" means an arylalkyl group that contains a
heteroatom in the aryl moiety. The term "oxy" denotes the presence of an oxygen atom. Thus,
"aikoxy" groups are alkyl groups that are attached through an oxygen atom, and
"carbonyloxy" groups are carbonyl groups that are attached through an oxygen atom.
As used herein, the terms "heterocycloalkyP and "heterocycloalkoxy" mean an alkyl
or an aikoxy group that has a heterocyclo group attached to the alkyl moiety thereof, and the
term "arylalkoxy" means an aikoxy group that has an aryl group attached to the alkyl moiety
thereof. As used herein, the term "alkylcarbonyloxy" means a group of formula -O-C(=O)-
alkyl.
As used herein, the term "alkyloxy-alkoxy" denotes an aikoxy group that contains an
alkyloxy substitucnt attached to its alkyl moiety. The term "alkoxy-alkylthio" means an
alkylthio group (i.e., a group of formula -S-alkyI) that contains an aikoxy substituent attached
to its alkyl moiety. The term "hydroxy-alkylthio" means an alkylthio group (i.e., a group of
formula -S-alkyl) that contains a hydroxy substituent attached to its alkyl moiety.
As used herein, the term "monosaccharide" has its accustomed meaning as a simple
sugar. As used herein, the term "amino acid" denotes a molecule containing both an amino
group and a carboxyl group. Embodiments of amino acids include a-amino acids; i.e.,
carboxylic acids of general formula HOOC-CH(NH2)-(side chain). Side chains of amino
acids include naturally occurring and non-naturally occurring moieties. Non-naturally
occurring (i.e., unnatural) amino acid side chains are moieties that are used in place of
naturally occurring amino acid side chains in, for example, amino acid analogs. See, for
example, Lehninger, Biochemistry, Second Edition, Worth Publishers. Inc. 1975. naees 73-75.
incorporated by reference herein. In certain embodiments, substituent groups for the
compounds of Formulas I, II, and III include the residue of an amino acid after removal of the
hydt yl moiety of the carboxyl group thereof; i.e., groups of Formula -C(=O)CH(NH2Hside
chain).
Functional groups present on the compounds of Formula I may also contain protecting
groups. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group and the
tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups may be found in
Greene, T.W. and Wuts, P.G.M., Protective Groups inOrganic Synthesis. Ed.. Wiley &
Sons, 1991, the disclosure of which is incorporated herein by reference.
As used herein, terms commonly used to describe the effects of therapeutic atoms in
biological systems, assays, and the like, are intended to have their art-recognized meanings.
As used herein, the term "effect" when used to modify the terms "function" and "survival"
means a positive or negative alteration or change. An effect which is positive may be referred
to herein as an "enhancement" or "enhancing", and an effect which is negative may be
referred to herein as "inhibition" or "inhibiting."
As used herein, the terms "enhance" or "enhancing" when used to modify the terms
"function" or "survival" means that the presence of an isomeric fused pyrrolocarbazole or
isoindolone compound has a positive effect on the function and/or survival of a trophic factor
responsive cell compared with a cell in the absence of the compound. For example, and
without limitation, with respect to the survival of, e.g., a cholinergic neuron, the compound
would evidence enhancement of survival of a choiinergic neuronal population at risk of dying
(due to, e.g., injury, a disease condition, a degenerative condition or natural progression) when
compared to a cholinergic neuronal population not presented with such compound, if the
treated population has a comparatively greater period of functionality than the non-treated
population.
As used herein, "inhibit" and "inhibition" mean that a specified response of a
designated material (e.g., enzymatic activity) is comparatively decreased in the presence of an
isomeric fused pyrrolocarbazole or isoindolone compound.
As used herein, the term "trk" refers to the family of high affinity neurotrophin
receptors presently comprising trie A, trk B, and trk C, and other membrane associated proteins
to which a neurotrophin can bind.
As used herein, the terms "cancer" and "cancerous" refer to any malignant
proliferation of cells in a mammal. Examples include prostate, benign prostate hyperplasia,
ovarian, breast, brain, lung, pancreatic, colorectal, gastric, stomach, solid tumors, head and
neck, neuroblastoma, renal cell carcinoma, lymphoma, leukemia, other recognized
malignancies of the hematopoietic systems, and other recognized cancers.
As used herein the terms "neuron," "cell of neuronal lineage" and "neuronal cell"
include, but are not limited to, a heterogeneous population of neuronal types having singular
or multiple transmitters and/or singular or multiple functions; preferably, these are cholinergic
and sensory neurons. As used herein, the phrase "cholinergic neuron" means neurons of the
Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter
is acetylcholine; exemplary are basal forebrain, striatal. and spinal cord neurons. As used
herein, the phrase "sensory neuron1" includes neurons responsive to environmental cues (e.g.,
temperature, movement) from, e.g., skin, muscle and joints: exemplary is a neuron from the
dorsal root ganglion.
As used herein, a "trophic factor-responsive cell," is a cell which includes a receptor to
which a trophic factor can specifically bind; examples include neurons (e.g., choltnergic and
sensory neurons) and non-neuronal cells (e.g., monocytes and neoplastic cells).
As used herein, a "therapeutical ly effective amount" refers to an amount of a
compound of the present invention effective to prevent or treat the symptoms of particular ,
disorder. Such disorders include, but are not limited to, those pathological and neurological
disorders associated with the aberrant activity of the receptors described herein, wherein the
treatment or prevention comprises inhibiting, inducing, or enhancing the activity thereof by
contacting the receptor with a compound of Formula I.
As used herein, the term "pharmaceutically acceptable" refers to those compounds,
materials, compositions, and/or dosage forms which are, within the scope of sound medical
judgment, suitable for contact with the tissues of human beings and animals without excessive
toxicity, irritation, allergic response, or other problem complications commensurate with a
reasonable benefit/risk ration.
As used herein, "pharmaceutical ly acceptable salts" refer to derivatives of the
disclosed compounds wherein the parent compound is modified by making acid or base salts
thereof. Examples of pharmaceutical ly acceptable salts include, but are not limited to, mineral
or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium salts of the parent compound
formed, for example, from non-toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from
organic acids such as acetic, propionic, succinic, giycolic, stearic, lactic, malic, tartaric, citric,
ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic,
2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic,
isethionic, and the like.
The pharmaceutical ly acceptable salts of the present invention can he synthesized from
the parent compound which contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting the free acid or base forms of
these compounds with a stoichiometric amount of the appropriate base or acid in water or in
an organic solvent, or in a mixture of the two. Generally, nonaqueous media like ether, ethyl
acetate, ethanoi, isopropanol, or acetonitriie are preferred. Lists of suitable salts are found in
Remington1s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA,
1985, p. 1418, the disclosure of which is hereby incorporated by reference.
As used herein, "prodrug" is intended to include any covalently bonded carriers which
release the active parent drug according to Formula (I) or other formulas or compounds of the
present invention in vivo when such prodrug is administered to a mammalian subject. Since
prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g.,
solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be
delivered in prodrug form. Thus, the present invention contemplates prodrugs of the claimed
compounds, compositions containing the same, and methods of delivering the same. Prodrugs
of a compound of the present invention, for example Formula I, may be prepared by
modifying functional groups present in the compound in such a way that the modifications are
cleaved, either in routine manipulation or in vivo, to the parent compound. Accordingly,
prodrugs include, for example, compounds of the present invention wherein a hydroxy, amino,
or carboxy group is bonded to any group that, when the prodrug is administered to a
mammalian subject, cleaves to form a five hydroxyl, free amino, or carboxylic acid,
respectively. Examples include, but are not limited to, acetate, formate and benzoate
derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl
esters such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl,
cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.
Synthesis
The compounds of the present invention may be prepared in a number of ways well
known to those skilled in the art. The compounds can be synthesized, for example, by the
methods described below, or variations thereon as appreciated by the skilled artisan. All
processes disclosed in association with the present invention are contemplated to be practiced
on any scale, including milligram, gram, multigram, kilogram, multikilogram or commercial
industrial scale.
It will be appreciated that the compounds of the present invention may contain one or
more asymmetrically substituted carbon atoms, and may be isolated in optically active or
racemic forms. Thus, all chiral, diastereomeric, racemic forms and all geometric isomeric
forms of a structure are intended, unless the specific stereochemistry or isomeric form is
specifically indicated. It is well known in the art how to prepare and isolate such optically
active forms. For example, mixtures of stereoisomers may be separated by standard
techniques including, but not limited to, resolution of racemic forms, normal, reverse-phase,
and chiral chromatography, preferential salt formation, rccrystallization. and the like, or by
chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral
centers.
As will be readily understood, functional groups present on the compounds of Formula
I may contain protecting groups during the course of synthesis. For example, the amino acid
side chain substituents of the compounds of Formula I can be substituted with protecting
groups such as benzyloxycarbonyl or t-butoxycarbonyl groups. Protecting groups are known
per se as chemical functional groups that can be selectively appended to and removed from
functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a
chemical compound to render such functionality inert to chemical reaction conditions to which
the compound is exposed. Any of a variety of protecting groups may be employed with the
present invention. Preferred protecting groups include the benzyloxycarbonyl (Cbz; Z) group
and the tert-butyloxycarbonyl (Boc) group. Other preferred protecting groups according to the
invention may be found in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic
Synthesis 2d. Ed., Wiley & Sons, 1991.
Compounds of the present invention may be prepared as outlined in the following
schemes. Generally, imide compounds may be prepared as shown in Scheme 1.
A cycloaddition reaction with maleimide and a cyclic-2-vinyl derivative (II) gives the
tetrahydrocarfoazole compounds of general structure (III), which can be dehydrogcnated by
methods well known in the art (Scheme 1). The cycloaddition reaction may be carried out in
the absence of a solvent at temperatures of about 1 SO to about 200 °C, or in a solvent such as
toluene, xylene or chlorobenzene at elevated temperatures with or without an added Lewis
acid catalyst. The dienes of general structure (II) may be prepared by addition of a 2-lithio
indole species, substituted or unsubstituted, to a cyclic (hetero)aryl 1-ketone, for example, 1-
indanone, 1-tetralone, 4-chromanonc, 4-keto-4,5,6,7-tetrahydrothianaphthlene, substituted or
unsubstituted, as described, for example, in Tetrahedron Lett.1985, 26, S93S, the disclosure of
which is hereby incorporated by reference.
Scheme 2 outlines the general approach for preparing lactam isomers, i.e.,
compounds wherein G-X-W is -C(=O)-N(R1)-C(B1B2)- or -C(A1A2)-N(RI)-C(=O)-.
Cycloaddition reaction of diencs of general structure III with ethyl cis-b-cyanoacry late under
conditions described for imides in Scheme 1 produces the cyanoester tetrahyrocarbazole
regioisomers of general structures V and VI. Standard procedures such as recrystallization or
chromatography may be used to separate the resulting regioisomers V and VI. The
tetrahydrocarbazole cyano-esters may be readily dehydrogenated according to conventional
processes with, for example, 2,3-dichloro-4,5-dicyano-l,4-benzoquinone to produce the
aromatized carbazoles of general structure VII and VIII (Scheme 2). Lactams of general
structure IX and X may be prepared separately or as a mixture by reductive cyclization of the
nhrile-esters using reducing agents, for example, raney nickel/Hj, PdO. and Pd or Pt on
activated charcoal. The imide derivative IV may also be readily be reduced to lactam isomers
IX and X by conventional processes such as zinc amalgam-HCI, Zn in acetic acid, or by
treatment with hydride reducing agents such as lithium aluminum hydride. Standard processes
such as recrystallization or chromatography may separate the resulting lactam regioisomers.
Compounds in which G-X-W is -CH(RlA)-C(=O)-N(R1)- or -N(R1)-C(=O)-CH(R1A)-,
as well as those in which G-X-W is a lactam or imide can be prepared by methods taught, for
example, in U.S. Pat. Nos. 5,616,724, and 5.801,190, the disclosures of which is hereby
incorporated herein by reference in its entirety.
Compounds containing heteroaryl groups in rings B or F may be prepared using the
described methods as demonstrated in Schemes 3 and 4. The phenyl ring of the indole may be
a heterocycle, for example, but not limited to, 7-azaindole.
Although the resulting alcohol derivative of general structure (I-i) shown in Scheme I
may be dehydrated to compounds of general structure (II) using conditions known in the art
5 such as HC1 in acetone or p-toluenesulfonic acid in benzene, dienes of general structure (II)
may be also be prepared using palladium catalyzed cross coupling methodology. For
example, coupling an appropriate bromo, iodo or a trifluoromethane sulfonate derivative with
a 2-stannyl- or 2-boronicacid tndole derivative as shown in Scheme 5.
The tetrahydrocarbazole cycloaddition adducts III can be readily dehydrogenated
according to conventional processes with, for example, with 2.3-dichloro-4.5-dicyano-1.4-
benzoquinone to give the aromatized carbazoles of general structure IV (Scheme 1).
Scheme 6 outlines an alternative method to prepare lactam isomer of general structure
X. A diene of general structure II, substituted or unsubstituted, is reacted with oxalyl chloride
and an alcohol to produce keto-esters of general structure XIX. Olefination reactions known
to those skilled in the art of organic synthesis, for example, reaction of ketone XIX with
diethyl cyanomethylphosphonate, readily produces cyano-ester XX. Aromatic ring closure,
under palladium catalyzed or oxidative conditions gives the cyano-ester carbazole of general
structure XXI (Scheme 6) or VIII (Scheme 2). Reductive cyclization produces the iactam of
general structure X (Scheme 2,6).
Compounds of the present invention in which general structures IV, IX or X have
Y = CH2 may be further substituted as shown in Scheme 7.
Generally, compounds in which R6 is hydrogen, can be alkylated in the presence of
base (e.g., hydrides, alkoxides, hydroxides of alkali or alkaline earth metals, or of organo-
lithium compounds) by treatment with R6L in which L is a leaving group such as a
halogen. The resulting pyrrolocarbazole may have an alkyl group, substituted or
unsubstituted bound to the indole nitrogen, for example IV-20.41. Compounds of general
formula IV, IX or X, in which R6 is N-hydrogen may be subjected to Michael reaction
conditions using a base, such as DBU and a Michael acceptor, such as an acrylic acid
derivative or acrylonitrile to produce compounds IV-20-22. Reactions of this type may be
further understood by reference to Scheme 8.
Palladium catalysed Heck reaction using IV-9 and a coupling partner such as a
vinyl aryl or herteroaryl derivative, acrylic acid derivative or acrylonitrile produces vinyl
derivatives IV-36, 37. 39,43. The vinyl derivative may be reduced to the alkane
derivatives such as IV-38, 40 using reducing conditions such as Palladium on carbon
under a hydrogen atmosphere.
Other features of the invention will become apparent in the course of the following
descriptions of exemplary embodiments. These examples are given for illustration of the
invention and are not intended to be limiting thereof.
Examples
Certain abbreviations used herein are defined as follows: "THF" for tetrahydrofuran,
"BuLi" for butyl lithium, "NMP" for N-methyl pyrrolidinone, "DMSO" for dimethylsulfoxide,
"CDCU" for deuterated chloroform, "RaNi" for raney nickel, TLC" for thin layer
chromatography, "EtOAc" for ethyl acetate, TBAF" for tetrabutylammonium fluoride, "ca"
for approximately, Hrt" for room temperature, "psi" for pounds per square inch, "mm" for
millimeters of Hg, "°C" for degrees Celsius, "d" for doublet, "dd" for doublet of doublets, "t"
for triplet, "m" for multiples "eq" for equivalents, "g" for gram or grams, "mg" for milligram
or milligrams. "mL" for milliliter or milliliters, "H" for hydrogen or hydrogens, "hr" or "h" for
hour or hours, "m" for multiple!, "M" for molar, "min" or "m" for minute or minutes, "MHz"
for megahertz, "mp" for melting point, "MS" for mass spectroscopy, "nmr" or "NMR" for
nuclear magnetic resonance spectroscopy.
Example 1
Compound IV-1
Step 1: Intermediate I-ia (Y = CH2, R:=R4=H, R6=H (2-( 1 -Hydroxy)indanyl)indole))
To a solution of indole (4.0 g, 34.1 mmol) in THF (200 mL) at -78 °C under a nitrogen
atmosphere was added BuLi (34.1 mmol, 13.7 mL of 2.5 M solution in hexanes) dropwise
over 15 min. Following stirring 30 min, CC2(g) was passed through the solution for 10 min
after which the clear solution was allowed to warm to ambient temperature, then concentrated
to half volume at reduced pressure. The volume of THF was brought to about 200 mL and
cooled to -78 °C. t-BuLi (34.1 mmol, 20 mL of 1.7 M solution in hexanes) was added slowly
while maintaining the temperature below -68 °C followed by stirring for 2 h at -78 °C. 1-
Indanone (5.0 g, 37.4 mmol) in THF (25 mL) was added, the mixture stirred for I h, quenched
by addition of water (5 mL), then poured into saturated NH4CI solution (250 mL). The
mixture was extracted with ether (1 x 200 mL), washed with 100 mL saturated NR=C1, dried
(MgSO4), and concentrated at reduced pressure to give an oil. Recrystaltization from EtjO-
hexane gave 5.1 g (63%) of I-i-a, mp 123-124 °C. 1H NMR (CDCI3): 8 2.3-2.5 (m, 1H),
2.55-2.7 (m, 2H), 2.9-3.05 (m, 1H), 3.1-3.2 (m, 1H), 6.15, s, 1H)T 7.05-7.4 (m, 7H), 7.5 (d,
lH),8.5(s, 1H).
Step 2: Intermediate Ua (Y - CH2, R2=R4=H, R6=H (2-(l-Indenyl)mdole))
A stirred solution of la (4.0 g, 16.1 mmol) in acetone (50 mL) was added 2 N HCI (5
mL). After stirring 15 min at room temperature water was added and the solid collected by
filtration, washed well with water and dried to give 3.7 g (100%) of intermediate Ila as a white
solid. lH NMR (CDC13): 8 3.6 (s, 2H), 6.75 (s, 1H), 6.95 (s, 1H) 7.1-7.5 (m. 5H), 7.6 (d, 1H),
7.7 (d, 1H), 7.9 (d, 1H), 8.35 (bs, 1H). MS (ES*) m/e 254 (M + 23).
Step 3: Intermediate Ilia, (Y = CH2, R2=R4=H. R6=H)
A mixture of intermediate Ha (660 mg, 2.9 mmol) and maleimide (550 mg, 5.7 mmol)
in a 10 cm sealed reaction vial was heated with stirring at 180-190 °C for 30 min. After
cooling to about 50-60 °C MeOH (3 mL) was added and the product was collected after
triturating to give 880 mg (92%) of Ilia as a white solid; mp 210-214 °C. 1H NMR (DMSO-
d6, 300 MHz): 5 3.1-3.4 (m, 2H), 3.8 (m. 2H). 3.95 (t, 1H), 4.35 (d, 1H), 6.9-7.4 (m, 7H), 7.75
(d, 1H), 11.05 (s, 1H). 11.25 (s. 1H). MS(ES"): m/e 327 (m - 1).
Step 4: Compound IV-1
To a suspension of intermediate Ilia (500 mg, 1.52 mmol) in toluene (60 mL) was
added solid 2r3-dichloro-5,6-dicyano-1.4-benzoquinone (865 mg, 3.81 mmol) in one portion.
The solution was maintained at 60-65 °C for 6 hours. After cooling on an ice bath, the solids
were collected by filtration, suspended in MeOH (20 mL) and the product collected by
filtration. Recrystallization from acetone gave 350 mg (71%) of compound IV-1 as a yellow
solid, mp > 300 °C. 1HNMR (DMSO-d6> 300 MHz): 5 4.38 (s, 2H), 7.38 (t. 1H), 7.45-7.5
(m, 1H), 7.6-77 (m, 2H), 7.8 (m, 2H), 8.6 (d, 1H), 8.95 (d. 1H), 11.15 (s. 1H), 12.15 (s, 1H).
MS(FAB): m/e 324 (m*). Anal. calc. for C21H12N2O2. 0.7 H2O: C, 74.86; H, 4.01; N, S.31.
Found; C, 74.85; H, 3.62; N, 8.52.
Example 2
Compound IV-2
To a stirred solution of Compound IV-1 in NMP (2 mL) was added NaH (10 mg of
95%) at room temperature. The reaction turned from orange to green in color. After 0.5 h,
water was added and the resulting red solid was collected, washed with water, and dried. *H
NMR (DMSO-d£, 300 MHz): S 7.34 (t, 1H), 7.45 (t. 1H), 7.6-7.75 (m, 4H), 8.35 (d, 1H), 8.95
(d, 1H). MS(ES"): m/e 337 (m-1).
Example 3.
Compound IX-1
Step 1: Intermediate Va (Y = CH2, R:=R4=H, R6=H)
Intermediate Ha (2.0 g, 8.7 mmol) and ethyl cis-p-cyanoacrylate (3.3 g, 26.0 mmol)
were heated in a round bottom flask under a stream of nitrogen at 190 °C with stirring for 1 h.
While cooling to room temperature MeOH (10 mL) was added and stirring was continued for
0.5 h. The solution remained at freezer temperature overnight and the solid which separated
was collected to give 880 mg (28%) of intermediate Va as a white solid. 1H NMR (DMSO-
d6, 300 MHz): 5 1.28 (t, J = 6.9 Hz, 3H), 3.00-3.08 (m. 1H), 3.30 (m, 1H). 3.47-3.51 (m. 1H),
3.62 (m, IH), 4.26 (q, J = 7.0 Hz, 2H), 4.54 (m, 1H), 4.72 (m, 1H), 6.97-7.09 (m, 2H), 7.16-
7.24 (m, 3H), 7.31 (d, J = 7.8 Hz, IH), 7.50 (d, J = 7.5 Hz, IH), 7.82 (d, J = 7.0 Hz. IH), 11.04
(s, IH). MS (ES+) m/e 357. 379 (M + 1, M + 23).
Steplb. The methanol layer from step la was concentrated at reduced pressure to an
oil and the excess cyanoacrylate was removed by Kugelrohr distillation (oven temperature 80
°C, 1 mm). The residue was triturated with ether to a yellow solid, which was collected. "H
NMR showed a 2:1 mixture of isomers Va and Via (Y = CH2); MS (ES*) m/is 357, 379 (M ¦+•
l.M + 23).
Step 2: Intermediate VIla (Y = CH2, R2=R4=H, R6=H)
To a suspension of intermediate Via from step la (650 mg, 1.8 mmol) in toluene (60
mL) was added solid 2,3-dichloro-5,6-dicyano-l ,4-benzoquinone (1.05 g. 4.6 mmol) in one
portion. The solution placed in an oil bath at 65 °C for 6 h. After cooling at freezer
temperature, the solids were collected by filtration, suspended in MeOH (20 mL) and the
product collected by filtration to give 620 mg (98%) of a yellow solid. 1H NMR (DMSO-d6,
300 MHz): 6 1.44 (t, J = 7.0 Hz. 3H), 4.36 (s, 2H), 4.45 (q, J = 7.18 Hz, 2H), 7.38 (t, 1H), 7.44
(t, IH), 7.54-7.63 (m, 2H), 7.71-7.78 (m, 2H), 8.55 (d, J = 7.5 Hz, IH), 8.63 (d, J = 8.0 Hz,
IH), 12.22 (s, IH). MS (ES*) m/e 353, 375 (M + 1, M + 23).
Step 3: Compound IX-1
The product from step 2 (intermediate VIla) (500 mg, 1.4 mmmol) in DMF (40 mL)
and RaNi catalyst (1 small spatula) was hydrogenated at 60 psi on a Parr Apparatus for 24 h or
until TLC (2:1. EtOAc:Hexanes) showed completion of reaction. The solvent was filtered
through celite to remove catalyst then concentrated at reduced pressure. The solid was
triturated with MeOH, collected and dried to give 325 mg (71%) of compound IX-1 as a white
solid, mp > 300 °C. JH NMR (DMSO-d6, 300 MHz): S 4.30 (s, 2H), 4.93 (s, 2H), 7.32-7.42
(m, 2H), 7.52-7.56 (m, 2H), 7.72-7.76 (m,2H), 8.05 (d, 1H). 8.51-8.54 (m. 2H), 11.92 (s. 1H)
MS(FAB): m/e 311 (m*).
Example 4
Compound X-l
Step 1: Intermediate Villa (Y = CH2, R2=R4=H, R6=H)
To a suspension of the cyano-ester isomers Va and Via from example 3 step lb (880
mg, 2.3 mmol) suspended in toluene (50 mL) was added solid 2.3-dichloro-5.6-dicyano-l,4-
benzoquinone (1.3 g, 5.6 mmol) in one portion. The solution was placed in an oil bath at 65
°C for 6 h. After cooling at freezer temperature, the solids were collected by filtration,
suspended in MeOH (20 mL) and the product collected by filtration to give 700 mg (88%) as a
mixture of two cyano-ester carbazole isomers in a ratio of approximately 2:1 (Villa: Vila) by
1H NMR. MS (ES*) m/e 353 (M + 1). The mixture was used directly in the next step.
Step 2: Compound X-1
A mixture of the cyano ester isomers Villa and Vila from step I (700 mg, 2.0 mmmol)
and RaNi catalyst ( one spatula full) in DMF (40 mL) was hydrogcnatcd at 60 psi on a Pan-
apparatus for 24 h or until TLC (2:1, EtOAcrHexanes) showed completion of reaction. The
solvent was filtered through celite to remove catalyst, then concentrated at reduced pressure.
The product was triturated with MeOH, collected and dried to give 550 mg (89%) of a white
solid. *H NMR (DMSO-d6. 300 MHz) showed a 2:1 mixture of compound X-l: IX-1. The
compound X-l was isolated by column chromatography (silica gel) and eluted with
toluenc:THF, increasing the THF from 30% to 50%. Fractions showing pure product were
combined and concentrated at reduced pressure. Th= product was collected after triturated
with MeOH, mp > 300 oC. 1H NMR (DMSO-d6, 300 MHz): d 4.08 (s, 2H), 4.59 (s, 2H), 7.20
(t, J - 7.5 Hz, 1H), 7.37-7.46 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.64-7.7.71 (m, 2H), 8.53-8.56
(s, 2H) 9.18 (d, J = 7.8 Hz, 1H), 11.71 (s, 1H). MS (ES*): m/e 311 (M + 1).
Example 5
Compound III-l
Step I: Intermediate I-ib (Y = CH2, R2=R4=H, R6=H (1 -Methyl-2-[( 1 -
hydroxy)indanyl)]indole))
BuLi (9.6 mL, 24.1 mmol) was added slowly to 1-methylindole (3.0 c. 22.9 mmol) in
ether (20 mL). The solution was stirred at reflux 4 h, cooled to room temperature, followed by
addition of 1-indanone in 10 mL ether. After stirring at room temperature for 2 h, the solution
was poured into a saturated NH4C1 solution (30 mL). The ether layer was washed with water
(2 x 20 mL), NaCl solution (2 x 20 mL) and dried (MgSO4). Trituration with ether-hexane
(2:1) gave 3.7 g (62%) of 1b. 1H NMR (DMSO-d6, 300 MHz): 5 2.5-2.6 (m, 1H), 2.7-2.8 (m,
1H), 2.9-3. (m, 1H), 3.1-3.2 (m, 1H), 3.95 (s, 3H), 6.0 (s, 1H), 7.05-7.30 (m, 2H), 7.45-7.5 (m,
7H).
Step 2: 1-MethyJ-2-(l-indeny])indole (Intermediate IIb)
A stirred solution of intermediate I-ib (500 mg, 1.9 mmol) in acetone was added 2 N
HC1 slowly at room temperature. After 2 h water was added and the precipitate collected by
filtration, washed well with water and dried to give 445 mg (96%) intermediate lib of a white
solid mp > 250 °C. 1H NMR (CDC13): 5 3.66 (s, 2H), 3.8 (s, 3H), 6.65 (s, 1H), 6.70 (s, 1H),
7.15-7.4 (m, 7.5-7.6 (m, 2H), 7.75 (d, 1H). MS (ES1) m/e 245 (M - 1).
Step-3. Compound III-l (Intermediate IIIb, Y = CH2, R2=R4=H, R6=H)
A mixture of IIb (380 mg, 1.6 mmol) and maleimide (190 mg, 1.9 mmol) in a 10 cm
sealed reaction vial was heated at 180 °C for 30 min. After allowing the mixture to cool below
60 °C, MeOH (3 mL) was added and the product collected after triturating to give 450 mg
(82%) of a white solid, mp 205-210 °C. 1H NMR (DMSO-d6,300 MHz): 8 2.9-295 (m, 1H),
3.05-3.15 (m, 2H), 3.5 (m, 1H), 3.9 (s, 3H), 7.0-7.3 (m, 5H), 7.45 (d, 1H), 7.55 (m, 1H), 7.85
(d, 1H), 11.05 (s 1H). MS (ES) m/e 341 (M- 1).
Example 6
Compound IV-3
To a suspension of compound III-l from example 5 (330 mg, 1.0 mmol) in toluene (50
mL) was added solid 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (550 mg, 2.5 mmol) in one
portion. The solution was maintained at reflux 4 hours. After cooling on an ice bath, the
solids were collected by filtration, suspended in MeOH (20 mL) and the product collected by
filtration to give 280 mg (86%) of a yellow solid, mp > 262-265 °C. 1H NMR (DMSO-d6,
300 MHz): 8 3.4 (s, 3H), 4.2 (s, 2H), 7.35-7.5 (m, 4H), 7.6-7.8 (m, 2H), 8.3 (d. 1H). 8.95 (d.
1H), 11.1 (s, 1H), MS (ES) m/e 337 (M - 1).
Example 7
Compound IV-4
Step !: Intermediate He (Y = CH2, R2=H, R4=5-Br. R6=H).
This compound was prepared by the same genera) procedure as Examples Ia-IIa using
indole (10.0 g, 85.3 mmol) and 5-bromo-l-indanone (19.0 g, 90 mmol) to give a crude alcohol
intermediate lc. The resulting crude alcohol as a dark oily residue, was dissolved in acetone
(250 mL) followed by the addition of 2N HCL (25 mL), and water (50 mL). After stirring 2 h
at room temperature the mixture was poured into water and extracted with EtOAc. The EtOAc
was washed with water and brine, dried over MgSo4, then concentrated at reduced pressure.
The product was triturated with Et2O and collected to give 8.7g of intermediate He. 1HNMR
(CDCI3): 6 3.56 (s, 2H), 6.68 (s, 1H), 6.90 (s, 1H), 7 12-7.25 (m, 3H), 7.40 (d, 1H), 7.52 (d,
1H), 7.66-7.74 (m, 3H), 8.26 (s, 1H). MS(ES*): m/e 311 (m + 1).
Step 2: Intermediate IIIc (Y = CH2, R2=H, R4=5-Br, R6=H)
This compound was prepared by the same general procedure as Example Ic using He
(300 mg, 0.97 mmol) and maleimide (300 mg, 3.1 mmol) to give 210 mg (57%) of
intermediate IIIc as a white solid. 1H NMR (DMSO-d6): 5 3.72-2.80 (m, 1H), 3.17-3.26 (m,
2H), 3.53 (m, 1H), 4.4 (m, 2H), 6.95-7.206 (m, 2H), 7.27 (d, 1H), 7.41-7.46 (m. 2H), 7.66-
7.75 (m, 2H), 10.69 (s, 1H), 11.33 (s, 1H). MS(ES"> m/e 407 (m*).
Step3. Compound IV-4
This compound was prepared by the same general procedure as compound IV-1 using
IIIc (160 mg, 0.4 mmol) and 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (228 mg, 1.0 mmol)
to give 158mg (100%) compound IV-4 as a yellow solid . ]H NMR (DMSO-d=): 5 434 (s,
2H), 7.36 (t, 1H), 7.62 (t, 1H), 7.73-7.82 (m, 2H), 7.98 (s, 1H), 8.52 (d, 1H), 8.93 (d, 1H),
11.18 (s, 1H), 12.18 (s, 1H). MS(ES): m/e402 (m - 1).
Example 8.
Compound IV-5
Step 1: Intermediate I-id (Y = CH;CH2, R2=R4=H, R6=H (2-(l-Hydroxy-1.2.3.4-
tetrahydronaphthyl)indole))
This compound was prepared by the same general procedure as 1-ia using indole (15 g,
132 mmol) and 1-tetralone (20 g, 139 mmol) to yield 18g (46%) of intermediate Id as a white
solid. 1H NMR (CDC13): 5 1.84-1.93 (m, 1H), 1.97-2.03 (m, 1H), 2.17-2.35 (m. 2H), 2.36 (s.
1H). 2.88-2.92 (, 2H). 6.10 (s, 1H), 7.07 (t, 1H), 7.13-7.19 (m 3H). 7.23-7.28 (m, 1H). 7.33-
7.36 (m, 2H), 7.51 (d, 1H), 8.42 (s, 1H).
Step 2: Intermediate lid (Y = CH2CH2, R2=R4=H, R6=H (2-[ 1-(3,4-Dihydro-
naphthyl)]indole))
To a solution of alcohol I-id (15 g, 57 mmol) in acetone (150 mL) was added 2N HCI
(3 mL). After stirring at room temperature for 1 h water was added to initiate precipitation of
a solid. The product was collected by filtration and dried to give 14 g (100%) of intermediate
Hd as a white solid. !H NMR (CDCI3): 6 2.39-2.46 (m 2H), 2.82-2.87 (m, 2H), 6.38 (t, 1H),
6.59 (s, 1H), 7.09-7.25 (m. 5H), 7.34-7.40 (m, 2H), 7.61 (d, 1H), 8.11 (s, 1H). MS (ES*) m/e
246 (M + 1).
Step 3: Intermediate Hid (Y - CH2CH2, R2=R4=H, R6=H)
A stirred mixture of diene lId (330 mg, 1.4 mmol) and maleimide was heated at 190
°C for 1 h. The mixture was cooled, dissolved in ethylacetate (50 mL) and washed repeatedly
with hot water to remove excess maleimide. The EtOAc layer was dried (MgSO4)
concentrated and the resulting solid dried under vacuum at 80 °C to give 425 mg (89%) of
Hid. MS (ES) m/e 341 (M - 1).
Step 4: Compound IV-5
To the imide intermediate Hid suspended in toluene (10 mL) was added 2,3-dichloro-
5,6-dicyano-l,4-benzoquinonc (160 mg, 0.7 mmol) in one portion followed by heating at 60-
65 °C for 16 h. The suspension was concentrated and the product purified by column
chromatography (silica gel, EtOAc:hexane; 1:1) to give 90 mg of a yellow solid. 1H NMR 5
2.81 (m, 2H). 3.16 (m, 2H), 7.27 (t. 1H), 7.40-7.54 (m, 4H), 7.67 (m, 1H), 8.12 (d, 1H). 8.88
(d, 1H), 11.10 (s. 1H), 11.85 (s, 1H). (DMSOd6, 300 MHz): 6 MS (ES) m/e 337 (M - 1).
Example 9
Compound IV-6
Step 1: Intermediate I-ie. (Y = CH2CH2, R2=5-OCH3, R4=H, R6=H (2-( 1-Hydroxy-1,2,3,4-
tetrahydronaphthyl)-5-methoxyindole))
Intermediate I-ie was prepared by the same general procedure as I-ia using 5-
methoxyindole (5.0g, 34 mmol) and 1-tetraione (5.3 g, 34 mmol) to yield 6.2g (62%) of
intermediate I-ie as a white solid. 1H NMR (CDC13): d 1.84-1.90 (m, 1H), 1.96-2.03 (m, 1H),
2.16-2.33 (m, 2H), 2.36 (s, 1H), 2.90 (m, 2H), 3.80 (s, 3H), 6.03 (s. 1H), 6.82 (m, 1H), 6.97 (s,
1H), 7.13-7.25 (m, 4H), 7.32 (d, 1H), 8.31 (s, 1H).
Step 2: Intermediate He (Y = CH2CH2, R2=5-OCH3, R4=H, R6=H (2-[l-(3,4-
Dihydronaphthyl)]-5-methoxyindole))
To a solution of alcohol I-ie (300mg, 1.0 mmol) in acetone (10 mL) was added 2N
HC1 (1 mL). After stirring at room temperature for 1 h, water was added to precipitate the
product which was collected by filtration and dried to give 200mg (73%) of lie as a red solid.
1H NMR (CDC13): 8 2.41-2.45 (m, 2H), 2.81-2.86 (m, 2H), 3.86 (s, 3H), 6.35 (m, 1H), 6.52
(s, 1H), 6.83 (m, 1H), 7.08 (s, 1H), 7.12-7.25 (m, 4H), 7.39 (m, 1H), 8.01 (s, 1H). MS (ES*)
m/e 276 (M + 1).
Step 3: Intermediate Hie. (Y - CH2CH2, R2=5-OCH3, R4=H, R6=H)
This compound was prepared using the same general procedure as Ilia using He (ISO
mg, 0.54 mmol) and maieimide (105mg. 1.1 mmol) to give 100 mg (50%) of Me as a white
solid. MS (ES*) m/e 373 (M + 1).
Step 4: Compound IV-6
This compound was prepared using the same general procedure as compound IV-1
using imide Hie from step 3 (80 mg, 0.22 mmol) and 2,3-dichloro-5,6-dicyano-l,4-
benzoquinone (103 mg, 0.45 mmol) in dioxane (3 mL) to give 75 mg (95%). *H NMR
(DMSO-d6): 8 2.82 (m, 2H), 3.2 (m. 2H), 3.84 (s. 3H), 7.15 (m. 1H), 7.36-7.59 (m. 3H). 7.57
(d, 1H), 8.11 (d, lH),8.46(s, 1H), 11.09 (s, 1H), 11.69(s, 1H). MS (ES) m/e 367 (M - 1).
Example 10
Compound IV-7
Step 1: Intermediate I-if (Y=CH2CH2, R:=H, R4=6-OCH3, R6=H (2-(l-Hydroxy-l,2,3,4-(6-
methoxy)tetrahydronaphthyl)-2-indolc))
Prepared by the same general procedure as intermediate I-ia using indole (7.0g. 59.8
mmol) and 6-methoxy-l-tetralone (11.6g g, 65.8 mmol) to yield 12.7 g (73%) of intermediate
I-if as a white solid. *H NMR (CDC13): 5 1.83-2.01 (m, 2H), 2.16-2.25 (m, 2H), 2.86 (m, 2H).
3.80 (s, 3H), 6.12 (s, 1H), 6.67-6.73 (m, 2H). 7.04-7.17 (m, 2H), 7.23 (m, 1H), 7.34 (d. 1H),
7.50 (d, 1H), 8.40 (bs, 1H).
Step 2: Intermediate Hf (Y = CH2CH2, R2=H, Rd=6*OCH3, R6=H (2-(6-Methoxy-(3,4-
dihydronaphthyl))-2-indole))
This compound was prepared using the same general procedure as Ha using
intermediate I-if (300 mg, 1.03 mmol) and 3 mL of 2N HC1 to give 280 mg (100%) of Ilf as a
white foam. lH NMR (CDCI3): 8 2.37-2.43 (m, 2H), 2.78-285 (m, 2H), 3.82 (s, 3H), 6.12 (s,
1H), 6.25 (m, 1H), 6.57 (s, IH), 6.70 (d, 1H), 6.79 (s, 1H), 7.09-7.18 (m. 2H), 7.33-7.35 (m,
2H), 7.61 (d, IH), 8.10 (bs, IH). MS (ES*) m/e 276 (M + 1).
Step 3: Intermediate IHf (Y - CH2CH2, R2=H, R4=6-OCH3, R6=H)
This compound was prepared using the same general procedure as Ilia using
intermediate Ilf (250 mg, 0.91 mmol) and maleimide (265 mg, 2.7 mmol) to give 225 mg
(67%) of IHf as a white foam. 1H NMR (CDC13): 8 1.60-1.72 (m, 2H), 2.70-2.9 (m, IH), 3.80 (s, 3H), 4.20 (m, IH), 4.30 (m, IH), 6.7 (s, IH), 6.9,(m, IH), 7.1-7.35 (m, 4H),
6.60 (s, IH), 6.80 (s, IH), 8.0 (d, IH). MS (ES) m/e 371 (M - 1).
Step 4: Compound IV-6
This compound was prepared using the same general procedure as compound IV-1
using imide IHf from step 3 (35 mg, 0.094 mmol) and 2,3-dichloro-5,6-dicyano-l,4-
benzoquinone (54 mg, 0.237 mmol) to give 31 mg (85%) of compound IV-6 as a yellow solid.
1H NMR (DMSO-ck): 6 2.80 (m, 2H). 3.2 (m, 2H). 3.83 (s, 3H), 7.03 (m. 2H). 7.27 (t. 1H),
7.50 (t, 1H), 7.66 (d, 1H), 8.06 (d, 1H), 8.87 (d, 1H), 11.05 (s, 1H), 11.76 (s. 1H). MS (ES~)
m/e 369 (M + 1), 391 (M + 23).
Example 11
Compound IV-8
Step 1: Intermediate I-ig (Y = CH2CH2, R-=6-OCH3, R4=5-(2-ethoxy)ethoxy), R6=H)
Prepared by the same general procedure as intermediate I-ia using 6-methoxyindole
(1.5 g, 9.8 mmol) and 5-[(2-ethoxy)ethoxy]-1-tetralone (2.35 g, 10.0 mmol) to yield 1.8 g
(47%) of intermediate I-ig as a white solid. 1H NMR (CDCI3): 6 1.23 (t. 3H), 1.83 (m. 1H),
1.94 (m, 1H), 2.10-2.32 (m, 4H), 2.74-2.83 (m, 2H), 3.64 (q, 2H), 3.83 (s, 3H), 4.15 (m, 2H),
6.02 (m, 1H), 6.72-6.80 (m, 3H), 7.00 (d, 1H), 7.12 (d, 1H), 7.25 (s, 1H), 7.36 (d. 1H). 8.41
(bs, 1H).
Step 2: Intermediate Hg (Y - CH2CH2 R2=6-OCH3, R4=5-(2-ethoxy)ethoxy), R6=H)
This compound was prepared using the same general procedure as Ha using
intermediate Ig (200 mg, C.52 mmol) and 2 mL of 2N HC1 to give 175 mg (95%) of
intermediate Hg as a white powder. 1H NMR (CDClj): 8 1.25 (t, 3H), 2.32-2.40 (m, 2H), 2.85
(m, 2H), 3.65 (q, 2H), 3.81-3.85 (m, 2H), 3.82 (s, 3H), 4.15 (m, 2H), 6.33 (m, 1H), 6.49 (s,
1H), 6.76-686 (m, 3H), 7.02-7.15 (m, 2H), 7.45 (m, 1H), 7.97 (bs, 1H). MS (ES*) m/e 364 (M
+ 1).
Step 3: Intermediate Illg. (Y = CH2CH2, R2~6-OCHj, R4=5-(2-ethoxy)ethoxy), R6=H)
This compound was prepared using the same general procedure as intermediate Ilia
using example Ilg (100 mg, 0.29 mmol) and maleimide (55 mg, 0.58 mmol) to give 55 mg
(41%) of Illg as a white foam. 1 MS (ES) m/e 459 (M - 1).
Step 4: Compound IV-8
This compound was prepared using the same general procedure as compound IV-1
using imide Illg from step 3 (SO mg, 0.11 mmol) and 23-dichloro-5,6-dicyano-l ,4-
benzoquinone (54 mg, 0.24 mmol) to give 45 mg (90%) of compound IV-8. 1H NMR (DMSO-
d6): 6 1.13 (t, 3H), 2.77 (m, 2H), 3.2 (m, 2H), 3.51 (q, 2H), 3.74 (m, 2H), 3.84 (s, 3H), 4.17
**(m, 2H), 6.88 (m, 1H), 7.10-7.16 (m. 2H), 7.42 (m, 1H). 7.72 (m, 1H), 8.7 (d, 1H). 1.04 (s,
1H), 11.65 (s, 1H). MS (ES) m/e 455 (M - 1).
Example 12
Compound IV-9
To compound IV-4 (50 mg, 0.15 mmol) in DMF (2 mL) was added NBS (31 mg, 0.18 mmol)
followed by stirring at room temperature for 2 h. The solution was concentrated at reduced
pressure. The residue was triturated with MeOH (3 mL) and the solid collected and washed
with MeOH to give 55 mg (89%) of compound IV-9 as a yellow solid, mp > 300 °C; 1H NMR
(DMSO-d6, 300 MHz): 8 2.82 (m. 2H), 3.12 (m, 2H), 7.43-7.53 (m, 4H), 7.68 (s, 1H). 8.14 (d,
1H), 9.06 (s, 1H), 11.24 (s, 1H), 12.05 (s, 1H). MS (ES) m/e 416 (M - 1).
Example 13
Compound X-2
Step 1: A mixture of intermediate H-d (2-[ 1-(3,4-dihydronaphthyl)]indole) (1.0 g, 4.1
mmol) and ethyl cis-P-cyanoacrylate (2.0 g, 16.0 mmol) was heated at 190 °C with stirring for
1 h. While cooling to room temperature, MeOH (10 mL) was added and stirring was
continued for 0.5 h. The solid which separated was collected to give 1.2 g of (79%) as a white
solid. The solid was a 1:1 mixture of 2 isomers and showed a mp > 300 °C, MS (ES*) m/e 371
(M +1). This intermediate was used directly in the next step.
Step 2: To the mixture of isomers from step 1 (500 mg, 1.35 mmol) in toluene (50
mL) was added solid 2,3-dichloro-5,6-dicyano-I,4-benzoquinone (678 mg, 3.0 mmol) in one
portion. The mixture was heated to 60-65 °C for 18 h. The reaction was concentrated at
reduced pressure. The resulting material was dissolved in EtOAc (75 mL), washed with 2N
NaOH (2x 50 mL), water (2x 50 mL), saturated NaCl solution (2x 50 mL), dried (MgSO4) and
concentrated to give 480 mg (97%) of the product as a 1:1 mixture of 3-cyano and 4-cyano
isomers. This intermediate was used directly in the next step.
Step 3: A 1:1 mixture of isomers (4S0 mg, 1.2 mmol) from step 3 in DMF:MeOH
(1:1,10 mL) and 1 spatula full of RaNi was hydrogenated at 55 psi for 18 h. The catalyst was
removed by filtration and the solvent removed at reduced pressure. The solid was triturated
with ether to give 350 mg (90%) of a 1:1 mixture of lactam isomers IX-2: X-2.
Step 4: Compound X-2
To the lactam isomers from step 3 (300 mg, 0.93 mmol) in DMF (10 mL) was added
triethylamine (190 mg, 0.25 mL)and t-Butyldimethylsilyl chloride (285 mg, 1.9 mmol). The
solution was stirred lh at room temperature at which time TLC (silica gel, etherhexane; 1:1)
showed the reaction to be ca 50% complete. The DMF was removed at reduced pressure and
the residue dissolved in EtOAc washed with water and NaCl solution and dried (MgSCM. The
solvent was removed and the resulting solid triturated with ether. Compound X-2 was
collected and dried: mp > 300 °C 1H NMR (DMSO-d6, 300 MHz): 8 2.8 (b, 4H), 4.5 (s, 2H).
7.21 (t. 1H), 7.37-7.51 (m, 4H). 7.65 (d, J = 8 Hz, 1H), 8.23 (d, J = 7.6 Hz. 1H), 8.63 (s, 1H),
9.14 (d, J = 7.7 Hz), 11.48 (s, 1H). MS (ES) m/e 371 (M + 1).
Example 14
Compound IX-2
The ether solution from example 13 step 4 was concentrated and THF added followed
by TBAF (2 mL, 1 M in THF). The solution was stirring at room temperature for 4 h, after
which the solvent was removed and the resulting solid triturated with water, collected. The
product was washed with ether and dried (60 °C, 1 mm) to give compound IX-2 as a white
solid, mp > 300 °C. 1H NMR (DMSO-d6, 300 MHz): 6 2.77-2.81 (m, 2H), 3.49-3.52 (m, 2H),
4.83 (s, 2H), 7.23-7.36 (m, 2H), 7.42-7.51 (m,3H), 7.70 (d, 1H), 7.78 (d, 1H), 8.15 (d, 1H),
8.46(s, 1H), 11.61 (s, 1H). MS (ES)m/e371 (M + 1).
Example 15
Compound XIII
Step 1: Intermediate XI (R2=R4=R6=H)
To a solution of 7-azaindole (5.2 g, 44 mmol) in dry THF (120 mL) cooled to -78 °C
under a nitrogen atmosphere was add BuLi (46.2 mmol, 18.5 mL of 2.5 M solution in
hexanes) slowly. Following stirring for 30 min, CC>2(g) was passed through the solution for
10 min after which the clear solution was concentrated to ca two-thirds volume at reduced
pressure. The volume of THF was brought to about 125 mL and cooled to -78 °C. t-BuLi (44
mmol, 26 mL of 1.7 M solution in hexancs) was added slowly while maintaining the
temperature below -68 °C followed by stirring for 2 h at -78 °C. To this orange solution was
added 1 -tetralone (6.8 g, 46.2 mmoi) in THF (10 mL) dropwise. The mixture stirred for 1.5 h,
then poured into 2N HC1 (150 mL) extracted with EtOAc ( Ix 150 mL) and the HC1 layer
stirred for 18 h. The HCI solution was made basic with 2N NaOH and the precipitate that
formed was collected to give 6.7 g (63%) of intermediate XIII. ]H NMR (DMSO-d6): 5 2.35
(m, 2H). 2.74 (m, 2H), 6.41 (s, 1H), 6.52 (m, 1H). 7.02 (m. 1H), 7.17-7.24 (m. 3H). 7.35 (m,
1H), 7.88 (m, 1H). 8.15 (m, 1H), 11.76 (s, IH). MS (ES*) m/e 247 (M + 1).
Step 2: Intermediate XII (R-=R4=R6=H)
A mixture of intermediate XI (100 mg, 0.41 mmol) and maleimide 79 mg, 0.81 mmol)
in xylenes (8 mL) was maintained at reflux 14 h. The reaction was cooled to room
temperature and the solid which separated was collected, washed with ether and dried to give
90 mg (64%) of compound XII as a tan solid; MS (ES") m/e 341 (M - 1).
Step 3: Compound XIII
To a suspension of XII (35 mg, 0.1 mmol) in dioxane (3.5 mL) was added solid DDQ
(45 mg, 0.2 mmol). The reaction was stirred at room temperature for 12 h. Methanol (5 mL)
was added and the mixture cooled in a freezer. A light tan precipitate was collected and dried
to give 20 mg (58%) of compound XIII. 1H NMR (DMSO-d6): 6 2.88 (m, 2H), 3.2 (m, 2H),
7.39-7.48 (m, 4H), 8.17 (d, IH), 8.62 (d, IH), 9.14 (d, IH), 11.25 (s, IH), 12.48 (s, IH).
MS(ES): m/e 338 (m - 1).
Example 16
Compound III-2
Step 1: Intermediate Hg (Y = S, R2=R4=R6=H (2-(3-Benzothieno)indole))
To a solution of 1 -carboxy-2-tributylstannylindole (9.5 g, 21.0 mmol) and 3-
bromobenzothiaphene (3.0 g. 14.1 mmol) in EtOH (75 mL) was added
dichlorobis(bistriphenylphosphine) palladium(H) (771 mg, 1.1 mmol). The mixture was
stirred at reflux under nitrogen for 16 h, cooled to room temperature and concentrated at
reduced pressure. The resulting dark oil was rinsed with an ether-hexane (1:1) solution and
decanted (2x) leaving a brown solid. This solid was recrystallized from hot MeOH to give
3.2g (65%) of a tan solid. 1 H NMR (DMSO-d6): 6 6.94 (s. 1H), 7.04 (t, 1H). 7.15 (t. 1H).
7.43-7.62 (m, 4H), 8.04 (s, 1H), 8.09 (d. 1H), 8.29 (d, 1H), 11.55 (s, 1H). MS(ES1): m/e 250
(m+1).
Step 2: Compound II1-2
2-(3-Benzothicno)indole (Ilg, step 1) (100 mg, 0.4 mmol), maleimide (77 mg, 0.8
mmol) and trifluoroacetic acid (ca 10 drops) in toluene (10 mL) was maintained at reflux 12 h.
The reaction was cooled to room temperature and the solid collected, and washed with toluene
and ether to give 75 mg (54%) of compound III-2 as a tan solid. 1H NMR (DMSO-d6): 5 3.73
(m, 1H), 4.47 (m, 1H), 4.90 (m, 1H). 4.96 (m. 1H), 6.96-7.06 (m, 2H), 7.17-7.30 (m, 3H), 7.68
(m, 1H), 7.77 (m, 1H), 10.45 (s, 1H), 11.38 (s, 1H). MS(ES): m/e 345 (m - 1).
Example 17
Compound IV-10
To a suspension of compound III-2 (IHg) (30 mg, 0.09 mmol) in dioxane (4 mL) was
added solid DDQ (60 mg, 0.26 mmol). After heating at 65 °C for 12 h, the mixture was
concentrated, the product triturated with methanol, collected and dried to give 24 mg (78%) of
IV-10. 1H NMR (DMSO-ds): 5 7.38 (t, 1H), 7.56-7.82 (m, 4H), 8.23 (d, 1H), 8.92 (d, 1H),
9.00 (d, 1H), 11.32 (s, 1H), 12.37 (s, 1H). MS(ES): m/e 341 (m - 1).
Example 18
Compound XVII
Step 1: Intermediate XIV (R:=H)
This compound was prepared by the same general procedure as intermediate I-ia
starting with indole (3.5 g, 29.9 mmol) and 4-keto-4.5,6,7-tetrahydrothianaphthlene (5.0 g,
32.9 mmol) to give 6.5 g (81%) of XIV as a white solid. 1H NMR (CDC13): 6 1.93-2.09 (m,
2H), 2.16-2.24 (m, 2H), 2.33 (s, 1H), 2.86-2.93 (m, 2H), 6.16 (s, 1H), 6.87 (d, 1H), 7.05-7.18
(m, 3H), 7.35 (d, 1H), 7.52 (d, 1H), 8.44 (s, 1H).
Step2. Intermediate XV (R2=H)
This compound was prepared by the same general procedure as I la using XIV (200
mg, 0.74 mmol) to give the diene XV as a white unstable glass. 1H NMR (CDC13): 5 2.52-
2.59 (m. 2H). 2.89-2.95 (m. 2H), 6.13 (m, 1H), 6.61 (s, 1H), 7.08-7.22 (m. 4H). 7.35 (d. 1H).
7.60 (d, 1H). 8.14 (s, 1 H).MS (ES*) m/e 252 (M + 1).
Step 3: Compound XVI (R2-H)
This compound was prepared by the same general procedure as Ilia using diene XV
(250 mg, 1.0 mmol) and malcimide (194 mg, 2.0 mmol) to give 225 mg (66%) from MeOH-
ether. MS (ES*) m/e 347 (M - 1).
Step 4: Compound XVII
A mixture of XVI (70 mg, 0.2 mmol) and DDQ (136 mg, 0.6 mmol) was heated at 65
°C for 40 h. The mixture was concentrated and the product (Rf 0.4) isolated by column
chromatography (silica gel, EtOAc: hex; 2:1) as a yellow solid. *H NMR (DMSO-d6- 300
MHz): 6 7.43 (t, IH), 7.63 (t, 1H), 7.96 (d, 1H), 8.33 (d, 1H), 8.43 (d, 1H), 8.96 (d. 1H). 9.07
(d, IH), 9.13 (d. IH), 11.25 (s, IH). 12.21 (s, IH). MS (ES~) m/e 341 (M - 1).
Example 19
Compound IV-11
Step 1: Intermediate I-ih (Y-CHjO, R2=R4=R6=H)
This compound was prepared by the same general procedure as I-ia using indole (7.0
g, 35 mmol) and 4-chromanone (9.74 g, 65.8 mmol) to give 12.5 g (79%) as a crude oil. A
sample was recrystallized from ether-hexane. 1H NMR (CDCI3): 6 2.30-2.49 (m, s. 3H), 4.26-
4.43 (m, 2H), 6.25 (s, IH), 6.86-6.93 (m, 2H), 7.07-7.27 (m, 3H), 7.35 (d, IH), 7.54 (d, IH),
8.39(s, IH).
Step 2: Intermediate Hh (Y=CH2O, R2-R4=R6=H)
The oil from step I was dissolved in acetone (125 mL) and added 2N HCI (20 mL)
followed by stirring 1 h at rt. The precipitate was collected washed with water and dried to
give 11 g (76% 2 steps). 1H NMR (CDC13): 6 4.82 (d, 2H), 6.06 (m, 1H), 6.64 (s, IH), 6.93-
6.97 (m, 2H), 7.11-7.25 (m, 3H), 7.36-7.43 (m, 2H). 7.62 (d, IH), 8.13 (s, IH). MS (ES~) m/e
248 (m + 1).
Step 3: Intermediate IHh (Y=CH2O, R2=R4=R6=H)
This compound was prepared by the same general procedure as Ilia using diene Ilh
(300 mg, 1.2 mmol) and maieimide (235 mg, 2.4 mmol). After cooling to room temperature
the residue was dissolved in EtOAc (50 mL) and washed with hot water (3 x 50 mL) dried
(MgSO Step 4 Compound IV-11
The product from step 3 (Ilh) in toluene (10 mL) was added DDQ (684 mg, 3.0 mmol)
and heated at 65 °C for 16 h. The mixture was cooled to room temperature and the solid
precipitate collected, washed with MeOH and dried to give 290 mg (71% 2 steps) of crude
solid. The product was purified by column chromatography (silica gel, toluene: THF; 10%-
30% THF). 1H NMR (DMSO-d6, 300 MHz): 5 7.24 (m, 1H), 7.33-7-38 (m. 2H), 7.59 (m,
1H), 7.62 (m, 2H), 7.80 (m, 1H), 8.38 (d, 1H), 8.98 (d, 1H), 11.30 (s, 1H), 12.08 (s. 1H). MS
(ES+)m/e339(M-l).
Example 20
Compound IX-3
Step I: A mixture of diene Ilh (880 mg, 3.6 mmol) and ethyl cis-0-cyanoacrylate (1.8
g, 14.4 mmol) was heated at 190 °C with stirring for 1 h. Methanol (IS mL) was added while
hot, followed by stirring at room temperature for 3 h. The solid which separated was collected
and dried under vacuum to give 550 mg (41%) of the 4-CN isomcr (intermediate V, Y =
CH2O, R2=R*=H) as a yellow solid. 1H NMR (DMSO-d6, 300 MHz): 6 1.33 (t, 3H), 3.11-
3.17 (m, 1H), 3.81-3.84 (m, 1H), 4.00-4.08 (m, 1H), 4.31-4.41 (m, 4H), 4.77 (d, 1H), 6.87 (d,
1H), 7.04-7.15 (m, 3H), 7.23 (t, 1H), 7.42 (d, 1H), 7.57 (d, 1H), 7.64 (d, 1H), 10.69 (s, 1H).
MS (ES*) m/e 373 (M + 1). The MeOH layer was reduced under pressure to about half
volume and ether was added to initiate precipitation. After cooling at freezer temperature
overnight, 325 mg of a solid was isolated as a 1:1 mixture of isomers V (Y = CHjO,
r2=r==H) and VI (Y - CH2O, R2=R4=H) by 1H NMR.
Step 2: The 4-CN isomcr from step 1 (500 mg, 1.3 mmol) and DDQ (740 mg, 3.3
mmol) in toluene was heated for 18 h at 60 °C. The solution was concentrated and the residue
dissolved in EtOAc, washed with 2N NaOH (2 x), water, brine and dried (MgSO4). After
concentrating the solvent, the product was triturated with MeOH to give 320 mg (67%). 1H
NMR (DMSO-d6, 300 MHz): 5 1.43 (t. 3H). 4.48 (q. 2H), 5.37 (s. 2H). 7.20 (d. 1H). 7.36-
7.49 )m. 3H), 7.65 (t, 1H), 7.81 (d. 1H). 8.25 (d. 1H). 8.58 (d, 1H.I. 12.12 (s. 1H). MS (ES~)
m/e 369 (M + 1).
Step 3: Compound IX-3
The cyano-ester product from step 2 (300 mg, 0.82 mmol) in DMFrMeOH (20 mL,
1:1) was added a spatula full of RaNi and hydrogenated at 55 psi on a Par apparatus for 14 h.
The solution was filter through celite and concentrated. The product was recrystallized from
MeOH to give 200 mg (75%) as a white solid. 1H NMR (DMSO-d6- 300 MHz): 5 4.90 (s,
2H). 5.75 (s, 2H), 7.15 (d, 1H), 7.29-7.38 (m, 3H), 7.52 (t, 1H), 7.75 (d. 1H). 8.02 (d. 1H).
8.22 (d, 1H), 8.62 (s, 1H). 11.73 (s. 1H). MS (ES~) m/e 326 (M=).
Example 21
Compound X-3
The mixture of isomers from step 1 in Example 20 (330 mg, 0.9 mmol) was oxidized
using DDQ (607 mg, 2.7 mmol) using the same general procedure as example 20, step 3, to
give 300 mg (90%). The isomers were dissolved in DMF:MeOH (1:1,30 mL) and
hydrogenated by the same general procedure as example 20 step 4 to give 175 mg. Compound
X-3 was obtained from MeOH. 1H NMR (DMSO-d6, 300 MHz): 5 4.58 (s, 2H)7 5.25 (s, 2H),
7.15-7.50 (m, 6H), 7.70 (d, 1H). 8.30 (d, 1H), 8.60 (s, 1H), 9.20 (d, 1H), 11.60 (s, 1H). MS
(ES~) m/e 326 (M*).
Example 22
Compound X-4
Step 1: Intermediate XVIII (R:=R4=H)
NaH (325 mg, 8.2 mmol. 60% oil dispersion) was added to a solution of diene Hd (1.0
g, 4.1 mmol) in dry DMF (40 mL). After stirring at room temperature 1 h., mesyl 2-
benzyloxyethanol was added (1.9 g, 8.2 mmol). The reaction was heated to 70 °C in an oil
bath for 18 h, cooled to room temperature and poured into water (100 mL). The product was
extracted with EtOAc (2 x 100 mL), followed by washing with water (2 x 100 mL) sodium
chloride solution (2 x 100 mL) and dried (MgSO4). The solution was concentrated at reduced
pressure and the resulting product was triturated with ether: hexane solution (1:1) to give 1.45
g (95%) of a tan solid. 1H NMR (CDCh,): 6 2.38 2H), 4.31 (s, 2H). 6.20 (L 1H), 647 (s, 1H), 6.74 (d, 1H), 7.02 (t, 1H), 7.10-7.25 (m. 9H). 7.38
(d, 1H). 7.62 (d, 1H). MS (ES*) m/e 380 (m + 1).
Step 2: Intermediate XIX b(R:=R4=H)
Oxalyl chloride (0.15 mL, 1.7 mmol) was added slowly to the product from step 1
(650 mg, 1.7 mmol) in CHjCli (25 mL) at ice bath temperature. The solution was stirred for
0.5 h, then anhydrous MeOH (2 mL) was added followed by stirring at room temperature for
0.5 h. The solution was concentrated, dissolved in EtOAc and washed with 2N NaOH (2x),
water (2x), sodium chloride solution (2x) dried (MgSO4) and concentrated to a dark oil.
Purification by column chromatography (silica gel, EtOAc: hex: 1:1) gave 0.5 g (63%) as an
oil. 1H NMR (CDCh,): 8 2.35-2.42 (m. 2H), 2.83-2.89 (m, 2H). 3.23 (s, 3H). 3.51-3.68 (m,
2H), 3.96-4.06 (m, 1H), 4.10-4.24 (m, 1H), 4.31 (s, 2H),6.11 (m, 1H), 6.70 (d, 1H), 7.04-7.09
(m, 2H), 7.18 (m, 2H), 7.24 (m. 4H), 7.32-7.39 (m, 2H), 7.40 (m, 1H), 8.45 (m, 1H). MS (ESI
m/e 466 (m + 1).
Step 3: Intermediate XX (R2=R4=H)
A mixture of diethyl cyanomethylphosphonate, intermediate XIX (160 mg, 0.34
mmol), and Na2CC>3 (43 mg, 0.41 mmol) in dry THF (25 mL) was stirred at reflux for 4 h.
The reaction was cooled to room temperature and concentrated. The residue was dissolved in
EtOAc (50 mL), washed 2x with 2N NaOH, water, brine, dried (MgSO4) and concentrated to
give 150 mg (90%) as a yellowish solid. 1H NMR (CDC13,): 5 2.40 (m, 2H), 2.80-2.87 (m,
2H), 3.20 (s, 3H), 3.5-3.65 (m, 2H), 2.95-4.05 (m, 1H), 4.15-4.25 (m, 1H), 4.3 (s, 2H), 5.95 (s,
1H), 6.05 (m, 1H), 6.65 (d, 1H), 7.05-7.1 (m, 2H), 7.18 (m, 2H), 7.2-7.4 (m, 6H), 7.45 (m,
1H), 7.7 (m, 1H). IR cm1 2240 (CN). MS (ES+) m/e 489 (m + 1).
Step 4: Intermediate XXI (R2=R4-H)
Intermediate XX (500 mg, 1.1 mmol), chloronil (270 mg, 1.2 mmol) and palladium
acetate (240 mg, 1.1 mmol) in dichlorobenzene (40 mL) was stirred at reflux under nitrogen
24 h. The solution was concentrated, the reside dissolved in EtOAc and extracted with 2M
Na2CO3 solution (3x) and dried (MgSO4). The product was purified by column
chromatography (Rf 0.5, silica gel. EtOAc: hexane: 1:1). MS (ES~) me 487 (m -*- 1). 509 (m -
23).
Step 5: Compound X-4
The product from step 4 in DMF-MeOH (10 mL + 5 mL) was added a spatula full of
RaNi, and hydrogenated on a Parr Apparatus for 14 h. The solution was filtered to remove
catalyst then concentrated at reduced pressure. The residue was dissolved in DMF-MeOH
(1:1, 15 mL) and PdfOHfe (50 mg. 20%/C) was added, and hydrogenated on a Parr Apparatus
for 12 h. The solution was filtered and concentrated at reduced pressure. The product was
triturated with Et2O-hexane and collected to give IX-4. 1H NMR (CDC13,): 5 2.95-3.0 (m,
4H), 4.20 (m, 1H), 4.4-4.5 (b, 6H), 7.21 (m. 1H), 7.28-7.46 (m, 4H), 7.57 (d, 1H). 7.66 (d,
1H), 8.60 (s, 1H), 9.18 (d, 1H). MS (ES*) m/e 369 (m + 1), 391 (m - 23).
Additional compounds IV-12 to IV-44, IX-4, IX-5. X-5, and X-6. and were prepared
by the methods consistent with Examples 1 to 22. These compounds as well as those set forth
in the foregoing examples may be further understood by reference to Tables 1 -4, presented for
illustrative purposes, wherein each entry corresponds to the accompanying structure.
Utility
The isomeric fused pyrrolocarbazoles and isoindolones of the present invention are
useful, inter alia, as therapeutic agents. Particularly, the compounds are useful for kinase
inhibition. The isomeric fused pyrrolocarbazoles and isoindolones have been shown to inhibit,
for example, one or more of trk kinase, platelet derived growth factor receptor (PDGFR)
kinasc. vascular endothelial growth factor receptor (VEGFR) kinase. or NGF-stimulated trk
phosphorylation.
The properties of the compounds of the present invention are beneficial in therapeutic
settings. The activities of the fused pyrrolocarbazoles and isoindolones toward certain
enzymes can be exploited to combat the deleterious consequences of these enzymes.
Particularly, inhibition of the Vascular Endothelial Growth Factor Receptor (VEGFR) implies
utility in, for example, diseases where angiogenesis plays important roles, such as cancer of
solid tumors, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, as well as
other ocular diseases and cancers. Inhibition of irk implies utility in, for example, diseases of
the prostate such as prostate cancer and benign prostate hyperplasia, and treatment of
inflammatory pain. Inhibition of the Platelet Derived Growth Factor Receptor (PDGFR)
implies utility in. for example, various forms of neoplasia. rheumatoid arthritis, pulmonary1
fibrosis, myelofibrosis. abnormal wound healing, diseases with cardiovascular end points,
such as atherosclerosis, rcstenosis, post-angioplasty restenosis, and the like.
The activities of isomeric fused pyrrolocarbazoles and isoindolones have also been
shown to have positive effects on the function and survival of trophic factor responsive cells
by promoting the survival of neurons. With respect to the survival of a cholinergic neuron, for
example, the compound may preserve the survival of a cholinergic neuronal population at risk
of dying (due to, e.g., injury, a disease condition, a degenerative condition or natural
progression) when compared to a cholinergic neuronal population not presented with such
compound, if the treated population has a comparatively greater period of functionality than
the non-treated population.
A variety of neurological disorders are characterized by neuronal cells which are
dying, injured, functionally compromised, undergoing axonal degeneration, at risk of dying,
etc. These disorders include, but are not limited to, Alzheimer1s disease; motor neuron
disorders (e.g. amyotrophic lateral sclerosis); Parkinson1s disease; cerebrovascular disorders
(e.g., stroke, ischaemia); Huntingdon1s disease; AIDS dementia; epilepsy; multiple sclerosis;
peripheral neuropathies (e.g., those affecting DRG neurons in chemotherapy-associated
peripheral neuropathy) including diabetic neuropathy; disorders induced by excitatory amino
acids; and disorders associated with concussive or penetrating injuries of the brain or spinal
cord.
The compounds are not only useful for enhancing trophic factor-induced activities of
trophic responsive cells, e.g., cholinergic neurons, but also may function as survival promoting
agents for other neuronal cell types, e.g., dopaminergic or glutamatergic. Growth factor may
regulate survival of neurons by signaling cascades downstream of the small GTP binding
proteins ras. rac, and cdc42 (Denhardt, D.T.. Biochem. J., 1996, 318, 729). Specifically,
activation of ras leads to phosphorylation and activation of extracellular receptor-activated
kinase (ERR), which has been linked to biological growth and differentiation processes.
Stimulation of rac/cdc42 leads to an increase in activation of JNK and p38, responses
that are associated with stress, apoptosis, and inflammation. Although growth factor
responses are primarily via the ERK pathway, affecting these latter processes may lead to
alternative mechanisms of neuronal survival which may mimic growth factor enhancing
survival properties (Xia et al., Science, 1995, 270, 1326). The compounds may also function
as survival promoting agents for neuronal and non-neuronal cells by mechanisms related to.
but also distinct from, growth factor mediated survival, for example, inhibition of the JNK and
p38 MAPK pathways which may lead to survival by inhibition of apoptotic cell death
processes.
The present compounds are also useful in the treatment of disorders associated with
decreased ChAT activity or the death, injury to spinal cord motoneurons, and also have utility
in, for example, diseases associated with apoptotic cell death of the central and peripheral
nervous system, immune system and in inflammatory diseases. ChAT catalyzes the synthesis
of the neurotransmitter acetylcholine, and it is considered an enzymatic marker for a
functional cholinergic neuron. A functional neuron is also capable of survival. Neuron
survival is assayed by quamitation of the specific uptake and enzymatic conversion of a dye
(e.g., calcein AM) by living neurons. The compounds described herein may also find utility in
the treatment of disease states involving malignant cell proliferation, such as many cancers.
Because of their varied utilities, the properties of isomeric fused pyrrolocarbazoles and
isoindolones may be exploited in other settings, such as research. For example, the
compounds can be used in the development of in vitro models of neuronal cell survival,
function, identification, or for the screening of other synthetic compounds which have
activities similar to that of the of isomeric fused pyrrolocarbazole and isoindolone compounds.
Thus, the compounds provided by this invention are useful as standard or reference
compounds for use in tests or assays for determining the activity of an agent in a
pharmaceutical research program.
The compounds can also be utilized to investigate, define and determine molecular
targets associated with functional responses. For example, by radiolabelling an isomeric fused
pyrrolocarbazole or isoindolone compound associated with a specific cellular function (e.g.,
mitogenesis), the target entity to which the derivative binds can be identified, isolated, and
purified for characterization. By way of further illustration, compounds may be used in the
development of assays and models for further enhancement of the understanding of the roles
that inhibition of serine/threonine or tyrosine protein kinase (e.g., PK.C, trk tyrosine kinase)
play in the mechanistic aspects of the associated disorders and diseases. Thus, the compounds
of the present invention are useful as diagnostic reagents in diagnostic assays, such as the
assays described herein.
The inhibition of enzymatic activity by the isomeric fused pyrrolocarbazole and
isoindolone compounds of the present invention can be determined using, for example, the
following assays:
1. Vascular Endothclial Growth Factor Receptor (VEGFR) kinase inhibition assay;
2. trk A Tyrosine Kinase Activity inhibition assay;
3. PKC activity inhibition assay; and
4. Platelet Derived Growth Factor Receptor (PDGFR) inhibition assay.
Descriptions of these assays follow, but results obtained therein are not to be construed
as limiting the scope of the disclosure. For convenience, certain abbreviations are used to
delineate the results which are defined in the body of the text. Others are defined as follows:
"ug" for microgram, "mg" for milligram, "g" for gram, "uL" for microliter, "mL" for
milliliter, "L" for liter, "nM" for nanomolar, "uM" for micromolar, "mM" for millimolar,
"M" for molar and "nm" for nanometer, "BSA" for benzene sulfonic acid, "ATP" for
adenosine triphosphate, and "EGTA" for I,2-di(2-aminoethoxy)ethane-N,N,N\N1-tetraac€tic
acid.
Inhibition of trkA Tyrosine Kinase Activity
Selected isomeric fused pyrrolocarbazole and isoindolone compounds were tested for
their ability to inhibit the kinase activity of baculovirus-expressed human trkA cytoplasmic
domain using an ELISA-based assay as previously described (Angeles et al.. Anal. Biochem.
236: 49-55. 1996). Briefly, the 96-well microtiter plate was coated with substrate solution
(recombinant human phospholipase C- yl/glutathione S-transferase fusion protein (Rotin et
al., EMBO J., 11: 559-567, 1992). Inhibition studies were performed in 100 u.1 assay mixtures
containing 50 mM Hepes. pH 7.4,40u.M ATP, 10 mM MnCl;. 0.1% BSA. 2% DMSO. and
various concentrations of inhibitor. The reaction was initiated by addition of trkA kinase and
allowed to proceed for 15 minutes at 37°C. An antibody to phosphotyrosine (UBI) was then
added, followed by a secondary enzyme-conjugated antibody, alkaline phosphatase-labelled
goat anti-mouse IgG (Bio-Rad). The activity of the bound enzyme was measured via an
amplified detection system (Gibco-BRL). Inhibition data were analyzed using the sigmoidal
dose-response (variable slope) equation in GraphPad Prism. The concentration that resulted in
50% inhibition of kinase activity is referred to as "IC50". The results are summarized in Table
Inhibition of Vascular Endotheiial Growth Factor Receptor Kinase Activity
Isomeric fused pyrrolocarbazole and isoindolone compounds were examined for their
inhibitory effects on the kinase activity of baculovirus-expresscd VEGF receptor (human flk-
1, KDR, VEGFR2) kinase domain using the procedure described for the trkA kinase ELISA
assay described above. The kinase reaction mixture, consisting of 50 mM Hepes, pH 7.4, 40
uM ATP, 10 mM MnCl2, 0.1% BSA, 2% DMSO, and various concentrations of inhibitor, was
transferred to PLC-y/GST-coated plates. VEGFR kinase was added and the reaction was
allowed to proceed for 15 min.at 37°C. Detection of phosphorylated product was
accomplished by addition of anti-phosphotyrosine antibody (UBI). A secondary enzyme-
conjugated antibody was delivered to capture the antibody-phosphorylated PLC-y/GST
complex. The activity of the bound enzyme was measured via an amplified detection system
(Gibco-BRL). Inhibition data were analyzed using the sigmoidal dose-response (variable
slope) equation in GraphPad Prism. Results are summarized in Table 6.
Inhibition of Platelet Derived Growth Factor Receptor Kinase Activity
Isomeric fused pyrrolocarbazole and isoindolone compounds were examined for their
inhibitory effects on the kinase activity of baculovirus-expressed PDGFp receptor kinase
domain using the trkA kinase ELISA described above. Assays were performed in substrate
(PLC-y/GST)-coated 96-weil microtiter plates. Each 100-ul reaction mixture contained 50
mM HEPES, pH 7.4, 20u,M ATP, 10 mM MnCl:, 0.1% BSA. 2% DMSO. and various
concentrations of inhibitor. The reaction was initiated by addition of prephosphorylated
recombinant human enzyme (10 ng/ml PDGFRP) and allowed to proceed for 15 minutes at 37
°C. The prephosphorylated enzyme was prepared prior to use by incubation of the kinase in
buffer containing 20 uM ATP and 10 mM MnCl: for 1 hour at 4 C. Detection of
phosphorylated product was done by adding horseradish peroxidase (HRP)-conjugated anti-
phosphotyrosine antibody (UBI). The HRP substrate solution containing 3, 31-5, 5-
tetramethylbenzidine and hydrogen peroxide was later added and the plates were incubated for
10 minutes at room temperature. The reaction was quenched with acid and the resulting
absorbance was read at 450 nm using a Microplate Bio-kinetics Reader (Bio-Tek Instrument
EL 312c). Inhibition data were analyzed using the sigmoidal dose-response (variable slope)
equation in GraphPad Prism. The results are summarized in Table 7.
Dosage and Formulation
For therapeutic purposes, the compounds of the present invention can be administered
by any means that results in the contact of the active agent with the agent1s site of action in the
body of a mammal. The compounds may be administered by any conventional means
available for use in conjunction with Pharmaceuticals, either as individual therapeutic agents
or in a combination of therapeutic agents. They are preferably administered as the sole active
agent in a pharmaceutical composition, but alternatively, they can be used in combination with
other active ingredients, e.g., other growth factors which facilitate neuronal survival or axonal
regeneration in diseases or disorders. The compounds are preferably combined with a
pharmaceutical carrier selected on the basis of the chosen route of administration and standard
pharmaceutical practice.
The compounds can be formulated into pharmaceutical compositions, for example, by
admixture with pharmaceutical iy acceptable nontoxic excipients and carriers. Such
compositions can be prepared for use in parenteral administration, particularly in the form of
liquid solutions or suspensions; or oral administration, particularly in the form of tablets or
capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or
dermally, via, for example, trans-dermal patches.
The composition can be conveniently administered in unit dosage form and may be
prepared by any of the methods well known in the pharmaceutical art. for example, as
described in Remington1s Pharmaceutical Sciences (Mack Pub. Co.. Easton, PA. 1980).
Formulations for parenteral administration may contain as common excipients sterile water or
saline, polyalkylene glycols such as polyethylene glycol. oils and vegetable origin,
hydrogenated naphthalenes and the like. In particular, biocompatible. biodegradable lactide
polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may
be useful excipients to control the release of the active compounds.
Other potentially useful parenteral delivery systems for these active compounds
include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion
systems, and iiposomes. Formulations for inhalation administration contain as excipients. for
example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene-9-
lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of
nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration
may also include glycocholate for buccal administration, a salicylate for rectal administration,
or citric acid for vaginal administration. Formulations for trans-dermal patches are preferably
iipophilic emulsions.
Compounds of Formula I and pharmaceutical ly acceptable salts thereof can be
administered orally or non-oral ly, e.g., as an ointment or an injection. The concentrations of
the compounds of this invention in a therapeutic composition can vary. The concentration will
depend upon factors such as the total dosage, of the drug to be administered, the chemical
characteristics (e.g., hydrophobicity) of the compounds employed, the route of administration,
the age, body weight and symptoms of a patient, etc.. The compounds of this invention may
be provided in an aqueous physiological buffer solution containing about 0.1 to 10% w/v
compound for parenteral administration. Typical dose ranges are from about 1 mg to about
1 ug/kg of body weight per day: a preferred dose range is from about 0.01 mg/kg to 100 mg/kg
of body weight per day, and preferably about 0.1 to 20 mg/kg once to four times per day. A
preferred dosage of drug to be administered is likely to depend on variables such as the type
and extent of progression of the disease or disorder, the overall health status of the particular
patient, the relative biological efficacy of the compound selected, and formulation of the
compound excipient, and its route of administration.
The pharmaceutical compositions in accordance with the present invention can be
prepared by uniformly mixing an effective amount of a compound of Formula I or a
pharmaceutically acceptable salt thereof, as an active ingredient, with a pharmaceuticaliy
acceptable carrier. The carrier may take a wide range of forms according to the forms of
composition suitable for administration. It is desired that such pharmaceutical compositions
are prepared in a unit dose form suitable for oral or non-oral administration. The forms for
non-oral administration include ointment and injection.
Tablets can be prepared using excipients such as lactose, glucose, sucrose, mannitol
and methyl cellulose, disintegrating agents such as starch, sodium aiginate. calcium
carboxymethyl cellulose and crystalline cellulose, lubricants such as magnesium stearatc and
talc, binders such as gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl
cellulose and methyl cellulose, surfactants such as sucrose fatty acid ester and sorbitol fatty
acid ester, and the like in a conventional manner. It is preferred that each tablet contains 15-
300 mg of the active ingredient.
Granules can be prepared using excipients such as lactose and sucrose, disintegrating
agents such as starch, binders such as gelatin, and the like in a conventional manner. Powders
can be prepared using excipients such as lactose and mannitol, and the like in a conventional
manner. Capsules can be prepared using gelatin, water, sucrose, gum arabic, sorbitol,
glycerin, crystalline cellulose, magnesium stearate, talc, and the like in a conventional manner.
It is preferred that each capsule contains 15-300 mg of the active ingredient.
Syrup preparations can be prepared using sugars such as sucrose, water, ethanol, and
the like in a conventional manner.
Ointment can be prepared using ointment bases such as vaseline, liquid paraffin,
lanolin and macrogol, emulsifiers such as sodium lauryl lactate, benzalkonium chloride,
sorbitan mono-fatty acid ester, sodium carboxymethyl cellulose and gum arabic, and the like
in a conventional manner.
Injectable preparations can be prepared using solvents such as water, physiological
saline, vegetable oils (e.g., olive oil and peanut oil), ethyl oleate and propylene glycol,
solubilizing agents such as sodium benzoate, sodium salicyiate and urethane, isotonicity
agents such as sodium chloride and glucose, preservatives such as phenol, cresol, p-
hydroxybenzoic ester and chlorobutanol, antioxidants such as ascorbic acid and sodium
pyrosulfite, and the like in a conventional manner.
As those skilled in the art will appreciate, numerous modifications and variations of
the present invention are possible in light of the above teachings. It is therefore understood
that within the scope of the appended claims, the invention may be practiced otherwise than as
specifically described herein, and the scope of the invention is intended to encompass ail such
variations.
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:
ring D is selected from phenyl and cyclohexene with double bond a-b;
ring B and ring F, independently, and each together with the carbon atoms to which
they are attached, are selected from:
a) a 6-membered carbocyclic ring in which from 1 to 3 carbon
atoms may be replaced by hetero atoms; and
b) a 5-membered carbocyclic ring in which either
1) one carbon atom may be replaced with an oxygen, nitrogen, or
sulfur atom;
2) two carbon atoms may be replaced with a sulfur and a nitrogen
atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or
3) three carbon atoms may be replaced with three nitrogen atoms, one
oxygen and two nitrogen atoms, or one sulfur and two nitrogen atoms;
G-X-W is selected from:
a) -{A1A2)C-NCR1KXB1B2)-;
b) -CH(RIA)-C(=O)-N(R1)-; and
c) -N(R1)-C(=O)-CH(R1A)-;
R1 is selected from:
a) H, substituted or unsubstituted alkyl of 1 to 6 carbons, substituted or
unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted hcteroarylalkyl;
b) -C(=O)R7. where R7 is selected from substituted or unsubstituted alkyl.
substituted or unsubstituted aryl. substituted or unsubstituted carbocyclic
group, and substituted or unsubstituted heterocyciyl groups:
c) -OR8, where R8 is selected from H and alkyl having from 1 to 6 carbons;
d) -C(=O)NHR8, -NR9R10, -(CH2)pNR9R10, -(CH2)pOR8, -O(CH2)pORs and
-O(CH;)PNR9R10. where p is from 1 to 4; and where either
I) R9 and R10 are each independently selected from H, unsubstituted
alkyl of 1 to 6 carbons, and substituted alkyl; or
2) R and R1 together form a linking group of the formula
-(CH;)2-X1-(CH:);-, wherein X1 is selected from -O-. -S-. and
-CH2-;
RIA is the same as R1;
R2, R3, R4 and R5 are each independently selected from:
a) H, aryl, carbocyclyl, heterocyciyl. -CN. CF3, -NO2. -OH, -OR7. Br, I.
-O(CH2)PNR9R10, -OC(=O)R7, -OC(=O)NR9R10. -O(CH2)POR8. F, Cl,
-CH3ORS, -NR9R10, -NRSS(=O);R:, -NRSC(=O)R7. or -NRSC(=S)R7;
b) -CH2OR11, where R11 is the residue of an amino acid after the hydroxyl
group of the carboxyl group is removed;
c) -NR8C(=O)NR9R10, -NR1C(=S)N1R9R10, -CO2RI?. -C(=O)R1*.
-C(=O)NR9R10, -C(=S)NR9R10, -CH=NOR1:!, -CH=NR7,
-CCH2)pNR9R10, -(CH2)pNHR". or -CH=NNR12Ri:2A; where
R12 is selected from H, alkyl of 1 to 6 carbons, -OH, alkoxy of 1 to 6
carbons, -OC(=O)R7, -OC(=O)NR9R10, -OC(=S)NR9R10,
-O(CH2)PNR9R10, -O(CH2)POR*, substituted or unsubstituted aryialkyl
having from 6 to 10 carbons, substituted or unsubstituted
hetcrocyclylalkyl, and a substituted or unsubstituted carbocyclic group;
RI2A is the same as R12;
d) -S(O)yR12, - e) alkyl of 1 to 8 carbons, alkenyl of 2 to 8 carbons, and alkynyl of 2 to 8
carbons, wherein:
J) each alkyl, aikenyl, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl or alkynyl group is substituted
with 1 to 3 groups selected from ary! of 6 to 10 carbons.
heterocyclyl, arylalkoxy, heterocycloalkoxy. hydroxylalkox\.
alkyloxy-alkoxy, hydroxyalkylthio,alkoxy-alkylthio. F. CI. Br. 1.
-CN,-NO2,-OH,-OR7,
-X-(CH2)pC(=O)NR'Rl0,-X-(CH2)pC(=S)NR9R!0>
-X2(CH,)pOC(=O)NR9R10,-X:(CH2)pCO2R-X2(CH2)pS(O)yR\.x2(CH2)pNR8C(=O)NR*R10.
-OC(=0)R7, -OC(=O)NHR12. O-tetrahydropyranyl,
-NR'R10, -NR8CO2R7, -NR8C(=O)NR9R10,
-NR8C(=S)NR'R'=. -NHC(=NH)NH2. -NR8C(=O)R7.
-NR8C(=S)R7, -NR*S(=O)2R7, -SCO=R7. -CO=R1".
-C(=O)NR9R10, -C(=S)NR9R'°. -C(=O)R'-. -CH:ORs.
-CH=NNRI2RIM, -CH=NORn, -CH=NR7.
-CH-NNHCH(N=NH)NH2,-S(=O),NRI2RIIA,
-P(=O)(OR8)2, -OR", and a monosaccharide of 5 to 7 carbons
where each hydroxyl group of the monosaccharide is
independently cither unsubstituted or is replaced by H, alkyl of 1 to
4 carbons, alkylcarbonyloxy of 2 to 5 carbons, or alkox*- of 1 to 4
carbons;
X-isO, S,orNR8;
Q is selected from -NR6
R6 is selected from H, -SOjR', -CO2R\ -C(=O)R7, -C(=O)NR9R10, alkyl of 1-8
carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
1) each alkyl, alkenyi, or alkynyl group is unsubstituted; or
2) each alkyl, alkenyl, or alkynyl group independently is
substituted, as defined for R2, R\ R4, and R5 in e) above;
Y is selected from:
a) an unsubstituted alkylcnc of 1 -3 carbons;
b) an alkylene of 1-3 carbons substituted with Ru, where R13 is selected from
R12, thioalkyl of 1-4 carbons, halogen, alkyl of 1-8 carbons, alkenyl of 2-8
carbons, and alkynyl of 2-8 carbons, where
i) each alkyl of 1-8 carbons alkenyl of 2-8 carbons, and alkynyl of 2-8
carbons is unsubstituted; or
ii) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8
carbons, independently, is substituted, as defined for R2, R3, R4, and
R5 in e) above; and
c) a functional group selected from -CH=CH-, -CH(OH)-CH(OH)-, -O, -S-
, -S(=O)-, -S(-O)2-, -C(R6)2-, -C=C(Ri3)2-, -C(=O)-, -C(=NOR12)-, -
C(OR12)R12-, -C(=O)CH(R6)-, -CH(R6)C(=O)-, C(=NOR12)CH(R6)-,
CHR8C(=NOR12)-, C(=O)N(R8)-, -N(R8)C(=O)-, -CH2Z-, -ZCH2-, and -
CH2ZCH2-, where Z is selected from -C(R12)-, -O-, -S-, -CO2R12, -
C(=NOR12)-, and-N(R12)-;
A1 and A2 are selected from H,H; H, OR12; H, -SR12; H, -N(R12)2; and a
group where A1 and A2 together form a moiety selected from =O, =S,
and =NR12; and B1 and B2 are selected from H, H; H, -OR12; H, -SR12;
H, -N(R12)2; and a group where B1 and B2 together form a moiety
selected from =O, =S, and =NR12; with the proviso that at least one of
the pairs A] and A2, or B1 and B2 form =O.
2. The compound as claimed in claim 1 wherein R1, R3 and R5 are H.
3. The compound as claimed in claim 2 wherein —G-X-W- is —
CH2N(R0C(=O)-, C(=O)N(R1)CH2-, or-C(=O)N(Ri)C(=O).
4. The compound as claimed in claim 1 wherein rings B and F are
independently substituted or unsubstituted phenyl or pyridyl.
5. The compound as claimed in claim 1 wherein Q is —NR6, and R6 is H or
substituted or unsubstituted alky of 1 to 4 carbons.
6. The compound as claimed in claim 1 wherein Y is an unsubstituted
alkylene of 1-3 carbons, -C(=O)-, -CH2O-, -S-, -O-, or -CH = CH
7. The compound as claimed in claim 1 having formula:

8. The compound as claimed in claim 7 wherein rings B and F are phenyl.
9. The compound as claimed in claim 8 wherein R1, R3, and R5 are H.
10. The compound as claimed in claim 8 wherein A1 and A2 are selected
from H,H; H, OH; H,OCH3; H, N(R12)2; B* and B2 are selected from
H,H; H,OH;H,-OCH3;H,N(R12)2; or a group where B1 and B2 together
form =O or =NRi2; and R12 is H, methyl, ethyl, propyl, -OH, or
methoxy.
11. The compound as claimed in claim 8 wherein R6 is H or substituted or
unsubstituted alkyl of 1 to 4 carbons.
14.A pharmaceutical composition comprising a compound as claimed in claim
1 and a pharmaceutically acceptable carrier.
15.A pharmaceutical composition comprising a compound as claimed in 13
and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition for treating or preventing prostate disorders
comprising z compound as claimed in claim 1 and a pharmacsuticaily
acceptable carrier.
17. The pharmaceutical composition as claimed in claim 16 wherein the
prostate disorder is prostate cancer or benign prostate hyperplasia.
18. A pharmaceutical composition for treating or preventing angiogenic
disorders comprising a compound as claimed in claim 1 and a
pharmaceutically acceptable carrier.
19. The pharmaceutical composition as claimed in claim 18 wherein the
angiogenic disorder is cancer of solid tumors, endometriosis, diabetic
retinopathy, psoriasis, hemangioblastoma, ocular disorders or macular
degeneration.
20. A pharmaceutical composition for treating or preventing neoplasia,
rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal
would healing, atherosclerosis, or restenosis comprising a compound of
claim 1 or claim 2 and a pharmaceutically acceptable carrier.
21. A pharmaceutical composition for treating or preventing Alzheimer1s
disease, amyotrophic lateral sclerosis, Parkinson1s disease, stroke,
ischaemia, Huntington1s disease, AIDS dementia, epilepsy, multiple
sclerosis, peripheral neuropathy, or injuries of the brain or spinal
chord comprising a compound as claimed in claim 1 or claim 2 and a
pharmaceutically acceptable carrier.
Dated this 11th day of February 2002.
The present invention is directed to novel fused pyrrofocarbazoles and
isoindolones, including pharmaceutical compositions, diagnostic kits, assay
standards or reagents containing the same, and methods of using the same as
therapeutics. The invention is also directed to intermediates and processes for
making these novel compounds.

Documents:

in-pct-2002-214-kol-granted-abstract.pdf

in-pct-2002-214-kol-granted-assignment.pdf

in-pct-2002-214-kol-granted-claims.pdf

in-pct-2002-214-kol-granted-correspondence.pdf

in-pct-2002-214-kol-granted-description (complete).pdf

in-pct-2002-214-kol-granted-examination report.pdf

in-pct-2002-214-kol-granted-form 1.pdf

in-pct-2002-214-kol-granted-form 18.pdf

in-pct-2002-214-kol-granted-form 26.pdf

in-pct-2002-214-kol-granted-form 3.pdf

in-pct-2002-214-kol-granted-form 5.pdf

in-pct-2002-214-kol-granted-reply to examination report.pdf

in-pct-2002-214-kol-granted-specification.pdf

in-pct-2002-214-kol-granted-translated copy of priority document.pdf


Patent Number 223420
Indian Patent Application Number IN/PCT/2002/214/KOL
PG Journal Number 37/2008
Publication Date 12-Sep-2008
Grant Date 10-Sep-2008
Date of Filing 11-Feb-2002
Name of Patentee CEPHALON, INC
Applicant Address 145 BRANDYWINE PARKWAY, WEST CHESTER, PA
Inventors:
# Inventor's Name Inventor's Address
1 HUDKINS, ROBERT, L 430 SOUTH SADDLEBROOK CIRCLE, CHESTER SPRINGS, PA 19425
PCT International Classification Number C07D 487/04
PCT International Application Number PCT/US00/22724
PCT International Filing date 2000-08-18
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/150, 1999-08-20 U.S.A.
2 09/640,825 2000-08-17 U.S.A.