Isomeric fused pyrrolocarbazoles and isoindolones

Details Isomeric fused pyrrolocarbazoles and isoindolones Isomeric fused pyrrolocarbazoles and isoindolones

2000-08-17

2002-06-04

Rotman, Alan L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S416000, C548S421000

Reexamination Certificate

active

06399780

ABSTRACT:

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 Nocardiosis sp. culture (Kase, 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. Pat. Nos. 4,877,776, 4,923,986, and 5,063,330; European Publication 238,011 in the name of Nomato); anti-insecticidal activity (See U.S. Pat. No. 4,735,939); inhibition of inflammation (See U.S. Pat. No. 4,816,450); treatment of diseases associated with neuronal cells (See U.S. Pat. Nos. 5,461,146; 5,621,100; 5,621,101; and WIPO Publication WO 94/02488, published Feb. 3, 1994 in the names of Cephalon, Inc. and Kyowa Hakko Kogyo Co., Ltd.); and treatment of prostate disease (See U.S. Pat. Nos. 5,516,771; and 5,654,427). K-252a also has been reported to inhibit IL-2 production (See Grove, D. 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; staurosporine (derived from Streptomyces sp.) and K-252a each further comprise a sugar moiety linked via two N-glycosidic bonds. Both K-252a and staurosporine 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 al., 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 indolocarbazole alkaloids represented by K-252a and staurosporine, synthetic small organic molecules which are biologically active and known as fused pyrrolocarbazoles have been prepared (See U.S. Pat. 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. Pat. No. 5,808,060 and WIPO Publication WO 97/21677). Certain bis-indolylmaleimide macrocyclic derivatives have also been reported (See for example U.S. Pat. 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 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 pharmaceutically 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 endothelial 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. R
2
, R
3
, R
4
, and R
5
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 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) —(A
1
A
2
)C—N(R
1
)—C(B
1
B
2
)—;
b) —CH(R
1A
)—C(═O)—N(R
1
)—; and
c) —N(R
1
)—C(═O)—CH(R
1A
)—;
R
1
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 heteroarylalkyl;
b) —C(═O)R
7
, where R
7
is selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted carbocyclic group, and substituted or unsubstituted heterocyclyl groups;
c) —OR
8
, where R
8
is selected from H and alkyl having from 1 to 6 carbons;
d) —C(═O)NHR
8
, —NR
9
R
10
, —(CH
2
)
p
NR
9
R
10
, —(CH
2
)
p
OR
8
, —O(CH
2
)
p
OR
8
and —O(CH
2
)
p
NR
9
R
10
, where p is from 1 to 4; and where either
 1) R
9
and R
10
are each independently selected from H, unsubstituted alkyl of 1 to 6 carbons, and substituted

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