Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-08-23
2004-05-25
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S530000
Reexamination Certificate
active
06740675
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel series of 3-substituted-3-(substitutedsulfonyl)pyrrolidine-2,5-diones, and 3-substituted-3-(substitutedsulfanyl)pyrrolidine-2,5-diones, to their use in cancer therapy, to pharmaceutical compositions containing them, and to a process for their preparation. The compounds are inhibitors of Ras FPTase, and may be used as an alternative to, or in conjunction with, traditional cancer therapy for treating ras oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid. Compounds in the invention may also be useful for controlling metastasis, suppressing angiogenesis, inducing apoptosis, and in treating Ras-associated proliferative diseases other than cancer, such as restenosis, neuro-fibromatosis, endometriosis, and psoriasis. These compounds may also inhibit prenylation of proteins other than Ras, and thus may be effective in the treatment of diseases associated with other prenyl modifications of proteins.
BACKGROUND OF THE INVENTION
Mammalian H-, K-, and N-Ras proteins, encoded by H-, K-, and N-ras proto-oncogenes, respectively, are 21 kD GTP-binding proteins which possess intrinsic GTPase activity and play a fundamental role in cell proliferation and differentiation (G. L. Bolton, J. S. Sebolt-Leopold, and J. C. Hodges,
Annu. Rep. Med. Chem
., 1994, 29, 165; R. J. A. Grand in “New Molecular Targets in Cancer Chemotherapy” J. D. Kerr, and P. Workman, Eds.,
CRC Press
, Boca Raton, Fla., 1994, p. 97). Specific mutations in the ras gene impair GTPase activity of Ras, leading to uninterrupted growth signals and to the transformation of normal cells into malignant phenotypes. Mutant ras oncogenes are found in approximately 25% of all human cancers, including 90% of pancreatic, 50% of colon, and 50% of thyroid tumors (J. L. Bos,
Cancer Res
., 1989, 49, 4682). It has been shown that normal cells transfected with mutant ras gene become cancerous and that unfarnesylated, cytosolic mutant Ras protein does not anchor in cell membranes and cannot induce this transformation (J. F. Hancock, H. Paterson, and C. J. Marshall,
Cell
, 1990, 63, 133). Posttranslational modification and plasma membrane association of mutant Ras is essential for this transforming activity. The first and required step in the processing of Ras is farnesylation at the cysteine residue of its carboxyl terminal motif, CAAX (C=Cys-186, A=aliphatic amino acid, X=usually methionine, serine or glutamine). Since its identification, the enzyme farnesyl-protein transferase (FPTase) that catalyzes this first processing step has emerged as a promising target for therapeutic intervention (H.-W. Park, S. R. Boduluri, J. F. Moomaw, P. J. Casey, and L. S. Beese,
Science
, 1997, 275, 1800; P. J. Casey, P. A. Solski, C. J. Der, and J. E. Buss,
Proc. Natl. Acad. Sci. U.S.A
., 1989, 86, 8323; S. Ayral-Kaloustian and J. S. Skotnicki,
Annu. Rep. Med. Chem
., 1996, 31, 165, and references therein). Major milestones have been achieved with small molecules, such as mimics of the tetrapeptide CAAX and analogs of farnesyl pyrophosphate, that show efficacy without toxicity in vitro as well as in mouse models bearing ras-dependent tumors or human xenografts with H-, N-, or K-ras mutations (S. Ayral-Kaloustian and J. S. Skotnicki,
Annu. Rep. Med. Chem
., 1996, 31, 165, and references therein; T. M. Williams,
Exp. Opin. Ther. Patents
, 1998, 8, 553, and references therein). Several low-molecular weight compounds that inhibit FPTase have entered Phase I trials in humans (SCH-66336
, Pharmaprojects
, 1998, No. 5128; R-115777
, Pharmaprojects
, 1998, No. 5532).
Accordingly, there is still a need for drugs for treating and preventing cancer. In particular, there is a need for drugs which inhibit or treat the growth of tumors expressing an activated Ras oncogene and which include cancers of the pancreas, colon, bladder and thyroid.
BRIEF SUMMARY OF THE INVENTION
The present invention discloses compounds represented by Formula (I):
wherein:
R
1
is a moiety
R
2
is a moiety
n is an integer of 1 and 3-9;
m is an integer of 0 or 2;
R
3
and R
4
are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halogen, nitro, trifluoromethoxy, phenoxy optionally mono or di substituted, and benzyloxy optionally mono or di substituted;
R
5
, and R
6
, are independently selected from the group consisting of hydrogen, alkyl of 1 to 10 carbon atoms, halogen, nitro, phenyl optionally mono or di-substituted, phenoxy optionally mono or di-substituted, trifluoromethyl, trifluoromethoxy, and methanesulphonyl.
or a pharmaceutically acceptable salt thereof.
Among the preferred groups of compounds of Formula (I) of this invention including pharmaceutically acceptable salts thereof are those in the subgroups below, wherein the other variables of Formula (I) in the subgroups are as defined above wherein:
a.) R
1
is 4-methoxyphenyl and R
2
is 4-chlorophenyl;
b.) n is 3 and m is 2;
Specifically preferred compounds of this invention according to Formula (I) for treating or controlling ras oncogene-dependent tumors and associated proliferative diseases in warm-blooded animals preferably mammals, most preferably humans in need thereof are the following compounds or a pharmaceutically acceptable salt thereof:
3-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(4-methoxybenzenesulfonyl)-pyrrolidine-2,5-dione; and
3-[3-(4-Chlorophenyl)prop-2-ynyl]-3-(4-methylbenzenesulfonyl)-pyrrolidine-2,5-dione.
It is understood that the definition of compounds of Formula (I) when R
1
, R
2
, R
3
, R
4
, R
5
, or R
6
contain asymmetric carbons, encompass all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, the definition encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques or enantiomer specific synthesis. It is understood that this invention encompasses all crystalline forms of compounds of Formula (I).
Pharmaceutically acceptable salts of the compounds in this invention may be formed with bases such as alkali metals (Na, K, Li) or alkaline earth metals (Ca or Mg).
For the compounds of Formula (I) defined above and referred to herein, unless otherwise noted, the following terms are defined:
Halogen, as used herein means chloro, fluoro, bromo and iodo.
Alkyl as used herein means a branched or straight chain having from 1 to 10 carbon atoms and more preferably from 1 to 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
Alkoxy as used herein means an —O-alkyl group in which the alkyl group is as previously described. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
Phenyl as used herein refers to a 6-membered aromatic ring, optionally substituted. Preferably, the phenyl ring is optionally mono or di substituted.
Where a group, e.g. phenyl, phenoxy, benzyloxy is described as optionally mono or di substituted, the substituents are preferably independently selected from alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy, methanesulphonyl, phenyl, phenoxy, and benzyloxy. Said phenyl, phenoxy and benzyloxy groups may themselves be mono or di-substituted by substituents independently selected from alkyl of 1 to 10 carbon atoms, alkoxy of 1 to 10 carbon atoms, halogen, nitro, trifluoromethyl, trifluoromethoxy, methanesulphonyl, and phenyl.
Additionally, this invention provides a method of treatment, by administration of an effective amount of compounds of Formula (I), of ras oncogene-dependent tumors, which include cancers of the pancreas, colon, bladder, and thyroid; a method of controlling metastasis, suppressing angiogenesis, and inducing apoptosis; a method of treating Ras-associated proliferative diseases other than cancer, which include restenosis, neuro-
Ayral-Kaloustian Semiramis
Epstein Joseph William
McKane Joseph K.
Moran Daniel B.
Shiao Robert
Wyeth Holdings Corporation
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