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
2004-04-06
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S183000
Reexamination Certificate
active
06716862
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel series of 5-(substituted)-5-(substitutedsulfonyl or sulfanyl)thiazolidine-2,4-diones, to pharmaceutical compositions containing them, to their use in cancer therapy and to a process for their preparation. The compounds inhibit 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 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. Skotniciki,
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).
5-[3-aryl-prop-2-ynyl]-5-(arylsulfonyl)thiazolidine-2,4-diones and 5-[3-aryl-prop-2-ynyl]-5-(arylsulfanyl)thiazolidine-2,4-diones which possess antihyperglycemic activity, are reported in U.S. Pat. Nos. 5,574,051 and 5,605,918.
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.
The present invention further provides a method of treatment of ras oncogene-dependent tumors, such as 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, such as restenosis, neuro-fibromatosis, endometriosis, and psoriasis. The compounds of the present invention may also inhibit prenylation of proteins other than Ras, and thus provide a method of treatment of diseases associated with other prenyl modifications of proteins.
SUMMARY OF THE INVENTION
The present invention discloses compounds represented by Formula (I):
wherein:
R
1
is hydrogen, —CH
2
—CO
2
R
9
, or —CH
2
—C(O)NHOR
10
;
n is an integer of 0 or 2;
v is an integer of 1 to 3;
each R
2
is independently hydrogen, alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl of 6 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, aryloxy of 6 to 12 carbon atoms, hydroxy, halo, amino, monoalkyl(1 to 12 carbon atoms)amino, di(alkyl of 1 to 12 carbon atoms)amino, monoaryl(6 to 12 carbon atoms)amino, alkyl(1 to 12 carbon atoms)aryl(6 to 12 carbon atoms)amino, di(aryl of 6 to 12 carbon atoms)amino, monocycloalkyl(3 to 7 carbon atoms)amino, di(cycloalkyl of 3 to 7 carbon atoms)amino, alkyl(1 to 12 carbon atoms)cycloalkyl(3 to 7 carbon atoms)amino, aryl(6 to 12 carbon atoms)cycloalkyl(3 to 7 carbon atoms)amino, mercapto, alkylthio of 1 to 12 carbon atoms, cycloalkylthio of 3 to 7 carbon atoms, arylthio of 6 to 12 carbon atoms, acyl of 1 to 12 carbon atoms, carboxyl, sulfo, carboxyalkyl(1 to 12 carbon atoms), carboxyaryl(6 to 12 carbon atoms), carboxycycloalkyl(3 to 7 carbon atoms), formyl, acyloxy of 1 to 12 carbon atoms, cyano, alkyl(1 to 12 carbon atoms)carbonyldioxy, aryl(6 to 12 carbon atoms)carbonyldioxy, cycloalkyl(3 to 7 carbon atoms)carbonyldioxy, carbamyl, acylamino of 1 to 12 carbon atoms, alkyl(1 to 12 carbon atoms)acylamino, cycloalkyl(3 to 7 carbon atoms)acylamino, aryl(6 to 12 carbon atoms)acylamino, nitro, monoalkyl(1 to 12 carbon atoms)carbamyl, di(alkyl of 1 to 12 carbon atoms)carbamyl, monoaryl(6 to 12 carbon atoms)carbamyl, di(aryl of 6 to 12 carbon atoms)carbamyl, monocycloalkyl(3 to 7 carbon atoms)carbamyl, di(cycloalkyl of 3 to 7 carbon atoms)carbamyl, aryl(6 to 12 carbon atoms)alkyl(1 to 12 carbon atoms)carbamyl, cycloalkyl(3 to 7 carbon atoms)alkyl(1 to 12 carbon atoms)carbamyl, or cycloalkyl(3 to 7 carbon atoms)aryl(6 to 12 carbon atoms)carbamyl monoalkyl(1 to 12 carbon atoms)sulfamyl, di(alkyl of 1 to 12 carbon atoms)sulfamyl, monoaryl(6 to 12 carbon atoms)sulfamyl, di(aryl of 6 to 12 carbon atoms)sulfamyl, monocycloalkyl(3 to 7 carbon atoms)sulfamyl, di(cycloalkyl of 3 to 7 carbon atoms)sulfamyl, aryl(6 to 12 carbon atoms)alkyl(1 to 12 carbon atoms)sulfamyl, cycloalkyl(3 to 7 carbon atoms)alkyl(1 to 12 carbon atoms)sulfamyl, or cycloalkyl(3 to 7 carbon atoms)aryl(6 to 12 carbon atoms)sulfamyl, aminocarbonyloxy, aminocarbonylamino, or optionally when v is an integer of 1, the moiety
wherein the moiety
is aryl of 6 to 12 carbon atoms optionally substituted with 1 to 3 groups independently selected from alkyl of 1 to 12 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl of 6 to 12 carbon atoms, alkoxy of 1 to 12 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, aryloxy of 6 to 12 carbon atoms, hydroxy, halo, amino, monoalkylamino of 1 to 12 carbon atoms, dialkylamino of 1 to 12 carbon atoms, monoarylamino of 6 to 12 carbon atoms, (alkyl of 1 to 12 carbon atoms)(aryl of 6 to 12 carbon atoms)amino, di(aryl of 6 to 12 carbon atoms)amino, monocycloalkylamino of 3 to 7 carbon atoms, di(cycloalkyl of 3 to 7 carbon atoms)amino, (alkyl of 1 to 12 carbon atoms)(cycloalkyl of 3 to 7 carbon atoms)amino, (aryl of 6 to 12 carbon atoms)(cycloalkyl of 3 to 7 carbon atoms)amino, mercapto, alkylthio of 1 to 12 carbon atoms, cycloalkylthio of 3 to 7 carb
Ayral-Kaloustian Semiramis
Epstein Joseph William
Salaski Edward James
Gerstl Robert
Moran Daniel B.
Wyeth Holdings Corporation
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