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
2003-08-12
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S314000, C514S342000
Reexamination Certificate
active
06605628
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a method of using novel 5-(arylsulfonyl)-, 5-(arylsulfinyl)- and 5-(arylsulfanyl)thiazolidine-2,4-diones of formula (I) as 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 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).
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.
BRIEF SUMMARY OF THE INVENTION
This invention is concerned with a method of treating, inhibiting or controlling a ras-associated disease by inhibiting farnesyl-protein transferase(FPTase) enzyme in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I):
wherein:
Ar is 1-naphthyl, 2-naphthyl, 8-quinolinyl, 2-thienyl, 5-chloro-2-thienyl, 5-(2-pyridyl)-2-thienyl, 2-pyridinyl, substituted 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-quinolinyl, 2-pyrimidinyl, 2-benzoxazolyl, 2-benzthiazolyl, 2-benzimidazolyl, 2-furanyl, 2-benzo-[b]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula:
R
1
is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, 4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy, phenoxy, or benzyloxy;
R
2
is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy;
m is 0, 1 or 2;
R
6
is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl, imidazolylpropyl, or —CO
2
Y;
Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, or substituted benzyl;
W is
E- and Z- —CH═CH—, —CONH—, —CONHCH
2
—, —CONHCH
2
CH
2
— or —CH
2
—CH
2
—;
n is an integer of 1 to 9;
Ar′ is thienyl, pyridinyl or a moiety of the formula
R
3
, R
4
, R
5
, are independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, —CO
2
R
7
, —CONHR
8
, —CH
2
CONHR
9
, —NHCO
2
R
10
, —NHCOR
11
, and —NHCONHR
12
;
R
7
is selected from H, and alkyl of 1 to 6 carbon atoms,
R
8
is selected from H, and alkyl of 1 to 6 carbon atoms;
R
9
is selected from H, and alkyl of 1 to 6 carbon atoms;
R
10
is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl;
R
11
is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl;
R
12
is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl;
provided that when W is
n is other than 2
or pharmaceutically acceptable salts 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
6
is hydrogen, n is 1, m is 2, W is
b.) R
6
is hydrogen, n is 3, m is 2, W is
c.) R
6
is hydrogen, n is 3-6, m is 2, W is
d.) R
6
is hydrogen, n is 1, m is 2, W is
Ar is a moiety of the formula
e.) R
6
is hydrogen, n is 3, m is 2, W is
Ar is a moiety of the formula
f.) R
6
is hydrogen, n is 3-6, m is 2, W is
Ar is a moiety of the formula
g.) R
6
is hydrogen, n is 1, m is 2, W is
Ar is a moiety of the formula
Ar′ is a moiety of the formula
h.) R
6
is hydrogen, n is 3, m is 2, W is
Ar is a moiety of the formula
Ar′ is a moiety of the formula
i.) R
6
is hydrogen, n is 3-6, m is 2, W is
Ar is a moiety of the formula
Ar′ is a moiety of the formula
j.) R
6
is hydrogen, n is 1, m is 2, W is
Ar is a moiety of the formula
Ar′ is thienyl or pyridinyl;
k.) R
6
is hydrogen, n is 3, m is 2, W is
Ar is a moiety of the formula
Ar′ is thienyl or pyridinyl;
l.) R
6
is hydrogen, n is 3-6, m is 2, W is
Ar is a moiety of the formula
Ar′ is thienyl or pyridinyl;
Additionally preferred compounds of this invention include compounds of Formula (I) in which m is 2, Ar is phenyl substituted in the 4-position by iodo, methoxy, trifluoromethoxy, 4-pyridyloxy; Ar′ is phenyl substituted in the 2-position by chloro or methyl, and in the 5-position by amino, chloro, a carbamic acid ester, a substituted carboxamide group, or in
Ayral-Kaloustian Semiramis
Birnberg Gary H.
Cheung Katherine
Epstein Joseph William
Macewan Gloria Jean
Moran Daniel B.
Reamer James H.
Wyeth Holdings Corporation
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