US20030144301A1

US20030144301A1 - Method of using 5-(arysulfonyl)-, 5-(arylsulfanyl)-and 5-(arylsulfanyl)thiazolidine-2,4-diones for inhibition of farnesyl-protein transferase

Info

Publication number: US20030144301A1
Application number: US10/226,815
Authority: US
Inventors: Semiramis Ayral-Kaloustian; Joseph Epstein; Gary Birnberg; Edward Salaski; Gloria Macewan; Katherine Cheung
Original assignee: American Cyanamid Co
Current assignee: Wyeth Holdings LLC
Priority date: 2001-08-24
Filing date: 2002-08-23
Publication date: 2003-07-31
Anticipated expiration: 2022-08-23
Also published as: US6605628B1

Abstract

This invention relates to a method of using novel 5-(arylsulfonyl)-, 5-(arylsulfinyl)- and 5-(arylsulfanyl)thiazolidine-2,4-diones of Formula (1), wherein Ar, Ar′, R₆, m and n are as defined in the specification 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.

Description

“This application claims priority from copending provisional application Serial No. 60/314,621 filed Aug. 24, 2001 the entire disclosures of which is hereby incorporated by reference.”[0001]

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 ₁is 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 ₂is 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 ₆is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl, imidazolylpropyl, or —CO₂Y;

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—, —CONHCH₂CH₂— or —CH₂—CH₂—;

n is an integer of 1 to 9;

Ar′ is thienyl, pyridinyl or a moiety of the formula

R ₃, R₄, R₅, 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, —CO₂R₇, —CONHR₈, —CH₂CONHR₉, —NHCO₂R₁₀, —NHCOR₁₁, and —NHCONHR₁₂;

R ₇is selected from H, and alkyl of 1 to 6 carbon atoms,

R ₈is selected from H, and alkyl of 1 to 6 carbon atoms;

R ₉is selected from H, and alkyl of 1 to 6 carbon atoms;

R ₁₀is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl;

R ₁₁is 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 ₁₂is 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 ₆is hydrogen, n is 1, m is 2, W is

b.) R ₆is hydrogen, n is 3, m is 2, W is

c.) R ₆is hydrogen, n is 3-6, m is 2, W is

d.) R ₆is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula

e.) R ₆is hydrogen, n is 3, m is 2, W is

Ar is a moiety of the formula

f.) R ₆is hydrogen, n is 3-6, m is 2, W is

Ar is a moiety of the formula

g.) R ₆is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula

Ar′ is a moiety of the formula

h.) R6 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 ₆is 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 ₆is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula

Ar′ is thienyl or pyridinyl;

k.) R ₆is hydrogen, n is 3, m is 2, W is

Ar is a moiety of the formula

Ar′ is thienyl or pyridinyl;

l.) R ₆is 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 the 4-position by nitro or a carbamic acid ester; W is an acetylenic group, and n is the integer 3.

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:

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)thiazolidine-2,4-dione,

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)thiazolidine-2,4-dione,

5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)thiazolidine-2,4-dione,

5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,

5-[11 -(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenyl-sulfonyl)thiazolidine-2,4-dione,

5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorobenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,

N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxothiazolidine-5-sulfonyl}phenyl)acetamide,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(quinoline-8-sulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-nitrobenzenesulfonyl)thiazolidine-2,4-dione,

5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-ynyl]thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1 -sulfonyl)thiazolidine-2,4-dione,

5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulfonyl]thiazolidine-2,4-dione,

5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-(4-lodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-Methoxybenzene sulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-Methoxybenzene sulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl] -5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-(4-lodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione

5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,

5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesulfonyl]-thiazolidine-2,4-dione,

5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzene-sulfonyl)thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-lodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thiazolidine-2,4-dione,

5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-ethoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,

(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,

(3-Chloro-4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,

N-tert-Butyl-3-{5-[5-(4-iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylbenzamide,

(3-{5-[5-(4-lodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,

(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylphenyl)carbamic Acid tert-Butyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,

(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-trifluoromethylphenyl)-carbamic Acid tert-Butyl Ester,

N-tert-Butyl-3-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benzamide,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-4-methylbenzoic Acid Methyl Ester,

5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}benzonitrile,

5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic Acid Methyl Ester,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-lodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-(3-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,

5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-ynyl)thiazolidine-2,4-dione,

5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione, (

3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Benzyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid 4-Nitro-Benzyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid 4-Chloro-phenyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Methyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Isopropyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Neopentyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Butyl Ester,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Isobutyl,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2-dimethylpropanamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,

N-Benzyl-N′-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,

N-(4-Methoxyphenyl)-N′-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,

N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-methylphenyl]-N′-(4-methylphenyl)urea,

4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,

4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,

N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1′-biphenyl]-4-carboxamide,

4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl),1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

tert-Butyl 3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,

tert-Butyl 3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,

tert-Butyl 3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl-carbamate,

tert-Butyl 3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5yl)-1-pentynyl]-4-methylphenyl-carbamate,

tert-Butyl 3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylphenyl-carbamate,

N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,

N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide,

N-(tert-Butyl)-3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,

N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,

4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic Acid,

N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide,

N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide,

5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

Enantiomer of(3-(5-[5-(4-Methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (less polar),

Enantiomer of(3-{5-[5-(4-Methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (more polar),

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)thiazolidine-2,4-dione,

Benzyl 5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

4-Nitrobenzyl 5-[(4-methoxyphenyl)sulfonyl]-5-{5-[2-methyl-5-({[(4-nitrobenzyl)oxy]carbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Methyl 5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Isopropyl 5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Neopentyl 5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Butyl 5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Isobutyl 5-(5-{5-[(isobutoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)thiazolidine-2,4-dione, and

5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester.

Additionally 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:

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(napthalene-2-sulfonyl)thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]thiazolidine-2,4-dione,

5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-fluoro-benzenesulfonyl)thiazolidine-2,4-dione,

5-(4-Chloro-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-(4-Bromo-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione,

5-(Naphthalene-2-sulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,

5-(Toluene-4-sulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3-(4-Methoxy-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-(4-Chloro-benzenesulfonyl)-5-[3-(4-fluoro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3(4-Chloro-phenyl)-prop-2-ynyl]-5(toluene-3-sulfonyl)thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-(3-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3(4-Chlorophenyl)-2-propynyl]-2-[(4-methylphenyl)sulfonyl]-2,4-thiazolidinedione,

5-[3(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)thiazolidine-2,4-dione,

5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-2-ynyl]thiazolidine-2,4-dione,

5-[3(4-Chloro-phenyl)-prop-2-ynyl]-5-(quinoline-2-sulfonyl)thiazolidine-2,4-dione,

5-[3-(3,5-Bis-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione, and

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(p-tolylsulfanyl)thiazolidine-2,4-dione.

It is understood that the definition of compounds of Formula (I) when R ₁to R₁₂, 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). The pharmaceutically acceptable salts of the basic compounds of this invention are those derived from such organic and inorganic acids as: lactic, citric, acetic, tartaric, fumaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where R₁to R₁₂, or Y contains a carboxyl group, 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 6 carbon atoms. Exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.

Aryl as used herein means an aromatic radical 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]-furanyl, 2-benzo-[b]-thienyl or a moiety of the formula:

and further defined an aromatic radical Ar′ is thienyl, pyridinyl or a moiety of the formula

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.

Alkyne as used herein means an alkynyl group

is present.

Phenyl as used herein refers to a 6-membered aromatic ring.

Carbamic acid ester is —NHCO ₂R₁₀where preferred R₁₀is alkyl of 1 to 6 carbon atoms.

Substituted carboxamide is —CONHR ₈wherein R₈is alkyl of 1 to 6 carbon atoms.

Substituted 2-pyridinyl and substituted benzyl, unless otherwise provided for herein, preferably has from 1 to 3 substituents independently selected from fluoro, chloro, bromo, iodo, nitro, cyano, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethyl and trifluoromethoxy.

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-fibromatosis, endometriosis, and psoriasis The compounds of Formula (I) 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.

The compounds of Formula (I) inhibit farnesyl-protein transferase and the farnesylation of the oncogene protein Ras. Thus, this invention further provides a method of inhibiting farnesyl protein transferase, (e.g., Ras farnesyl protein transferase) in mammals, especially humans, by the administration of an effective amount of the compounds of Formula (I). The administration of the compounds of this invention to patients, to inhibit farnesyl protein transferase, is useful in the treatment of the cancers and other diseases described below.

This invention provides a method for inhibiting or treating the abnormal growth of cells, including transformed cells by administering an effective amount of a compound of Formula (I). Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes abnormal growth of tumor cells (tumors) expressing an activated Ras oncogene; tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and benign and malignant cells of other proliferative diseases in which aberrant Ras activation occurs.

This invention also provides a method for inhibiting or treating tumor growth by administering an effective amount of a compound of Formula (I), described herein, to a mammal (e.g., a human) in need of such treatment. In particular, this invention provides a method for inhibiting or treating the growth of tumors expressing an activated Ras oncogene by administration of an effective amount of a compound of Formula (I). Examples of tumors which may be inhibited or treated include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, for example, exocrine pancreatic carcinoma), colon cancers (e.g., colorectal carcinomas, such as, for example, colon adenocarcinoma and colon adenoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), bladder carcinoma, epidermal carcinoma, breast cancer and prostate cancer.

This invention also provides a method for inhibiting or treating proliferative diseases, both benign and malignant, wherein Ras proteins are aberrantly activated as a result of oncogenic mutation in other genes-i.e., the Ras gene itself is not activated by mutation to an oncogenic form-with said inhibition or treatment being accomplished by the administration of an effective amount of a compound of Formula (I), to a mammal (e.g., a human) in need of such treatment. For example, the benign proliferative disorder neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (e.g., neu, src, abl, lck, and fyn), may be inhibited or treated by the compounds of Formula (I).

Additionally, this invention provides a method of inhibition or treating the abnormal growth of cells, by administration of an effective amount of compounds of Formula (I), of ras-oncogene-dependent tumors, which tumors include cancers of the pancreas, colon, bladder, and thyroid. Without wishing to be bound by theory, these compounds may function through the inhibition of G-protein function, such as ras p21, by blocking G-protein isoprenylation, thus making them useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by theory, the compounds of Formula (I) inhibit Ras farnesyl-protein transferase, and thus antiproliferative activity of ras-transformed cells and other prenyl modifications of proteins.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of this invention may be prepared according to the methods and procedures described in U.S. Pat. Nos. 5,605,918 and 5,574,051, which are hereby incorporated herein by reference; in Wrobel, J., et al., J. Med. Chem. 1998, 41 (7), 1084-91 and as outlined in Schemes I through XI described herein.

As shown in Scheme I, arylthiol VI where Ar is hereinbefore defined is reacted with 2 or more equivalents of a strong base such as lithium diisopropylamide, lithium bis(trimethylsilylamide), and the like followed by reaction with one or more equivalents of 5-bromothiazolidine-2,4-dione IV(Zask et al, J. Med. Chem. 1990, 33, 1418-1423) to produce a 5-arylsulfanylthiazolidine-2,4-dione VII in an aprotic solvent such as tetrahydrofuran (THF) or hexane at temperatures (e.g. 0° to −78° C.) followed by warming to about ambient temperature for 1 to 10 h.

The 5-arylsulfanylthiazolidine-2,4-dione VII may then be oxidized to afford 5-arylsulfonylthiazolidine-2,4-dione V. Following the procedure of Zask et al (J. Med. Chem. 1990, 33, 1418-1423), the oxidation is conveniently performed using excess (2 to 20 equivalents) aqueous hydrogen peroxide in acetic acid at ambient or higher (30° to 80° C.) reaction temperatures for 1 to 10 h.

The 5-arylsulfanylthiazolidine-2,4dione VII may also be oxidized to afford 5-arylsulfinylthiazolidine-2,4-dione Va by bubbling oxygen in the presence of isobutyraldehyde in a solvent which includes acetonitrile for 18 hours.

The 5-arylsulfonylthiazolidine-2,4-dione V may also be prepared by reacting one or more equivalents of an alkali metal arylsulfinate VIII, where M is an alkali metal with 5-bromothiazolidine-2,4-dione IV in suitable solvents which include polar aprotic solvents such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF) or protic solvents such as low molecular weight alcohols (methyl alcohol, ethyl alcohol and isopropanol and the like), or water.

Alternatively, the alkali metal arylsulfinate VIII can also be prepared by reduction of an arylsulfonyl chloride with sodium iodide in acetone (Harwood, Julia, and Thuillier, Tetrahedron, 1980, 36, 2483-2487).

As shown in Scheme II arylalkynes XI, wherein Ar′ is as previously defined, and LG is a suitable leaving group which include iodo, bromo and p-toluenesulfonyloxy, can be prepared via a two step process from commercially available aryl iodides or aryl bromides where Ar′ is hereinbefoe defined or those aryl iodides or aryl bromides described in the the art. In the first step, alcohol X is prepared by the reaction of the appropriate aryl iodide or bromide with one or more equivalents of a terminal alkyne-ol IX, in the presence of a catalytic amount of a palladium(II) reagent such as dichlorobis(triphenylphosphine)palladium(II) and a catalytic amount of a copper(I) reagent such as copper(I) iodide. This reaction is also performed in the presence of one or more equivalents of a secondary or tertiary amine such as diethylamine or triethylamine. The secondary or tertiary amine may be used as solvent, or alternatively a halocarbon solvent such as chloroform may be s employed. Temperatures up to 80° C. are commonly used, with reaction times varying from 1 h to 2 days. Alkyne XI wherein Ar′ is hereinbefore defined and LG is p-toluenesulfonyloxy is most conveniently prepared from alcohol X by reaction with p-toluenesulfonyl chloride in a solvent such as dichloromethane and in the presence of N,N-dimethylaminopyridine and triethylamine at 0° C. to 30° C., from one hour to 6 hours; or when LG is iodo, alcohol X is reacted with iodine, in the presence of triphenylphosphine and imidazole in a solvent such as ether, or acetonitrile, at a temperature of 0° C. to room temperature for 8 hours to 24 hours; alternatively alkyne XI wherein LG is p-toluenesulfonyloxy is reacted with sodium iodide in acetone at room temperature from 8 hours to 36 hours to give alkyne XI wherein LG is iodo; or when LG is bromo, X is reacted with carbon tetrabromide in the presence of triphenylphosphine in a solvent such as THF at 0° C. to 35° C. for 8 hours to 72 hours to give alkyne XI wherein LG is bromo.

Referring to Scheme III: 5-substituted-5-(arylsulfanyl)thiazolidine-2,4-diones of Formula (I) may be prepared by reaction of the appropriate 5-(arylsulfanyl)thiazolidine-2,4-dione VII with 2 or more equivalents of a base. Two equivalents of base effect deprotonation of both the thiazolidinedione nitrogen atom and at the C-5 position to form a dianion. Common bases to accomplish this deprotonation include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyl lithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide. Convenient solvents include THF and DMF. Reaction temperatures may be varied from −78° C. to room temperature. Two minutes to 1 h after the base is introduced, one or more equivalents of the appropriate alkylating agent, alkyne XI is added to the reaction mixture and this is allowed to stir at 0° C. or room temperature for a period of from 1 h to 3 days. Alkylation occurs primarily on the thiazolidindione C-5 carbon atom to afford the 5-substituted-5-(arylsulfanyl)thiazolidine-2,4-dione of Formula (I), m=0 which may then be oxidized to afford 5-arylsulfonylthiazolidine-2,4-dione of Formula (I) wherein m=2 by the procedure of Zask et al (J. Med. Chem. 1990, 33, 1418-1423). The oxidation is conveniently performed using excess (2 to 20 equivalents) aqueous hydrogen peroxide in acetic acid at ambient or higher (30° C. to 80° C.) reaction temperatures for 1 to 10 h.

Referring to Scheme IIIa: 5-substituted-5-(arylsulfinyl)thiazolidine-2,4-diones of Formula (I) may be prepared by reaction of the appropriate 5-(arylsulfinyl)thiazolidine-2,4-dione Va in the presence of a base. Common bases include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyl lithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide. Convenient solvents include THF and DMF. Reaction temperatures may be varied from −78° C. to room temperature. Two minutes to 1 h after the base is introduced, one or more equivalents of the appropriate alkylating agent, alkyne XI is added to the reaction mixture and this is allowed to stir at 0° C. or room temperature for a period of from 1 h to 3 days. Alkylation occurs primarily on the thiazolidindione C-5 carbon atom to afford the 5-substituted-5-(arylsulfinyl)thiazolidine-2,4-dione of Formula (I), m=1.

As shown in Scheme IV: 5-substituted-5-(arylsulfonyl)thiazolidine-2,4-diones of Formula (I) may be prepared by reaction of the appropriate 5-(arylsulfonyl)thiazolidine-2,4-dione V with 2 or more equivalents of a base. Two equivalents of base effect deprotonation of both the thiazolidinedione nitrogen atom and at the C-5 position to form a dianion. Common bases to accomplish this deprotonation include alkali metal hydrides such as sodium hydride, alkali metal alkyls such as butyl lithium or alkali metal amide bases such as lithium diisopropylamide or lithium bis(trimethylsilyl)amide. Convenient solvents include THF and DMF. Reaction temperatures vary from −78° C. to room temperature. Two minutes to 1 h after the base is introduced, one or more equivalents of the appropriate alkylating agent, alkyne XI is added to the reaction mixture and the reaction is allowed to stir at 0° C. or room temperature for a period of from 1 h to 3 days. Alkylation occurs exclusively on the thiazolidindione C-5 carbon atom to afford the 5-substituted-5-(arylsulfonyl)thiazolidine-2,4-dione of formula (I).

As shown in Scheme V, a compound of Formula (I), wherein at least one of R ₃, R₄, or R₅of the moiety

is a nitro group, and as shown in formula I′ where R ₃is a nitro group, is reacted with a reducing agent, such as iron in acetic acid or tin in hydrochloric acid, or other agents known to effect this reduction to give an amine XIII.

As further shown in Scheme V, compounds of Formula (I), wherein at least one of R ₃, R₄, or R₅is amino, as shown in amine XIII can be prepared by hydrolysis of carbamate XII, wherein at least one of R₃, R₄, or R₅of Formula (I) is a t-butoxycarbonylamino group, by the use of an acid, such as trifluoroacetic acid, or aqueous hydrochloric acid at 0° C. to 60° C., from 0.5 h to 4 h.

Substituted amine XIV, wherein at least one of R ₃, R₄, or R₅is —NHCO₂R₁₀wherein R₁₀is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, chlorophenyl; substituted amine XV, wherein at least one of R₃, R₄, or R₅is —NHCOR₁₁, wherein R₁₁is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, biphenyl; substituted amine XVI wherein at least one of R₃, R₄, or R₅is —NHCONHR₁₂wherein R₁₂is benzyl, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl can each be prepared by reaction of the amine XIII, respectively with an appropriate alkoxycarbonyl or aryloxycarbonylchloride; acid chloride, or similarly activated acyl compound; or an isocyanate, in an inert solvent, in the presence of an acid scavenger such as triethylamine, at 0° C. to 40° C., for 0.5 h to 24 h.

Referring to Scheme VI: compounds of formula (I), wherein at least one of R ₃, R₄, or R₅is the azido group, as in azide XVII may be prepared from amine XIII, by reaction with sodium nitrite in acetic acid at 0° C. to 20° C., for 10 min to 30 min, followed by a metal azide, such as lithium azide for 1 h to 3 h at 10° C. to 25° C.

Referring to Scheme VII: compounds of formula (I), wherein at least one of R ₃, R₄, or R₅is a carboxyl group as in carboxylic acid XIX can be prepared from the corresponding ester, such as the methyl ester as in ester XVIII by hydrolysis with a base such as potassium carbonate in a solvent such as methanol, or water, followed by acidification with an acid, such as hydrochloric acid.

Referring to Scheme VIII: Compounds of Formula (I), wherein Ar′ is hereinbefore define and at least one of R ₃, R₄, or R₅are as described above, and W is Z- —CH═CH— in alkene XXI may be prepared from the corresponding compounds of formula (I) wherein W is

in alkyne XX by reduction with hydrogen and a catalyst, such as platinum or palladium in a solvent such as an alcohol, or THF at 0° to 30° C. for ½ h to 8 h;

As shown in Scheme IX: compounds of Formula (I) as in alkene XXVI, wherein either R ₃, R₄, and R₅are as previously defined as substituents on Ar′+0, and W is E- —CH═CH—, may be prepared by alkylation of 5-arylsulfonylthiazolidine-2,4-dione V with an alkene XXV under conditions as described in Scheme III for the corresponding alkyne. Alkenes XXIV wherein W is E- —CH═CH—, can be prepared by coupling an iodophenyl compound where Ar′ is hereinbefore defined with an E-stannane XXII in the presence of tetrakistriphenyl-phosphine palladium(0) and copper(I) iodide in a solvent such as DMF at room temperature for 1 h to 3 days and subsequent conversion to alcohol XXIII to alkene XXIV, wherein LG is iodo, may be accomplished in a manner analogous to that shown in Scheme II. A compound such as XXV, above, wherein LG is a leaving group, such as, bromo or iodo is used to alkylate 5-arylsulfonylthiazolidine-2,4-dione V as described herein before in Scheme III.

Referring to Scheme X: compounds of formula (I), wherein Ar′ is herein before described and W is —CH ₂—CH₂— as in dione XXVII, can be prepared from a compound of formula (I) wherein W is either

or E- or Z- —CH═CH—, by hydrogenation in the presence of palladium or platinum in a solvent such as methanol plus 5% water; alternatively, 5-arylsulfonylthiazolidine-2,4-dione V can be alkylated with XXVIII to give dione XXVII.

STANDARD PHARMACOLOGICAL TEST PROCEDURES

The ability of the compounds of this invention to inhibit FPTase was evaluated in the standard pharmacological in vitro test procedures described below. Data for representative examples is summarized in Table I.

Enzyme test procedure: FPTase inhibition in vitro assay was performed according to James, G. L., Brown, M. S., and Goldstein, J. L., Methods in Enzymology, 1995, 255, 38-46; and Garcia, M. A., et al., J. Biol. Chem., 1993, 268, 18415-18420.

Materials—Purified FPTase (Moomaw, J. F. and Casey, P. J., J. Biol. Chem., 1992, 267, 17438-17443), purified His₆-Ras, inhibitor compounds at 10 mg/ml or 10 mM in 100% DMSO, ³H—FPP (50,000 dpm/pmol) Amersham, TCA/SDS (6%/2%), TCA (6%), Glass fiber filters (0.22-0.45 m), vacuum manifold or 96 well filtration plates.

Methods—1. Dilute FPTase inhibitors from stock solutions to 2.5× in 2.5% DMSO, 10 mM DTT, 0.5% octyl-B-glucoside. 2. Solution #1 is added to FPTase reaction in a volume of 20 ml. 3. Standard reaction mix, 50 ml, contains 50 mM Tris (7.5), 10 mM ZnCl ₂, 3 mM MgCl₂, 20 mM KCl, 5 mM DTT, 0.2% octyl-B-glucoside, 1% DMSO, 40 mM His₆-Ras, 10 ng FPTase, and various concentrations of FPTase inhibitors. 4. Incubate for 30-90 min at 25° C. 5. Stop reactions with TCA/SDS (6%/2%), hold at 40° C. for 45-60 min. 6. Filter by manifold or 96 well plate, wash filter 3-5× with TCA (6%). 7. Add scintillant to filters, measure ³H—FPP incorporation into Ras protein.

Analysis of Results—Percent inhibition by test compounds is determined by the following:

(cpm from precipitated Ras with test compounds)−(background cpm)×100=% inhibition.

(cpm from precipitated Ras without test compounds)−(background cpm)

Cell-based test procedure: Tumor inhibition in vitro assay was performed according to P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. McMohan, D. Vistica, J. Warren, H. Bokesh, S. Kenney, and M. R. Boyd, J. Natl. Cancer Instit., 1990, 82 (13), 1107-1112; L. V. Rubinstein, R. H. Shoemaker, K. D. Paull, R. M. Simon, S. Tosini, P. Skehan, D. A. Scudiero, A. Monks, and M. R. Boyd, J. Natl. Cancer Instit., 1990, 82 (13), 1113-1118; A. Monks, et al., J. Natl. Cancer Instit., 1991, 83, 757-766; M. R. Boyd and K. D. Paull, Drug Development Res., 1995, 34, 91-109; and S. P. Fricker and R. G. Buckley, Anticancer Research, 1996, 16, 3755-3760.

Materials—Cell Lines: Human tumor cell lines LS174T, HTB39, LoVo and CaCo2. Cell Media: RPMI 1640 (or DMEM medium and McCoy's medium) with 10% Fetal Bovine Serum supplemented with L-glutamine and Pennicilin/Streptomycin. Compounds: Supplied usually as a 10 mM stock in 100% DMSO. Normal Saline: 150 mM NaCl Trichloroacetic Acid (TCA): 50% (w/v) in water. Sulforhodamine (SRB): 0.4% (w/v) in 1% Acetic Acid. Tris Base: 10 mM in water.

Methods—Cells are plated at 2000 cells per well, per 200 μl media, and allowed to adhere overnight at 37° C. At 24 h post plating, compounds are added directly at a volume of 0.5 μl. Compound is first diluted in DMSO to generate concentrations of compound or reference standard of: 1, 5, 10 and 25 μM. Dilutions can be made in an identical 96 well plate so that compounds can be added using a multichannel micropipettor set at 0.5 μl. The cells are then incubated for four days after which the media is removed using a 12 well manifold by first tipping the plate forward at a 45 degree angle and then inserting the manifold in an upright orientation to prevent the tips of the manifold from disturbing cells at the bottom of the plate. 200 μl of normal saline is then added to each well using an 8 well multichannel pipettor, followed by the careful addition of 50 μl of 50% TCA. The plates are then incubated for 2 h at 4° C, after which the supernatant is removed using the same technique as above and the plates washed twice with 200 μl water. The plates are then air dried and 50 μl of SRB stock solution is carefully added so that the entire bottom of each well is covered. This again can be used using an 8 well multichannel pipettor. The SRB is incubated with fixed cells for 15 min at room temperature, after which the SRB is removed with the manifold as described above and the plates washed twice with 350 μl of 1% acetic acid per well each time. The plates are then air dried after which the bound SRB is released from protein by the addition of 200 μl of Tris base. Resolubilizing the SRB is aided by placing the plates on a rotator for 15-30 min. The absorbance of each well is determined at 550 or 562 nm using a microtiter plate reader.

Analysis of Results—Each compound or dilution thereof is performed in triplicate. Outliers are identified by visual inspection of the data. Each plate should have a control (vehicle only). A standard curve is constructed by plotting the concentration of compound against the average absorbance calculated at that concentration. A curve is plotted and the concentration at which the curve passes through the 50% absorbance mark seen in the control well is the IC ₅₀calculated for that compound.

TABLE I


in vitro FTase Inhibition Assay

	IC₅₀ H-Ras*	IC₅₀ K-Ras*
Ex. No.	μM	μM

96	0.7
97	0.075-0.15	3.5-5.5
101	0.01-0.03	0.11-1.0
102	0.03-0.032	1.4
103	0.03-0.05	0.9-10
104	0.03-0.054	0.23-0.9
105	0.05-0.15	1.5-1.7
106	0.23-0.25	1.3-1.7
107	0.18-0.2	0.62-0.7
108	0.13-0.18	9->10
109	0.065-0.13	1.4-2.1
110	0.4	7
111	0.11-0.15	0.3-0.55
112	0.59-0.60	1.4-1.5
113	0.05-0.06	0.75-0.8
114	0.013-0.032	0.032-0.32
115	0.012-0.32	0.16-0.23
116	0.005-0.01	0.017-0.04
117	0.02-0.03	0.51-1.0
118	0.07	1.9
119	0.13-0.14	1.3-1.7
120	0.018-0.032	0.53-1.0
121	0.12	1.6
122	0.03-0.05	0.23-1.0
123	0.08-0.082	1.0-2.8
124	0.052-0.08	0.91-1.3
125	0.03	0.4
126	0.09	1.7
127	0.12-0.14	1.3-1.5
128	0.001-0.032	0.02-0.22
129	0.1	0.6-0.79
130	0.023-0.056	0.32-1.0
131	0.006-0.032	0.08-0.31
132	0.041-0.073	0.21-1.0
133	0.04-0.2	0.054-1.0
134	0.014-0.85	0.43-0.68
135	0.02-0.032	1.9-2.1
136	0.043-0.05	1.0-1.9
137	0.021-0.4	0.037-0.8
138	0.023-0.032	0.3-0.42
139	0.17-0.14	0.6-5.0
140	0.15-0.3	1.0-3.6
141	0.021-0.032	0.30-0.34
142	0.017-0.03	0.04-1.0
143	0.03	0.85
144	0.04-0.041	0.32-0.55
145	1.2-1.7	5.6-10
147	0.0068-0.21	0.08-0.1
148	0.0045-0.12	0.023-0.031
149	0.45-0.5	1.0-4.9
150	0.0074-0.032	0.016-0.068
151	0.53-0.7	0.21-1.0
152	0.011-0.016	0.1-0.23
153	0.17-0.2	1.0-6.1
154	0.07-0.15	1.0-2.5
155	0.01-0.32	0.42-0.44
157	0.27	5.0
158	0.15	3.8
159	0.65	>10
161	0.9	10
162	1.21	4.0
163	1.3	10
164	0.15	>10
166	0.15	5.3
167	1.5	10
168	0.28	10
169	0.1	1.8
170	0.38	4.7
171	0.2	3.3
175	0.01-0.032	0.053-0.52
176	0.0032-0.032	0.03-0.32
177	0.011-0.032	0.086-0.1
178	0.017-0.032	0.01
179	0.002-0.032	0.005-0.07
180	0.002-0.032	0.007-0.09
181	0.01-0.032	0.10-0.13
182	0.005-0.01	0.032-0.056
189	0.10	1.2
217	0.10	8.5
220	0.09	3.0
222	0.0033	0.033
223	0.063	>1
226	0.03-0.05	0.1-3.2
227	0.007-0.01	0.21-0.4
228	0.004-0.07	0.23-1
229	0.006-0.02	0.1-0.7
230	0.003-0.0035	0.02-0.5
231	0.01-0.021	0.1-1
232	0.005-0.01	0.04-0.64
233	2.9	10

Compounds of this invention were tested in cell-based assays against human tumor cell lines DLD-1 and LoVo and ras-transformed rat fibroblast cell lines, RAT-H-ras and RAT-K-ras, and the parent cell line RAT-2, as described under Assays. The range observed for inhibition of cell growth was IC ₅₀=7 to 18 μM. The results are displayed in Table I.

The following examples (239-267) of the invention were tested using the procedure described above with changes in the materials used as described below. The results are displayed in Table II.

Materials—Cell Lines: Human tumor cell lines DLD-1 and LoVo; ras-transformed rat fibroblast cell lines, RAT-H-ras and RAT-K-ras (growth inhibited by standard FPTase inhibitors), and the parent cell line RAT-2 (resistant to standard FPTase inhibitors). Cell Media: RPMI 1640 (or DMEM medium and McCoy's medium) with 10% Fetal Bovine Serum supplemented with L-glutamine and Pennicilin/Streptomycin. Compounds: Supplied usually as a 10 mM stock in 100% DMSO. Normal Saline: 150 mM NaCl Trichloroacetic Acid (TCA): 50% (w/v) in water. Sulforhodamine (SRB): 0.4% (w/v) in 1% Acetic Acid. Tris Base: 10 mM in water.

	TABLE II


	in vitro FTase Inhibition
	Assay

	IC₅₀ (wi. H-	IC₅₀ (wi. K-
	Ras)	Ras)
Ex. No.	μM	μM

239	0.7	10
240	0.5	>10
241	1.5	>10
242	1	>10
243	0.3	10
244	0.1	7
245	0.05	3
246	0.3	10
247	0.3	10
248	0.45	5.5
249	0.4	6
250	1.5	10
251	0.15	8.5
252	0.08	8
253	0.09	4.5
254	0.5	>10
255	0.15	10
256	0.8	10
257	0.035	>10
258	2	10
259	0.15	6.5
260	0.1	3
261	0.3	3
262	0.07	2
263	0.15	6.5
264	0.3	>10
265	1.5	>10
266	0.5	>10
267	5	>10

Examples 239-267of this invention were tested in cell-based assays against human tumor cell lines DLD-1 and LoVo and ras-transformed rat fibroblast cell lines, RAT-H-ras and RAT-K-ras, and the parent cell line RAT-2, as described under Assays. The range observed for inhibition of cell growth was IC ₅₀=7 to >40 μM. Results are displayed in Table II.

Compounds of this invention were tested for in vivo effects in rats against various tumors. For the compound of example 114, when tested against a K-ras dependent human colon carcinoma (LoVo), the following results were obtained (Table III):

TABLE III


In Vivo Data for the Compound of Example 114

A
Drug
Treatment
mg/kg	b	c	d	b	c	d	b	c	d
per dose	Day 8	% T/C	(p)	Day 15	% T/C	(p)	Day 22	% T/C	(p)

0.5%	88			308			598
Methocel
0.4%
Tween 80
Cpd.	61	70	0.10	238	77	0.14	454	76	0.08
(100 PO)
Cpd.	45	51	0.02	110	36	<.01	255	43	<.01
(75 IP)
Cpd.	65	74	0.15	146	47	0.02	258	43	<0.01
(50 IP)
Cpd.	31	35	<0.01	125	41	<.01	251	42	<.01
(100 IP)
Vincristine	14	16	<0.01	24	8	<.01	84	14	<.01
(1 IP)
2% Tween	39			121			198
in D5W
Cpd.	86	221	0.95	182	150	0.84	324	163	0.92
(75* IP)
20% BCD	62			146			339
in
0.1 N HCl
Cpd.	50	81	0.22	138	95	0.44	299	88	0.31
(100 PO)

A
Drug
Treatment
mg/kg	b	c	d	b	c	d	e
per dose	Day 29	% T/C	(p)	Day 36	% T/C	(p)	S/T

0.5%	748			1264			10/10
Methocel
0.4%
Tween 80
Cpd.	608	81	0.20	934	74	0.09	10/10
(100 PO)
Cpd.	504	67	0.09	764	60	0.03	8/10
(75 IP)
Cpd.	445	59	0.07	964	76	0.16	5/10
(50 IP)
Cpd.	341	46	0.01	559	44	0.01	9/10
(100 IP)
Vincristine	139	19	<0.01	194	15	<.01	9/10
(1 IP)
2% Tween	287			424			10/10
in D5W
Cpd.	478	167	0.92	666	157	0.91	10/10
(75* IP)
20% BCD	499			813			10/10
in
0.1 N HCl
Cpd.	641	128	0.77	872	107	0.60	9/10
(100 PO)

Examples 100, and 103,when tested in rats against Rat-2 fibroblasts transformed by oncogenic H-ras for 11 days, i.p., the following results were obtained for day 11 (Table IV):

TABLE IV


Ex. No.	Dose, mg/kg	% T/C

100	100	44
100	30	60
100	10	100
103	100	No efficacy at this
		dose

In a similar model when tested in rats against Rat-2 fibroblasts transformed by oncogenic K-ras for 25 days, i.p, the compound of example 100 showed no efficacy at 100 mg/kg.

Based on the results of these standard pharmacological test procedures, the compounds of this invention are useful as agents for treating, inhibiting or controlling ras-associated diseases by inhibiting farnesyl-protein transferase enzyme, when administered in amounts ranging from about 10 to about 200 mg/kg of body weight per day. A preferred regimen for optimum results would be from about 10 mg to about 100 mg/kg of body weight per day and such dosage units are employed that a total of from about 100 mg to about 1000 mg of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period.

The dosage regimen for treating mammals may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. A decidedly practical advantage is that these active compounds may be administered in any convenient manner such as by the oral, intravenous, intramuscular or subcutaneous routes.

The active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet. For oral therapeutic administration, these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between 10 and 1000 mg of active compound. The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agnet such as peppermint, oil of wintergreen or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained-release preparations and formulations.

These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures therof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth or microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and starage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid poly-ethylene glycol), suitable mixtures thereof, and vegetable oils.

The present invention accordingly provides a pharmaceutical composition which comprises a compound of Formula (I) of this invention in combination or association with a pharmaceutically acceptable carrier. In particular, the present invention provides a pharmaceutical composition which comprises an effective amount of a compound of this invention and a pharmaceutically acceptable carrier.

As used in accordance with this invention, the term providing an effective amount of a compound means either directly administering such compound, or administering a prodrug, derivative, or analog which will form an effective amount of the compound within the body.

The present invention 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.

The invention will be more fully described in conjunction with the following specific examples which are not to be construed as limiting the scope of the invention.

EXAMPLE 1

5-(3-Methoxyphenyl-4-sulfonyl)-thiazolidine-2,4-dione

To a solution of 5-bromothiazolidine-2,4-dione (6.66 g, 34.0 mmol, Zask et al, J. Med. Chem. 1990, 33, 1418-1423) and 3-methoxybenzenethiol (5.00 g, 35.7 mmol) in dry THF (150 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1.0M in THF, 56 mL, 56 mmol) dropwise. After 30 min. the reaction mixture was warmed to room temperature. After an additional hour, 2N HCl was added to pH=1. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was dried (MgSO4), concentrated and flash chromatographed (3:1 hexanes:ethyl acetate) to provide 5-(3-methoxyphenyl-4-sulfanyl)thiazolidine-2,4-dione, as a white solid (4.86 g, 56%); a sample of 5-(3-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-dione (4.70 g, 18.4 mmol) was oxidized with 9.4 ml of 30% hydrogen peroxide in 50 ml of acetic acid at 45° C. for 3 hours to give 3.4 g (64%) of the title compound as a glass; NMR(CDCl[0296] ₃) δ3.9 (s,3H), 5.53 (s,1H), 7.3 (m,1H), 7.42 (s,1H), 7.53 (m,2H); MS m/Z 285.9 (M−H) (calcd. For C₁₀H₉NO₅S₂)

EXAMPLE 2

5-(4-Fluorophenyl-4-sulfonyl)-thiazolidine-2,4-dione

In the manner of Example 1 above 4-fluorobenzenethiol and bromothiazolidinedione gave 5-(4-fluorophenyl-4-sulfanyl)-thiazolidine-2,4-dione, which on oxidation gave the title compound [U.S. Pat. No. 5,605,918; February 1997;Wrobel, et al.]. [0297]

EXAMPLE 3

5-(4-lodophenyl-4-sulfonyl)-thiazolidine-2,4-dione

To a solution of 5-bromothiazolidinedione (5.94 g, 30.3 mmol) in 100 ml of absolute ethanol was added sodium 4-iodophenylsulfinate (9.67 g, 33.3 mmol)and this slurry was stirred for about 18 hours at room temperature. Solvent was removed and the residue was combined with water and was acidified with 2N hydrochloric acid. The organic portion was chromatographed on silica gel with hexanes-ethyl acetate (3:1) to give 5.8 g (50%) of the title compound, mp 190-193° C. [0298]

In a like manner to the procedure of Example 3 above, the following aryl sulfinate salts which are either commercially available, or are prepared by the reduction of the corresponding sulfonyl chloride with sodium iodide in acetone (Harwood, Julia, and Thuillier, Tetrahedron, 1980, 36, 2483-2487), were reacted with 5-bromothiazolidinedione to give the indicated product, 5-arylsulfonylthiazolidinediones of Examples 4-17:



EX.
No.	SULFINATE SALT	PRODUCT	MELTING POINT ° C.

4	Sodium 4-Trifluoro-	5-(4-Trifluoromethoxy-	108-110
	methoxybenzenesulfinate	benzenesulfonyl)-thiazol-
		idine-2,4-dione
5	Sodium 3-Nitrobenzene	5-(3-Nitrobenzenesulfonyl)-	139-140
	sulfinate	thiazolidine-2,4-dione
6	Sodium 4-Nitrobenzene	5-(4-Nitrobenzenesulfonyl)-	182-183
	sulfinate	thiazolidine-2,4-dione
7	Sodium 4-(Pyridin-4-	5-[4-(Pyridin-4-yloxy)-	160 with
	yloxy)benzenesulfinate	benzenesulfonyl]-thiazolidine-2,4-	decomp.
		dione
8	Sodium 4-Phenoxy-	5-(4-Phenoxybenzene sulfonyl)-	160-162
	benzene-sulfinate	thiazolidine-2,4-dione
9	Sodium 4-Benzyloxy-	5-(4-Benzyloxybenzene-	190-200
	benzenesulfinate	sulfonyl)-thiazolidine-2,4-dione	decomp.
10	Sodium 3,4-Dimethoxy-	5-(3,4-Dimethoxybenzene-	220-222
	benzene sulfinate	sulfonyl)-thiazolidine-2,4-dione
11	Sodium N-Acetyl-3-amino-	N-[5-(2,4-Dioxothiazolidine-5-	217-219
	4-methoxyphenyl-sulfinate	sulfonyl)-2-methoxy-phenyl]-
		acetamide
12	Sodium 5-Chloro-	5-(5-Chloro-thiophene-2-	133-135
	thiophene-2-sulfinate	sulfonyl)-thiazolidine-2,4-dione
13	Sodium Thiophene-2-	5-(Thiophene-2-sulfonyl)-	176-177
	sulfinate	thiazolidine-2,4-dione
14	Sodium 5-Pyridin-2-yl-	5-(5-Pyridin-2-yl-thiophene-2-	168-170
	thiophene-2-sulfinate	sulfonyl)-thiazolidine-2,4-dione
15	Sodium 4-Butoxybenzene	5-(4-Butoxybenzenesulfonyl)-	120-121
	sulfinate	thiazolidine-2,4-dione
16	Sodium 1-Naphthalenyl)	5-[(1-Naphthalenyl)sulfonyl]-2,4-	187-188
	sulfinate	thiazolidinedione
17	Sodium (8-Quinolinyl)	5-[(8-Quinolinyl)sulfonyl]-2,4-	amorphous
	sulfinate	thiazolidinedione	solid

EXAMPLE 18

5-(2,5-Dichlorophenyl)pent-4-yn-1-ol

A solution of 1,4-dichloro-2-iodobenzene (20.0 g, 73.3 mmol), 4-pentyn-1-ol (6.17 g, 73.3 mmol), bistriphenylphosphine(Pd II) chloride (1.03 g, 1.47 mmol), and copper(I) iodide (0.14 g, 0.733 mmol) in 400 ml of diethylamine was stirred under nitrogen for three days. This was diluted with dichloromethane and the oily layer was adsorbed onto silica gel and eluted with hexanes-ethyl acetate (5:1) to give 5-(2,5-dichloro-phenyl)pent-4-yn-1-ol, 13.7 g (82%); NMR (CDCl3) δ1.9 (m,2H), 2.6 (t,2H), 3.85 (t,2H), 7.2 (dd,1H), 7.28 (m,1H), 7.4 (d,2H). [0300]

EXAMPLE 19

5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol

Preparation of the title compound with 4-bromophenyl methyl sulphone (5.87 g, 25 mmol) and 4-pentyn-1-ol (2.1 g, 25 mmol) according to the procedure in Example 18 yielded 5.12 g (87%) of yellow oil which was characterized as 5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol: NMR (CDCl[0301] ₃) δ1.88-1.93 (m,2H), 2.56-2.60 (t, J=6.99, 2H), 3.04 (s,3H), 3.80-3.84 (t, J=6.15,2H), 7.56 (d, J=5.1, 2H), 7.85 (d,J=4.8, 2H). MS m/Z 239 (M+H cald. for C₁₂H₁₄O₃S 238.3)

In a manner described in Example 19 immediately above the following acetylenic alcohols of Examples 20-48 were prepared from the corresponding iodobenzene or bromobenzene and 4-pentyn-1-ol (structures were confirmed as above by NMR):



EX. No.	PRODUCT	Mass Spectrum M+

20	5-(2-Methyl-5-nitrophenyl)pent-4-yn-1-ol	220 (M + H)
21	5-(2-Methoxy-5-nitrophenyl)pent-4-yn-1-ol	235.0
22	5-(2-Methoxy-4-nitrophenyl)pent-4-yn-1-ol	235.0
23	5-(4-Nitro-2-trifluoromethylphenyl)pent-4-yn-1-ol	273.0
24	5-(3-Fluoro-5-nitrophenyl)pent-4-yn-1-ol	223.0
25	5-(3-Fluoro-4-methoxy-5-nitrophenyl)pent-4-yn-1-ol	254.2 (M + H)
26	5-(4-Methoxy-2-nitrophenyl)pent-4-yn-1-ol	234.2 (M + H)
27	[3-Chloro-4-(5-hydroxypent-1-ynyl)phenyl]-carbamic
	Acid tert-Butyl Ester
28	5-(4-Pyrrol-1-ylphenyl)pent-4-yn-1-ol	226.2 (M + H)
29	5-(2,5-Dimethylphenyl)pent-4-yn-1-ol	189.1 (M + H)
30	5-(5-Chloro-2-methylphenyl)pent-4-yn-1-ol	208.8 (M + H)
31	5-(4-Chloro-2-methylphenyl)pent-4-yn-1-ol	208.0
32	5-(2,4-Dimethylphenyl)pent-4-yn-1-ol	188.1
33	5-(2-Methyl-4-nitrophenyl)pent-4-yn-1-ol	219.0
34	5-(4-Bromo-2-methylphenyl)pent-4-yn-1-ol	253.0
35	3-(5-Hydroxypent-1-ynyl)-4-methylbenzoic Acid Methyl	232.1
	Ester
36	4-(5-Hydroxypent-1-ynyl)-3-methylbenzoic Acid Methyl	232.1
	Ester
37	5-(4-tert-Butylphenyl)pent-4-yn-1-ol
38	[4-Methyl-3-(5-hydroxypent-1-ynyl)phenyl] carbamic
	Acid tert-Butyl Ester
39	5-(2-Chlorophenyl)pent-4-yn-1-ol
40	5-(2,4-Dichlorophenyl)pent-4-yn-1-ol
41	4-(5-Hydroxypent-1-ynyl)trifluoromethyl benzene
42	4-(5-Hydroxypent-1-ynyl)trifluoromethoxy-benzene
43	[3-Methyl-4-(5-hydroxypent-1-ynyl)phenyl] carbamic
	Acid tert-Butyl Ester
44	N-tert-Butyl-3-(5-hydroxypent-1-ynyl)-4-
	methylbenzamide
45	4-(5-Hydroxypent-1-ynyl)phenylcarbamic Acid tert-Butyl
	Ester
46	3-(5-Hydroxypent-1-ynyl)-4-methylbenzoic Acid Methyl
	Ester
47	5-(4-Chlorophenyl)pent-4-yn-1-ol
48	5-(3-Chlorophenyl)pent-4-yn-1-ol

EXAMPLE 49

6-(4-Chlorophenyl)hex-5-yn-1-ol

In a manner described in Example 18 above, 5-hexyn-1-ol was reacted with 1-chloro-4-iodobenzene to give the title compound, MS m/Z exact mass 209.724 (M+H) (calcd. For C[0303] ₁₂H₁₃OCl 209.70).

EXAMPLE 50

11-(4-Chlorophenyl)undec-10-yn-1-ol

In a manner described in Example 18 above, 10-undecyn-1-ol was reacted with 1-chloro-4-iodobenzene to give the title compound; NMR (CDCl[0304] ₃) δ1.21-1.50 (m, 10H), 1.50-1.65 (m, 4H), 2.36-2.41 (m,2H), 3.61-3.66(m,2H), 7.16-7.31 (m, 4H).

EXAMPLE 51

3-(4-Phenoxyphenyl)prop-2-yn-1-ol

Preparation of the title compound with commercial available 4-bromo-diphenyl ether (5.93 g, 23.8 mmol) according to the procedure in Example 18 yielded 440 mg (8.2%) of brown oil which was characterized as 3-(4-phenoxyphenyl)prop-2-yn-1-ol: [0305]
NMR (CDCl[0306] ₃) δ4.50 (d, J=6), 6.91 (d, J=2.01, 1H), 6.93 (d, J=2.01, 1H), 7.01 (d, J=0.63, 1H), 7.04 (d, J=1.17, 1H), 7.11-7.16 (m, 1H), 7.36 (d, J=0.6, 1H),7.38 (d, J=2.52, 2H), 7.41 (d, J=1.92, 1H). MS m/z 224.08 (M+ calcd. for C₁₅H₁₂O₂=224.08)

EXAMPLE 52

3-Biphenyl-4-yl-prop-2-yn-1-ol

In a manner described in Example 18 above, propargyl alcohol was reacted with 4-bromobiphenyl to give the title compound as white crystals: NMR (CDCl[0307] ₃) δ4.53 (d, J=4.74, 2H), 7.38 (d, J=7.17, 1H), 7.42-7.60 (m, 8H). MS m/z 208 (M+ calcd. for C₁₅H₁₂O=208.3).

EXAMPLE 53

3-Thiophene-2-yl-prop-2-yn-1-ol

In a manner described in Example 18 above, propargyl alcohol was reacted with 2-bromothiophene to give the title compound as a brown oil which was used in the next step without further purification. [0308]

EXAMPLE 54

1-Chloro-4-(5-iodopent-1-ynyl)benzene

5-(4-Chlorophenyl)pent-4-yn-1-ol (35.7 g, 182 mmol), 4-dimethylaminopyridine (8.9 g, 73 mmol), p-toluenesulfonyl chloride (34.7 g, 182 mmol), and 62 ml of triethylamine were combined in 330 ml of dichloromethane at 0° C. The mixture was stirred for 30 min. at 0° then 18 hours at room temperature. Dilution with 200 ml of dichloromethane followed by washing with brine, drying over magnesium sulfate, filtration through silica gel with hexane-ethyl acetate, 8:1, gave a yellow solid on evaporation. Crystallization from ether gave 5-(4-Chlorophenyl)pent-4-yn-1-ol p-toluenesulfonate as colorless crystals (31.7 g, 49% yield). This was converted to the title compound by reaction with sodium iodide in acetone, and was used in subsequent reactions with no further purification; MS m/z 303.9 (M+ calcd. for C[0309] ₁₁H₁₀ClI=304.6).

EXAMPLE 55

1-(5-lodo-pent-1 -ynyl)-4-methanesulfonylbenzene

Preparation of the title compound with tosylated alcohol of Example 19, 5-(4-methanesulfonylphenyl)pent-4-yn-1-ol (3.14 g, 8.35 mmol), NaI (6.26 g, 41.76 mmol) following the procedure of Example 54 yielded 2.8 g (96%) of the title compound as a red oil: NMR (CDCl[0310] ₃) δ2.06-2.15 (m, 2H), 2.58-2.63 (t, J=6.78, 2H), 3.04 (s, 3H), 3.33-3.37 (t, J=6.69, 2H), 7.57 (d, J=1.77, 2H), 7.85 (d, J=4.95, 2H). MS m/z 348.9 (M+H cald. for C₁₂H₁₃O₂S 348=349.2).

EXAMPLE 56

1,4-Dichloro-2-(5-iodopent-1-ynyl)benzene

5-(2,5-Dichlorophenyl)pent-4-yn-1-ol (13.7 g, 59.8 mmol), triphenylphosphine (20.4 g, 77.8 mmol), and imidazole (5.71 g, 83.8 mmol) in a mixed solvent (100 ml acetonitrile-150 ml ether) was stirred under nitrogen at 0° C., and to this was slowly added iodine (21.3 g, 83.8 mmol). The solution was allowed to warm to room temperature and stirring was continued for 18 hours. This was chromatographed on silica gel with hexane to give the title compound (14.7 g,72%), MS m/z 337.9 (M−H calcd. for C[0311] ₁₁H₉Cl₂I=338.0).

In the manner described in Example 55, above, the following alcohols were converted to the corresponding iodides of Examples 56-88, and structures were confirmed as above by NMR:



EX.
No.	ALCOHOL	PRODUCT	MASS SPECTRUM

56	5-(2,4-Dichlorophenyl)-pent-	1,5-Dichloro-2-(5-iodo-	337.9
	4-yn-1-ol	pent-1-ynyl)benzene
57	5-(2-Methyl-5-nitro-	2-(5-Iodopent-1-ynyl)-1-	330
	phenyl)pent-4-yn-1-ol	methyl-4-nitro-benzene
58	5-(2-Methoxy-5-nitro-	2-(5-Iodopent-1-ynyl)-1-	345.1
	phenyl)pent-4-yn-1-ol	methoxy-4-nitro-benzene
59	5-(2-Methoxy-4-nitro-	1-(5-Iodopent-1-ynyl)-2-	345.0
	phenyl)pent-4-yn-1-ol	methoxy-4-nitro-benzene
60	5-(4-Nitro-2-trifluoro-methyl-	1-(5-Iodopent-1-ynyl)-4-	383.0
	phenyl)pent-4-yn-1-ol	nitro-2-trifluoro-
		methylbenzene
61	5-(3-Fluoro-5-nitro-	1-Fluoro-3-(5-iodopent-1-	334
	phenyl)pent-4-yn-1-ol	ynyl)-5-nitrobenzene
62	5-(3-Fluoro-4-methoxy-5-	1-Fluoro-5-(5-iodopent-1-
	nitrophenyl)pent-4-yn-1-ol	ynyl)-2-methoxy-3-
		nitrobenzene
63	5-(4-Methoxy-2-nitro-	1-(5-Iodopent-1-ynyl)-4-
	phenyl)pent-4-yn-1-ol	methoxy-2-nitro-benzene
64	[3-Chloro-4-(5-hydroxy-pent-	[3-Chloro-4-(5-iodo-pent-1-	[mp 104-
	1-ynyl)-phenyl]-carbamic	ynyl)phenyl]-carbamic acid	106° C.]
	acid tert-butyl ester	tert-butyl ester
65	5-(4-Pyrrol-1-yl-phenyl)-pent-	1-[4-(5-Iodopent-1-ynyl)-	335.7
	4-yn-1-ol	phenyl]-1H-pyrrole
66	5-(2,5-Dimethylphenyl)-	1-(5-Iodopent-1-ynyl)-2,5-	298.0
	pent-4-yn-1-ol	dimethyl-benzene
67	5-(5-Chloro-2-methyl-	4-Chloro-2-(5-iodopent-1-	317.9
	phenyl)-pent-4-yn-1-ol	ynyl)-1-methyl-benzene
68	5-(4-Chloro-2-methyl-	4-Chloro-1-(5-iodopent-1-	317.9
	phenyl)pent-4-yn-1-ol	ynyl)-2-methyl-benzene
69	5-(2,4-Dimethyl-phenyl)pent-	1-(5-Iodopent-1-ynyl)-2,4-	298.0
	4-yn-1-ol	dimethyl-benzene
70	5-(2-Methyl-4-nitro-phenyl)-	1-(Iodopent-1-ynyl)-2-	328.9
	pent-4-yn-1-ol	methyl-4-nitrobenzene
71	5-(4-Bromo-2-methyl-phenyl)	4-Bromo-1-(5-iodopent-1-	361.9
	pent-4-yn-1-ol	ynyl)-2-methyl-benzene
72	3-(5-Hydroxypent-1-ynyl)-4-	3-(5-Iodopent-1-ynyl)-4-	341.9
	methylbenzoic acid methyl	methylbenzoic acid methyl
	ester	ester
73	4-(5-Hydroxy-pent-1-ynyl)-3-	3-(5-Iodopent-1-ynyl)-4-	341.9
	methylbenzoic acid methyl	methylbenzoic Acid Methyl
	ester	Ester
74	[4-Methyl-3-(5-hydroxypent-	[3-(5-Iodopent-1-ynyl)-4-	399.9
	1-ynyl)phenyl]carbamic acid	methylphenyl]carbamic
	tert-butyl ester	acid tert-butyl ester
75	5-(2-Chlorophenyl)-pent-4-	1-Chloro-2-(5-iodopent-1-	304.0
	yn-1-ol	ynyl)benzene
76	5-(2,4-Dichlorophenyl)pent-	2,4-Dichloro-1-(5-iodo-	337.9
	4-yn-1-ol	pent-1-ynyl)benzene
77	4-(5-Hydroxypent-1-	1-(5-Iodopent-1-ynyl)-4-	337.9
	ynyl)trifluoromethyl-benzene	trifluoromethylbenzene
78	4-(5-Hydroxypent-1-	1-(5-Iodopent-1-ynyl)-4-
	ynyl)trifluoromethoxy-	trifluoromethoxy-benzene
	benzene
79	[3-Methyl-4-(5-hydroxypent-	[4-(5-Iodopent-1-ynyl)-3-	399.9
	1-ynyl)-phenyl]carbamic	methylphenyl]carbamic
	Acid tert-Butyl Ester	Acid tert-Butyl Ester
80	N-tert-Butyl-3-(5-	N-tert-Butyl-3-(5-iodo-pent-	383.8
	hydroxypent-1-ynyl)-4-	1-ynyl)-4-methyl-
	methylbenzamide	benzamide
81	4-(5-hydroxypent-1-	[4-(5-Iodopent-1-ynyl)-	385.9
	ynyl)phenylcarbamic Acid	phenyl]carbamic Acid tert-
	tert-Butyl Ester	Butyl Ester
82	3-(5-Hydroxypent-1-ynyl)-4-	3-(5-Iodopent-1-ynyl)-4-
	methylbenzoic Acid Methyl	methylbenzoic Acid Methyl
	Ester	Ester
83	5-(3-Nitrophenyl)pent-4-yn-	1-(5-Iodopent-1-ynyl)-3-	315.8
	1-ol	nitrobenzene
84	5-(4-Nitrophenyl)pent-4-yn-	1-(5-Iodopent-1-ynyl)-4-	315.9
	1-ol	nitrobenzene
85	5-(4-tert-Butylphenyl)pent-4-	1-tert-Butyl-4-(5-iodo-pent-	326.0
	yn-1-ol	1-ynyl)benzene
86	5-(3-Chlorophenyl)pent-4-	1-Chloro-3-(5-iodopent-1-	304.0
	yn-1-ol	ynyl)benzene
87	6-(4-Chlorophenyl)hex-5-yn-	1-(4-Chlorophenyl)-6-iodo-
	1-ol	1-hexyne
88	11-(4-Chlorophenyl)-undec-	1-(4-Chlorophenyl)-11-
	10-yn-1-ol	iodo-1-undecyne

EXAMPLE 89

1-(3-Bromo-1-propynyl)-4-phenoxybenzene

A solution of 3-(4-phenoxyphenyl)prop-2-yn-1-ol of Example 51 (415 mg, 1.85 mmol), triphenylphosphine (514 mg, 1.96 mmol), carbon tetrabromide (650 mg, 1.96 mmol) in THF (3 ml) was stirred at room temperature for 3 days. Evaporation of the solution, and chromatography of the residue gave the title compound as a brown oil: NMR (CDCl[0313] ₃) δ4.16 (s, 2H), 6.91 (d, J=2.1, 1H), 6.93 (d, J=2.1, 1H), 7.01 (d, J=0.93, 1H), 7.04 (d, J=1.14, 1H), 7.12-7.17 (m, 1H), 7.36 (d, J=0.75, 1H), 7.39 (d, J=1.98, 2H), 7.42 (d, J=2.64, 1H). MS m/z 288 (M+1 calcd. for C₁₅H₁₁BrO 287.155).

In the manner described in Example 89, above, the following alcohols were converted to the corresponding bromides of Examples 90-91:



			mass
EX. No.	ALCOHOL	PRODUCT	spectrum

90	3-Thiophene-2-ylprop-2-	2-(3-Bromoprop-1-ynyl)-thiophene	201.9 (M + H)
	yn-1-ol
91	3-Biphenyl-4-ylprop-2-yn-	4-(3-Bromoprop-1-ynyl)-	270 (M − H)
	1-ol	biphenyl

EXAMPLE 92

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione

To a solution of 5-(4-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-dione [U.S. Pat No. 5,605,918; February 1997; Wrobel, et al.](1.00 g, 3.92 mmol)in THF (40 ml) was added NaH (0.34 g, 8.62 mmol) at 0° C. and stirring was continued for 30 minutes. To this was added a solution of 1-(4-chlorophenyl)-5-iodo-1-pentyne (1.25 g, 4.12 mmol)in 3 ml of THF. This was then stirred at room temperature for 18 hours, and then quenched in water. The resultant oil was chromatographed on silica gel using hexane:ethyl acetate (4:1) to give the title compound as a pale yellow solid, m.p. 106-109° C. [0315]
In the manner described in Example 92 immediately above, the appropriate substituted alkyl iodide was reacted with a substituted-phenyl thiazolidinedione to give the following compounds of Examples 93-96: [0316]

EXAMPLE 93

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione

MS m/z 444.2 (calcd for C[0317] ₂₂H₂₀ClNO₃S₂445.99).

EXAMPLE 94

5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)-thiazolidine-2,4-dione

mp 54-56° C., MS m/z 514.0 (calcd. for C[0318] ₂₇H₃₀ClNO₃516.1).

EXAMPLE 95

5-(4-Methoxyphenyisulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione

This was used in the next step without further purification [0319]

EXAMPLE 96

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)-thiazolidine-2,4-dione

This was used in the next step without further purification [0320]

EXAMPLE 97

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione

To a solution of 5-[5-(4-Chlorphenyl)pent-4-ynyl]-5-(4-methoxyphenyl sulfanyl)-thiazolidine-2,4-dione of Example 92 above, (0.87 g, 2.0 mMol) in glacial acetic acid (30 ml) at 60° C. was added 30% hydrogen peroxide (0.82 ml, 8.0 mmol). After 30 minutes the reaction mixture was evaporated and the residue was subjected to chromatography to give the title compound, MS (M−H) m/z 462.0 (calcd. For C[0321] ₂₁H₁₈CINO₅S₂463.96).

EXAMPLE 98

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione (0.30 g, 0.81 mmol) and isobutyraldehyde (0.37 ml, 4.04 mmol) were dissolved in acetonitrile (40 ml). Oxygen was bubbled through this solution for 18 hours, and then the solution was evaporated and the residue was subjected to chromatography on silica gel (hexane-ethyl acetate, 1:1) to give 0.108 g, 28% yield of the title compound, mp 145-148° C., MS m/z 476.0. [0322]

EXAMPLE 99

5-[1-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione

5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione was converted to the title compound using the procedure of Example 98 immediately above, mp 114-121° C. [0323]

EXAMPLE 100

To a solution of 5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.]((2.74 g, 9.5 mMol) in DMF (50 ml) was added sodium hexamethyldisilazide (1.0 M solution in THF—19.0 ml, 19.0 mmol) at room temperature, under nitrogen, and this was stirred for 15 minutes. To this was added 1-(4-chlorophenyl)-5-iodo-1-pentyne (2.70 g, 9.5 mmol) over 5 minutes, and this solution was stirred overnight at room temperature. The reaction mixture was quenched in water, and the solid that was obtained was recrystallized from methanol to give 1.59 g of the title compound as colorless crystals, m.p. 172-174°; NMR (CDCl[0324] ₃) δ1.59 (m, 1H); 2.0(m, 1H); 2.36 (dq (doublet of quartets?), 1H); 2.5 (t, 2H); 2.67 (dq, 1H); 3.88 (s, 3H); 7.0 (d, 2H); 7.26 (s, 4H) 7.86 (d, 2H)

In a manner essentially that of Example 100, the following products of Examples 101-171 were obtained by alkylation of an arylthiazolidine-2,4-dione with the appropriate iodo or bromo compound. All structures were verified by NMR and gave spectra consistent with that shown in Example 100:



Ex.		melting	mass
No.	Product	point ° C.	spectrum m/z (M − H)

101	5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-	133-135	463.0
	methoxybenzenesulfonyl)thiazolidine-2,4-
	dione
102	5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-	134-136	463.0
	methoxybenzenesulfonyl)thiazolidine-2,4-
	dione
103	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-	176-177	447.0
	tolylsulfonyl)thiazolidine-2,4-dione
104	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-	157-159	558.8
	iodobenzenesulfonyl)thiazolidine-2,4-dione
105	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-		450.9
	fluorobenzenesulfonyl)thiazolidine-2,4-
	dione
106	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-	193-194	525.0
	phenoxybenzenesulfonyl)-thiazolidine-2,4-
	dione
107	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-	150-153	483.0
	(naphthalene-2-sulfonyl)thiazolidine-2,4-
	dione
108	N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-	232	490.0
	dioxothiazolidine-5-	decomp.
	sulfonyl}phenyl)acetamide
109	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-	pale	484.0
	(quinoline-8-sulfonyl)thiazolidine-2,4-dione	yellow
		solid
110	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-	tan solid	477.9
	nitrobenzenesulfonyl)thiazolidine-2,4-dione
111	5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-	181-184	539.0
	chlorophenyl)pent-4-ynyl]-thiazolidine-2,4-
	dione
112	5-(4-Butoxybenzenesulfonyl)-5-[5-(4-	116-118	505.0
	chlorophenyl)-pent-4-ynyl]-thiazolidine-2,4-
	dione
113	5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-	172-174	483.0
	(naphthalene-1-sulfonyl)-thiazolidine-2,4-
	dione
114	5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-	124-126	497.4
	methoxy-benzenesulfonyl)-thiazolidine-2,4-
	dione
115	5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-	yellow	593.3
	iodobenzenesulfonyl)-thiazolidine-2,4-dione	amorphous
		solid
116	5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-	179-180	560.5
	(pyridin-4-yloxy)benz-	decomp.
	enesulfonyl]thiazolidine-2,4-dione
117	5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-	129-133	497.4
	methoxybenzenesulfonyl)-thiazolidine-2,4-
	dione
118	5-(4-Methoxybenzenesulfonyl)-5-[5-(3-	126-130	473.5
	nitrophenyl)pent-4-ynyl]thiazolidine-2,4-
	dione
119	5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-	190-191	535.6
	phenoxybenzenesulfonyl)thiazolidine-2,4-
	dione
120	5-(4-Iodobenzenesulfonyl)-5-[5-(4-	205-207	569.4
	nitrophenyl)pent-4-ynyl]thiazolidine-2,4-
	dione
121	5-(4-Methoxybenzene sulfonyl)-5-[5-(4-	156-158	473.5
	nitrophenyl)pent-4-ynyl]thiazolidine-2,4-
	dione
122	5-(4-Methoxybenzene sulfonyl)-5-[5-(2-	yellow oil	487.5
	methyl-5-nitrophenyl)pent-4-
	ynyl]thiazolidine-2,4-dione
123	5-(4-Methoxybenzenesulfonyl)-5-[5-(2-	orange	503.5
	methoxy-5-nitrophenyl)pent-4-	solid
	ynyl]thiazolidine-2,4-dione
124	5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-	203-204	549.6
	(4-phenoxybenzenesulfonyl-thiazolidine-
	2,4-dione
125	5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-	188-190	583.4
	nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-
	dione
126	5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-	168-172	507.6
	5-(naphthalene-1-sulfonyl)-thiazolidine-2,4-
	dione
127	5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-	197-200	507.6
	(naphthalene-2-sulfonyl)-thiazolidine-2,4-
	dione
128	5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-	199	572.6
	[4-(pyridin-4-yloxy)-	decomp.
	benzenesulfonyl]thiazolidine-
	2,4-dione
129	5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-	210-212	549.6
	(4-phenoxybenzenesulfonyl)-thiazolidine-
	2,4-dione
130	5-(4-Methoxybenzenesulfonyl)-5-[5-(2-	yellow	487.5
	methyl-4-nitrophenyl)-pent-4-ynyl]-	glass
	thiazolidine-2,4-dione
131	5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-	150-152	657.5
	nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-
	dione
132	5-(4-Methoxybenzenesulfonyl)-5-[5-(2-	yellow	503.5
	methoxy-4-nitrophenyl)pent-4-	gum
	ynyl]thiazolidine-2,4-dione
133	5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-	white	491.5
	(4-methoxybenzenesulfonyl)-thiazolidine-	solid
	2,4-dione
134	5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-	129-130	552.4
	iodobenzenesulfonyl)-thiazolidine-2,4-dione
135	5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-	149-150	456.6
	methoxybenzenesulfonyl)-thiazolidine-2,4-
	dione
136	5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-	155-156	456.6
	methoxybenzenesulfonyl)-thiazolidine-2,4-
	dione
137	5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-	153-154	552.4
	iodobenzenesulfonyl)-thiazolidine-2,4-dione
138	5-[5-(5-Chloro-2-methylphenyl)pent-4-	121-122	477.0
	ynyl]-5-(4-methoxybenzene-sulfonyl)-
	thiazolidine-2,4-dione
139	5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-	196	549.0
	5-(4-trifluoromethoxybenzene-sulfonyl)-	decomp.
	thiazolidine-2,4-dione
140	5-[5-(4-Chloro-2-methylphenyl)pent-4-	197	559.9
	ynyl]-5-(4-trifluoromethoxy-	decomp.
	benzenesulfonyl)-thiazolidine-2,4-dione
141	5-[5-(4-Chloro-2-methylphenyl)-pent-4-	93-99	591.4
	ynyl]-5-(4-iodobenzene-sulfonyl)-
	thiazolidine-2,4-dione
142	5-[5-(4-Chloro-2-methylphenyl)pent-4-	yellow	477.0
	ynyl]-5-(4-methoxybenzene-sulfonyl)-	foam
	thiazolidine-2,4-dione
143	5-[5-(4-Bromo-2-methy-phenyl)pent-4-	white	540.0
	ynyl]-5-(4-methoxybenzene-sulfonyl)-	foam
	thiazolidine-2,4-dione
144	5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-	146-147	617.3
	5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-
	dione
145	(4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-	yellow	543.7
	dioxothiazolidin-5-yl]pent-1-	solid
	ynyl}phenyl)carbamic Acid tert-Butyl Ester
146	(3-Chloro-4-{5-[5-(4-methoxybenzene	yellow oil	578.1
	sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-
	ynyl}phenyl)carbamic Acid tert-Butyl Ester
147	N-tert-Butyl-3-{5-[5-(4-iodo-	white	637.5
	benzenesulfonyl)-2,4-dioxothiazol-idin-5-	powder
	yl]-pent-1-ynyl}-4-methyl-benzamide
148	(3-{5-[5-(4-Iodobenzenesulfonyl)-2,4-	172-175	653.5
	dioxothiazolidin-5-yl]-pent-1-ynyl}-4-
	methylphenyl)carbamic Acid tert-Butyl Ester
149	(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	yellow	557.7
	dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-	solid
	methylphenyl)carbamic Acid tert-Butyl Ester
150	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	116-118	557.7
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid tert-Butyl Ester
151	(4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	tan solid	611.6
	dioxothiazolidin-5-yl]pent-1-ynyl}-3-
	trifluoromethylphenyl)-carbamic Acid tert-
	Butyl Ester
152	N-tert-Butyl-3-{5-[5-(4-methoxy-	205-208	541.7
	benzenesulfonyl)-2,4-dioxothiazol-idin-5-
	yl]pent-1-ynyl}-4-methyl-benzamide
153	5-(4-Methoxybenzenesulfonyl)-5-[5-(4-	160-163	496.5
	trifluoromethylphenyl)pent-4-
	ynyl]thiazolidine-2,4-dione
154	5-(4-Methoxybenzenesulfonyl)-5-[5-(4-	120-123	512.5
	trifluoromethoxyphenyl)pent-4-
	ynyl]thiazolidine-2,4-dione
155	3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	119-121	500.6
	dioxo-thiazolidin-5-yl]-pent-1-ynyl}-4-
	methylbenzoic Acid Methyl Ester
156	5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-	yellow oil	484.6
	methoxybenzenesulfonyl)-thiazolidine-2,4-
	dione
157	5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-	134-138	468.6
	(toluene-4-sulfonyl)thiazolidine-2,4-dione
158	4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	174-178	453.5
	dioxo-thiazolidin-5-yl]pent-1-
	ynyl}benzonitrile
159	5-[5-(4-Methanesulfonylphenyl)-pent-4-	190-193	490.6
	ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-
	dione
160	4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	128-130	500.6
	dioxothiazolidin-5-yl]pent-1-ynyl}-3-
	methylbenzoic Acid Methyl Ester
161	5-(4-Methoxybenzenesulfonyl)-5-[5-(4-	206-207	493.6
	pyrrol-1-yl-phenyl)pent-4-ynyl]-thiazolidine-
	2,4-dione
162	5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-	194-195	589.5
	yl-phenyl)pent-4-ynyl]-thiazolidine-2,4-dione
163	5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-	204-206	547.6
	trifluoromethoxybenzenesulfonyl)-
	thiazolidine-2,4-dione
164	5-(3-Methoxybenzenesulfonyl)-5-(5-	133-135	434.5
	thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-
	dione
165	5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-	brown	390.5
	yl-pent-4-ynyl)-thiazolidine-2,4-dione	gum
166	5-(4-Methoxybenzenesulfonyl)-5-(5-	60-66	434.5
	thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-
	dione
167	5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-	tan solid	403.0
	3-ylprop-2-ynyl)-thiazolidine-2,4-dione
168	5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-	brown	392.1
	4-sulfonyl)-thiazolidine-2,4-dione	solid
169	5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-	179-180	462
	4-sulfonyl)-thiazolidine-2,4-dione
170	5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-	64-66	478.1
	(toluene-4-sulfonyl)-thiazolidine-2,4-dione
171	5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-	orange
	methoxybenzenesulfonyl)-thiazolidine-2,4-	oil
	dione

EXAMPLE 172

5-Pent-4-ynyl-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

In the manner of Example 100 above, 5-iodo-1-pentyne is reacted with 5-(toluene-4-sulfonyl)thiazolidine-2,4-dione to give the title compound, mp 226° C., THEORY: C,53.4, H,4.48, N,4.15 FOUND: C,53.3, H,4.58, N,4.13. [0326]

EXAMPLE 173

5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

A solution of 5-pent-4-ynyl-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione(1.0 mmol), 4-pentyn-1-ol (1.0 mmol), bistriphenylphosphine(Pd II) chloride (0.20 mmol), and copper(I) iodide (0.10 mmol) in 50 ml of diethylamine was stirred under nitrogen for three days. This was diluted with dichloromethane and the product was purified by chromatography to give the title compound as a light beige solid, mp 173-176° C., THEORY: C,57.95, H,4.38 N,6.76. FOUND: C,57.68, H,4.35, N,6.70. [0327]

EXAMPLE 174

5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic acid, tert-butyl ester was subjected to acid hydrolysis which gave the title compound as a brown solid, MS m/Z 458.9 (calcd. For C[0328] ₂₂H₂₂N₂O₅S₂458.56).

EXAMPLES 175 TO 194

The following general procedure was used to prepare the compounds of Examples 175 to 194. A solution of 1.15 g (2.5 mmol) of compound of Example 174, above, in a total of 50 mL of dichloromethane was divided equally in ten-20 mL scintillation vials. To each vessel was added 0.13 mL (3 eq), of diisopropylethylamine, the appropriate acylating agent (1.2 eq, 0.3 mmol) and the mixture was allowed to react in an orbital shaker overnight. Crude reaction mixtures were checked by Mass Spec for product. Once product formation was confirmed, the solutions were evaporated to dryness under reduced pressure, taken up in 1 mL of dichloromethane and purified via preparative HPLC. Each product fraction was then evaporated to dryness in the vacuum apparatus, characterized via mas spectrometry.



Ex.		Mass Spectrum
No.	Product	(M − H)

175	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	591.1
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid Benzyl Ester
176	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	636.1
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid 4-Nitro-Benzyl Ester
177	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	611.0
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid 4-Chloro-phenyl Ester
178	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	515.0
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid Methyl Ester
179	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	543.1
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid Isopropyl Ester
180	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	571.1
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid Neopentyl Ester
181	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	557.1
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid Butyl Ester
182	(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-	557.1
	dioxothiazolidin-5-yl]pent-1-ynyl}-4-
	methylphenyl)carbamic Acid Isobutyl
183	N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-	526.9
	thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-
	methylpropanamide
184	N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-	555.0
	thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3-
	dimethylbutanamide
185	N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-	541.0
	thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2-
	dimethylpropanamide
186	N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-	574.9
	thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-
	phenylacetamide
187	N-Benzyl-N′-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-	589.9
	dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea
188	N-(4-Methoxyphenyl)-N′-[3-(5-{5-t(4-methoxy	606.0
	phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
	methylphenyl]urea
189	N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxy-	609.9
	phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
	methylphenyl]urea
190	N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-	590.0
	thiazolidin-5-yl}-1-pentynyl)- -methylphenyl]-N′-(4-
	methylphenyl)urea
191	4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-	596.0
	1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide
192	4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-	590.9
	dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
	methylphenyl]benzamide
193	N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-	636.9
	thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1′-biphenyl]-
	4-carboxamide
194	4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-	617.0
	dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
	methylphenyl]benzamide

EXAMPLES 195 TO 213

The following general procedure was used to prepare the compounds of Examples 195 to 213. A solution of 800 mg of each sulfone in 20 mL anhydrous DMF was distributed evenly among 4 vials (0.57-0.75 mmol each). To each was added 2.1 eq 1.0M NaHMDS under a stream of N2 and reacted in an orbital shaker for 45 min. 1.05 equivalents of the appropriate alkylating agent was dissolved in 2 mL DMF and added under N2 to the above vials. The reactions were allowed to shake overnight at room temp. [0330]

Each vial was diluted with 5 ml H ₂O, acidified with 2NHCl, then extracted with ethyl acetate. Crude extracts were evaporated to dryness under reduced pressure in a vacuum apparatus, dissolved in 1 mL of dichloromethane, then purified via preparative HPLC. The product fractions were collected, and evaporated to dryness under reduced pressure and analyzed via MS and NMR.



		Mass
Ex.		Spectrum
No.	Product	(M − H)

195	5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-	473.8
	thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione
196	5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-	439.9
	thienylsulfonyl)-1,3-thiazolidine-2,4-dione
197	5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-	494.0
	dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione
198	5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-	527.0
	pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-
	dione
199	5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-	516.9
	2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione
200	5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-	509.8
	dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4-
	dione
201	5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-	473.8
	thienylsulfonyl)-1,3-thiazolidine-2,4-dione
202	5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-	527.9
	dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione
203	5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-	560.9
	pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-
	dione
204	5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-	550.9
	pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-
	dione
205	tert-Butyl 3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-	569.0
	dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
	methylphenylcarbamate
206	tert-Butyl 3-{5-[2,4-dioxo-5-(2-thienyl-sulfonyl)-1,3-	533.0
	thiazolidin-5-yl]-1-pentyn-yl}-4-
	methylphenylcarbamate
207	tert-Butyl 3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]-	587.1
	2,4-dioxo-1,3-thiazol-idin-5-yl}-1-pentynyl)-4-
	methylphenylcarbamate
208	tert-Butyl 3-[5-(2,4-dioxo-5-{[4-(4-	620.1
	pyridinyloxy)phenyl]sulfonyl}-1,3-thiazol-idin-5-yl)-
	1-pentynyl]-4-methylphenylcarbamate
209	tert-Butyl 3-[5-(2,4-dioxo-5-{[5-(2-pyrid-inyl)-2-	610.0
	thienyl]sulfonyl}-1,3-thiazol-idin-5-yl)-1-pentynyl]-4-
	methylphenylcarbamate
210	N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-	553.0
	2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-
	methylbenzamide
211	N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-	517.1
	1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide
212	N-(tert-Butyl)-3-(5-{5-[(3,4-	571.1
	dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-
	5-yl}-1-pentynyl)-4-methylbenzamide
213	N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-	594.0
	thienyl]sulfonyl}-1,3-
	thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide

EXAMPLE 214

4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic Acid

To a solution of 4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic acid methyl ester (Example 160) (0.29 g, 0.536 mmol) in THF (30 ml plus sufficient methanol to dissolve the substrate) was added lithium hydroxide (0.75 ml of 1.0M in water), and this solution was stirred at room temperature for 3 days. Dilution with water and acidification gave a solid which was crystallized from hexane-ethyl acetate to give the title compound as a light yellow solid mp 182-184° C. THEORY: C, 56.66, H,4.34, N,2.87. FOUND: C,56.39, H,4.60, N,2.80. [0332]

EXAMPLE 215

N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide

To a solution of 5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.] ((5.0 g, 17.4 mmol) in 150 ml of DMF was added sodium bistrimethylsilylamide (36.6 ml of 1.0 M solution in THF) and this solution was stirred for 15 minutes. To this was added methyl 3-iodopropionate (17.4 mmol) and this solution was stirred for three hours and then was subjected to an aqueous workup. The product was chromatographed (silica gel, hexane-ethyl acetate-dichloromethane, 1:1:1) to give methyl 3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-4-yl]propionate, 4.48 g. This was hydrolyzed with lithium hydroxide, THF, methanol to give 3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-4-yl]propionic acid which was used without further purification in the following procedure: [0333]
To a solution of the above acid (0.4 g, 1.1 mmol) in 15 ml of dichloromethane plus 2 ml of DMF was added 4-chlorobenzylamine (0.2 ml, 1.67 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.255 g, 1.33 mmol), and this was stirred at room temperature for 18 hours. Aqueous workup, and chromatography (silica gel, chloroform-methanol—5%) gave the title compound as a colorless solid, mp 90° C. and decomposes over wide range. [0334]

EXAMPLE 216

N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5yl]propionamide

In a like procedure to Example 215, above, 4-chlorophenethylamine gave the title compound as a white powder, mp 189° C. with decomposition. [0335]

EXAMPLE 217

5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

A sample of 5-[5-(4-chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)-thiazolidine-2,4-dione (Example 103) was hydrogenated in the presence of Lindlars catalyst in ethanol to give the title compound as a white solid, NMR (CDCl[0336] ₃) δ2.47 (s, 3H), 5.57 (apparent d of triplets, J=7.3, 11.6 Hz, 1H), 6.42 (br d, J=11.6 Hz, 1H) MS m/Z 499.0495 (M+ calcd. for C₂₁H₂₀ClNO₄S₂499.0523).

EXAMPLE 218

5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

A mixture of 4-pentyn-1-ol, 1.05 eq tri-n-butyltinhydride and a catalytic amount of 1,1′-azobis(cyclohexanecarbonitrile), was heated to 55° C. overnight. The mixture was cooled, then purified on silica gel using 6:1 hex: EtOAc to 4:1 as eluent to give 86% yield of tri-n-butyl(4-pentenol)-5-ylstannane as a clear liquid which contained both cis and trans isomers. Then, 4-chloroiodobenzene (1.0 equiv.) was dissolved in anhydrous DMF under a nitrogen atmosphere. Tri-n-butyl(4-pentenol)-5-ylstannane(1.0 equiv.) was added, followed by tetrakis-triphenylphosphinePd(0)(0.1 equiv.) and Cul (0.75 equiv.). The reaction was stirred at room temperature overnight. The reaction was diluted with ether, filtered through a small pad of celite and an excess of saturated aqueous NH[0337] ₄Cl was added, and this was stirred for 1 h. Combined organics were washed with brine, and dried over MgSO₄to afford a tan semi-solid. This was purified using silica and 4:1 Hex: MeOtBu to 1:1. Obtained three cuts: 20% pure ‘Z’ isomer, 26% mix, 19.6% ‘E’ isomer (desired trans isomer) which was a light tan low melting solid.
A solution of imidazole (1.3 equiv.) and triphenylphosphine (1.3 equiv.) in acetonitrile-ether was cooled to 0° C. Iodine (1.4 equiv.) was added in three portions, and the solution was then allowed to warm to room temp overnight. [0338]
The mixture was dissolved in methylene chloride, and directly preadsorbed onto silica gel and purified using 25:1 Hexanes: EtOAc as eluent to give the iodo-compound as a clear liquid. In an oven-dried round bottom flask under nitrogen was dissolved the sulfone in anhydrous DMF. Sodium hexamethyldisilazide (1.0 M solution in THF—2.1 equiv.) was added dropwise at room temperature and allowed to react at room temp for one hour. The iodide (1.1 equiv.) was dissolved in DMF, then added in one portion to the above solution., and allowed to react overnight. [0339]
The reaction was diluted with water, acidified to approx. pH 2 using 2N HCl, extracted with ethyl acetate (3×), combined organics, washed with brine, dried over MgSO[0340] ₄and concentrated to afford an oil which was purified on silica gel using 1:2:1 CH₂Cl₂: hex: EtOAc to afford the title compound, 36% as an off-white solid, mp 182-184° C., E-double bond—NMR (CDCl₃) δ6.18 (td, 1H, J=22.5 Hz), 6.31 (d, 1H, J=22.5 Hz).

EXAMPLE 219

5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

A sample of 5-[3-(4-Chlorophenyl)prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)-thiazolidine-2,4-dione (U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.) was hydrogenated in the presence of palladium on charcoal (10%) in methanol plus 2% water to give the title compound as a colorless glass, NMR (CDCl[0341] ₃) δ1.57 (m, 1H); 1.97 (m, 1H); 2.20 (triplet of doublet), 1H); 2.45 (m, 1H); 2.61 (q, 2H); 3.92 (s, 3H); 7.0 (dd, 4H); 7.26 (d, 2H) 7.98 (d, 2H).

EXAMPLE 220

5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

A sample of 5-(4-methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione of Example 118 was reduced with iron in acetic acid to give the title compound as crystals, m.p. 135-138° C. [0342]

EXAMPLE 221

5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

Alkylation with cinnamyl bromide (222 mg, 1.13 mmol) of 5-(4-methylphenylsulfonyl)-thiazolidine-2,4-dione (271 mg, 1.00 mmol) following the procedure in Example 3 yield 32 mg (8%) of light yellow oil which was identified as 5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione: NMR (CDCl[0343] ₃) δ2.49 (s, 3H), 3.06-3.13 (m, 1H), 3.34-3.42 (m, 1H), 6.01-6.11 (m, 1H), 6.60 (d, J=15.69, 1H), 7.26-7.26-7.31 (m, 5H), 7.42 (d, J=8.13, 2H), 7.85 (d, J=8.34, 2H) MS m/z 388.1 (M+H cald. for C₁₉H₁₇NO₄S₂387.48)

EXAMPLE 222

Enantiomer of(3-{5-[5-(4-Methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (less polar)

The compound of Example 150 was chromatographed on a chiral column with hexane-ethanol 4:1 to give a less polar enantiomer, retention time 14.5-16 min. [0344]

EXAMPLE 223

Enantiomer of(3-{5-[5-(4-Methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (more polar)

Continued chromatography of the compounds in Example 223 gave a more polar enantiomer, retention time 19-21 min. [0345]

EXAMPLE 224

5-(4-methoxyphenyl-4-sulfinyl)-thiazolidine-2,4-dione

5-(4-methoxyphenyl-4-sulfanyl)-thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.] was oxidized as described for Example 98 to give the title compound: NMR (CDCl[0346] ₃) δ3.80 (S, 3H), 5.77 (S, 1H), 7.04 (d, 2H), 7.62 (d, 2H).

EXAMPLE 225

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)-thiazolidine-2,4-dione

By the method of Example 92, the compound of Example 224, above, is converted to the title compound. [0347]

EXAMPLES 226-233

In the isolation of products of Examples 175 to 194 the N-3-acylated products of Examples 227 to 234 were isolated and the structures were verified by mass spectrometry and NMR:



Ex. No.	Compound

226	Benzyl 5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-
	methylphenyl)pent-4-ynyl]-5-[(4-
	methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-
	3-carboxylate
227	4-Nitrobenzyl 5-[(4-methoxyphenyl)sulfonyl]-5-{5-[2-
	methyl-5-({[(4-nitro benzyl)oxy]carbonyl}amino)
	phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-
	carboxylate
228	Methyl 5-(5-{5-[(methoxycarbonyl)amino]-2-
	methylphenyl}pent-4-ynyl)-5-[(4-
	methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-
	3-carboxylate
229	Isopropyl 5-(5-{5-[(isopropoxycarbonyl)-amino]-2-
	methylphenyl}pent-4-ynyl)-5-[(4-
	methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-
	3-carboxylate
230	Neopentyl 5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-
	methyl-5-{[(neopentyloxy)carbonyl]-
	amino}phenyl)pent-4-ynyl]-2,4-dioxo-1,3-
	thiazolidine-3-carboxylate
231	Butyl 5-(5-{5-[(butoxycarbonyl)amino]-2-
	methylphenyl}pent-4-ynyl)-5-[(4-methoxy-
	phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-
	carboxylate
232	Isobutyl 5-(5-{5-[(isobutoxycarbonyl)-amino]-2-
	methylphenyl}pent-4-ynyl)-5-[(4-
	methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-
	3-carboxylate

EXAMPLE 233

5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione

The compound of Example 97 is reacted with 1,3-dibromopropane and potassium carbonate in DMF to give 5-[5-(4-chlorophenyl)pent-4-ynyl]-3-(3-bromopropyl)-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione, and this is reacted with imidazole, sodium salt in DMF, and in the presence of a catalytic amount of potassium iodide to give the title compound as a light tan solid, mp 111-113° C. [0349]

EXAMPLE 234

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione (Example 100) is reated with sodium hydride in DMF, followed by methyl iodide to give the title compound as colorless crystals, mp 113-115° C. [0350]

EXAMPLE 235

3-(2,4-Diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

5-(Toluene-4-sulfonyl)thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.] was reacted with 2,4-diethoxybenzyl alcohol in the presence of triphenylphosphine and diethyl diazodicarboxylate to give the title compound as colorless crystals, mp 121-123° C. [0351]

EXAMPLE 236

5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione

The product of Example 237 is reacted with sodium hexamethyldisilazide in DMF, followed by the addition of 1-chloro-4-(5-iodopent-1-ynyl)-benzene to give the title compound as colorless crystals, mp 151-153° C. [0352]

EXAMPLE 237

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidine-2,4-dione is reacted with 4-nitrobenzyl bromide and potassium carbonate in DMF to give the title compound as a light tan solid, mp 172-175° C. [0353]

EXAMPLE 238

[0354] 5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester
5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione is reacted with (2-methoxyethoxy)chloroformate and diisopropylethylamine in methylene chloride to give the title compound as a solid, MS m/z 599.8 (calcd. for C[0355] ₂₅H₂₃Cl₂NO₈S₂600.5).
Examples 239-267 were synthesized using the methods described in U.S. Pat. Nos. 5,605918 and 5,574051 and in Wrobel, J., et al., [0356] J. Med. Chem. 1998, 41 (7), 1084-91.

EXAMPLE 239

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(napthalene-2-sulfonyl)-thiazolidine-2,4-dione [0357]

EXAMPLE 240

5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0358]

EXAMPLE 241

5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]-thiazolidine-2,4-dione [0359]

EXAMPLE 242

5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2,4-dione [0360]

EXAMPLE 243

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-fluoro-benzenesulfonyl)-thiazolidine-2,4-dione [0361]

EXAMPLE 244

5-(4-Chloro-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0362]

EXAMPLE 245

5-(4-Bromo-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0363]

EXAMPLE 246

5-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [0364]

EXAMPLE 247

5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0365]

EXAMPLE 248

5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2,4-dione [0366]

EXAMPLE 249

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)-thiazolidine-2,4-dione [0367]

EXAMPLE 250

5-(Naphthalene-2-sulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2,4-dione [0368]

EXAMPLE 251

5-(Toluene-4-sulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0369]

EXAMPLE 252

5-[3-(4-Methoxy-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [0370]

EXAMPLE 253

5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [0371]

EXAMPLE 254

5-Benzenesulfonyl-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0372]

EXAMPLE 255

5-(4-Chloro-benzenesulfonyl)-5-[3-(4-fluoro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0373]

EXAMPLE 256

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-3-sulfonyl)-thiazolidine-2,4-dione [0374]

EXAMPLE 257

5-[3-(3-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [0375]

EXAMPLE 258

5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0376]

EXAMPLE 259

5-Benzenesulfonyl-5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0377]

EXAMPLE 260

5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione [0378]

EXAMPLE 261

5-Benzenesulfonyl-5-[3-(3-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0379]

EXAMPLE 262

5-[3-(4-Chlorophenyl)-2-propynyl]-2-[(4-methylphenyl)sulfonyl]-2,4-thiazolidinedione [0380]

EXAMPLE 263

5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)-thiazolidine-2,4-dione [0381]

EXAMPLE 264

5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0382]

EXAMPLE 265

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(quinoline-2-sulfonyl)-thiazolidine-2,4-dione [0383]

EXAMPLE 266

5-[3-(3,5-Bis-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione [0384]

EXAMPLE 267

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(p-tolylsulfanyl)-thiazolidine-2,4-dione [0385]

Claims

What we claim is:

1. 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:

R₁is 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;

R₂is 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;

R₆is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl, imidazolylpropyl, or —CO₂Y;

E- and Z- —CH═CH—, —CONH—, —CONHCH₂—, —CONHCH₂CH₂— or —CH₂—CH₂—;

n is an integer of 1 to 9;

Ar′ is thienyl, pyridinyl or a moiety of the formula

R₃, R₄, R₅, 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, —CO₂R₇, —CONHR₈, —CH₂CONHR₉, —NHCO₂R₁₀, —NHCOR₁₁, and —NHCONHR₁₂;

R₇is selected from H, and alkyl of 1 to 6 carbon atoms,

R₈is selected from H, and alkyl of 1 to 6 carbon atoms;

R₉is selected from H, and alkyl of 1 to 6 carbon atoms;

R₁₀is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl;

R₁₁is 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;

R₁₂is 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.

2. The method according to claim 1 wherein R₆is hydrogen, n is 1, m is 2, W is

or a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 wherein R₆is hydrogen, n is 3, m is 2, W is

or a pharmaceutically acceptable salt thereof.

4. The method according to claim 1 wherein R₆is hydrogen, n is 3-6, m is 2, W is

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 1 wherein R₆is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 1 wherein R₆is hydrogen, n is 3, m is 2, W is

Ar is a moiety of the formula

or a pharmaceutically acceptable salt thereof.

7. The method according to claim 1 wherein R₆is hydrogen, n is 3-6, m is 2, W is

Ar is a moiety of the formula

or a pharmaceutically acceptable salt thereof.

8. The method according to claim 1 wherein R₆is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula

Ar′ is a moiety of the formula

or a pharmaceutically acceptable salt thereof.

9. The method according to claim 1 wherein R₆is hydrogen, n is 3 , m is 2, W is

Ar is a moiety of the formula

Ar′ is a moiety of the formula

or a pharmaceutically acceptable salt thereof.

10. The method according to claim 1 wherein R₆is hydrogen, n is 3-6, m is 2, W is

Ar is a moiety of the formula

Ar′ is a moiety of the formula

or a pharmaceutically acceptable salt thereof.

11. The method according to claim 1 wherein R₆is hydrogen, n is 1, m is 2, W is

Ar is a moiety of the formula

Ar′ is thienyl or pyridinyl;

or a pharmaceutically acceptable salt thereof.

12. The method according to claim 1 wherein R₆is hydrogen, n is 3, m is 2, W is

Ar is a moiety of the formula

Ar′ is thienyl or pyridinyl;

or a pharmaceutically acceptable salt thereof.

13. The method according to claim 1 wherein R₆is hydrogen, n is 3-6, m is 2, W is

Ar is a moiety of the formula

Ar′ is thienyl or pyridinyl;

or a pharmaceutically acceptable salt thereof.

14. The method according to claim 1 wherein 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 the 4-position by nitro or a carbamic acid ester; W is an acetylenic group, and n is the integer 3 or a pharmaceutically acceptable salt thereof.

15. The method of claim 1 wherein the compound is selected from the group consisting of

5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl) thiazolidine-2,4-dione,

5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl) thiazolidine-2,4-dione,

5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,

5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione,

5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesulfonyl]thiazolidine-2,4-dione,

5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]thiazolidine-2,4-dione,

5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione, p1 5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thiazolidine-2,4-dione,

5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benzamide,

N-tert-Butyl-3-{5-[5-(4-methoxy-benzenesulfonyl)-2,4-dioxothiazol-idin-5-yl]pent-1-ynyl}-4-methyl-benzamide,

5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]thiazolidine-2,4-dione,

5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,

(3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Benzyl Ester,

N-(4-Methoxyphenyl)-N′-[3-(5-{5-[(4-methoxy phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,

N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,

4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione, 5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl-1,3-thiazolidine-2,4-dione,

tert-Butyl 3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate, tert-Butyl 3-{5-[2,4-dioxo-5-(2-thienyl-sulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,

tert-Butyl 3-(5-{5-[(3,4-dimethoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,

tert-Butyl 3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylphenyl-carbamate,

tert-Butyl 3-[5-(2,4-dioxo-5-{[5-(2-pyrid-inyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5yl)-1-pentynyl]-4-methylphenyl-carbamate,

5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl) thiazolidine-2,4-dione,

5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

Enantiomer of(3-{5-[5-(4-Methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester (less polar),

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)-thiazolidine-2,4-dione,

4-Nitrobenzyl 5-[(4-methoxyphenyl) sulfonyl]-5-{5-[2-methyl-5-({[(4-nitrocarbonyl}amino)phenyl]pent-4-ynyl}-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

Isobutyl 5-(5-{5-[(isobutoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione,

5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione, and

16. The method of claim 1 wherein the compound is selected from the group consisting of

5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]thiazolidine-2,4-dione,

5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,

5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,

5-(Naphthalene-2-sulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-3-sulfonyl)thiazolidine-2,4-dione,

5-[3-(3-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,

5-Benzenesulfonyl-5-[3-(3-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3-(4-Chlorophenyl)-2-propynyl]-2-[(4-methylphenyl)sulfonyl]-2,4-thiazolidinedione,

5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)thiazolidine-2,4-dione,

5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(quinoline-2-sulfonyl)thiazolidine-2,4-dione,

5-[3-(3,5-Bis-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione, and

5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(p-tolylsulfanyl)thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof.

17. The method of claim 1 wherein the ras-associated disease in mammals is selected from the group consisting of cancers of the pancreas, breast, lung, colon, epidermis, prostate, bladder, thyroid,myelodysplastic tumors and myeloid leukemia.

18. The method of claim 1 wherein the ras-associated disease in mammals is selected from metastasis, suppressing angiogenesis, and inducing apoptosis.

19. The method of claim 1 wherein the ras-associated proliferative disease in mammals is restenosis, neurofibromatosis, endometriosis, and psoriasis.

20. The method of claim 1 wherein the ras-associated disease in mammals is prenyl modifications or proteins.