5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones useful for inhibition of farnesyl-protein transferase Number:6,784,184 from the United States Patent and Trademark Office (PTO) owispatent This invention relates to a method of using novel 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones of Formula (I), wherein Ar, Ar', R.sub.6, 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. ##STR1##<H thiazolidine, arylsulfanyl, 5, arylsulfonyl, , 6784184.html, Patent, pto, 6784184

Title: 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones useful for inhibition of farnesyl-protein transferase

Abstract: This invention relates to a method of using novel 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones of Formula (I), wherein Ar, Ar', R.sub.6, 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. ##STR1##

Patent Number: 6,784,184 Issued on 08/31/2004 to Epstein, et al.

Inventors: Epstein; Joseph William (Monroe, NY), Ayral-Kaloustian; Semiramis (Tarrytown, NY), Birnberg; Gary Harold (Tuxedo Park, NY), Salaski; Edward James (Tenafly, NJ), Macewan; Gloria Jean (Monroe, NY), Cheung; Katherine (Paramus, NJ)
Assignee: Wyeth Holdings Corporation (Madison, NJ)

Appl. No.: 10/227,084

Filed: August 23, 2002

Current U.S. Class: 514/256 ; 514/314; 514/342; 514/367; 514/369; 544/335; 546/175; 546/269.7; 548/181; 548/183

Field of Search: 514/256,314,342,367,369 544/335 546/175,269.7 548/181,183

References Cited [Referenced By]

U.S. Patent Documents


5574051	November 1996	Wrobel et al.
5576313	November 1996	Fisher et al.
5605918	February 1997	Wrobel et al.

Foreign Patent Documents


0618221	Oct., 1994	EP
WO 95/24400	Sep., 1995	WO
WO9535108	Dec., 1995	WO
WO 99/05117	Feb., 1999	WO
WO0198302	Dec., 2001	WO

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P. Skehan, R. Storeng, D. Scudiero, A. Monks, J. Mcmohan, D: Vistica, J. Warren, J. Bokesh, S. Kenney, 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, 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, K.D. Paull, Drug Development Res., 1995, 34, 91-109. .
S.P. Fricker, R.G. Buckley, Anticancer Research, 1996, 16, 3755-3760. .
J. Wrobel, L. Zenan, A. Dietrich, M. McCaleb, B. Mihan, J. Stredy, D. Sullivan, J. Med. Chem., 1998, 41, 1084-1091. .
Semiramis Ayral-Kaloustian, et al., "Thiazolidinediones as Novel Farnesyltransferase Inhibitors"; Abstracts of Papers; American Chemical Society; vol. 222, No. 1-2, p. MED183, 2001. .
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PCT International Search Report--Date of Mailing--Jul. 2, 2003..

Primary Examiner: Wilson; James O.
Assistant Examiner: McKenzie; Thomas
Attorney, Agent or Firm: Moran; Daniel B.

Parent Case Text

"This application claims priority from copending provisional applications Serial No. 60/314,586 and 60/314,621 filed on Aug. 24, 2001 the entire disclosure of which are hereby incorporated by reference."

Claims

What is claimed is:

1. A compound of Formula (I) represented by the structure: ##STR56##

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: ##STR57## R.sub.1 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy, phenoxy, or benzyloxy; R.sub.2 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy; m is 0, 1 or 2; R.sub.6 is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl, imidazolylpropyl, or --CO.sub.2 Y; Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, or substituted benzyl; W is ##STR58## E-- and Z----CH.dbd.CH--, --CONH--, --CONHCH.sub.2 --, CONHCH.sub.2 CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --; n is an integer of 1 to 9; Ar' is thienyl, pyridinyl or a moiety of the formula: ##STR59## R.sub.3, R.sub.4, R.sub.5, are independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, --CO.sub.2 R.sub.7, --CONHR.sub.8, --CH.sub.2 CONHR.sub.9, --NHCO.sub.2 R.sub.10, --NHCOR.sub.11, and --NHCONHR.sub.12 ; R.sub.7 is selected from H, and alkyl of 1 to 6 carbon atoms, R.sub.8 is selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.9 is selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.10 is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl; R.sub.11 is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl; R.sub.12 is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl; provided when W is ##STR60## then n is other than 2; further provided that when n is 1, m is 0 or 2, R.sub.6 is H and W is ##STR61## then: Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, 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-thienyl, or 2-benzo-[b]-thienyl; and Ar' is not phenyl, alkyl substituted phenyl, perfluoroalkyl (mono or di)substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, perfluoroalkoxy substituted phenyl or alkylthio substituted phenyl; or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR62##

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR63##

Ar is a moiety of the formula: ##STR64##

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR65##

Ar is a moiety of the formula: ##STR66## Ar' is a moiety of the formula: ##STR67## or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR68##

Ar is a moiety of the formula: ##STR69## Ar' is thienyl or pyridinyl or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR70##

or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR71##

Ar is a moiety of the formula: ##STR72## or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR73##

Ar is a moiety of the formula: ##STR74## Ar' is a moiety of the formula: ##STR75## or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR76##

Ar is a moiety of the formula: ##STR77## Ar' is thienyl or pyridinyl or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR78##

or a pharmaceutically acceptable salt thereof.

11. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR79##

Ar is a moiety of the formula: ##STR80## or a pharmaceutically acceptable salt thereof.

12. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR81##

Ar is a moiety of the formula: ##STR82## Ar' is a moiety of the formula: ##STR83## or a pharmaceutically acceptable salt thereof.

13. A compound according to claim 1 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR84##

Ar is a moiety of the formula: ##STR85## Ar' is thienyl or pyridinyl or a pharmaceutically acceptable salt thereof.

14. A compound 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 compound of claim 1 selected from the group consisting of: 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-methoxyphenylsulfanyl)-thiazolidi ne-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-methoxyphenylsulfonyl)thiazolidin e-2,4-dione, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)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}ph enyl)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]thiazolidin e-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)thiazol idine-2,4-dione, 5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidin e-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)thiazolid ine-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-Iodobenzenesulfonyl)-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]thia zolidine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiaz olidine-2,4-dione, 5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazoli dine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazo lidine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazol idine-2,4-dione, 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulf onyl]-thiazolidine-2,4-dione, 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiaz olidine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]thia zolidine-2,4-dione, 5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazoli dine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]thia zolidine-2,4-dione, 5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thia zolidine-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)thiazolid ine-2,4-dione, 5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolid ine-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)thia zolidine-2,4-dione, 5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulf onyl)thiazolidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulf onyl)thiazolidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazo lidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl) pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione, 5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiaz olidine-2,4-dione, 5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazoli dine-2,4-dione, (4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}ph enyl)carbamic Acid tert-Butyl Ester, (3-Chloro-4-{5-[5-(4-methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester, N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl]-pe nt-1-ynyl}-4-methyl-benzamide, (3-{5-[5-(4-Iodobenzenesulfonyl)-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-methoxy-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl] pent-1-ynyl}-4-methyl-benzamide, 5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]thia zolidine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]thi azolidine-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)thiazolid ine-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}b enzonitrile, 5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolid ine-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]thiazol idine-2,4-dione, 5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolid ine-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-dion e, 5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dion e, 5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-d ione, 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)thiaz olidine-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-pe ntynyl)-4-methylphenyl]-2-methylpropanamide, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pe ntynyl)-4-methylphenyl]-3,3-dimethylbutanamide, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pe ntynyl)-4-methylphenyl]-2,2-dimethylpropanamide, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pe ntynyl)-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-methoxy phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylpheny l]urea, N-(4-Chlorophenyl)-N'-[3-(5-{5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-t hiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pen tynyl)-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-pe ntynyl)-4-methylphenyl][1,1'-biphenyl]-4-carboxamide, 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-y l)-1-pentynyl]-4-methylphenylcarbamate, tert-Butyl 3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-1- pentynyl]-4-methylphenylcarbamate, N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazol idin-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-thiazo lidin-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-thiaz olidin-5-yl]propionamide, 4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazo lidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide, 5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thia zolidine-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-thi azolidine-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-thiazolidin e-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 }-3-thiazolidine-2,4-dione,

5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfony l}-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, 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-methoxybenzene sulfonyl)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-me thoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, 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, Methyl 5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxy phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Isopropyl 5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-met hoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Neopentyl 5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-a mino}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-meth oxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybe nzenesulfonyl)thiazolidine-2,4-dione, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thi azolidine-2,4-dione, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfo nyl)thiazolidine-2,4-dione, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzy l)thiazolidine-2,4-dione, and 5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-diox othiazolidine-3-carboxylic acid 2-methoxy ethyl ester.

16. A pharmaceutical composition comprising an effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable carriers.

17. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR86##

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR87##

Ar is a moiety of the formula: ##STR88## or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR89##

Ar is a moiety of the formula: ##STR90## Ar' is a moiety of the formula: ##STR91## or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR92##

Ar is a moiety of the formula: ##STR93## Ar' is thienyl or pyridinyl or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR94##

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR95##

Ar is a moiety of the formula: ##STR96## or a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR97##

Ar is a moiety of the formula: ##STR98## Ar' is a moiety of the formula: ##STR99## or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR100##

Ar is a moiety of the formula: ##STR101## Ar' is thienyl or pyridinyl or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR102##

or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR103##

Ar is a moiety of the formula: ##STR104## or a pharmaceutically acceptable salt thereof.

27. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR105##

Ar is a moiety of the formula: ##STR106## Ar' is a moiety of the formula: ##STR107## or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition according to claim 16 wherein R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR108##

Ar is a moiety of the formula: ##STR109## Ar' is thienyl or pyridinyl or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition according to claim 16 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.

30. A pharmaceutical composition according to claim 16 wherein the compound is selected from the group consisting of: 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)thiazolidi ne-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-methoxyphenylsulfonyl)thiazolidin e-2,4-dione, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)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}ph enyl)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]thiazolidin e-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)thiazol idine-2,4-dione, 5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidin e-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)thiazolid ine-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-Iodobenzenesulfonyl)-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]thia zolidine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiaz olidine-2,4-dione, 5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazoli dine-2,4-dione, 5-(5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazo lidine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazol idine-2,4-dione, 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesul fonyl]thiazolidine-2,4-dione, 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiaz olidine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]thia zolidine-2,4-dione, 5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazoli dine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]thia zolidine-2,4-dione, 5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thia zolidine-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)thiazolid ine-2,4-dione, 5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolid ine-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)thia zolidine-2,4-dione, 5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulf onyl)thiazolidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxy-benzenesul fonyl)thiazolidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazol idine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thia zolidine-2,4-dione, 5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiaz olidine-2,4-dione, 5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazoli dine-2,4-dione, (4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}ph enyl)carbamic Acid tert-Butyl Ester, (3-Chloro-4-{5-[5-(4-methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester, N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazol-idin-5-yl]-p ent-1-ynyl}-4-methyl-benzamide, (3-{5-[5-(4-Iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-m ethylphenyl)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-methoxy-benzenesulfonyl)-2,4-dioxothiazolidin-5-yl] pent-1-ynyl}-4-methyl-benzamide, 5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]thia zolidine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]thi azolidine-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)thiazolid ine-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}b enzonitrile, 5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolid ine-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]thiazol idine-2,4-dione, 5-(4-Iodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolid ine-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-dion e, 5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dion e, 5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-d ione, 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)thiaz olidine-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-pe ntynyl)-4-methylphenyl]-2-methylpropanamide, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pe ntynyl)-4-methylphenyl]-3,3-dimethylbutanamide, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pe ntynyl)-4-methylphenyl]-2,2-dimethylpropanamide, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pe ntynyl)-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-methoxy phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylpheny l]urea, N-(4-Chlorophenyl)-N'-[3-(5-{5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-t hiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea, N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pe ntynyl)-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-pe ntynyl)-4-methylphenyl][1,1'-biphenyl]-4-carboxamide, 4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazo lidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide, 5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thia zolidine-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-thi azolidine-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-thiazolidin e-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]sulfony l}-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-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-pyrid-inyl)-2-thienyl]sulfonyl}-1,3-thiazolidine- 5-yl)-1-pentynyl]-4-methylphenyl-carbamate, N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazol idin-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-thiazo lidin-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-thiaz olidin-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)thiazoli dine-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-me thoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, 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, Methyl 5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxy phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Isopropyl 5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-met hoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, Neopentyl 5-[(4-methoxyphenyl)sulfonyl]-5-[5-(2-methyl-5-{[(neopentyloxy)carbonyl]-a mino}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-meth oxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybe nzenesulfonyl)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-sulfo nyl)thiazolidine-2,4-dione, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzy l)thiazolidine-2,4-dione, and 5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-diox othiazolidine-3-carboxylic acid 2-methoxy ethyl ester.

31. A process for the preparation of a compound of Formula (I): ##STR110##

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: ##STR111## R.sub.1 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy, phenoxy, or benzyloxy; R.sub.2 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy; m is 0, 1 or 2; R.sub.6 is hydrogen; Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, or substituted benzyl; W is ##STR112## E-- and Z----CH.dbd.CH--, --CONH--, --CONHCH.sub.2 --, --CONHCH.sub.2 CH.sub.2 -- or --CH.sub.2 --CH.sub.2 --; n is an integer of 1 to 9; Ar' is thienyl, pyridinyl or a moiety of the formula: ##STR113## R.sub.3, R.sub.4, R.sub.5, are independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, --CO.sub.2 R.sub.7, --CONHR.sub.8, --CH.sub.2 CONHR.sub.9, --NHCO.sub.2 R.sub.10, --NHCOR.sub.11, and --NHCONHR.sub.12 ; R.sub.7 is selected from H, and alkyl of 1 to 6 carbon atoms, R.sub.8 is selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.9 is selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.10 is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl; R.sub.11 is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl; R.sub.12 is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl; provided that when W is ##STR114## then n is other than 2; further provided that when n is 1, m is 0 or 2, R.sub.6 is H and W is ##STR115## then: Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, 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-thienyl, 2-benzo-[b]-thienyl; and Ar' is not phenyl, alkyl substituted phenyl, perfluoroalkyl (mono or di)substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, perfluoroalkoxy substituted phenyl and alkylthio substituted phenyl; or pharmaceutically acceptable salts thereof, which comprises: reacting a compound of the formula: ##STR116## with an alkyne of the formula:

Ar'W--(CH.sub.2).sub.m --LG

wherein LG is a leaving group, in the presence of a base to give a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

32. The process according to claim 31 wherein the base is selected from alkali metal hydrides, alkali metal alkyls and alkali metal amide bases.

33. The process according to claim 32 wherein the alkali metal hydride is sodium hydride.

34. The process according to claim 32 wherein the alkali metal alkyl is butyl lithium.

35. The process according to claim 32 wherein the alkali metal amide base is selected from lithium diisopropylamide and lithium bis(trimethylsilyl)amide.

36. The process according to claim 31 wherein the leaving group is p-toluenesulfonyloxy.

Description

FIELD OF THE INVENTION

This invention relates to a novel series of 5-(arylsulfonyl)-,5-(arylsulfinyl), and 5-(arylsulfanyl)-thiazolidine-2,4-diones of formula (I) to their use in cancer therapy, to pharmaceutical compositions containing them, and to a process for their preparation. The compounds are inhibitors of Ras FPTase, and may be used as an alternative to, or in conjunction with, traditional cancer therapy for treating ras- oncogene-dependent tumors, such as cancers of the pancreas, colon, bladder, and thyroid. Compounds in the invention may also be useful for controlling metastasis, suppressing angiogenesis, inducing apoptosis, and in treating Ras-associated proliferative diseases other than cancer, such as restenosis, neuro-fibromatosis, endometriosis, and psoriasis. These compounds may also inhibit prenylation of proteins other than Ras, and thus 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

The present invention disclosed compounds represented by Formula (I): ##STR2##

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: ##STR3## R.sub.1 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy, phenoxy, or benzyloxy; R.sub.2 is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy; m is 0, 1 or 2; R.sub.6 is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl, imidazolylpropyl, or --CO.sub.2 Y; Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, or substituted benzyl; W is ##STR4## E-- and Z----CH.dbd.CH--, --CONH--, --CONHCH.sub.2 --, --CONHCH.sub.2 CH.sub.2 --, or --CH.sub.2 --CH.sub.2 --; n is an integer of 1 to 9; Ar' is thienyl, pyridinyl or a moiety of the formula: ##STR5## R.sub.3, R.sub.4, R.sub.5, are independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, --CO.sub.2 R.sub.7, --CONHR.sub.8, --CH.sub.2 CONHR.sub.9, --NHCO.sub.2 R.sub.10, --NHCOR.sub.11, and --NHCONHR.sub.12 ; R.sub.7 is selected from H, and alkyl of 1 to 6 carbon atoms, R.sub.8 is selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.9 is selected from H, and alkyl of 1 to 6 carbon atoms; R.sub.10 is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl; R.sub.11 is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl; R.sub.12 is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl; provided that when W is ##STR6## then n is other than 2; further provided that when n is 1, m is 0 or 2, R.sub.6 is H and W is ##STR7## then: Ar is not phenyl, 2-naphthyl, alkyl substituted phenyl, alkoxy substituted phenyl, halogen substituted phenyl, 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-thienyl, 2-benzo-[b]-thienyl; and Ar' is not phenyl, alkyl substituted phenyl, perfluoroalkyl (mono or di)substituted phenyl, halogen substituted phenyl, alkoxy substituted phenyl, perfluoroalkoxy substituted phenyl and alkylthio substituted phenyl;

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.sub.6 is hydrogen, n is 3, m is 2, W is ##STR8## b.) R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR9## Ar is a moiety of the formula: ##STR10## c.) R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR11## Ar is a moiety of the formula: ##STR12## Ar' is a moiety of the formula: ##STR13## d.) R.sub.6 is hydrogen, n is 3, m is 2, W is ##STR14## Ar is a moiety of the formula: ##STR15## Ar' is thienyl or pyridinyl; e.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR16## f.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR17## Ar is a moiety of the formula: ##STR18## g.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR19## Ar is a moiety of the formula: ##STR20## Ar' is a moiety of the formula: ##STR21## h.) R.sub.6 is hydrogen, n is 3-6, m is 2, W is ##STR22## Ar is a moiety of the formula: ##STR23## Ar' is thienyl or pyridinyl; i.) R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR24## j.) R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR25## Ar is a moiety of the formula: ##STR26## k.) R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR27## Ar is a moiety of the formula: ##STR28## Ar' is a moiety of the formula: ##STR29## l.) R.sub.6 is hydrogen, n is 1, m is 2, W is ##STR30## Ar is a moiety of the formula: ##STR31## 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-methoxyphenylsulfanyl)-thiazolidi ne-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-methoxyphenylsulfonyl)-thiazolidi ne-2,4-dione, 5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-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-dion e, 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}ph enyl)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]-thiazolidi ne-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)-thiazo lidine-2,4-dione, 5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidi ne-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)-thiazoli dine-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-Iodobenzenesulfonyl)-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]thia zolidine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)-thia zolidine-2,4-dione, 5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]-thiazol idine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)-pent-4-ynyl]-5-(naphthalene-1-sulfonyl)-thiaz olidine-2,4-dione, 5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)-thiazo lidine-2,4-dione, 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesul fonyl]-thiazolidine-2,4-dione, 5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzene-sulfonyl)-thi azolidine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)-pent-4-ynyl]-thi azolidine-2,4-dione, 5-(4-Iodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]-thiazol idine-2,4-dione, 5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]-thi azolidine-2,4-dione, 5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thia zolidine-2,4-dione, 5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidin e-2,4-dione, 5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazoli dine-2,4-dione, 5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-thiazoli dine-2,4-dione, 5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazolidin e-2,4-dione, 5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-th iazolidine-2,4-dione, 5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzene-sul fonyl)-thiazolidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxy-benzenesul fonyl)-thiazolidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiaz olidine-2,4-dione, 5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-th iazolidine-2,4-dione, 5-[5-(4-Bromo-2-methy-phenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thi azolidine-2,4-dione, 5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-thiazol idine-2,4-dione, (4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}ph enyl)carbamic Acid tert-Butyl Ester, (3-Chloro-4-{5-[5-(4-methoxybenzene sulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester, N-tert-Butyl-3-{5-[5-(4-iodo-benzenesulfonyl)-2,4-dioxothiazol-idin-5-yl]-p ent-1-ynyl}-4-methyl-benzamide, (3-{5-[5-(4-Iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-