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′, R 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.

Description:
[0001]    “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.” 
     
    
     
       FIELD OF THE INVENTION  
         [0002]    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  
         [0003]    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).  
           [0004]    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.  
           [0005]    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  
         [0006]    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):  
                         
 
           [0007]    wherein:  
           [0008]    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:  
                         
 
           [0009]    R 1  is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms,4-pyridyloxy, azido, nitro, acetamido, trifluoromethoxy, phenoxy, or benzyloxy;  
           [0010]    R 2  is hydrogen, fluoro, bromo, chloro, iodo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, trifluoromethoxy, phenoxy, or benzyloxy;  
           [0011]    m is 0, 1 or 2;  
           [0012]    R 6  is hydrogen, alkyl of 1 to 6 carbon atoms, benzyl, substituted benzyl, imidazolylpropyl, or —CO 2 Y;  
           [0013]    Y is 2-methoxyethyl, alkyl is 1 to 6 carbon atoms, benzyl, or substituted benzyl; W is  
                         
 
           [0014]    E- and Z- —CH═CH—, —CONH—, —CONHCH 2 —, —CONHCH 2 CH 2 — or —CH 2 —CH 2 —;  
           [0015]    n is an integer of 1 to 9;  
           [0016]    Ar′ is thienyl, pyridinyl or a moiety of the formula  
                         
 
           [0017]    R 3 , R 4 , R 5 , are independently selected from hydrogen, alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, fluoro, bromo, chloro, iodo, nitro, amino, hydroxy, azido, cyano, phenyl, phenoxy, trifluoromethyl, trifluoromethoxy, methanesulphonyl, 1-pyrrolyl, —CO 2 R 7 , —CONHR 8 , —CH 2 CONHR 9 , —NHCO 2 R 10 , —NHCOR 11 , and —NHCONHR 12 ;  
           [0018]    R 7  is selected from H, and alkyl of 1 to 6 carbon atoms,  
           [0019]    R 8  is selected from H, and alkyl of 1 to 6 carbon atoms;  
           [0020]    R 9  is selected from H, and alkyl of 1 to 6 carbon atoms;  
           [0021]    R 10  is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, and chlorophenyl;  
           [0022]    R 11  is selected from alkyl of 1 to 6 carbon atoms, benzyl, phenyl, halophenyl, alkyl(1 to 6 carbon atoms)phenyl, alkoxy(1 to 6 carbon atoms)phenyl, and biphenyl;  
           [0023]    R 12  is benzyl, alkyl of 1 to 6 carbon atoms, alkoxy(1 to 6 carbon atoms)phenyl, halophenyl, and alkyl(1 to 6 carbon atoms)phenyl;  
           [0024]    provided that when W is  
                         
 
           [0025]    n is other than 2 or pharmaceutically acceptable salts thereof.  
           [0026]    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:  
           [0027]    a.) R 6  is hydrogen, n is 1, m is 2, W is  
                         
 
           [0028]    b.) R 6  is hydrogen, n is 3, m is 2, W is  
                         
 
           [0029]    c.) R 6  is hydrogen, n is 3-6, m is 2, W is  
                         
 
           [0030]    d.) R 6  is hydrogen, n is 1, m is 2, W is  
                         
 
           [0031]    Ar is a moiety of the formula  
                         
 
           [0032]    e.) R 6  is hydrogen, n is 3, m is 2, W is  
                         
 
           [0033]    Ar is a moiety of the formula  
                         
 
           [0034]    f.) R 6  is hydrogen, n is 3-6, m is 2, W is  
                         
 
           [0035]    Ar is a moiety of the formula  
                         
 
           [0036]    g.) R 6  is hydrogen, n is 1, m is 2, W is  
                         
 
           [0037]    Ar is a moiety of the formula  
                         
 
           [0038]    Ar′ is a moiety of the formula  
           [0039]    h.) R6 is hydrogen, n is 3, m is 2, W is  
                         
 
           [0040]    Ar is a moiety of the formula  
                         
 
           [0041]    Ar′ is a moiety of the formula  
                         
 
           [0042]    i.) R 6  is hydrogen, n is 3-6, m is 2, W is  
                         
 
           [0043]    Ar is a moiety of the formula  
                         
 
           [0044]    Ar′ is a moiety of the formula  
           [0045]    j.) R 6  is hydrogen, n is 1, m is 2, W is  
                         
 
           [0046]    Ar is a moiety of the formula  
                         
 
           [0047]    Ar′ is thienyl or pyridinyl;  
           [0048]    k.) R 6  is hydrogen, n is 3, m is 2, W is  
                         
 
           [0049]    Ar is a moiety of the formula  
                         
 
           [0050]    Ar′ is thienyl or pyridinyl;  
           [0051]    l.) R 6  is hydrogen, n is 3-6, m is 2, W is  
                         
 
           [0052]    Ar is a moiety of the formula  
                         
 
           [0053]    Ar′ is thienyl or pyridinyl;  
           [0054]    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.  
           [0055]    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:  
           [0056]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfanyl)thiazolidine-2,4-dione,  
           [0057]    5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)thiazolidine-2,4-dione,  
           [0058]    5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)thiazolidine-2,4-dione,  
           [0059]    5-(4-Methoxyphenylsulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,  
           [0060]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)thiazolidine-2,4-dione,  
           [0061]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,  
           [0062]    5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,  
           [0063]    5-[11 -(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenyl-sulfonyl)thiazolidine-2,4-dione,  
           [0064]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)thiazolidine-2,4-dione,  
           [0065]    5-[5-(2-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0066]    5-[5-(3-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0067]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(p-tolylsulfonyl)thiazolidine-2,4-dione,  
           [0068]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0069]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0070]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0071]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,  
           [0072]    N-(4-{5-[5-(4-Chlorophenyl)pent-4-ynyl]-2,4-dioxothiazolidine-5-sulfonyl}phenyl)acetamide,  
           [0073]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(quinoline-8-sulfonyl)thiazolidine-2,4-dione,  
           [0074]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-nitrobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0075]    5-(4-Benzyloxybenzenesulfonyl)-5-[5-(4-chlorophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0076]    5-(4-Butoxybenzenesulfonyl)-5-[5-(4-chlorophenyl)-pent-4-ynyl]thiazolidine-2,4-dione,  
           [0077]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(naphthalene-1 -sulfonyl)thiazolidine-2,4-dione,  
           [0078]    5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione,  
           [0079]    5-[5-(2,5-Dichloro-phenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0080]    5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)benzenesulfonyl]thiazolidine-2,4-dione,  
           [0081]    5-[5-(2,4-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0082]    5-(4-Methoxybenzenesulfonyl)-5-[5-(3-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0083]    5-[5-(3-Nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0084]    5-(4-lodobenzenesulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0085]    5-(4-Methoxybenzene sulfonyl)-5-[5-(4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0086]    5-(4-Methoxybenzene sulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0087]    5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0088]    5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl] -5-(4-phenoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0089]    5-(4-lodobenzenesulfonyl)-5-[5-(2-methyl-5-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0090]    5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-1-sulfonyl)thiazolidine-2,4-dione  
           [0091]    5-[5-(2-Methyl-5-nitrophenyl)pent-4-ynyl]-5-(naphthalene-2-sulfonyl)thiazolidine-2,4-dione,  
           [0092]    5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-[4-(pyridin-4-yloxy)-benzenesulfonyl]-thiazolidine-2,4-dione,  
           [0093]    5-[5-(2-Methyl-4-nitrophenyl)pent-4-ynyl]-5-(4-phenoxybenzene-sulfonyl)thiazolidine-2,4-dione,  
           [0094]    5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0095]    5-(4-lodobenzenesulfonyl)-5-[5-(2-methyl-4-nitrophenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0096]    5-(4-Methoxybenzenesulfonyl)-5-[5-(2-methoxy-4-nitrophenyl)pent-4-ynyl]-thiazolidine-2,4-dione,  
           [0097]    5-[5-(3-Fluoro-5-nitrophenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)thiazolidine-2,4-dione,  
           [0098]    5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0099]    5-[5-(2,5-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0100]    5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0101]    5-[5-(2,4-Dimethylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0102]    5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0103]    5-[5-(5-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0104]    5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0105]    5-[5-(4-Chloro-2-methylphenyl)-pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0106]    5-[5-(4-Chloro-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0107]    5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-ethoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0108]    5-[5-(4-Bromo-2-methylphenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)thiazolidine-2,4-dione,  
           [0109]    (4-{5-[5-(4-Methoxybenzensulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,  
           [0110]    (3-Chloro-4-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}phenyl)carbamic Acid tert-Butyl Ester,  
           [0111]    N-tert-Butyl-3-{5-[5-(4-iodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylbenzamide,  
           [0112]    (3-{5-[5-(4-lodobenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,  
           [0113]    (4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-3-methylphenyl)carbamic Acid tert-Butyl Ester,  
           [0114]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid tert-Butyl Ester,  
           [0115]    (4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-trifluoromethylphenyl)-carbamic Acid tert-Butyl Ester,  
           [0116]    N-tert-Butyl-3-{5-[5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methyl-benzamide,  
           [0117]    5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethylphenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0118]    5-(4-Methoxybenzenesulfonyl)-5-[5-(4-trifluoromethoxyphenyl)pent-4-ynyl]-thiazolidine-2,4-dione,  
           [0119]    3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}-4-methylbenzoic Acid Methyl Ester,  
           [0120]    5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0121]    5-[5-(4-tert-Butylphenyl)pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0122]    4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]pent-1-ynyl}benzonitrile,  
           [0123]    5-[5-(4-Methanesulfonylphenyl)-pent-4-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0124]    4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic Acid Methyl Ester,  
           [0125]    5-(4-Methoxybenzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0126]    5-(4-lodo-benzenesulfonyl)-5-[5-(4-pyrrol-1-yl-phenyl)pent-4-ynyl]thiazolidine-2,4-dione,  
           [0127]    5-[5-(4-Pyrrol-1-ylphenyl)pent-4-ynyl]-5-(4-trifluoromethoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0128]    5-(3-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,  
           [0129]    5-(4-Methylphenylsulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,  
           [0130]    5-(4-Methoxybenzenesulfonyl)-5-(5-thiophen-2-yl-pent-4-ynyl)thiazolidine-2,4-dione,  
           [0131]    5-(4-Methoxybenzenesulfonyl)-5-(3-pyridin-3-ylprop-2-ynyl)thiazolidine-2,4-dione,  
           [0132]    5-(3-Thiophen-2-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0133]    5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0134]    5-[3-(4-Phenoxyphenyl)prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0135]    5-(3-Biphenyl-4-yl-prop-2-ynyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0136]    5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0137]    5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione, ( 
           [0138]    3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Benzyl Ester,  
           [0139]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid 4-Nitro-Benzyl Ester,  
           [0140]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid 4-Chloro-phenyl Ester,  
           [0141]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Methyl Ester,  
           [0142]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Isopropyl Ester,  
           [0143]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Neopentyl Ester,  
           [0144]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Butyl Ester,  
           [0145]    (3-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-4-methylphenyl)carbamic Acid Isobutyl,  
           [0146]    N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-methylpropanamide,  
           [0147]    N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-3,3-dimethylbutanamide,  
           [0148]    N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2,2-dimethylpropanamide,  
           [0149]    N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]-2-phenylacetamide,  
           [0150]    N-Benzyl-N′-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,  
           [0151]    N-(4-Methoxyphenyl)-N′-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,  
           [0152]    N-(4-Chlorophenyl)-N′-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]urea,  
           [0153]    N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-methylphenyl]-N′-(4-methylphenyl)urea,  
           [0154]    4-Chloro-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,  
           [0155]    4-Methoxy-N-[3-(5-{5-[(4-methoxyphenyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,  
           [0156]    N-[3-(5-{5-[(4-Methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl][1,1′-biphenyl]-4-carboxamide,  
           [0157]    4-(tert-Butyl)-N-[3-(5-{5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl]benzamide,  
           [0158]    5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(5-chloro-2-thienyl)sulfonyl]-1,3-thiazolidine-2,4-dione,  
           [0159]    5-[5-(4-Chlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,  
           [0160]    5-[5-(4-Chlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,  
           [0161]    5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidine-2,4-dione,  
           [0162]    5-[5-(4-Chlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,  
           [0163]    5-[(5-Chloro-2-thienyl)sulfonyl]-5-[5-(2,5-dichlorophenyl)-4-pentynyl]-1,3-thiazolidine-2,4-dione,  
           [0164]    5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-(2-thienylsulfonyl)-1,3-thiazolidine-2,4-dione,  
           [0165]    5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-[(3,4-dimethoxyphenyl)sulfonyl]-1,3-thiazolidine-2,4-dione,  
           [0166]    5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl),1,3-thiazolidine-2,4-dione,  
           [0167]    5-[5-(2,5-Dichlorophenyl)-4-pentynyl]-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidine-2,4-dione,  
           [0168]    tert-Butyl 3-(5-{5-[(5-chloro-2-thienyl)-sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenylcarbamate,  
           [0169]    tert-Butyl 3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentyn-yl}-4-methylphenylcarbamate,  
           [0170]    tert-Butyl 3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylphenyl-carbamate,  
           [0171]    tert-Butyl 3-[5-(2,4-dioxo-5-{[4-(4-pyridinyloxy)phenyl]sulfonyl}-1,3-thiazolidin-5yl)-1-pentynyl]-4-methylphenyl-carbamate,  
           [0172]    tert-Butyl 3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylphenyl-carbamate,  
           [0173]    N-(tert-Butyl)-3-(5-{5-[(5-chloro-2-thienyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,  
           [0174]    N-(tert-Butyl)-3-{5-[2,4-dioxo-5-(2-thienylsulfonyl)-1,3-thiazolidin-5-yl]-1-pentynyl}-4-methylbenzamide,  
           [0175]    N-(tert-Butyl)-3-(5-{5-[(3,4-dimethoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidin-5-yl}-1-pentynyl)-4-methylbenzamide,  
           [0176]    N-(tert-Butyl)-3-[5-(2,4-dioxo-5-{[5-(2-pyridinyl)-2-thienyl]sulfonyl}-1,3-thiazolidin-5-yl)-1-pentynyl]-4-methylbenzamide,  
           [0177]    4-{5-[5-(4-Methoxybenzenesulfonyl)-2,4-dioxothiazolidin-5-yl]pent-1-ynyl}-3-methylbenzoic Acid,  
           [0178]    N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide,  
           [0179]    N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5-yl]propionamide,  
           [0180]    5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0181]    5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0182]    5-[3-(4-Chlorophenyl)propyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0183]    5-[5-(3-Aminophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0184]    5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0185]    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),  
           [0186]    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),  
           [0187]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfinyl)thiazolidine-2,4-dione,  
           [0188]    Benzyl 5-[5-(5-{[(benzyloxy)carbonyl]-amino}-2-methylphenyl)pent-4-ynyl]-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,  
           [0189]    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,  
           [0190]    Methyl 5-(5-{5-[(methoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,  
           [0191]    Isopropyl 5-(5-{5-[(isopropoxycarbonyl)-amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,  
           [0192]    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,  
           [0193]    Butyl 5-(5-{5-[(butoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxy-phenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,  
           [0194]    Isobutyl 5-(5-{5-[(isobutoxycarbonyl)amino]-2-methylphenyl}pent-4-ynyl)-5-[(4-methoxyphenyl)sulfonyl]-2,4-dioxo-1,3-thiazolidine-3-carboxylate,  
           [0195]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(3-imidazol-1-yl-propyl)-5-(4-methoxybenzenesulfonyl)thiazolidine-2,4-dione,  
           [0196]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione,  
           [0197]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0198]    5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)thiazolidine-2,4-dione, and  
           [0199]    5-[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester.  
           [0200]    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:  
           [0201]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(napthalene-2-sulfonyl)thiazolidine-2,4-dione,  
           [0202]    5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0203]    5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0204]    5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,  
           [0205]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-fluoro-benzenesulfonyl)thiazolidine-2,4-dione,  
           [0206]    5-(4-Chloro-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0207]    5-(4-Bromo-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0208]    5-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0209]    5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0210]    5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,  
           [0211]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)thiazolidine-2,4-dione,  
           [0212]    5-(Naphthalene-2-sulfonyl)-5-(3-phenyl-prop-2-ynyl)thiazolidine-2,4-dione,  
           [0213]    5-(Toluene-4-sulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0214]    5-[3-(4-Methoxy-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0215]    5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0216]    5-Benzenesulfonyl-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0217]    5-(4-Chloro-benzenesulfonyl)-5-[3-(4-fluoro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0218]    5-[3(4-Chloro-phenyl)-prop-2-ynyl]-5(toluene-3-sulfonyl)thiazolidine-2,4-dione,  
           [0219]    5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0220]    5-Benzenesulfonyl-5-[3(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0221]    5-[3(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5(toluene-4-sulfonyl)thiazolidine-2,4-dione,  
           [0222]    5-Benzenesulfonyl-5-[3-(3-chloro-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione,  
           [0223]    5-[3(4-Chlorophenyl)-2-propynyl]-2-[(4-methylphenyl)sulfonyl]-2,4-thiazolidinedione,  
           [0224]    5-[3(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)thiazolidine-2,4-dione,  
           [0225]    5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-2-ynyl]thiazolidine-2,4-dione,  
           [0226]    5-[3(4-Chloro-phenyl)-prop-2-ynyl]-5-(quinoline-2-sulfonyl)thiazolidine-2,4-dione,  
           [0227]    5-[3-(3,5-Bis-trifluoromethyl-phenyl)-prop-2-ynyl]thiazolidine-2,4-dione, and  
           [0228]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(p-tolylsulfanyl)thiazolidine-2,4-dione.  
           [0229]    It is understood that the definition of compounds of Formula (I) when R 1 to R 12 , 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 R 1  to R 12 , 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).  
           [0230]    For the compounds of Formula (I) defined above and referred to herein, unless otherwise noted, the following terms are defined:  
           [0231]    Halogen, as used herein means chloro, fluoro, bromo and iodo.  
           [0232]    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.  
           [0233]    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:  
                         
 
           [0234]    and further defined an aromatic radical Ar′ is thienyl, pyridinyl or a moiety of the formula  
                         
 
           [0235]    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.  
           [0236]    Alkyne as used herein means an alkynyl group  
                         
 
           [0237]    is present.  
           [0238]    Phenyl as used herein refers to a 6-membered aromatic ring.  
           [0239]    Carbamic acid ester is —NHCO 2 R 10  where preferred R 10  is alkyl of 1 to 6 carbon atoms.  
           [0240]    Substituted carboxamide is —CONHR 8  wherein R 8  is alkyl of 1 to 6 carbon atoms.  
           [0241]    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.  
           [0242]    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.  
           [0243]    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.  
           [0244]    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.  
           [0245]    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.  
           [0246]    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).  
           [0247]    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  
         [0248]    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.  
                         
 
           [0249]    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.  
           [0250]    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.  
           [0251]    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.  
           [0252]    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.  
           [0253]    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).  
                         
 
           [0254]    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.  
                         
 
           [0255]    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.  
                         
 
           [0256]    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.  
                         
 
           [0257]    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).  
           [0258]    As shown in Scheme V, a compound of Formula (I), wherein at least one of R 3 , R 4 , or R 5  of the moiety  
                         
 
           [0259]    is a nitro group, and as shown in formula I′ where R 3  is 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.  
                         
 
           [0260]    As further shown in Scheme V, compounds of Formula (I), wherein at least one of R 3 , R 4 , or R 5 is amino, as shown in amine XIII can be prepared by hydrolysis of carbamate XII, wherein at least one of R 3 , R 4 , or R 5  of 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.  
           [0261]    Substituted amine XIV, wherein at least one of R 3 , R 4 , or R 5  is —NHCO 2 R 10  wherein R 10  is selected from alkyl of 1 to 6 carbon atoms, benzyl, nitrobenzyl, chlorophenyl; substituted amine XV, wherein at least one of R 3 , R 4 , or R 5  is —NHCOR 11 , wherein R 11  is 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 R 3 , R 4 , or R 5  is —NHCONHR 12  wherein R 12  is 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.  
                         
 
           [0262]    Referring to Scheme VI: compounds of formula (I), wherein at least one of R 3 , R 4 , or R 5 is 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.  
                         
 
           [0263]    Referring to Scheme VII: compounds of formula (I), wherein at least one of R 3 , R 4 , or R 5  is 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.  
                         
 
           [0264]    Referring to Scheme VIII: Compounds of Formula (I), wherein Ar′ is hereinbefore define and at least one of R 3 , R 4 , or R 5  are 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  
                         
 
           [0265]    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;  
                         
 
           [0266]    As shown in Scheme IX: compounds of Formula (I) as in alkene XXVI, wherein either R 3 , R 4 , and R 5  are 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.  
                         
 
           [0267]    Referring to Scheme X: compounds of formula (I), wherein Ar′ is herein before described and W is —CH 2 —CH 2 — as in dione XXVII, can be prepared from a compound of formula (I) wherein W is either  
                         
 
           [0268]    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  
         [0269]    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.  
           [0270]    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.  
           [0271]    Materials—Purified FPTase (Moomaw, J. F. and Casey, P. J.,  J. Biol. Chem.,  1992, 267, 17438-17443), purified His 6 -Ras, inhibitor compounds at 10 mg/ml or 10 mM in 100% DMSO,  3 H—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.  
           [0272]    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 MgCl 2 , 20 mM KCl, 5 mM DTT, 0.2% octyl-B-glucoside, 1% DMSO, 40 mM His 6 -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  3 H—FPP incorporation into Ras protein.  
           [0273]    Analysis of Results—Percent inhibition by test compounds is determined by the following:  
           [0274]    (cpm from precipitated Ras with test compounds)−(background cpm)×100=% inhibition.  
           [0275]    (cpm from precipitated Ras without test compounds)−(background cpm)  
           [0276]    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.  
           [0277]    Materials—Cell Lines: Human tumor cell lines LS174T, HTB39, LoVo and CaCo2. Cell Media: RPMI 1640 (or DMEM medium and McCoy&#39;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.  
           [0278]    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.  
           [0279]    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 50  calculated for that compound.  
                                           TABLE I                           in vitro FTase Inhibition Assay                IC 50  H-Ras*   IC 50  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-&gt;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   &gt;10       161   0.9   10       162   1.21   4.0       163   1.3   10       164   0.15   &gt;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   &gt;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                          
 
           [0280]    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.  
           [0281]    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.  
           [0282]    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&#39;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                IC 50  (wi. H-   IC 50  (wi. K-           Ras)   Ras)       Ex. No.   μM   μM                    239   0.7   10       240   0.5   &gt;10       241   1.5   &gt;10       242   1   &gt;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   &gt;10       255   0.15   10       256   0.8   10       257   0.035   &gt;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   &gt;10       265   1.5   &gt;10       266   0.5   &gt;10       267   5   &gt;10                          
 
           [0283]    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 &gt;40 μM. Results are displayed in Table II.  
           [0284]    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   &lt;.01   255   43   &lt;.01       (75 IP)       Cpd.   65   74   0.15   146   47   0.02   258   43   &lt;0.01       (50 IP)       Cpd.   31   35   &lt;0.01   125   41   &lt;.01   251   42   &lt;.01       (100 IP)       Vincristine   14   16   &lt;0.01   24   8   &lt;.01   84   14   &lt;.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   &lt;0.01   194   15   &lt;.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)                                                                                  
 
           [0285]    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                                  
 
           [0286]    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.  
           [0287]    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.  
           [0288]    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.  
           [0289]    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.  
           [0290]    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.  
           [0291]    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.  
           [0292]    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.  
           [0293]    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.  
           [0294]    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.  
           [0295]    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  
       [0296]    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 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 C 10 H 9 NO 5 S 2 )  
       EXAMPLE 2  
     5-(4-Fluorophenyl-4-sulfonyl)-thiazolidine-2,4-dione  
       [0297]    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.].  
       EXAMPLE 3  
     5-(4-lodophenyl-4-sulfonyl)-thiazolidine-2,4-dione  
       [0298]    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.  
         [0299]    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  
       [0300]    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).  
       EXAMPLE 19  
     5-(4-Methanesulfonylphenyl)pent-4-yn-1-ol  
       [0301]    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 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 C 12 H 14 O 3 S 238.3)  
         [0302]    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  
       [0303]    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 12 H 13 OCl 209.70).  
       EXAMPLE 50  
     11-(4-Chlorophenyl)undec-10-yn-1-ol  
       [0304]    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 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  
       [0305]    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:  
         [0306]    NMR (CDCl 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 C 15 H 12 O 2 =224.08)  
       EXAMPLE 52  
     3-Biphenyl-4-yl-prop-2-yn-1-ol  
       [0307]    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 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 C 15 H 12 O=208.3).  
       EXAMPLE 53  
     3-Thiophene-2-yl-prop-2-yn-1-ol  
       [0308]    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.  
       EXAMPLE 54  
     1-Chloro-4-(5-iodopent-1-ynyl)benzene  
       [0309]    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 11 H 10 ClI=304.6).  
       EXAMPLE 55  
     1-(5-lodo-pent-1 -ynyl)-4-methanesulfonylbenzene  
       [0310]    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 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 C 12 H 13 O 2 S 348=349.2).  
       EXAMPLE 56  
     1,4-Dichloro-2-(5-iodopent-1-ynyl)benzene  
       [0311]    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 11 H 9 Cl 2 I=338.0).  
         [0312]    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  
       [0313]    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 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 C 15 H 11 BrO 287.155).  
         [0314]    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  
       [0315]    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.  
         [0316]    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:  
       EXAMPLE 93  
     5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfanyl)-thiazolidine-2,4-dione  
       [0317]    MS m/z 444.2 (calcd for C 22 H 20 ClNO 3 S 2  445.99).  
       EXAMPLE 94  
     5-[11-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxy-phenylsulfanyl)-thiazolidine-2,4-dione  
       [0318]    mp 54-56° C., MS m/z 514.0 (calcd. for C 27 H 30 ClNO 3  516.1).  
       EXAMPLE 95  
     5-(4-Methoxyphenyisulfanyl)-5-(5-thiophen-2-yl-pent-4-ynyl)-thiazolidine-2,4-dione  
       [0319]    This was used in the next step without further purification  
       EXAMPLE 96  
     5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-fluorophenylsulfanyl)-thiazolidine-2,4-dione  
       [0320]    This was used in the next step without further purification  
       EXAMPLE 97  
     5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione  
       [0321]    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 21 H 18 CINO 5 S 2  463.96).  
       EXAMPLE 98  
     5-[6-(4-Chlorophenyl)hex-5-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione  
       [0322]    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.  
       EXAMPLE 99  
     5-[1-(4-Chlorophenyl)undec-10-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione  
       [0323]    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.  
       EXAMPLE 100  
     5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione  
       [0324]    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 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)  
         [0325]    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  
       [0326]    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.  
       EXAMPLE 173  
     5-(5-Pyridin-3-yl-pent-4-ynyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       [0327]    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.  
       EXAMPLE 174  
     5-[5-(5-Amino-2-methylphenyl)pent-4-ynyl]-5-(4-methoxybenzene-sulfonyl)-thiazolidine-2,4-dione  
       [0328]    (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 22 H 22 N 2 O 5 S 2  458.56).  
       EXAMPLES 175 TO 194  
       [0329]    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  
       [0330]    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.  
         [0331]    Each vial was diluted with 5 ml H 2 O, 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  
       [0332]    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.  
       EXAMPLE 215  
     N-(4-Chlorobenzyl)-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-4-yl]propionamide  
       [0333]    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:  
         [0334]    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.  
       EXAMPLE 216  
     N-[2-(4-Chlorophenyl)ethyl]-3-[5-(4-methoxybenzenesulfonyl)-2,4-dioxo-thiazolidin-5yl]propionamide  
       [0335]    In a like procedure to Example 215, above, 4-chlorophenethylamine gave the title compound as a white powder, mp 189° C. with decomposition.  
       EXAMPLE 217  
     5-[(4Z)-5-(4-Chloro-phenyl)pent-4-enyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       [0336]    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 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 C 21 H 20 ClNO 4 S 2  499.0523).  
       EXAMPLE 218  
     5-[(4E)-5-(4-Chlorophenyl)pent-4-enyl]-5-(4-methoxybenzenesulfonyl)-thiazolidine-2,4-dione  
       [0337]    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 4 Cl was added, and this was stirred for 1 h. Combined organics were washed with brine, and dried over MgSO 4  to 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.  
         [0338]    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.  
         [0339]    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.  
         [0340]    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 4  and concentrated to afford an oil which was purified on silica gel using 1:2:1 CH 2 Cl 2 : hex: EtOAc to afford the title compound, 36% as an off-white solid, mp 182-184° C., E-double bond—NMR (CDCl 3 ) 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  
       [0341]    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 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  
       [0342]    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.  
       EXAMPLE 221  
     5-(3-Phenylallyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       [0343]    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 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 C 19 H 17 NO 4 S 2  387.48)  
       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)  
       [0344]    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.  
       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)  
       [0345]    Continued chromatography of the compounds in Example 223 gave a more polar enantiomer, retention time 19-21 min.  
       EXAMPLE 224  
     5-(4-methoxyphenyl-4-sulfinyl)-thiazolidine-2,4-dione  
       [0346]    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 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  
       [0347]    By the method of Example 92, the compound of Example 224, above, is converted to the title compound.  
       EXAMPLES 226-233  
       [0348]    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  
       [0349]    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.  
       EXAMPLE 234  
     5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-3-methyl-thiazolidine-2,4-dione  
       [0350]    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.  
       EXAMPLE 235  
     3-(2,4-Diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       [0351]    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.  
       EXAMPLE 236  
     5-[5-(4-Chlorophenyl)pent-4-ynyl]-3-(2,4-diethoxybenzyl)-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       [0352]    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.  
       EXAMPLE 237  
     5-[5-(4-Chlorophenyl)pent-4-ynyl]-5-(4-iodobenzenesulfonyl)-3-(4-nitrobenzyl)-thiazolidine-2,4-dione  
       [0353]    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.  
       EXAMPLE 238  
       
       [0354]    [0354] 5 -[5-(2,5-Dichlorophenyl)pent-4-ynyl]-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidine-3-carboxylic acid 2-methoxy ethyl ester  
         [0355]    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 25 H 23 Cl 2 NO 8 S 2  600.5).  
         [0356]    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.,  J. Med. Chem.  1998, 41 (7), 1084-91.  
       EXAMPLE 239  
       [0357]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(napthalene-2-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 240  
       [0358]    5-Benzenesulfonyl-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 241  
       [0359]    5-Benzenesulfonyl-5-[3-phenyl-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 242  
       [0360]    5-(4-Chloro-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2,4-dione  
       EXAMPLE 243  
       [0361]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-fluoro-benzenesulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 244  
       [0362]    5-(4-Chloro-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 245  
       [0363]    5-(4-Bromo-benzenesulfonyl)-5-[3-(4-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 246  
       [0364]    5-[3-(4-Fluoro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 247  
       [0365]    5-(Toluene-4-sulfonyl)-5-[3-(p-tolyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 248  
       [0366]    5-(4-Bromo-benzenesulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2,4-dione  
       EXAMPLE 249  
       [0367]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(4-methoxy-benzenesulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 250  
       [0368]    5-(Naphthalene-2-sulfonyl)-5-(3-phenyl-prop-2-ynyl)-thiazolidine-2,4-dione  
       EXAMPLE 251  
       [0369]    5-(Toluene-4-sulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 252  
       [0370]    5-[3-(4-Methoxy-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 253  
       [0371]    5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 254  
       [0372]    5-Benzenesulfonyl-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 255  
       [0373]    5-(4-Chloro-benzenesulfonyl)-5-[3-(4-fluoro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 256  
       [0374]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-3-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 257  
       [0375]    5-[3-(3-Chloro-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 258  
       [0376]    5-Benzenesulfonyl-5-[3-(2-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 259  
       [0377]    5-Benzenesulfonyl-5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 260  
       [0378]    5-[3-(3,5-bis-trifluoromethyl-phenyl)-prop-2-ynyl]-5-(toluene-4-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 261  
       [0379]    5-Benzenesulfonyl-5-[3-(3-chloro-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 262  
       [0380]    5-[3-(4-Chlorophenyl)-2-propynyl]-2-[(4-methylphenyl)sulfonyl]-2,4-thiazolidinedione  
       EXAMPLE 263  
       [0381]    5-[3-(4-Bromo-phenyl)-prop-2-ynyl]-5-(4-chloro-benzenesulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 264  
       [0382]    5-(4-Fluoro-benzenesulfonyl)-5-[3-(4-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 265  
       [0383]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(quinoline-2-sulfonyl)-thiazolidine-2,4-dione  
       EXAMPLE 266  
       [0384]    5-[3-(3,5-Bis-trifluoromethyl-phenyl)-prop-2-ynyl]-thiazolidine-2,4-dione  
       EXAMPLE 267  
       [0385]    5-[3-(4-Chloro-phenyl)-prop-2-ynyl]-5-(p-tolylsulfanyl)-thiazolidine-2,4-dione