Methods and compositions for the treatment of cancer and related hyperproliferative disorders

Abstract

The present invention relates to methods of treating a disease related to cell hyper-proliferation via administration of a therapeutically effective amount of a compound having a general tripartite structure A-B-C. In the tripartite structure A, B, and C are identical or non-identical structures, for example, but not limited to, heterocyclic, phenyl or benzyl ring structures with or without substitutions and are described in detail herein. The methods may utilize particular compounds, for example, having a piperidinyl, a pyrrolinyl or pyridinyl A ring, a thiazole B ring, and a phenyl C ring which may be further substituted independently.

What is claimed is: 
     
         1 . A method for treating a disease related to cell hyper-proliferation in a patient in need thereof, comprising the step of administering to the patient, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound having a structure:
   A—B—C
   wherein A is a pyridine or a substituted pyridine, a piperidine or a substituted piperidine, a pyrrolidine or a substituted pyrrolidine, a thiazole or a substituted thiazole, a phenyl ring or a substituted phenyl ring;   B is a thioazole or a substituted thioazole, a piperazine or a substituted piperazine, a phenyl ring or a substituted phenyl ring; and   C is a phenyl ring or a substituted phenyl ring, a pyridine or a substituted pyridine, a thioazole or a substituted thioazole;   or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.   
     
     
         2 . The method of  claim 1 , wherein the chemical structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein R 1  is H, halogen, —OH, C 1 - 3 alkyl, —OR 3 , —NHR 5    
         R 3  is C 1 -C 3  alkyl, Bz or —OCH 2 —C(O)OR 4 ; 
         R 4  is H or C 1 -C 3  alkyl; 
         R 5  is H, C 1 -C 4  alkyl, methylcyclopropane, cyclohexane, benzyl, —NHC(O)R 6 , or —SO 2 —R 7 ; 
         R 6  is C 1 -C 3 alkyl or —O-tert-butyl; 
         R 7  is methyl, thiophenyl or quinolinyl; 
         R 2  is C 2 -C 4 alkyl or —C(O)OR 8 , and 
         R 8  is C 3 -C 5  alkyl or aryl; or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
       
     
     
         3 . The method of  claim 2 , wherein said halogen is bromine. 
     
     
         4 . The method of  claim 2 , wherein the compound is:
 4-(4-bromophenyl)-2-(pyrrolidin-2-yl)thiazole,   4-(4-bromophenyI)-2-(1-propylpyrrolidin-2-yl)thiazole,   tert-butyl 2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate,   benzyl 2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate, or   benzyl (R)-2-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-1-carboxylate.   
     
     
         5 . The method of  claim 1 , wherein the chemical structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein R 1  is H, halogen, —OH, C 1 - 3 alkyl, —OR 3 , or —NHR 5 ; 
         R 3  is C 1 -C 3  alkyl, Bz or —OCH 2 —C(O)OR 4 ; 
         R 4  is H or C 1 -C 3  alkyl; 
         R 5  is H, C 1 -C 4  alkyl, methylcyclopropane, cyclohexane, benzyl, —C(O)R 6 , or —SO 2 -R 7 ; 
         R 6  is C 1 -C 3  alkyl or —O-tert-butyl; 
         R 7  is methyl, thiophenyl or quinolinyl; 
         R 2  is C 2 -C 4  alkyl or —C(O)OR 8 , and 
         R 8  is C 3 -C 5  alkyl or aryl; or 
         a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
       
     
     
         6 . The method of  claim 5 , wherein said halogen is bromine. 
     
     
         7 . The method of  claim 5 , wherein the compound is:
 3-(4-(4-bromophenyl)thiazol-2-yl)-1-propylpiperidine,   tert-butyl 3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,   benzyl 3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,   benzyl 4-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,   benzyl 3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate, or   benzyl 4-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate.   
     
     
         8 . The method of  claim 1 , wherein the chemical structure of the compound is: 
       
         
           
           
               
               
           
         
         wherein R 9  is H, halogen, —OH, —OR 11  or —NHR 13 ; 
         R 11  is C 1 -C 3  alkyl, Bz or —OCH 2 —C(O)OR 12 ; 
         R 12  is H or C 1 -C 3  alkyl; 
         R 13  is H, C 1 -C 4  alkyl, methylcyclopropane, cyclohexane, benzyl, or —C(O)R 14 , or —SO 2 —R 15 ; 
         R 14  is C 1 -C 3  alkyl or —O-tert-butyl; 
         R 15  is methyl, thiophenyl, quinolinyl, or phenylR is ; 
         R 16  is 4-chloro, 4-methyl or 3-chloro-4-methyl; 
         R 10  is nitrogen or methylene, 
         n is 0 or 1 and when n is 1, Z is —C═O; and 
         A is 
       
       
         
           
           
               
               
           
         
       
       wherein R 17  is H or C 1 -C 3  alkyl group; or
 a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
 
     
     
         9 . The method of  claim 8 , wherein the compound is:
 3-chloro-4-methyl-N-(6-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yppyridin-3-yl)benzene sulfonamide,   (4-(5-chloro-2-methylphenyl)piperazin-1-yI)(4-(tosylamino)phenyl) methanone,   4-(4-((1-methyl-1H-benzo[d]imidazole-2-yl)methyl)piperazin-1-yl)-N-tosylbenzenamine, or   4-chloro-N-(4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)phenyl) benzenesulfonamide.   
     
     
         10 . The method of  claim 1 , wherein the chemical structure of the compound is: 
       
         
           
           
               
               
           
         
         The method of  claim 10 , wherein the compound is: 
         4-(3-(pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-tosylbenzenamine; 
         (Z)-4-(3-cyano-3-(4-(2,4-dimethylphenyl)thiazol-2-yl)allyl)-N-(thiazol-2-yl)benzenesulfonamide; 
         N-(3-(H-imidazo[1,2-a]pyridine-2-yl)phenyI)-4-methyl-2-phenylthiazole-5-carboxamide; 
         N-(3-(benzo[d]thiazol-2-yl)phenyl)isonicotinamide; 
         3-(4-chlorophenyl)-4,5-dihydro-1-phenyl-5-(2-phenylthiazol-4-yl)-1H-pyrazole; 
         N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-m-tolylmethylsulfonamido) acetamide; or 
         N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-p-tolylmethylsulfonamido) acetamide. 
       
     
     
         11 . The method of  claim 1 , wherein the disease related to cell hyper-proliferation is cancer. 
     
     
         12 . The method of  claim 11 , wherein the cancer is a cancer of the breast, respiratory tract, brain, reproductive organs, prostate, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid, lymphoma, sarcoma, melanoma, leukemia or a distant metastasis of a solid tumor. 
     
     
         13 . A method for treating a cancer in a patient in need thereof, comprising the step of administering to the patient, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound having the chemical structure: 
       
         
           
           
               
               
           
         
         wherein R is H, isopropyl, benzyl, cyclohexyl, cyclopropylmethyl, —COMe, tert-butyloxycarbonyl, or methylsulfonyl, or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
       
     
     
         14 . The method of  claim 13 , wherein the chemical structure of the compound is: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method of  claim 13 , wherein the compound is:
 4-(4-bromophenyI)-2-(1-propylpyrrolidin-2-yl)thiazole,   N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide,   4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine,   N-isopropyl-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine,   N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenypacetamide,   N-(cyclopropylmethyl)-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine,   N-benzyl-4-(2-(2-propylpyridin-4-yl)thiazol-4- yl)benzenamine,   N-cyclohexyl-4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)benzenamine,   4-(3-(pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-tosylbenzenamine,   (Z)-4-(3-cyano-3-(4-(2,4-dimethylphenyl)thiazol-2-yl)allyl)-N-(thiazol-2-yl)benzenesulfonamide,   N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-m-tolylmethylsulfonamido)acetamide, or   N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-p-tolylmethylsulfonamido) acetamide.   
     
     
         16 . The method of  claim 13 , wherein the cancer is a cancer of the respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid, lymphoma, sarcoma, melanoma, leukemia or a distant metastasis of a solid tumor. 
     
     
         17 . A method for treating a disease related to cell hyper-proliferation in a patient in need thereof, comprising the step of administering to the patient, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound that is:
 4-(4-bromophenyl)-2-(pyrrolidin-2-yl)thiazole,   4-(4-bromophenyI)-2-(1-propylpyrrolidin-2-yl)thiazole,   tert-butyl 2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate,   benzyl 2-(4-(4-bromophenyl)thiazol-2-yl)pyrrolidine-1-carboxylate,   benzyl (R)-2-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)pyrrolidine-1-carboxylate,   3-(4-(4-bromophenyl)thiazol-2-yl)-1-propylpiperidine,   tert-butyl 3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,   benzyl 3-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,   benzyl 4-(4-(4-bromophenyl)thiazol-2-yl)piperidine-1-carboxylate,   benzyl 3-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate,   benzyl 4-(4-(4-(methylsulfonamido)phenyl)thiazol-2-yl)piperidine-1-carboxylate,   3-chloro-4-methyl-N-(6-(4-(3-(trifluoromethyl)benzyl)piperazin-1-yppyridin-3-yl)benzene sulfonamide,   (4-(5-chloro-2-methylphenyl)piperazin-1-yI)(4-(tosylamino)phenyl) methanone,   4-(4-((1-methyl-1H-benzo[d]imidazole-2-yl)methyl)piperazin-1-yl)-N-tosylbenzenamine,   4-chloro-N-(4-(4-((1-methyl-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)phenyl) benzenesulfonamide,   4-(3-(pyridin-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-N-tosylbenzenamine;   (Z)-4-(3-cyano-3-(4-(2,4-dimethylphenyl)thiazol-2-yl)allyl)-N-(thiazol-2-yl)benzenesulfonamide;   N-(3-(H-imidazo[1,2-a]pyridine-2-yl)phenyl)-4-methyl-2-phenylthiazole-5-carboxamide;   N-(3-(benzo[d]thiazol-2-yl)phenyl)isonicotinamide;   3-(4-chlorophenyl)-4,5-dihydro-1-phenyl-5-(2-phenylthiazol-4-yl)-1H-pyrazole;   N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-m-tolylmethylsulfonamido) acetamide; or   N-(4-(6-methylbenzo[d]thiazol-2-yl)phenyl)-2-(N-p-tolylmethylsulfonamido) acetamide.   
     
     
         18 . The method of  claim 17 , wherein the disease related to cell hyper-proliferation is cancer. 
     
     
         19 . The method of  claim 18 , wherein the cancer is a cancer of the breast, respiratory tract, brain, reproductive organs, prostate, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid, lymphoma, sarcoma, melanoma, leukemia or a distant metastasis of a solid tumor.