Method of inhibiting neoplastic cells with benzimidazole derivatives

Abstract

A method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to benzimidazole derivatives.

We claim  
     
         1 . A method of treating a mammal having precancerous lesions sensitive to the compounds of formula I comprising administering to said mammal a pharmacologically effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from a group consisting of substituted or unsubstituted pyridyl, dibenzofuranyl, dioxymethylene benzyl, naphthyl, quinolinyl or isoquinolinyl and wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, halo- or cyano-substituted or unsubstituted phenyloxy or benzyloxy, lower haloalkyl, CN, amino, nitro, phenyl, thiadiazole, aryloxy, arylsulfonyl methyl, arylsulfonyl amino, benzoyl, benzylamidyl, benzenesulfonyl methyl, phenylethyl, and phenylethenyl, wherein said aryl group is selected from the group consisting of phenyl, benzyl and pyridyl;  
 R 2  is selected from a group consisting of hydrogen, lower alkyl, haloalkyl and lower alkoxy, amino, alkylamino, lower alkoxyalkyl, or carboxyl;  
 R 3  is selected from a group consisting of halo, halo-carbonyl, carboxyl, haloalkyl carbonyl, lower alkoxy carbonyl, carboxyalkenyl, alkoxycarbonylalkenyl, aminosulfonyl, CN, —C(O)—NR 4 R 5 , substituted or unsubstituted carbamoylalkyl, carbamoylalkenyl, or aryloxy carbonyl, wherein said aryl group is selected from the group consisting of benzyl, phenyl and pyridyl, and wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, CN, amino, and nitro, or said substituent is one selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, benzenesulfonyl, alkyl sulfonyl, and alkyl carbonyl.  
 R 4  and R 5  are independently selected from a group consisting of hydrogen, lower alkyl, —SO 2 R 6 , substituted or unsubstituted aryl, wherein said aryl group is selected from the group consisting of phenyl, benzyl or pyridyl, pyridylmethyl, pyridinyl-oxide-2-methyl, piperonyl, quinolinyl, thiazolyl, tetrazolyl, thiadiazolyl, and triazolyl, and wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, amino, and dimethylamino; or  
 R 4  and R 5  together form substituted or unsubstituted morpholinyl, thiomorpholinyl, propansultamyl, homopiperidyl, or pyrrolidyl, wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, or carboxyl;  
 R 6  is selected from a group consisting of substituted or unsubstituted lower alkyl, benzyl, phenyl, naphthyl and tolyl, wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, alkylmercapto, haloalkyl, trimethylsilyl, nitro, phenyloxy, and benzyloxy; and  
 y is 0, 1, or 2; and  
 n is 0, 1, or 2.  
 
     
     
         2 . A method for inhibiting the growth of neoplastic cells sensitive to the compounds of formula I comprising exposing the cells to a growth inhibiting effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from a group consisting of substituted or unsubstituted pyridyl, dibenzofuranyl, dioxymethylene benzyl, naphthyl, quinolinyl or isoquinolinyl and wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, halo- or cyano-substituted or unsubstituted phenyloxy or benzyloxy, lower haloalkyl, CN, amino, nitro, phenyl, thiadiazole, aryloxy, arylsulfonyl methyl, arylsulfonyl amino, benzoyl, benzylamidyl, benzenesulfonyl methyl, phenylethyl, and phenylethenyl, wherein said aryl group is selected from the group consisting of phenyl, benzyl and pyridyl;  
 R 2  is selected from a group consisting of hydrogen, lower alkyl, haloalkyl and lower alkoxy, amino, alkylamino, lower alkoxyalkyl, or carboxyl;  
 R 3  is selected from a group consisting of halo, halo-carbonyl, carboxyl, haloalkyl carbonyl, lower alkoxy carbonyl, carboxyalkenyl, alkoxycarbonylalkenyl, aminosulfonyl, CN, —C(O)—NR 4 R 5 , substituted or unsubstituted carbamoylalkyl, carbamoylalkenyl, or aryloxy carbonyl, wherein said aryl group is selected from the group consisting of benzyl, phenyl and pyridyl, and wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, CN, amino, and nitro, or said substituent is one selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, benzenesulfonyl, alkyl sulfonyl, and alkyl carbonyl.  
 R 4  and R 5  are independently selected from a group consisting of hydrogen, lower alkyl, —SO 2 R 6 , substituted or unsubstituted aryl, wherein said aryl group is selected from the group consisting of phenyl, benzyl or pyridyl, pyridylmethyl, pyridinyl-oxide-2-methyl, piperonyl, quinolinyl, thiazolyl, tetrazolyl, thiadiazolyl, and triazolyl, and wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, amino, and dimethylamino; or  
 R 4  and R 5  together form substituted or unsubstituted morpholinyl, thiomorpholinyl, propansultamyl, homopiperidyl, or pyrrolidyl, wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, or carboxyl;  
 R 6  is selected from a group consisting of substituted or unsubstituted lower alkyl, benzyl, phenyl, naphthyl and tolyl, wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, alkylmercapto, haloalkyl, trimethylsilyl, nitro, phenyloxy, and benzyloxy; and  
 y is 0, 1, or 2; and  
 n is 0, 1, or 2.  
 
     
     
         3 . A method for regulating apoptosis in human cells comprising exposing said cells to an effective amount of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is selected from a group consisting of hydrogen, lower alkyl, benzenesulfonyl, and substituted or unsubstituted aryl, wherein said aryl group is selected from the group consisting of phenyl, benzyl, pyridyl, dibenzofuranyl, dioxymethylene benzyl, naphthyl, quinolinyl or isoquinolinyl and wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, halo- or cyano-substituted or unsubstituted phenyloxy or benzyloxy, lower haloalkyl, CN, amino, nitro, phenyl, thiadiazole, aryloxy, arylsulfonyl methyl, arylsulfonyl amino, benzoyl, benzylamidyl, benzenesulfonyl methyl, phenylethyl, and phenylethenyl, wherein said aryl group is selected from the group consisting of phenyl, benzyl and pyridyl;  
 R 2  is selected from a group consisting of hydrogen, lower alkyl, haloalkyl, lower alkoxy, amino, alkylamino, lower alkoxyalkyl, or carboxyl;  
 R 3  is selected from a group consisting of halo-carbonyl, carboxyl, haloalkyl carbonyl, lower alkoxy carbonyl, carboxyalkenyl, alkoxycarbonylalkenyl, aminosulfonyl, CN, —C(O)—NR 4 R 5 , substituted or unsubstituted carbamoylalkyl, carbamoylalkenyl, or aryloxy carbonyl, wherein said aryl group is selected from the group consisting of benzyl, phenyl and pyridyl, and wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, CN, amino, and nitro, or said substituent is one selected from the group consisting of phenyl, benzyl, pyridyl, pyridylmethyl, benzenesulfonyl, alkyl sulfonyl, and alkyl carbonyl.  
 R 4  and R 5  are independently selected from a group consisting of hydrogen, lower alkyl, —SO 2 R 6 , substituted or unsubstituted aryl, wherein said aryl group is selected from the group consisting of phenyl, benzyl or pyridyl, pyridylmethyl, pyridinyl-oxide-2-methyl, piperonyl, quinolinyl, thiazolyl, tetrazolyl, thiadiazolyl, and triazolyl, and wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, amino, and dimethylamino; or  
 R 4  and R 5  together form substituted or unsubstituted morpholinyl, thiomorpholinyl, propansultamyl, homopiperidyl, or pyrrolidyl, wherein said substituents are one to three independently selected from the group consisting of halogen, lower alkyl, lower alkoxy, or carboxyl;  
 R 6  is selected from a group consisting of substituted or unsubstituted lower alkyl, benzyl, phenyl naphthyl and tolyl, wherein said substituents are one to three selected from the group consisting of halogen, lower alkyl, lower alkoxy, alkylmercapto, haloalkyl, trimethylsilyl, nitro, phenyloxy, and benzyloxy; and  
 y is 0, 1, or 2; and  
 n is 0, 1, or 2.