Novel HSP90 Inhibitor

Abstract

Disclosed is a triazole derivative(s) represented by the general formula (1) below or a pharmacologically acceptable salt(s) thereof. Also disclosed are a prodrug(s) of such a triazole derivative(s) and an HSP90 inhibitor(s) containing any one of them as an active constituent. (1) (In the formula, X represents a halogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group or the like; Y represents a mercapto group, a hydroxyl group, an optionally substituted sulfonyl group, an optionally substituted amino group or the like; and R represents an optionally substituted aryl or alkyl group or the like.)

1 . A method of treating cancer or inhibiting HSP90 activity in a mammal, comprising administering to the mammal an effective amount of a triazole derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
       
       wherein N represents a nitrogen atom; X represents a mercapto group, hydroxy group, halogen atom, nitro group, cyano group, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, an optionally substituted carbocyclic or heterocyclic aryl group, an optionally substituted alkylthio group, an optionally substituted arylthio group, an optionally substituted alkylsulfinyl group, an optionally substituted arylsulfinyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted sulfamoyl group, an optionally substituted alkoxyl group, an optionally substituted aryloxy group, an optionally substituted acyloxy group, an optionally substituted alkoxycarbonyloxy group, an optionally substituted carbamoyloxy group, an optionally substituted amino group, an optionally substituted acylamino group, an optionally substituted alkoxycarbonylamino group, an optionally substituted ureido group, an optionally substituted sulfonylamino group, an optionally substituted sulfamoylamino group, a formyl group, an optionally substituted acyl group, carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, or an optionally substituted silyl group; Y represents a mercapto group, hydroxy group, halogen atom, cyano group, a sulfonyl group, an alkylthio group, an arylthio group, an alkylsulfinyl group, an arylsulfinyl group, a sulfamoyl group, an alkoxyl group, an aryloxy group, an acyloxy group, an alkoxycarbonyloxy group, a carbamoyloxy group, an optionally substituted amino group, an acylamino group, an alkoxycarbonylamino group, a ureido group, a sulfonylamino group, a sulfamoylamino group, a formyl group, an acyl group or a silyl group; R is represented by the following general formula (2), 
       
         
           
           
               
               
           
         
       
       wherein m is an integer from 0 to 5, A represents an optionally substituted cyclic or non-cyclic amino group, an acylamino group or a sulfonylamino group, in said general formula (1), or a pharmaceutically acceptable salt thereof. 
     
     
         2 . The method according to  claim 1 , wherein X is located at the 5 position of 2,4-dihydroxyphenyl group which binds to the triazole ring at 1 position in said general formula (1), or a pharmaceutically acceptable salt thereof. 
     
     
         3 . The method according to  claim 1  or  2 , wherein X is an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group, or a halogen atom in said general formula (1), or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method according to  claim 1 , wherein Y is any of a mercapto group, hydroxy group, an optionally substituted sulfonyl group or alkylthio group in said general formula (1), or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method according to  claim 1 , wherein Y is a hydroxy group in said general formula (1), or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method according to  claim 1 , wherein m is 0 or 1, and A is a cyclic amino group in the general formula (2), or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method according to  claim 1 , wherein the compound represented by the general formula (1) is represented by the following general formula (4), 
       
         
           
           
               
               
           
         
       
       wherein X represents a chlorine atom, ethyl group, isopropyl group, tert-butyl group, 2,2-dimethylpropyl group, 2-propynyl group or 2-butynyl group; Y represents a mercapto group, an optionally substituted alkylsulfonyl group or hydroxy group; m is 0 or 1; and A represents a cyclic amino group, or a pharmaceutically acceptable salt thereof. 
     
     
         8 . The method according to  claim 1 , wherein said triazole derivative is selected from the group consisting of:
 4-isopropyl-6-{5-mercapto-4-[4-(morpholin-4-yl)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol (SH-a01),   4-isopropyl-6-{5-mercapto-4-[4-(morpholin-4-ylmethyl)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol (SH-a02),   4-{5-hydroxy-4-[4-(morpholin-4-yl)-phenyl]-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol (OH-a01),   4-{5-hydroxy-4-[4-(morpholin-4-ylmethyl)-phenyl]-4H-[1,2,4]triazol-3-yl}-6-isopropyl-benzene-1,3-diol (OH-a02),   5-[5-(but-2-ynyl)-2,4-dihydroxy-phenyl]-4-[4-(morpholin-4-ylmethyl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (OH-c02),   4-(but-2-ynyl)-6-{5-mercapto-4-[4-(morpholin-4-ylmethyl)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol (SH-c02),   4-bromo-6-{5-mercapto-4-[4-(morpholin-4-yl)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol (SH-d01),   4-isopropyl-6-{5-methanesulfonyl-4-[4-(morpholin-4-ylmethyl)-phenyl]-4H-[1,2,4]triazol-3-yl}-benzene-1,3-diol (SFN-a02),   5-[2,4-dihydroxy-5-(prop-2-ynyl)-phenyl]-4-[4-(morpholin-4-ylmethyl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (OH-e02), and   5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-one (OH-a13), or a pharmaceutically acceptable salt thereof.   
     
     
         9 . The method according to  claim 1 , wherein said cancer is breast cancer. 
     
     
         10 . The method according to  claim 1 , wherein said cancer is lung cancer.