Agent for overcoming resistance to anti-cancer agent

Abstract

An agent comprising, as an active ingredient, a xanthine oxidase inhibitor such as 2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine potassium salt, 2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine, 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine potassium salt, 2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine, TMX-67, and FYX-051, which can be used as an agent for overcoming anti-cancer agent resistance.

1 . An agent containing a compound having the following formula (I) or a salt thereof as an active ingredient for overcoming drug resistance: 
     
       
         
         
             
             
         
       
       wherein R 1  is C 2-8  alkenyl, C 6-10  aryl, or heteroaryl in which the aryl and heteroaryl can have a substituent selected from the group consisting of C 1-8  alkyl, C 1-8  alkyl substituted with halogen, C 1-8  alkoxy, C 1-8  alkoxy substituted with halogen, C 2-8  alkoxycarbonyl, formyl, carboxyl, halogen, hydroxyl, nitro, cyano, amino, C 6-10  aryl, and C 6-10  aryloxy; 
       R 2  is cyano, nitro, formyl, carboxyl, carbamoyl, or C 2-8  alkoxycarbonyl; 
       X is oxygen, —N(R 3 )—, or —S(O) n —, and R 3  is a hydrogen, C 1-8  alkyl, or the group mentioned above for R 1 , or R 1  and R 3  are combined to form morpholinyl, thiomorpholinyl, or piperazinyl, and n is an integer of 0 to 2; and 
       Y is oxygen, sulfur, or NH. 
     
   
   
       2 . An agent containing a compound having the following formula (II) or a salt thereof as an active ingredient for overcoming drug resistance: 
     
       
         
         
             
             
         
       
       wherein R 1  is C 6-10  aryl or heteroaryl in which the aryl and heteroaryl can have a substituent selected from the group consisting of C 1-8  alkyl, C 1-8  alkyl substituted with halogen, C 1-8  alkoxy, C 1-8  alkoxy substituted with C 1-8  alkoxy, C 2-8  alkoxycarbonyl, formyl, carboxyl, halogen, hydroxyl, nitro, cyano, amino, C 6-10  aryl, and C 6-10  aryloxy; 
       R 2  is cyano, nitro, formyl, carboxyl, carbamoyl, or C 2-8  alkoxycarbonyl; 
       R 3  is hydroxyl, amino, carboxyl, mercapto, OR 4 , or NHR 5 , and each of R 4  and R 5  is C 1-8  alkyl or C 1-8  alkyl substituted with a group or atom selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, C 6-10  aryl, and C 6-10  aryloxy; 
       X is oxygen, —N(R 6 )—, or —S(O) n —, and R 6  is a hydrogen, alkyl, or the group mentioned above for R 1 , and n is an integer of 0 to 2; and 
       Y is oxygen or sulfur. 
     
   
   
       3 . An agent containing a compound selected from the group consisting of 2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine, 2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine, 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, potassium salt of 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, and potassium salt of 2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine as an active ingredient for overcoming drug resistance. 
   
   
       4 . An agent containing Febuxostat or 4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile as an active ingredient for overcoming drug resistance. 
   
   
       5 . An agent containing a compound having the following formula (I) or a salt thereof as an active ingredient for overcoming anti-cancer agent resistance: 
     
       
         
         
             
             
         
       
       wherein R 1  is C 2-8  alkenyl, C 6-10  aryl, or heteroaryl in which the aryl and heteroaryl can have a substituent selected from the group consisting of C 1-8  alkyl, C 1-8  alkyl substituted with halogen, C 1-8  alkoxy, C 1-8  alkoxy substituted with halogen, C 2-8  alkoxycarbonyl, formyl, carboxyl, halogen, hydroxyl, nitro, cyano, amino, C 6-10  aryl, and C 6-10  aryloxy; 
       R 2  is cyano, nitro, formyl, carboxyl, carbamoyl, or C 2-8  alkoxycarbonyl; 
       X is oxygen, —N(R 3 )—, or —S(O) n —, and R 3  is a hydrogen, C 1-8  alkyl, or the group mentioned above for R 1 , or R 1  and R 3  are combined to form morpholinyl, thiomorpholinyl, or piperazinyl, and n is an integer of 0 to 2; and 
       Y is oxygen, sulfur, or NH. 
     
   
   
       6 . An agent containing a compound having the following formula (II) or a salt thereof as an active ingredient for overcoming anti-cancer agent resistance: 
     
       
         
         
             
             
         
       
       wherein R 1  is C 6-10  aryl or heteroaryl in which the aryl and heteroaryl can have a substituent selected from the group consisting of C 1-8  alkyl, C 1-8  alkyl substituted with halogen, C 1-8  alkoxy, C 1-8  alkoxy substituted with C 1-8  alkoxy, C 2-8  alkoxycarbonyl, formyl, carboxyl, halogen, hydroxyl, nitro, cyano, amino, C 6-10  aryl, and C 6-10  aryloxy; 
       R 2  is cyano, nitro, formyl, carboxyl, carbamoyl, or C 2-8  alkoxycarbonyl; 
       R 3  is hydroxyl, amino, carboxyl, mercapto, OR 4 , or NHR 5 , and each of R 4  and R 5  is C 1-8  alkyl or C 1-8  alkyl substituted with a group or atom selected from the group consisting of halogen, hydroxyl, nitro, cyano, amino, C 6-10  aryl, and C 6-10  aryloxy; 
       X is oxygen, —N(R 6 )—, or —S(O) n —, and R 6  is a hydrogen, C 1-8  alkyl, or the group mentioned above for R 1 , and n is an integer of 0 to 2; and 
       Y is oxygen or sulfur. 
     
   
   
       7 . An agent containing a compound selected from the group consisting of 2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine, 2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine, 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, potassium salt of 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, and potassium salt of 2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine as an active ingredient for overcoming anti-cancer agent resistance. 
   
   
       8 . An agent containing Febuxostat or 4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile as an active ingredient for overcoming resistance to an anti-cancer agent. 
   
   
       9 . An agent for overcoming resistance to an anti-cancer agent defined in any one of  claims 5  to  8 , wherein overexpression of BCRP in a cancer cell is involved in acquiring anti-cancer agent resistance. 
   
   
       10 . A therapeutic composition against a cancer cell of multidrug resistance, wherein the composition comprises an anti-cancer agent and a compound selected from the group consisting of 2-(3-cyano-4-phenoxyphenyl)thiazolo[5,4-d]pyrimidine, 2-[3-cyano-4-(4-fluorophenoxy)phenyl]thiazolo[5,4-d]pyrimidine, 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, potassium salt of 2-(3-cyano-4-phenoxyphenyl)-4-hydroxythiazolo[5,4-d]pyrimidine, potassium salt of 2-[3-cyano-4-(4-fluorophenoxy)phenyl]-4-hydroxythiazolo[5,4-d]pyrimidine, Febuxostat, and 4-[5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl]pyridine-2-carbonitrile.