4-oxoquinoline compound and use thereof as hiv integrase inhibitor

Abstract

An anti-HIV agent containing, as an active ingredient, a 4-oxoquinoline compound represented by the following formula [I] wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. The compound of the present invention has HIV integrase inhibitory action and is useful as an anti-HIV agent for the prophylaxis or therapy of AIDS. Moreover, by a combined use with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, the compound can become a more effective anti-HIV agent. Since the compound has high inhibitory activity specific for integrases, it can provide a safe pharmaceutical agent with a fewer side effects for human.

1 - 41 . (canceled) 
     
     
         42 . An anti-HIV agent comprising a compound of formula [I] or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient: 
       
         
           
           
               
               
           
         
         wherein 
         ring Cy is a C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A
 wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C 1-4  alkyl group, halo C 1-4  alkyl group, halo C 1-4  alkyloxy group, —OR a1 , —SR a1 , —NR a1 R a2 , —CONR a1 R a2 , —SO 2 NR a1 R a2 , —COR a3 , —NR a1 COR a3 , —SO 2 R a3 , —NR a1 SO 2 R a3 , —COOR a1  and —NR a2 COOR a3  
 wherein R a1  and R a2  are the same or different and each is hydrogen atom, C 1-4  alkyl group or benzyl group and R a3  is C 1-4  alkyl group; 
 
 
         R 1  is a substituent selected from the following group B or a C 1-10  alkyl group optionally substituted by 1 to 3 substituents selected from halogen atoms and the following group B
 wherein group B is a group consisting of C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR a4 , —SR a4 , —NR a4 R a5 , —CONR a4 R a5 , —SO 2 NR a4 R a5 , —COR a6 , —NR a4 COR a6 , —SO 2 R a6 , —NR a4 SO 2 R a6 , —COOR a4  and —NR a5 COOR a6  
 wherein R a4  and R a5  are the same or different and each is selected from a hydrogen atom, C 1-4  alkyl group, C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R a6  is selected from a C 1-4  alkyl group, C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A; 
 
 
         R 2  is selected from a hydrogen atom or a C 1-4  alkyl group; 
         R 31  is selected from a hydrogen atom, a cyano group, a hydroxy group, an amino group, a nitro group, a halogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a C 1-4  alkylsulfanyl group, a halo C 1-4  alkyl group or a halo C 1-4  alkyloxy group; 
         X is selected from a C—R 32  or a nitrogen atom; and 
         Y is selected from a C—R 33  or a nitrogen atom
 wherein R 32  and R 33  are the same or different and each is selected from a hydrogen atom, cyano group, nitro group, halogen atom, C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or, C 1-10  alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, 
 —OR a7 , —SR a7 , —NR a7 R a8 , —NR a7 COR a9 , —COOR a10  or —N═CH—NR a10 R a11  
 wherein R a7  and R a8  are the same or different and each is selected from a hydrogen atom, group B or C 1-10  alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the above-mentioned group B, R a9  is selected from C 1-4  alkyl group, and R a10  and R a11  are the same or different and each is selected from a hydrogen atom or C 1-4  alkyl group. 
 
 
       
     
     
         43 . The anti-HIV agent of  claim 42 , wherein X is C—R 32  and Y is C—R 33 . 
     
     
         44 . The anti-HIV agent of  claim 42 , wherein ring Cy is 
       
         
           
           
               
               
           
         
         wherein 
         R 4  and R 6  are the same or different and each is a substituent selected from the following group A
 wherein group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C 1-4  alkyl group, halo C 1-4  alkyl group, halo C 1-4  alkyloxy group, —OR a1 , —SR a1 , —NR a1 R a2 , —CONR a1 R a2 , —SO 2 NR a1 R a2 , —COR a3 , —NR a1 COR a3 , —SO 2 R a3 , —NR a1 SO 2 R a3 , —COOR a1  and —NR a2 COOR a3  
 wherein R a1  and R a2  are the same or different and each is selected from a hydrogen atom, C 1-4  alkyl group or benzyl group and R 3  is C 1-4  alkyl group; 
 
 
         R 5  is a substituent selected from hydrogen atom and group A, and R 4  and R 5  may form a fused ring together with a benzene ring they substitute; and 
         m is 0 or an integer of 1 to 3, and when m is 2 or 3, then R 6  of each m may be the same or different. 
       
     
     
         45 . The anti-HIV agent of  claim 42 , wherein R 2  is a hydrogen atom. 
     
     
         46 . An anti-HIV agent comprising a compound of formula (III) or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient: 
       
         
           
           
               
               
           
         
         wherein 
         ring Cy is a C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A
 wherein the heterocyclic group is a saturated or unsaturated ring containing, besides carbon atom(s), at least one heteroatom selected from a nitrogen atom, an oxygen atom and a sulfur atom, group A is a group consisting of cyano group, phenyl group, nitro group, halogen atom, C 1-4  alkyl group, halo C 1-4  alkyl group, halo C 1-4  alkyloxy group, —OR a1 , —SR a1 , —NR a1 R a2 , —CONR a1 R a2 , —SO 2 NR a1 R a2 , —COR a3 , —NR a1 COR a3 , —SO 2 R a3 , —NR a1 SO 2 R a3 , —COOR a1  and —NR a2 COOR a3  
 wherein R a1  and R a2  are the same or different and each is selected from a hydrogen atom or C 1-4  alkyl group and R a3  is C 1-4  alkyl group; 
 
 
         R 1  is a substituent selected from the following group B or a C 1-6  alkyl group optionally substituted by 1 to 3 substituents selected from halogen atom and the following group B
 wherein group B is a group consisting of C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, —OR a4 , —SR a4 , —NR a4 R a5 , —CONR a4 R a5 , —SO 2 NR a4 R a5 , —COR a6 , —NR a4 COR a6 , —SO 2 R a6 , —NR a4 SO 2 R a6 , —COOR a4  and —NR a5 COOR a6  
 wherein R a4  and R a5  are the same or different and each is selected from a hydrogen atom, C 1-4  alkyl group, C 3-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A, and R a6  is selected from C 1-4  alkyl group, C 1-10  carbon ring group optionally substituted by 1 to 5 substituents selected from the above-mentioned group A or heterocyclic group (as defined above) optionally substituted by 1 to 5 substituents selected from the above-mentioned group A; 
 
 
         R 2  is selected from a hydrogen atom or a C 1-4  alkyl group; 
         R 3  is selected from a cyano group, a hydroxy group, an amino group, a nitro group, a halogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group, a C 1-4  alkylsulfanyl group, a halo C 1-4  alkyl group or a halo C 1-4  alkyloxy group; 
         n is selected from 0 or an integer of 1 to 3 and when n is 2 or 3, R 3  each may be the same or different. 
       
     
     
         47 . A method for the prophylaxis or treatment of an HIV infection or AIDS, which comprises administering a compound according to  claim 46 , or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof to a mammal. 
     
     
         48 . The method according to  claim 47 , wherein the compound is administered at a dosage for inhibiting activity specific for integrases. 
     
     
         49 . A method for inhibiting integrase, comprising administering a compound according to  claim 46  or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof to a mammal. 
     
     
         50 . A method for the prophylaxis or treatment of a retrovirus infection, comprising administering a compound according to  claim 46  or a solvate thereof or a stereoisomer thereof or a tautomer thereof or a pharmaceutically acceptable salt thereof to a mammal.