Polycyclic carbamoylpyridone derivative having hiv integrase inhibitory activity

Abstract

The present invention is to provide a novel compound (I) shown below, having the anti-virus activity; particularly the HIV integrase inhibitory activity, and a drug containing the same, particularly an anti-HIV drug, as well as a process and an intermediate thereof. (wherein Z 1 is NR 4 ; R 1 is hydrogen or lower alkyl; X is a single bond, a hetero atom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene in which the hetero atom group may intervene; R 2 is optionally substituted aryl; R 3 is hydrogen, a halogen, hydroxy, optionally substituted lower alkyl etc; and R 4 and Z 2 part taken together forms a ring, to form a polycyclic compound, including e.g., a tricyclic or tetracyclic compound.

1 - 56 . (canceled) 
     
     
         57 . A method of treating HIV comprising administering to a patient infected with HIV a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein, 
       ring A is 
       
         
           
           
               
               
           
         
         Z is oxygen; 
         R 20 , R 21 , R 22 , R 23 , R 24  and R 25  are independently hydrogen or unsubstituted lower C 1 -C 3  alkyl; 
         the stereochemistry of an asymmetric carbon represented by * shows R- or S-configuration, or a mixture thereof; 
         R X  is hydrogen; 
         R 14  is hydrogen; 
         R 3  is hydrogen; 
         R 1  is hydrogen; 
         R is fluoro; and 
         m is 2 or 3; 
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         58 . The method of  claim 57 , wherein m is 2. 
     
     
         59 . The method of  claim 58 , wherein one R is located at the 4-position. 
     
     
         60 . The method of  claim 59 , wherein one R is located at the 4-position, and the other R is located at the 2-position. 
     
     
         61 . The method of  claim 60 , wherein R 20  is lower C 1 -C 3  alkyl; and R 21 , R 22 , R 23 , R 24  and R 25  are each hydrogen. 
     
     
         62 . The method of  claim 61 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         63 . The method of  claim 59 , wherein R 20  and R 25  are each lower C 1 -C 3  alkyl; and R 21 , R 22 , R 23  and R 24  are each hydrogen. 
     
     
         64 . The method of  claim 60 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         65 . The method of  claim 57 , wherein m is 3. 
     
     
         66 . The method of  claim 65 , wherein one R is located at the 4-position. 
     
     
         67 . The method of  claim 66 , wherein one R is located at the 4-position, and one R is located at the 2-position. 
     
     
         68 . The method of  claim 67 , wherein R 20  is lower C 1 -C 3  alkyl; and R 21 , R 22 , R 23 , R 24  and R 25  are each hydrogen. 
     
     
         69 . The method of  claim 68 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         70 . The method of  claim 67 , wherein R 20  and R 25  are each lower C 1 -C 3  alkyl; and R 21 , R 22 , R 23  and R 24  are each hydrogen. 
     
     
         71 . The method of  claim 70 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         72 . The method of  claim 57 , wherein the stereochemistry of the asymmetric carbon represented by * is in the S-configuration. 
     
     
         73 . The method of  claim 57 , wherein the administration is oral. 
     
     
         74 . The method of  claim 57 , wherein the compound is selected from
 (3S,9aS)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (3R,9aR)-5-Hydroxy-3-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (4S,9aR)-5-Hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (2S,9aR)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (2R,9aS)-2-Ethyl-5-hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (2S,9aS)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (2R,9aR)-5-Hydroxy-2-isopropyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (2R,9aS)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   (2S,9aR)-5-Hydroxy-2-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   5-Hydroxy-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide;   enantiomers thereof; diastereomers thereof; mixtures of enantiomers thereof; mixtures of diastereomers thereof; mixtures of enantiomers and diastereomers thereof; and pharmaceutically acceptable salts thereof.   
     
     
         75 . A method of treating HIV comprising administering to a patient infected with HIV (4R,9aS)-5-hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide: 
       
         
           
           
               
               
           
         
       
       an enantiomer thereof; a diastereomer thereof; mixtures of enantiomers thereof; mixtures of diastereomers thereof; mixtures of enantiomers and diastereomers thereof; or a pharmaceutically acceptable salt thereof. 
     
     
         76 . The method of  claim 75 , wherein the compound is (4R,9aS)-5-hydroxy-4-methyl-6,10-dioxo-3,4,6,9,9a,10-hexahydro-2H-1-oxa-4a,8a-diaza-anthracene-7-carboxylic acid 2,4-difluoro-benzylamide, or a pharmaceutically acceptable salt thereof. 
     
     
         77 . The method of  claim 75 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         78 . The method of  claim 75 , wherein the administration is oral. 
     
     
         79 . The method of  claim 76 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         80 . The method of  claim 76 , wherein the administration is oral. 
     
     
         81 . A method of treating HIV comprising administering to a patient infected with HIV a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein, 
       ring A is 
       
         
           
           
               
               
           
         
         Z is oxygen; 
         R 21 , R 22 , R 23  and R 24  are each hydrogen; 
         R 20  is methyl; 
         R 25  is hydrogen or methyl; 
         the stereochemistry of an asymmetric carbon represented by * shows R- or S-configuration, or a mixture thereof; 
         R X  is hydrogen; 
         R 14  is hydrogen; 
         R 3  is hydrogen; 
         R 1  is hydrogen; 
         R is fluoro; 
         m is 2 or 3; and 
         wherein one R is located at the 4-position, and one R is located at the 2-position or a pharmaceutically acceptable salt thereof. 
       
     
     
         82 . The method of  claim 81 , wherein R 25  is hydrogen. 
     
     
         83 . The method of  claim 82 , wherein m is 3. 
     
     
         84 . The method of  claim 81 , wherein R 25  is methyl. 
     
     
         85 . The method of  claim 84 , wherein m is 3. 
     
     
         86 . The method of  claim 81 , wherein the pharmaceutically acceptable salt is a sodium salt. 
     
     
         87 . The method of  claim 81 , wherein the administration is oral.