Combination Therapy

Abstract

The present invention relates to a combination therapy for treating an HIV infection or inhibiting integrase comprising (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (“Compound A”) or a pharmaceutically acceptable solvate or salt thereof in combination with at least one other anti-HIV agent. In some embodiments of the present invention, the other anti-HIV agents are chosen from reverse transcriptase inhibitors and protease inhibitors. In certain embodiments of the present invention, the other anti-HIV agents are chosen from AZT, 3TC, PMPA, efavirenz, indinavir, nelfinavir, a combination of AZT/3TC, and a combination of PMPA/3TC. Since Compound A has a high inhibitory activity specific for integrases, when used in combinations with other anti-HIV agents it can provide a combination therapy with fewer side effects for humans.

1 . A method for treating an HIV infectious disease comprising administering the combination of (a) and (b) to a mammal, wherein
 (a) is an effective amount of (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable solvate or salt thereof, and   (b) is an effective amount of at least one other anti-HIV active substance.   
     
     
         2 . The method of  claim 1 , wherein the at least one other anti-HIV active substance comprises at least one reverse transcriptase inhibitor. 
     
     
         3 . The method of  claim 2 , wherein the at least one reverse transcriptase inhibitor is chosen from zidovudine (AZT), lamivudine (3TC), tenofovir (PMPA), and efavirenz. 
     
     
         4 . The method of  claim 2 , wherein the at least one reverse transcriptase inhibitor is a combination chosen from (i) AZT combined with 3TC and (ii) PMPA combined with 3TC. 
     
     
         5 . The method of  claim 1 , wherein the at least one other anti-HIV active substance comprises at least one protease inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the at least one protease inhibitor is chosen from indinavir and nelfinavir. 
     
     
         7 . The method of  claim 1 , wherein said administration of (a) and (b) is sequential. 
     
     
         8 . The method of  claim 1 , wherein said administration of (a) and (b) is simultaneous. 
     
     
         9 . The method of  claim 1 , wherein said administration of at least one of (a) and (b) is oral. 
     
     
         10 . The method of  claim 1 , wherein said administration of at least one of (a) and (b) is parenteral. 
     
     
         11 . The method of  claim 10 , wherein said parenteral administration is intravenous. 
     
     
         12 . The method of  claim 1 , wherein (a) and (b) are formulated together and administered as a single therapeutic composition. 
     
     
         13 . The method of  claim 1 , wherein the at least one other anti-HIV active substance is an inhibitor of HIV-1 protease. 
     
     
         14 . The method of  claim 1 , wherein (a), (b), or both (a) and (b) are administered daily. 
     
     
         15 . The method of  claim 1 , wherein said effective amount of (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable solvate or salt thereof is in the range from about 0.01 mg to about 1 g per administration. 
     
     
         16 . A method for inhibiting integrase comprising administering the combination of (a) an (b) to a mammal, wherein
 (a) is an effective amount of (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable solvate or salt thereof, and   (b) is an effective amount of at least one other anti-HIV active substance.   
     
     
         17 . A method for inhibiting HIV replication comprising administering the combination of (a) and (b) to a mammal, wherein
 (a) is an effective amount of (S)-6-(3-Chloro-2-fluorobenzyl)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid or a pharmaceutically acceptable solvate or salt thereof, and   (b) is an effective amount of at least one other anit0-HIV active substance.   
     
     
         18 - 24 . (canceled)