Compounds, compositions, and methods for treating human immunodeficiency virus

Abstract

Disclosed herein are compounds useful for treating and/or preventing HIV infections and the transmission of HIV from an infected subject.

What is claimed is: 
     
         1 . A composition for treating HIV, comprising:
 a) one or more compounds that inhibit Vif self-association, enhances APOBEC3G activity or causes RNA mutations that produce defective HIV virions; and   b) a pharmaceutically acceptable carrier.   
     
     
         2 . The composition according to  claim 1 , wherein the compound is chosen from:
 i) [(S)-4,11-diethyl-4,9-dihydroxy-1,2-dihydroquinolino[2′,3′:3,4]-pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula I:   
       
         
           
           
               
               
           
         
         ii) (S)-9-Amino-4,11-diethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula II: 
       
       
         
           
           
               
               
           
         
       
       or
 iii) (S)-10-Amino-4-ethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula III: 
 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         3 . The composition according to either  claim 1  or  2 , wherein the compound is [(S)-4,11-diethyl-4,9-dihydroxy-1,2-dihydroquinolino[2′,3′:3,4]-pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione. 
     
     
         4 . The composition according to either  claim 1  or  2 , wherein the compound is (S)-9-Amino-4,11-diethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione. 
     
     
         5 . The composition according to either  claim 1  or  2 , wherein the compound is (S)-10-Amino-4-ethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione. 
     
     
         6 . The composition according to any one of  claims 1  to  5 , further comprising a pharmaceutically acceptable ingredient. 
     
     
         7 . The composition according to  claim 6 , wherein the pharmaceutically acceptable ingredient is a stabilizer. 
     
     
         8 . The composition according to  claim 6 , wherein the pharmaceutically acceptable ingredient is a buffer. 
     
     
         9 . The composition according to any one of  claims 1  to  8 , further comprising a carrier. 
     
     
         10 . The composition according to any one of  claims 1  to  9 , wherein the carrier is water. 
     
     
         11 . A composition comprising:
 a) one or more compounds that inhibit Vif self-association, enhances APOBEC3G activity or causes RNA mutations that produce defective HIV virions; and   b) one or more anti-HIV therapies that do not inhibit Vif self-association.   
     
     
         12 . The composition according to  claim 11 , wherein the compound that inhibits Vif self-association, enhances APOBEC3G activity or causes RNA mutations that produce defective HIV virions is chosen from:
 i) [(S)-4,11-diethyl-4,9-dihydroxy-1,2-dihydroquinolino[2′,3′:3,4]-pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula I:   
       
         
           
           
               
               
           
         
         ii) (S)-9-Amino-4,11-diethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula II: 
       
       
         
           
           
               
               
           
         
       
       or
 iii) (S)-10-Amino-4-ethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula III: 
 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salts thereof. 
     
     
         13 . The composition according to  claim 11  or  12 , wherein the anti-HIV therapy that does not inhibit Vif self-association is chosen from indinavir, raltegravir, nevirapine, azidothymidine, camptothecin or mixtures thereof 
     
     
         14 . A composition comprising:
 A) a therapeutic system containing:
 a) from about 1% to about 99% by weight of one or more compounds that inhibit Vif self-association, enhances APOBEC3G activity or causes RNA mutations that produce defective HIV virions; and 
 b) from about 1% to about 99% by weight of one or more anti-HIV therapies that do not inhibit Vif self-association; and 
   B) a carrier.   
     
     
         15 . A composition comprising a prodrug that inhibits Vif self-association, enhances APOBEC3G activity or causes RNA mutations that produce defective HIV virions. 
     
     
         16 . The composition according to  claim 15 , wherein the prodrug is (S)-4,11-diethyl-4-hydroxy-3,14-dioxo-1,2,3,4,12,14-hexahydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridin-9-yl [1,4′-bipiperidine]-1′-carboxylate having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . A method for treating a subject having an HIV infection, comprising contacting the subject with an effective amount of a compound that prevents Vif self-association. 
     
     
         18 . The method according to  claim 17 , wherein the compound is chosen from:
 i) [(S)-4,11-diethyl-4,9-dihydroxy-1,2-dihydroquinolino[2′,3′:3,4]-pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula I:   
       
         
           
           
               
               
           
         
         ii) (S)-9-Amino-4,11-diethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula II: 
       
       
         
           
           
               
               
           
         
       
       or
 iii) (S)-10-Amino-4-ethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione having Formula III: 
 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         19 . The method according to either  claim 17  or  18 , wherein the compound is [(S)-4,11-diethyl-4,9-dihydroxy-1,2-dihydroquinolino[2′,3′:3,4]-pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione. 
     
     
         20 . The method according to either  claim 17  or  18 , wherein the compound is (S)-9-Amino-4,11-diethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione. 
     
     
         21 . The method according to either  claim 17  or  18 , wherein the compound is (S)-10-Amino-4-ethyl-4-hydroxy-1,2-dihydroquinolino[2′,3′:3,4]pyrrolo[1,2-b][2,7]naphthyridine-3,14(4H,12H)-dione. 
     
     
         22 . The method according to any one of  claims 17  to  21 , further comprising administering a second anti-HIV therapy, wherein the second therapy does not inhibit Vif self-association. 
     
     
         23 . The method according to any one of  claims 17  to  22 , wherein the second therapy is a compound chosen from indinavir, raltegravir, nevirapine, azidothymidine, or camptothecin. 
     
     
         24 . A formulation comprising a composition according to any one of  claims 1 - 16 . 
     
     
         25 . The formulation according to  claim 24 , wherein said formulation is suitable for oral, rectal, vaginal, peritoneal, topical, pulmonary, intranasal, buccal, ophthalmic, or another route of administration. 
     
     
         26 . The formulation according to  claim 24 , wherein said formulation includes projected nanoparticles, liposomal preparations, resealed erythrocytes containing active ingredient, and/or immunologically-based formulations.