Trizol-1-ol analogs anti-retroviral latency drugs

Abstract

In one aspect, the invention relates to triazol-1-ol compounds, analogs thereof, compositions comprising same, and methods of using same, alone or in combination with other agents, to reactivate latent retroviruses, and more particularly to reactivate latent HIV-1. Such compounds, compositions, and methods can be used, for example, in connection with diagnosing and/or treating a retrovirus, and more specifically HIV-1. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

1 . A method of activating a latent retrovirus in a subject, the method comprising the step of administering to the subject an effective amount of a compound represented by a formula: 
       
         
           
           
               
               
           
         
         wherein n is 0 or 1; 
         wherein R 1  is selected from H, C1-C4 alkyl, C1-C6 aryl, C(O)Ar, C(O)N(CH 3 ) 2 , SO 2 N(CH 3 ) 2 , fluorenylmethyloxycarbonyl, N-((dimethylamino)methylene)-N-methylmethanaminium tetrafluoroborate, N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V), tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), tris(dimethylamino)phosphonium hexafluorophosphate (V), 1-(pyrrolidin-1-ylmethylene)pyrrolidin-1-ium hexafluorophosphate (V), and 1-(piperidin-1-ylmethylene)piperidin-1-ium hexafluorophosphate (V); 
         wherein R 2  is selected from H and C1-C4 alkyl; and 
         wherein R 3  is selected from H and C1-C4 alkyl; 
         or wherein R 2  and R 3  are covalently bonded and, together with the intermediate atoms, comprise an optionally substituted fused six-membered aryl or heteroaryl ring. 
       
     
     
         2 - 11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from H, C1-C4 alkyl, C1-C6 aryl, C(O)Ar, C(O)N(CH 3 ) 2 , SO 2 N(CH 3 ) 2 , fluorenylmethyloxycarbonyl, N-((dimethylamino)methylene)-N-methylmethanaminium tetrafluoroborate, N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V), tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), tris(dimethylamino)phosphonium hexafluorophosphate (V), 1-(pyrrolidin-1-ylmethylene)pyrrolidin-1-ium hexafluorophosphate (V), and 1-(piperidin-1-ylmethylene)piperidin-1-ium hexafluorophosphate (V); and
 wherein each of R 4 , R 5 , and R 6  is independently selected from H, Cl, CH 3 , and NO 2 . 
 
     
     
         13 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H and N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V); and 
         wherein each of R 4 , R 5 , and R 6  is independently selected from H, Cl, CH 3 , and NO 2 . 
       
     
     
         14 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 4 , R 5 , and R 6  is independently selected from H, Cl, CH 3 , and NO 2 . 
       
     
     
         15 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
         wherein each of R 4 , R 5 , and R 6  is independently selected from H, Cl, CH 3 , or NO 2 . 
       
     
     
         18 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, C1-C4 alkyl, C1-C6 aryl, C(O)Ar, C(O)N(CH 3 ) 2 , SO 2 N(CH 3 ) 2 , fluorenylmethyloxycarbonyl, N-((dimethylamino)methylene)-N-methylmethanaminium tetrafluoroborate, N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V), tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), tris(dimethylamino)phosphonium hexafluorophosphate (V), 1-(pyrrolidin-1-ylmethylene)pyrrolidin-1-ium hexafluorophosphate (V), and 1-(piperidin-1-ylmethylene)piperidin-1-ium hexafluorophosphate (V). 
       
     
     
         20 - 21 . (canceled) 
     
     
         22 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, C1-C4 alkyl, C1-C6 aryl, C(O)Ar, C(O)N(CH 3 ) 2 , SO 2 N(CH 3 ) 2 , fluorenylmethyloxycarbonyl, N-((dimethylamino)methylene)-N-methylmethanaminium tetrafluoroborate, N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V), tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), tris(dimethylamino)phosphonium hexafluorophosphate (V), 1-(pyrrolidin-1-ylmethylene)pyrrolidin-1-ium hexafluorophosphate (V), and 1-(piperidin-1-ylmethylene)piperidin-1-ium hexafluorophosphate (V); and 
         wherein each of R 7 , R 8 , and R 9  is independently selected from H, Cl, CH 3 , and NO 2 . 
       
     
     
         23 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H and N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V); and 
         wherein each of R 7 , R 8 , and R 9  is independently selected from H, Cl, CH 3 , and NO 2 . 
       
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         26 . The method of  claim 1 , wherein the compound is represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, C1-C4 alkyl, C1-C6 aryl, C(O)Ar, C(O)N(CH 3 ) 2 , SO 2 N(CH 3 ) 2 , fluorenylmethyloxycarbonyl, N-((dimethylamino)methylene)-N-methylmethanaminium tetrafluoroborate, N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V), tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), tris(dimethylamino)phosphonium hexafluorophosphate (V), 1-(pyrrolidin-1-ylmethylene)pyrrolidin-1-ium hexafluorophosphate (V), and 1-(piperidin-1-ylmethylene)piperidin-1-ium hexafluorophosphate (V). 
       
     
     
         27 - 41 . (canceled) 
     
     
         42 . The method of  claim 1 , further comprising treating the patient with at least one agent that can be used to treat HIV-1. 
     
     
         43 . The method of  claim 42 , wherein the at least one agent is selected from entry inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, integrase inhibitors, or maturation inhibitors, or a mixture thereof. 
     
     
         44 . The method of  claim 42 , wherein the at least one agent is selected from nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, or integrase inhibitors, or a mixture thereof. 
     
     
         45 . The method of  claim 42 , wherein the at least one agent is selected from Maraviroc, Enfuvirtide, Zidovudine, Didanosine, Zalcitabine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Tenofovir, Adefovir, Efavirenz, Nevirapine, Delavirdine, Rilpivirine, Raltegravir, Saquinavir, Ritonavir, Indinavir, Nelfinavir, or Amprenavir, or a mixture thereof. 
     
     
         46 . The method of  claim 42 , wherein the at least one agent is HAART. 
     
     
         68 . A pharmaceutical composition comprising a compound represented by a formula: 
       
         
           
           
               
               
           
         
         wherein n is 0 or 1; 
         wherein R 1  is selected from H, C1-C4 alkyl, C1-C6 aryl, C(O)Ar, SO 2 N(CH 3 ) 2 , fluorenylmethyloxycarbonyl, N-((dimethylamino)methylene)-N-methylmethanaminium tetrafluoroborate, N-((dimethylamino)methylene)-N-methylmethanaminium hexafluorophosphate (V), tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate (V), tris(dimethylamino)phosphonium hexafluorophosphate (V), 1-(pyrrolidin-1-ylmethylene)pyrrolidin-1-ium hexafluorophosphate (V), and 1-(piperidin-1-ylmethylene)piperidin-1-ium hexafluorophosphate (V); 
         wherein R 2  is selected from H and C1-C4 alkyl; 
         wherein R 3  is selected from H and C1-C4 alkyl; 
         or wherein R 2  and R 3  are covalently bonded and, together with the intermediate atoms, comprise an optionally substituted fused six-membered aryl or heteroaryl ring; 
         and a pharmaceutically acceptable carrier or diluent. 
       
     
     
         69 . (canceled) 
     
     
         70 . The composition of  claim 68 , further comprising a therapeutic agent that can be used to treat a retrovirus. 
     
     
         71 - 74 . (canceled)