Combinations of A Pyrimidine Containing NNRTI with RT Inhibitors

Abstract

The present invention concerns combinations of a pyrimidine containing NNRTI with nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors useful for the treatment of HIV infected patients or for the prevention of HIV transmission or infection.

1 . A combination comprising
 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof or a pharmaceutically acceptable salt thereof;   a nucleoside reverse transcriptase inhibitor; and   a nucleotide reverse transcriptase inhibitor;   wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, the nucleotide reverse transcriptase inhibitor, and the nucleoside reverse transcriptase inhibitor are therapeutically effective HIV inhibitors at a dose that can be administered once daily.   
     
     
         2 . The combination according to  claim 1 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile. 
     
     
         3 . The combination according to  claim 1 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride. 
     
     
         4 . The combination according to  claim 1 , wherein the nucleotide reverse transcriptase inhibitor and/or the nucleoside reverse transcriptase inhibitor select mutations in the reverse transcriptase that do not cause resistance to E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile. 
     
     
         5 . The combination according to  claim 1 , wherein the nucleotide reverse transcriptase inhibitor is tenofovir or its prodrug tenofovir disoproxil fumarate. 
     
     
         6 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is emtricitabine, racemic FTC, lamivudine, abacavir, or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is emtricitabine. 
     
     
         8 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is lamivudine. 
     
     
         9 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is abacavir or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The combination according to  claim 1  wherein the combination comprises
 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; 
 tenofovir or its prodrug tenofovir disoproxil fumarate, and 
 lamivudine. 
 
     
     
         11 . The combination according to  claim 9 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile. 
     
     
         12 . The combination according to  claim 9 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride. 
     
     
         13 . The combination according to  claim 1  that comprises
 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; 
 tenofovir or its prodrug tenofovir disoproxil fumarate, and 
 abacavir or a pharmaceutically acceptable salt thereof. 
 
     
     
         14 . The combination according to  claim 13 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile. 
     
     
         15 . The combination according to  claim 13 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride. 
     
     
         16 . The combination according to  claim 1  that comprises
 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; 
 lamivudine, and 
 emtricitabine. 
 
     
     
         17 . The combination according to  claim 16 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile. 
     
     
         18 . The combination according to  claim 16 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride. 
     
     
         19 . The combination according to  claim 1  that comprises
 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof or a pharmaceutically acceptable salt thereof; and 
 abacavir, or a pharmaceutically acceptable salt thereof; and 
 emtricitabine. 
 
     
     
         20 . The combination according to  claim 19 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile. 
     
     
         21 . The combination according to  claim 19 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride. 
     
     
         22 . The combination according to  claim 1  that comprises 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof;
 lamivudine, and 
 abacavir, or a pharmaceutically acceptable salt thereof. 
 
     
     
         23 . The combination according to  claim 22 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile. 
     
     
         24 . The combination according to  claim 22 , wherein the 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile is E-4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile hydrochloride. 
     
     
         25 . The combination according to  claim 1 , wherein the weight ratio of each couple of components of the combination vary in a range from 1/10 to 10/1. 
     
     
         26 . A product containing a combination as claimed in  claim 1  in a single unit dosage form. 
     
     
         27 . A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a combination as claimed in  claim 1 . 
     
     
         28 . A kit comprising the combination of  claim 1  packaged with instructions for use. 
     
     
         29 . A method of treating HIV infection in a patient comprising administering to the patient a combination as claimed in  claim 1 .