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/or 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
 (i) 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]-amino]-2-pyrimidinyl]-amino]-benzonitrile, also named TMC278, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and   (ii) a nucleoside reverse transcriptase inhibitor and/or a nucleotide reverse transcriptase inhibitor; wherein TMC278 and 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  comprising
 (i) TMC278, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and   (ii) a nucleoside reverse transcriptase inhibitor; wherein TMC278 and the nucleoside reverse transcriptase inhibitor are therapeutically effective HIV inhibitors at a dose that can be administered once daily.   
     
     
         3 . The combination according to  claim 1  comprising
 (i) TMC278, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and   (ii) a nucleotide reverse transcriptase inhibitor; wherein TMC278 and the nucleotide reverse transcriptase inhibitor are therapeutically effective HIV inhibitors at a dose that can be administered once daily.   
     
     
         4 . The combination according to  claim 1  comprising
 (i) TMC278, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and   (ii) a nucleoside reverse transcriptase inhibitor; and   (iii) a nucleotide reverse transcriptase inhibitor; wherein TMC278 and 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.   
     
     
         5 . The combination according to  claim 1  comprising
 (i) TMC278, or a stereoisomeric form thereof; or a pharmaceutically acceptable salt thereof; or a prodrug thereof; and   (ii) a nucleoside reverse transcriptase inhibitor; and   (iii) a second nucleoside reverse transcriptase inhibitor other than the nucleoside reverse transcriptase inhibitor of (ii); wherein TMC278 and the nucleoside reverse transcriptase inhibitors are therapeutically effective HIV inhibitors at a dose that can be administered once daily.   
     
     
         6 . The combination according to  claim 1 , wherein TMC278 occurs in its E-isomeric form. 
     
     
         7 . The combination according to  claim 1 , wherein the nucleotide reverse transcriptase inhibitor and/or the nucleoside reverse transcriptase inhibitor or inhibitors select mutations in the reverse transcriptase that do not cause resistance to TMC278. 
     
     
         8 . The combination according to  claim 1  wherein the nucleotide reverse transcriptase inhibitor is tenofovir or its prodrug tenofovir disoproxil fumarate. 
     
     
         9 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is emtricitabine, racemic FTC, lamivudine (also named 3TC), abacavir or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is emtricitabine. 
     
     
         11 . The combination according to  claim 1  wherein the combination comprises
 (i) TMC278 or a pharmaceutically acceptable salt, and   (ii) tenofovir or its prodrug tenofovir disoproxil fumarate, and   (iii) emtricitabine.   
     
     
         12 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is lamivudine. 
     
     
         13 . The combination according to  claim 8  wherein the combination comprises
 (i) TMC278 or a pharmaceutically acceptable salt, and   (ii) tenofovir or its prodrug tenofovir disoproxil fumarate, and   (iii) lamivudine.   
     
     
         14 . The combination according to  claim 1  wherein the nucleoside reverse transcriptase inhibitor is abacavir or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The combination according to  claim 14  wherein the combination comprises
 (i) TMC278 or a pharmaceutically acceptable salt, and   (ii) tenofovir or its prodrug tenofovir disoproxil fumarate, and   (iii) abacavir or a pharmaceutically acceptable salt thereof.   
     
     
         16 . The combination according to  claim 1  wherein the combination comprises
 (i) TMC278 or a pharmaceutically acceptable salt, and   (ii) lamivudine, and   (iii) emtricitabine.   
     
     
         17 . The combination according to  claim 1  wherein the combination comprises
 (i) TMC278 or a pharmaceutically acceptable salt, and   (ii) abacavir, or a pharmaceutically acceptable salt thereof; and   (iii) emtricitabine.   
     
     
         18 . The combination according to  claim 1  wherein the combination comprises
 (i) TMC278 or a pharmaceutically acceptable salt, and   (ii) lamivudine, and   (iii) abacavir, or a pharmaceutically acceptable salt thereof.   
     
     
         19 . The combination according to  claim 1  wherein weight ratio of each couple of components of the triple combination taken on a daily basis may vary in a range from 1/4 to 4/1. 
     
     
         20 . A product containing a combination as claimed in  claim 1  as a combined preparation for simultaneous, separate or sequential use against HIV infection. 
     
     
         21 . A pharmaceutical formulation comprising a pharmaceutically acceptable carrier and a combination as claimed in  claim 1 . 
     
     
         22 . The formulation of  claim 21  comprising as active ingredients (i) TMC278 or its stereoisomeric form or pharmaceutically acceptable salt or its prodrug, and (ii) a nucleoside reverse transcriptase inhibitor, and (iii) a nucleotide reverse transcriptase inhibitor. 
     
     
         23 . A combination as claimed in  claim 1  for use as a medicine. 
     
     
         24 . Use of a combination as claimed in  claim 1  for the manufacture of a medicament for the prevention of HIV infection or transmission via sexual intercourse or related intimate contact between partners.