Azapeptide derivatives

Abstract

This invention relates to novel compounds that are azapeptides, and pharmaceutically acceptable salts thereof. More specifically, the invention relates to novel azapeptide compounds that are derivatives of the HIV protease inhibitor atazanavir sulfate. This invention also provides pyrogen-free compositions comprising one or more compounds of the invention and a carrier, and the use of the disclosed compounds and compositions in methods of treating diseases and conditions that are treated by administering HIV protease inhibitors. The invention also relates to the use of one or more of the disclosed compounds as reagents in analytical studies involving atazanavir.

1 . A compound of the Formula Ib: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 each of R 1a  and R 1b  is independently selected from —CD 3  and —CH 3 ; 
 R 3  is selected from —C(CD 3 ) 3  and —C(CH 3 ) 3 ; and 
 Y 1a  and Y 1b  are the same and are selected from H and D. 
 
   
   
       2 . The compound of  claim 1 , wherein the compound is selected from; 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     acceptable salt of any of the foregoing. 
   
   
       3 . The compound of  claim 2 , wherein the compound is selected from Compound 114, Compound 120, Compound 122 and Compound 131 or a pharmaceutically acceptable salt of any of the foregoing. 
   
   
       4 . A compound selected from: 
     
       
         
         
             
             
         
       
     
     pharmaceutically acceptable salt of either of the foregoing. 
   
   
       5 . The compound of any one of  claims 1  to  4 , wherein any atom not designated as deuterium is present at its natural isotopic abundance. 
   
   
       6 . A pharmaceutical composition comprising a compound of Formula Ib: 
     
       
         
         
             
             
         
       
       pharmaceutically acceptable salt thereof, wherein:
 each of R 1a  and R 1b  is independently selected from —CD 3  and —CH 3 ; 
 R 3  is selected from —C(CD 3 ) 3  and —C(CH 3 ) 3 ; and 
 Y 1a  and Y 1b  are the same and are selected from H and D; and a pharmaceutically acceptable carrier. 
 
     
   
   
       7 . The composition of  claim 6 , wherein the compound is selected from:
 Compound 131; Compound 122; Compound 114; Compound 106; Compound 104; Compound 120; and Compound 123 or a pharmaceutically acceptable salt of any of the foregoing.   
   
   
       8 . The composition of  claim 6 , additionally comprising a second therapeutic agent selected from a second HIV protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, a nucleoside/nucleotide reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, an immune based antiretroviral agent, a viral maturation inhibitor, a cellular inhibitor, or combinations of two or more of the above. 
   
   
       9 . The composition of  claim 8 , wherein the second therapeutic agent is selected from ritonavir, efavirenz, didanosine, tenofovir disoproxil, nelfinavir mesilate, amprenavir, raltegravir potassium, saquinavir, lopinavir, nevirapine, emtricitabine, abacavir, lamivudine, zidovudine, maraviroc, stavudine, darunavir, fosamprenavir, vicriviroc, a pharmaceutically acceptable salt of any of the foregoing, and combinations thereof. 
   
   
       10 . The composition of  claim 9 , wherein the second therapeutic agent is selected from ritonavir, efavirenz, didanosine, raltegravir, tenofovir disoproxil, lamivudine, abacavir, zidovudine, emtricitabine, efavirenz, a pharmaceutically acceptable salt of any of the foregoing, and combinations thereof. 
   
   
       11 . The composition of  claim 10 , comprising two to three additional second therapeutic agents independently selected from ritonavir, efavirenz, didanosine, raltegravir, tenofovir disoproxil, lamivudine, abacavir, zidovudine, emtricitabine, efavirenz, and a pharmaceutically acceptable salt of any of the foregoing. 
   
   
       12 . The composition of  claim 11 , comprising two additional second agents independently selected from ritonavir, efavirenz, didanosine, raltegravir, tenofovir disoproxil, lamivudine, abacavir, zidovudine, emtricitabine, efavirenz, and a pharmaceutically acceptable salt of any of the foregoing. 
   
   
       13 . A method of treating HIV infection in a patient in need thereof comprising the step of administering to the patient an effective amount of a compound according to any one of Formula Ib: 
     
       
         
         
             
             
         
       
       pharmaceutically acceptable salt thereof, wherein:
 each of R 1a  and R 1b  is independently selected from —CD 3  and —CH 3 ; 
 R 3  is selected from —C(CD 3 ) 3  and —C(CH 3 ) 3 ; and 
 
       Y 1a  and Y 1b  are the same and are selected from H and D. 
     
   
   
       14 . The method of  claim 13 , further comprising administering to the patient a second therapeutic agent selected from a second HIV protease inhibitor, a non-nucleoside reverse transcriptase inhibitor, a nucleoside/nucleotide reverse transcriptase inhibitor, a viral entry inhibitor, an integrase inhibitor, an immune based antiretroviral agent, a viral maturation inhibitor, a cellular inhibitor, and combinations of two or more of the above. 
   
   
       15 . The method of  claim 14 , wherein the second therapeutic agent is selected from ritonavir, efavirenz, didanosine, tenofovir disoproxil, nelfinavir mesilate, amprenavir, raltegravir potassium, saquinavir, lopinavir, nevirapine, emtricitabine, abacavir, lamivudine, zidovudine, maraviroc, stavudine, darunavir, fosamprenavir, vicriviroc, a pharmaceutically acceptable salt of any of the foregoing, and combinations thereof. 
   
   
       16 . The method of  claim 15 , wherein the second therapeutic agent is selected from ritonavir, efavirenz, didanosine, raltegravir, tenofovir disoproxil, lamivudine, abacavir, zidovudine, emtricitabine, efavirenz, a pharmaceutically acceptable salt of any of the foregoing, and combinations thereof. 
   
   
       17 . The method of  claim 13 , further comprising administering to the patient two to three additional second therapeutic agents independently selected from ritonavir, efavirenz, didanosine, raltegravir, tenofovir disoproxil, lamivudine, abacavir, zidovudine, emtricitabine, efavirenz, and a pharmaceutically acceptable salt of any of the foregoing. 
   
   
       18 . The method of  claim 13 , further comprising administering to the patient two additional second therapeutic agents independently selected from ritonavir, efavirenz, didanosine, raltegravir, tenofovir disoproxil, lamivudine, abacavir, zidovudine, emtricitabine, efavirenz, and a pharmaceutically acceptable salt of any of the foregoing. 
   
   
       19 . A pharmaceutical composition comprising a compound selected from: 
     
       
         
         
             
             
         
       
       pharmaceutically acceptable salt of either of the foregoing; and a pharmaceutically acceptable carrier. 
     
   
   
       20 . A method of treating HIV infection in a patient in need thereof comprising the step of administering to the patient an effective amount of a compound selected from: 
     
       
         
         
             
             
         
       
       pharmaceutically acceptable salt of either of the foregoing.