Sulfonylalkanoylamino hydroxyethylamino sulfonamide retroviral protease inhibitors

Abstract

Selected sulfonylalkanoylamino hydroxyethylamine sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to such retroviral protease inhibitors and, more particularly, relates to selected novel compounds, composition and method for inhibiting retroviral proteases, such as human immunodeficiency virus (HIV) protease, prophylactically preventing retroviral infection or the spread of a retrovirus, and treatment of a retroviral infection.

1 . A compound represented by the formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein n and t each independently represents 0, 1 or 2; 
 R 1  represents a hydrogen radical, alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkynyl of 2-5 carbon atoms, hydroxyalkyl of 1-3 carbon atoms, alkoxyalkyl of 1-3 alkyl and 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3 alkyl carbon atoms, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 S(O) 2 NH 2 , —CH 2 SCH 3 , —CH 2 S(O)CH 3  or —CH 2 S(O) 2 CH 3 ;  
 R 3  represents alkyl of 1-5 carbon atoms, cyloalkyl of 5-8 ring members or cycloalkylmethyl of 3-6 ring members;  
 R 4  represents benzo fused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ring member heterocyclo radicals, wherein, in each case, the sulfonamide sulfur atom is bound to a carbon atom of the benzo ring, or a radical of the formula:  
                     
 wherein A and B each independently represent O, S, SO or SO 2 ; R 6  represents deuterium, alkyl of 1-5 carbon atoms, fluoro or chloro; R 7  represents hydrogen, deuterium, methyl, fluoro or chloro; or a radical of the formula:  
                     
 wherein Z represents O, S or NH; and R 9  represents a radical of formula:  
                     
 wherein Y represents O, S or NH; X represents a bond, O or NR 21 ;  
 R 20  represents hydrogen, alkyl of 1 to 5 carbon atoms, alkenyl of 2 to 5 carbon atoms, alkynyl of 2 to 5 carbon atoms, aralkyl of 1 to 5 alkyl carbon atoms, heteroaralkyl of 5 to 6 ring members and 1 to 5 alkyl carbon atoms, heterocycloalkyl of 5 to 6 ring members and 1 to 5 alkyl carbon atoms, aminoalkyl of 2 to 5 carbon atoms, N-mono-substituted or N,N-disubstituted aminoalkyl of 2 to 5 alkyl carbon atoms having one or two substituents independently selected from the group consisting of alkyl of 1 to 3 carbon atoms, aralkyl of 1 to 3 alkyl carbon atoms, carboxyalkyl of 1 to 5 carbon atoms, alkoxycarbonylalkyl of 1 to 5 alkyl carbon atoms, cyanoalkyl of 1 to 5 carbon atoms and hydroxyalkyl of 2 to 5 carbon atoms;  
 R 21  represents a hydrogen radical or alkyl of 1 to 3 carbon atoms; or the radical of formula —NR 20 R 21  represents a 5 to 6 ring member heterocyclo radical; and  
 R 22  represents alkyl of 1 to 3 carbon atoms or R 20 R 21 N-alkyl of 1 to 3 alkyl carbon atoms; and  
 R 5  represents alkyl of 1-5 carbon atoms, alkenyl of 2-5 carbon atoms, alkynyl of 2-5 carbon atoms or aralkyl of 1-5 alkyl carbon atoms.  
 
   
   
       2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein n represents 1; 
 t represents 1 or 2;    R 1  represents a hydrogen radical, alkyl of 1-3 carbon atoms, alkenyl of 2-3 carbon atoms, alkynyl of 2-3 carbon atoms or cyanomethyl;    R 3  represents alkyl of 1-5 carbon atoms, cycloalkylmethyl of 3-6 ring members, cyclohexyl or cycloheptyl;    R 4  represents 2-amino-benzothiazol-5-yl, 2-amino-benzothiazol-6-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl or 1,4-benzodioxan-6-yl; or a radical of the formula:                          wherein A and B each represent O; R 6  represents deuterium, methyl, ethyl, propyl, isopropyl or fluoro; and R 7  represents hydrogen, deuterium, methyl or fluoro; or a radical of the formula:                          wherein Z represents O, S or NH; and R 9  represents a radical of formula:                          wherein Y represents O, S or NH; X represents a bond, O or NR 21 ;    R 20  represents a hydrogen radical, alkyl of 1 to 5 carbon atoms, phenylalkyl of 1 to 3 alkyl carbon atoms, heterocycloalkyl of 5 to 6 ring members and 1 to 3 alkyl carbon atoms, or N-mono-substituted or N,N-disubstituted aminoalkyl of 2 to 3 alkyl carbon atoms and having one or two substituents of alkyl of 1 to 3 carbon atoms; and    R 21  represents a hydrogen radical or methyl; or the radical of formula —NR 20 R 21  represents pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, morpholinyl or thiamorpholinyl;    R 22  represents alkyl of 1 to 3 carbon atoms; and    R 5  represents alkyl of 1-5 carbon atoms, alkenyl of 3-4 carbon atoms, alkynyl of 3-4 carbon atoms or aralkyl of 1-4 alkyl carbon atoms.    
   
   
       3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein 
 R 1  represents hydrogen, methyl, ethyl or cyanomethyl;    R 3  represents propyl, isoamyl, isobutyl, butyl, cyclohexyl, cycloheptyl, cyclopentylmethyl or cyclohexylmethyl; and    R 4  represents benzothiazol-5-yl, benzothiazol-6-yl, benzoxazol-5-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideutero-1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl or 1,4-benzodioxan-6-yl; or a radical of the formula:                          wherein Z represents O, S or NH; and R 9  represents a radical of formula:                          wherein Y represents O, S or NH; X represents a bond, O or NR 21 ;    R 20  represents a hydrogen radical, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, 2-(1-pyrrolidinyl)ethyl, 2-(1-piperidinyl)ethyl, 2-(1-piperazinyl)ethyl, 2-(4-methylpiperazin-1-yl)ethyl, 2-(1-morpholinyl)ethyl, 2-(1-thiamorpholinyl)ethyl or 2-(N,N-dimethylamino)ethyl;    R 21  represents a hydrogen radical;    R 22  represents methyl; and    R 5  represents an alkyl of 1-5 carbon atoms or phenylalkyl of 2-4 alkyl carbon atoms.    
   
   
       4 . The compound of  claim 3  or a pharmaceutically acceptable salt, thereof, wherein 
 R 1  represents methyl or ethyl;    R 2  represents benzyl, 4-fluorophenylmethyl or cyclohexylmethyl;    R 4  represents benzothiazol-5-yl, benzothiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methyl-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3-benzodioxol-5-yl, 2,2-dideutero-1,3-benzodioxol-5-yl, 2,2-difluoro-1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2-(methoxycarbonylamino)benzothiazol-6-yl or 2-(methoxycarbonylamino)benzimidazol-5-yl; and    R 5  represents methyl, ethyl, propyl, isopropyl or 2-phenylethyl.    
   
   
       5 . (canceled)  
   
   
       6 . A composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
   
   
       7 . A method of inhibiting a retroviral protease comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       8 . A method of treating a retroviral infection comprising administering an effective amount of a composition of  claim 6 .  
   
   
       9 . A method of preventing replication of a retrovirus comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       10 . A method of preventing replication of a retrovirus in vitro comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       11 . A method of treating AIDS comprising administering an effective amount of a composition of  claim 6 .  
   
   
       12 . A compound of  claim 1  represented by the formula:  
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound of  claim 12  represented by the formula:  
     
       
         
         
             
             
         
       
     
   
   
       14 . The compound of  claim 13  represented by the formula: