Heterocyclecarbonyl amino acid hydroxyethylamino sulfonamide retroviral protease inhibitors

Abstract

Selected heterocyclecarbonyl amino acid hydroxyethylamino 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, compositions, and methods 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 represents 0 or 1; 
 R 1  represents 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 carbon atoms and 1-3 alkoxy carbon atoms, cyanoalkyl of 1-3 alkyl carbon atoms, imidazolylmethyl, —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 , —CH 2 S(O) 2 CH 3 , —C(CH 3 ) 2 SCH 3 , —C(CH 3 ) 2 S(O)CH 3  or —C(CH 3 ) 2 S(O) 2 CH 3 ;  
 R 2  represents alkyl of 1-5 carbon atoms, aralkyl of 1-3 alkyl carbon atoms, alkylthioalkyl of 1-3 alkyl carbon atoms, arylthioalkyl of 1-3 alkyl carbon atoms or cycloalkylalkyl of 1-3 alkyl carbon atoms and 3-6 ring member carbon atoms;  
 R 4  represents aryl, benzo fused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ring member heterocyclo radicals; 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 a hydrogen radical, 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 wherein said substituents are 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 or 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 an —R 2 OR 21 N-alkyl radical of 1 to 3 alkyl carbon atoms;  
 R 10  represents a hydrogen radical, alkyl of 1-3 carbon atoms, benzyl, phenylmethoxycarbonyl, tert-butoxycarbonyl or (4-methoxyphenylmethoxy)carbonyl radicals;  
 R 11  represents a hydrogen radical, hydroxyalkyl of 1-3 carbon atoms or alkoxyalkyl of 1-3 alkyl carbon atoms; and  
 R 12  and R 13  each independently represent a hydrogen radical, hydroxy, alkoxy of 1-3 carbon atoms, 2-hydroxyethoxy, hydroxyalkyl of 1-3 carbon atoms or alkoxyalkyl of 1-3 alkyl carbon atoms; or R 11  and R 12  or R 12  and R 13  along with the carbon atoms to which they are attached represent a benzo radical, which is optionally substituted with at least one hydroxy or alkoxy of 1-3 carbon atoms,  
 wherein aryl, alone or in combination, is a phenyl or naphthyl radical optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, heterocyclo, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidino, alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido, aralkoxycarbonylamino, alkylthio, alkylsulfinyl, and alkylsulfonyl;  
 wherein cycloalkyl, alone or in combination, is a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical optionally substituted with one or more substituents as defined with respect to aryl;  
 wherein heterocyclo, alone or in combination, is a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle radical having at least one nitrogen, oxygen, or sulfur atom ring member, or a corresponding sulfone, sulfoxide, or N-oxide derivative of said heterocycle radical, wherein said heterocycle radical is optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, hydroxy, oxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidino, alkoxycarbonylamino, and alkylsulfonylamino, is optionally substituted on a secondary nitrogen atom with a substituent selected from the group consisting of hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, heteroaralkyl, phenyl and phenylalkyl, and is optionally substituted on a tertiary nitrogen atom by oxido; and  
 wherein heteroaryl, alone or in combination, is an aromatic heterocycle radical optionally substituted with one or more substituents as defined with respect to aryl or heterocyclo.  
 
   
   
       2 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein 
 R 1  represents alkyl of 1-4 carbon atoms, alkenyl of 2-3 carbon atoms, alkynyl of 3-4 carbon atoms, cyanomethyl, imidazolylmethyl, —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 , —CH 2 S(O) 2 CH 3 , —C(CH 3 ) 2 SCH 3 , —C(CH 3 ) 2 S(O)CH 3  or —C(CH 3 ) 2 S(O) 2 CH 3 ;    R 2  represents alkyl of 3-5 carbon atoms, arylmethyl, alkylthioalkyl of 1-3 alkyl carbon atoms, arylthiomethyl or cycloalkylmethyl of 5-6 ring member carbon atoms; 
 R 4  represents phenyl, 2-naphthyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3,4-dimethoxyphenyl, 3-aminophenyl, 4-aminophenyl, 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 radicals, 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 wherein said substituents are alkyl of 1 to 3 carbon atoms;    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; and    R 22  represents alkyl of 1 to 3 carbon atoms.    
   
   
       3 . The compound of  claim 2 , or a pharmaceutically acceptable salt thereof, wherein n is 0; 
 R 1  represents iso-propyl, sec-butyl, tert-butyl, 3-propynyl, imidazolylmethyl, —CH 2 CONH 2 , —CH 2 SCH 3 , —CH 2 S(O)CH 3 , —CH 2 S(O) 2 CH 3 , —C(CH 3 ) 2 SCH 3 , —C(CH 3 ) 2 S(O)CH 3  or —C(CH 3 ) 2 S(O) 2 CH 3 ;    R 2  represents isobutyl, n-butyl, CH 3 SCH 2 CH 2 —, phenylthiomethyl, (2-naphthylthio)methyl, benzyl, 4-methoxyphenylmethyl, 4-hydroxyphenylmethyl, 4-fluorophenylmethyl or cyclohexylmethyl;    R 4  represents phenyl, 2-naphthyl, 4-methoxyphenyl, 4-hydroxyphenyl, 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 radicals; 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; and    R 22  represents methyl;    R 10  represents a hydrogen radical, methyl or benzyl;    R 11  represents a hydrogen radical; and    R 12  and R 13  each independently represent a hydrogen radical, hydroxy or methoxy; or R 11  and R 12  along with the carbon atoms to which they are attached represent a benzo radical, which is optionally substituted with at least one hydroxy or methoxy.    
   
   
       4 . The compound of  claim 3  or a pharmaceutically acceptable salt thereof, wherein 
 R 1  represents sec-butyl, tert-butyl, iso-propyl, 3-propynyl or —C(CH 3 ) 2 S(O) 2 CH 3 ;    R 2  represents benzyl, 4-fluorophenylmethyl or cyclohexylmethyl radicals;    R 4  represents phenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 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;    R 10  represents a hydrogen radical or methyl;    R 12  represents a hydrogen radical or hydroxy, and    R 13  represents a hydrogen radical.    
   
   
       5 . The compound of  claim 1  wherein said pharmaceutically acceptable salt is hydrochloric acid salt, sulphuric acid salt, phosphoric acid salt, oxalic acid salt, maleic acid salt, succinic acid salt, citric acid salt or methanesulfonic acid salt.  
   
   
       6 . The compound of  claim 5  wherein said pharmaceutically acceptable salt is hydrochloric acid salt, oxalic acid salt, citric acid salt or methanesulfonic acid salt.  
   
   
       7 . A composition comprising a compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.  
   
   
       8 . A method of inhibiting a retroviral protease comprising administering an effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt thereof.  
   
   
       9 . A method of treating a retroviral infection comprising administering an effective amount of a composition of  claim 7 .  
   
   
       10 . 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.  
   
   
       11 . 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.  
   
   
       12 . A method of treating AIDS comprising administering an effective amount of a composition of  claim 7 .  
   
   
       13 . The compound of  claim 1  represented by the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.