Bis-sulfonamide hydroxyethylamino retroviral protease inhibitors

Abstract

Bis-sulfonamido hydroxyethylamino compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease. The present invention relates to retroviral protease inhibiting compounds of the formula: or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein the variables are as defined herein.

1 . A compound represented by the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  represents a hydrogen radical, alkyl, or a side chain of an amino acid selected from the group consisting of leucine, norleucine, isoleucine, allo-isoleucine, alanine, tert-leucine, and valine; 
         R 2  represents cycloalkyl or aralkyl; 
         R 3  represents alkyl, cycloalkyl, or cycloalkylalkyl; 
         R 4  represents heterocyclo, heteroaryl, or aryl; 
         R 6  represents a hydrogen radical or alkyl; 
         R 7  and R 8  each independently represent a hydrogen radical or alkyl; 
         w and x are independently 0, 1 or 2; 
         t is an integer from 1 to 6, and 
         R 10  and R 11  together with the nitrogen atom to which they are bonded represent heterocyclo, heteroaryl, aralkylheteroaryl, aralkylheterocyclo, heteroaralkylheteroaryl or heteroaralkylheterocyclo; 
       
       wherein heteroaryl, as used alone or in combination, is optionally substituted with one or more radicals selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, alkanoylamino, amido, amidino, N-alkylamidino, alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido alkoxycarbonylamino, and alkylsulfonylamino: 
       wherein cycloalkyl, and aryl, as used alone or in combination, are optionally substituted with one or more radicals selected from the group consisting of alkyl, alkoxy, hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, amino, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, alkanoylamino, amido, amidino, N-alkylamidino, alkylamino, dialkylamino, N-alkylamido, N,N-dialkylamido, and alkoxycarbonylamino; and 
       wherein heterocyclo, as used alone or in combination, is optionally substituted with one or more radicals selected from the group consisting of alkyl, alkoxy, hydroxy, amidino, N-alkylamidino, alkoxycarbonylamino, and alkylsulfonylamino. 
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 10  and R 11  together with the nitrogen atom to which they are bonded represent heterocyclo which is optionally substituted on a nitrogen ring atom with alkyl. 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 10  and R 11  together with the nitrogen atom to which they are bonded represent piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, amidinopyrrolidinyl, (N-methylamidino)pyrrolidinyl, pyrrolyl, amidinopyrrolyl, (N-methylamidino)pyrrolyl, N-benzylpiperazinyl, N-(pyridylmethyl)piperazinyl, N-[(N-methylaminothiazolyl)methyl]piperazinyl, N-[(N,N-dimethylaminothiazolyl)methyl]piperazinyl, N-(thiazolylmethyl)piperazinyl, or N-[(isopropylthiazolyl)methyl]piperazinyl. 
     
     
         4 . The compound of  claim 3  or a pharmaceutically acceptable salt thereof, wherein R 10  and R 11  together with the nitrogen atom to which they are bonded represent piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, pyrrolyl, N-benzylpiperazinyl, N-(pyridylmethyl)piperazinyl, or N-(thiazolylmethyl)piperazinyl. 
     
     
         5 . The compound of  claim 4  or a pharmaceutically acceptable salt thereof, wherein R 10  and R 11  together with the nitrogen atom to which they are bonded represent piperidinyl, morpholinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, N-benzylpiperazinyl, or N-(pyridylmethyl)piperazinyl. 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein R 1  represents a hydrogen radical, methyl, ethyl, isopropyl, propyl, or a side chain of an amino acid selected from the group consisting of alanine and valine. 
     
     
         7 . The compound of  claim 6  or a pharmaceutically acceptable salt thereof, wherein R 1  represents a hydrogen radical or methyl. 
     
     
         8 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  represents benzyl, fluorobenzyl, or cyclohexylmethyl. 
     
     
         9 . The compound of  claim 8  or a pharmaceutically acceptable salt thereof, wherein R 2  represents benzyl. 
     
     
         10 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 3  represents isoamyl, isobutyl, cyclohexyl, cycloheptyl, cyclohexylmethyl, or cyclopentylmethyl. 
     
     
         11 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 3  represents isobutyl. 
     
     
         12 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4  represents phenyl, naphthyl, benzothiazolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, benzimidazolyl, benzimidazolonyl, or benzoxazolyl, or phenyl having one or more substituents selected from the group consisting of methyl, methoxy, ethoxy, methylthio, fluoro, chloro, amino, and methoxycarbonylamino. 
     
     
         13 . The compound of  claim 12  or a pharmaceutically acceptable salt thereof, wherein R 4 represents phenyl, 4-methoxyphenyl, or 1,3-benzodioxolyl. 
     
     
         14 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 6  represents a hydrogen radical. 
     
     
         15 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 7  and R 8  each represent a hydrogen radical. 
     
     
         16 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein, in said formula, the stereochemistry of the carbon atom bonded to the substituent R 2  is designated as (S). 
     
     
         17 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein, in said formula, the stereochemistry of the carbon atom bonded to the hydroxyl radical is designated as (R). 
     
     
         18 . A pharmaceutically acceptable salt of the compound of  claim 1 , wherein said pharmaceutically acceptable salt is derived from an acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, and citric acid. 
     
     
         19 . A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         20 . A compound represented by the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R 1  represents a hydrogen radical, —CH 2 SO 2 NH 2 , —CH 2 CO 2 CH 3 , —CO 2 CH 3 , —CONH 2 , —CH 2 C(O)NHCH 3 , —C(CH 3 ) 2 (SH), —C(CH 3 ) 2 (SCH 3 ), —C(CH 3 ) 2 (S[O]CH 3 ), —C(CH 3 ) 2 (S[O] 2 CH 3 ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aminosulfonylalkyl, N-alkylaminosulfonylalkyl, N,N-dialkylaminosulfonylalkyl or heteroaralkyl, or a side chain of an amino acid selected from the group consisting of asparagine, lysine, aspartic acid, aspartic acid methyl ester, methionine or the sulfoxide or sulfone derivative thereof, S-methyl cysteine or the sulfoxide or sulfone derivative thereof, ornithine, leucine, isoleucine, norleucine, allo-isoleucine, alanine, phenylalanine, histidine, tert-leucine, glutamine, threonine, allo-threonine, serine, O-alkyl serine, beta-cyano alanine, and valine; 
         R 2  represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, each optionally substituted with one or more alkyl, halogen, —NO 2 , —CN, —CF 3 , —OR 9  or —SR 9 , wherein R 9  represents a hydrogen radical, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclo; 
         R 3  represents hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, thioalkyl or the corresponding sulfone or sulfoxide derivative thereof, alkylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof, arylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof, aminoalkyl, or N-monosubstituted aminoalkyl or N,N-disubstituted aminoalkyl having one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocyclo and heterocycloalkyl; 
         R 4  represents alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, heteroaryl, heteroaralkyl, alkoxycarbonylaminoheteroaryl, aryl, aralkyl, aralkenyl, thioalkyl or the corresponding sulfone or sulfoxide derivative thereof, alkylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof, arylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof, aminoalkyl, or N-monosubstituted aminoalkyl or N,N-disubstituted aminoalkyl having one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocyclo, heterocycloalkyl, thioalkyl or the corresponding sulfone or sulfoxide derivative thereof, alkylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof, and arylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof; 
         R 6  represents a hydrogen radical or alkyl; 
         each R 7  independently represents a hydrogen radical, —CH 2 SO 2 NH 2 , —CH 2 CO 2 CH 3 , —CO 2 CH 3 , —CONH 2 , —CH 2 C(O)NHCH 3 , —(CH 3 ) 2 (SH), —C(CH 3 ) 2 (SCH 3 ), —C(CH 3 ) 2 (S[O]CH 3 ), —C(CH 3 ) 2 (S[O] 2 CH 3 ), carboxy, amidino, N-alkylamidino, alkyl, aryl or aralkyl; or R 7  together with R 1  and the carbon atoms to which R 7  and R 1  are attached, represent cycloalkyl or heterocyclo; 
         each R 8  independently represents a hydrogen radical or alkyl; 
         R 10  represents a hydrogen radical, alkyl, aryl, aralkyl, heterocyclo, heterocycloalkyl, heteroaryl or heteroaralkyl; 
         R 11  represents a hydrogen radical, alkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclo, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heteroarylcarbonylalkyl, arylcarbonylalkyl, thioalkyl or the corresponding sulfone or sulfoxide derivative thereof, alkylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof, or arylthioalkyl or the corresponding sulfone or sulfoxide derivative thereof, aminoalkyl, or N-monosubstituted aminoalkyl or N,N-disubstituted aminoalkyl having one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocyclo and heterocycloalkyl; or R 10  and R 11  together with the nitrogen to which they are attached represent aralkylheteroaryl, aralkylheterocyclo, heteroaralkylheteroaryl or heteroaralkylheterocyclo radicals; 
         x and w each independently represent 0, 1, or 2; 
         t represents 0-4; and 
         Y represents O, S or NH.