α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

Abstract

α- and β-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

1. A compound represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein
 R 2  is an alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radical, which radical is optionally substituted with a radical selected from the group consisting of alkyl, halo, nitro, cyano, CF 3 , —OR 9 , and —SR 9  radicals, wherein R 9  is hydrogen or alkyl radicals; 
 R 3  is alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl or heteroaralkyl radicals; 
 R 4  is heterocycloalkyl, heteroaryl or aryl radicals; 
 Y is O or S; and 
 A is heterocycloalkyl, heterocycloalkoxy, heterocycloalkylalkyl, heterocycloalkylalkoxy, heteroaralkyl, heteroaralkoxy, heteroaryloxy or heteroaryl radicals; and 
 wherein alkyl, alone or in combination, is a straight-chain or branched-chain alkyl radical containing 1 to 8 carbon atoms; alkenyl, alone or in combination, is a straight-chain or branched-chain hydrocarbon radial having at least one double bond and containing 2 to 8 carbon atoms; alkynyl, alone or in combination, is a straight-chain or branched chain hydrocarbon radical having at least one triple bond and containing 2 to 10 carbon atoms; aryl, alone or in combination, is an unsubstituted phenyl or naphthyl radical or a phenyl or naphthyl radical substituted with alkyl, alkoxy, halogen, hydroxy, amino, alkylamino, dialkylamino, nitro, cyano, carboxy, alkoxycarbonyl, amido, alkylamido, dialkylamido, trifluoromethyl, methylthio, methylsulfinyl or methylsulfonyl radicals; cycloalkyl, alone or in combination, is a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains 3 to 8 carbon atoms; heterocycloalkyl, alone or in combination, is a monocyclic, bicyclic or tricyclic heterocycle radical having 1-4 nitrogen, nitrogen oxide, oxygen, sulphur, sulfone or sulfoxide heteroatom ring members, optionally benz-fused and optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl or aralkyl radicals, or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl radicals; and heteroaryl, alone or in combination, is an aromatic heterocycloalkyl, optionally substituted with respect to aryl and heterocycloalkyl radicals. 
 
     
     
       2. Compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein
 R 2  represents alkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with alkyl, halogen or —OR 9  radicals, wherein R 9  represents hydrogen or alkyl radicals; and 
 R 3  is alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, aralkyl or heteroaralkyl radicals; 
 wherein heterocycloalkyl, alone or in combination, is a 5-6 ring membered monocyclic heterocycle radical having 1-4 nitrogen, nitrogen oxide, oxygen, sulphur, sulfone or sulfoxide heteroatom ring members, optionally benz-fused and optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo, aryl or aralkyl radicals, or on a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl radicals; and heteroaryl, alone or in combination, is an aromatic heterocycloalkyl, optionally substituted with respect to aryl and heterocycloalkyl radicals. 
 
     
     
       3. Compound of  claim 2  or a pharmaceutically acceptable salt thereof wherein
 A is heterocycloalkyl, heterocycloalkoxy, heterocycloalkylalkyl, heteroaralkoxy or heteroaryl radicals; 
 R 3  represents alkyl, cycloalkyl or cycloalkylalkyl radicals; and 
 R 4  is heterocycloalkyl or aryl radicals; 
 wherein alkyl, alone or in combination, is a straight-chain or branched-chain hydrocarbon radical containing from 1-5 carbon atoms; alkenyl, alone or in combination, is a straight-chain or branched-chain hydrocarbon radical having at least one double bond and containing from 2-5 carbon atoms; alkynyl, alone or in combination, is a straight-chain or branched-chain hydrocarbon radical having at least one triple bond and containing from 2-5 carbon atoms; heterocycloalkyl, alone or in combination, is a 5-6 ring membered heterocycle or a benzfused 5-6 ring membered heterocycle having one or two nitrogen, nitrogen oxide, oxygen, sulphur, sulfone or sulfoxide heteroatoms; and heteroaryl means an aromatic 5-6 ring membered heterocycle or an aromatic benzfused 5-6 ring membered heterocycle having one or two nitrogen, nitrogen oxide, oxygen, sulphur or sulfone heteroatoms. 
 
     
     
       4. Compound of  claim 3  or a pharmaceutically acceptable salt thereof wherein
 A is heterocycloalkyl or heterocycloalkoxy radicals; 
 R 2  represents alkyl, cycloalkylalkyl or aralkyl radicals; 
 R 3  represents alkyl, cycloalkyl or cycloalkylalkyl radicals; 
 R 4  is an aryl radical; and 
 Y is O; 
 wherein heterocycloalkyl, alone or in combination, is a 5-6 ring membered heterocycle having an oxygen, sulphur, sulfone or sulfoxide heteroatom. 
 
     
     
       5. Compound of  claim 4  or a pharmaceutically acceptable salt thereof wherein
 A is heterocycloalkyl or heterocycloalkoxy radicals; 
 R 2  represents butyl, benzyl, cyclohexylmethyl or 2-naphthylmethyl radicals; 
 R 3  represents isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl or n-propyl radicals; and 
 R 4  is phenyl, methoxyphenyl, cyanophenyl, chlorophenyl, hydroxyphenyl, nitrophenyl, fluorophenyl or aminophenyl radical; 
 wherein heterocycloalkyl, alone or in combination, is a 5-6 ring membered heterocycle having an oxygen, sulphur, sulfone or sulfoxide heteroatom. 
 
     
     
       6. Compound of  claim 2  or a pharmaceutically acceptable salt thereof wherein
 R 2  is butyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl or naphthylmethyl radicals; 
 R 3  is methyl, ethyl, propyl, butyl, pentyl, hexyl, iso-butyl, iso-amyl, 3-methoxypropyl, 3-methylthiopropyl, 4-methylthiobutyl, 4-methylsulfonylbutyl, 2-(1-morpholino)ethyl, 4-hydroxybutyl, allyl, propargyl, cyclohexylmethyl, cyclopropylmethyl, phenyl, benzyl, 4-fluorobenzyl, 4-methoxybenzyl, 1-phenylethyl, 2-phenylethyl, naphthylmethyl, 3-pyridylmethyl or 4-pyridylmethyl radicals; 
 R 4  is phenyl, naphthyl, chlorophenyl, fluorophenyl, hydroxyphenyl, methylphenyl, methoxyphenyl, ethoxyphenyl, methylthiophenyl, methylsulfinylphenyl, methylsulfonylphenyl, acetamidophenyl, methoxycarbonylphenyl, aminophenyl, dimethylaminophenyl, nitrophenyl, trifluoromethylphenyl or thienyl radicals; 
 Y is O; and 
 A is quinolinyl, indolyl, pyridyl, methylpyridyl, furanyl, oxazolyl, thiazolyl, pyridylmethoxy, hydroxypyridylmethoxy, aminopyridylmethoxy, pyrimidinylmethoxy, N-oxo-pyrimidinylmethoxy, thiazolylmethoxy, tetrahydrothiophenoxy, 1,1-dioxotetrahydrothiophenoxy or tetrahydrofuranoxy radicals. 
 
     
     
       7. A compound of  claim 1  which is
 Carbamic acid, [2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, 3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; 
 Carbamic acid, [2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, 3(S)-1,1-dioxotetrahydrothiophen-3-yl-ester; 
 Carbamic acid, [2R-hydroxy-3-[(4-methoxyyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, 3-S-tetrahydrothiophen-3-yl-ester; 
 Carbamic acid, [2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, 3-S-tetrahydrothiophen-3-yl-ester; 
 Carbamic acid, [2R-hydroxy-3-[(4-hydroxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, 3-S-tetrahydrofuran-3-yl-ester; 
 Carbamic acid, [2R-hydroxy-3-[(4-methoxyphenylsulfonyl)(2-methylpropyl)amino]-1S-(phenylmethyl)propyl-, 3-S-tetrahydrofuran-3-yl-ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 5-(thiazolyl)methyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 5-(thiazolyi)methyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-(6-aminopyridyl)methyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-(6-aminopyridyl)methyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-(6-hydroxypyridyl)methyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 5-pyrimidyimethyl ester; 
 4-Pyridinecarboxamide, N-[2R-hydroxy-3-[[(4-methoxyphenyl) sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]; 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester, N-oxide; 
 Carbamic acid, [2R-hydroxy-3-[[phenylsulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 4-pyridylmethyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 4-pyridylmethyl ester, N-oxide; 
 Carbamic acid, [2R-hydroxy-3-[[(4-chlorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-nitrophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-fluorophenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; 
 Carbamic acid, [2R-hydroxy-3-[[(4-hydroxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 3-pyridylmethyl ester; or 
 Carbamic acid, [2R-hydroxy-3-[[(4-methoxyphenyl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-, 5-pyrimidylmethyl ester. 
 
     
     
       8. A pharmaceutical composition comprising a compound of claim  1  13 and a pharmaceutically acceptable carrier. 
     
     
       9. The compound of  claim 1  wherein said heterocycloalkyl or heteroaryl is selected from optionally substituted pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, pyrrolyl, imidazolyls, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, furyl, thienyl, triazolyl, oxazolyl, thiazolyl, indolyls, quinolynyls, isoquinolinyls, tetrahydroquinolinyls, 1,2,3,4-tetrahydroisoquinolinyls, quinoxalinyl, β-carbolinyl, 2-benzofurancarbonyl, and benzimidazolyls radicals. 
     
     
       10. A compound represented by the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein
 R 2  is an aralkyl radical; 
 R 3  is alkyl; 
 R 4  is an aryl radical; 
 Y is O; and 
 A is a 5-membered ring containing one oxygen or one sulfur atom. 
 
     
     
       11. Compound of  claim 1  wherein said heterocycloalkyl is a 5-6 ring membered monocyclic, heterocycle radical having 1-4 nitrogen, nitrogen oxide, oxygen, sulphur, sulfone or sulfoxide heteroatom ring members, optionally benzfused and optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy, hydroxy, oxo aryl or aralkyl radicals, or on a secondary nitrogen atom by hydroxy alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl radicals, and said heteroaryl is an aromatic heterocycloalkyl optionally benzfused and optionally substituted. 
     
     
       12. Compound of  claim 11  wherein said heterocycloalkyl is a 5-6 ring membered heterocycle or a benzfused 5-6 ring membered heterocycle having one or two nitrogen, nitrogen oxide, oxygen, sulfur, sulfone or sulfoxide heteroatoms; and said heteroaryl is an aromatic 5-6 ring membered heterocycle or an aromatic benzfused 5-6 ring membered heterocycle having one or two nitrogen, nitrogen oxide, oxygen sulphur or sulfone heteroatoms. 
     
     
       13. A compound represented by the formula 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein
 R 2  is an aralkyl radical; 
 R 3  is an alkyl radical; 
 R 4  is a heterocycloalkyl or an aryl radical; 
 Y is O; and 
 A is a heterocycloalkoxy radical; 
 wherein alkyl, alone or in combination, is a straight-chain or branched-chain alkyl radical containing 1 to 8 carbon atoms; 
 aryl, alone or in combination, is a phenyl radical optionally substituted with an amino radical; and 
 heterocycloalkyl, alone or in combination, is a bicyclic heterocycle radical having 1-4 oxygen heteroatom ring members. 
 
     
     
       14. The compound of claim 13 wherein R 2  is unsubstituted phenylalkyl. 
     
     
       15. The compound of claim 13 wherein R 2  is benzyl.