Patent EA-000533-B1 (EA)
Title: Sulfonylalkanoylaminohydroxyethylaminosulfonamide retroviral protease inhibitors
Inventor: GETMAN DANIEL P
IPC: C07D263/56
Filed: 1996-03-07
Abstract: 1. Compound represented by the formula:   or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein n and t each independently represent 0, 1 or 2; R<1> represents hydrogen, 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, -CH2 CONH2, -CH2CH2CONH2, -CH2S(O)2NH2, -CH2SCH3, -CH2 S(O)CH3 or -CH2 S(O)2CH3 radicals; R<2> represents radicals of 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 cycloalkylaikyl of 1-3 alkyl carbon atoms and 3-6 ring member carbon atoms; R<3> represents radicals of alkyl radical of 1-5 carbon atoms, cycloalkyl of 5-8 ring members or cycloalkylmethyl radical of 3-6 ring members; R<4> represents benzo fused 5 to 6 ring member heteroaryl or benzo fused 5 to 6 ring member heterocycle radicals. or a radical of the formula   wherein A and B each independently represent O, S, SO or SO2; R<6> represents deuterium, alkyl of 1-5 carbon atoms, fluoro or chloro radicals; R<7> represents hydrogen, deuterium, methyl, fluoro or chloro 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 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 wherein said substituents are radicals of alkyl of 1 to 3 carbon atoms, aralkyl of 1 to 3 alkyl carbon atoms radicals, 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 hydrogen radical or alkyl radical of 1 to 3 carbon atoms; or the radical of formula -NR<20>R<21> represents a 5 to 6 ring member heterocycle radical; and R<22> represents alkyl radical of 1 to 3 carbon atoms or R<20>R<21>N-alkyI radical of 1 to 3 alkyl carbon atoms; and R<5> represents an alkyl radical of 1-5 carbon atoms, alkenyl radical of 2-5 carbon atoms, alkynyl radical of 2-5 carbon atoms or aryl substituted alkyl radical of 1-5 carbon atoms. 2. Compound of Claim 1, or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein n represents 1; t represents 1 or 2; R<1> represents hydrogen radical, alkyl radical of 1-3 carbon atoms, alkenyl radical of 2-3 carbon atoms, alkynyl radical of 2-3 carbon atoms radicals or cyanomethyl; R<2> represents radicals of alkyl of 3-5 carbon atoms, arylmethyl, alkylthioalkyl of 1-3 alkyl carbon atoms, arylthiomethyl or cycloalkylmethyl of 5-6 ring member carbon atoms radicals; R<3> represents alkyl of 1-5 carbon atoms, cycloalkylmethyl of 3-6 ring members, cyclohexyl or cycloheptyl radicals; R<4> represents 2-amino-benzofchiazol-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 radicals; and R<7> represents hydrogen, deuterium, methyl or fluoro 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 hydrogen, 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 radicals of 1 to 3 carbon atoms; and R<21> represents hydrogen or methyl radicals; or the radical of formula -NR<20>R<21> represents pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, morpholinyl or thiamorpholinyl radicals; and R<22> represents alkyl radical of 1 to 3 carbon atoms; and R<5> represents an alkyl radical of 1-5 carbon atoms, alkenyl radical of 3-4 carbon atoms, alkynyl radical of 3-4 carbon atoms or aryl substituted alkyl radical of 1-4 carbon atoms. 3. Compound of Claim 2, or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein R<1> represents hydrogen, methyl, ethyl or cyanomethyl radicals; R<2> represents isobutyl, n-butyl, CH3SCH2CH2-, phenylthiomethyl, (2-naphthylthio)methyl, benzyl, 4-methoxyphenylmethyl, 4-hydroxyphenylmethyl, 4-fluorophenylmethyl or cyclohexylmethyl radicals; R<3> represents propyl, isoarnyl, isobutyl, butyl, cyclohexyl, cycloheptyl, cyclopentylmethyl or cyclohexylmethyl radicals; 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-l,3-benzodioxol-5-yl, 2,2-dimethyl-l,3-benzodioxol-5-yl, 2,2-dideutero-l,3-benzodioxol-5-yl, 2,2-difluoro-l,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 hydrogen, 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 radicals; R<21> represents a hydrogen radical; and R<22> represents methyl radical; and R<5> represents an alkyl radical of 1-5 carbon atoms or phenyl substituted alkyl radical of 2-4 carbon atoms. 4. Compound of Claim 3 or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein R<1> represents methyl or ethyl radicals; R<2> represents benzyl, 4-fluorophenylmethyl or cyclohexylmethyl radicals; R<4> represents benzothiazol-5-yl, benzothiazol-6-yl, 2,3-dihydrobenzofuran-5-yl, benzofuran-5-yl, 1,3-benzodioxol-5-yl, 2-methy1-1,3-benzodioxol-5-yl, 2,2-dimethyl-1,3 -benzodioxol-5-yl, 2,2-dideutero-l,3-benzodioxol-5-yl, 2,2-difluoro-l,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2-(methoxycarbonylammo)benzothiazol-6-yl or 2-(methoxycarbonylamino)benzimidazol-5-yl radicals; and R<5> represents methyl, ethyl, propyl, isopropyl or 2-phenylethyl radicals. 5. Compound of Claim 1 which is N-[2R-hydroxy-3-[(2-methylpropyl)[(1,3-benzodioxol-5-yl) sulfonyl]ammo]-1S-(phenylmethyl)propyl]-2S-methyl-3-(methylsulfonyl)propanamide; N-[2R-hydroxy-3-[(2-methylpropyl)[(1,4-benzodioxan-6-yl) sulfonyl] ammo]-1S-(phenylmethyl) propyl]-2S-methyl-3-(methylsulfonyl)propanamide; N-[2R-hydroxy-3-[(2-methylpropyl)[(benzothiazol-6-yl) sulfonyl]ammo]-1S-(phenylmethyl)propyl]-2S-methyl-3-(methylsulfonyl)propanamide; N-[2R-hydroxy-3-[(2-methylpropyl)[(benzothiazol-5-yl) sulfonyl]ammo]-1S-(phenylmethyl)propyl]-2S-methyl-3-(methylsulfonyl)propanamide; or N-[2R-hydroxy-3-[(2-methylpropyl)[(2,3-dihydrobenzofuran-5-yl) sulfonyl] amino]-1S-(phenylmethyl)propyl]-2S-methyl-3-(methylsulfonyl)propanamide. 6. Pharmaceutical composition comprising a compound of Claim 1 and a pharmaceutically acceptable carrier. 7. Method of inhibiting a retroviral protease comprising administering an effective amount of a compound of Claim 1. 8. Method of treating a retroviral infection comprising administering an effective amount of a composition of Claim 6. 9. Method of preventing replication of a retrovirus comprising administering an effective amount of a compound of Claim 1. 10. Method of preventing replication of a retrovirus in vitro comprising administering an effective amount of a compound of Claim 1. 11. Method of treating AIDS comprising administering an effective amount of a composition of Claim 6.