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US 5,482,947 AGranted
Retroviral protease inhibitors
OwnerJohn J. Talley, Daniel P. Getman +9inventors
InventorsJohn J. Talley, Daniel P. Getman, Gary A. DeCrescenzo, Ko-Chung Lin, Michael L. Vazquez, Richard A. Mueller, Kathryn L. Reed, Robert M. Heintz, Michael Clare, John N. Freskos, Eric T. Sun
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Abstract
Urea-containing hydroxyethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Claims18
Method of inhibiting a retroviral protease comprising administering an effective amount of a compound represented by the formula ##STR174## or a pharmaceutically acceptable salt, prodrug or ester thereof wherein t represents O or 1;
- Y and Y' each independently represent O or S;
- R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aroyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclylalkanoyl, heteroaroyl, heteroaralkanoyl, alkyl, aralkyl, 3-carboxypropionyl, methyloxaloyl, bromoacetyl, trifluoroacetyl, methoxyacetyl, hydroxyacetyl, hydroxypropionyl, aminocarbonyl, N-alkylaminocarbonyl, N- mono- or N,N-disubstituted aminoalkanoyl radicals wherein said substituents are alkyl, aryl, aralkyl, cycloalkyl, heteroaralkyl, heterocycloalkyl, hydroxyethyl or methoxyethyl radicals, or in the case of a disubstituted aminoalkanoyl radical, said substituents along with the nitrogen atom to which they are attached form heterocyclyl or heteroaryl radicals, with the proviso that said heteroaryl radical is other than a quaternary nitrogen containing heteroaryl radical;
- R' represents hydrogen, alkyl or aralkyl radicals;
- or R and R' together with the nitrogen to which they are attached form heterocycloalkyl or heteroaryl radicals, with the proviso that said heteroaryl radical is other than a quaternary nitrogen containing heteroaryl radical;
- R.sup.1 represents hydrogen, --CF.sub.3, --CH(CF.sub.3).sub.2, --CH.sub.2 SO.sub.2 NH.sub.2, --CO.sub.2 CH.sub.3, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --CH.sub.2 C(O)NHCH.sub.3, --CH.sub.2 C(O)N(CH.sub.3 ).sub.2, --CONH.sub.2, --C(CH.sub.3).sub.2 (SCH.sub.3), --C(CH.sub.3).sub.2 (S(O)CH.sub.3), --C(CH.sub.3).sub.2 (S(O).sub.2 CH.sub.3), alkyl, haloalkyl, alkenyl or alkynyl radicals, or the side chain of the amino acid asparagine, S-methyl cysteine or the corresponding sulfoxide or sulfone derivatives thereof, leucine, isoleucine, allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine, histidine, norleucine, glutamine, valine, threonine, serine, aspartic acid, betacyano alanine or allothreonine;
- R.sup.1' represents hydrogen or alkyl radicals;
- R.sup.1" represents hydrogen, --CO.sub.2 CH.sub.3, --CONH.sub.2 or alkyl radicals;
- or R.sup.1' together with R.sup.1 and the carbon atoms to which they are attached represent a cycloalkyl radical;
- R.sup.2 represents alkyl, cycloalkylalkyl or aralkyl radicals, each of which is optionally substituted with --OR.sup.9, --SR.sup.9 or halogen radicals, wherein R.sup.9 represents hydrogen or alkyl radicals;
- R.sup.3 represents alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl, aralkyl or heteroaralkyl radicals;
- R.sup.4 represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or aralkyl radicals;
- R.sup.5 represents hydrogen or alkyl radicals;
- or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are bonded represent a heterocycloalkyl radical;
- and
- R.sup.6 represents hydrogen or alkyl radicals;
- and
- wherein alkyl, alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to 8 carbon atoms;
- alkenyl, alone or in combination, means a straight-chain or branched-chain hydrocarbon radial having one or more double bonds and containing from 2 to 8 carbon atoms;
- alkynyl, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing from 2 to 10 carbon atoms;
- cycloalkyl, alone or in combination, means a cyclic alkyl radical which contains from 3 to 8 carbon atoms;
- aryl, alone or in combination, means a phenyl or naphthyl radical which is optionally substituted with one or more alkyl, alkoxy, halogen, hydroxy, amino or nitro radicals;
- heterocyclyl or heterocycloalkyl, alone or in combination, means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle which contains one or more nitrogen, oxygen or sulfur heteroatoms, which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy or oxo, or on a secondary nitrogen atom by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl, or on a tertiary nitrogen atom by oxido;
- and heteroaryl, alone or in combination, means an aromatic heterocyclyl.
20 more elements
Compound represented by the formula ##STR176## or a pharmaceutically acceptable salt, prodrug or ester thereof wherein t represents O or 1;
- Y and Y' each independently represent O or S;
- R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aroyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclylalkanoyl, heteroaroyl, heteroaralkanoyl, alkyl, aralkyl, 3-carboxypropionyl, methyloxaloyl, bromoacetyl, trifluoroacetyl, methoxyacetyl, hydroxyacetyl, hydroxypropionyl, aminocarbonyl, N-alkylaminocarbonyl, N- mono- or N,N-disubstituted aminoalkanoyl radicals wherein said substituents are alkyl, aryl, aralkyl, cycloalkyl, heteroaralkyl, heterocycloalkyl, hydroxyethyl or methoxyethyl radicals, or in the case of a disubstituted aminoalkanoyl radical, said substituents along with the nitrogen atom to which they are attached form heterocyclyl or heteroaryl radicals, with the proviso that said heteroaryl radical is other than a quaternary nitrogen containing heteroaryl radical;
- R' represents hydrogen, alkyl or aralkyl radicals;
- or R and R' together with the nitrogen to which they are attached form heterocycloalkyl or heteroaryl radicals, with the proviso that said heteroaryl radical is other than a quaternary nitrogen containing heteroaryl radical;
- R.sup.1 represents hydrogen, --CF.sub.3, --CH(CF.sub.3).sub.2, --CH.sub.2 SO.sub.2 NH.sub.2, --CO.sub.2 CH.sub.3, --CONHCH.sub.3, --CON(CH.sub.3).sub.2, --CH.sub.2 C(O)NHCH.sub.3, --CH.sub.2 C(O)N(CH.sub.3).sub.2, --CONH.sub.2, --C(CH.sub.3).sub.2 (SCH.sub.3), --C(CH.sub.3).sub.2 (S(O)CH.sub.3), --C(CH.sub.3).sub.2 (S(O).sub.2 CH.sub.3), alkyl, haloalkyl, alkenyl or alkynyl radicals, or the side chain of the amino acid asparagine, S-methyl cysteine or the corresponding sulfoxide or sulfone derivatives thereof, leucine, isoleucine, allo-isoleucine, tert-leucine, phenylalanine, ornithine, alanine, norleucine, glutamine, valine, threonine, serine, aspartic acid, beta-cyano alanine or allothreonine;
- R.sup.1' represents hydrogen or alkyl radicals;
- R.sup.1" represents hydrogen, --CO.sub.2 CH.sub.3, --CONH.sub.2 or alkyl radicals;
- or R.sup.1' together with R.sup.1 and the carbon atoms to which they are attached represent a cycloalkyl radical;
- R.sup.2 represents alkyl, cycloalkylalkyl or aralkyl radicals, each of which is optionally substituted with --OR.sup.9, --SR.sup.9 or halogen radicals, wherein R.sup.9 represents hydrogen or alkyl radicals;
- R.sup.3 represents alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aralkyl or heteroaralkyl radicals, with the proviso that said radicals are attached to the nitrogen atom through an unbranched methylene radical;
- R.sup.4 represents alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, aryl or aralkyl radicals;
- R.sup.5 represents hydrogen or alkyl radicals;
- or R.sup.4 and R.sup.5 together with the nitrogen atom to which they are bonded represent a heterocycloalkyl radical;
- and
- R.sup.6 represents hydrogen or alkyl radicals;
- and
- wherein alkyl, alone or in combination, means a straight-chain or branched-chain alkyl radical containing from 1 to 8 carbon atoms;
- alkenyl, alone or in combination, means a straight-chain or branched-chain hydrocarbon radial having one or more double bonds and containing from 2 to 8 carbon atoms;
- alkynyl, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and containing from 2 to 10 carbon atoms;
- cycloalkyl, alone or in combination, means a cyclic alkyl radical which contains from 3 to 8 carbon atoms;
- aryl, alone or in combination, means a phenyl or naphthyl radical which is optionally substituted with one or more alkyl, alkoxy, halogen, hydroxy, amino or nitro radicals;
- heterocyclyl or heterocycloalkyl, alone or in combination, means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle which contains one or more nitrogen, oxygen or sulfur heteroatoms, which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy or oxo, or on a secondary nitrogen atom by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl, or on a tertiary nitrogen atom by oxido;
- and heteroaryl, alone or in combination, means an aromatic heterocyclyl.
20 more elements
Dependencies are inferred from the claim text.