Back to results
US 5,965,588 AGranted
Sulfonylalkanoylamino hydroxyethylamimo sulfonamides useful as retroviral protease inhibitors
AssigneeG.D. Searle & Co.
InventorsMichael L. Vazquez, Richard A. Mueller, John J. Talley, Daniel Getman, Gary A. DeCrescenzo, John N. Freskos
Life of this patent
Estimating the term…
Abstract
Sulfonamide-containing hydroxyethylamine compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Claims20
A compound represented by the formula:
- ##STR96## or a pharmaceutically acceptable salt, prodrug, or ester thereof, wherein:
- R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aminocarbonylalkyl, aminoalkylcarbonylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, aryloxyalkylcarbonylalkyl, and aralkoxycarbonylalkyl radicals;
- R.sup.1 represents hydrogen, --CH.sub.2 SO.sub.2 NH.sub.2, --CH.sub.2 CO.sub.2 CH.sub.3, --CO.sub.2 CH.sub.3, --CONH.sub.2, --CH.sub.2 C(O)NHCH.sub.3, --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 (SH), --C(CH.sub.3).sub.2 (S[O].sub.2 CH.sub.3), alkyl, haloalkyl, alkenyl, alkynyl, and cycloalkyl radicals, and amino acid side chains selected from asparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone (SO.sub.2) derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, O-methyl serine, aspartic acid, beta-cyano alanine, and valine side chains;
- R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl radicals, which radicals are optionally substituted with a group selected from halogen and alkyl radicals, NO.sub.2, --C.quadbond.N, CF.sub.3, OR.sup.9 and SR.sup.9 wherein R.sup.9 represents hydrogen and alkyl radicals;
- and
- R.sup.3 and R.sup.4 independently represent alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl, and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical;
- with the proviso that at least one of R.sup.3 and R.sup.4 represents cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical.
4 more elements
A compound represented by the formula:
- ##STR97## or a pharmaceutically acceptable salt, prodrug, or ester thereof, wherein:
- R represents alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aminocarbonylalkyl, aminoalkylcarbonylalkyl, hydroxyalkyl, alkoxyalkyl, alkylcarbonylalkyl, aryloxyalkylcarbonylalkyl, and aralkoxycarbonylalkyl radicals;
- R.sup.1 represents hydrogen, --CH.sub.2 SO.sub.2 NH.sub.2, --CH.sub.2 CO.sub.2 CH.sub.3, --C.sub.0.sub.2 CH.sub.3, --CONH.sub.2, --CH.sub.2 C(O)NHCH.sub.3, --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 (SH), --C(CH.sub.3).sub.2 (S[O].sub.2 CH.sub.3), alkyl, haloalkyl, alkenyl, alkynyl, and cycloalkyl radicals, and amino acid side chains selected from asparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone (SO.sub.2) derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, O-methyl serine, aspartic acid, beta-cyano alanine, and valine side chains;
- R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl radicals, which radicals are optionally substituted with a group selected from halogen and alkyl radicals, NO.sub.2, --C.quadbond.N, CF.sub.3, OR.sup.9 and SR.sup.9 wherein R.sup.9 represents hydrogen and alkyl radicals;
- and
- R.sup.3 and R.sup.4 independently represent alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl, and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical;
- with the proviso that at least one of R.sup.3 and R.sup.4 represents cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical.
4 more elements
A compound represented by the formula:
- ##STR98## or a pharmaceutically acceptable salt, prodrug, or ester thereof, wherein:
- R represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, aminocarbonylalkyl, aminoalkylcarbonylalkyl, aminoalkyl, alkylcarbonylalkyl, aryloxyalkylcarbonyl-alkyl, aralkoxycarbonylalkyl radicals;
- and mono- and disubstituted aminocarbonylalkyl, aminoalkylcarbonylalkyl, and aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical;
- each x independently represents 0, 1, or 2;
- t represents either 0 or 1;
- R.sup.1, R.sup.20, and R.sup.21 independently represent hydrogen, --CH.sub.2 SO.sub.2 NH.sub.2, --CH.sub.2 CO.sub.2 CH.sub.3, --CO.sub.2 CH.sub.3, --CONH.sub.2, --CH.sub.2 C(O)NHCH.sub.3, --C(CH.sub.3).sub.2 (SH), --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, alkynyl, and cycloalkyl radicals, and amino acid side chains selected from asparagine, S-methyl cysteine and the sulfoxide (SO) and sulfone (SO.sub.2) derivatives thereof, isoleucine, allo-isoleucine, alanine, leucine, tert-leucine, phenylalanine, ornithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, O-alkyl serine, aspartic acid, beta-cyano alanine, and valine side chains;
- R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, and aralkyl radicals, which radicals are optionally substituted with a group selected from halogen and alkyl radicals, NO.sub.2, --C.quadbond.N, CF.sub.3, --OR.sup.9 and --SR.sup.9 wherein R.sup.9 represents hydrogen and alkyl radicals;
- R.sup.3 represents hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl, and mono- and disubstituted aminoalkyl radicals, wherein said substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl radicals, or in the case of a disubstituted aminoalkyl radical, said substituents along with the nitrogen atom to which they are attached, form a heterocycloalkyl or a heteroaryl radical;
- Y represents O, S, and NR.sup.15 wherein R.sup.15 represents hydrogen and radicals as defined for R.sup.3 ;
- R.sup.4 represents radicals as defined for R.sup.3 except for hydrogen;
- and
- R.sup.6 represents hydrogen and alkyl radicals.
9 more elements
Dependencies are inferred from the claim text.