US 5,843,946 AGranted

.alpha.-and .beta.-amino acid hydroxyethylamino 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

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Abstract

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

Claims14

Dependent claims

A compound represented by the formula:

##STR360## wherein P.sup.1 represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl or heteroaroyl radicals;
P.sup.2 represents hydrogen;
R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with alkyl, halogen, --NO.sub.2, --CN, CF.sub.3, --OR.sup.9 or --SR.sup.9 radicals, wherein R.sup.9 represents hydrogen or alkyl radicals;
R.sup.3 represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, aryl, aralkyl or heteroaralkyl radicals;
and
R.sup.4 represents represents alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl or aralkyl radicals;
and
wherein alkyl, alone or in combination, is a straight-chain or branched-chain hydrocarbon radical having 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 from 2 to 8 carbon atoms;
alkynyl, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and from 2 to 10 carbon atoms;
cycloalkyl, alone or in combination, is a hydrocarbon ring containing from 3 to 8 carbon atoms;
aryl, alone or in combination, means a phenyl or naphthyl radical optionally substituted with alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano or haloalkyl radicals;
heterocyclyl or heterocycloalkyl means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having one or more nitrogen, oxygen or sulphur heteroatoms, which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy or oxo radicals, or on a secondary nitrogen atom by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl radicals, or on a tertiary nitrogen atom by oxido radical;
and heteroaryl means an aromatic heterocyclyl radical which is optionally substituted as defined above with respect to the definition of heterocyclyl.

11 more elements

A compound selected from

Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(phenylsulfonyl)amino!-1S-(phenylmethyl)pro pyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-methoxyphenylsulfonyl)amino!-1S-(phenylm ethyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-fluorophenylsulfonyl)amino!-1S-(phenylme thyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-nitrophenylsulfonyl)amino!-1S-(phenylmet hyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-chlorophenylsulfonyl)amino!-1S-(phenylme thyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-acetamidophenylsulfonyl)amino!-1S-(pheny lmethyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-aminophenylsulfonyl)amino!-1S-(phenylmet hyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(3-methylbutyl)(4-methoxyphenylsulfonyl)amino!-1S-(phenylme thyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(3-methylbutyl)(4-fluorophenylsulfonyl)amino!-1S-(phenylmet hyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(3-methylbutyl)(4-nitrophenylsulfonyl)amino!-1S-(phenylmeth yl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(3-methylbutyl)(4-chlorophenylsulfonyl)amino!-1S-(phenylmet hyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-methoxyphenylsulfonyl)amino!-1S-(4-fluor ophenylmethyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(2-methylpropyl)(4-fluorophenylsulfonyl)amino!-1S-(4-fluoro phenylmethyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(butyl)(phenylsulfonyl)amino!-1S-(phenylmethyl)propyl!carba mate;
Phenylmethyl 2R-hydroxy-3-(cyclohexylmethyl) (phenylsulfonyl)amino!-1S-(phenylmethyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(cyclohexyl)(phenylsulfonyl) amino!-1S-(phenylmethyl)propyl!carbamate;
Phenylmethyl 2R-hydroxy-3-(propyl)(phenylsulfonyl)amino!-1S-(phenylmethyl)propyl!carb amate;
2S-(dimethylamino)acetyl!amino!-N-2R-hydroxy-3-(3-methylpropyl)(4-methox yphenylsulfonyl)amino!-1S-(phenylmethyl)propyl!-3S-methylpentanamide;
2S-(methylamino)acetyl!amino!-N-2R-hydroxy-3-(4-methylbutyl)(phenylsulfo nyl)amino!-1S-(phenylmethyl)propyl!-3S-methylpentanamide;
2S-(dimethylamino)acetyl!amino!-N-2R-hydroxy-3-(4-methylbutyl)(phenylsul fonyl)amino!-1S-(phenylmethyl)propyl!-3S-methylpentanamide;
N-2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl) amino!-1S-(phenylmethyl)propyl!-4-pyridinecarboxamide;
N-2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl) amino!-1S-(phenylmethyl)propyl!-2,6-dimethylbenzamide;
N-2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl) amino!-1S-(phenylmethyl)propyl!-2-methylbenzamide;
N-2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl) amino!-1S-(phenylmethyl)propyl!-2-ethylbenzamide;
N-2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl) amino!-1S-(phenylmethyl)propyl!-2-chlorobenzamide;
2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenyl methyl)propyl!carbamic acid, 3-pyridylmethyl ester;
2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenyl methyl)propyl!carbamic acid, 3-pyridylmethyl ester, N-oxide;
2R-hydroxy-3-phenylsulfonyl!(2-methylpropyl)amino!-1S-(phenylmethyl)prop yl!carbamic acid, 3-pyridylmethyl ester;
2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenyl methyl)propyl!carbamic acid, 4-pyridylmethyl ester;
2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenyl methyl)propyl!carbamic acid, 4-pyridylmethyl ester, N-oxide;
2R-hydroxy-3-(4-chlorophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylm ethyl)propyl!carbamic acid, 3-pyridylmethyl ester;
2R-hydroxy-3-(4-nitrophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylme thyl)propyl!carbamic acid, 3-pyridylmethyl ester;
2R-hydroxy-3-(4-fluorophenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenylm ethyl)propyl!carbamic acid, 3-pyridylmethyl ester;
2R-hydroxy-3-(4-hydroxyphenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenyl methyl)propyl!carbamic acid, 3-pyridylmethyl ester;
or
2R-hydroxy-3-(4-methoxyphenyl)sulfonyl!(2-methylpropyl)amino!-1S-(phenyl methyl)propyl!carbamic acid, 5-pyrimidylmethyl ester.

33 more elements

Dependencies are inferred from the claim text.

Facts

Application: 08/110,911Filed 24 Aug 1993 · continuation in part
Priority: 25 Aug 1992
Granted: 1 Dec 1998
Term ends: Not estimatedThe source records don’t support an estimate.

Classification54 codes

C07C 311/05
Having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms: to acyclic carbon atoms of hydrocarbon…
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 31/14
Antivirals: for RNA viruses
A61P 31/18
For RNA viruses: for HIV

Family

Serial934,984Parent of this continuation-in-part · filed 25 Aug 1992
US 5,843,946 AThis patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

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

A compound represented by the formula:

##STR360## wherein P.sup.1 represents alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl or heteroaroyl radicals;
P.sup.2 represents hydrogen;
R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with alkyl, halogen, --NO.sub.2, --CN, CF.sub.3, --OR.sup.9 or --SR.sup.9 radicals, wherein R.sup.9 represents hydrogen or alkyl radicals;
R.sup.3 represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, aryl, aralkyl or heteroaralkyl radicals;
and
R.sup.4 represents represents alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl or aralkyl radicals;
and
wherein alkyl, alone or in combination, is a straight-chain or branched-chain hydrocarbon radical having 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 from 2 to 8 carbon atoms;
alkynyl, alone or in combination, means a straight-chain hydrocarbon radical having one or more triple bonds and from 2 to 10 carbon atoms;
cycloalkyl, alone or in combination, is a hydrocarbon ring containing from 3 to 8 carbon atoms;
aryl, alone or in combination, means a phenyl or naphthyl radical optionally substituted with alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano or haloalkyl radicals;
heterocyclyl or heterocycloalkyl means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having one or more nitrogen, oxygen or sulphur heteroatoms, which is optionally substituted on one or more carbon atoms by halogen, alkyl, alkoxy or oxo radicals, or on a secondary nitrogen atom by alkyl, aralkoxycarbonyl, alkanoyl, phenyl or phenylalkyl radicals, or on a tertiary nitrogen atom by oxido radical;
and heteroaryl means an aromatic heterocyclyl radical which is optionally substituted as defined above with respect to the definition of heterocyclyl.

11 more elements

Facts

Application

08/110,911Filed 24 Aug 1993 · continuation in part

Priority

25 Aug 1992

Granted

1 Dec 1998

Term ends

Not estimatedThe source records don’t support an estimate.

Classification54 codes

C07C 311/05
Having the nitrogen atoms of the sulfonamide groups bound to hydrogen atoms or to acyclic carbon atoms: to acyclic carbon atoms of hydrocarbon…
A61P 31/12
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics: antivirals
A61P 31/14
Antivirals: for RNA viruses
A61P 31/18
For RNA viruses: for HIV