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Claims for Patent: 5,843,946

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Claims for Patent: 5,843,946

Title: .alpha.-and .beta.-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors
Abstract:.alpha.- and .beta.-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.
Inventor(s): Vazquez; Michael L. (Gurnee, IL), Mueller; Richard A. (Glencoe, IL), Talley; John J. (St. Louis, MO), Getman; Daniel (Chesterfield, MO), DeCrescenzo; Gary A. (St. Peters, MO), Freskos; John N. (Clayton, MO)
Assignee: G.D. Searle & Co. (Skokie, IL)
Application Number:08/110,911
Patent Claims: 1. 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.

2. Compound of claim 1 wherein P.sup.1 represents alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkoxycarbonyl, aroyl, heteroaroyl, alkanoyl or cycloalkanoyl radicals;

R.sup.2 represents alkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with halogen, --OR.sup.9 or --SR.sup.9 radicals, wherein R.sup.9 represents hydrogen or alkyl radicals;

R.sup.3 represents alkyl, cycloalkyl or cycloalkylalkyl radicals; and

R.sup.4 represents represents alkyl, aryl or heteroaryl radicals.

3. Compound of claim 2 wherein P.sup.1 represents 3-pyridylmethyloxycarbonyl, 3-pyridylmethyloxycarbonyl N-oxide, 4-pyridylmethyloxycarbonyl, 4-pyridylmethyloxycarbonyl N-oxide, 5-pyrimidylmethyloxycarbonyl, tert-butyloxycarbonyl, allyloxycarbonyl, 2-propyloxycarbonyl, benzyloxycarbonyl, cycloheptylcarbonyl, cyclohexylcarbonyl, cyclopentylcarbonyl, benzoyl, 2-substituted benzoyl, 4-pyridylcarbonyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2-chlorobenzoyl, 2-ethylbenzoyl, 2,6-dimethylbenzoyl, 2,3-dimethylbenzoyl, 2,4-dimethylbenzoyl or 2,5-dimethylbenzoyl radicals;

R.sup.2 represents benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl or n-butyl radicals;

R.sup.3 represents isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl or n-propyl radicals; and

R.sup.4 represents phenyl, para-methoxyphenyl, para-cyanophenyl, para-chlorophenyl, para-hydroxyphenyl, para-nitrophenyl, para-fluorophenyl, 2-naphthyl, 3-pyridyl, 3-pyridyl N-oxide, 4-pyridyl or 4-pyridyl N-oxide radicals.

4. Compound of claim 1 wherein P.sup.1 represents heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl or heteroaroyl radicals;

R.sup.2 represents alkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with halogen, --OR.sup.9 or --SR.sup.9 radicals, wherein R.sup.9 represents hydrogen or alkyl radicals;

R.sup.3 represents alkyl, cycloalkyl or cycloalkylalkyl radicals; and

R.sup.4 represents represents alkyl, aryl or heteroaryl radicals; and

wherein heterocyclyl or heterocycloalkyl means a 5-6 ring membered heterocycle or a benzfused 5-6 ring membered heterocycle having one or two nitrogen, oxygen or sulphur 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, oxygen or sulphur heteroatoms.

5. Compound of claim 4 wherein P.sup.1 represents heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl or heteroaroyl radicals;

R.sup.2 represents benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl or n-butyl radicals;

R.sup.3 represents isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl or n-propyl radicals; and

wherein heterocyclyl or heterocycloalkyl means a 5-6 ring membered heterocycle having one or two nitrogen, oxygen or sulphur heteroatoms; and heteroaryl means an aromatic 5-6 ring membered heterocycle having one or two nitrogen, oxygen or sulphur heteroatoms.

6. 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.

7. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

8. Method of inhibiting a retrovirus protease comprising administering a protease inhibiting amount of a composition of claim 7.

9. Method of claim 8 wherein the retrovirals protease is HIV protease.

10. Method of treating a retrovirus infection comprising administering an effective amount of a composition of claim 7.

11. Method of claim 10 wherein the retrovirals infection is an HIV infection.

12. Method for treating AIDS comprising administering an effective amount of a composition of claim 7.

13. The compound of claim 1 wherein said heterocyclyl, 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, .beta.-carbolinyl, 2-benzofurancarbonyl, and benzimidazolyls radicals.

14. Compound of claim 1 wherein said heterocyclyl or hetercycloalkyl is a 5-6 ring membered heterocycle or a benzfused 5-6 ring membered heterocycle having one or two nitrogen, oxygen or sulfur 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, oxygen or sulfur heteroatoms.
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