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Details for Patent: 6,472,407

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Details for Patent: 6,472,407

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. (Chicago, IL)
Filing Date:Feb 22, 2000
Application Number:09/511,005
Claims:1. A pharmaceutically acceptable salt, prodrug, or ester of a retroviral protease inhibiting compound of the formula: ##STR361##

wherein: P.sup.1 represents alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylaLkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaroyl, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoalkanoyl, and mono- and disubstituted aminocarbonyl and mono- and disubstituted aminoalkanoyl radicals wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heterocycloalkyalkyl radicals, or where said aminoalkanoyl radical is disubstituted, said substituents along with the nitrogen atom to which they are attached form a heterocycloalkyl or heteroaryl radical; P.sup.2 represents hydrogen; R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radicals, --NO.sub.2, --C.ident.N, CF.sub.3, --OR.sup.9, --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; and R.sup.4 represents radicals as defined by R.sup.3 except for hydrogen.

2. Compound of claim 1 wherein P.sup.1 represents alkoxycarbonyl, aralkyloxycarbonyl, heteroaralkoxycarbonyl, aroyl, heteroaroyl, alkanoyl, cycloalkanoyl, 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; R.sup.2 represents cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, para-methoxybenzyl, is butyl, or n-butyl; R.sup.3 represents alkyl, cycloalkyl, cycloalkylalkyl, isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, or n-propyl; and R.sup.4 represents aryl, alkyl, aryl, para-substituted aryl, heteroaryl, 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.

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

4. Method of inhibiting a retroviral protease comprising administering a protease inhibiting amount of a composition of claim 3.

5. Method of claim 4 wherein the retroviral protease is HIV protease.

6. Method of treating a retroviral infection comprising administering an effective amount of a composition of claim 3.

7. Method of claim 6 wherein the retroviral infection is an HIV infection.

8. Method for treating AIDS comprising administering an effective amount of a composition of claim 3.

9. 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 alkyl, aryl or heteroaryl radicals.

10. Compound of claim 9 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.

11. 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 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.

12. Compound of claim 11 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; R.sup.4 represents phenyl optionally susbstituted with alkyl, alkoxy, halogen, hydroxy, amino, nitro, cyano, or haloalkyl; 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.

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

14. Method of inhibiting a retrovirus protease comprising administering a protease inhibiting amount of a composition of claim 13.

15. Method of claim 14 wherein the retrovirals protease is HIV protease.

16. Method of treating a retrovirus infection comprising administering an effective amount of a composition of claim 13.

17. Method of claim 16 wherein the retrovirals infection is an HIV infection.

18. Method for treating AIDS comprising administering an effective amount of a composition of claim 13.

19. 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.

20. Compound of claim 1 wherein R.sup.2 represents cycloalkylalkyl, aralkyl, alkyl, benzyl, cyclohexylmethyl, 2-naphthylmethyl, para-fluorobenzyl, para-methoxybenzyl, isobutyl, or n-butyl; R.sup.3 represents alkyl, cycloalkyl, cycloalkylalkyl, isobutyl, isoamyl, cyclohexyl, cyclohexylmethyl, n-butyl, or n-propyl; and R.sup.4 represents aryl, alkyl, aryl, para-substituted aryl, heteroaryl, 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.
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