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Details for Patent: 6,534,493

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Details for Patent: 6,534,493

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 (Chicago, IL)
Filing Date:Oct 24, 2000
Application Number:09/694,785
Claims:1. Compound represented by the formula: ##STR370##

wherein: R represents hydrogen, 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, or mono- or disubstituted aminocarbonyl or mono- or disubstituted aminoalkanoyl radicals, wherein the substituents are selected from alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, and heterocycloalkylalkyl 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; R' represents hydrogen or radicals as defined for R.sup.3 or R and R' together with the nitrogen to which they are attached represent heterocycloalkyl or heteroaryl radical; 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 (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 or cycloalkyl radicals, or 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, omithine, histidine, norleucine, glutamine, threonine, glycine, allo-threonine, serine, O-methyl serine, asparatic acid, beta-cyano alanine and valine side chains; R.sup.2 represents (i) alkyl, (ii) aryl, (iii) cycloalkyl, (iv) cycloalkylalkyl or (v) aralkyl radicals, which radicals (i)-(v) are optionally substituted with a group selected from alkyl and halogen radicals, --NO.sub.2, --C.ident.N, CF.sub.3, --OR.sup.9, and --SR.sup.9, wherein R.sup.9 represents hydrogen or alkyl radicals, or (vi) halogen radicals; R.sup.3 represents alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, aminoalkyl or mono- or 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.

2. Compound of claim 1 wherein R.sup.1 represents alkyl, alkynyl or alkenyl radicals, or amino acid side chains selected from the group consisting of asparagine, valine, threonine, allo-threonine, isoleucine, S-methyl cysteine and the sulfone and sulfoxide derivatives thereof, alanine, and allo-isoleucine.

3. Compound of claim 1 wherein R.sup.1 represents methyl, propargyl, t-butyl, isopropyl or sec-butyl radicals, or amino acid side chains selected from the group consisting of asparagine, valine, S-methyl cysteine, allo-iso-leucine, iso-leucine, threonine, serine, asparatic acid, beta-cyano alanine, and allo-threonine side chains.

4. Compound of claim 1 wherein R.sup.1 represents propargyl or t-butyl radicals.

5. Compound of claim 1 wherein R.sup.1 represents a t-butyl radical.

6. Compound of claim 1 wherein R.sup.1 represents a t-butyl radical.

7. Compound of claim 1 wherein R.sup.2 represents alkyl, cycloalkylalkyl or aralkyl radicals, which radicals are optionally substituted with halogen radicals or radicals represented by the formula --OR.sup.9 or --SR.sup.9 wherein R.sup.9 represents hydrogen or alkyl radicals.

8. Compound of claim 1 wherein R.sup.2 represents alkyl, cycloalkylalkyl or aralkyl radicals.

9. Compound of claim 1 wherein R.sup.2 represents aralkyl radicals.

10. Compound of claim 1 wherein R.sup.2 represents CH.sub.3 SCH.sub.2 CH.sub.2 --, iso-butyl, n-butyl, benzyl, 4-fluorobenzyl, 2-naphthylmethyl or cyclohexylmethyl radicals.

11. Compound of claim 1 wherein R.sup.2 represents benzyl, 4-fluorobenzyl, or 2-naphthylmethyl radicals.

12. Compound of claim 1 wherein R.sup.3 and R.sup.4 independently represent alkyl haloalkyl, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, aralkyl or heteroaralkyl radicals.

13. Compound of claim 12 wherein R.sup.4 represents phenyl.

14. Compound of claim 12 wherein R.sup.3 and R.sup.4 independently represent alkyl, aryl or aralkyl radicals.

15. Compound of claim 12 wherein R.sup.4 represents phenyl or substituted phenyl radicals.

16. Compound of claim 1 wherein R.sup.3 represents alkyl radicals having from about 2 to about 5 carbon atoms.

17. Compound of claim 1 wherein R.sup.3 represent n-pentyl, n-hexyl, n-propyl, i-butyl, cyclohexyl, neo-pentyl, i-amyl, or n-butyl radicals.

18. Compound of claim 1 wherein R.sup.3 represent isobutyl, n-propyl, n-butyl, isoamyl, cyclohexyl, or cyclohexylmethyl radicals and R.sup.4 is phenyl or substituted phenyl radicals.

19. Compound of claim 1 wherein R.sup.3 is i-amyl or i-butyl and R.sup.4 is phenyl or substituted phenyl selected from para-chlorophenyl, para-fluorophenyl, para-nitrophenyl, para-aminophenyl, and para-methoxyphenyl.

20. Compound of claim 1 wherein R.sup.4 represents aryl radicals.

21. Compound of claim 1 where R.sup.1 represents a t-butyl or a propargyl radical or an amino acid side chain of valine or isoleucine.

22. Compound of claim 21 where R represents an arylalkanoyl, aryloxycarbonyl, alkanoyl, aminocarbonyl, mono-substituted aminoalkanoyl, or disubstituted aminoalkanoyl, or mono- or dialkylaminocarbonyl radical.

23. Compound of claim 21 where R represents an aminocarbonyl radical, a monosubstituted aminoalkanoyl radical or disubstituted aminoalkanoyl radical.

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

25. Method of inhibiting a retroviral protease comprising administering a protease inhibiting amount of a composition of claim 24.

26. Method of claim 25 wherein the retroviral protease is HIV protease.

27. Method of treating a retroviral infection comprising administering an effective amount of a composition of claim 24.

28. Method of claim 27 wherein the retroviral infection is an HIV infection.

29. Method for treating AIDS comprising administering an effective amount of a composition of claim 24.
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