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Details for Patent: 5,744,481

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Details for Patent: 5,744,481

Title: .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. (St. Louis, MO)
Filing Date:Apr 25, 1997
Application Number:08/845,392
Claims:1. Compound represented by the formula: ##STR360## wherein: R represents hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxycarbonylalkyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylalkanoyl, heterocyclylalkoxycarbonyl, heteroaralkanoyl, heteroaralkoxycarbonyl, heteroaryloxy-carbonyl, 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;

R' represents hydrogen and radicals as defined for R.sup.3 or R and R' together with the nitrogen to which they are attached represent heterocycloalkyl and 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 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, allothreonine, serine, aspartic acid, beta-cyano alanine and valine side chains;

R.sup.1 ' and R.sup.1 " independently represent hydrogen and radicals as defined for R.sup.1, or one of R.sup.1 ' and R.sup.1 ", together with R.sup.1 and the carbon atoms to which R.sup.1, R.sup.1 ' and R.sup.1 " are attached, represent a cycloalkyl radical;

R.sup.2 represents alkyl, aryl, cycloalkyl, cycloalkylalkyl and aralkyl radicals, which radicals are optionally substituted with a group selected from alkyl and halogen radials, --NO.sub.2, --C.tbd.N, CF.sub.3, --OR.sup.9, --SR.sup.9, wherein R.sup.9 represents hydrogen and alkyl radicals;

R.sup.3 represents 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.

2. Compound of claim 1 wherein R' represents hydrogen and R represents aralkoxycarbonyl and heteroaroyl radicals.

3. Compound of claim 1 wherein R' is hydrogen and R represents carbobenzoxy, 2-benzofurancarbonyl, and 2-quinolinylcarbonyl radicals.

4. Compound of claim 1 wherein R' is hydrogen and R is 2-quinolinylcarbonyl.

5. Compound of claim 1 wherein R.sup.1, R.sup.1 ' and R.sup.1 " independently represent hydrogen and alkyl radicals having from 1 to about 4 carbon atoms, alkenyl, alkynyl, aralkyl radicals and radicals selected from --CH.sub.2 SO.sub.2 NH.sub.2, --CO.sub.2 CH.sub.3, --CONCH.sub.3, --CON(CH.sub.3).sub.2, --CH.sub.2 C(O)NHCH.sub.3, --CH.sub.2 C(O)N(CH.sub.3).sub.2, --CONH.sub.2, --C(CH.sub.3).sub.2 (SCH.sub.3), --C(CH.sub.3).sub.2 (S[O]CH.sub.3) and --C(CH.sub.3).sub.2 (S[O]CH.sub.3).

6. Compound of claim 1 wherein R.sup.1, R.sup.1 ' and R.sup.1 " independently represent hydrogen, methyl, ethyl, benzyl, phenylpropyl, propargyl, hydroxyl and radicals selected from --C(O)OCH.sub.3, --C(O)NH.sub.2, --C(O)OH.

7. Compound of claim 1 wherein R.sup.1 and R.sup.1 ' are both hydrogen and R.sup.1 " is C(O)NH.sub.2.

8. Compound of claim 1 wherein R represents aralkoxycarbonyl and heteroaroyl radicals.

9. Compound of claim 1 wherein R.sup.1 and R.sup.1 ' are both hydrogen and R.sup.1 " is methyl.

10. Compound of claim 1 wherein R.sup.1 ' is hydrogen and R.sup.1 and R.sup.1 " together with the carbon atoms to which they are attached form a three to six-membered cycloalkyl radical.

11. Compound of claim 7 wherein R is carbobenzoxy, 2-quinolinylcarbonyl and 2-benzofuran carbonyl radicals.

12. Compound of claim 1 wherein R.sup.1 and R.sup.1 ' are both hydrogen and R.sup.1 " is propargyl.

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

14. Compound of claim 1 wherein R.sup.2 represents alkyl, cycloalkylalkyl and aralkyl radicals.

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

16. Compound of claim 1 wherein R.sup.2 represents CH.sub.3 SCH.sub.2 CH.sub.2 -, iso-butyl, n-butyl, benzyl, 2-naphthylmethyl and cyclohexylmethyl radicals.

17. Compound of claim 1 wherein R.sup.2 represents an n-butyl and iso-butyl radicals.

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

19. Compound of claim 1 wherein R.sup.2 represents a cyclohexylmethyl radical.

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

21. Compound of claim 1 wherein R.sup.3 represents alkyl and alkenyl radicals and R.sup.4 represents aryl radicals.

22. Compound of claim 20 wherein R.sup.3 and R.sup.4 independently represent alkyl and alkenyl radicals.

23. Compound of claim 1 wherein R.sup.3 and R.sup.4 independently represent alkyl and alkoxyalkyl radicals.

24. Compound of claim 1 wherein R.sup.3 and R.sup.4 independently represent alkyl, cycloalkyl and cycloalkylalkyl radicals.

25. Compound of claim 1 wherein R.sup.3 and R.sup.4 independently represent alkyl, heterocycloalkyl and heterocycloalkylalkyl radicals.

26. Compound of claim 1 wherein R.sup.3 and R.sup.4 independently represent alkyl, aryl and aralkyl radicals.

27. Compound of claim 1 wherein R.sup.3 and R.sup.4 independently represent alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, aryl, aralkyl, and heteroaralkyl radicals.

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

29. Compound of claim 1 wherein R.sup.3 independently represent n-propyl, i-butyl, cyclohexyl, cyclohexylmethyl, i-amyl, and n-butyl radicals and R.sup.4 represents phenyl and substituted phenyl radicals.

30. Compound of claim 1 wherein R.sup.3 and R.sup.4 independently represent alkyl radicals having from about 2 to about 5 carbon atoms, cycloalkylalkyl radicals, aryl radicals, heteroaryl radicals, aralkyl radicals, heterocycloalkylalkyl radicals and heteroaralkyl radicals.

31. Compound of claim 1 wherein R.sup.3 represents benzyl, para-fluorobenzyl, para-methoxybenzyl, para-methylbenzyl, and 2-naphthylmethyl radicals and R.sup.4 represents phenyl and substituted phenyl radicals wherein substituents of the substituted phenyl radical are selected from chloro fluoro, nitro, methoxy and amino substituents.

32. Compound of claim 1 wherein R.sup.3 is cyclohexylmethyl and R.sup.4 is phenyl or substituted phenyl selected from para-chlorophenyl, para-fluorophenyl, para-nitrophenyl, p-methoxyphenyl and para-aminophenyl.

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

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

35. Compound of claim 1 wherein R.sup.3 is benzyl or p-fluorobenzyl and R.sup.4 is phenyl or substituted phenyl selected from para-chlorophenyl, para-fluorophenyl, para-nitrophenyl, p-methoxyphenyl and para-aminophenyl.

36. Compound of claim 1 wherein R.sup.3 is cyclohexyl and R.sup.4 is phenyl or substituted phenyl selected from para-chlorophenyl, para-fluorophenyl, para-nitrophenyl, p-methoxyphenyl and para-aminophenyl.

37. Compound of claim 1 wherein R.sup.4 represents alkyl and aryl radicals.

38. Compound of claim 1 wherein R.sup.4 represents phenyl, para-chlorophenyl, para-fluorophenyl, para-nitrophenyl, p-methoxyphenyl and para-aminophenyl.

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

40. Compound of claim 1 wherein R.sup.3 represents heteroaralkyl radicals and R.sup.4 is aryl.

41. Compound of claim 1 wherein R.sup.3 is a p-fluorobenzyl radical and R.sup.4 is phenyl or substituted phenyl selected from para-chlorophenyl, para-fluorophenyl, para-nitrophenyl, p-methoxyphenyl and para-aminophenyl.

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

43. Method of inhibiting a retroviral protease comprising administering a protease inhibiting amount of a composition of claim 42.

44. Method of claim 43 wherein the retroviral protease is HIV protease.

45. Method of treating a retroviral infection comprising administering an effective amount of a composition of claim 42.

46. Method of claim 45 wherein the retroviral infection is an HIV infection.

47. Method for treating AIDS comprising administering an effective amount of a composition of claim 42.
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