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Details for Patent: 5,786,483

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Details for Patent: 5,786,483

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) Monsanto Company (St. Louis, MO)
Filing Date:Jun 07, 1995
Application Number:08/487,662
Claims:1. A compound represented by the formula: ##STR359## or a pharmaceutically acceptable salt, prodrug or ester thereof 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, alkynyl, 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 wherein said aminocarbonyl and aminoalkanoyl radicals are 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"SO.sub.2 -- wherein R" represents 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, allo-threonine, serine, O-alkyl 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 radicals, --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 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;

R.sup.4 represents radicals as defined by R.sup.3 except for hydrogen;

R.sup.6 represents hydrogen and alkyl radicals;

x represents 0, 1, or 2;

t represents either 0 or 1; and

Y represents O, S and NR.sup.15 wherein R.sup.15 represents hydrogen and radicals as defined for R.sup.3.

2. Compound of claim 1 wherein R.sup.1 ' and R.sup.1 " are both hydrogen and R.sup.1 represents an alkyl radical having from 1 to about 4 carbon atoms.

3. Compound of claim 1 where R.sup.1 is a methyl radical.

4. Compound of claim 3 where R represents an alkanoyl, arylalkanoyl, aryloxyalkanoyl or arylalkyloxylcarbonyl radical.

5. Compound of claim 3 where R represents a phenoxyacetyl, 2-naphthyloxyacetyl, benzyloxycarbonyl or p-methoxybenzyloxycarbonyl radical.

6. Compound of claim 3 wherein R represents an N,N-dialkylaminocarbonyl radical.

7. Compound of claim 3 wherein R represents an aminocarbonyl or an alkylaminocarbonyl radical.

8. Compound of claim 3 where R represents an N-methylaminocarbonyl radical.

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

10. Method of inhibiting a retroviral protease comprising administering a protease inhibiting amount of a composition of claim 9.

11. Method of claim 10 wherein the retroviral protease is HIV protease.

12. Method of treating a retroviral infection comprising administering an effective amount of a composition of claim 9.

13. Method of claim 12 wherein the retroviral infection is an HIV infection.

14. Method for treating AIDS comprising administering an effective amount of a composition of claim 9.

15. A compound of claim 1 wherein R.sup.1 ' and R.sup.1 " are both hydrogen and R.sup.1 represents --CH.sub.2 SO.sub.2 NH.sub.2, [CO.sub.2 NH.sub.2 ], CONH.sub.2, CO.sub.2 CH.sub.3, alkyl and cycloalkyl radicals and amino acid side chains selected from asparagine, s-methyl cysteine and the sulfone and sulfoxide derivatives thereof, histidine, norleucine, glutamine, glycine, allo-isoleucine, alanine, threonine, isoleucine, leucine, tert-leucine, phenylalanine, ornithine, allo-threonine, serine, aspartic acid, beta-cyano alanine and valine side chains.

16. A compound of claim 1 which is:

Phenylmethyl[2R-hydroxy-3-[(3-methyl-butyl)(methylsulfonyl)amino]-1S-(pheny lmethyl)propyl]carbamate;

Phenylmethyl[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-1S-(pheny lmethyl)propyl]carbamate;

N1-[2R-hydroxy-3-[(3-methylbutyl)(methyl-sulfonyl)amino]-1S-(phenylmethyl)p ropyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide;

N1-[2R-hydroxy-3-[(3-methylbutyl)(methylsulfonyl)amino]-1S-(phenylmethyl)pr opyl]-2S-[(phenylmethylooxcarbonyl)-amino]butanediamide;

N1-[2R-hydroxy-3[(3-methylbutyl)(phenylsulfonyl)amino]1S-(phenylmethyl)prop yl]2S-[(2-quinolinylcarbonyl)amino]butanediamide;

N1-[2R-hydroxy-3[(3-methylbutyl)(phenylsulfonyl)-amino]-1S-(phenylmethyl)pr opyl]-2S-[(phenylmethyloxycarbonyl)amino]butanediamide;

2S-[[dimethylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsu lfonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide;

2S-[[(methylamino)acetyl]amino]-N-[2R-hydroxy-3-[(3-methyl-butyl)(phenylsul fonyl)amino]-1S-(phenylmethyl)propyl]-3,3-dimethylbutaneamide;

N1-[2R-hydroxy-3-[(3-methylbutyl)(phenyl-sulfonyl)amino]-N4-methyl-1S-(phen ylmethyl)propyl]-2S-[(2-quinolinylcarbonyl)amino]butanediamide; or

[3-[[2-hydroxy-3-[(3-methylbutyl)(phenylsufonyl)amino]-1-(phenylmethyl)prop yl]amino]2-methyl-3-oxopropyl]-,(4-methoxyphenyl)methyl ester, [1S-[1R*(S*),2S*]].

17. A compound of claim 1 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

18. A compound of claim 2 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

19. A compound of claim 3 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

20. A compound of claim 4 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

21. A compound of claim 5 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

22. A compound of claim 6 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

23. A compound of claim 7 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

24. A compound of claim 8 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.

25. A compound of claim 9 wherein the R.sup.2 substituent of the compound has an (S) absolute stereochemical configuration and the adjacent hydroxyl group of the compound has an (R) absolute stereochemical configuration.

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

27. Method for treating AIDS comprising administering a protease inhibiting amount of a composition of claim 25.

28. A compound of claim 15 wherein the R.sup.2 substituent has an (S) absolute stereochemical configuration and the adjacent hydroxyl group has an (R) absolute stereochemical configuration.
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