Thiomethylene group-containing aldehyde cysteine and serine protease inhibitors

• US 5,744,339 A
• Filed: 08/30/1996
• Issued: 04/28/1998
• Est. Priority Date: 08/30/1996
• Status: Expired due to Term

• Current Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Cephalon Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Chatterjee, Sankar
• Primary Examiner(s): Witz, Jean C.
• Assistant Examiner(s): HANLEY, SUSAN MARIE
• Application Number:
  US08/706,184
• Time in Patent Office: 606 Days
• Field of Search: 435/219, 435/184, 435/212, 564/162, 514/618
• US Class Current: 435/184
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/60 with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms

Abstract

The present invention is directed to thiomethylene group-containing aldehyde inhibitors of cysteine or serine proteases. Methods for the use of the protease inhibitors are also described.

Claims

1. A compound of the structure:

##STR13## wherein;

Q is aryl having from 6 to 14 carbons, heteroaryl having from 6 to 14 ring atoms, aralkyl having from 7 to 15 carbons, heteroalkyl having from 2 to 7 carbons, or arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring;

m is 0, 1, or 2;

R¹ and R² are independently H, alkyl having from 1 to 14 carbons, cycloalkyl having 3 to 10 carbons, or a natural or unnatural side chain of an L-amino acid, said alkyl and cycloalkyl groups being optionally substituted with one or more J groups; and

J is halogen, lower alkyl, aryl, heteroaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, alkoxy, hydroxy, or carboxy.

2. The compound of claim 1 wherein R¹ is selected from the group consisting of isobutyl, benzyl, and ethyl.

3. The compound of claim 2 wherein R² is isobutyl.

4. The compound of claim 3 wherein R² is isobutyl.

5. The compound of claim 1 wherein Q is aryl.

6. The compound of claim 2 wherein Q is aryl.

7. The compound of claim 6 wherein Q is 2-naphthyl.

8. The compound of claim 1 wherein m is 0.

9. The compound of claim 1 wherein m is 1.

10. The compound of claim 4 wherein m is 2.

11. The compound of claim 7 wherein m is 0.

12. The compound of claim 7 wherein m is 1.

13. The compound of claim 7 wherein m is 2.

14. The compound of claim 13 wherein R¹ and R² are each isobutyl.

15. A composition for inhibiting a serine protease or a cysteine protease comprising a compound of the structure:

##STR14## wherein;

Q is aryl having from 6 to 14 carbons, heteroaryl having from 6 to 14 ring atoms, aralkyl having from 7 to 15 carbons, heteroalkyl having from 2 to 7 carbons, or arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring;

m is 0, 1, or 2;

R¹ and R² are independently H, alkyl having from 1 to 14 carbons, cycloalkyl having 3 to 10 carbons, or a natural or unnatural side chain of an L-amino acid, said alkyl and cycloalkyl groups being optionally substituted with one or more J groups; and

J is halogen, lower alkyl, aryl, heteroaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, alkoxy, hydroxy, or carboxy.

16. A method for inhibiting serine proteases or cysteine proteases comprising contacting a protease selected from the group consisting of serine proteases and cysteine proteases with an inhibitory amount of a compound of the structure:

##STR15## wherein;

Q is aryl having from 6 to 14 carbons, heteroaryl having from 6 to 14 ring atoms, aralkyl having from 7 to 15 carbons, heteroalkyl having from 2 to 7 carbons, or arylheteroalkyl wherein the aryl portion can be unfused or fused with the heteroalkyl ring;

m is of 1, or 2;

R¹ and R² are independently H, alkyl having from 1 to 14 carbons, cycloalkyl having 3 to 10 carbons, or a natural or unnatural side chain of an L-amino acid, said alkyl and cycloalkyl groups being optionally substituted with one or more J groups; and

J is halogen, lower alkyl, aryl, heteroaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, alkoxy, hydroxy, or carboxy.