Inhibitors of trypsin-like enzymes

• US 6,114,308 A
• Filed: 05/14/1998
• Issued: 09/05/2000
• Est. Priority Date: 04/28/1988
• Status: Expired due to Fees

• Current Assignee: Thrombosis Research Institute
• Original Assignee: Trigen Limited
• Inventors: Phillip, Manfred Hans Wilhelm, Claeson, Goran
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US09/079,243
• Time in Patent Office: 845 Days
• Field of Search: 514/15-19, 530/330, 530/331
• US Class Current: 514/13.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: C07K 5/0827 containing heteroatoms different from O, S, or N
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Pharmaceutical compositions comprising compounds of the formula: ##STR1## in which X═H or is an N-protecting group; Y is 1-10 α-amino acids; Q1 and Q2 taken together represent the residue of a diol; R is C_1-4, alkyl; and the asymmetric carbon atom marked * may have the D- or L-configuration, are useful in therapeutic methods of inhibiting thrombin.

Claims

1. A compound having thrombin inhibiting activity and produced by the process of reacting a compound of the formula:

##STR19## wherein X represents H or an N-protecting group, Y represents a sequence of 2-10 α

-amino acids wherein D-Phe-Pro is attached to --NH, and

Q₁ and Q₂ are --OH, or Q₁ and Q₂ taken together represent a residue of a diol,

with methanol at temperatures of from 0-50°

C. in the presence of guanidine.

2. The compound of claim 1 wherein Q₁ and Q₂ taken together represent a residue of an aliphatic compound having hydroxy groups that are substituted on carbon atoms substituted by another carbon.

3. The compound of claim 2 wherein X is of the formula R₇ OCO--, wherein R₇ is C₁ -C₆ alkyl, phenyl, benzyl or naphthyl.

4. The compound of claim 3 wherein R₇ is benzyl.

5. The compound of claim 4 wherein Y is D-Phe-Pro.

6. The compound of claim 3 wherein Y is D-Phe-Pro.

7. The compound of claim 1 wherein Q₁ and Q₂ are --OH.

8. The compound of claim 7 wherein X is of the formula R₇ OCO--, wherein R₇ is C₁ -C₆ alkyl, phenyl, benzyl or naphthyl.

9. The compound of claim 8 wherein R₇ is benzyl.

10. The compound of claim 8 wherein Y is D-Phe-Pro.

11. The compound of claim 9 wherein Y is D-Phe-Pro.

12. The compound of claim 1 wherein Y is D-Phe-Pro.

13. A method of inhibiting thrombin in the treatment of disease comprising administering to a mammal a therapeutically effective amount of a compound having thrombin inhibiting activity and produced by the process of reacting a compound of the formula:

##STR20## wherein wherein X represents H or an N-protecting group,

Y represents a sequence of 2-10 α

-amino acids wherein D-Phe-Pro is attached to --NH, and

Q₁ and Q₂ are --OH, or Q₁ and Q₂ taken together represent a residue of a diol,

with methanol at temperatures of from 0-50°

C. in the presence of guanidine.

14. The method of claim 13 wherein Q₁ and Q₂ taken together represent a residue of an aliphatic compound having hydroxy groups that are substituted on carbon atoms substituted by another carbon.

15. The method of claim 14 wherein X is of the formula R₇ OCO--, wherein R₇ is C₁ -C₆ alkyl, phenyl, benzyl or naphthyl.

16. The method of claim 15 wherein R₇ is benzyl.

17. The method of claim 16 wherein Y is D-Phe-Pro.

18. The method of claim 15 wherein Y is D-Phe-Pro.

19. The method of claim 13 wherein Q₁ and Q₂ are --OH.

20. The method of claim 19 wherein X is of the formula R₇ OCO--, wherein R₇ is C₁ -C₆ alkyl, phenyl, benzyl or naphthyl.

21. The method of claim 20 wherein R₇ is benzyl.

22. The method of claim 20 wherein Y is D-Phe-Pro.

23. The method of claim 21 wherein Y is D-Phe-Pro.

24. The method of claim 13 wherein Y is D-Phe-Pro.

25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound having thrombin inhibiting activity and produced by the process of reacting a compound of the formula:

##STR21## wherein X represents H or an N-protecting group, Y represents a sequence of 2-10 α

-amino acids wherein D-Phe-Pro is attached to --NH, and

Q₁ and Q₂ are --OH, or Q₁ and Q₂ taken together represent a residue of a diol,

with methanol at temperatures of from 0-50°

C. in the presence of guanidine.

26. The composition of claim 25 wherein Q₁ and Q₂ taken together represent a residue of an aliphatic compound having hydroxy groups that are substituted on carbon atoms substituted by another carbon.

27. The composition of claim 26 wherein X is of the formula R₇ OCO--, wherein R₇ is C₁ -C₆ alkyl, phenyl, benzyl or naphthyl.

28. The composition of claim 25 wherein R₇ is benzyl.

29. The composition of claim 28 wherein Y is D-Phe-Pro.

30. The composition of claim 27 wherein Y is D-Phe-Pro.

31. The composition of claim 25 wherein Q₁ and Q₂ are --OH.

32. The composition of claim 31 wherein X is of the formula R₇ OCO--, wherein R₇ is C₁ -C₆ alkyl, phenyl, benzyl or naphthyl.

33. The composition of claim 32 wherein R₇ is benzyl.

34. The composition of claim 32 wherein Y is D-Phe-Pro.

35. The composition of claim 33 wherein Y is D-Phe-Pro.

36. The composition of claim 25 wherein Y is D-Phe-Pro.