Inhibitors of trypsin-like enzymes

• US 6,313,096 B1
• Filed: 04/07/2000
• Issued: 11/06/2001
• Est. Priority Date: 04/28/1988
• Status: Expired due to Fees

• Current Assignee: Thrombosis Research Institute
• Original Assignee: Trigen Limited
• Inventors: Claeson, Goran, Philipp, Manfred Hans Wilhelm
• Primary Examiner(s): CELSA, BENNETT M
• Application Number:
  US09/543,675
• Time in Patent Office: 578 Days
• Field of Search: 514/15-19, 530/330-331
• 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 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06043 Leu-amino acid
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/0806 the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
• CPC Class Codes: C07K 5/0808 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• CPC Class Codes: C07K 5/101 the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
• 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:

in which X=H or is an N-protecting group; Y is 1-10 á-amino acids; Q1 and Q2 taken together represent the residue of a diol; R is C_1-4alkyl; 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 of Formula XIIIa:

wherein,

X is a member selected from the group consisting of H and NH-protecting groups;

Y is a sequence of from 2 to 10 covalently linked α

-amino acids comprising D-Phe-Pro wherein, D-Phe-Pro is attached to —

NH—

,

Q₁, and Q₂ are —

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

R is C_1-4 alkyl, wherein the asymmetric carbon marked * of Formula XIIIa has D- or L-configuration.

2. The compound of claim 1 wherein Y is a sequence of from 2 to 4 α

-amino acids.

3. 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.

4. The compound of claim 1 wherein Q₁ and Q₂ taken together have a structure according to Formula XVIII:

5. The compound of claim 3 wherein X is of the formula R₇OCO—

, wherein R₇ is a member selected from the group consisting of C₁-C₆ alkyl, phenyl, benzyl and naphthyl.

6. The compound of claim 5 wherein R₇ is benzyl.

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

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

14. The compound of claim 1 wherein R is CH₃ and Y is D-Phe-Pro.

8. The compound of clam 1 wherein Q₁ and Q₂ are —

OH.

9. The compound of claim 8 wherein X is R₇OCO—

, wherein R₇ is C₁-C₆ alkyl, phenyl, benzyl or naphthyl.

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

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

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

15. The compound of claim 8 wherein R is CH₃ and Y is D-Phe-Pro.

16. A method of inhibiting thrombin in the treatment of disease comprising administering to a mammal a therapeutically effective amount of a compound according to Formula XIIIa:

wherein,

X is a member selected from the group consisting of H and NH-protecting groups;

Y is a sequence of from 2 to 10 covalently linked α

-amino acids comprising D-Phe-Pro wherein, D-Phe-Pro is attached to —

NH—

,

Q₁ and Q₂ are —

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

R is C_1-4 alkyl, wherein the asymmetric carbon marked * of Formula XIIIa has D- or L-configuration.

17. The method of claim 16 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.

18. The method of claim 17 wherein X is of the formula R₇OCO—

, wherein R₇ is benzyl.

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

20. The method of claim 16 wherein Q₁ and Q₂ are —

OH.

21. The method of claim 20 wherein X is of the formula R₇OCO—

, wherein R₇ is a member selected from the group consisting of C₁-C₆ alkyl, phenyl, benzyl or naphthyl.

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

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

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

25. The method of claim 16 wherein R is CH₃ and Y is D-Phe-Pro.

26. The method of claim 20 wherein R is CH₃ and Y is D-Phe-Pro.

27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to Formula XIIIa:

wherein,

X is a member selected from the group consisting of H and NH-protecting groups;

Y is a sequence of from 2 to 10 covalently linked α

-amino acids comprising D-Phe-Pro wherein, D-Phe-Pro is attached to —

NH—

,

Q₁ and Q₂ are —

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

R is C_1-4 alkyl, wherein the asymmetric carbon marked * of Formula XIIIa has D- or L-configuration.

28. The composition of claim 27 wherein Y is a sequence of from 2 to 4 α

-amino acids.

29. The composition of claim 27 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.

30. The composition of claim 29 wherein X is of the formula R₇OCO—

, wherein R₇ is benzyl.

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

32. The composition of claim 27 wherein Q₁ and Q₂ are —

OH.

33. The composition of claim 32 wherein X is of the formula R₇OCO—

, wherein R₇ is a member selected from the group consisting of C₁-C₆ alkyl, phenyl, benzyl or naphthyl.

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

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

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

37. The composition of claim 27 wherein R is CH₃ and Y is D-Phe-Pro.

38. The composition of claim 32 wherein R is CH₃ and Y is D-Phe-Pro.

39. A method of inhibiting thrombin activity in a mammalian subject, said method comprising, delivering to the blood of said subject a pharmaceutical formulation comprising an amount of a compound having a structure according to Formula XVIII:

X is a member selected from the group consisting of H and NH-protecting groups;

Y is a sequence of from 2 to 10 covalently linked α

-amino acids comprising D-Phe-Pro wherein, D-Phe-Pro is attached to —

NH—

; and

R is C_1-4 alkyl, wherein the asymmetric carbon marked * of Formula XVIII has D- or L-configuration, said amount being effective to inhibit said thrombin activity.

40. A method of inhibiting thrombin activity in a mammalian subject, said method comprising administering to said subject an amount of a pharmaceutical formulation which delivers to said thrombin a compound having a structure according to Formula XVIII:

wherein,

X is a member selected from the group consisting of H and NH-protecting groups;

Y is a sequence of from 2 to 10 covalently linked α

-amino acids comprising D-Phe-Pro wherein, D-Phe-Pro is attached to —

NH—

; and

R is C_1-4 alkyl;

the asymmetric carbon marked * of Formula XVIII has D- or L-configuration, said amount being effective to inhibit said thrombin activity.

41. A method of inhibiting thrombin activity in a mammalian subject, said method comprising contacting said thrombin with an amount of a compound having a structure according to Formula XVIII:

wherein,

X is a member selected from the group consisting of H and NH-protecting groups;

Y is a sequence of from 2 to 10 covalently linked α

-amino acids comprising D-Phe-Pro wherein, D-Phe-Pro is attached to —

N—

; and

R is C_1-4 alkyl;

the asymmetric carbon marked * of Formula XVIII has D- or L-configuration, said amount being effective to inhibit said thrombin activity.