Peptide boronic acid compounds useful in anticoagulation

• US 20050282757A1
• Filed: 03/09/2005
• Published: 12/22/2005
• Est. Priority Date: 09/09/2002
• Status: Abandoned Application

• Current Assignee: Paion Deutschland GmbH (PAION AG)
• Original Assignee: Trigen Limited
• Inventors: Allen, Graham Douglas, Krimmer, Dieter, Kennedy, Anthony James, Combe-Marzelle, Sophie Marie, Withington, Roger
• Application Number:
  US11/078,097
• Publication Number:
  US 20050282757A1
• Time in Patent Office: Days
• US Class Current: 514/14.9
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/05 Dipeptides

Abstract

A method for preventing thrombosis in a setting where rapid onset and/or rapid offset of anticoagulation is required, comprising administering a compound selected from the group consisting of boronic acids which have a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, and pharmaceutically acceptable salts, prodrugs and pharmaceutically acceptable prodrug salts of such acids.

Claims

1. A method for preventing thrombosis in the haemodialysis circuit of a patient undergoing haemodialysis, comprising administering into the haemodialysis circuit or intravenously into the patient an aqueous solution of a compound selected from the group consisting of active principles which are boronic acids which have a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, and pharmaceutically acceptable salts, prodrugs and pharmaceutically acceptable prodrug salts of such acids, the active principle being in a concentration of about 10 mM or more.

2. The method of claim 1 wherein the active principle is in a concentration of about 18 mM or more.

3. The method of claim 1 wherein the active principle is in a concentration of about 35 mM or more.

4. The method of claim 1 wherein the boronic acid is of formula (I):

5. The method of claim 4 wherein R⁹ is an alkoxyalkyl group.

6. The method of claim 1 wherein the boronic acid is of formula (III):

7. The method of claim 6 wherein aa¹ is of (R)-configuration, aa² is of (S)-configuration and fragment —

NH—

CH(R¹)—

B(OH)₂ is of (R)-configuration.

8. The method of claim 6 wherein the boronic acid is of formula (VIII):

X—

(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(VIII).

9. The method of claim 6 wherein the boronic acid is Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

10. The method of claim 1 wherein the compound is a base addition salt of the boronic acid.

11. The method of claim 1 wherein the compound is a base addition salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

12. The method of claim 11 wherein the salt has an observed stoichiometry consistent with the organoboronic acid being in the form of a salt comprising organoboronate anions and cations and of which a predominant portion has an anion:

cation stoichiometry of about n;

1, where n is the valency of the cation.

13. The method of claim 1 wherein the compound comprises a reaction product of the boronic acid and reactant selected from the group consisting of basic sodium compounds and organic nitrogen-containing compounds having a pKb of at least about 7.

14. The method of claim 1 wherein the compound comprises a reaction product of the boronic acid and an amino sugar or a basic amino acid.

15. A method for preventing thrombosis during cardiovascular surgery on a patient, comprising administering intravenously into the patient or, when the patient is connected to a cardiopulmonary bypass, into a cardiopulmonary bypass circuit connected to the patient, an aqueous solution of a compound selected from the group consisting of boronic acids which have a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, and pharmaceutically acceptable salts, prodrugs and pharmaceutically acceptable prodrug salts of such acids.

16. The method of claim 15 wherein the boronic acid is of formula (I):

17. The method of claim 16 wherein R⁹ is an alkoxyalkyl group.

18. The method of claim 15 wherein the boronic acid is of formula (III):

19. The method of claim 18 wherein aa¹ is of (R)-configuration, aa² is of (S)-configuration and fragment —

NH—

CH(R¹)—

B(OH)₂ is of (R)-configuration.

20. The method of claim 15 wherein the boronic acid is of formula (VIII):

X—

(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(VIII).

21. The method of claim 15 wherein the boronic acid is Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

22. The method of claim 15 wherein the compound is a base addition salt of the boronic acid.

23. The method of claim 15 wherein the compound is a base addition salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

24. The method of claim 22 wherein the salt has an observed stoichiometry consistent with the organoboronic acid being in the form of a salt comprising organoboronate anions and cations and of which a predominant portion has an anion:

cation stoichiometry of about n;

1, where n is the valency of the cation.

25. The method of claim 15 wherein the compound comprises a reaction product of the boronic acid and a reactant selected from the group consisting of basic sodium compounds, basic magnesium compounds, basic calcium compounds, basic zinc compounds and organic nitrogen-containing compounds having a pKb of at least about 7.

26. The method of claim 15 wherein the compound comprises a reaction product of the boronic acid and an amino sugar or basic amino acid.

27. The method of claim 15 wherein the compound is selected from the group consisting of the hemicalcium, hemimagnesium and hemizinc salts of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

28. A pharmaceutical formulation adapted to be injected or infused into the blood of a patient, whether intravenously or in an extracorporeal blood circuit, comprising an aqueous solution of a pharmaceutically acceptable multivalent metal salt of a boronic acid which has a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites.

29. The formulation of claim 28 wherein the boronic acid is of formula (I):

30. The formulation of claim 29 wherein R⁹ is an alkoxyalkyl group.

31. The formulation of claim 28 wherein the boronic acid is of formula (III):

32. The formulation of claim 31 wherein aa¹ is of (R)-configuration, aa² is of (S)-configuration and fragment —

NH—

CH(R¹)—

B(OH)₂ is of (R)-configuration.

33. The formulation of claim 28 wherein the boronic acid is of formula (VIII):

X—

(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(VIII).

34. The formulation of claim 28 wherein the boronic acid is Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

35. The formulation of claim 28 wherein the salt is a divalent metal salt of the boronic acid.

36. The formulation of claim 28 wherein the salt is a divalent metal salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

37. The formulation of claim 33 wherein the salt is a hemi salt of calcium, magnesium or zinc.

38. The formulation of claim 28 wherein the salt is a hemicalcium salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.