Peptide boronic acid inhibitors

• US 20060084592A1
• Filed: 03/09/2005
• Published: 04/20/2006
• Est. Priority Date: 09/09/2002
• Status: Abandoned Application

• Current Assignee: Trigen Limited
• Original Assignee: Trigen Limited
• Inventors: Boucher, Oliver Vimpany Arnold
• Application Number:
  US11/077,620
• Publication Number:
  US 20060084592A1
• Time in Patent Office: Days
• US Class Current: 514/1.100
• 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 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

A pharmaceutically acceptable base addition salt of an organoboronic acid of formula (XXX): wherein: P is hydrogen or an amino-group protecting moiety; R is hydrogen or alkyl; A is 0, 1 or 2;

• • R¹, R² and R³ are independently hydrogen, alkyl, cycloalkyl, aryl or —CH₂—R⁵;
  • R⁵, in each instance, is one of aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, heteroaryl, or —W—R⁶, where W is a chalcogen and R⁶ is alkyl; and
  • where the ring portion of any of said aryl, aralkyl, alkaryl, cycloalkyl, heterocyclyl, or heteroaryl in R¹, R², R³ or R⁵ can be optionally substituted.

Claims

1. A pharmaceutically acceptable base addition salt of an organoboronic acid of formula (XXX):

2. The salt of claim 1 which has an observed stoichiometry consistent with the organoboronic acid being in the form of a salt of which a single —

OH group of the trigonally-represented boronyl group —

B(OH)₂ is deprotonated or, in an alternative expression of the same deprotonation state, in which the boronyl group carries a single negative charge and is in a form selected from the group consisting of the following equilibrium species or a combination thereof;

4. A salt of claim 1 wherein the organoboronic acid is N-(2-pyrazine) carbonyl-phenylalanine-leucine boronic acid.

5. A salt of claim 2 wherein the organoboronic acid is N-(2-pyrazine) carbonyl-phenylalanine-leucine boronic acid.

7. A salt of claim 2 which comprises a salt of the organoboronic acid with an alkali metal.

8. A salt of claim 2 which comprises a salt of the organoboronic acid with a strongly basic organic nitrogen-containing compound.

9. A salt of claim 2 which comprises a salt of the organoboronic acid with a multivalent metal.

10. A salt of claim 4 which consists essentially of a monosodium salt.

11. A salt of claim 4 which which consists essentially of a hemicalcium salt.

12. A salt of claim 5 which consists essentially of a salt of the organoboronic acid with a strongly basic organic nitrogen-containing compound.

27. The salt of claim 1, when provided in a sealed container and stored for a period of at least six months at a temperature of at least 0°

C.

3. A pharmaceutically acceptable base addition salt of an organoboronic acid of formula (II) below, the salt having 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, formula (II) being;

6. A salt of claim 3 wherein the organoboronic acid is N-(2-pyrazine) carbonyl-phenylalanine-leucine boronic acid.

13. A method for preparing a product, the method comprising contacting an organoboronic acid of formula (XXX) below with a pharmaceutically acceptable base, formula (XXX) being:

14. The method of claim 13, wherein the pharmaceutically acceptable base provides cations having a valency n and the base is added in such an amount that the organoboronic acid and the cations are in a stoichiometry of n:

1 (organoboronic acid;

cations).

15. The method of claim 13 wherein the base is a basic metal compound.

16. The method of claim 15 wherein the metal is sodium.

17. The method of claim 15 wherein the metal is a divalent.

18. The method of claim 13 wherein the base is an organic nitrogen-containing compound.

19. The method of claim 13 wherein the base is an aminosugar or an amine of formula (XI):

20. The method of claim 14 wherein the base is an aminosugar.

21. The method of claim 20 wherein the aminosugar is a glucamine.

22. The method of claim 20 wherein the organoboronic acid is N-(2-pyrazine) carbonyl-phenylalanine-leucine boronic acid and the method further comprises formulating the product into an intravenous pharmaceutical formulation.

23. A method of stabilising an organoboronic acid of formula (XXX) below, comprising providing it in the form of a pharmaceutically acceptable base addition salt thereof, formula (XXX) being:

24. A method of claim 23, wherein the organoboronic acid is N-(2-pyrazine) carbonyl-phenylalanine-leucine boronic acid.

25. A pharmaceutical formulation, whether in ready-to-use form or in a form requiring reconstitution prior to administration, adapted for intravenous administration and comprising the reaction product obtained by combining a pharmaceutically acceptable base with N-(2-pyrazine) carbonyl-phenylalanine-leucine boronic acid.

26. A formulation of claim 25, wherein the boronic acid and cations of the salt are in an observed stoichiometry consistent with an acid:

cation stoichiometry of about n;

1, where n would be the valency of the cations.