Boronic acid salts useful in parenteral formulations

• US 7,371,729 B2
• Filed: 09/09/2003
• Issued: 05/13/2008
• Est. Priority Date: 09/09/2002
• Status: Expired due to Fees

• Current Assignee: Paion Deutschland GmbH (PAION AG)
• Original Assignee: Trigen Limited
• Inventors: Deadman, John Joseph, Kennedy, Anthony James, Kakkar, Sanjay Kumar, Dolman, Mark, Combe-Marzelle, Sophie Marie, Madge, David Jonathan
• Primary Examiner(s): KWON, YONG SOK
• Application Number:
  US10/658,971
• Publication Number:
  US 20040138175A1
• Time in Patent Office: 1,708 Days
• Field of Search: 514/310, 514/391, 514/18, 514/2, 514/19, 514/64
• US Class Current: 514/14.7
• 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: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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

Salts of a peptide boronic acid drug, for example of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂. The counter-ion to the boronate may be an alkali metal or derived from a strongly basic organic nitrogen-containing compound.

Claims

1. A parenteral pharmaceutical formulation comprising a pharmaceutically acceptable base addition salt of a boronic acid of formula (VIII):

X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(VIII),

wherein X is R⁶—

(CH₂)_p—

C(O)—

, R⁶—

(CH₂)_p—

S(O)₂—

, R⁶—

(CH₂)_p—

NH—

C(O)—

or R⁶—

(CH₂)_p—

O—

C(O)—

, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R⁶ is H or a 5 to 13-membered cyclic group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen;

amino;

nitro;

hydroxy;

a C₅-C₆ cyclic group;

C₁-C₄ alkyl and C₁-C₄ alkyl containing, or linked to the cyclic group through, an in-chain O atom, the aforesaid alkyl groups optionally being substituted by a substituent selected from halogen, amino, nitro, hydroxy and a C₅-C₆ cyclic group,

wherein the salt in the parenteral pharmaceutical formulation is a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI);

2. The parenteral pharmaceutical formulation of claim 1, wherein X is R⁶—

(CH₂)_p—

O—

C(O)— and

p is 0 or 1.

3. The parenteral pharmaceutical formulation of claim 1, wherein R⁶ is a 6-membered cyclic group that is unsubstituted and p is 1.

4. The parenteral pharmaceutical formulation of claim 1, wherein the salt is an alkali metal salt.

5. The parenteral pharmaceutical formulation of claim 4, wherein the alkali metal salt is a sodium salt.

6. The parenteral pharmaceutical formulation of claim 1, wherein the formulation comprises a salt of the boronic acid with an aminosugar.

7. The parenteral pharmaceutical formulation of claim 1, wherein the formulation comprises a salt of the boronic acid with a guanidine.

8. The parenteral pharmaceutical formulation of claim 1, wherein the formulation comprises a salt of the boronic acid with an amine of formula (XI):

9. The parenteral pharmaceutical formulation of claim 1, wherein the formulation is an aqueous solution comprising the salt.

10. The parenteral pharmaceutical formulation of claim 9, wherein the aqueous solution further comprises a tonicity agent.

11. The parenteral pharmaceutical formulation of claim 1, which comprises the boronic acid in the form of an anhydride.

12. The parenteral pharmaceutical formulation of claim 1, wherein the boronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)-boroMpg-OH, boroMpg-OH being a residue of an aminoboronic acid of the formula H₂N—

CH((CH₂)₃OMe)B(OH)₂, and wherein the formulation comprises anhydride species of the acid.

13. The parenteral pharmaceutical formulation of claim 1 wherein the boronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

14. The parenteral pharmaceutical formulation of claim 1, wherein the salt is an alkali metal salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

15. The parenteral pharmaceutical formulation of claim 14, wherein the salt is a sodium salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

16. The parenteral pharmaceutical formulation of claim 1, further comprising at least one cardiovascular treatment agent selected from the group consisting of a lipid-lowering drug, an anti-oxidant, a GP IIb/IIIa antagonist, an aldosterone inhibitor, an adenosine A2 antagonist, an adenosine A3 agonist, a beta-blocker, acetylsalicylic acid, a loop diuretic, an ACE inhibitor, an antithrombotic agent with a different mechanism of action from the salt of formula (VIII), an antiplatelet agent, a thromboxane receptor inhibitor, a synthetase inhibitor, a fibrinogen receptor antagonist, a prostacyclin mimetic, a phosphodiesterase inhibitor, an ADP-receptor (P₂T) antagonist, a thrombolytic, and a COX-2 inhibitor, and combinations thereof.

17. The parenteral pharmaceutical formulation of claim 1, wherein the salt is a sodium salt of a boronic acid of the formula Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂, and wherein the salt is in an aqueous solution.

18. The parenteral pharmaceutical formulation of claim 15 wherein the salt is the monosodium salt and the formulation either is an aqueous solution or is in solid form for making up into an aqueous solution for administration.

19. A pharmaceutical product comprising a sealed container containing in the form of a finely divided solid, ready for reconstitution to form a liquid parenteral formulation, a pharmaceutically acceptable base addition salt of a boronic acid of formula (VIII), wherein the boronic acid is pharmaceutically active:

X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(VIII),

wherein X is R⁶—

(CH₂)_p—

C(O)—

, R⁶—

(CH₂)_p—

S(O)₂—

, R⁶—

(CH₂)_p—

NH—

C(O)—

or R⁶—

(CH₂)_p—

O—

C(O)—

, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R⁶ is H or a 5 to 13-membered cyclic group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen;

amino;

nitro;

hydroxy;

a C₅-C₆ cyclic group;

C₁-C₄ alkyl and C₁-C₄ alkyl containing, or linked to the cyclic group through, an in-chain O atom, the aforesaid alkyl groups optionally being substituted by a substituent selected from halogen, amino, nitro, hydroxy and a C₅-C₆ cyclic group,

wherein the salt in the pharmaceutical product is a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI);

20. The pharmaceutical product of claim 19, wherein X is R⁶—

(CH₂)_p—

O—

C(O)— and

p is 0 or 1.

21. The pharmaceutical product of claim 19, wherein R⁶ is a 6-membered cyclic group that is unsubstituted and p is 1.

22. The pharmaceutical product of claim 21, wherein the salt is an alkali metal salt.

23. The pharmaceutical product of claim 22, wherein the alkali metal salt is a sodium salt.

24. The pharmaceutical product of claim 19, wherein the boronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

25. The pharmaceutical product of claim 19, wherein the salt is an alkali metal salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

26. The pharmaceutical product of claim 25, wherein the salt is a sodium salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

27. The pharmaceutical product of claim 26 wherein the salt is a monosodium salt.

28. A method of treating thrombosis, comprising parenterally administering to a mammal suffering from, or at risk of suffering from, thrombosis a therapeutically effective amount of a composition comprising a pharmaceutically acceptable base addition salt of a boronic acid of formula (VIII):

X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(VIII),

wherein X is R⁶—

(CH₂)_p—

C(O)—

, R⁶—

(CH₂)_p—

S(O)₂—

, R⁶—

(CH₂)_p—

NH—

C(O)—

or R⁶—

(CH₂)_p—

O—

C(O)—

, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R⁶ is H or a 5 to 13-membered cyclic group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen;

amino;

nitro;

hydroxy;

a C₅-C₆ cyclic group;

C₁-C₄ alkyl and C₁-C₄ alkyl containing, or linked to the cyclic group through, an in-chain O atom, the aforesaid alkyl groups optionally being substituted by a substituent selected from halogen, amino, nitro, hydroxy and a C₅-C₆ cyclic group,

wherein the salt is a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI);

29. The method of claim 28, wherein X is R⁶—

(CH₂)_p—

O—

C(O)— and

p is 0 or 1.

30. The method of claim 28, wherein R⁶ is a 6-membered cyclic group that is unsubstituted and p is 1.

31. The method of claim 28, wherein the salt is an alkali metal salt.

32. The method of claim 28, wherein the alkali metal salt is a sodium salt.

33. The method of claim 28, wherein the boronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)- Mpg-B(OH)₂.

34. The method of claim 28, wherein the salt is an alkali metal salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

35. The method of claim 34, wherein a salt is the sodium salt of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

36. The method of claim 28, wherein the formulation is administered intravenously.

37. The method of claim 28, further comprising co-administering at least one additional cardiovascular treatment agent selected from the group consisting of a lipid-lowering drug, an anti-oxidant, a GP IIb/IIIa antagonist, an aldosterone inhibitor, an adenosine A2 antagonist, an adenosine A3 agonist, a beta-blocker, acetylsalicylic acid, a loop diuretic, an ACE inhibitor, an antithrombotic agent with a different mechanism of action from the salt of formula (VIII), an antiplatelet agent, a thromboxane receptor inhibitor, a synthetase inhibitor, a fibrinogen receptor antagonist, a prostacyclin mimetic, a phosphodiesterase inhibitor, an ADP-receptor (P₂T) antagonist, a thrombolytic, and a COX-2 inhibitor, and combinations thereof.

38. The method of claim 35 wherein the composition comprises an aqueous solution of the salt.

39. A pharmaceutical formulation adapted for parenteral administration, whether directly or after combining with a liquid, and the pharmaceutical formulation comprising:

a) a first component selected from the group consisting of (i) a boronic acid of formula (VIII) below, (ii) boronate ions of the boronic acid of formula (VIII) below, and (iii) an equilibrium form of the boronic acid of formula (VIII) below and boronate ions of the boronic acid of formula (VIII) below, and (iv) combinations thereof;

X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(VIII),

wherein X is R⁶—

(CH₂)_p—

C(O)—

, R⁶—

(CH₂)_p—

S(O)₂—

, R⁶—

(CH₂)_p—

NH—

C(O)—

or R⁶—

(CH₂)_p—

O—

C(O)—

, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R⁶ is H or a 5 to 13-membered cyclic group which is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen;

amino;

nitro;

hydroxy;

a C₅-C₆ cyclic group;

C₁-C₄ alkyl and C₁-C₄ alkyl containing, or linked to the cyclic group through, an in-chain O atom, the aforesaid alkyl groups optionally being substituted by a substituent selected from halogen, amino, nitro, hydroxy and a C₅-C₆ cyclic group; and

(b) a second, pharmaceutically acceptable, component selected from the group consisting of alkali metal ions, aminosugars, guanidines and amines of formula (XI);

40. The pharmaceutical formulation of claim 39 wherein X is R⁶—

(CH₂)_p—

C(O)—

, R₆ is a 6-membered cyclic group that is unsubstituted and p is 1.

41. The pharmaceutical formulation of claim 40 wherein the second component is N-methyl-D-glucamine.

42. The pharmaceutical formulation of claim 40 wherein the second component is L-lysine.

43. The pharmaceutical formulation of claim 40 wherein the second component is L-arginine.

44. The pharmaceutical formulation of claim 40 wherein the second component is lithium.

45. The pharmaceutical formulation of claim 40 wherein the second component is potassium.

46. The pharmaceutical formulation of claim 40 wherein the second component is sodium.

47. The pharmaceutical formulation of claim 39 wherein the boronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2.

48. The pharmaceutical formulation of claim 46 wherein the boronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.