Multivalent metal salts of boronic acids

• US 7,112,572 B2
• Filed: 09/09/2003
• Issued: 09/26/2006
• Est. Priority Date: 09/09/2002
• Status: Expired due to Fees

• Current Assignee: Paion Deutschland GmbH (PAION AG)
• Original Assignee: Trigen Limited
• Inventors: Dolman, Mark, Madge, David Jonathan, Deadman, John Joseph, Boucher, Oliver Vimpany Arnold, Chahwala, Suresh Babubhai, Kennedy, Anthony James, Kakkar, Sanjay Kumar, Combe-Marzelle, Sophie Marie
• Primary Examiner(s): Campell, Bruce R.
• Assistant Examiner(s): Cordero Garcia, Marcela M
• Application Number:
  US10/659,179
• Publication Number:
  US 20040147453A1
• Time in Patent Office: 1,113 Days
• Field of Search: 514/2
• 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: 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 pharmaceutically acceptable divalent metal and an organoboronic acid drug. Examples of such metals are calcium, magnesium and zinc. The organoboronic acid drug may be a boropeptide protease inhibitor. The salts may be formulated in oral dosage form.

Claims

1. A salt of a pharmaceutically acceptable multivalent metal and an organoboronic acid inhibitor of thrombin having a neutral thrombin S1-binding moiety linked to a hydrophobic thrombin S2/S3-binding moiety.

2. A salt of claim 1 wherein the organoboronic acid is of Formula (III):

3. A salt of claim 2 wherein R⁹ is an alkoxyalkyl group.

4. A salt of claim 2 wherein Y comprises an amino acid which binds to the S2 subsite of thrombin and is linked to —

CH(R⁹)—

B(OH)₂ by a peptide linkage, the amino acid being N-terminally linked to a moiety which binds the S3 subsite of thrombin.

5. A salt of claim 4 wherein Y comprises an N-terminally protected dipeptide residue which binds to the S3 and S2 binding sites of thrombin and is linked to —

CH(R⁹)—

B(OH)₂ by a peptide linkage.

6. The salt of claim 1 wherein the boronic acid has a Ki for thrombin of about 100 nM or less.

7. The salt of claim 5 wherein the Y dipeptide is N-terminally protected or N-terminally unprotected, and the peptide linkages in the dipeptide are unsubstituted or independently N-substituted by a C₁–

C₁₃ hydrocarbyl, wherein the C₁–

C₁₃ hydrocarbyl contains no heteratoms or at least one in-chain or in-ring nitrogen, oxygen or sulfur atom, and the C₁–

C₁₃ hydrocarbyl is unsubstituted or substituted by a substituent selected from halo, hydroxy and trifluoromethyl.

8. The salt of claim 1 wherein the multivalent metal comprises calcium, magnesium or zinc.

9. The salt of claim 1 wherein the salt consists essentially of an acid salt in which one B—

OH group of formula (I), when trigonally represented, remains protonated.

10. The salt of claim 7 wherein the salt comprises boronate ions derived from the peptide boronic acid and has a stoichiometry consistent with the boronate ions carrying a single negative charge.

11. The salt of claim 3 wherein the salt consists essentially of a hemicalcium or hemimagnesium salt of the boronic acid.

12. The salt of claim 1 wherein the peptide boronic acid is of formula (IV):

13. The salt of claim 12 wherein aa¹ is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof.

14. The salt of claim 13 wherein aa¹ is of R-configuration.

15. The salt of claim 12 wherein aa² is a residue of an imino acid of formula (V)

16. The salt of claim 15 wherein aa² is of S-configuration.

17. The salt of claim 12, wherein aa¹-aa² is (R)-Phe-(S)-Pro and the fragment —

NH—

CH(R¹)—

B(OH)₂ is of R-configuration.

18. The salt of claim 13 wherein the boronic acid is of formula (IX):

X—

(R)-Phe-(S)-Pro-(R)-boroMpg-OH 

 

(IX).

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

boroMpg-OH is a residue of an aminoboronic acid of the formula H₂N—

CH((CH₂)₃OMe)B(OH)₂.

19. The salt of claim 12 which comprises a divalent metal salt of the peptide boronic acid.

20. A pharmaceutical formulation adapted for oral administration which comprises a salt of claim 1.

21. The salt of claim 1 wherein the organoboronic acid is of formula (III) below when included in a pharmaceutical formulation adapted for oral administration and comprising

a) a first species selected from a boronic acid of formula (III), or said boronic acid when in the form of boronate ions thereof, or equilibrium forms of said boronic acid and of said boronate ions, or combinations thereof:

22. A method of inhibiting thrombin comprising parenterally administering to a mammal suffering from thrombosis a therapeutically effective amount of the salt defined in claim 1.

23. A medicament adapted for oral administration and comprising a therapeutically effective amount of a salt of claim 1.

24. A medicament of claim 23 which is in solid dosage form.

25. A medicament of claim 24 wherein the boronic acid has a Ki for thrombin of about 100 nM or less.

26. The salt of claim 12, wherein:

aa¹ is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof;

aa² is a residue of an imino acid of formula (V);

27. The salt of claim 26 wherein aa¹ is of(R)-configuration, aa² is of (S)-configuration, and chiral centre —

NH—

CH(R⁹)—

B(OH)₂ is of (R)-configuration.

28. The salt of claim 27 wherein R⁹ is alkoxyalkyl containing 4 carbon atoms, aa¹ is Phe or a wholly or partially hydrogenated analogue thereof and aa² is azetidine-2-carboxylic acid or proline.

29. The salt of claim 28 wherein R⁹ is 3-methoxypropyl.

30. The salt of claim 27 wherein the multivalent metal is calcium, magnesium or zinc.

31. The salt of claim 28 which is a hemicalcium, hemimagnesium or hemizinc salt.

32. The salt of claim 29 which is a hemicalcium salt.

33. The salt of claim 18 wherein X is R⁶—

(CH₂)_p—

O—

C(O)—

, where R⁶ is 5 to 13-membered aromatic or heteroaromatic group and p is 0 or 1.

34. The salt of claim 1 wherein the boronic acid is of the formula:

Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂.

35. The salt of claim 34 wherein the multivalent metal is calcium, magnesium or zinc.

36. The salt of claim 34 which is a hemicalcium salt.

37. The salt of claim 4 wherein R⁹ is 3-methoxypropyl and the carbon atom to which R⁹ is bonded comprises a chiral centre of (R)-configuration.

38. The salt of claim 37 which consists essentially of a hemicalcium, hemimagnesium or hemizinc salt.

39. The salt of claim 37 which comprises a hemicalcium or hemimagnesium salt.

40. The salt of claim 34 which comprises a hemicalcium or hemimagnesium salt and which comprises anhydride species of the acid.

41. The salt of claim 1 which comprises the boronic acid in anhydride form.

42. The salt of claim 11 which comprises the boronic acid in the form of an anhydride.

43. The salt of claim 21 wherein the first species comprises the organoboronic acid in the form of an anhydride.

44. The salt of claim 36 which comprises the boronic acid in the form of an anhydride.

45. The pharmaceutical formulation of claim 20 wherein the formulation is in the form of a tablet or a capsule.

46. The pharmaceutical formulation of claim 45 wherein the tablet or capsule is enterically coated.

47. The pharmaceutical formulation of claim 45 wherein the tablet or capsule is not enterically coated.

48. The pharmaceutical formulation of claim 20 further comprising at least one further pharmaceutically active agent in addition to the salt of claim 1.

49. The pharmaceutical formulation of claim 48 wherein the further pharmaceutically active agent comprises a cardiovascular treatment agent.

50. A pharmaceutical formulation adapted for oral administration which comprises at least one salt of claim 11.

51. A pharmaceutical formulation adapted for oral administration which comprises at least one salt of claim 37.

52. The pharmaceutical formulation of claim 51 wherein the salt comprises the boronic acid in anhydride form.

53. The pharmaceutical formulation of claim 52 wherein said at least one salt consists essentially of a single said metal and a single said boronic acid, the metal being selected from calcium and magnesium.

54. The pharmaceutical formulation of claim 51 wherein the formulation is in the form of a tablet that is not enterically coated or a capsule that is not enterically coated.

55. A pharmaceutical formulation adapted for oral administration which comprises as an active agent a salt of claim 34.

56. The pharmaceutical formulation of claim 55 wherein the salt is selected from the hemicalcium and hemimagnesium salts of a boronic acid of the formula Cbz-(R)-Phe-(S)-Pro-(R)-boroMpg-OH;

wherein boroMpg-OH is a residue of an aminoboronic acid of the formula H₂N—

CH((CH₂)₃OMe)B(OH)₂.

57. The pharmaceutical formulation of claim 56 wherein the active agent is the hemicalcium salt.

58. The pharmaceutical formulation of claim 57 wherein the salt comprises the boronic acid in anhydride form.

59. The pharmaceutical formulation of claim 57 which is in the form of an enterically coated tablet or capsule.

60. The pharmaceutical formulation of claim 57 which is in the form of a tablet or capsule which is not enterically coated.

61. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the salt of claim 1.

62. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the salt of claim 11.

63. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the salt of claim 34.

64. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the pharmaceutical formulation of claim 56.

65. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the pharmaceutical formulation of claim 57.

66. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the pharmaceutical formulation of claim 58.

67. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the pharmaceutical formulation of claim 59.

68. A method of inhibiting thrombin comprising orally administering to a mammal suffering from thrombosis a therapeutically effective amount of the pharmaceutical formulation of claim 60.

69. The method of claim 64 wherein the salt is in solid dosage form.

70. The method of claim 65 wherein the salt is in solid dosage form and comprises the boronic acid in anhydride form.

71. The salt of claim 1 wherein the salt comprises anhydride species.

72. The salt of claim 11 wherein the salt comprises anhydride species.

73. The salt of claim 36 wherein the salt comprises anhydride species.

74. The salt of claim 1 which is substantially anhydride-free.

75. The salt of claim 11 which is substantially anhydride-free.

76. The salt of claim 36 which is substantially anhydride-free.

77. The pharmaceutical formulation of claim 20 wherein the salt is substantially anhydride-free.

78. The method of claim 64 wherein the salt is substantially anhydride-free.

79. The salt of claim 1 wherein the salt comprises an acid salt in which both B—

OH groups of formula (I), when trigonally represented, are deprotonated.

80. The pharmaceutical formulation of claim 20 which comprises a mixture of multivalent metals.

81. The salt of claim 12 wherein the salt is of formula (VI)

82. The salt of claim 81 wherein Mⁿ⁺ is Ca²⁺.

83. A pharmaceutical formulation adapted for oral administration which comprises at least one salt of claim 81.

84. The pharmaceutical formulation of claim 83 which comprises a mixture of cations.

85. The salt of claim 1 wherein the organoboronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)-boroMpg-OH wherein boroMpg-OH is a residue of an aminoboronic acid of the formula H₂N—

CH((CH₂)₃OMe)B(OH)₂, and is included in a pharmaceutical formulation adapted for oral administration, the salt comprising

a) a first species selected from (i) said boronic acid or (ii) said boronic acid when in the form of boronate ions thereof, or equilibrium forms of said boronic acid and of said boronate ions, or combinations thereof and

b) a second species selected from multivalent metal ions.

86. The salt of claim 85 wherein the pharmaceutical formulation further comprises one or more additional components selected from a) fillers or extenders;

b) binders;

c) humectants;

d) disintegrating agents;

e) solution retarding agents;

f) absorption accelerators;

g) wetting agents;

h) absorbents;

i) lubricants; and

j) dissolution aids, or mixtures thereof.

87. The pharmaceutical formulation of claim 53 wherein the metal is calcium.

88. A composition of matter comprising the salt of claim 1 wherein the organoboronic acid is of the formula Cbz-(R)-Phe-(S)-Pro-(R)-boroMpg-OH wherein boroMpg-OH is a residue of an aminoboronic acid of the formula H₂N—

CH((CH₂)₃OMe)B(OH)₂, the salt consisting essentially of;

a) a first species selected from (i) said boronic acid or (ii) said boronic acid when in the form of boronate ions thereof, or equilibrium forms of said boronic acid and of said boronate ions, or combinations thereof; and

b) a second species selected from calcium and magnesium ions, the composition of matter optionally further comprising one or more additional components selected from at least one pharmaceutically acceptable, orally suitable adjuvant, diluent or carrier; and

at least one cardiovascular treatment agent.

89. The composition of claim 88 wherein the second species is calcium ions and the first species comprises boronate species having the characteristics of boronate species derived at least from a molecule of the boronic acid which has been singly deprotonated.

90. The composition of claim 88 wherein the second species is magnesium ions and the first species comprises boronate species having the characteristics of boronate species derived at least from a molecule of the boronic acid which has been singly deprotonated.

91. The composition of claim 89 which is adapted for oral administration.

92. A method for making a salt of claim 12, comprising:

combining in a solvent diethanolamine and an ester of a boronic acid as defined in claim 12;

allowing or causing a precipitate to form and recovering the precipitate;

converting the precipitated material into the free organoboronic acid by contacting the precipitated material with an aqueous acid or base; and

reacting the organoboronic acid with a base of a pharmaceutically acceptable multivalent metal to form to a salt as defined in claim 12.