Multivalent metal salts of boronic acids

• US 20060229257A1
• Filed: 05/22/2006
• Published: 10/12/2006
• Est. Priority Date: 09/09/2002
• Status: Abandoned Application

• Current Assignee: Trigen Limited
• Original Assignee: Trigen Limited
• Inventors: Deadman, John Joseph, Boucher, Oliver Vimpany Arnold, Chahwala, Suresh Babubhai, Kennedy, Anthony James, Kakkar, Sanjay Kumar, Dolman, Mark, Combe-Marzelle, Sophie Marie, Madge, David Jonathan
• Application Number:
  US11/438,823
• Publication Number:
  US 20060229257A1
• Time in Patent Office: Days
• US Class Current: 514/200
• 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 pharmaceutical formulation adapted for oral administration and comprising

a) a first species selected from the group consisting of a boronic acid of formula (III), said acid when in the form of a boronate ion thereof, an equilibrium form of said boronic acid and of said boronate ion, and combinations thereof:

wherein

Y comprises a moiety which, together with the aminoboronic acid residue —

NHCH(R⁹)—

B(OH)₂, has affinity for the substrate binding site of thrombin; and

R⁹ is a straight chain alkyl group interrupted by one or more ether linkages and in which the total number of oxygen and carbon atoms is 3, 4, 5 or 6 or R⁹ is —

(CH₂)_m—

W where m is from 2, 3, 4 or 5 and W is —

OH or halogen; and

(b) a second species selected from the group consisting of multivalent metal ions.

2. The formulation of claim 1 wherein R⁹ is an alkoxyalkyl group.

3. The formulation of claim 1 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.

4. The formulation of claim 1 wherein Y comprises a 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.

5. The formulation of claim 1 wherein the boronic acid or boronate ion has a Ki for thrombin of about 100 nM or less.

6. The formulation of claim 4 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 heteroatoms 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 or trifluoromethyl.

7. The formulation of claim 1 wherein the multivalent metal comprises calcium, magnesium or zinc.

8. The formulation of claim 7 which has an observed stoichiometry which would be consistent with the first species being a boronate ion carrying a single negative charge.

9. The formulation of claim 2 wherein the second species is calcium or magnesium ions and the observed stoichiometry of the first species to the second species is about 2 to 1.

10. The formulation of claim 1 wherein the boronic acid is a peptide boronic acid of formula (IV):

13. The formulation of claim 10 wherein aa² is a residue of an imino acid of formula (V)

14. The formulation of claim 13 wherein aa² is of S-configuration.

15. The formulation of claim 14 wherein aa¹ is of (R)-configuration and the fragment —

NH—

CH(R¹)—

B(OH)₂ is of (R)-configuration.

17. The formulation of claim 10 wherein R¹ is methoxypropyl, aa² is of (S)-configuration, aa¹ is of (R)-configuration and the fragment —

NH—

CH(R¹)—

B(OH)₂ is of (R)-configuration.

18. The formulation of claim 17 wherein the second species consists essentially of a calcium ion or a magnesium ion.

19. The formulation of claim 10 wherein the boronic acid is of formula (IX):

X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)₂ 

 

(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.

20. The formulation of claim 10 wherein the second species is selected from a divalent metal ion.

21. The formulation of claim 1 which further comprises a pharmaceutically acceptable diluent, excipient or carrier.

22. The formulation of claim 1 wherein the first species comprise anhydride species

23. The formulation of claim 17 wherein the first species comprise anhydride species.

24. The formulation of claim 1 wherein the boronic acid is Cbz-(R)-Phe-(S)-Pro-(R)-boroMpg-OH, the first species comprise anhydride species and the second species consists essentially of calcium ions, and wherein the formulation further includes a pharmaceutically acceptable diluent, excipient or carrier.

11. The formulation of claim 11 wherein aa¹ is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof.

12. The formulation of claim 11 wherein aa¹ is of R-configuration.

16. The formulation of claim 11, wherein aa¹-aa² is (R)-Phe-(S)-Pro and the fragment —

NH—

CH(R¹)—

B(OH)₂ is of R-configuration.

25. A medicament adapted for oral administration and comprising a therapeutically effective amount of a multivalent metal salt of a boronic acid which is a selective thrombin inhibitor and has a neutral aminoboronic acid residue capable of binding to the thrombin S1 subsite linked through a peptide linkage to a hydrophobic moiety capable of binding to the thrombin S2 and 53 subsites, the salt comprising a cation having a valency n and having an observed stoichiometry consistent with a notional stoichiometry (boronic acid:

cation) of n;

1.

26. A medicament of claim 25 which is in solid dosage form.

27. A medicament of claim 26 wherein the boronic acid has a Ki for thrombin of about 100 nM or less.

28. A method for preventing thrombosis in a haemodialysis circuit of a patient, for preventing a cardiovascular event in a patient with end stage renal disease, for preventing venous thromboembolic events in a patient receiving chemotherapy through an indwelling catheter, for preventing thromboembolic events in a patient undergoing a lower limb arterial reconstructive procedure, or for treating by way of therapy or prophylaxis an arterial disease selected from acute coronary syndromes, cerebrovascular thrombosis, peripheral arterial occlusion and arterial thrombosis resulting from atrial fibrillation, valvular heart disease, arterio-venous shunts, indwelling catheters or coronary stents, the method comprising parenterally administering to a mammal a therapeutically effective amount of a salt of a pharmaceutically acceptable multivalent metal and a peptide boronic acid of formula (IV):