Multivalent metal salts of boronic acids

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.

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(R 9 )—B(OH) 2 , has affinity for the substrate binding site of thrombin; and 
         R 9  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 R 9  is —(CH 2 ) 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 R 9  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(R 9 )—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(R 9 )—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 C 1 -C 13  hydrocarbyl, wherein the C 1 -C 13  hydrocarbyl contains no heteroatoms or at least one in-chain or in-ring nitrogen, oxygen or sulfur atom, and the C 1 -C 13  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): 
       
         
           
           
               
               
           
         
       
       where:
 X is H or an amino-protecting group; 
 aa 1  is an amino acid having a hydrocarbyl side chain containing no more than 20 carbon atoms and comprising at least one cyclic group having up to 13 carbon atoms; 
 aa 2  is an imino acid having from 4 to 6 ring members; 
 R 1  is a group of the formula —(CH 2 ) s -Z, where s is 2, 3 or 4 and Z is —OH, —OMe, —OEt or halogen. 
 
     
     
         11 . The formulation of  claim 11  wherein aa 1  is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof. 
     
     
         12 . The formulation of  claim 11  wherein aa 1  is of R-configuration. 
     
     
         13 . The formulation of  claim 10  wherein aa 2  is a residue of an imino acid of formula (V) 
       
         
           
           
               
               
           
         
         where R 11  is —CH 2 —, —CH 2 —CH 2 —, —S—CH 2 —, —S—C(CH 3 ) 2 — or —CH 2 —CH 2 —CH 2 —, and, when the formula (V) ring is 5- or 6-membered, the formula (V) ring is unsubstituted or is substituted at one or more —CH 2 — groups by from 1 to 3 C 1 -C 3  alkyl groups. 
       
     
     
         14 . The formulation of  claim 13  wherein aa 2  is of S-configuration. 
     
     
         15 . The formulation of  claim 14  wherein aa 1  is of (R)-configuration and the fragment —NH—CH(R 1 )—B(OH) 2  is of (R)-configuration. 
     
     
         16 . The formulation of  claim 11 , wherein aa 1 -aa 2  is (R)-Phe-(S)-Pro and the fragment —NH—CH(R 1 )—B(OH) 2  is of R-configuration. 
     
     
         17 . The formulation of  claim 10  wherein R 1  is methoxypropyl, aa 2  is of (S)-configuration, aa 1  is of (R)-configuration and the fragment —NH—CH(R 1 )—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 R 6 (CH 2 ) p —C(O)—, R 6 —(CH 2 ) p —S(O) 2 —, R 6 —(CH 2 ) p —NH—C(O)— or R 6 —(CH 2 ) p —O—C(O)— wherein p is 0, 1, 2, 3, 4, 5 or 6 and R 6  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 C 5 -C 6  cyclic group; C 1 -C 4  alkyl and C 1 -C 4  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 C 5 -C 6  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. 
     
     
         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 S3 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): 
       
         
           
           
               
               
           
         
         where: 
         X is H or an amino-protecting group; 
         aa 1  is an amino acid having a hydrocarbyl side chain containing no more than 20 carbon atoms and comprising at least one cyclic group having up to 13 carbon atoms; 
         aa 2  is an imino acid having from 4 to 6 ring members; 
         R 1  is a group of the formula —(CH 2 ) s -Z, where s is 2, 3 or 4 and Z is —OH, —OMe, —OEt or halogen. 
       
     
     
         29 . The formulation of  claim 1  wherein the boronic acid is Cbz-(R)-Phe-(S)-Pro-(R)-boroMpg-OH. 
     
     
         30 . The formulation of  claim 1  wherein the second species is calcium.