Boronic Acid Salts Useful in Parenteral Formulations

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.

1 . A parenteral pharmaceutical formulation comprising a therapeutically effective amount of a pharmaceutically acceptable base addition salt of a boronic acid of formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         Y comprises a hydrophobic 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 —H or halogen. 
       
     
     
         2 . The formulation of  claim 1  wherein R 9  is an alkoxyalkyl group. 
     
     
         3 . The formulation of  claim 1  wherein YCO— comprises an amino acid residue which binds to the 52 subsite of thrombin, the amino acid residue being N-terminally linked to a moiety which binds the 53 subsite of thrombin. 
     
     
         4 . The formulation of  claim 1  wherein Y comprises a dipeptide which binds to the S3 and S2 binding sites of thrombin. 
     
     
         5 . The formulation of  claim 4  wherein the 53-binding amino acid residue is of (R)-configuration, the 52-binding residue Is of (S)-configuration, and the fragment —NHCH(R 9 )—B(OH) is of (R)-configuration. 
     
     
         6 . The formulation of  claim 1  wherein R 9  is an alkoxyalkyl group. 
     
     
         7 . The formulation of  claim 1  wherein the boronic acid has a Ki for thrombin of about 100 nM or less. 
     
     
         8 . The formulation of  claim 1  wherein the salt comprises a salt of the boronic acid with metal or a strongly basic organic nitrogen-containing compound. 
     
     
         9 . The formulation of  claim 1  wherein the salt comprises a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI): 
       
         
           
           
               
               
           
         
         where n is from 1 to 6, R 2  is H, carboxylate or derivatised carboxylate, R 3  is H, C 1 -C 4  alkyl or a residue of a natural or unnatural amino acid. 
       
     
     
         10 . 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 heteratoms 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 and trifluoromethyl. 
     
     
         11 . The formulation 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. 
     
     
         12 . The formulation of  claim 9  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. 
     
     
         13 . The formulation of  claim 6  wherein the salt consists essentially of a monosodium or monolithium salt of the boronic acid. 
     
     
         14 . The pharmaceutical formulation of  claim 9  which is adapted for intravenous administration. 
     
     
         15 . A formulation in parenteral dosage form comprising a therapeutically effective amount of a pharmaceutically acceptable base addition salt of a boronic acid of formula (II): 
       
         
           
           
               
               
           
         
         where: 
         X is H or an amino-protecting group; 
         aa 1  is an amino acid residue 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 residue 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. 
       
     
     
         16 . The formulation of  claim 15  wherein aa 1  is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof. 
     
     
         17 . The formulation of  claim 16  wherein aa 1  is of R-configuration. 
     
     
         18 . The formulation of  claim 15  wherein aa 2  is a residue of an imino add of formula (IV) 
       
         
           
           
               
               
           
         
         where R 1  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 (IV) ring is 5- or 6-membered, the formula (IV) ring is unsubstituted or is substituted at one or more —CH 2 — groups by from 1 to 3 C 1 -C 3  alkyl groups. 
       
     
     
         19 . The formulation of  claim 18  wherein aa 2  is of S-configuration. 
     
     
         20 . The formulation of  claim 15 , wherein aa 1 -aa 2  is (R)-Phe-(S)—Pro and the fragment —NH—CH(R 1 )—B(OH) 2  is of R-configuration. 
     
     
         21 . The formulation of  claim 16  wherein the boronic acid Is of formula (VIII):
   X—(R)-Phe-(S)—Pro-(R)-Mpg-B(OH) 2   (VIII),   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.   
     
     
         22 . The formulation of  claim 16  wherein the salt comprises a salt of the boronic acid with an alkali metal, an aminosugar or an amine of formula (XI): 
       
         
           
           
               
               
           
         
         where n is from 1 to 6, R 2  is H, carboxylate or derivatised carboxylate, R 3  is H, C 1 -C 4  alkyl or a residue of a natural or unnatural amino acid. 
       
     
     
         23 . 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 therapeutically effective amount of a boronate salt which consists essentially of a single pharmaceutically acceptable base addition salt of a boronic add formula (II): 
       
         
           
           
               
               
           
         
         where: 
         X is H or an amino-protecting group; 
         aa 1  is an amino acid residue of R-configuration 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 residue of S-configuration having from 4 to 6 ring members; 
         C* is a chiral centre of R-configuration; and 
         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. 
       
     
     
         24 . A pharmaceutical formulation adapted for parenteral administration, whether directly or after combining with a liquid, and comprising
 a) a first species selected from a boronic acid of formula (I), and boronate ions of said boronic acid and equilibrium forms of said boronic acid and said boronate ions:   
       
         
           
           
               
               
           
         
         wherein 
         Y comprises a hydrophobic 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 pharmaceutically acceptable metal ions, said metal ions having a valency of n, lysine, arginine and aminosugars, 
         wherein the formulation has an observed stoichiometry of first to second species essentially consistent with a notional stoichiometry of 1:1 when the second species is a metal ion with a valency of 1 or is lysine, arginine or an aminosugar, or an observed stoichiometry of n:1 when the second species is a metal ion with a valency of greater than 1. 
       
     
     
         25 . A method of inhibiting thrombin in the prophylaxis or therapy of disease, comprising parenterally administering to a mammal suffering from, or at risk of suffering from, thrombosis a therapeutically effective amount of the salt defined in  claim 1 . 
     
     
         26 . 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 the salt defined in  claim 16 . 
     
     
         27 . A method for making a salt of  claim 1 , comprising:
 combining in a solvent diethanolamine and an ester of a boronic acid as defined in  claim 1 ;   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 1 .   
     
     
         28 . A medicament adapted for parenteral administration and comprising a therapeutically effective amount of a pharmaceutically acceptable base addition 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. 
     
     
         29 . A medicament of  claim 28  wherein the boronic acid has a Ki for thrombin of about 100 nM or less.