Boronate Medicaments for Preventing Thrombosis During Surgery
The use for the manufacture of a medicament for preventing unwanted coagulation during surgery, and particularly a Coronary Artery By pass Graft (CABG) procedure, of boronic acids of formula (I), and salts, prodrugs and prodrug salts thereof; wherein Y comprises a moiety which, together with the fragment —CH(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 (2, 3, 4) or (5) and W is —OH or halogen (F, CI, Br or I).
1 . A method for preventing unwanted coagulation during a Coronary Artery Bypass Graft (CABG) procedure, comprising administering a therapeutically effective amount of a compound selected from boronic acids of formula (I), and salts, prodrugs and prodrug salts thereof and combinations of the aforegoing:
wherein
Y comprises a moiety which, together with the fragment —CH(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 2, 3, 4 or 5 and W is —OH or halogen, wherein halogen is F, Cl, Br or I.
2 . The method of claim 1 wherein R 9 is an alkoxyalkyl group.
3 . The method of claim 1 , wherein Y comprises an amino group bonded to structural fragment —CH(R 9 )—B(OH) 2 and a hydrophobic moiety which is linked to said amino group and which, together with said structural fragment, has affinity for the substrate binding site of thrombin.
4 . The method of claim 1 wherein the boronic acid is of the formula (II):
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, 2, 3, 4 or 5 and W is —OH or halogen, and when Y′CO— is an optionally N-terminally protected dipeptide which binds to the S3 and S2 binding sites of thrombin, the peptide linkages in the acid are optionally and independently N-substituted by a C 1 -C 13 hydrocarbyl group optionally containing in-chain or in-ring nitrogen, oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl.
5 . The method of claim 4 wherein Y′CO— comprises an amino acid which binds to the S2 subsite of thrombin, the amino acid being N-terminally linked to a moiety which binds the S3 subsite of thrombin.
6 . The method of claim 4 wherein Y′CO— is an optionally N-terminally protected dipeptide which binds to the S3 and S2 binding sites of thrombin.
7 . The method of claim 5 wherein Y′CO— is N-terminally protected.
8 . The method of claim 6 wherein the S3-binding amino acid residue is of (R)-configuration, the S2-binding residue is of (S)-configuration, and the fragment —NHCH(R 9 )—B(OH) 2 is of (R)-configuration.
9 . The method of claim 8 wherein the boronic acid has a Ki for thrombin of about 100 nM or less.
10 . The method of claim 1 , wherein the boronic acid is of formula (III):
where:
X is H (to form NH 2 ) 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 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.
11 . The method of claim 10 wherein aa 1 is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof.
12 . The method of claim 10 wherein aa 2 is a residue of an imino acid of formula (IV)
where R 11 is —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —S—CH 2 —, —S—C(CH 3 ) 2 — or —CH 2 —CH 2 —CH 2 —, which residue, when the ring contained therein is 5- or 6-membered, is optionally substituted at one or more —CH 2 — groups by from 1 to 3 C 1 -C 3 alkyl groups.
13 . The method of claim 10 wherein aa 1 is of (R)-configuration, aa 2 is of (S)-configuration the fragment —NH—CH(R 1 )—B(OH) 2 is of (R)-configuration.
14 . The method of claim 10 wherein R 1 is 2-bromoethyl, 2-chloroethyl, 2-methoxyethyl, 3-bromopropyl, 3-chloropropyl or 3-methoxypropyl.
15 . The method of claim 10 where 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 optionally substituted by one or more 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, and/or linked to the cyclic group through, an in-chain O, the aforesaid alkyl groups optionally being substituted by a substituent selected from halogen, amino, nitro, hydroxy and a C 5 -C 6 cyclic group.
16 . The method of claim 10 wherein the boronic acid is of formula (VIII):
X—(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 (VIII).
17 . The method of claim 10 wherein the boronic acid is of the formula:
Cbz-(R)-Phe-(S)-Pro-(R)-boroMpg-OH.
18 . The method of claim 1 wherein the prodrugs are boronic acid derivatives capable of hydrolysing to release the free boronic acid.
19 . The method of claim 1 wherein the prodrugs comprise a cyclic derivative in which the boronyl group is derivatised to form a moiety of the formula:
where V and W are heteroatoms and the arcuate line represents a linear or branched chain of atoms.
20 . The method of claim 1 wherein the compound does not comprise a choline or ammonium salt.
21 . The method of claim 1 wherein the compound is a base addition salt of the boronic acid.
22 . The method of claim 21 wherein the compound comprises a salt of the boronic acid with an alkali metal or a strongly basic organic nitrogen-containing compound.
23 . The method of claim 21 wherein the compound comprises a salt of the boronic acid with a metal.
24 . The method of claim 23 wherein the metal is sodium or lithium.
25 . The method of claim 23 wherein the metal is an alkaline earth metal.
26 . The method of claim 1 wherein the compound comprises boronate ions derived from the boronic acid and has a stoichiometry consistent with the boronate ions carrying a single negative charge.
27 . The method of claim 1 wherein the compound is administered intravenously.
28 . The method of claim 1 further comprising administering a cardiovascular treatment agent selected from a lipid-lowering drug, a fibrate, niacin, a statin, a CETP inhibitor, a bile acid sequestrant, an anti-oxidant, a IIb/IIIa antagonist, an aldosterone inhibitor, an A2 antagonist, an A3 agonist, a beta-blocker, acetylsalicylic acid, a loop diuretic, an ace inhibitor, an antithrombotic agent with a different mechanism of action, an antiplatelet agent, a thromboxane receptor and/or synthetase inhibitor, a fibrinogen receptor antagonist, a prostacyclin mimetic, a phosphodiesterase inhibitor, an ADP-receptor (P2 T) antagonist, a thrombolytic, a cardioprotectant and a COX-2 inhibitor.
29 . A method for the prevention of thrombosis during coronary artery bypass grafting, comprising administering intravenously to a subject a therapeutically effective amount of a selective thrombin inhibitor which is a boronic acid having 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, or is a salt, prodrug or prodrug salt of such an acid.
30 . A cardiopulmonary bypass apparatus comprising a cardiopulmonary bypass circuit, wherein the circuit, or a part thereof, is coated with a compound as defined in claim 1 .
31 . A method or preventing unwanted coagulation or thrombosis during surgery, comprising administering a therapeutically effective amount of a compound selected from boronic acids as defined in claim 1 , and acid addition salts and prodrugs thereof.
32 . The method of claim 31 , wherein the prodrugs are boronic acid derivatives capable of hydrolysing to release the free boronic acid.
33 . The method of claim 1 wherein the compound is administered to a patient undergoing such a procedure or into an extracorporeal blood circuit connected to such a patient.
34 . A method for preventing unwanted coagulation during a procedure selected from the group consisting of surgery involving an extracorporeal blood circuit and surgery not involving an extracorporeal blood circuit, comprising administering a therapeutically effective amount of a compound selected from the group consisting of boronic acids as defined in claim 1 , and acid addition salts and prodrugs thereof to a patient undergoing such a procedure or into an extracorporeal blood circuit connected to such a patient.
35 . The method of claim 34 wherein the boronic acid is of formula (I):
wherein
Y comprises a moiety which, together with the fragment —CH(R 9 )—B(OH) 2 , has affinity for the substrate binding site of thrombin and wherein Y comprises an amino acid which binds to the S2 subsite of thrombin, the amino acid being N-terminally linked to a moiety which binds the S3 subsite of thrombin, R 9 is an alkoxyalkyl group; and wherein the S3-binding amino acid residue is of (R)-configuration, the S2-binding residue is of (S)-configuration, and the fragment —CH(R 9 )—B(OH) 2 is of (R)-configuration.
36 . The method of claim 34 wherein the boronic acid is of formula (III):
where:
X is H (to form NH 2 ) 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; 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, wherein halogen is F, Cl, Br or I.
37 . The method of claim 34 wherein the boronic acid is a compound designated TRI 50c of the following formula:
Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 .
38 . A method of for preventing thrombosis during Coronary Artery Bypass Grafting, comprising administering a therapeutically effective amount of a composition of matter comprising:
a) a first species selected from the group consisting of a boronic acid of formula (I) below, said acid when in the form of a boronate anion thereof, and an equilibrium form of said boronic acid and of said boronate ion, and combinations thereof:
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 2, 3, 4 or 5 and W is —OH or halogen, wherein halogen is F, Cl, Br or I; and
(b) a second species selected from the group consisting of pharmaceutically acceptable metal ions and strongly basic organic nitrogen-containing compounds.
39 . The method of claim 11 wherein aa 1 is selected from Dpa, Phe, Dcha and Cha.
40 . The method of claim 12 wherein aa 2 is an (S)-proline residue.
41 . The method of claim 15 wherein the 5 to 13-membered cyclic group is aromatic or heteroaromatic.
42 . The method of claim 22 wherein the strongly basic organic nitrogen-containing compound is guanidine, a guanidine analog or an amine.