Boronate Medicaments Suitable for Short Duration Anticoagulation
An oral dosage form of a compound selected from boronic acids which have a neutral thrombin (P1) domain linked to a hydrophobic moiety capable of binding to the thrombin (S2) and (S3) subsites, and salts, prodrugs and prodrug salts of such acids, the dosage form comprising a solid phase formulation comprising the compound and being adapted for reconstitution of the formulation to form a liquid preparation.
1 . An oral dosage form of a compound selected from boronic acids which have a neutral thrombin PI domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, and salts, prodrugs and prodrug salts of such acids, the dosage form comprising a solid phase formulation comprising the compound and being adapted for reconstitution of the formulation to form a liquid preparation.
2 . The dosage form of claim 1 wherein the thrombin P1 domain comprises a neutral aminoboronic acid residue.
3 . The dosage form of claim 1 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
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, wherein halogen is F, Cl, Br or I.
4 . The dosage form of claim 3 wherein R 9 is an alkoxyalkyl group.
5 . The dosage form of claim 3 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.
6 . The dosage form of claim 5 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.
7 . The dosage form of claim 6 wherein Y is an optionally N-terminally protected dipeptide which binds to the S3 and S2 binding sites of thrombin and the peptide linkages in the acid are optionally and independently N-substituted by a C 1 -C 13 hydrocarbyl optionally containing in-chain or in-ring nitrogen, oxygen or sulfur and optionally substituted by a substituent selected from halo, hydroxy and trifluoromethyl.
8 . The dosage form of claim 7 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 dosage form of claim 1 wherein said compound is a pharmaceutically acceptable base addition salt of a said acid.
10 . An oral pharmaceutical dosage form adapted to be reconstituted either
prior to administration into a liquid for oral administration, or
in the mouth,
and comprising a compound selected from boronic acids of formula (III) and salts, prodrugs and prodrug salts thereof:
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.
11 . The dosage form of claim 10 wherein aa 1 is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof.
12 . The dosage form 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 2 ═CH 2 —, —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 dosage form of claim 10 wherein aa 1 is of (R)-configuration, aa 2 is of (S)-configuration and the fragment —NH—CH(R 1 )—B(OH) 2 is of (R)-configuration.
14 . The dosage form of claim 10 wherein R 1 is 2-bromoethyl, 2-chloroethyl, 2-methoxyethyl, 3-bromopropyl, 3-chloropropyl or 3-methoxypropyl.
15 . The dosage form 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 halogens and/or by 1, 2 or 3 substituents selected from 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 dosage form of claim 10 wherein the boronic acid is of formula (VIII):
X—(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 (VIII).
17 . The dosage form of claim 9 wherein the salt comprises a salt of the boronic acid with a metal.
18 . The dosage form of claim 17 wherein the metal comprises an alkali metal.
19 . The dosage form of claim 1 which comprises boronate ions derived from the boronic acid and has a stoichiometry consistent with the boronate ions carrying a single negative charge.
20 . The dosage form of claim 1 which comprises:
a pharmaceutical formulation which contains said compound and is in the form of powder or granules; and
a sealed container in which the formulation is contained and from which the formulation is to be dispensed for reconstitution.
21 - 22 . (canceled)
23 . The dosage form of claim 20 wherein the container is a sachet.
24 . The dosage form of claim 1 wherein the solid phase formulation is a pharmaceutical formulation in the form of an effervescent tablet which contains an effervescent system, or is a fast melt pharmaceutical formulation.
25 . (canceled)
26 . The dosage form of claim 20 which comprises from about 0.2 to about 1.5 mol of the compound, calculated on the basis of the boronic acid.
27 . (canceled)
28 . The dosage form of claim 1 which is adapted to be reconstituted to form a solution having a volume of from about 50 ml to about 150 ml.
29 . A pharmaceutical formulation comprising a pharmaceutically acceptable base addition salt of the acid Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 , the formulation being in the form of a powder or granules in a sachet or of an effervescent tablet.
30 . A method of making an oral dosage form for preventing thrombosis, comprising:
reacting a boronic acid which has a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites with a base selected from the group consisting of basic metal compounds and organic nitrogen-containing compounds having a pKb of at least 7, to form a reaction product; and
formulating the reaction product into a solid phase formulation which comprises the reaction product and is adapted for reconstitution of the formulation to form a liquid preparation.
31 . A method for the manufacture of a medicament to be reconstituted to form a drinkable preparation, comprising making the medicament with a compound as defined in claim 1 .
32 - 33 . (canceled)
34 . A method of preparing an anticoagulant preparation, comprising reconstituting, into a liquid preparation for oral administration a solid phase formulation 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, 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.
35 . A method of inhibiting thrombin in the treatment of disease, comprising administering perorally to a subject in need thereof a therapeutically effective amount of a compound as defined in claim 1 , said compound being put into solution or suspension from a solid phase formulation prior to the compound entering the stomach.
36 . The method of claim 35 , wherein the compound is put into solution or suspension by reconstituting with a liquid prior to administration or in saliva in the mouth.
37 . A method of preventing thrombosis in the haemodialysis circuit of a patient, comprising reconstituting into a drinkable preparation a solid formulation comprising a salt as defined in claim 9 , and orally administering the drinkable preparation.
38 - 39 . (canceled)
40 . A method of preventing deep vein thrombosis during an airplane flight in a subject comprising administering to the subject a therapeutically effective amount of a compound as defined in claim 1 .
41 - 42 . (canceled)
43 . A method of preventing thrombosis in intermittent apheresis comprising administering a therapeutically effective amount of a compound as defined in claim 1 , wherein said intermittent apheresis is not hemodialysis.
44 . The method of claim 43 , wherein the intermittent apheresis is extracorporeal liver detoxification.
45 . The method of claim 43 , wherein the compound is an oral medicament or is a parenteral medicament.
46 . A method for the prevention of thrombosis in the haemodialysis circuit of a patient undergoing haemodialysis, comprising administering a therapeutically effective amount of a compound selected from boronic acids which have a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, and salts, prodrugs and prodrug salts of such acids, the compound not being a base addition salt of such a boronic acid.
47 . The method of claim 46 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 R 9 is an alkoxyalkyl group, 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, 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.
48 . The method of claim 46 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;
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.
49 . The method of claim 46 wherein the boronic acid is a compound designated TRI 50c of the following formula
Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 .
50 . The dosage form of claim 10 wherein the prodrugs are boronic acid derivatives capable of hydrolysing to release the free boronic acid.
51 . A method for preventing flight deep vein thrombosis or thrombosis in intermittent apheresis, wherein said intermittent apheresis is not hemodialysis, 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, 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.
52 . An aqueous solution comprising a pharmaceutically acceptable base addition salt of a boronic acid which has a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites, the solution having a pH of about 9 or more.
53 . The solution of claim 52 wherein the pH is about 9 to about 9.5.
54 . An aqueous solution comprising a pharmaceutically acceptable base addition salt of a boronic acid which has a neutral thrombin P1 domain linked to a hydrophobic moiety capable of binding to the thrombin S2 and S3 subsites and a pharmaceutically acceptable organic acid, the solution having a pH of from about 4 to about 8.