US2008234228A1PendingUtilityA1
Boronic acid salts
Est. expirySep 9, 2022(expired)· nominal 20-yr term from priority
Inventors:David Jonathan MadgeMark DolmanJohn Joseph DeadmanAnthony James KennedySophie Marie Combe-MarzelleSanjay Kumar Kakkar
A61P 7/00C07K 5/06191A61P 9/00C07K 5/06078A61P 7/02A61K 38/00
57
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Claims
Abstract
Salts of a peptide boronic add 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.
Claims
exact text as granted — not AI-modified1 . 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 2, 3, 4 or 5 and W is —OH or halogen (F, Cl, Br or I).
2 . A salt of paragraph 1 wherein R 9 is an alkoxyalkyl group.
3 . A salt of paragraph 1 or paragraph 2 wherein YCO— 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.
4 . A salt of paragraph 1 or paragraph 2 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.
5 . A salt of paragraph 4 wherein said dipeptide is N-terminally protected.
6 . A salt of paragraph 4 or paragraph 5 wherein all the peptide linkages in the acid are unsubstituted.
7 . A salt of any of paragraphs 1 to 6 wherein 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) is of R configuration.
8 . A salt of any of paragraphs 1 to 7 wherein the boronic acid has a Ki for thrombin of about 100 nM or less.
9 . A salt of paragraph 8 wherein the boronic add has a Ki for thrombin of about 20 nM or less.
10 . A pharmaceutically acceptable base addition salt of a boronic acid of formula (II):
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 amino 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 (F, Cl, Br or I).
11 . A salt of paragraph 10 wherein aa 1 is selected from Phe, Dpa and wholly or partially hydrogenated analogues thereof.
12 . A salt of paragraph 10 wherein aa 1 is selected from Dpa, Phe, Dcha and Cha.
13 . A salt of any of paragraphs 10 to 12 wherein aa 1 is of R-configuration.
14 . A salt of paragraph 10 wherein aa 1 is (R)-Phe or (R)-Dpa.
15 . A salt of paragraph 10 wherein aa 1 is (R)-Phe.
16 . A salt of any of paragraphs 10 to 15 wherein aa 2 is a residue of an imino add of formula (IV)
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 —, which group, when the ring 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.
17 . A salt of paragraph 16 wherein aa 2 is of S-configuration.
18 . A salt of paragraph 16 wherein aa 2 is an (S)-proline residue.
19 . A salt of paragraph 10 , wherein aa 1 -aa 2 is (R)-Phe-(S)-Pro.
20 . A salt of any of paragraphs 10 to 19 wherein the fragment —NH—CH(R 1 )—B(OH) 2 is of R configuration.
21 . A salt of any of paragraphs 10 to 20 wherein R 1 is 2-bromoethyl, 2-chloroethyl, 2-methoxyethyl, 3-bromopropyl, 3-chloropropyl or 3-methoxypropyl.
22 . A salt of any of paragraphs 10 to 20 wherein R 1 is 3-methoxypropyl.
23 . A salt of paragraph 10 which is a salt of a compound of formula (VIII):
X—(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 (VIII).
24 . A salt of any of paragraphs 10 to 23 where X is R 6 —(CH 2 ) p —C(O)—, R 6 —(CH 2 ) p —S(O) 2 —, R 6 —(CH 2 )pNH—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 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, 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.
25 . A salt of paragraph 24 wherein said 5 to 13-membered cyclic group is aromatic or heteroaromatic.
26 . A salt of paragraph 25 wherein said 5 to 13-membered cyclic group is phenyl or a 6-membered heteroaromatic group.
27 . A salt of any of paragraphs 24 to 26 wherein X is R 6 —(CH 2 )pC(O)— or R 6 —(CH 2 )p-O—C(O)— and p is 0 or 1.
28 . A salt of any of paragraphs 10 to 22 wherein X is benzyloxycarbonyl.
29 . A salt of any of paragraphs 1 to 28 which does not comprise a choline or ammonium salt.
30 . A salt of any of paragraphs 1 to 29 which comprises boronate ions derived from the boronic acid and monovalent counter-ions.
31 . A salt of any of paragraphs 1 to 29 which is a salt of the peptide boronic acid with an alkali metal or a strongly basic organic nitrogen-containing compound.
32 . A salt of paragraph 21 wherein the strongly basic organic nitrogen compound has a pKb of about 7 or more, e.g. about 7.5 or more.
33 . A salt of paragraph 31 or paragraph 32 wherein the strongly basic organic nitrogen-containing compound is a guanidine, a guanidine analogue or an amine.
34 . A salt of any of paragraphs 1 to 33 which is a salt of the boronic acid with a metal.
35 . A salt of any of paragraphs 1 to 28 which is 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.
36 . A salt of any of paragraphs 1 to 28 which is a salt of the boronic acid with a guanidine or with an amine of formula (IX):
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.
37 . A salt of paragraph 36 which is a guanidine salt of the boronic acid.
38 . A salt of paragraph 37 which is a salt of the boronic acid with L-arginine or an L-arginine analogue.
39 . A salt of paragraph 38 wherein the L-arginine analogue is D-arginine, or the D- or L-isomers of homoarginine, agmatine [(4-aminobutyl)guanidine], NG-nitro-L-arginine methyl ester, or a 2-amino pyrimidines.
40 . A salt of paragraph 37 which is a salt of the boronic acid with a guanidine of formula (VII)
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.
41 . A salt of paragraph 40 where the derivatised carboxylate forms a C 1 -C 4 alkyl ester or amide.
42 . A salt of paragraph 40 or paragraph 41 wherein the compound of formula (VII) Is of L-configuration.
43 . A salt of paragraph 37 which is an L-arginine salt of the peptide boronic acid.
44 . A salt of paragraph 36 which is a salt of the boronic acid with an amine of formula (IX).
45 . A salt of paragraph 41 where the derivatised carboxylate forms a C 1 -C 4 alkyl ester or amide.
46 . A salt of paragraph 44 or paragraph 45 wherein the amine of formula (1X) is of L-configuration.
47 . A salt of paragraph 44 which is an L-lysine salt of the boronic acid.
48 . A salt of any of paragraphs 1 to 28 which is a potassium salt.
49 . A salt of any of paragraphs 1 to 28 which is a sodium salt.
50 . A salt of any of paragraphs 1 to 28 which is a lithium salt.
51 . A salt of any of paragraphs 1 to 28 which is an aminosugar salt.
52 . A salt of paragraph 51 wherein the aminosugar is a ring-opened sugar.
53 . A salt of paragraph 52 wherein the aminosugar is a glucamine.
54 . A salt of paragraph 51 wherein the aminosugar is a cyclic aminosugar.
55 . A salt of any of paragraphs 51 to 54 wherein the aminosugar is N-unsubstituted.
56 . A salt of any of paragraphs 51 to 54 wherein the aminosugar is N-substituted by one or two substituents.
57 . A salt of paragraph 56 wherein the or each substituent is a hydrocarbyl group.
58 . A salt of paragraph 57 wherein the or each substituent Is selected from the group consisting of C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 and C 8 alkyl groups
59 . A salt of any of paragraphs 56 to 58 wherein there is a single N-substituent.
60 . A salt of paragraph 51 wherein the glucamine is N-methyl-D-glucamine.
61 . A salt of any of paragraphs 1 to 60 which comprises boronate ions derived from the peptide boronic acid and has a stoichiometry consistent with the boronate ions carrying a single negative charge.
62 . A salt of any of paragraphs 1 to 60 wherein the salt consists essentially of acid salt in which one B—OH group of the boronate group, when trigonally represented, remains protonated.
63 . A salt of any of paragraphs 1 to 62 wherein the salt comprises a boronate ion derived from the peptide boronic acid and a counter-ion and wherein the salt consists essentially of a salt having a single type of counter-ion.
64 . A salt of any of paragraphs 1 to 28 which is a monolithium or monosodium salt.
65 . A salt of paragraph 23 which is a monolithium or monosodium salt.
66 . A solid phase monosodium or monolithium salt, containing no more than 1% water by weight, of Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 .
67 . A salt of paragraph 66 which contains no more than 0.5% water by weight.
68 . A salt of paragraph 66 which contains no more than 0.1% water by weight.
69 . A salt of any of paragraphs 66 to 68 which is the monosodium salt.
70 . A salt of any of paragraphs 1 to 65 which is in the solid phase.
71 . A salt of paragraph 70 which is substantially dry.
72 . A product for use as a pharmaceutical, comprising a salt of any of paragraphs 1 to 71 .
73 . A pharmaceutical formulation in oral dosage form comprising a salt of any of paragraphs 1 to 71 and a pharmaceutically acceptable diluent, excipient or carrier.
74 . A formulation of paragraph 73 which is a solid formulation.
75 . A pharmaceutical formulation of paragraph 74 which is adapted to release the salt in the duodenum.
76 . A pharmaceutical formulation of paragraph 75 which is enterically coated.
77 . The use of a salt of any of paragraphs 1 to 71 for the manufacture of a medicament for treating thrombosis.
78 . The use of paragraph 77 wherein the disease is an acute coronary syndrome.
79 . The use of paragraph 77 wherein the disease is acute myocardial infarction.
80 . The use of paragraph 77 wherein the disease is a venous thromboembolic event, selected from the group consisting of deep vein thrombosis and pulmonary embolism.
81 . The use of a salt of any of paragraphs 1 to 71 for the manufacture of an oral medicament 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, or for preventing thromboembolic events in a patient undergoing a lower limb arterial reconstructive procedure.
82 . The use of a salt of any of paragraphs 1 to 71 for the manufacture of an oral medicament 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.
83 . An oral pharmaceutical formulation comprising a combination of (i) a salt of any of paragraphs 1 to 71 and (ii) a further pharmaceutically active agent.
84 . An oral pharmaceutical formulation comprising a combination of (i) a salt of any of paragraphs 1 to 71 and (ii) another cardiovascular treatment agent.
85 . A formulation of paragraph 84 wherein the other cardiovascular treatment agent comprises a lipid-lowering drug, a fibrate, niacin, a statin, a CETP inhibitor, a bile acid sequestrant, an anti-oxidant, a IIb/IIa antagonist, an aidosterone Inhibitor, an A2 antagonist, an A3 agonist, a betablocker, 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 (P 2 T) antagonist, a thrombolytic, a cardloprotectant or a COX-2 inhibitor.
86 . A formulation of any of paragraphs 83 to 85 which is substantially dry.
87 . The use of a salt of any of paragraphs 1 to 71 for the manufacture of a medicament for treating, for example preventing, a cardiovascular disorder in co-administration with another cardiovascular treatment agent.
88 . A oral medicament comprising a salt of a boronic acid which is a selective thrombin inhibitor and has a neutral aminoboronic acid residue capable of binding to the thrombin Si 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:l.
89 . A medicament of paragraph 88 wherein the boronic acid has a Ki for thrombin of about 100 nM or less, and optionally of about 20 nM or less.
90 . A pharmaceutical formulation adapted for oral administration and comprising in the solid phase a compound which is a source of boronate species corresponding to the acid Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH) 2 and a source of pharmaceutically acceptable cations other than choline and ammonium.
91 . A method for forming a boronic acid of formula (I) or a product capable of being a source of such a boronic acid in vivo:
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 (F, CI, Br or I), the method comprising:
providing a diethylether solution of an ester of the acid;
dissolving diethanolamine in the solution;
allowing or causing a precipitate to form and recovering the precipitate, and
converting the precipitated material into an end product selected from the free organoboronic acid or a product capable when in vivo of being a source of such a boronic acid.
92 . The method of paragraph 91 , which further comprises formulating said end product into a pharmaceutical composition.
93 . A method for forming a salt of any of paragraphs 1 to 71 , comprising: combining an acetonitrile solution of the corresponding boronic add with a pharmaceutically acceptable base to form the salt.
94 . A method of stabilising an organoboronic acid, comprising providing it in the form of a salt thereof.
95 . A method of presenting an organoboronic add drug in stabilised form for pharmaceutical use, comprising providing the organoboronic acid drug in the form of a pharmaceutically acceptable base addition salt thereof in the solid phase.Join the waitlist — get patent alerts
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