Methods for synthesizing organoboronic compounds and products thereof
First Claim
Patent Images
1. A process for converting a diethanolamine adduct of a boronic acid of formula (I) below to the free acid of formula (I), the process comprising:
- dissolving the adduct in an organic solvent selected from a halohydrocarbon or a mixture of halohydrocarbons;
agitating the resulting organic solution with an aqueous acid having a pH of below 3 whereby the dissolved adduct is converted to the formula (I) acid, the duration of contact between the organic solution and the aqueous acid being limited sufficiently to avoid substantial C—
B bond breakage; and
recovering the formula (I) acid by evaporation, formula (I) being;
wherein Y comprises a hydrophobic moiety which, together with the aminoboronic acid residue —
NHCH(R9)—
B(OH)2, has affinity for the substrate binding site of thrombin; and
R9 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 R9 is —
(CH2)m—
W where m is from 2, 3, 4 or 5 and W is —
OH or halogen selected from F, Cl, Br or I.
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Abstract
Organoboronic acids, for example Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2, are made by hydrolysing their diethanolamine adducts under conditions which avoid substantial C—B bond breakage. The product acids are substantially free of degradation product derived from cleavage of the C—B bond thereof. The acids are used to make base addition salts thereof. The salts are formulated into anti-thrombotic pharmaceutical formulations.
59 Citations
36 Claims
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1. A process for converting a diethanolamine adduct of a boronic acid of formula (I) below to the free acid of formula (I), the process comprising:
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dissolving the adduct in an organic solvent selected from a halohydrocarbon or a mixture of halohydrocarbons;
agitating the resulting organic solution with an aqueous acid having a pH of below 3 whereby the dissolved adduct is converted to the formula (I) acid, the duration of contact between the organic solution and the aqueous acid being limited sufficiently to avoid substantial C—
B bond breakage; and
recovering the formula (I) acid by evaporation, formula (I) being;
wherein Y comprises a hydrophobic moiety which, together with the aminoboronic acid residue —
NHCH(R9)—
B(OH)2, has affinity for the substrate binding site of thrombin; and
R9 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 R9 is —
(CH2)m—
W where m is from 2, 3, 4 or 5 and W is —
OH or halogen selected from F, Cl, Br or I. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
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19. A boronic acid which is substantially free of degradation product derived from cleavage of the C—
- B bond thereof, formula (I) being;
- View Dependent Claims (20, 21, 22)
- B bond thereof, formula (I) being;
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23. Cbz-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2 when in a diastereomeric excess of at least about 98% over the corresponding (R,S,S) isomer and substantially free of the compound:
- 24. A process for separating diastereomers of a boronic acid of formula (I):
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27. A process for making a pharmaceutically acceptable base addition salt of a boronic acid of formula (I) below, comprising:
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dissolving the boronic acid in acetonitrile;
combining the resultant solution with an aqueous solution or suspension of a pharmaceutically acceptable base, and causing or allowing the base and the boronic acid to react;
evaporating to dryness to obtain an evaporation residue;
redissolving the evaporation residue in acetonitrile and evaporating the resulting solution to dryness; and
repeating the preceding step as often as necessary to obtain a substantially dry evaporation residue, formula (I) being;
wherein Y comprises a hydrophobic moiety which, together with the aminoboronic acid residue —
NHCH(R9)—
B(OH)2, has affinity for the substrate binding site of thrombin; and
R9 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 R9 is —
(CH2)m—
W where m is from 2, 3, 4 or 5 and W is —
OH or halogen selected from F, Cl, Br or I.
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- 28. A compound selected from the group consisting of diethanolamine esters and pharmaceutically acceptable base addition salts of boronic acids of formula (I),
- 30. A compound selected from the group consisting of diethanolamine esters and pharmaceutically acceptable base addition salts of boronic acids of formula (IIIa) and in a diastereomeric excess of about 99% or more over the (R,S,S) isomer of the compound:
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35. A pharmaceutically acceptable base addition salt of a boronic acid of formula (I) below which contains a trace amount of an aliphatic or cycloaliphatic solvent, formula (I) being:
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36. A pharmaceutical formulation which comprises the following first and second species and optionally one or more other pharmaceutically acceptable components:
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a) a therapeutically effective amount of a first species selected from (i) boronic acids of formula (IIa), (ii) boronate anions of the acid, (iii) any equilibrium form of (i) or (ii), and (iv) any combination of the aforegoing;
where;
X is H (to form NH2) or an amino-protecting group;
aa1 is an amino acid 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;
aa2 is an imino acid of (S)-configuration having from 4 to 6 ring members;
C* is a chiral center of (R)-configuration;
R1 is a group of the formula —
CH2)s-Z, where s is 2, 3 or 4 and Z is —
OH, —
OMe, —
OEt or halogen selected from F, Cl, Br or I,b) a second species selected from the group consisting of (v) pharmaceutically acceptable alkali metal ions, (vi) pharmaceutically acceptable basic organic nitrogen-containing compounds having a pKb of about 7 or more, (vii) any equilibrium form of (v), and (viii) any combination of the aforegoing, wherein the formulation is substantially free of degradation product derived from cleavage of the C—
B bond of the first species.
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Specification