Boronic acid salts useful in parenteral formulations
First Claim
Patent Images
1. A parenteral pharmaceutical formulation comprising a pharmaceutically acceptable base addition salt of a boronic acid of formula (VIII):
-
X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2
(VIII),wherein X is R6—
(CH2)p—
C(O)—
, R6—
(CH2)p—
S(O)2—
, R6—
(CH2)p—
NH—
C(O)—
or R6—
(CH2)p—
O—
C(O)—
, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R6 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 C5-C6 cyclic group;
C1-C4 alkyl and C1-C4 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 C5-C6 cyclic group,wherein the salt in the parenteral pharmaceutical formulation is a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI);
3 Assignments
0 Petitions
Accused Products
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.
-
Citations
48 Claims
-
1. A parenteral pharmaceutical formulation comprising a pharmaceutically acceptable base addition salt of a boronic acid of formula (VIII):
-
X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2
(VIII),wherein X is R6—
(CH2)p—
C(O)—
, R6—
(CH2)p—
S(O)2—
, R6—
(CH2)p—
NH—
C(O)—
or R6—
(CH2)p—
O—
C(O)—
, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R6 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 C5-C6 cyclic group;
C1-C4 alkyl and C1-C4 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 C5-C6 cyclic group,wherein the salt in the parenteral pharmaceutical formulation is a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI); - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
-
-
19. 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 pharmaceutically acceptable base addition salt of a boronic acid of formula (VIII), wherein the boronic acid is pharmaceutically active:
-
X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2
(VIII),wherein X is R6—
(CH2)p—
C(O)—
, R6—
(CH2)p—
S(O)2—
, R6—
(CH2)p—
NH—
C(O)—
or R6—
(CH2)p—
O—
C(O)—
, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R6 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 C5-C6 cyclic group;
C1-C4 alkyl and C1-C4 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 C5-C6 cyclic group,wherein the salt in the pharmaceutical product is a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI); - View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27)
-
-
28. A method of treating thrombosis, comprising parenterally administering to a mammal suffering from, or at risk of suffering from, thrombosis a therapeutically effective amount of a composition comprising a pharmaceutically acceptable base addition salt of a boronic acid of formula (VIII):
-
X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2
(VIII),wherein X is R6—
(CH2)p—
C(O)—
, R6—
(CH2)p—
S(O)2—
, R6—
(CH2)p—
NH—
C(O)—
or R6—
(CH2)p—
O—
C(O)—
, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R6 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 C5-C6 cyclic group;
C1-C4 alkyl and C1-C4 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 C5-C6 cyclic group,wherein the salt is a salt of the boronic acid with an alkali metal, an aminosugar, a guanidine or an amine of formula (XI); - View Dependent Claims (29, 30, 31, 32, 33, 34, 35, 36, 37, 38)
-
-
39. A pharmaceutical formulation adapted for parenteral administration, whether directly or after combining with a liquid, and the pharmaceutical formulation comprising:
-
a) a first component selected from the group consisting of (i) a boronic acid of formula (VIII) below, (ii) boronate ions of the boronic acid of formula (VIII) below, and (iii) an equilibrium form of the boronic acid of formula (VIII) below and boronate ions of the boronic acid of formula (VIII) below, and (iv) combinations thereof;
X-(R)-Phe-(S)-Pro-(R)-Mpg-B(OH)2
(VIII),wherein X is R6—
(CH2)p—
C(O)—
, R6—
(CH2)p—
S(O)2—
, R6—
(CH2)p—
NH—
C(O)—
or R6—
(CH2)p—
O—
C(O)—
, wherein p is 0, 1, 2, 3, 4, 5 or 6 and R6 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 C5-C6 cyclic group;
C1-C4 alkyl and C1-C4 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 C5-C6 cyclic group; and(b) a second, pharmaceutically acceptable, component selected from the group consisting of alkali metal ions, aminosugars, guanidines and amines of formula (XI); - View Dependent Claims (40, 41, 42, 43, 44, 45, 46, 47, 48)
-
Specification