Process for the preparation of a hydrate of an anthranilic acid derivative
View Patent ↗A hydrate of an acid addition bis-salt of an anthranilic acid derivative is produced by a process which comprises: (a) combining, in any order, the anthranalic acid derivative, a pharmaceutically acceptable organic solvent, an excess of water and a pharmaceutically acceptable strong acid to form a mixture; (b) warming the mixture until a clear solution forms; (c) filtering the solution while it is warm, to yield a filtrate; and (d) recovering the hydrate as defined above from the filtrate. The hydrate has a defined number of moles of water of crystallization and possesses better storage stability and dissolution characteristics than conventionally produced hydrates of such acid addition bis-salts.
1. A process for producing a hydrate of an acid addition salt of a compound of formula (I):
wherein R 11 and R 21 , which may be the same or different, are each hydrogen or alkoxy;
R 31 and R 41 , which may be the same or different, are each independently selected from H, C 1 -C 6 alkyl, CF 3 , a halogen, NH 2 , NO 2 , NHOH, C 1 -C 6 alkoxy, hydroxy and phenyl; or R 31 and R 41 , when situated on adjacent carbon atoms, form together with the carbon atoms to which they are attached a benzene ring or a methylenedioxy substituent;
R 51 is a group selected from pyridine, quinoline, isoquinoline, 5,6,7,8-tetrahydroquinoline and 5,6,7,8-tetrahydroisoquinoline, the group being unsubstituted or substituted by C 1 -C 6 alkyl or C 1 -C 6 alkoxy;
r is 0 or 1, and
s is 1, 2, or 3;
which process comprises:
(a) combining, in any order, a compound of formula (I) as defined above, a pharmaceutically acceptable organic solvent, an excess of water and a pharmaceutically acceptable strong acid to form a mixture;
(b) warming the mixture until a clear solution forms;
(c) filtering the solution while it is warm, to yield a filtrate; and
(d) recovering the hydrate as defined above from the filtrate.
2. A process according to claim 1 wherein the hydrate is recovered by diluting the filtrate with an anti-solvent.
3. A process according to claim 2 wherein the anti-solvent is pre-filtered acetone.
4. A process according to claim 1 wherein the pharmaceutically acceptable solvent is an alcohol.
5. A process according to claim 4 wherein the alcohol is selected from ethanol, npropanol, isopropanol, benzyl alcohol and propylene glycol.
6. A process according to claim 1 wherein the pharmaceutically acceptable strong acid is methanesulphonic acid.
7. A process according to claim 1 wherein the compound of formula (I) is quinoline-3-carboxylic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenylcarbamoyl}-4,5-dimethoxyphenyl) amide.
8. A hydrate of an acid addition salt of a compound of formula I as defined in claim 1 , formed with a pharmaceutically acceptable strong acid, wherein the hydrate incorporates x moles of a water of crystallisation per mole of the compound, in which x is an integer from 1 to 6.
9. A hydrate according to claim 8 wherein the pharmaceutically acceptable strong acid is methanesulphonic acid.
10. A hydrate according to claim 8 which is the hexahydrate of the bismesylate of quinoline-3-carboxylic acid (2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin -2-yl)-ethyl]-phenylcarbamoyl}-4,5-dimethoxyphenyl) amide.
11. A hydrate which is obtainable by a process as defined in claim 1 .
12. A pharmaceutical or veterinary composition comprising a hydrate as defined in claim 8 and a pharmaceutically or veterinarily acceptable carrier or diluent.
13. A hydrate as defined in claim 8 for use in a method of medical treatment of the human or animal body by therapy.