Patent EA-004510-B1 (EA)
Title: Polymorphic form of hemisulphate 3-(n-methyl)-2(r)-pyrrolidinylmethyl)-5-(2-phenylsulphonylethyl)-1h-indole
Inventor: BENTLEY ARTHUR
IPC: C07D403/06
Filed: 2000-09-14
Abstract: 1. A crystalline, polymorphic form of a compound of formula (I) characterized by any of a powder X-ray diffraction pattern obtained using copper K-alpha1 radiation (λ=0.15046 nm) which shows main peaks at 9.28; 10.38; 11.37; 12.40; 16.84; 17.46; 17.53; 17.78; 17.98; 19.48; 20.70; 21.29; 21.45; 22.21; 22.64; 23.08; 25.20 and 25.79. 2. A compound according to claim 1 further characterized by an infrared spectrum as a KBr disc which shows significant absorption bands at nu=3385.3, 3172.0, 3143.8, 3058.0, 3022.6, 2954.8, 2928.3, 2893.5, 2650.7, 2436.4, 1622.6, 1584.1, 1480.8, 1445.6, 1362.4, 1354.4, 1304.8, 1246.0, 1229.9, 1164.3, 1149.6, 1137.5, 1087.1, 1071.7, 1019.5, 958.9, 929.8, 899.1, 878.9, 842.6, 793.8, 759.3, 751.4, 731.3, 690.4, 619.9, 606.3, 564.9, 533.7, 512.2, 503.6, 485.3, 457.5 and 428.9 cm<-1>. 3. A compound according to claim 2 further characterized by a DSC trace which shows a sharp endotherm at 226 degree C. 4. A pharmaceutical composition comprising a compound according to any one of claims 1-3 together with a pharmaceutically acceptable excipient, diluent, or carrier. 5. A pharmaceutical composition comprising a compound according to claim 4 in solid or liquid dosage form. 6. A pharmaceutical composition according to claim 5 which is a conventional, controlled release, or fast dispersion tablet or an intranasal or intravenous solution. 7. A compound according to any one of claims 1-3 for use as a medicament. 8. A compound according to any one of claims 1-3 for use in curative or prophylactic treatment of a medical condition for which an agonist of 5-HT1 receptors is indicated. 9. A compound according to claim 8 for use wherein the medical condition is migraine or an associated condition such as cluster headache, chronic paroxymal hemicrania, or headache associated with vascular disorder. 10. A compound according to claim 8 for use wherein the medical condition is depression, anxiety, an eating disorder, obesity drug abuse, hypertension, or emesis. 11. A method of curative or prophylactic treatment of a medical condition for which an agonist of 5-HT1 receptors is indicated which comprises the administration of a therapeutically effective amount of a compound according to any one of claims 1-3. 12. A method according to claim 11 wherein the medical condition is migraine or an associated condition such as cluster headache, chronic paroxymal hemicrania, or headache associated with vascular disorder. 13. A method according to claim 11 wherein the medical condition is depression, anxiety, an eating disorder, obesity drug abuse, hypertension, or emesis. 14. A process for the preparation of a crystalline, polymorphic form of a compound of formula (I) characterized by any of a powder X-ray diffraction pattern obtained using copper K-alpha1 radiation (λ=0.15046 nm) which shows main peaks at 9.28; 10.38; 11.37; 12.40; 16.84; 17.46; 17.53; 17.78; 17.98; 19.48; 20.70; 21.29; 21.45; 22.21; 22.64; 23.08; 25.20 and 25.79. which comprises treatment of a solution of a compound of formula (II) in a first suitable solvent with concentrated sulphuric acid, followed by either (a) heating under reflux in the first solvent, cooling and isolating desired polymorph; or (b) isolating the resulting slurry, taking up in second solvent, heating under reflux, cooling and isolating desired polymorph. 15. A process according to claim 14 wherein the first solvent is acetone or tetrahydrofuran. 16. A process according to claim 14 wherein the first solvent is acetone or tetrahydrofuran and the second solvent is acetone, tetrahydrofuran, ethanol, isopropanol, or industrial methylated spirit. 17. A process according to any one of claims 14-16 wherein crystallization of desired polymorph is induced by seeding. 18. A process according to any of claims 14-17 wherein the polymorph so obtained is further characterised by its infrared spectrum as a KBr disc which shows significant absorption bands at nu=3385.3; 3172.0; 3143.8; 3058.0; 3022.6; 2954.8; 2928.3; 2893.5; 2650.7; 2436.4; 1622.6; 1584.1; 1480.8; 1445.6; 1362.4; 1354.4; 1304.8; 1246.0; 1229.9; 1164.3; 1149.6; 1137.5; 1087.1; 1071.7; 1019.5; 958.9; 929.8; 899.1; 878.9; 842.6; 793.8; 759.3; 751.4; 731.3; 690.4; 619.9; 606.3; 564.9; 533.7; 512.2; 503.6; 485.3; 457.5 and 428.9 cm<-1>. 19. A process according to claim 18 wherein the hemisulphate polymorph so obtained is further characterised by a DSC trace which shows a sharp endotherm at 226 degree C.