Patent EA-004748-B1 (EA)
Title: 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylat and polymorphs
Inventor: BASFORD PATRICIA ANN
IPC: C07D401/14
Filed: 2001-02-23
Abstract: 1. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate of the formula 2. The mesylate salt as claimed in claim 1, characterised in that it exhibits an endothermic thermal event at about 279 degree C during differential scanning calorimetry. 3. The mesylate salt as claimed in claim 1 or claim 2, characterised by a powder X-ray diffraction pattern obtained by irradiation with copper K-alpha, X-rays of wavelength 1.5406A, having the following main peaks: Angle 2-Theta	Intensity, % 7.392	22.9 14.733	22.6 14.813	40.1 17.694	31 18.964	40.5 19.297	57.9 20.265	51 21.414	40 22.136	24 22.934	32.8 23.842	49.4 24.795	100 27.012	30.3 28.673	22.3 29.305	24.6 4. A substantially pure anhydrous crystalline free base form of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline (designated Form E) a sample of which contains more than 90% of a single polymorphic form, characterized in that it exhibits both an endothermic thermal event at about 279 degree C and a powder X-ray diffraction pattern obtained by irradiation with copper K-alpha, X-rays of wavelength 1.5406A, having the following main peaks: Angle 2-Theta	Intensity, % 9.675	23.0 16.914	30.8 19.315	38.5 19.358	42.2 19.444	31.1 19.778	26.6 23.852	100.0 25.280	28.2 32.760	25.6 5. A free base form as claimed in claim 4, characterised in that a sample of which contains more than 99% of a single polymorphic form. 6. A pharmaceutical formulation containing 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt, as defined in any one of claims 1 to 5 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 7. 4-Amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt, as defined in any one of claims 1 to 5, for use as a pharmaceutical. 8. The use of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt, as defined in any one of claims 1 to 5 in the manufacture of a medicament for the treatment of benign prostatic hyperplasia. 9. A method of treatment of benign prostatic hyperplasia, which comprises administering a therapeutically effective amount of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in the form of the anhydrous free base or the mesylate salt, as defined in any one of claims 1 to 5 to a patient suffering from such a disorder. 10. A process for the preparation of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline mesylate, as defined in claim 1, which comprises the addition of methanesulphonic acid to a suspension or solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline of the formula in a suitable solvent, and collection of the precipitated solid. 11. A process as claimed in claim 10, wherein the solution of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is maintained at a temperature above room temperature before the addition of the methanesulphonic acid. 12. A process as claimed in claim 19 or 11, wherein the solvent used is a mixture of butanone and water. 13. A process as claimed in any one of claims 10, 11 and 12, wherein the solvent is a 10:1 by volume mixture of butanone and water. 14. A process as claimed in claim 12 or 13, comprising the steps of: (a) heating a suspension of 4-amino-6,7-dimethoxy-2-(5-methanesulfonamid-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline in butanone/water to reflux; (b) adding butanone/water until a solution is achieved; (c) cooling the solution; (d) adding methanesulfonic acid; and (e) collecting the resulting solid by filtration. 15. A process as claimed in any one of claims 10 to 14, wherein the 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl)quinazoline is present as Form E, as defined in claim 4 or 5.