RU2000105271A - CRYSTALLINE DERIVATIVE OF DIBENZOTIAZEPINE AND ITS USE AS AN AGENT FOR ANTI-PSYCHOSIS - Google Patents

Claims (22)

1. The compound, which is a crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine.  2. The compound according to claim 1, in which the degree of purity of crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine exceeds 90%.  3. The compound according to claim 2, in which the degree of purity of crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine exceeds 99%. 4. A method for producing crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine or a pharmaceutically acceptable salt thereof, which comprises the steps of 11- crystallization (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine from a non-aromatic solvent;
and then, if a pharmaceutically acceptable salt is required, a reaction of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine with an acid that provides a pharmaceutically acceptable anion.  5. A method of obtaining crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine or its pharmaceutically acceptable salt, which includes crystallization of 11- ( 4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine from a non-aromatic solvent, and in which the solution is substantially free of water. 6. The method according to any one of p. 4 or 5, characterized in that the non-aromatic solvent is selected from an ester of the formula R ¹ CO ₂ R ² where R ¹ and R ² are alkyl groups; an ether of formula R ³ OR ⁴ where R ³ and R ⁴ are alkyl groups; and a ketone of formula R ⁵ COR ⁶ , wherein R ⁵ and R ⁶ are alkyl groups. 7. The method according to p. 6, characterized in that R ¹ , R ² , R ³ and R ⁴ are selected from (1-4 C) alkyl groups.  8. The method according to p. 6, characterized in that the non-aromatic solvent is selected from ethyl acetate, isobutyl acetate, methyl isobutyl ketone and methyl tert-butyl ether.  9. The method according to any one of paragraphs. 4-8, characterized in that the solvent is selected from methyl tert-butyl ether.  10. The method of purification of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine, including crystallization of 11- (4- [2- (2 hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine from methyl tert-butyl ether in the absence of water. 11. The method according to any one of paragraphs. 4-10, characterized in that 11-4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine and a non-aromatic solvent are heated to obtain a solution, and the temperature a solution containing 11- (4- (2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine is reduced to room temperature and then reduced to approximately 0 ^{° C.} for a period of time exceeding 1 hour. 12. The method according to p. 11, characterized in that the temperature is reduced from room temperature to 0 ^o C for a period of time in the range of from about 2 to 4 hours 13. The method according to p. 11 or 12, characterized in that the temperature is reduced from room temperature to 0 ^o With a period of time approximately equal to 3 hours  14. The method according to any one of paragraphs. 4-13, characterized in that the amount of non-aromatic solvent is such that when dissolved in it 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine receive a concentration (before crystallization) in the range of about 120 to 160 mg / ml.  15. The method according to p. 14, characterized in that the amount of non-aromatic solvent gives a concentration in the range from 135 to 145 mg / ml  16. The method according to any one of paragraphs. 4-15, characterized in that it includes the reaction of crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine with fumaric acid to for the preparation of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine salt fumarate. 17. A method of obtaining crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine or its pharmaceutically acceptable salt from a solution of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] - [1,4] thiazepine in an aromatic solvent, the method comprising the steps of:
a) adding water and acid to a solution of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine in an aromatic solvent;
b) separation of the aqueous and organic phases;
c) adding to the aqueous phase a non-aromatic solvent and base;
d) separating the aqueous phase and the non-aromatic solvent phase;
e) drying the non-aromatic solvent phase;
f) crystallization of 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine from a non-aromatic solvent; and then, if a pharmaceutically acceptable salt is required, reacting 11- (4- [2- (2-hydroxyethoxy) ethyl] piperazinyl) dibenzo [b, f] [1,4] thiazepine with an acid that provides a pharmaceutically acceptable anion.  18. The method according to p. 17, characterized in that the aromatic solvent is toluene.  19. The method according to p. 17 or 18, characterized in that stage (f) is carried out according to any one of paragraphs. 4-17.  20. A pharmaceutical composition comprising crystalline 11- (4- [2- (2-hydroxyethoxy) ethyl] -1-piperazinyl) dibenzo [b, f] [1,4] thiazepine and a pharmaceutically acceptable diluent or carrier.  21. The compound of claim 1 for the manufacture of a medicament for the treatment of neuropsychiatric disorders.  22. The compound of claim 1 for the manufacture of a medicament for the treatment of psychosis.