Polymorphic form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for the treatment of Alzheimer's disease

Patent metadata

Field	Value
Publication number	US-10071963-B2
Application number	US-201515323426-A
Country	US
Kind code	B2
Filing date	Jul 3, 2015
Priority date	Jul 4, 2014
Publication date	Sep 11, 2018
Grant date	Sep 11, 2018

Abstract

The present invention relates to a novel polymorphic form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

First claim

The invention claimed is:

1. The polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride, characterized by:
(A) an X-Ray powder diffractogram showing peaks at the following 2θ-angles: 4.63°, 6.94°, 13.89 °, 17.26° and 19.97°; or
(B) an FTIR spectrum having at least a relatively strong band intensity at the following band positions [cm −1 ]: 3426, 1586, 1089, 762 and a shoulder at 1099 cm −1 .

2. The polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride according to claim 1 , wherein said polymorphic form is characterized by said X-Ray powder diffractogram peaks, wherein said X-Ray powder diffractogram additionally shows peaks at the following 2θ-angles: 18.95°, 22.53° and 23.65°.

3. The polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride according to claim 1 , wherein said compound exhibits an X-Ray powder diffractogram as shown in FIG. 5 .

4. A process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride comprising:
(A) stirring a suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from:
(i) the group consisting of: acetonitrile, proprionitrile, acetone, methanol, ethanol, heptane, toluene, ortho xylene, meta xylene, and para xylene; or
(ii) a mixture of two or more of said organic solvents;
at a temperature below 60° C. for at least one week; and

(B) capturing said polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

5. The process according to claim 4 , wherein the organic solvent is a mixture of acetone and heptane in the ratio 1:4 or is a mixture of methanol and toluene in the ratio 1:4.

6. The process according to claim 4 , wherein said temperature below 60° C. is 45° C.-55° C.

7. The process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride of claim 4 , wherein (A) additionally comprises
adding polymorphic I, form II, amorphous or a mixture of the forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to said organic solvent at said temperature below 60° C., to produce a suspension.

8. The process according to claim 7 , wherein the organic solvent is a mixture of acetone and heptane in the ratio 1:4 or is a mixture of methanol and toluene in the ratio 1:4.

9. A process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride comprising:
(A) seeding a suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from:
(i) the group consisting of: acetonitrile, proprionitrile, acetone, methanol, ethanol, heptane, toluene, ortho xylene, meta xylene, and para xylene; or
(ii) a mixture of two or more of said organic solvents;
at a temperature below 60° C., with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride;

(B) stirring said seeded suspension for at least two days; and
(C) capturing said polymorphic form III of N-[2-(6-fluoro-1H-indol-3yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

10. The process according to claim 9 , wherein the organic solvent is a mixture of acetone and heptane in the ratio 1:4 or is a mixture of methanol and toluene in the ratio 1:4.

11. A process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride comprising:
(A) adding polymorphic I, form II, amorphous or a mixture of the forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to an organic solvent selected from:
(i) the group consisting of: acetonitrile, proprionitrile, acetone, methanol, ethanol, heptane, toluene, ortho xylene, meta xylene, and para xylene; or
(ii) a mixture of two or more of said organic solvents;
at a temperature below 60° C., to produce a suspension; and

(B) seeding with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride at a temperature below 60° C.; and
(C) capturing polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

12. The process according to claim 11 , wherein the organic solvent is a mixture of acetone and heptane in the ratio 1:4 or is a mixture of methanol and toluene in the ratio 1:4.

13. A pharmaceutical composition comprising the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride of claim 1 , and a pharmaceutically acceptable carrier or diluent.

14. A pharmaceutical composition comprising the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride of claim 2 , and a pharmaceutically acceptable carrier or diluent.

15. A pharmaceutical composition comprising the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride of claim 3 , and a pharmaceutically acceptable carrier or diluent.

16. A method of treating Alzheimer's disease as adjunctive therapy to acetylcholinesterase treatment comprising administering an effective daily dose of the pharmaceutical composition of claim 13 to a patient in need of such treatment.

17. The method according to claim 16 , wherein the effective daily dose administered to the patient of said compound is between about 30 and about 60 mg.

18. A method of treating Alzheimer's disease as adjunctive therapy to acetylcholinesterase treatment comprising administering an effective daily dose of the pharmaceutical composition of claim 14 to a patient in need of such treatment.

19. The method according to claim 18 , wherein the effective daily dose administered to the patient of said compound is between about 30 and about 60 mg.

20. A method of treating Alzheimer's disease as adjunctive therapy to acetylcholinesterase treatment comprising administering an effective daily dose of the pharmaceutical composition of claim 15 to a patient in need of such treatment.

21. The method according to claim 20 , wherein the effective daily dose administered to the patient of said compound is between about 30 and about 60 mg.

Assignees

• H Lundbeck As

Inventors

• Andersen Kristine Birklund
• Rock Michael Harold
• De Diego Heidi Lopez
• Therkelsen Frans Dennis

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D209/14 Primary

  Radicals substituted by nitrogen atoms, not forming part of a nitro radical · CPC title

• A61K31/404 Primary

  Indoles, e.g. pindolol · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4045

  Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin · CPC title