Crystal forms of {[(2r)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride

• US 20060252825A1
• Filed: 04/21/2006
• Published: 11/09/2006
• Est. Priority Date: 04/22/2005
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Yu, Qing, Tadayon, Abdolsamad, Bernatchez, Michel
• Application Number:
  US11/409,303
• Publication Number:
  US 20060252825A1
• Time in Patent Office: Days
• US Class Current: 514/469
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 307/81 Radicals substituted by nitrogen atoms not forming part of a nitro radical

Abstract

The present invention is directed to crystalline forms of the 5-HT_2C agonist {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride, as well as compositions, processes of preparation, and uses thereof.

Claims

1. A crystalline polymorph (Form I) of {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride having a powder X-ray diffraction pattern comprising a characteristic peak, in terms of 2θ

, at about 10.2° and

at least one characteristic peak, in terms of 2θ

, selected from about 27.0° and

about 25.8°

.

2. The polymorph of claim 1 wherein said powder X-ray diffraction pattern comprises at least four characteristic peaks, in terms of 2θ

, selected from about 9.2°

, about 10.2°

, about 12.1°

, about 13.9°

, about 15.4°

, about 18.9°

, about 22.3°

, about 22.7°

, about 23.3°

, about 25.8°

, about 27.0°

, and about 33.0°

.

3. The polymorph of claim 1 having a powder X-ray diffraction pattern substantially as shown in FIG. 1.

4. The polymorph of claim 1 having a differential scanning calorimetry endotherm at about 234°

C.

5. A composition comprising the polymorph of claim 1.

6. The composition of claim 5 wherein at least about 90% by weight of total {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride in said composition is present as said polymorph.

7. A composition comprising the polymorph of claim 1 and a pharmaceutically acceptable carrier.

8. A composition consisting essentially of the compound {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride wherein at least 95% by weight of said compound is present in said composition as the polymorph of claim 1.

9. A process for preparing the polymorph of claim 1 comprising precipitating said polymorph from a solution comprising {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride and a crystallizing solvent.

10. The process of claim 9 wherein said crystallizing solvent comprises t-butylmethyl ether.

11. A polymorph prepared by the process of claim 9.

12. A crystalline polymorph (Form II) of {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride having a powder X-ray diffraction pattern comprising a characteristic peak, in terms of 2θ

, at about 10.3° and

at least one characteristic peak, in terms of 2θ

, selected from about 25.3°

, about 26.0°

, and about 28.4°

.

13. The polymorph of claim 12 wherein said powder X-ray diffraction pattern comprises characteristic peaks, in terms of 2θ

, at about 10.3°

, about 25.3°

, and about 26.0°

.

14. The polymorph of claim 12 wherein said powder X-ray diffraction pattern comprises at least four characteristic peaks, in terms of 2θ

, selected from about 9.3°

, about 10.3°

, about 11.9°

, about 12.4°

, about 15.5°

, about 19.1°

, about 21.1°

, about 22.3°

, about 22.8°

, about 23.4°

, about 24.0°

, about 25.3°

, about 26.0°

, and about 28.4°

.

15. The polymorph of claim 12 having a powder X-ray diffraction pattern substantially as shown in FIG. 2.

16. The polymorph of claim 12 having a differential scanning calorimetry endotherm at about 234°

C.

17. The polymorph of claim 12 having a crystal habit which is substantially needle-shaped.

18. A composition comprising the polymorph of claim 12.

19. The composition of claim 18 wherein at least about 50% by weight of total {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride in said composition is present as said polymorph.

20. The composition of claim 18 wherein at least about 90% by weight of total {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride in said composition is present as said polymorph.

21. The composition of claim 18 wherein at least about 99.0% by weight of total {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride in said composition is present as said polymorph.

22. A composition comprising the polymorph of claim 12 and a pharmaceutically acceptable carrier.

23. A composition consisting essentially of the compound {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride wherein at least 95% by weight of said compound is present in said composition as the polymorph of claim 12.

24. A composition consisting essentially of the compound {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride wherein at least 99.0% by weight of said compound is present in said composition as the polymorph of claim 12.

25. A process for preparing the polymorph of claim 12 comprising precipitating said polymorph from a solution comprising {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride and a crystallizing solvent.

26. The process of claim 25 wherein said crystallizing solvent comprises an alcohol.

27. The process of claim 26 wherein said alcohol is isopropanol.

28. The process of claim 25 further comprising seeding said solution with seed crystals of Form II of {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride.

29. The process of claim 25 wherein said precipitating is carried out by cooling said solution.

30. A polymorph prepared by the process of claim 25.

36. A method for treating schizophrenia, schizophreniform disorder, schizoaffective disorder, delusional disorder, substance-induced psychotic disorder, L-DOPA-induced psychosis, psychosis associated with Alzheimer'"'"'s dementia, psychosis associated with Parkinson'"'"'s disease, psychosis associated with Lewy body disease, dementia, memory deficit, or intellectual deficit disorder associated with Alzheimer'"'"'s disease comprising administering to a patient a therapeutically effective amount of a polymorph of claim 12.

37. The method of claim 36 wherein said patient is suffering from schizophrenia.

38. A method for treating bipolar disorders, depressive disorders, mood episodes, anxiety disorders, adjustment disorders, or eating disorders comprising administering to a patient a therapeutically effective amount of a polymorph of claim 12.

39. The method of claim 38 wherein the bipolar disorder is bipolar I disorder, bipolar II disorder, or cyclothymic disorder;

the depressive disorder is major depressive disorder, dysthymic disorder, or substance-induced mood disorder;

the mood episode is major depressive episode, manic episode, mixed episode, or hypomanic episode;

the anxiety disorder is panic attack, agoraphobia, panic disorder, specific phobia, social phobia, obsessive compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, separation anxiety disorder, or substance-induced anxiety disorder.

40. A method for treating pain, urinary incontinence, substance abuse, addiction to alcohol and other drugs, epilepsy, sleep disorders, migraines, sexual dysfunction, gastrointestinal disorders, or obesity comprising administering to a patient a therapeutically effective amount of the polymorph of claim 12.

31. A crystalline polymorph (Form II) of {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride having a powder X-ray diffraction pattern comprising characteristic peaks, in terms of 2θ

, at about 10.3° and

about 14.4° and

having an absence of peaks from about 17.0°

to about 22.0°

.

32. The polymorph of claim 31 having an absence of peaks from about 18.0°

to about 21.0°

.

33. The polymorph of claim 31 having an X-ray powder diffraction pattern substantially as shown in FIG. 3.

34. A composition comprising the polymorph of claim 31.

35. A process for preparing the polymorph of claim 31 comprising slurrying crystalline {[(2R)-7-(2,6-dichlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methyl}amine hydrochloride having Form I in water.