Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms

• US 20060106063A1
• Filed: 09/26/2005
• Published: 05/18/2006
• Est. Priority Date: 09/27/2004
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Blatter, Fritz, Thygesen, Mikkel Boas, Schlienger, Nathalie, Tolf, Bo-Ragnar, Andersson, Carl-Magnus A., Berghausen, Jorg
• Granted Patent: US 7,732,615 B2
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 211/58 attached in position 4

Abstract

Disclosed herein are methods for synthesizing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide. Also disclosed herein is the hemi-tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide and methods for obtaining the salt. Further disclosed are various crystalline forms of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)-phenylmethyl)carbamide and its hemi-tartrate salt including various polymorphs and solvates.

Claims

1. A method for the preparation of a compound of formula I

2. The method of claim 1, wherein about 0.9 to about 1.1 equivalents of the (4-fluorobenzyl)-(1-methylpiperidin-4-yl)amine is used per equivalent of the 4-(2-methylpropyloxy)phenylmethyl-isocyanate.

4. A method for the preparation of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide hemi-tartrate, comprising performing the reaction of claim 1;

adding tartaric acid after the reaction; and

isolating the hemi-tartrate salt formed.

5. The method of claim 4, wherein the isolating comprises obtaining the hemi-tartrate salt from a suspension formed after addition of tartaric acid.

6. The method of claim 4, wherein the isolating comprises precipitating the hemi-tartrate salt by cooling, solvent removal, adding a non-solvent, or a combination of these methods.

33. The method of claim 1, further comprising isolating the compound of formula I after said reacting.

34. The method of claim 33, wherein the isolating comprises:

adding a salt-forming acid after said reacting;

isolating the formed salt by solvent removal, precipitation, or both solvent removal and precipitation;

adding the isolated salt to a two phase system comprising an organic solvent phase and an alkaline aqueous phase; and

obtaining the compound of formula I from the organic solvent phase.

35. The method of claim 34, wherein the salt forming acid is selected from the group consisting of one or more of the following:

mineral acids, mono- or dicarboxylic acids, and sulfonic acids.

36. The method of claim 34, wherein the pH of the aqueous phase is greater than about 8.5.

37. The method of claim 1, wherein the reaction is carried out in the presence of an inert organic solvent.

38. The method of claim 37, wherein the inert organic solvent is selected from the group consisting of one or more of the following:

aliphatic ethers, esters of aliphatic carboxylic acids, alcohols, lactones, halogenated hydrocarbons, and aliphatic C₃-C₈ketones.

39. The method of claim 1, wherein the reaction is carried out at a temperature from about −

30°

C. to about 60°

C.

40. The method of claim 34, further comprising adding an aqueous alkaline metal hydroxide.

3. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide hemi-tartrate of formula IV,

53. A method of delivering the compound of formula I to a host:

54. A method of inhibiting an activity of a monoamine receptor, comprising administering to a subject the compound of claim 3.

55. A method for the treatment of neuropsychiatric diseases, comprising administering to a subject the compound of claim 3.

56. The method of claim 55, wherein the neuropsychiatric disease is selected from the group consisting of psychosis, schizophrenia, schizoaffective disorders, mania, psychotic depression, affective disorders, dementia, anxiety, sleep disorders, appetite disorders, bipolar disorder, psychosis secondary to hypertension, migraine, vasospasm, and ischemia, motor tics, tremor, psychomotor slowing, bradykinesia, and neuropathic pain.

57. A method for the treatment of neurodegenerative diseases, comprising administering to a subject the compound of claim 3.

58. The method of claim 57, wherein the neurodegenerative disease is selected from the group consisting Parkinson'"'"'s disease, Huntington'"'"'s disease, Alzheimer'"'"'s disease, Spinocerebellar Atrophy, Tourette'"'"'s Syndrome, Friedrich'"'"'s Ataxia, Machado- Joseph'"'"'s disease, Lewy Body Dementia, Dystonia, Progressive Supranuclear Palsy, and Frontotemporal Dementia.

59. A method for treating dyskinesia associated with dopaminergic therapy, comprising administering to a subject the compound of claim 3.

60. A method for treating dystonia, myoclonus, or tremor associated with dopaminergic therapy, comprising administering to a subject the compound of claim 3.

61. A method for treating a thrombotic condition, comprising administering to a subject the compound of claim 3.

62. The method of claim 61, wherein the thrombotic condition is selected from the group consisting of myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopenic purpura, peripheral vascular disease, and Raynaud'"'"'s disease.

7. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide hemi-tartrate that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 18.6, about 16.7, about 10.2, about 6.2, about 6.1, about 4.63, about 4.49, about 4.44, and about 3.96.

8. The crystalline form of claim 7 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 18.6, about 16.7, about 10.2, about 8.2, about 7.7, about 7.4, about 6.5, about 6.2, about 6.1, about 5.86, about 5.14, about 5.03, about 4.78, about 4.69, about 4.63, about 4.49, about 4.44, about 4.35, about 4.10, about 3.96, and about 3.66.

9. A method for the preparation of the crystalline form of claim 7, comprising:

dissolving the compound of formula IV in ethanol or an admixture of ethanol and isopropanol;

cooling the solution to a temperature of less than about 20°

C.; and

isolating any resulting precipitated solid.

10. The method of claim 9, wherein the temperature during the dissolution step is about 55 to about 90°

C.

11. The method of claim 9, wherein the cooling rate during the cooling step is about 0.1 to about 3°

C./minute.

50. A pharmaceutical composition comprising the crystalline form of claim 7 and a pharmaceutically acceptable carrier or diluent.

12. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate produced by a method comprising;

dissolving the compound of formula IV in ethanol or an admixture of ethanol and isopropanol at a temperature of about 55 to about 90°

C.;

cooling the solution to a temperature of less than about 20°

C. at a rate of about 0.1 to about 3°

C./minute; and

isolating any resulting precipitated solid.

13. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 17.4, about 10.2, about 5.91, about 4.50, about 4.37, and about 3.87.

14. The crystalline form of claim 13 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 17.4, about 10.2, about 8.8, about 6.4, about 5.91, about 5.46, about 4.99, about 4.90, about 4.62, about 4.50, about 4.37, about 4.20, about 3.87, about 3.73, about 3.58, about 3.42, and about 2.90.

51. A pharmaceutical composition comprising the crystalline form of claim 13 and a pharmaceutically acceptable carrier or diluent.

15. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 12.0, about 10.7, about 5.86, about 4.84, about 4.70, about 4.57, and about 3.77.

16. The crystalline form of claim 15 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 12.0, about 10.7, about 7.4, about 6.9, about 6.6, about 6.2, about 5.86, about 5.53, about 5.28, about 5.16, about 4.84, about 4.70, about 4.57, about 4.38, about 4.09, about 3.94, about 3.77, about 3.71, about 3.49, about 3.46, about 3.25, about 3.08, and about 2.93.

17. A method for the preparation of the crystalline form of claim 15, comprising:

suspending of a solid form of a compound of formula IV in an aprotic solvent;

stirring the suspension while adding crystal seeds of the crystalline form of claim 15;

and

isolating the crystalline form of claim 15 from the suspension.

18. The method of claim 17, wherein the temperature of the solvent during the suspending step is from about 30 to about 100°

C.

19. The method of claim 17, wherein the aprotic solvent is selected from the group comprising of one or more of the following:

aliphatic or cyclic ethers, carboxylic esters, lactones, alkanes, and aliphatic C₃-C₈ketones.

20. The method of claim 17, wherein the seeding is carried out at a temperature from about 40 to about 80°

C.

21. The method of claim 17, further comprising cooling the suspension at a rate from about 0.1 to about 1°

C./minute.

22. The method of claim 21, wherein the suspension is cooled to about room temperature.

23. A method for the preparation of the crystalline form of claim 15, comprising:

suspending a crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate or mixtures of crystalline forms of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate in a polar and aprotic solvent at temperatures from about 30 to about 70°

C.;

stirring the suspension while adding crystal seeds of the crystalline form of claim 15;

and

isolating of the crystalline solid from the suspension.

24. A method for the preparation of the crystalline form of claim 15, comprising:

dissolving a tartrate salt of N-(4-fluorobenzyl)-N-(1 -methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide in a solvent at temperatures from about 0 to about 70°

C.;

stirring the resulting solution at a temperature of about 50 to about 70°

C. while adding crystal seeds of the crystalline form of claim 15;

cooling the obtained suspension at a cooling rate of about 5 to about 15°

C. per hour to a temperature of about −

20°

C. to about room temperature; and

isolating crystalline solid from the suspension.

25. The method of claim 24, wherein the solvent is tetrahydrofuran.

26. The method of claim 24, wherein the solvent is selected from the group consisting of acetone, dichloromethane, 1,4-dioxane, ethanol, isopropanol, and acetonitrile.

27. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate produced by a process comprising;

suspending a crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate or mixtures of crystalline forms of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate in a polar and aprotic solvent at temperatures from about 30 to about 70°

C.;

stirring the suspension while adding crystal seeds of the crystalline form of claim 15;

and

isolating of the crystalline solid from the suspension.

28. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate produced by a process comprising;

dissolving a tartrate salt of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide in tetrahydrofuran or acetone at temperatures from about 0 to about 70°

C.;

stirring the resulting solution at a temperature of about 50 to about 70°

C. while adding crystal seeds of the crystalline form of claim 15;

cooling the obtained suspension at a cooling rate of about 5 to about 15°

C. per hour to a temperature of about −

20°

C. to about room temperature; and

isolating crystalline solid from the suspension.

52. A pharmaceutical composition comprising the crystalline form of claim 15 and a pharmaceutically acceptable carrier or diluent.

29. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate comprising from about 0% to about 6.6% isopropanol or ethanol that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 17.2, about 16.0, about 6.1, about 4.64, about 4.54, and about 4.37.

30. The crystalline form of claim 29 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 17.2, about 16.0, about 10.7, about 9.8, about 6.6, about 6.1, about 6.00, about 5.73, about 5.33, about 5.17, about 4.91, about 4.64, about 4.54, about 4.37, about 4.10, about 3.91, about 3.84, about 3.67, about 3.55, about 3.42, about 3.32, about 3.13, and about 3.06.

31. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate comprising about 5% t-butyl methyl ether that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 17.3, about 16.2, about 10.6, about 9.8, about 8.1, about 7.5, about 6.6, about 6.0, about 5.28, about 5.09, about 4.90, about 4.72, about 4.51, about 4.39, about 4.26, about 4.04, about 3.86, about 3.70, about 3.54, about 3.48, and about 3.02.

32. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate comprising about 3% of tetrahydrofuran that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 19.0, about 16.0, about 13.0, about 7.8, about 6.4, about 6.2, about 5.74, about 5.29, about 5.04, about 4.83, about 4.62, about 4.50, about 4.34, about 4.24, about 4.05, about 3.89, about 3.76, about 3.58, and about 3.27.

41. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide produced by the process comprising;

dissolving a hemi-tartrate salt of a compound of formula I in water;

adding an amount of an organic aprotic solvent to the aqueous salt solution sufficient to dissolve the compound of formula I;

adjusting the pH of the aqueous salt solution to a value of at least about 8.5 by addition of a base;

extracting the aqueous solution with the organic solvent and collecting all organic phases;

removing a part of the organic aprotic solvent;

cooling the remaining organic aprotic solution to less than 15°

C.; and

isolating any precipitate formed.

42. A crystalline form of N-(4-fluorobenzyl)-N-(1 -methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide that exhibits a melting point of about 124°

C., determined with Differential Scanning Calorimetry (DSC) at a heating rate of 10°

C./minute.

43. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 13.0, about 10.9, about 6.5, about 4.7, about 4.3, about 4.22, and about 4.00.

44. The crystalline form of claim 43 that exhibits a X-ray powder diffraction pattern comprising peaks having d-values in angstroms of about 13.0, about 10.9, about 6.8, about 6.5, about 6.2, about 5.2, about 4.7, about 4.5, about 4.3, about 4.22, about 4.00, about 3.53, about 3.40, about 3.28, about 3.24, about 3.19, about 3.08, about 2.91, and about 2.72.

45. A method for the preparation of the crystalline form of claim 43, comprising

dissolving a salt of a compound of formula I in water:

adding an amount of an organic aprotic solvent to the aqueous salt solution sufficient to dissolve the compound of formula I;

adjusting the pH of the aqueous salt solution to a value greater than about 8.5 by addition of a base;

removing a part of the organic aprotic solvent;

cooling the remaining organic aprotic solution to less than 15°

C.; and

isolating any precipitate formed.

46. The method of claim 45, wherein the salt of the compound of formula I is a hemi-tartrate salt.

47. The method of claim 45, further comprising extracting the aqueous solution with the organic solvent and collecting all organic phases prior to removing a part of the organic solvent.

48. The method of claim 45, wherein the organic solvent is selected from the group consisting of one or more of the following:

hydrocarbons, halogenated hydrocarbons, esters of aliphatic carboxylic acids, alcohols, lactones, ethers, and aliphatic C₄-C₈ ketones.

49. A pharmaceutical composition comprising the compound of formula IV and a pharmaceutically acceptable carrier or diluent: