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

• US 7,732,615 B2
• Filed: 09/26/2005
• Issued: 06/08/2010
• Est. Priority Date: 09/27/2004
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Berghausen, Jorg, Blatter, Fritz, Thygesen, Mikkel Boas, Schlienger, Nathalie, Tolf, Bo-Ragnar, Andersson, Carl-Magnus A.
• Primary Examiner(s): Desai; Rita J
• Assistant Examiner(s): Mabry; John
• Application Number:
  US11/235,558
• Publication Number:
  US 20060106063A1
• Time in Patent Office: 1,716 Days
• Field of Search: 546/223, 514/317
• US Class Current: 546/223
• 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 crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′

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

18. Crystalline form C of claim 1, having a melting temperature of 177°

C. as measured by differential scanning calorimetry.

19. The crystalline form of claim 18, wherein the enthalpy of fusion is about 129 J/g.

22. The crystalline form of claim 1 wherein the crystalline form is in at least about a 95% pure crystalline form.

23. The crystalline form of claim 1 wherein the crystalline form is in at least about a 98% pure crystalline form.

24. Crystalline form B of claim 1 wherein the crystalline form exhibits a melting point of about 135°

C. with an enthalpy of fusion of about 71 J/g, as determined by differential scanning calorimetry.

2. Crystalline form B 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, and about 4.37.

3. The crystalline form of claim 2 that exhibits a X-ray powder diffraction pattern further comprising peaks having d-values in angstroms of about 4.50 and about 3.87.

13. A pharmaceutical composition comprising the crystalline form of claim 2 and a pharmaceutically acceptable carrier or diluent.

4. Crystalline form C 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 10.7, about 4.84, about 4.57, and about 3.77.

5. The crystalline form of claim 4 that exhibits a X-ray powder diffraction pattern further comprising peaks having d-values in angstroms of about 5.28 and about 4.70.

6. Crystalline form C 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 4; and

isolating of the crystalline solid from the suspension.

7. Crystalline form C 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 4;

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.

14. A pharmaceutical composition comprising the crystalline form of claim 4 and a pharmaceutically acceptable carrier or diluent.

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

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate comprising at least about 90% of the crystalline form of claim 4.

16. A solid form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) -N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate comprising at least about 95% of the crystalline form of claim 4.

17. A solid form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl) -N′

-(4-(2-methylpropyloxy)phenylmethyl)carbamide tartrate comprising at least about 98% of the crystalline form of claim 4.

20. The crystalline form of claim 4 that has less than 1000 ppm of residual solvent.

21. The crystalline form of claim 4 that has crystals with a particle size in the range of about 1 μ

m to about 200 μ

m.

8. Crystalline form D 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 6.1, about 4.54, and about 4.37.

9. The crystalline form of claim 8 that exhibits a X-ray powder diffraction pattern further comprising peaks having d-values in angstroms of about 4.91, and about 4.10.

10. Crystalline form E 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 6.0, about 4.72, and about 4.26.

11. Crystalline form F 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 13.0, about 6.4, about 4.62, and about 4.24.

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