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Claims for Patent: 7,732,615

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Claims for Patent: 7,732,615

Title:N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phe- nylmethyl)carbamide and its tartrate salt and crystalline forms
Abstract: Disclosed herein are methods for synthesizing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)-p- henylmethyl)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)-p- henylmethyl)carbamide and its hemi-tartrate salt including various polymorphs and solvates.
Inventor(s): Thygesen; Mikkel Boas (Copenhagen East, DK), Schlienger; Nathalie (Frederiksberg, DK), Tolf; Bo-Ragnar (Malmo, SE), Andersson; Carl-Magnus A. (Hjarup, SE), Blatter; Fritz (Reinach, CH), Berghausen; Jorg (Lorrach, DE)
Assignee: ACADIA Pharmaceuticals Inc. (San Diego, CA)
Application Number:11/235,558
Patent Claims: 1. A crystalline form of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)ph- enylmethyl)carbamide tartrate of formula IV, ##STR00032## wherein the crystalline form is at least about an 80% pure crystalline form selected from the group consisting of form B, form C, form D, form E and form F.

2. Crystalline form B of N-(4-fluorobenzyl) -N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbami- de 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.

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)carbami- de 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.degree. 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)carbami- de 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.degree. C.; stirring the resulting solution at a temperature of about 50 to about 70.degree. 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.degree. C. per hour to a temperature of about -20.degree. C. to about room temperature; and isolating crystalline solid from the suspension.

8. Crystalline form D of N-(4-fluorobenzyl) -N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbami- de 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)carbami- de 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)carbami- de 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: ##STR00033## wherein the crystalline form is a at least about an 80% pure crystalline form selected from the group consisting of form B, form C. form D, form E and form F.

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

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.

18. Crystalline form C of claim 1, having a melting temperature of 177.degree. C. as measured by differential scanning calorimetry.

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

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 .mu.m to about 200 .mu.m.

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