Synthesis and crystalline forms of NPY5 antagonist

1. A process for preparing a compound of formula I, or a salt or polymorph thereof,

wherein the salt is the mesylate or fumarate salt and the polymorph is pure Form A or Form C,

comprising the step of coupling a compound of formula II

with a compound of formula III, or a salt thereof,

in the presence of SOCl 2 and dimethylacetamide,

wherein the mesylate salt of Compound I has an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 19.90°;

wherein the fumarate salt of Compound I has an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 9.59°;

wherein pure Form A of Compound I has an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 22.42°; and

wherein Form C of Compound I has an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 27.0-28.0°.

2. The process of claim 1 further comprising isolating the compound of formula I by crystallizing from dimethylformamide/methanol/water or dimethylacetamide/water.

3. A compound which is crystalline Form C of Compound I

having an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 27.0-28.0°.

4. The compound of claim 3 having an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 27.59°.

5. The compound of claim 3 having an x-ray powder diffraction pattern obtained using Cu radiation containing the following angle 2 theta values: 27.6° and 17.5°.

6. The compound of claim 3 having an x-ray powder diffraction pattern obtained using Cu radiation containing the following angle 2 theta values: 27.6°, and 17.5°, and at least one angle theta value selected from the group consisting of: 23.8°, 21.5°, 14.9°, 17.7°, and 20.2°.

7. The compound of claim 3 having an x-ray powder diffraction pattern obtained using Cu radiation characterized by a reflection at a d-spacing of 5.95 Å.

8. The compound of claim 3 having an x-ray powder diffraction pattern obtained using Cu radiation characterized by a reflection at a d-spacing of 5.95 Å, and at least one reflection at a d-spacing selected from the group consisting of: 5.07 Å, 5.00 Å, 4.40 Å, 4.13 Å, 3.74 Å, and 3.23 Å.

9. The compound of claim 3 having an x-ray powder diffraction pattern obtained using Cu radiation characterized by reflections at d-spacings of about 3.2, 5.1 and 3.7 angstroms.

10. The compound of claim 9 further comprising an x-ray powder diffraction pattern obtained using Cu radiation characterized by reflections at d-spacings of about 4.1, 5.9 and 5.0 angstroms.

11. The compound of claim 10 further comprising an x-ray powder diffraction pattern obtained using Cu radiation characterized by reflections at d-spacings of about 4.40 angstroms.

12. The compound of claim 3 having a differential scanning calorimetry (DSC) peak melting temperature of about 216.7° C.

13. The compound of claim 3 characterized by the carbon-13 cross-polarization magic-angle spinning nuclear magnetic resonance spectrum of FIG. 5 .

14. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form C of Compound I of claim 3 , and a pharmaceutically acceptable carrier.

15. A method of treating obesity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the crystalline Form C of Compound I of claim 3 .

16. The compound of claim 3 prepared by a process comprising the steps of:

(a) dissolving the compound of formula I in dimethylformamide to form a mixture;

(b) heating the mixture of step (a) to about 50-55° C.;

(c) filtering the mixture of step (b) to form a solution;

(d) adding methanol to the solution of step (c) to give a solution;

(e) seeding the solution of step (d) with one or more crystals of compound I form C;

(f) aging the solution of step (e) at about 48-50° C.; and

(g) adding deionized water to the solution of step (f).

17. A compound which is pure crystalline Form A of Compound I

having an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 22.42°.

18. A compound which is the mesylate salt of Compound I

having an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 19.90°.

19. A compound which is the fumarate salt of Compound I

having an x-ray powder diffraction pattern obtained using Cu radiation containing an angle 2 theta value of 9.59°.