Crystalline form of pyrimido[6,1-A] isoquinolin-4-one compound

1. A compound N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea, in the form of a crystalline solid consisting of greater than 99% by weight of N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea,

at least 95% in the polymorphic form of a thermodynamically stable polymorph (I) of N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea, said polymorph (I) having the following structural parameters obtained by single crystal analysis:

Wavelength

0.71073 Å

Crystal system

Triclinic

Space group

P-1

Unit cell dimensions

a = 8.1246(4) Å

α = 91.583(4)°.

b = 11.4573(5) Å

β = 90.299(4)°.

c = 13.2398(6) Å

γ = 99.628(4)°.

Volume

1214.56(10) Å 3 .

Z

2.

2. A crystalline polymorph (I) of N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea having a powder X-ray diffraction pattern comprising characteristic peaks, in terms of 2θ, at 10.1° and 12.9°.

3. The polymorph of claim 2 wherein said powder X-ray diffraction pattern further comprises characteristics peaks, in terms of 2θ, at 15.3° and 17.6°.

4. The polymorph of claim 2 wherein said powder X-ray diffraction pattern comprises at least 5 characteristic peaks, in terms of 2θ, selected from 6.4°, 10.1°, 12.6°, 12.9°, 13.6°, 14.2°, 14.7°, 15.3°, 15.4°, 15.8°, 17.0°, 17.6°, 18.9°, 20.9°, 22.4°, 22.8°, and 28.7°.

5. A solid composition comprising the polymorph of claim 2 and a pharmaceutically acceptable carrier.

6. The composition of claim 5 wherein at least 50% by weight of total N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea in said composition is present as said polymorph.

7. The composition of claim 5 wherein at least 70% by weight of total N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea in said composition is present as said polymorph.

8. The composition of claim 5 wherein at least 90% by weight of total N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea in said composition is present as said polymorph.

9. The composition of claim 5 wherein at least 97% by weight of total N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea in said composition is present as said polymorph.

10. A solid composition comprising the polymorph of claim 1 and one or more additional compounds.

11. The solid composition of claim 10 , wherein the additional compound is a known therapeutic.

12. A process for preparing the polymorph of claim 2 comprising:

(a) combining N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea with a solvent to form a mixture, and

(b) heating said mixture at or above a temperature of about 50° C. for a time and under conditions suitable for forming said polymorph.

13. A process for preparing the polymorph of claim 2 comprising:

(a) combining N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea with a solvent to form a mixture,

(b) filtering said mixture to form a filtered mixture

(c) heating said filtered mixture at or above a temperature of about 55° C. for a time and under conditions suitable for forming said polymorph; and

(d) filtering and drying said polymorph.

14. The process of claim 12 , wherein the solvent is DMSO, ethanol, methanol, isopropanol, hexanes, pentane, ethyl acetate, dichloromethane, or chloroform.

15. The process of claim 14 , wherein the solvent is DMSO or ethanol.

16. The process of claim 12 wherein said filtered mixture is maintained at or above a temperature of about 50° C. for about 24 to 96 hours.

17. The process of claim 16 , wherein said filtered mixture is maintained at or above a temperature of about 50° C. for about 72 hours.

18. The process of claim 12 wherein said filtered mixture is maintained at or above a temperature of about 55° C. for about 24 to 96 hours.

19. The process of claim 16 , wherein said filtered mixture is maintained at or above a temperature of about 55° C. for about 72 hours.

20. The process of claim 12 wherein said mixture is dried in vacuo at between 25 and 50° C.

21. The process of claim 20 wherein said mixture is dried in vacuo at 40° C.

22. The polymorph of claim 2 , prepared by the method comprising

(a) combining N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea with a solvent to form a mixture, and

(b) heating said mixture at or above a temperature of 50° C. for a time and under conditions suitable for forming said polymorph.

23. The polymorph of claim 2 , prepared by the method comprising

(a) combining N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]thyl}urea with a solvent to form a mixture,

(b) filtering said mixture to form a filtered mixture,

(c) heating said filtered mixture at or above a temperature of 55° C. for a time and under condition suitable for forming said polymorph; and

(d) filtering and drying said polymorph.

24. A method to treat chronic obstructive pulmonary disease (COPD), in a mammal suffering from COPD, which method comprises administering to said mammal an effective amount of a crystalline polymorph of N-{2-[(2E)-2-(mesitylimino)-9,10-dimethoxy-4-oxo-6,7-dihydro-2H-pyrimido[6,1-a]-isoquinolin-3(4H)-yl]ethyl}urea.

25. The method of claim 24 , wherein the mammal is a human.