Polymorphs of N-[(6-cyano-2-fluoro)-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide as kallikrein inhibitors

1. A crystalline form of N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide, that is:

(a) crystalline Form 1, which exhibits at least X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 9.0±0.3, 14.3±0.3, 18.1±0.3, 19.6±0.3 and 24.0±0.3; or

(b) crystalline Form 2, which exhibits at least X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 8.3±0.3, 10.5±0.3, 16.6±0.3, 19.6±0.3, and 23.8±0.3; or

(c) crystalline Form 3, which exhibits at least X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 7.3±0.3, 10.2±0.3, 12.4±0.3, 12.9±0.3 and 18.1±0.3; or

(d) crystalline Form 4, which exhibits at least X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 9.0±0.3, 14.3±0.3, 15.0±0.3, 18.1±0.3, and 19.5±0.3.

2. The crystalline form 1 of claim 1 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 .

3. The crystalline form 1 of claim 1 , which exhibits an endothermic peak in its DSC thermograph at 149±3° C.

4. The crystalline form 1 of claim 1 having a DSC thermograph substantially the same as that shown in FIG. 3 .

5. A crystalline form 1 of N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide, which exhibits an endothermic peak in its DSC thermograph at 149±3° C.

6. The crystalline form 1 of claim 5 having a DSC thermograph substantially the same as that shown in FIG. 3 .

7. The crystalline form 2 of claim 1 , which exhibits at least X ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 8.3±0.3, 10.5±0.3, 16.6±0.3, 19.6±0.3 and 23.8±0.3.

8. The crystalline form 2 of claim 7 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 5 .

9. The crystalline form 3 of claim 1 , which exhibits at least X ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 7.3±0.3, 10.2±0.3, 12.4±0.3, 12.9±0.3 and 18.1±0.3.

10. The crystalline form 3 of claim 9 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 6 .

11. The crystalline form 4 of claim 1 , which exhibits at least X ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 9.0±0.3, 14.3±0.3, 15.0±0.3, 18.1±0.3 and 19.5±0.3.

12. The crystalline form 4 of claim 11 having an X-ray powder diffraction pattern substantially the same as that shown in FIG. 7 .

13. A pharmaceutical composition comprising a crystalline form of claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.

14. A method for treating a disease or condition mediated by plasma kallikrein, comprising administering a crystalline form of claim 1 to a patient having said disease or condition.

15. The method of claim 14 , wherein the disease or condition mediated by plasma kallikrein is impaired visual acuity, diabetic retinopathy, retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema, hereditary angioedema, diabetes, pancreatitis, cerebral haemorrhage, nephropathy, cardiomyopathy, neuropathy, inflammatory bowel disease, arthritis, inflammation, septic shock, hypotension, cancer, adult respiratory distress syndrome, disseminated intravascular coagulation, blood coagulation during cardiopulmonary bypass surgery, or bleeding from post-operative surgery.

16. The method of claim 14 , wherein the disease or condition mediated by plasma kallikrein is retinal vascular permeability associated with diabetic retinopathy, diabetic macular edema, or hereditary angioedema.

17. The method of claim 16 , wherein the disease or condition mediated by plasma kallikrein is retinal vascular permeability associated with diabetic retinopathy, or diabetic macular edema.

18. The method of claim 16 , wherein the disease or condition mediated by plasma kallikrein is hereditary angioedema.

19. The method of claim 16 , wherein the disease or condition mediated by plasma kallikrein is diabetic macular edema.

20. The method of claim 14 , wherein the disease or condition mediated by plasma kallikrein is retinal vein occlusion.

21. The method of claim 17 wherein said crystalline form is administered in a form suitable for injection into the ocular region of the patient.

22. The method of claim 14 , wherein said crystalline form is in a form suitable for oral administration.

23. The method of claim 14 , wherein the crystalline form is administered orally.

24. A process for preparing the crystalline form 1 of claim 1 , comprising crystallising said crystalline form 1 from a mixture of N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and isopropyl alcohol.

25. The process of claim 24 , wherein said mixture is heated to a temperature of approximately 60-85° C.

26. The process of claim 25 , wherein, after heating, said mixture is cooled to a temperature of approximately 0-40° C.

27. A process for preparing the crystalline form 2 of claim 1 , comprising crystallising said crystalline form from a mixture of N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide, isopropyl alcohol (IPA) and methyl tert-butyl ether.

28. The process of claim 27 , wherein after adding the N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide to IPA, the combined mixture is added to methyl tert-butyl ether.

29. A process for preparing the crystalline form 3 of claim 1 , comprising crystallising said crystalline form from a mixture of N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide, isopropyl alcohol (IPA), and water.

30. The process of claim 29 , wherein after adding the N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide to IPA and water, the combined mixture is heated before cooling to a temperature of about 0 to −80° C.

31. A process for preparing the crystalline form 4 of claim 1 , comprising crystallising said crystalline form from a mixture of N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and (i) dichloromethane or (ii) anisole and methyl tert-butyl ether.

32. The process of claim 31 , wherein the crystallizing is performed with dichloromethane.

33. The process of claim 32 , wherein after adding the N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide to dichloromethane, the combined mixture is heated before cooling to a temperature of about 0 to −80° C.

34. The process of claim 31 , wherein the crystallizing is performed with anisole and methyl tert-butyl ether.

35. The process of claim 34 , wherein after adding the N-[(6-cyano-2-fluoro-3-methoxyphenyl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide to anisole, the combined mixture is added to methyl tert-butyl ether.

36. The crystalline Form 1 of claim 1 , which exhibits at least X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 9.0±0.3, 14.3±0.3, 18.1±0.3, 19.6 ±0.3, and 24.0±0.3.

37. The method of claim 21 , wherein said solid form is administered in a form suitable for intra-vitreal injection.