Polymorphs of n-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[2-oxopyridin-1-yl)methyl]phenyl} methyl)pyrazole-4-carboxamide as iallikrein inhibitors
The invention provides new polymorphs of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and salts thereof, pharmaceutical compositions containing them and their use as kallikrein inhibitors in therapy.
1. A crystalline form of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide, that is
crystalline form 1 of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide, which exhibits at least X-ray powder diffraction peaks (Cu Kα radiation, expressed in degrees 2θ) at 11.2±0.3, 12.5±0.3, 13.2±0.3, 14.5±0.3, and 16.3±0.3.
2. The crystalline form 1 of claim 1 having an X-ray powder diffraction pattern that is substantially the same as that shown in FIG. 2 a.
3. The crystalline form 1 of claim 1 , which exhibits an endothermic peak in its DSC thermograph at 151±3° C.
4. The crystalline form 1 of claim 1 having a DSC thermograph substantially the same as that shown in FIG. 4 .
5. A crystalline form 1 of N-[(3-fluoro-4-methoxypyridin-2-yl)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 151±3° C.
6. The crystalline form 1 of claim 5 having a DSC thermograph substantially the same as that shown in FIG. 4 .
7. A pharmaceutical composition comprising a crystalline form of claim 1 and a pharmaceutically acceptable adjuvant, diluent or carrier.
8. A process for preparing a crystalline form 1 of claim 1 , comprising heating a mixture of N-[(3-fluoro-4-methoxypyridin-2-yl)methyl]-3-(methoxymethyl)-1-({4-[(2-oxopyridin-1-yl)methyl]phenyl}methyl)pyrazole-4-carboxamide and acetonitrile or isopropanol; and then cooling the mixture.
9. The process of claim 8 , wherein the temperature of the heating is 60 to 85° C.
10. The process of claim 9 , wherein the temperature for the cooling is 0 to 40° C.
11. A method for preparing a pharmaceutical composition comprising combining the crystalline form of claim 1 and one or more pharmaceutically acceptable carrier, diluent, or excipient.