Patent EA-004706-B1 (EA)
Title: POLYMORPHS OF N-METHYL-N-(3-{3-[2-THIENYLCARBONYL]-PYRAZOL-[1,5-alpha]-PYRIMIDIN-7-YL}PHENYL)ACETAMIDE AND COMPOSITIONS AND METHODS RELATED THERETO
Inventor: THIELE WILLIAM J
IPC: C07D487/02
Filed: 2000-09-01
Abstract: 1. A substantially pure polymorph Form I of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-.alpha.]-pyrimidin-7-yl}phenyl)acetamide exhibiting a predominant endotherm at about 192-198 degree C as measured by Differential Scanning Calorimeter. 2. The substantially pure polymorph Form I of claim 1, wherein said polymorph Form I comprises less than about 6% by weight of a polymorph Form II. 3. The substantially pure polymorph Form I of claim 2, wherein said polymorph Form I comprises less than about 2% by weight impurities, less than about 1% by weight water, and less than about 0.5% by weight residual organic solvent. 4. The substantially pure polymorph Form I of claim 2, wherein said polymorph exhibits a predominant endotherm at about 195-197 degree C. 5. The substantially pure polymorph Form I of claim 2, wherein said polymorph has about 2 molecules per cell and is of the P1 bar space group as determined by single-crystal X-ray crystallography. 6. The substantially pure polymorph Form I of claim 2, wherein said polymorph has crystal dimensions of about 0.12 mm x 0.05 mm x 0.015 mm and a volume of about 913, as determined by single-crystal X-ray crystallography. 7. The substantially pure polymorph Form I of claim 2, wherein said polymorph has a calculated density of about 1.37, as determined by single-crystal X-ray crystallography. 8. The substantially pure polymorph Form I of claim 2, further characterized by the following single-crystal X-ray crystallography bond distances: 9. A substantially pure polymorph Form II of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide exhibiting a predominant endotherm at about 172-179 degree C as measured by a Differential Scanning Calorimeter. 10. The substantially pure polymorph Form II of claim 9, wherein said polymorph Form II comprises less than about 20% by weight of a polymorph Form I. 11. The substantially pure polymorph Form II of claim 10, wherein said polymorph Form II comprises less than about 2% by weight impurities, less than about 1% by weight water, and less than about 0.5% by weight residual organic solvent. 12. The substantially pure polymorph Form II of claim 10, wherein said polymorph exhibits a predominant endotherm at about 173-177 degree C. 13. The substantially pure polymorph Form II of claim 10, wherein said polymorph has about 4 molecules per cell and is of the P2/a1 space group, as determined by single-crystal X-ray crystallography. 14. The substantially pure polymorph Form II of claim 10, wherein said polymorph has crystal dimensions of about 0.35 mm x 0.20 mm x 0.12 mm and a volume of about 1797, as determined by single-crystal X-ray crystallography. 15. The substantially pure polymorph Form II of claim 10, wherein said polymorph has a calculated density of about 1.39, as determined by single-crystal X-ray crystallography. 16. The substantially pure polymorph Form II of claim 10, further characterized by the following single-crystal X-ray crystallography bond distances: 17. A process for preparing substantially pure Form I of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide, comprising the steps of: forming a solution of a crystallization solvent comprising acetone and N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide; and cooling the solution to form a mass of crystals, and collecting the crystals to the Form I. 18. The process of claim 17 further comprising the step of: drying the collected crystals to yield substantially pure Form I. 19. The process of claim 17, wherein the step of forming a solution comprises the steps of: providing N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)-acetamide; and contacting the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)-acetamide with a crystallization solvent. 20. The process of claim 19, wherein the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide is provided as a solid. 21. The process of claim 19, wherein the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide is provided as a concentrate in an organic cosolvent. 22. The process of claim 21, wherein the cosolvent comprises methylene chloride. 23. The process of claim 19 further comprising the step of: heating the crystallization solvent to effect dissolution of the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide. 24. A polymorph Form I of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide made according to the process of any one of claims 17-23. 25. A process for preparing substantially pure Form II of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide comprising the steps of: forming a solution of a crystallization solvent comprising methanol and N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide; and cooling the solution to form a mass of crystals, and collecting the crystals to the Form II. 26. The process of claim 25 further comprising the step of: drying the collected crystals to yield substantially pure Form II. 27. The process of claim 25, wherein the step of forming a solution comprises the steps of: providing N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)-acetamide; and contacting the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)-acetamide with a crystallization solvent. 28. The process of claim 27, wherein the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide is provided as a solid. 29. The process of claim 27, wherein the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide is provided as a concentrate in an organic cosolvent. 30. The process of claim 29, wherein the cosolvent comprises methylene chloride. 31. The process of claim 27 further comprising the step of: heating the crystallization solvent to effect dissolution of the N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide. 32. A process for converting a polymorph Form II of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide to a polymorph Form I, the process comprising the steps of: providing a composition comprising the polymorph Form II according to claim 9; heating the composition to a temperature higher than the melting point of the polymorph Form II; and cooling the composition to form the polymorph Form I according to claim 1. 33. A polymorph Form I of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide made according to the process of claim 32. 34. A process for converting a polymorph Form II of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide to a polymorph Form I, the process comprising the steps of: providing a composition comprising the polymorph Form II according to claim 9; and milling the composition one or more times to form the polymorph Form I according to claim 1. 35. A polymorph Form I of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide made according to the process of claim 34. 36. A process for converting a polymorph Form II of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide to a polymorph Form I, the process comprising the steps of: providing a composition comprising the polymorph Form II according to claim 9; heating the composition at a temperature above ambient temperature but below the melting point of the polymorph Form II for a period of time sufficient to convert the polymorph Form II to the polymorph Form I according to claim 1; and cooling the polymorph Form I. 37. A polymorph Form I of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide made according to the process of claim 36. 38. A composition comprising substantially pure Form I of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide according to claim 2 and a pharmaceutically acceptable carrier. 39. The composition of claim 38, wherein the composition is formulated for oral administration. 40. The composition of claim 39, wherein the composition is in the form of a pill, capsule or tablet. 41. The composition of claim 40, wherein the Form I is present in a unit dosage form at an amount of about 0.1 to 250 mg. 42. A composition comprising substantially pure Form II of N-methyl-N-(3-{3-[2-thienylcarbonyl]-pyrazol-[1,5-alpha]-pyrimidin-7-yl}phenyl)acetamide according to claim 10 and a pharmaceutically acceptable carrier. 43. The composition of claim 42, wherein the composition is formulated for oral administration. 44. The composition of claim 43, wherein the composition is in the form of a pill, capsule or tablet. 45. The composition of claim 44, wherein the Form II is present in a unit dosage form at an amount of about 0.1 to 250 mg. 46. A method for treating insomnia in a patient in need thereof, comprising administering to the patient an effective amount of substantially pure Form I of claim 1. 47. A method for inducing sleep in a patient in need thereof, comprising administering to the patient an effective amount of substantially pure Form I of claim 1. 48. A method for inducing sedation or hypnosis in a patient in need thereof, comprising administering to the patient an effective amount of substantially pure Form 1 of claim 1. 49. A method for inducing skeletal muscle relaxation in a patient in need thereof, comprising administering to the patient an effective amount of substantially pure Form I of claim 1. 50. A method for treating insomnia in a patient in need thereof, comprising administering to the patient an effective amount of substantially