Processes for the preparation of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]-pyrazin-8-yl)-n-(2,2,2-trifluoroethyl)pyrrolidine-1-carb oxamide and solid state forms thereof
The present disclosure relates to processes for preparing (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, solid state forms thereof, and corresponding pharmaceutical compositions, methods of treatment (including treatment of rheumatoid arthritis), kits, methods of synthesis, and products-by-process.
1. A method of treating moderately to severely active rheumatoid arthritis in a subject in need thereof, comprising orally administering once daily to the subject (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in an amount sufficient to deliver 15 mg, per unit dosage form, of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the subject achieves an ACR70 score by week twelve of treatment.
2. The method of claim 1 , wherein the subject is an adult subject.
3. The method of claim 1 , wherein the subject has had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
4. The method of claim 1 , wherein the subject has had an inadequate response or intolerance to methotrexate.
5. The method of claim 1 , wherein the subject has had an inadequate response or intolerance to an anti-TNF biologic agent.
6. The method of claim 1 , wherein (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is a free base crystalline hemihydrate.
7. The method of claim 6 , wherein the free base crystalline hemihydrate has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
8. The method of claim 6 , wherein the free base crystalline hemihydrate is Freebase Hydrate Form C.
9. A method of treating moderately to severely active rheumatoid arthritis in a subject in need thereof, comprising orally administering once daily to the subject (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in an amount sufficient to deliver 15 mg, per unit dosage form, of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the subject achieves a DAS28(CRP) score of <2.6 by week twelve of treatment.
10. The method of claim 9 , wherein the subject is an adult subject.
11. The method of claim 9 , wherein the subject has had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
12. The method of claim 9 , wherein the subject has had an inadequate response to methotrexate.
13. The method of claim 9 , wherein the subject has had an inadequate response or intolerance to an anti-TNF biologic agent.
14. The method of claim 9 , wherein (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is a free base crystalline hemihydrate.
15. The method of claim 14 , wherein the free base crystalline hemihydrate has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
16. The method of claim 14 , wherein the free base crystalline hemihydrate is Freebase Hydrate Form C.
17. A method of treating moderately to severely active rheumatoid arthritis in a subject in need thereof, comprising orally administering once daily to the subject (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide in an amount sufficient to deliver 15 mg, per unit dosage form, of (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide free base equivalent, wherein the subject achieves a Clinical Disease Activity Index (CDAI) score of 2.8 or less by week twelve of treatment.
18. The method of claim 17 , wherein the subject is an adult subject.
19. The method of claim 17 , wherein the subject has had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs.
20. The method of claim 17 , wherein the subject has had an inadequate response to methotrexate.
21. The method of claim 17 , wherein the subject has had an inadequate response or intolerance to an anti-TNF biologic agent.
22. The method of claim 17 , wherein (3S,4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide is a free base crystalline hemihydrate.
23. The method of claim 22 , wherein the free base crystalline hemihydrate has an X-ray powder diffraction pattern characterized by peaks at 13.4±0.2, 15.1±0.2, and 21.7±0.2 degrees two theta when measured at about 25° C. with monochromatic Kα1 radiation.
24. The method of claim 22 , wherein the free base crystalline hemihydrate is Freebase Hydrate Form C.