Patent EA-002405-B1 (EA)
Title: Polymorphic form of the tachykininreceptor antagonists 2-(r)-(1-(r)-(3,5-bis(trifluoromethyl) phenyl)ethoxy)-3 (s)-(4-fluoro) phenyl-4-3-(5-oxo-1h,4h-1,2,4-triazolo)methylmorpholine
Inventor: CROCKER LOUIS
IPC: A61P25/04
Filed: 1998-07-01
Abstract: 1. A polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine designated as Form I, essentially characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8, and 24.8 degree  (2 theta). 2. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the polymorphic form of Claim 1. 3. A method for antagonizing the effect of neurokinin-1 at its receptor site or for the blockade of neurokinin-1 receptors in a mammal which comprises the administration to the mammal of the polymorphic form of Claim 1 in an amount that is effective for antagonizing the effect of neurokinin-1 at its receptor site in the mammal. 4. A method for treating or preventing a condition selected from the group consisting of diabetic neuropathy; peripheral neuropathy; AIDS related neuropathy; chemotherapy-induced neuropathy; and neuralgia, in a mammal in need thereof which comprises the administration to the mammal of an effective amount of the polymorphic form of Claim 1. 5. A method for treating or preventing emesis in a mammal in need thereof which comprises the administration to the mammmal of an effective amount of the polymorphic form of Claim 1. 6. A method for treating or preventing a disorder of the central nervous system in a mammal in need thereof which comprises the administration to the mammal of an effective amount of the polymorphic form of Claim 1. 7. A method for treating or preventing depression in a mammal in need thereof which comprises the administration to the mammal of an effective amount of the polymorphic form of Claim 1. 8. A method for treating or preventing depression in a mammal in need thereof which comprises the administration to the mammal of the polymorphic form of Claim 1 and an antidepressant agent such that together they give effective relief. 9. A method for treating or preventing anxiety in a mammal in need thereof which comprises the administration to the mammal of an effective amount of the polymorphic form of Claim 1. 10. A method for treating or preventing anxiety in a mammal in need thereof which comprises the administration to the mammal of the polymorphic form of Claim 1 and an anti-anxiety agent such that together they give effective relief. 11. A method for treating or preventing schizophrenia in a mammal in need thereof which comprises the administration to the mammal of an effective amount of the polymorphic form of Claim 1. 12. A method for treating or preventing schizophrenia in a mammal in need thereof which comprises the administration to the mammal of the polymorphic form of Claim 1 and an antipsychotic agent such that together they give effective relief. 13. A process for the preparation of Form I of 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine which comprises: equilibrating Form II of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-lH, 4H-1,2,4-triazolo)methyl)morpholine in a solvent which is selected from: ethanol, 2-propanol, acetonitrile, and isopropylacetate. 14. A product produced by the process of Claim 13. 15. A process for the preparation of Form I of 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)morpholine which comprises: heating a sample of 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-lH, 4H-1,2,4-triazolo)methyl)morpholine of Form II to a temperature range of 215 to 230 degree C; and then returning the sample to ambient temperature. 16. The process of Claim 15 wherein the Form II of the starting 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-lH, 4H-1,2,4-triazolo)methyl)morpholine characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9, and 24.8 degree  m (2 theta). 17. A process for the preparation of Form I of 2-(R)-(l-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)morpholine which comprises: suspending 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-lH, 4H-1,2,4-triazolo)methyl)morpholine of Form II in solution of methanol/water; adding seed crystals of Form I of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)morpholine; stirring the resultant mixture at about 0-50 degree C for a period sufficient to result in the formation of Form I of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)morpholine; and collecting the resultant Form I of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(3)-(4-fluoro)phenyl-4-(3-(5-oxo-1H, 4H-1,2,4-triazolo)methyl)morpholine. 18. The process of Claim 17 wherein the Form II of the starting 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-lH, 4H-1,2,4-triazolo)methyl)morpholine is characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9 and 24.8 degree  (2 theta). 19. A product produced by the process of Claim 18. 20. A polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, essentially characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8, and 24.8 degree  (2 theta), which actually does not comprise a polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis (tri-fluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine, characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9, and 24.8 degree  (2 theta). 21. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.0, 15.3, 16.6, 17.0, 17.6, 19.4, 20.0, 21.9, 23.6, 23.8, and 24.8 degree  (2 theta), which actually does not comprise a polymorphic form of the compound 2-(R)-(1-(R)-(3,5-bis (trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, characterized by an X-ray powder diffraction pattern with key reflections at approximately: 12.6, 16.7, 17.1, 17.2, 18.0, 20.1, 20.6, 21.1, 22.8, 23.9, and 24.8 degree  (2 theta).