Claims for Patent: 9,199,995

Summary for Patent: 9,199,995

Title:	4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrro- lo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt and salt crystals
Abstract:	The present invention relates to 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrr- olo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone tosylate salt in crystalline and in solid forms, the method of making and using such crystals.
Inventor(s):	Tomesch; John (New York, NY), Wennogle; Lawrence P. (New York, NY)
Assignee:	INTRA-CELLULAR THERAPIES, INC. (New York, NY)
Application Number:	14/177,689
Patent Claims:	1. A method for modulating 5-hydroxytryptamine 2 receptor activity in a patient, comprising administering to a patient in need thereof an effective amount of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4': 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid salt crystal, wherein said salt crystal exhibits an X-ray powder diffraction pattern comprising at least two peaks having 2-theta values selected from the group consisting of 5.68.degree., 12.11.degree., 16.04.degree., 17.03.degree., 18.16.degree., 19.00.degree., 21.67.degree., 22.55.degree., 23.48.degree. and 24.30.degree., wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter. 2. A method for modulating 5-hydroxytryptamine 2A receptor activity in a patient, comprising administering to a patient in need thereof an effective amount of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4': 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluene sulfonic acid salt crystal, wherein said salt crystal exhibits an X-ray powder diffraction pattern comprising at least two peaks having 2-theta values selected from the group consisting of 5.68.degree., 12.11.degree., 16.04.degree., 17.03.degree., 18.16.degree., 19.00.degree., 21.67.degree., 22.55.degree., 23.48.degree. and 24.30.degree., wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter. 3. The method according to claim 2, wherein said salt crystal exhibits an X-ray powder diffraction pattern according to FIG. 7, FIG. 7A or FIG. 7B. 4. The method according to claim 3, wherein said salt crystal exhibits a differential scanning calorimetry pattern or a thermogravimetric analysis profile according to FIG. 8. 5. The method according to claim 2, wherein said salt crystal exhibits an X-ray powder diffraction pattern comprising at least five peaks having 2-theta values selected from the group consisting of: 5.68.degree., 12.11.degree., 16.04.degree., 17.03.degree., 18.16.degree., 19.00.degree., 21.67.degree., 22.55.degree., 23.48.degree. and 24.30.degree., wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter. 6. The method according to claim 2, wherein said salt crystal exhibits an X-ray powder diffraction pattern according to FIG. 7. 7. The method according to claim 2, wherein said salt crystal exhibits an X-ray powder diffraction pattern according to FIG. 7A. 8. The method according to claim 2, wherein said salt crystal exhibits a differential scanning calorimetry pattern or a thermogravimetric analysis profile according to FIG. 8. 9. A method for modulating 5-hydroxytryptamine 2A receptor activity in a patient, comprising administering to a patient in need thereof an effective amount of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4': 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid salt crystal, wherein said salt crystal is prepared from a process comprising the steps of: a) reacting 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4': 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone free base with p-toluenesulfonic acid in the presence of 2-propanol; or b) dissolving 4-46bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4': 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt in 2-propanol; and c) optionally cooling the resulting solution or mixture from step (a) or step (b) to 0.degree.-25.degree. C. 10. The method according to claim 9, wherein said salt crystal is prepared from a process comprising the steps of: a) reacting 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3',4': 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone free base with p-toluenesulfonic acid in the presence of 2-propanol, wherein the amount of 2-propanol is in an amount of 2-5 mL per gram of free base; b) optionally cooling the resulting solution or mixture from step (a) to 0.degree.-25.degree. C. 11. The method according to claim 10, which further comprises the step of adding an anti-solvent. 12. The method according to claim 10, which further comprises the step of adding water. 13. The method according to claim 9, which further comprises the step of adding an anti-solvent. 14. The method according to claim 9, which further comprises the step of adding water.