USRE48825EActiveUtilityPatentIndex 93

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 forms

Assignee: INTRA CELLULAR THERAPIES INCPriority: Mar 12, 2008Filed: Mar 6, 2019Granted: Nov 23, 2021

Est. expiryMar 12, 2028(~1.7 yrs left)· nominal 20-yr term from priority

Inventors:TOMESCH JOHN WENNOGLE LAWRENCE P

C07D 471/16C07C 309/30C07B 2200/13A61P 43/00A61P 25/28A61P 25/24A61P 25/22A61P 25/20A61P 25/18A61P 25/06A61P 25/00A61P 15/00A61P 3/04A61P 1/00

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Claims

Abstract

The present invention relates to toluenesulfonic acid addition salt crystals 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, and methods of using such crystals as 5-hydroxytryptamine 2 receptor agonists and antagonists in treating disorders of the central nervous system.

Claims

exact text as granted — not AI-modified

The invention claimed is: 
     
       1. A 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 addition salt crystal form, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least two peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°±0.2° 2θ. 
     
     
       2. A pharmaceutical composition comprising the salt crystal form according to  claim 1 , as active ingredient, together with a pharmaceutically acceptable diluent or carrier. 
     
     
       3. The salt crystal form according to claim 1, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.  
     
     
       4. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, ±0.2° 2θ, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.  
     
     
       5. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, ±0.2° 2θ, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.  
     
     
       6. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, ±0.2° 2θ, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.  
     
     
       7. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least two peaks having D-spacing values selected from the group consisting of 15.543Å, 7.303Å, 5.520Å, 5.202Å, 4.882Å, 4.668Å, 4.097Å, 3.940Å, 3.786Å and 3.660Å, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.  
     
     
       8. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least five peaks having D-spacing values selected from the group consisting of 15.543Å, 7.303Å, 5.520Å, 5.202Å, 4.882Å, 4.668Å, 4.097Å, 3.940Å, 3.786Å and 3.660Å, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.  
     
     
       9. The salt crystal form according to claim 1, wherein said salt crystal form exhibits a differential scanning calorimetry pattern comprising a peak temperature range of 180° C. to 181° C.  
     
     
       10. A pharmaceutical composition comprising the salt crystal form according to claim 3, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.  
     
     
       11. A pharmaceutical composition comprising the salt crystal form according to claim 6, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.  
     
     
       12. A pharmaceutical composition comprising the salt crystal form according to claim 7, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.  
     
     
       13. A pharmaceutical composition comprising the salt crystal form according to claim 8, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.  
     
     
       14. A pharmaceutical composition comprising the salt crystal form according to claim 9, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.  
     
     
       15. The pharmaceutical composition according to claim 10, wherein the composition comprises up to 10% by weight of other crystal forms 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 addition salt.  
     
     
       16. The pharmaceutical composition according to claim 10, wherein the composition comprises up to 10% by weight of amorphous forms 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 addition salt.  
     
     
       17. A 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 addition salt crystal form, wherein said salt crystal form is in triclinic, monoclinic, orthorhombic, tetragonal, rhombohedral, hexagonal or cubic crystal form.  
     
     
       18. The salt crystal form according to claim 17, wherein the salt crystal form exists as flakes or needles.  
     
     
       19. A method of manufacturing a pharmaceutical composition comprising 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 addition salt, wherein the method comprises the step of combining the salt crystal form according to claim 1 with at least one pharmaceutically acceptable diluent or carrier.  
     
     
       20. The method according to claim 19, wherein the 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 addition salt is the active ingredient of the pharmaceutical composition.  
     
     
       21. The method according to claim 19, wherein the 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 addition salt consists 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 free base and toluenesulfonic acid in a 1:1 molar ratio.  
     
     
       22. A method of manufacturing a pharmaceutical composition comprising 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 addition salt, wherein the method comprises the step of combining the salt crystal form according to claim 3 with at least one pharmaceutically acceptable diluent or carrier.  
     
     
       23. A method of manufacturing a pharmaceutical composition comprising 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 addition salt, wherein the method comprises the step of combining the salt crystal form according to claim 6 with at least one pharmaceutically acceptable diluent or carrier.

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