Bibliographic Details
| Title: |
Polymorphic Forms of a Gabaa Agonist |
| Document Number: |
20080085913 |
| Publication Date: |
April 10, 2008 |
| Appl. No: |
11/813796 |
| Application Filed: |
January 26, 2006 |
| Abstract: |
The present invention is directed to novel polymorphic forms of the compound 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol hydrate (gaboxadol monohydrate). The invention is further concerned with pharmaceutical compositions containing the polymorphic forms as an active ingredient, methods for treatment of disorders susceptible to amelioration by GABAA receptor agonism with the polymorphic forms, and processes for the preparation of the polymorphic forms. |
| Inventors: |
Kumke, Daniel J. (Rahway, NJ, US); Murry, Jerry A. (Rahway, NJ, US); Simmons, Bryon L. (Rahway, NJ, US); Xu, Feng (Rahway, NJ, US) |
| Assignees: |
H. LUNDBECK A/S (Valby-Copenhagen, DK) |
| Claim: |
1. A compound gaboxadol monohydrate in a polymorphic form which is characterized by characteristic absorption bands obtained from an X-ray powder diffraction pattern at spectral d-spacings of 5.1 and 3.7 angstroms. |
| Claim: |
2. The compound of claim 1 which is further characterized by characteristic absorption bands obtained from an X-ray powder diffraction pattern at spectral d-spacings of 7.5, 3.6, 3.3 and 2.5 angstroms. |
| Claim: |
3. The compound of claim 2 which is further characterized by a solid state carbon-13 nuclear magnetic resonance spectrum with a peak at 16.9 ppm with reference to a value of 176.03 ppm for the carbonyl peak of glycine. |
| Claim: |
4. The compound of claim 3 which is further characterized by a solid state carbon-13 nuclear magnetic resonance spectrum with peaks at 40.4, 102.3, 103.9, 159.6, 172.6 and 174.0 ppm with—reference to a value of 176.03 ppm for the carbonyl peak of glycine. |
| Claim: |
5. A compound gaboxadol monohydrate in a polymorphic form which is characterized by characteristic absorption bands obtained from an X-ray powder diffraction pattern at spectral d-spacings of 4.8 and 3.5 angstroms. |
| Claim: |
6. The compound of claim 5 which is further characterized by characteristic absorption bands obtained from an X-ray powder diffraction pattern at spectral d-spacings of 7.5, 4.1, 3.6 and 3.1 angstroms. |
| Claim: |
7. The compound of claim 6 which is further characterized by a solid state carbon-13 nuclear magnetic resonance spectrum with a peak at 17.2 ppm with reference to a value of 176.03 ppm for the carbonyl peak of glycine. |
| Claim: |
8. The compound of claim 7 which is further characterized by a solid state carbon-13 nuclear magnetic resonance spectrum with peaks at 40.4, 102.3, 103.3, 159.5, and 172.8 ppm with reference to a value of 176.03 ppm for the carbonyl peak of glycine. |
| Claim: |
9. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier. |
| Claim: |
10. A pharmaceutical composition comprising the compound of claim 5 and a pharmaceutically acceptable carrier. |
| Claim: |
11. A method for the treatment of epilepsy, Parkinson's disease, schizophrenia, Huntington's disease, sleep disorder, premenstrual syndrome, hearing disorder, vestibular disorder, attention deficit/hyperactivity disorder, intention tremor, or restless leg syndrome comprising administering a therapeutically effective amount of a compound of claim 1. |
| Claim: |
12. A method for the treatment of epilepsy, Parkinson's disease, schizophrenia, Huntington's disease, sleep disorder, premenstrual syndrome, hearing disorder, vestibular disorder, attention deficit/hyperactivity disorder, intention tremor, or restless leg syndrome comprising administering a therapeutically effective amount of a compound of claim 5. |
| Claim: |
13. A process for preparing the compound of claim 1 comprising the steps of: (a) dissolving an acid addition salt of gaboxadol in water/isopropanol (35% v:v); (b) adding sufficient base to provide a pH of about 7; (c) aging the resulting mixture for the mixture for at least 1 hour at 40° C. and at least 5 hours at ambient temperature; and (d) collecting the compound. |
| Claim: |
14. A process for preparing the compound of claim 5 comprising the steps of: (a) dissolving an acid addition salt of gaboxadol in a solvent selected from: water/isopropanol (30% v:v); water/acetonitrile (60% v:v); and water/dimethoxyethane (67% v:v); (b) adding sufficient base to provide a pH of about 7; (c) aging the resulting mixture for the mixture for at least 2 hours at 40° C.; and (d) collecting the compound. |
| Claim: |
15. A process for preparing the compound of claim 5 comprising the steps of: (a) dissolving an acid addition salt of gaboxadol in water/acetonitrile (40% v:v); (b) adding sufficient base to provide a pH of about 7; (c) aging the resulting mixture for the mixture for at least 3 hours at 40° C.; and (d) collecting the compound. |
| Claim: |
16. A process for preparing the compound of claim 5 comprising the steps of: (a) dissolving an acid addition salt of gaboxadol in water/n-propanol (30% v:v); (b) adding sufficient base to provide a pH of about 7; (c) aging the resulting mixture for the mixture for at least 1 hour at 40° C.; and (d) collecting the compound. |
| Claim: |
17. A process for preparing gaboxadol monohydrate which is characterized by a solid state carbon-13 nuclear magnetic resonance spectrum with peaks at 17.5, 40.3, 102.2, 158.5 and 172.5, with reference to a value of 176.03 ppm for the carbonyl peak of glycine, comprising the steps of: (a) dissolving an acid addition salt of gaboxadol in water; (b) adding sufficient base to provide a pH of about 6.5; (c) adding isopropanol to the mixture; and (d) collecting the product. |
| Claim: |
18. The process of claim 17 wherein the acid addition salt of gaboxadol is selected from gaboxadol hydrochloride and gaboxadol hydrobromide. |
| Claim: |
19. The process of claim 17 wherein the base is aqueous sodium hydroxide. |
| Claim: |
20. The process of claim 17 wherein seed crystals of gaboxadol monohydrate which is characterized by a solid state carbon-13 nuclear magnetic resonance spectrum with peaks at 17.5, 40.3, 102.2, 158.5 and 172.5 are added after 0.3 to 0.4 equivalents of base have been added. |
| Claim: |
21. The process of claim 17 wherein after step (b) the mixture is aged at least one hour. |
| Claim: |
22. The process of claim 17 wherein in step (c) at least an equal volume of isopropanol is added slowly. |
| Claim: |
23. The process of claim 17 wherein after addition of isopropanol, the mixture is aged at least one hour. |
| Claim: |
24. The process of claim 17 wherein the slurry obtained after step (c) is wet-milled. |
| Claim: |
25. The process of claim 24 wherein in step (d) the product is collected by filtration and washed with aqueous isopropanol. |
| Current U.S. Class: |
514302/000 |
| Current International Class: |
61; 61; 61; 07 |
| Accession Number: |
edspap.20080085913 |
| Database: |
USPTO Patent Applications |
