Organic compounds
This invention relates to particular substituted heterocycle fused gamma-carbolines, their prodrugs, in free, solid, pharmaceutically acceptable salt and/or substantially pure form as described herein, pharmaceutical compositions thereof, and methods of use in the treatment of diseases involving 5-HT 2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D 1 /D 2 receptor signaling systems, and/or the treatment of residual symptoms.
1. A method for the treatment of a central nervous system disorder selected from anxiety, depression, psychosis, schizophrenia, post-traumatic stress disorder, impulse control disorders and intermittent explosive disorder, comprising administering to a patient in need thereof a therapeutically effective amount of compound of formula I:
wherein:
R 1 is CH 3 ;
R 2 and R 3 are each independently H or D;
R 4 and R 5 are each H;
provided that R 2 and R 3 are not both H,
and wherein D is deuterium;
in free or salt form;
wherein the compound of formula I is administered in the form of a sustained or delayed release pharmaceutical composition comprising the compound of formula I dispersed or dissolved in a polymeric matrix, and wherein the pharmaceutical composition is formulated for administration by injection.
2. The method according to claim 1 , wherein R 2 and R 3 are both D.
3. The method according to claim 1 , wherein R 2 is D and R 3 is H.
4. The method according to claim 1 , wherein said compound is in salt form.
5. The method according to claim 4 , wherein the salt is a toluenesulfonic acid addition salt.
6. The method according to claim 1 , wherein said disorder is selected from a group consisting of anxiety, depression, psychosis, and schizophrenia.
7. The method according to claim 6 , wherein said disorder is schizophrenia.
8. The method according to claim 6 , wherein said disorder is anxiety.
9. The method according to claim 1 , wherein the polymeric matrix comprises a polylactide, a polyglycolide, and/or a poly(d,l-lactide-co-glycolide) (PLGA).
10. The method according to claim 9 , wherein the polymeric matrix comprises PLGA 50:50, PLGA 75:25, PLGA 85:15, PLGA 90:10, or a combination thereof.
11. The method according to claim 9 , wherein the polymeric matrix comprises PLGA copolymer having a 75:25 to 50:50 molar ratio of lactide to glycolide.
12. The method according to claim 9 , wherein the polymeric matrix comprises PLGA copolymer having a weight-average molecular weight of 5,000 to 500,000 daltons, or a weight average molecular weight of about 150,000 daltons.
13. The method according to claim 1 , wherein the composition is formulated for intramuscular or subcutaneous injection.
14. The method according to claim 1 , wherein the composition releases the compound of formula I upon degradation of the polymeric matrix over a period of 30 to 180 days.
15. The method according to claim 1 , wherein the composition releases the compound of formula I upon degradation of the polymeric matrix over a period of 14 to 30 days.
16. The method according to claim 1 , wherein the composition comprises the polymeric matrix in the form of microparticles.
17. The method according to claim 1 , wherein the composition does not comprise the polymeric matrix in the form of microparticles.
18. The method according to claim 1 , wherein the composition comprises the polymeric matrix admixed with a water-miscible diluent or carrier.
19. The method according to claim 1 , wherein R 2 is D and R 3 is D, and wherein the compound of formula I is in the form of a toluenesulfonic acid addition salt, and wherein the polymeric matrix comprises a polylactide, a polyglycolide, and/or a poly(d,l-lactide-co-glycolide) (PLGA), and wherein the composition is formulated for intramuscular or subcutaneous injection.
20. The method according to claim 19 , wherein the polymeric matrix comprises PLGA copolymer having a 75:25 to 50:50 molar ratio of lactide to glycolide.
21. The method according to claim 20 , wherein the composition comprises the polymeric matrix admixed with a water-miscible diluent or carrier.
22. The method according to claim 1 , wherein R 2 is D and R 3 is D, and wherein the compound of formula I is free base form, and wherein the polymeric matrix comprises a polylactide, a polyglycolide, and/or a poly(d,l-lactide-co-glycolide) (PLGA), and wherein the composition is formulated for intramuscular or subcutaneous injection.
23. The method according to claim 22 , wherein the polymeric matrix comprises PLGA copolymer having a 75:25 to 50:50 molar ratio of lactide to glycolide.
24. The method according to claim 23 , wherein the composition comprises the polymeric matrix admixed with a water-miscible diluent or carrier.
25. The method according to claim 1 , wherein said disorder is bipolar depression.