Organic compounds
The invention relates to particular substituted deuterated 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-HT2A receptor, serotonin transporter (SERT) and/or pathways involving dopamine D1/D2 receptor signaling systems, and/or the treatment of residual symptoms.
1. A method for the treatment of bipolar disorder or bipolar depression comprising administering to a patient in need thereof a therapeutically effective amount of the compound of formula I,
in free or salt form, or
the compound of formula II,
in free or salt form, or
the compound of formula III,
in free or salt form.
2. The method according to claim 1 , wherein said compound is in salt form.
3. The method according to claim 2 , wherein the salt is a toluenesulfonic acid addition salt.
4. The method according to claim 1 , wherein the compound is the compound of Formula II in free or salt form.
5. The method according to claim 1 , wherein bipolar disorder is bipolar disorder with psychotic symptoms.
6. The method according to claim 1 , wherein the effective amount is 2.5 mg-50 mg per day, measured as the free base equivalent.
7. The method according to claim 6 , wherein the effective amount is 1 mg-40 mg per day, measured as the free base equivalent.
8. The method according to claim 1 , wherein the compound is administered by injection for sustained or delayed release.
9. The method according to claim 1 , wherein the method further comprises the administration of one or more other therapeutic agents.
10. The method according to claim 9 , wherein the one or more other therapeutic agents are selected from compounds that modulate GABA activity, a GABA-B agonist, a 5-HT modulator, a melatonin agonist, an ion channel modulator, a serotonin-2 antagonist/reuptake inhibitor (SARIs), a 5-HT 6 antagonist, an orexin receptor antagonist, an H3 agonist, a noradrenergic antagonist, a galanin agonist, a CRH antagonist, human growth hormone, a growth hormone agonist, estrogen, an estrogen agonist, a neurokinin-1 drug; and antipsychotic agents; in free or pharmaceutically acceptable salt form.
11. The method according to claim 10 , wherein the one or more other therapeutic agents are anti-depressive agents selected from one or more of amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelazine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and venlafaxine.
12. The method according to claim 9 , wherein the one or more other therapeutic agents are anti-depressive agents, and wherein said anti-depressive agents are selective serotonin re-uptake inhibitors.
13. The method according to claim 1 , wherein the patient does not respond to a selective serotonin re-uptake inhibitor.
14. The method according to claim 13 , wherein the selective serotonin re-uptake inhibitor is selected from one or more of citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, vilazodone, and zimelidine.
15. The method according to claim 1 , wherein the patient is also receiving a selective serotonin re-uptake inhibitor.
16. The method according to claim 15 , wherein the selective serotonin re-uptake inhibitor is selected from one or more of citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, vilazodone, and zimelidine.
17. The method according to claim 1 , wherein the compound has greater than 90% incorporation of deuterium at the indicated deuterium positions of the structure.
18. The method according to claim 1 , wherein the compound has greater than 97% incorporation of deuterium, at the indicated deuterium positions of the structure.
19. The method according to claim 1 , wherein the therapeutically effective amount of the compound of Formula I or the compound of Formula II or the compound of Formula III is comprised in a pharmaceutical composition for sustained or delayed release, which is formulated for administration by injection, and which comprises the compound of Formula I or II or III dispersed or dissolved in a polymeric matrix.
20. The method according to claim 19 , wherein the polymeric matrix comprises polylactide, poly-d,l-lactide, polyglycolide, or a poly(d,l-lactide-co-glycolide) copolymer (PLGA).
21. The method according to claim 20 , wherein the polymeric matrix comprises a poly(d,l-lactide-co-glycolide) copolymer (PLGA).
22. The method according to claim 21 , wherein the PLGA copolymer has a lactide to glycolide ratio from 50:50 to 90:10.
23. The method according to claim 21 , wherein the PLGA copolymer is selected from PLGA 50:50, PLGA 75:25, PLGA 85:15, and PLGA 90:10.
24. The method according to claim 21 , wherein the PLGA copolymer has a weight-average molecular weight from 5,000 to 500,000 daltons.
25. The method according to claim 1 , wherein the compound is the compound of Formula I in free or salt form.
26. The method according to claim 25 , wherein said compound is in salt form.
27. The method according to claim 26 , wherein the salt is a toluenesulfonic acid addition salt.
28. The method according to claim 4 , wherein the salt is a toluenesulfonic acid addition salt.
29. The method according to claim 1 , wherein the compound is the compound of Formula III in free or salt form.
30. The method according to claim 29 , wherein said compound is in salt form.
31. The method according to claim 30 , wherein the salt is a toluenesulfonic acid addition salt.
32. The method according to claim 19 , wherein the compound is the compound of Formula II in free or toluenesulfonic acid addition salt form.
33. The method according to claim 21 , wherein the compound is the compound of Formula II in free or toluenesulfonic acid addition salt form.
34. The method according to claim 22 , wherein the compound is the compound of Formula II in free or toluenesulfonic acid addition salt form.