Methods and compositions for sleep disorders and other disorders

Abstract

Use of particular substituted heterocycle fused gamma-carboline compounds as pharmaceuticals and pharmaceutical compositions comprising them for the treatment of one or more disorders involving the 5-HT2A, SERT and/or dopamine D2 pathways are disclosed. In addition, the compounds may be combined with other therapeutic agents for the treatment of one or more sleep disorders, depression, psychosis, dyskinesias, and/or Parkinson's disease or any combinations.

The invention claimed is: 
     
       1. A method for the treatment of one or more 5-HT 2A -related disorders, comprising administering to a patient in need thereof a Compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein X is O, —NH or —N(CH 3 ); and Y is —O— or —C(O)—, in free or pharmaceutically acceptable salt form, in a dose which selectively blocks the 5-HT 2A  receptor. 
     
     
       2. The method according to  claim 1  wherein said one or more disorders is psychosis. 
     
     
       3. The method according to  claim 1  wherein said one or more disorders is schizophrenia. 
     
     
       4. The method according to  claim 1  wherein said one or more disorders is depression. 
     
     
       5. The method according to  claim 1  wherein said patient is unable to tolerate the side effects of conventional antipsychotic drugs. 
     
     
       6. The method according to  claim 5  wherein said antipsychotic drugs are selected from the group consisting of haloperidol, aripiparazole aripiprazole, clozapine, olanzapine, quetiapine, risperidone and zipasidone ziprasidone. 
     
     
       7. The method according to  claim 1  wherein said one or more disorders is depression and said patient is a patient suffering from psychosis or Parkinson's disease. 
     
     
       8. The method according to  claim 1  wherein said one or more disorders is sleep disorder and said patient is suffering from depression. 
     
     
       9. The method according to  claim 1  wherein said one or more disorders is sleep disorder and said patient is suffering from psychosis. 
     
     
       10. The method according to  claim 1  wherein said one or more disorders is sleep disorder and said patient is suffering from Parkinson's disease. 
     
     
       11. The method according to  claim 1  wherein said one or more disorders is sleep disorder and said patient is suffering from depression and psychosis or Parkinson's disease. 
     
     
       12. The method according to  claim 1  wherein at least one of the disorders is dyskinesia. 
     
     
       13. The method of  claim 12  wherein the disorder is levodopa-induced dyskinesia in a patient suffering from Parkinson's disease. 
     
     
       14. The method according to  claim 1 , further comprising administration to the patient of one or more therapeutic agents selected from the group consisting of compounds that modulate GABA activity, a GABAB agonist, a 5-HT modulator, a melatonin agonist, an ion channel modulator, a serotonin-2 antagonist/reuptake inhibitor (SARIs), 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, an anti-depressant, and an antipsychotic agent, in free or pharmaceutically acceptable salt form. 
     
     
       15. The method according to  claim 1 , further comprising administering to the patient one or more therapeutic agents selected from the group consisting of modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol gaboxadol, vigabatrin, tiagabine, EVT 201, estazolam, ketanserin, risperidone, eplivanserin, volinanserin pruvanserin, MDL 100907, HY10275, APD125, AVE8488, repinotan, sarizotan, eptapirone, buspirone, MN-305, melatonin, ramelteon, VEC-162, PD-6735, agomelatine, lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea, SB-334867-a, GW649868, a benzamide derivative, Org 50081, ritanserin, nefazodone, serzone, trazodone, Casopitant, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitaloprame escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine phenelzine sulfate, protiptyline protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, velafaxine venlafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molidone molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiparazole aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone, in free or pharmaceutically acceptable salt form. 
     
     
       16. A method for the treatment of one or more sleep disorders comprising administering to a patient in need thereof a Compound of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein X is O, —NH or —N(CH 3 ); and Y is —O— or —C(O)—, in free or pharmaceutically acceptable salt form, in an amount that selectively blocks the 5-HT 2A  receptor, such that it
 a) is sufficient to block said 5-HT 2A  receptor; and 
 b) either does not block, or minimally blocks the dopamine D2 receptor. 
 
     
     
       17. The method according to  claim 16 , wherein the sleep disorder is sleep maintenance insomnia. 
     
     
       18. The method according to  claim 16 , further comprising administration to the patient of one or more therapeutic agents selected from the group consisting of compounds that modulate GABA activity, a GABAB agonist, a 5-HT modulator, a melatonin agonist, an ion channel modulator, a serotonin-2 antagonist/reuptake inhibitor (SARIs), 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-I drug, an anti-depressant, and an antipsychotic agent, in free or pharmaceutically acceptable salt form. 
     
     
       19. The method according  claim 16 , further comprising administering to the patient one or more therapeutic agents selected from the group consisting of modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam, oxazepam, temazapam temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gabaxadol gaboxadol, vigabatrin, tiagabine, EVT 201, estazolam, ketanserin, risperidone, eplivanserin, volinanserin, pruvanserin, MDL 100907, HY10275, APD125, AVE8488, repinotan, sarizotan, eptapirone, buspirone, MN-305, melatonin, ramelteon, VEC-162, PD-6735, agomelatine, lamotrigine, gabapentin, pregabalin, orexin, a 1,3-biarylurea, SB-334867-a, GW649868, a benzamide derivative, Org 50081, ritanserin, nefazodone, serzone, trazodone, Casopitant, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin, duloxetine, escitaloprame escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenlzine phenelzine sulfate, protiptyline protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, velafaxine venlafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine, molidone molindone, perphenazine, pimozide, prochlorperazine, promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiparazole aripiprazole, olanzapine, quetiapine, risperidone, ziprasi- done and paliperidone, in free or pharmaceutically acceptable salt form. 
     
     
       20. The method according to  claim 16 , wherein the effective amount of the Compound of Formula I administered is 0.5-10 mg. 
     
     
       21. The method according to  claim 16 , wherein the amount of the Compound of Formula I administered is 2.5-5 mg. 
     
     
       22. The method according to  claim 16 , wherein the amount of the Compound of Formula I administered is less than 5 mg. 
     
     
       23. The method according to  claim 16 , wherein the amount of the Compound of Formula I administered is less than 2.5 mg. 
     
     
       24. The method of  claim 16  wherein the sleep disorder is insomnia in a patient suffering from depression. 
     
     
       25. The method according to  claim 1 , further comprising administering to the patient one or more therapeutic agents selected from a group consisting of as L-dopa, co-careldopa, duodopa, stalova, symmetrel, benzotropine benztropine, biperiden, bromocryiptine bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone. 
     
     
       26. The method according to  claim 16 , further comprising administering to the patient one or more therapeutic agents selected from a group consisting of as L-dopa, co-careldopa, duodopa, stalova, symmetrel, benzotropine benztropine, biperiden, bromocryiptine bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone. 
     
     
       27. The method according to  claim 1 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
       28. The method according to  claim 1 , wherein the dose of said Compound of Formula I is from 2.5 mg to 50 mg. 
     
     
       29. The method according to  claim 16 , wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
     
     
       30. The method according to claim 1, wherein the compound of Formula I has the structure: 
       
         
           
           
               
               
           
         
       
       in toluenesulfonic acid salt form. 
     
     
       31. The method according to claim 30, wherein the dose of said Compound of Formula I is from 2.5 to 50 mg, the weight being calculated as the free base form. 
     
     
       32. The method according to claim 31, wherein said one or more disorders is schizophrenia. 
     
     
       33. The method according to claim 32, wherein said Compound of Formula I in toluenesulfonic acid salt form is in crystal form. 
     
     
       34. The method according to claim 32, wherein said Compound of Formula I in toluenesulfonic acid salt form is in amorphous form. 
     
     
       35. The method according to claim 31, wherein said one or more disorders is bipolar depression. 
     
     
       36. The method according to claim 35, wherein said Compound I in toluene sulfonic acid salt form is in crystal form. 
     
     
       37. The method according to claim 35, wherein said Compound I in toluene sulfonic acid salt form is in amorphous form.