# US 10,117,867 B2 · Methods and compositions for sleep disorders and other disorders

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- Number: US 10,117,867 B2
- Document ID: US10117867B2
- Status: Granted
- Kind: B2
- Application number: 15/467,867
- Filed: 2017-03-23
- Published: 2017-07-06
- Granted: 2018-11-06
- Earliest claimed: 2008-05-27
- Assignees: Intra-Cellular Therapies, Inc.
- Applicants: Intra-Cellular Therapies, Inc.
- Inventors: Sharon Mates; Allen Fienberg; Lawrence P. Wennogle
- Web page: https://patentgrep.com/patent/US10117867B2

## CPC

- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/198: Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00)
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 5/06: of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 471/14: Ortho-condensed systems
- C07D 498/14: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

A method for the treatment of bipolar depression, comprising administering to a patient in need thereof a Compound of Formula I:
wherein X is O, —NH or —N(CH3); and Y is —O— or —C(O)—, in free or pharmaceutically acceptable salt form.

### Claim 2 (depends on 1)

The method of claim 1, wherein the Compound of Formula I is
in free or pharmaceutically acceptable salt form.

### Claim 3 (depends on 1)

The method according to claim 1 wherein said patient is unable to tolerate the side effects of conventional antipsychotic drugs.

### Claim 4 (depends on 3)

The method according to claim 3 wherein said antipsychotic drugs are selected from the group consisting of haloperidol, aripiprazole, clozapine, olanzapine, quetiapine, risperidone and zipasidone.

### Claim 5 (depends on 1)

The method according to claim 1, wherein said patient is suffering from psychosis or Parkinson's disease.

### Claim 6 (depends on 1)

The method according to claim 1, wherein patient is suffering from depression.

### Claim 7 (depends on 1)

The method according to claim 1, wherein said patient is suffering from psychosis.

### Claim 8 (depends on 1)

The method according to claim 1, further comprising administration 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, an antipsychotic agent, and an atypical antipsychotic agent, in free or pharmaceutically acceptable salt form.

### Claim 9 (depends on 1)

The method according to claim 1, further comprising administering 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, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, 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, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone, in free or pharmaceutically acceptable salt form.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the amount of said Compound of Formula I administered is from 0.1 mg to 20 mg, in free or pharmaceutically acceptable salt form, provided that in the case of a salt, the weight is calculated as the free base.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the amount of the Compound of Formula I administered is 0.5-10 mg.

### Claim 12 (depends on 10)

The method according to claim 10, wherein the amount of the Compound of Formula I administered is 2.5-5 mg.

### Claim 13 (depends on 10)

The method according to claim 10, wherein the amount of the Compound of Formula I administered is less than 5 mg.

### Claim 14 (depends on 10)

The method according to claim 10, wherein the amount of the Compound of Formula I administered is less than 2.5 mg.

### Claim 15 (depends on 2)

The method of claim 2 wherein the Compound of Formula I is in the form of the tosylate salt.

### Claim 16 (depends on 1)

The method according to claim 1, further comprising administering one or more therapeutic agents selected from a group consisting of L-dopa, co-careldopa, duodopa, symmetrel, benzotropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone.

### Claim 17 (depends on 10)

The method according to claim 10, further comprising administering one or more therapeutic agents selected from a group consisting of L-dopa, co-careldopa, duodopa, stalova, symmetrel, benzotropine, biperiden, bromocriptine, entacapone, pergolide, pramipexole, procyclidine, ropinirole, selegiline and tolcapone.

### Claim 18

A method for promoting regular sleep in the treatment:
of bipolar depression;
comprising administering to a patient in need thereof:
an atypical stimulant; and
a Compound of Formula I:
wherein X is O, —NH or —N(CH3); and Y is —O— or —C(O)—, in free or pharmaceutically acceptable salt form.

### Claim 19 (depends on 18)

The method according to claim 18, wherein the compound of Formula I has the structure:

### Claim 20 (depends on 19)

The method according to claim 19 wherein the Compound of Formula I is in the form of the tosylate salt.

### Claim 21 (depends on 20)

The method according to claim 20, wherein the amount of said Compound of Formula I administered is from 0.1 mg to 20 mg, in free or pharmaceutically acceptable salt form, provided that in the case of a salt, the weight is calculated as the free base.

### Claim 22 (depends on 21)

The method according to claim 21, wherein the amount of the Compound of Formula I administered is 0.5-10 mg.

### Claim 23 (depends on 22)

The method according to claim 22, wherein the amount of the Compound of Formula I administered is 2.5-5 mg.

### Claim 24 (depends on 22)

The method according to claim 22, wherein the amount of the Compound of Formula I administered is less than 5 mg.

### Claim 25 (depends on 22)

The method according to claim 22, wherein the amount of the Compound of Formula I administered is less than 2.5 mg.

### Claim 26 (depends on 18)

The method according to claim 18, wherein the atypical stimulant is selected from the group consisting of modafinil, adrafinil and armodafinil.

### Claim 27 (depends on 18)

The method according to claim 18, further comprising administration 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.

### Claim 28 (depends on 18)

The method according to claim 18, further comprising administration of 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, temazepam, triazolam, indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, 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, escitalopram, fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine sulfate, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, venlafaxine, chlorpromazine, haloperidol, droperidol, fluphenazine, loxapine, mesoridazine molindone, perphenazine, pimozide, prochlorperazine promazine, thioridazine, thiothixene, trifluoperazine, clozapine, aripiparazole, olanzapine, quetiapine, risperidone, ziprasidone and paliperidone, in free or pharmaceutically acceptable salt form.