# US 10,117,851 B2 · Composition of a 5-HT2A serotonin receptor modulator useful for the treatment of disorders related thereto

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- Number: US 10,117,851 B2
- Document ID: US10117851B2
- Status: Granted
- Kind: B2
- Application number: 15/718,886
- Filed: 2017-09-28
- Published: 2018-03-29
- Granted: 2018-11-06
- Earliest claimed: 2008-10-28
- Assignees: Arena Pharmaceuticals, Inc.
- Applicants: Arena Pharmaceuticals, Inc
- Inventors: Lee Alani Selvey; Marlon Carlos; Paul Maffuid; Yun Shan; William L. Betts, III; Deam Windate Given, III; Ryan M. Hart; Zezhi Jesse Shao
- Web page: https://patentgrep.com/patent/US10117851B2

## CPC

- A61K 31/415: 1,2-Diazoles
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/20: Hypnotics; Sedatives
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- C07D 231/16: Halogen atoms or nitro radicals
- 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

The present invention relates to certain compositions of a 5-HT2A serotonin receptor modulator and methods for their preparation. The compositions disclosed herein are useful for increasing slow wave sleep, improving sleep consolidation, improving sleep maintenance and improving sleep quality, and for treating insomnia and related sleep disorders, dyssomnias, parasomnias and nonrestorative sleep and the like. The compositions disclosed herein are further useful for treating platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, thrombosis, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic-related disorders and progressive multifocal leukoencephalopathy and the like.

## Claims

### Claim 1

A pharmaceutical composition comprising:
a. Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea; and wherein said Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea has an x-ray powder diffraction pattern comprising a peak expressed in terms of 2θ, at about 8.2°, about 11.5°, about 12.3°, about 19.9°, about 20.4°, about 24.6°, and about 24.7°
b. an excipient selected from: PVP and coPVP
wherein Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and said excipient are present in a ratio of between about 1:20 and about 1:1 by weight, and
wherein the composition comprises less than 0.9 mole % of 1-(2,4-difluorophenyl)-3-(4-methoxy-3-(1-methyl-1H-pyrazol-5-yl)phenyl)urea.

### Claim 2 (depends on 1)

The pharmaceutical composition according to claim 1, comprising said Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and said excipient in a ratio of about 1:8 by weight.

### Claim 3 (depends on 1)

The pharmaceutical composition according to claim 1, further comprising methyl cellulose.

### Claim 4 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said excipient is PVP.

### Claim 5 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said excipient is coPVP.

### Claim 6 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition further comprises at least one ingredient selected from: lactose monohydrate, microcrystalline cellulose, crospovidone, sodium lauryl sulfate, magnesium stearate and silicon dioxide.

### Claim 7 (depends on 1)

The pharmaceutical composition according to claim 1, comprising said Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition.

### Claim 8 (depends on 1)

The pharmaceutical composition according to claim 1, comprising said excipient in an amount of about 40% by weight of the total composition.

### Claim 9 (depends on 1)

The pharmaceutical composition according to claim 1, comprising:
a. Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition;
b. said excipient in an amount of about 40% by weight of the total composition; and
c. methyl cellulose in an amount of about 2% by weight of the total composition.

### Claim 10 (depends on 1)

The pharmaceutical composition according to claim 1, comprising:
a. Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition;
b. Plasdone™ K-29/32 PVP or Kollidon™ 30 PVP in an amount of about 40% by weight of the total composition;
c. 4000 cps methyl cellulose in an amount of about 2% by weight of the total composition;
d. Fast-Flo™ 316 lactose monohydrate in an amount of about 21.25% by weight of the total composition;
e. Avicel™ PH102 microcrystalline cellulose in an amount of about 25% by weight of the total composition;
f. Kollidon™ CL crospovidone in an amount of about 4% by weight of the total composition;
g. sodium lauryl sulfate in an amount of about 2% by weight of the total composition;
h. HyQual™ 5712 magnesium stearate in an amount of about 0.5% by weight of the total composition; and
i. Cab-o-sil™ colloidal silicon dioxide in an amount of about 0.25% by weight of the total composition.

### Claim 11 (depends on 1)

The pharmaceutical composition according to claim 1, comprising:
a. Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea in an amount of about 5% by weight of the total composition;
b. Kollidon™ VA 64 coPVP in an amount of about 40% by weight of the total composition;
c. 4000 cps methyl cellulose in an amount of about 2% by weight of the total composition;
d. Fast-Flo™ 316 lactose monohydrate in an amount of about 21.25% by weight of the total composition;
e. Avicel™ PH102 microcrystalline cellulose in an amount of about 25% by weight of the total composition;
f. Kollidon™ CL crospovidone in an amount of about 4% by weight of the total composition;
g. sodium lauryl sulfate in an amount of about 2% by weight of the total composition;
h. HyQual™ 5712 magnesium stearate in an amount of about 0.5% by weight of the total composition; and
i. Cab-o-sil™ colloidal silicon dioxide in an amount of about 0.25% by weight of the total composition.

### Claim 12 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said pharmaceutical composition is in the form of a pill, capsule or tablet.

### Claim 13 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 5% by weight of said composition.

### Claim 14 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea constitutes at least about 30 mg by weight of said composition.

### Claim 15 (depends on 1)

The pharmaceutical composition according to claim 1, further comprising a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

The pharmaceutical composition according to claim 1, wherein said composition is in the form of a pill, capsule or tablet.

### Claim 17 (depends on 1)

A kit comprising a container and a pharmaceutical composition according to claim 1.

### Claim 18

A method for treating agitation or a symptom thereof in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and an excipient selected from the group consisting of PVP and coPVP.

### Claim 19

A method for treating agitation or a symptom thereof in an individual in need thereof, where the individual is a cognitively intact elderly patient, comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and an excipient selected from the group consisting of PVP and coPVP.

### Claim 20

A method for the treatment of agitation or a symptom thereof in an individual in need thereof suffering from dementia comprising administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and an excipient selected from the group consisting of PVP and coPVP.

### Claim 21 (depends on 20)

The method of claim 20, wherein the dementia is due to a degenerative disease of the nervous system.

### Claim 22 (depends on 20)

The method of claim 20, wherein the dementia is selected from the group consisting of Alzheimer's disease, Lewy Body, Parkinson's disease, Huntington's disease, dementia due to diseases that affect blood vessels, dementia due to stroke, multi-infarct dementia, and any combination thereof.