# US 11,304,932 B2 · Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of hallucinations associated with a neurodegenerative disease

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- Number: US 11,304,932 B2
- Document ID: US11304932B2
- Status: Granted
- Kind: B2
- Application number: 17/100,528
- Filed: 2020-11-20
- Published: 2021-06-17
- Granted: 2022-04-19
- Earliest claimed: 2015-07-15
- Assignees: Axovant Sciences GmbH
- Applicants: Axovant Sciences GmbH
- Inventors: Lawrence Tim Friedhoff; Shankar Ramaswamy; Yandong Wen
- Web page: https://patentgrep.com/patent/US11304932B2

## CPC

- A61K 31/415: 1,2-Diazoles
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 31/13: Amines {(A61K31/04 takes precedence)}
- A61K 31/135: having aromatic rings {, e.g. ketamine, nortriptyline (methadone A61K31/137)}
- 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 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K 31/5513: 1,4-Benzodiazepines, e.g. diazepam {or clozapine}
- A61K 31/554: having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- 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

## Abstract

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT2A serotonin receptor and their uses for the treatment and prophylaxis of visual hallucinations associated with Lewy Body dementia.

## Claims

### Claim 1

A method for the treatment of visual hallucinations, in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a 5-HT2A inverse agonist, wherein the 5-HT2A inverse agonist is nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is selected from the group consisting of Form I of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea, Form II of 1-[3-(4-bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)-urea and a combination thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from about 10 mg to about 160 mg.

### Claim 4 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

### Claim 5 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin is about 10 mg, about 20 mg, about 40 mg, about 80 mg, or about 160 mg.

### Claim 6 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin is about 10 mg.

### Claim 7 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin is about 20 mg.

### Claim 8 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin is about 40 mg.

### Claim 9 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin is about 80 mg.

### Claim 10 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of nelotanserin is about 160 mg.

### Claim 11 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of the 5-HT2A inverse agonist is administered once a day, twice a day, three times a day, or four times a day.

### Claim 12 (depends on 1)

The method of claim 1, wherein the 5-HT2A inverse agonist is in a pharmaceutical composition configured for immediate release, for extended release, for delayed release, or any combination thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the 5-HT2A inverse agonist is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration.

### Claim 14 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of the 5-HT2A inverse agonist is administered about one to about four times per day, once daily in the morning, once daily about 1 hour prior to the subject's bedtime, or twice daily.

### Claim 15 (depends on 1)

The method of claim 1, wherein the subject is a human.

### Claim 16 (depends on 15)

The method of claim 15, wherein the human is an adult with a diagnosis of a condition selected from Lewy Body Dementia, probable Dementia with Lewy bodies, Dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof.

### Claim 17 (depends on 15)

The method of claim 15, wherein the human has a concurrent diagnosis of visual hallucinations, and a condition selected from Lewy Body Dementia, probable Dementia with Lewy bodies, Dementia with Lewy bodies, Parkinson's disease dementia, Parkinson's disease, multiple system atrophy, Alzheimer's disease, vascular dementia, dementia, mild cognitive impairment, Parkinson's disease psychosis, Alzheimer's disease psychosis, a sleep disturbance, insomnia, delusions, agitation, Alzheimer's agitation, aggression, REM sleep behavior disorder, schizophrenia, and any combination thereof.

### Claim 18 (depends on 15)

The method of claim 15, wherein the human has a diagnosis of probable Dementia with Lewy Bodies.

### Claim 19 (depends on 18)

The method of claim 18, wherein the diagnosis of probable Dementia with Lewy bodies is defined by the presence of dementia and at least one of:
at least two Core Criteria selected from visual hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof, and
one Core Criteria selected from visual hallucinations, cognitive fluctuations, and Parkinsonism, and any combination thereof; and at least one Suggestive Criteria selected from REM Sleep Behavior Disorder, Severe Neuroleptic Sensitivity, Low Dopamine Transporter Uptake on DaT SPECT Imaging Scan; and any combination thereof.

### Claim 20 (depends on 15)

The method of claim 15, wherein the human has a diagnosis of Dementia with Lewy Bodies.

### Claim 21 (depends on 15)

The method of claim 15, wherein the human has a Mini Mental State Examination score of greater than, or equal to, about 18.

### Claim 22 (depends on 15)

The method of claim 15, wherein the human is an adult with a diagnosis of visual hallucinations associated with Dementia with Lewy Bodies.

### Claim 23 (depends on 15)

The method of claim 15, wherein the human is an adult aged 50-85 inclusive.

### Claim 24 (depends on 15)

The method of claim 15, wherein the human has experienced persistent visual hallucinations.

### Claim 25 (depends on 24)

The method of claim 24, wherein the presence of persistent hallucinations is defined by a score of four or greater on the hallucinations component of the Neuropsychiatric Inventory (NPI Item B) at screening.

### Claim 26 (depends on 15)

The method of claim 15, wherein the human has experienced visual hallucinations on at least five days in a week.

### Claim 27 (depends on 1)

The method of claim 1, wherein the subject is concurrently receiving a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of melatonin, quetiapine, clonazepam, levodopa, carbidopa, an antiparkinsonian drug, an acetylcholinesterase inhibitor, NMDA receptor antagonist, and a combination thereof.

### Claim 28 (depends on 27)

The method of claim 27, wherein the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist and any combination thereof.