# US 11,078,183 B2 · Tetrahydrate of H3 ligand, its process of preparation and pharmaceutical compositions comprising the same

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- Number: US 11,078,183 B2
- Document ID: US11078183B2
- Status: Granted
- Kind: B2
- Application number: 16/496,013
- Filed: 2018-03-20
- Published: 2020-01-23
- Granted: 2021-08-03
- Earliest claimed: 2017-03-21
- Assignees: Bioprojet
- Applicants: Bioprojet
- Inventors: Marc Capet; Jeanne-Marie Lecomte; Jean-Charles Schwartz
- Web page: https://patentgrep.com/patent/US11078183B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention concerns the tetrahydrate form of the compound: (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide, dihydrochloride, its process of preparation and therapeutical uses thereof.

## Claims

### Claim 1

The tetrahydrate form of the compound of formula (A):
(A): (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide, dihydrochloride.

### Claim 2 (depends on 1)

The tetrahydrate form according to claim 1 which exhibits a melting peak of 191° C. when measured by capillary tube method.

### Claim 3 (depends on 1)

The tetrahydrate form according to claim 1 which comprises a water content of 15.3±0.7% in weight.

### Claim 4 (depends on 1)

The tetrahydrate form according to claim 1 which exhibits the powder X-ray diffractogram lines: 2-Theta° (d in Ångstroms)=9.7 (9.1), 12.5 (7.1), 14.6 (6.1), 15.2 (5.8), 16.5 (5.4), 19.0 (4.7), 19.5 (4.6), 22.0 (4.1), 24.3 (3.7), 24.8 (3.6), 26.2 (3.4), 28.4 (3.1).

### Claim 5 (depends on 1)

A process of preparation of the tetrahydrate form according to claim 1 comprising the following steps:
dissolving compound (A) in water;
concentrating up to crystallization;
filtering; and
drying.

### Claim 6 (depends on 1)

A process of preparation of the tetrahydrate form according to claim 1 comprising the following steps:
dissolving compound (A) in water;
adding acetone and lowering temperature up to crystallization;
filtering; and
drying.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising the tetrahydrate form according to claim 1, together with at least one pharmaceutically acceptable excipient.

### Claim 8 (depends on 1)

A method for treating Alzheimer's disease; attention; wakefulness and memorization disorders; cognitive deficits in psychiatric pathologies; mood, vigilance or cognitive disorders in aged persons; depressive or asthenic states; Parkinson's disease; obstructive sleep apnea; dementia with Lewy bodies; vascular dementia; vertigo; motion sickness; obesity; diabetes and the metabolic syndrome; sleep disorders; stress; psychotropic disorders; epilepsy; depression; narcolepsy with or without cataplexy; disorders of the hypothalamohypophyseal secretion, the cerebral circulation and/or immune system; excessive daytime sleepiness and fatigue associated with Parkinson's disease, obstructive sleep apnea or dementia and/or for facilitating night works or adaptation to time shift in healthy humans; attention deficit disorders; substance abuse abuse disorders; substance abuse withdrawal syndromes; post-stroke fatigue, mood, cognitive and vigilance disorders; cognitive disorders in autism; attention and vigilance disorders of attention-deficit hyperactivity disorder (ADHD) in children or adults, said method comprising:
administering the tetrahydrate form according to claim 1 to a human patient in need thereof.

### Claim 9 (depends on 1)

A method for treating sleep disorders, insomnia, disorders of sleep initiation and maintenance, sleep fragmentation, parasomnias, sleep disordered breathing, circadian dysrhythmia, narcolepsy with or without cataplexy, excessive daytime sleepiness, excessive daytime sleepiness associated with Parkinson's disease, obstructive sleep apnea or dementia; substance abuse disorders, alcohol abuse, mood cognitive and vigilance disorders associated with stroke; cognitive and attention disorders in ADHD,
said method comprising administering the tetrahydrate form according to claim 1 to a human patient in need thereof.

### Claim 10 (depends on 8)

The method according to claim 8 comprising the administration of said tetrahydrate of compound (A) in a human at a dose comprised between 10 and 90 μg relative to the base of compound (A) a day.

### Claim 11

The tetrahydrate form of the compound of formula (A):
(A): (3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide, dihydrochloride, which exhibits the powder X-ray diffractogram lines: 2-Theta° (d in Ångstroms)=9.7 (9.1), 12.5 (7.1), 14.6 (6.1), 15.2 (5.8), 16.5 (5.4), 19.0 (4.7), 19.5 (4.6), 22.0 (4.1), 24.3 (3.7), 24.8 (3.6), 26.2 (3.4), 28.4 (3.1).