# US 2014/0155453 A1 · SYNTHESIS PROCESS, AND CRYSTALLINE FORM OF 4-{3[CIS-HEXAHYDROCYCLOPENT A[CjPYRROL-2( 1 H)-YLjPROPOXYj BENZAMI DE HYDROCHLORI DE AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT

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- Number: US 2014/0155453 A1
- Document ID: US20140155453A1
- Status: Published application
- Kind: A1
- Application number: 14/174,272
- Filed: 2014-02-06
- Published: 2014-06-05
- Earliest claimed: 2011-06-08
- Assignees: Les Laboratoires Servier
- Applicants: Les Laboratoires Servier
- Inventors: Nicolas ROBERT; Jean-Michel LERESTIF; Jean-Pierre LECOUVE; Marina GAILLARD; Loic MEUNIER; Philippe LETELLIER; Mathieu BOIRET
- Web page: https://patentgrep.com/patent/US20140155453A1

## CPC

- A61P 3/04: Anorexiants; Antiobesity agents
- C07C 309/63: Esters of sulfonic acids
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- 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 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 235/46: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 209/52: condensed with a ring other than six-membered
- C07D 317/22: etherified
- C07D 319/06: not condensed with other rings
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Medicinal products containing the crystalline form I of the compound of formula (I): and/or crystalline form I of the associated free base which are useful in the treatment of disorders of the histaminergic system.

## Claims

### Claim 1

A method of treating disorders of the histaminergic system, in a subject in need thereof, comprising administration of an effective amount of a compound selected from the group consisting of a crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride of formula (I):
having an X-ray powder diffraction diagram exhibiting the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 16.97°, 17.84°, 18.90°, 20.32°, 23.87°, 27.10°, 27.86° and 30.34°, and a crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide:
having an X-ray powder diffraction diagram exhibiting the following diffraction lines (Bragg's angle 2 theta, expressed in degrees ±0.2°): 6.25°, 12.55°, 17.74°, 18.19°, 19.43°, 20.72°, 21.00°, 23.50° and 27.00°.

### Claim 2 (depends on 1)

The method of claim 1, wherein the disorder of the histaminergic system is selected from the group consisting of cognitive and psycho-behavioural disorders associated with cerebral aging and with neurodegenerative diseases, mood disorders, attention-deficit hyperactivity syndrome, obesity and pain.

### Claim 3 (depends on 2)

The method of claim 2, wherein the disorder of the histaminergic system is selected from the group consisting of cognitive and psycho-behavioural disorders associated with Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoffs disease, Lewy body dementias, frontal and subcortical dementias, frontotemporal dementias and vascular dementias.

### Claim 4 (depends on 1)

The method of claim 1, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride is administered.

### Claim 5 (depends on 4)

The method of claim 4, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°) and interplanar distance d (expressed in Å):
Angle 2-theta
Interplanar
Line no.
(degrees)
distance (Å)
1
16.97
5.219
2
17.84
4.967
3
18.90
4.690
4
20.32
4.366
5
23.87
3.724
6
27.10
3.288
7
27.86
3.200
8
30.34
2.943

### Claim 6 (depends on 4)

The method of claim 4, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride has a Raman spectrum exhibiting a significant peak at the location 1606 cm−1 or 1676 cm−1.

### Claim 7 (depends on 4)

The method of claim 4, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide hydrochloride has a Raman spectrum exhibiting significant peaks at the locations 1676 cm−1, 1606 cm−1, 1564 cm−1, 1152 cm−1, 830 cm−1 and 296 cm−1.

### Claim 8 (depends on 1)

The method of claim 1, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide is administered.

### Claim 9 (depends on 8)

The method of claim 8, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has the following X-ray powder diffraction diagram, measured using a PANalytical X'Pert Pro MPD diffractometer with an X'Celerator detector, and expressed in terms of line position (Bragg's angle 2 theta, expressed in degrees ±0.2°) and interplanar distance d (expressed in Å):
Angle 2-theta
Interplanar
Line no.
(degrees)
distance (Å)
1
6.25
14.131
2
12.55
7.049
3
17.74
4.997
4
18.19
4.873
5
19.43
4.565
6
20.72
4.284
7
21.00
4.226
8
23.50
3.782
9
27.00
3.297

### Claim 10 (depends on 8)

The method of claim 8, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has a Raman spectrum exhibiting a significant peak at the location 1683 cm−1.

### Claim 11 (depends on 8)

The method of claim 8, wherein the crystalline form I of 4-{3-[cis-hexahydrocyclopenta[c]pyrrol-2(1H)-yl]propoxy}benzamide has a Raman spectrum exhibiting significant peaks at the locations 292 cm−1, 618 cm−1, 1045 cm−1, 1483 cm−1, 1568 cm−1, 1683 cm−1.