# US 9,040,725 B2 · Benzocycloheptane and benzoxepine derivatives

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- Number: US 9,040,725 B2
- Document ID: US9040725B2
- Status: Granted
- Kind: B2
- Application number: 14/202,136
- Filed: 2014-03-10
- Published: 2014-07-03
- Granted: 2015-05-26
- Earliest claimed: 2008-04-28
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: Bruno Schoentjes; Alain Philippe Poncelet; Julien Georges Pierre-Olivier Doyon; Joannes Theodorus Maria Linders; Lieven Meerpoel; Luc August Laurentius Ver Donck
- Web page: https://patentgrep.com/patent/US9040725B2

## CPC

- C07C 215/42: having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/10: Laxatives
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/20: Hypnotics; Sedatives
- 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]
- C07C 35/52: Alcohols with a condensed ring system
- C07C 43/192: containing halogen
- C07C 215/64: with rings other than six-membered aromatic rings being part of the carbon skeleton
- C07C 217/08: the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
- C07C 217/74: with rings other than six-membered aromatic rings being part of the carbon skeleton
- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 213/53: Nitrogen atoms
- C07D 213/65: attached in position 3 or 5
- C07D 215/14: Radicals substituted by oxygen atoms
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 295/092: with aromatic radicals attached to the chain
- C07D 295/096: with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 295/16: acylated on ring nitrogen atoms
- C07D 313/08: condensed with one six-membered ring
- C07D 317/58: Radicals substituted by nitrogen atoms (nitro radicals C07D317/52)
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 407/04: directly linked by a ring-member-to-ring-member bond
- C07C 2602/12: the other ring being at least seven-membered
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a compound of formula (I) including any stereochemically isomeric form thereof, wherein the substituents are as defined in the specification and the claims; a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof; provided that the compound is other than or a pharmaceutically acceptable salt thereof. The claimed compounds are useful for the treatment of a disease, the treatment of which is affected, mediated or facilitated by activating the GHS1A-r receptor. The invention also relates to pharmaceutical compositions thereof and processes for the preparation thereof.

## Claims

### Claim 1

A method of treating cognitive impairment comprising administering to a warm-blooded mammal in need of such treatment an effective amount of a compound of formula
including any stereochemically isomeric form thereof, wherein
A represents phenyl, thienyl, furanyl or a 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms; wherein said phenyl, thienyl, furanyl or 6-membered aromatic heterocycle may optionally be fused with phenyl or a 6-membered aromatic heterocycle containing 1 or 2 nitrogen atoms;
Z represents CH2 or O;
R1 represents halo, hydroxyl, C1-4alkyl, C1-4alkyloxy, polyhaloC1-4alkyl, cyano, nitro, amino, mono or di(C1-4alkyl)amino; or
in case A represents phenyl then two adjacent R1 substituents may be taken together to form a radical of formula
—O—CH2—O— (a-1); or
—O—CH2—CH2—O— (a-2);
R2 represents hydrogen or C1-4alkyl;
R3 and R4 each independently represent hydrogen, C1-6alkyl, C1-4alkyloxyC1-6alkyl or phenylC1-4alkyl; or
R3 and R4 are taken together with the nitrogen to which they are attached to form a radical of formula (b-1) or (b-2)
with X1 representing CH2 or CHOH; and X2 representing CH2, O or NR6;
R5 represents hydrogen, halo, C1-4alkyl, C1-4alkyloxy or trifluoromethyl;
R6 represents hydrogen, C1-4alkyl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, phenyloxycarbonyl;
n represents an integer of value 0, 1, 2, 3, 4 or 5;
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
provided that the compound is other than
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method as claimed in claim 1 wherein A represents phenyl or phenyl substituted with 1, 2 or 3 R1 substituents.

### Claim 3 (depends on 1)

The method as claimed in claim 1 wherein A represents a radical of formula

### Claim 4 (depends on 1)

The method as claimed in claim 1 wherein A represents pyridyl, pyrimidinyl or quinolinyl, each of said pyridyl, pyrimidinyl or quinolinyl optionally being substituted with 1, 2 or 3 R1 substituents.

### Claim 5 (depends on 1)

The method as claimed in claim 1 wherein Z represents CH2.

### Claim 6 (depends on 1)

The method as claimed in claim 1 wherein Z represents O.

### Claim 7 (depends on 1)

The method as claimed in claim 1 wherein R1 represents halo, hydroxyl, C1-4alkyl or C1-4alkyloxy.

### Claim 8 (depends on 1)

The method as claimed in claim 1 wherein R2 represents hydrogen.

### Claim 9 (depends on 1)

The method as claimed in claim 1 wherein R3 and R4 each independently represent hydrogen, C1-6alkyl, C1-4alkyloxyC1-6alkyl, or phenyl-C1-4alkyl; or
R3 and R4 are taken together with the nitrogen to which they are attached to form a radical of formula (b-1) or (b-2)
with X1 representing CH2 or CHOH; and X2 representing CH2.

### Claim 10 (depends on 9)

The method as claimed in claim 9 wherein R3 and R4 each independently represent hydrogen, C1-6alkyl, C1-4alkyloxyC1-6alkyl, or phenylC1-4alkyl; or
R3 and R4 are taken together with the nitrogen to which they are attached to form a radical of formula (b-1)
with X1 representing CH2 or CHOH.

### Claim 11 (depends on 1)

The method as claimed in claim 1 wherein n represents an integer of value 1 or 2.

### Claim 12 (depends on 1)

The method as claimed in claim 1 wherein n is O.

### Claim 13 (depends on 1)

The method as claimed in claim 1 wherein A represents phenyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, pyridyl, pyrimidinyl, quinolinyl; each of said rings optionally being substituted with 1 or 2 substituents each independently selected from halo, hydroxyl, C1-4alkyl or C1-4alkyloxy; R3 and R4 each independently represent hydrogen, C1-4alkyl, C1-4alkyloxyC1-4alkyl, phenylC1-4alkyl; or R3 and R4 are taken together with the nitrogen to which they are attached to form pyrrolidinyl optionally substituted in position 3 with hydroxyl; piperidinyl; morpholinyl; piperazinyl optionally substituted with C1-4alkyl or C1-4alkylcarbonyl; R2 represents hydrogen or methyl.

### Claim 14 (depends on 1)

The method as claimed in claim 1 wherein the substituents on the cycloheptane or oxepine ring have a cis configuration.

### Claim 15 (depends on 14)

The method as claimed in claim 14 wherein the compound is an enatiomeric pure form.

### Claim 16 (depends on 1)

The method as claimed in claim 1 wherein the compound is selected from
(±)cis-6-(4-Chloro-3-methoxy-phenyl)-5-(3-diethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-6-(3-Chloro-phenyl)-5-(3-diethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-4-(4-Chloro-3-methoxy-phenyl)-5-(3-diethylamino-propyl)-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ol oxalate;
(±)cis-6-(3-Chloro-phenyl)-5-(3-dimethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-6-(4-Chloro-3-methoxy-phenyl)-5-(3-dimethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;
(±)cis-6-(4-Chloro-phenyl)-5-(3-dimethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-5-(3-Dimethylamino-propyl)-6-(3-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-5-(3-Dimethylamino-propyl)-6-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-5-(3-Dimethylamino-propyl)-6-phenyl-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-5-ol oxalate;
(±)cis-6-(4-Chloro-3-methoxy-phenyl)-5-{3-[(2-methoxy-ethyl)-methyl-amino]-propyl}-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-5-(3-Dimethylamino-propyl)-6-p-tolyl-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-5-ol oxalate;
(±)cis-5-(3-Diethylamino-propyl)-6-(4-fluoro-phenyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-6-(2,4-Difluoro-phenyl)-5-(3-dimethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-4-(4-Chloro-3-methoxy-phenyl)-5-(3-dimethylamino-propyl)-2,3,4,5-tetrahydro-benzo[b]oxepin-5-ol oxalate;
(±)cis-5-(3-Diethylamino-propyl)-6-p-tolyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-5-(3-Diethylamino-propyl)-6-(3-methoxy-phenyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol hydrochloride;
(±)cis-6-(4-Bromo-phenyl)-5-(3-dimethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol oxalate;
(±)cis-6-(5-Chloro-pyridin-3-yl)-5-(3-dimethylamino-propyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol hydrochloride;
(±)cis-5-(3-Dimethylamino-propyl)-6-quinolin-3-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol;
(±)cis-5-(3-Dimethylamino-propyl)-6-(6-methyl-pyridin-3-yl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol hydrochloride.