1,3-dihydro-1,4-benzodiazepine-2-thiones for the treatment of CNS related diseases

Patent metadata

Field	Value
Publication number	US-11021448-B2
Application number	US-201916399134-A
Country	US
Kind code	B2
Filing date	Apr 30, 2019
Priority date	Nov 1, 2016
Publication date	Jun 1, 2021
Grant date	Jun 1, 2021

Abstract

The present invention provides compounds that are muscarinic M1 receptor positive allosteric modulators (PAM) and useful in the treatment of diseases, mediated by the muscarinic M1 receptor, such as Alzheimer's disease, cognitive impairment, schizophrenia, pain or sleep disorders, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances.

First claim

The invention claimed is:

1. A compound of formula I, selected from the group consisting of:
(3R)-3-benzyl-7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3R)-7-chloro-3-(2-methylsulfanylethyl)-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3R)-7-chloro-3-isopropyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3R)-7-chloro-5-(2-fluorophenyl)-3-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3R)-7-chloro-5-(2-fluorophenyl)-3-isopropyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-3-benzyl-7-chloro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-3-isopropyl-5,7-diphenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-3-isopropyl-5-phenyl-7-(trifluoromethoxy)-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-3-isopropyl-5-phenyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-3-isopropyl-7-methoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-5-(2-fluorophenyl)-3-isopropyl-7-methyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-bromo-3-isopropyl-5-(2-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-bromo-3-isopropyl-5-(3-pyridyl)-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-3-(2-methylsulfanylethyl)-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-3-(cyclopropylmethyl)-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-3-cyclopropyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-3-ethyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-3-isobutyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-3-isopropyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-3-methyl-5-phenyl-3-propyl-1H-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-(2-fluorophenyl)-3-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-(2-fluorophenyl)-3-isobutyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-(2-fluorophenyl)-3-isopropyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-(2-fluorophenyl)-3-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-(3-chlorophenyl)-3-isopropyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-cyclohexyl-3-isopropyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-phenyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-7-chloro-5-phenyl-3-propyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
(3S)-8-chloro-5-(2-fluorophenyl)-3-isopropyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
[7-chloro-5-(2-fluorophenyl)-2-thioxo-1,3-dihydro-1-benzazepin-3-yl] acetate,
(3S)-5-(4-fluorophenyl)-3-isopropyl-7-(trifluoromethoxy)-1,3-dihydro-1,4-benzodiazepine-2-thione,
3-[(3,4-dichlorophenyl)methyl]-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
3-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
3-methyl-7-nitro-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
7-amino-3-ethyl-5-(2-fluorophenyl)-1,3-dihydro-1,4-benzodiazepine-2-thione,
7-chloro-3-(1-hydroxy-1-methyl-ethyl)-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
7-chloro-3-(1-methoxyethyl)-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,
7-chloro-3,5-diphenyl-1,3-dihydro-1,4-benzodiazepine-2-thione, and
7-chloro-3-isopropyl-5-phenyl-1,3-dihydro-1,4-benzodiazepine-2-thione,

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

3. A compound selected from the group consisting of 5-cyclohexyl-7-(trifluoromethyl)-1,3-dihydro-1,4-benzodiazepine-2-thione, 7-chloro-5-propyl-1,3-dihydro-1,4-benzodiazepine-2-thione, or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising a compound of claim 3 and a pharmaceutically acceptable carrier.

Assignees

• Hoffmann La Roche

Inventors

• Flohr Alexander

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P25/28

  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 · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title