Aromatic ring compound

Patent metadata

Field	Value
Publication number	US-10548877-B2
Application number	US-201716083295-A
Country	US
Kind code	B2
Filing date	Mar 9, 2017
Priority date	Mar 11, 2016
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

Provided is a compound having a cholinergic muscarine M1 receptor positive allosteric modulator activity. A compound represented by the formula (I):

wherein each symbol is as described in the DESCRIPTION, or a salt thereof has a cholinergic muscarine M1 receptor positive allosteric modulator activity, and is useful as a prophylactic or therapeutic drug for Alzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson's disease dementia, dementia with Lewy bodies and the like.

First claim

The invention claimed is:

1. A compound represented by the formula:

wherein
R 1 is (A) a C 1-6 alkyl group substituted by 1 to 3 substituents selected from (1) a halogen atom, (2) a hydroxy group, (3) an optionally substituted C 3-10 cycloalkyl group, and (4) an optionally substituted non-aromatic heterocyclic group, (B) an optionally substituted C 3-10 cycloalkyl group, or (C) an optionally substituted non-aromatic heterocyclic group;
R 2 is a fluorine atom or an optionally substituted C 1-6 alkoxy group;
R 3 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted C 3-10 cycloalkyloxy group;
R 4 is a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted C 3-10 cycloalkyloxy group;
R 5 and R 6 are each independently a hydrogen atom or a halogen atom; and
ring A is an optionally further substituted benzene ring or an optionally further substituted 6-membered aromatic heterocycle

(excluding N-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-(4-fluorobenzyl)-2-methoxybenzamide) or a salt thereof.

2. The compound according to claim 1 , wherein R 1 is an optionally substituted 3- to 8-membered monocyclic non-aromatic heterocyclic group, or a salt thereof.

3. The compound according to claim 1 , wherein R 1 is (A) a C 1-6 alkyl group substituted by 1 to 3 substituents selected from non-aromatic heterocyclic groups, (B) a non-crosslinked C 3-10 cycloalkyl group optionally substituted by a hydroxy group, or (C) a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by a hydroxy group;
R 2 is
a fluorine atom, or
a C 1-6 alkoxy group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 3-10 cycloalkyl group;
R 3 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
R 4 is a cyano group or a C 1-6 alkyl group;
R 5 and R 6 are both hydrogen atoms; and
ring A is
a benzene ring optionally further substituted by 1 to 3 substituents selected from 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups, or
a 6-membered aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from a C 1-6 alkyl group and a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C 1-6 alkyl groups,

or a salt thereof.

4. The compound according to claim 1 , wherein R 1 is a non-crosslinked C 3-10 cycloalkyl group optionally substituted by a hydroxy group or a 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted by a hydroxy group;
R 2 is a fluorine atom or a C 1-6 alkoxy group;
R 3 is a halogen atom or a C 1-6 alkyl group;
R 4 is a C 1-6 alkyl group;
R 5 and R 6 are both hydrogen atoms; and
ring A is a benzene ring optionally further substituted by 1 to 3 substituents selected from 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups,

or a salt thereof.

5. The compound according to claim 4 , wherein R 1 is

and
ring A is a benzene ring optionally further substituted by 1 to 3 substituents selected from 5- or 6-membered monocyclic aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups,

or a salt thereof.

6. The compound according to claim 1 , wherein R 1 is

R 2 is a fluorine atom or a C 1-6 alkoxy group;
R 3 is a C 1-6 alkyl group;
R 4 is a C 1-6 alkyl group;
R 5 and R 6 are both hydrogen atoms; and
ring A is a benzene ring further substituted by a 5- or 6-membered monocyclic aromatic heterocyclic group optionally substituted by one C 1-6 alkyl group,

or a salt thereof.

7. 2-Fluoro-N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-3,4-dimethyl-5-(4-(1H-pyrazol-1-yl)benzyl)benzamide, or a salt thereof.

8. N-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-2-methoxy-3,4-dimethyl-5-(4-(1-methyl-1H-1,2,3-triazol-4-yl)benzyl)benzamide, or a salt thereof.

9. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof and pharmaceutical acceptable carrier.

10. A method of cholinergic muscarinic M1 receptor positive allosteric modulation in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

11. A method for the treatment of Alzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson's disease dementia, or dementia with Lewy bodies in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Ogino Masaki
• Kimura Eiji
• Suzuki Shinkichi
• Fuji Kouji
• Ohashi Tomohiro
• Fushimi Makoto
• Masuda Kei
• Koike Tatsuki
• Wakabayashi Takeshi
• Yonemori Jinichi
• Yamada Masami

Classifications

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · 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

• C07D417/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title