2,3-dihydro-4H-1,3-benzoxazin-4-one derivatives as modulators of cholinergic muscarinic M1 receptor

• US 10,323,027 B2
• Filed: 06/23/2016
• Issued: 06/18/2019
• Est. Priority Date: 06/26/2015
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Sugimoto, Takahiro, Suzuki, Shinkichi, Sakamoto, Hiroki, Yamada, Masami, Nakamura, Minoru, Kamata, Makoto, Shimokawa, Kenichiro, Murakami, Masataka, Yonemori, Jinichi, Kojima, Takuto
• Primary Examiner(s): Reese, Heidi
• Application Number:
  US15/735,418
• Publication Number:
  US 20180162850A1
• Time in Patent Office: 1,090 Days
• Field of Search: None
• CPC Class Codes: 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
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07D 265/22 Oxygen atoms
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/107 with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07F 7/02 Silicon compounds
• CPC Class Codes: C07F 7/0814 said ring is substituted at a C ring atom by Si

Abstract

The present invention provides a compound having a cholinergic muscarinic M1 receptor positive allosteric modulator activity, which may be 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. The present invention relates to a compound represented by the formula (I) or a salt thereof: wherein each symbol is as defined in the attached DESCRIPTION.

Claims

1. A compound represented by the formula

2. The compound according to claim 1, wherein R¹ is a hydrogen atom, a halogen atom or a C_1-6 alkyl group;

R² is a hydrogen atom, a halogen atom, a C_1-6 alkyl group, a C_2-6 alkenyl group or a C_1-6 alkoxy group

R³ is

(1) a hydrogen atom,

(2) a C_1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a hydroxy group and a 3- to 14-membered non-aromatic heterocyclic group,

(3) a C_3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups,

(4) a C_6-14 aryl group optionally substituted by 1 to 3 halogen atoms or

(5) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups; and

ring A is a 6-membered aromatic ring optionally further substituted by 1 to 5 substituents selected from

(i) a halogen atom,

(ii) a cyano group,

(iii) a C_1-6 alkyl group,

(iv) a C_2-6 alkenyl group,

(v) a C_2-6 alkynyl group optionally substituted by a tri-C_1-6 alkylsilyl group,

(vi) a C_1-6 alkoxy group and

(vii) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C_1-6 alkyl group,

or a salt thereof.

3. The compound according to claim 1, wherein R¹ is a hydrogen atom, a halogen atom or a C_1-6 alkyl group;

R² is a C_1-6 alkyl group, a C_2-6 alkenyl group or a C_1-6 alkoxy group;

R³ is

(1) a C_3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups or

(2) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups; and

ring A is a C_6-14 aromatic hydrocarbon ring, a 3- to 14-membered non-aromatic heterocycle or a 5- to 14-membered aromatic heterocycle, each of which is optionally further substituted by 1 to 5 substituents selected from

(i) a halogen atom,

(ii) a cyano group,

(iii) a C_1-6 alkyl group,

(iv) a C_1-6 alkoxy group and

(v) 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 R¹ is a hydrogen atom, a halogen atom or a C_1-6 alkyl group:

R² is a C_1-6 alkyl group, a C_2-6 alkenyl group or a C_1-6 alkoxy group;

R³ is

(1) a C_3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups or

(2) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups; and

ring A is a C_6-14 aromatic hydrocarbon ring, a 3- to 14-membered non-aromatic heterocycle or a 5- to 14-membered aromatic heterocycle, each of which is optionally further substituted by 1 to 5 substituents selected from

(i) a halogen atom,

(ii) a cyano group,

(iii) a C_1-6 alkyl group,

(iv) a C₁-₆ alkoxy group and

(v) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C_1-6 alkyl groups,

or a salt thereof.

5. The compound according to claim 1, wherein R¹ is a hydrogen atom or a halogen atom:

R² is a C_1-6 alkyl group;

R³ is

(1) a C_3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups or

(2) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups; and

ring A is a C_6-14 aromatic hydrocarbon ring or a 5- to 14-membered aromatic heterocycle, each of which is optionally further substituted by 1 to 5 substituents selected from

(i) a halogen atom,

(ii) a C_1-6 alkyl group and

(iii) a 5- to 14-membered aromatic heterocyclic group optionally substituted by 1 to 3 C_1-6 alkyl groups,

or a salt thereof.

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