IP Library › Granted Patent US 10,548,899

Granted Patent B2

US 10,548,899 · App. 15/769,295 · Granted Feb 4, 2020

Quinazolinone and benzotriazinone compounds with cholinergic muscarinin M1 receptor positive allosteric modulator activity

Inventors: Takahiro Sugimoto (Kanagawa, JP); Shinkichi Suzuki (Kanagawa, JP); Hiroki Sakamoto (Kanagawa, JP); Masami Yamada (Kanagawa, JP); Minoru Nakamura (Kanagawa, JP); Makoto Kamata (Kanagawa, JP); Kenichiro Shimokawa (Kanagawa, JP); Masaki Ogino (Kanagawa, JP); Eiji Kimura (Kanagawa, JP); Masataka Murakami (Kanagawa, JP); Takuto Kojima (Kanagawa, JP); Jinichi Yonemori (Kanagawa, JP)

Assignee: Takeda Pharmaceutical Company Limited

A61K31/53 A61K31/517 A61P25/04 A61P25/16 A61P25/18 A61P25/28 C07D239/88 C07D401/06 C07D401/14 C07D403/06 C07D403/10 C07D405/14

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Quick Facts

Patent No.: US 10,548,899
App. No.: 15/769,295
Granted: Feb 4, 2020
Kind: B2

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Abstract

The present invention provides a compound which has a cholinergic muscarinic M1 receptor positive allosteric modulator activity and may be useful as a medicament such as an agent for the prophylaxis or treatment of Alzheimer's disease, schizophrenia, pain, sleep disorder, Parkinson's disease dementia, Lewy body dementia and the like. The present invention relates to a compound represented by the formula (I) or a salt thereof. In the formula (I), each symbol is as described in the attached specification.

Claims (119)

1. A compound represented by the formula:

wherein

R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;

R 2 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;

R 3 is

(1) a hydrogen atom,

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

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

(4) a 5- to 14-membered aromatic heterocyclic group optionally substituted 1 to 3 cyano groups,

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

(6) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom, and

(b) a cyano group;

ring A is

(1) a benzene ring optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a cyano group,

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

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a C 1-6 alkyl group, and

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a cyano group, and

(b) a 5- to 14-membered aromatic heterocyclic group; and

X is CH or N,

or a salt thereof.

2. The compound according to claim 1 , wherein

R 1 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;

R 2 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;

when one of R 1 and R 2 is a hydrogen atom, then the other is other than a hydrogen atom;

R 3 is

(1) a hydrogen atom,

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

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

(4) a 5- to 14-membered aromatic heterocyclic group optionally substituted 1 to 3 cyano groups,

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

(6) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom, and

(b) a cyano group;

ring A is

(1) a benzene ring optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a cyano group,

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

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a C 1-6 alkyl group, and

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a cyano group, and

(b) a 5- to 14-membered aromatic heterocyclic group; and

X is CH or N,

or a salt thereof.

3. The compound according to claim 1 , wherein

R 1 is a hydrogen atom, a halogen atom or a C 1-6 alkyl group;

R 2 is a C 1-6 alkyl group;

R 3 is

(1) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups,

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

(3) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups;

ring A is

(1) a benzene ring optionally further substituted by 1 to 3, 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups,

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom, and

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

(3) a 4- to 6-membered monocyclic non-aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a cyano group, and

(b) a 5- to 14-membered aromatic heterocyclic group; and

X is CH or N,

or a salt thereof.

4. The compound according to claim 1 , wherein

R 1 is a halogen atom or a C 1-6 alkyl group;

R 2 is a C 1-6 alkyl group;

R 3 is

(1) a 3- to 14-membered non-aromatic heterocyclic group optionally substituted by 1 to 3 hydroxy groups, or

(2) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups;

ring A is

(1) a benzene ring optionally further substituted by 1 to 3, 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups, or

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3, 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups; and

X is CH or N,

or a salt thereof.

5. 8-Fluoro-3-((3S,4S)-4-hydroxytetrahydro-2H-pyran-3-yl)-7-methyl-6-(4-(1H-pyrazol-1-yl)benzyl)quinazolin-4(3H)-one, or a salt thereof.

6. 3-((3S,4S)-4-Hydroxytetrahydro-2H-pyran-3-yl)-7,8-dimethyl-6-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)-1,2,3-benzotriazin-4(3H)-one, or a salt thereof.

7. 3-((1S,2S)-2-Hydroxycyclohexyl)-7,8-dimethyl-6-((6-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)methyl)quinazolin-4(3H)-one, or a salt thereof.

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

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

10. The compound according to claim 2 , wherein

R 3 is

(1) a C 1-6 alkyl group substituted by 1 to 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups,

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

(3) a 5- to 14-membered aromatic heterocyclic group optionally substituted 1 to 3 cyano groups,

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

(5) a C 6-14 aryl group optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom, and

(b) a cyano group; and

ring A is

(1) a benzene ring optionally further optionally substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a cyano group,

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

(2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom,

(b) a C 1-6 alkyl group, and

or a salt thereof.

11. The compound according to claim 3 , wherein

R 3 is

(1) a C 1-6 alkyl group substituted by 1 to 3 substituents selected from 3- to 14-membered non-aromatic heterocyclic groups,

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

(3) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 hydroxy groups; and

ring A is

(1) a benzene ring optionally further substituted by 1 to 3, 5- to 14-membered aromatic heterocyclic groups optionally substituted by 1 to 3 C 1-6 alkyl groups, or (2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from

(a) a halogen atom, and

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

or a salt thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 8, 2019

From: SUGIMOTO, TAKAHIRO; SUZUKI, SHINKICHI; SAKAMOTO, HIROKI; YAMADA, MASAMI; NAKAMURA, MINORU; KAMATA, MAKOTO; SHIMOKAWA, KENICHIRO; OGINO, MASAKI; KIMURA, EIJI; MURAKAMI, MASATAKA; KOJIMA, TAKUTO; YONEMORI, JINICHI

To: TAKEDA PHARMACEUTICAL COMPANY LIMITED

Reel/Frame 050656/0621 →

Priority Claims (1)

JP 2015-206780 · Oct 20, 2015 · national

Continuity (1)

Related Publication 20180303841A1 · Oct 25, 2018

Cited By (1)

US 12,378,256