Aromatic compound

Patent metadata

Field	Value
Publication number	US-2016115128-A1
Application number	US-201414898633-A
Country	US
Kind code	A1
Filing date	Aug 8, 2014
Priority date	Aug 9, 2013
Publication date	Apr 28, 2016
Grant date	—

Abstract

Provided is a novel aromatic ring compound having a GPR40 agonist activity and a GLP-1 secretagogue action. A compound represented by the formula:

wherein each symbol is as described in the DESCRIPTION, or a salt thereof has a GPR40 agonist activity and a GLP-1 secretagogue action, is useful for the prophylaxis or treatment of cancer, obesity, diabetes, hypertension, hyperlipidemia, cardiac failure, diabetic complications, metabolic syndrome, sarcopenia and the like, and affords superior efficacy.

First claim

1 . A compound represented by the formula (I):

wherein
ring A is a further optionally substituted aromatic ring;
ring B is a further optionally substituted 4-6-membered nitrogen-containing saturated ring;
X is —N═ or —CH═;
R 1 and R 2 are each independently a hydrogen atom or a substituent;
R 1 and R 2 are optionally bonded to each other to form, together with die adjacent nitrogen atom, an optionally substituted 3- to 10-membered ring;
R 3 and R 4 are each independently a hydrogen atom, a halogen atom or a C 1-6 alkyl group;
R 5 , R 7 , R 8 and R 9 are each independently a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
R 6 is a halogen atom, an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group or an optionally substituted C 3-10 cycloalkyl group; and
R 6 and R 7 are optionally bonded to each other to form, together with the adjacent carbon atom, an optionally substituted 3- to 10-membered ring,

or a salt thereof.

2 . The compound according to claim 1 , wherein ring A is a benzene ring optionally further substituted by 1 or 2 substituents selected from
(1) a C 1-6 alkylsulfonyl group; (2) a carbamoyl group; (3) a hydroxy group; (4) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms; (5) a C 1-6 alkylthio group; (6) a cyano group; (7) a halogen atom; and (8) a C 1-6 alkyl group,
or a salt thereof.

3 . The compound according to claim 1 , wherein ring B is
(1) an azetidine ring, (2) a pyrrolidine ring or (3) a piperidine ring optionally further substituted by 1 or 2 substituents selected from a halogen atom and a C 1-6 alkyl group, or a salt thereof.

4 . The compound according to claim 1 , wherein X is —N═, or a salt thereof.

5 . The compound according to claim 1 , wherein R 1 and R 2 are each independently
(i) a C 1-8 alkyl group optionally substituted by 1 or 2 substituents selected from (1) cyano, (2) hydroxy, (3) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group, (4) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, (5) a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms, (6) an aromatic heterocyclic group, (7) a nonaromatic heterocyclic group, (8) a C 1-6 alkylsulfonyl group, (9) a mono- or di-C 1-6 alkyl-amino group optionally substituted by 1 to 3 halogen atoms and (10) a halogen atom, or (ii) an aromatic heterocyclic group optionally substituted by 1 or 2 substituents selected from (1) cyano, (2) a halogen atom, (3) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (4) a C 3-10 cycloalkyl group, (5) a C 1-6 alkoxy group, (6) a nitrogen-containing heterocyclyl-carbonyl group and (7) a mono- or di-C 1-6 alkyl-carbamoyl group, or a salt thereof.

6 . The compound according to claim 1 , wherein R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are hydrogen atoms, or a salt thereof.

7 . The compound according to claim 1 , wherein R 6 is a C 3-10 cycloalkyl group, or a salt thereof.

8 . The compound according to claim 1 , wherein ring A is a benzene ring optionally further substituted by 1 or 2 substituents selected from
(1) a C 1-6 alkylsulfonyl group; (2) a carbamoyl group; (3) a hydroxy group; (4) an C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms; (5) a C 1-6 alkylthio group; (6) a cyano group; (7) a halogen atom; and (8) a C 1-6 alkyl group,
ring B is (1) an azetidine ring, (2) a pyrrolidine ring or (3) a piperidine ring optionally further substituted by 1 or 2 substituents selected from a halogen atom and a C 1-6 alkyl group,
X is —N═,
R 1 and R 2 are each independently
(i) a C 1-8 alkyl group optionally substituted by 1 or 2 substituents selected from (1) cyano, (2) hydroxy, (3) a C 3-10 cycloalkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkyl group, (4) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms, (5) a C 6-14 aryl group optionally substituted by 1 to 3 halogen atoms, (6) an aromatic heterocyclic group, (7) a nonaromatic heterocyclic group, (8) a C 1-6 alkylsulfonyl group, (9) a mono- or di-C 1-6 alkyl-amino group optionally substituted by 1 to 3 halogen atoms and (10) a halogen atom, or (ii) an aromatic heterocyclic group optionally substituted by 1 or 2 substituents selected from (1) cyano, (2) a halogen atom, (3) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms, (4) a C 3-10 cycloalkyl group, (5) a C 1-6 alkoxy group, (6) a nitrogen-containing heterocyclyl-carbonyl group and (7) a mono- or di-C 1-6 alkyl-carbamoyl group,
R 3 , R 4 , R 5 , R 7 , R 8 and R 9 are hydrogen atoms, and
R 6 is a C 3-10 cycloalkyl group,

or a salt thereof.

9 . (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy pyridin 4-yl)propanoic acid or a salt thereof.

10 . (3S)-3-cyclopropyl-3-(2-((1-(2-((2,2-dimethylpropyl)(4,6-dimethylpyrimidin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid or a salt thereof.

11 . (3S)-3-cyclopropyl(2-((1-(2-((2,2-dimethylpropyl)(pyridin-2-yl)carbamoyl)-5-methoxyphenyl)piperidin-4-yl)methoxy)pyridin-4-yl)propanoic acid or a salt thereof.

12 . A medicament comprising the compound according to claim 1 or a salt thereof.

13 . The medicament according to claim 12 , which is a GPR40 receptor function regulator.

14 . The medicament according to claim 12 , which is a prophylactic or therapeutic agent for diabetes.

15 . A method of preventing or treating diabetes in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

16 . A method of regulating GPR40 receptor function in a mammal, comprising administering an effective amount of the compound according to claim 1 or a salt thereof to the mammal.

17 . Use of the compound according to claim 1 or a salt thereof for the production of an agent for the prophylaxis or treatment of diabetes.

18 . The compound according to claim 1 or a salt thereof for use for the prophylaxis or treatment of diabetes.

Assignees

• Takeda Pharmaceutical

Inventors

• Aida Jumpei
• Yoshitomi Yayoi
• Hitomi Yuko
• Noguchi Naoyoshi
• Hirata Yasuhiro
• Furukawa Hideki
• Shibuya Akito
• Watanabe Koji
• Miyamoto Yasufumi
• Okawa Tomohiro
• Takakura Nobuyuki
• Miwatashi Seiji

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D213/30

  Oxygen atoms · CPC title