Tetrahydrooxepinopyridine compound

Patent metadata

Field	Value
Publication number	US-9670219-B2
Application number	US-201615258241-A
Country	US
Kind code	B2
Filing date	Sep 7, 2016
Priority date	Aug 19, 2015
Publication date	Jun 6, 2017
Grant date	Jun 6, 2017

Abstract

[Problem] Provided is a compound having a positive allosteric modulating activity (PAM activity) on an α7 nicotinic acetylcholine receptor (α7 nACh receptor).
[Means for Solution] The present inventors have studied on a PAM activity on an α7 nACh receptor, and they have found that a tetrahydrooxepinopyridine compound has a PAM activity on an α7 nACh receptor, thereby completing the present invention. The tetrahydrooxepinopyridine compound of the present invention has a PAM activity on an α7 nACh receptor and can be expected as an agent for preventing or treating dementia, cognitive impairment, schizophrenia, Alzheimer's disease, CIAS, negative symptoms of schizophrenia, inflammatory diseases, or pain.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein:
R 1 is H or lower alkyl,
R 2 is H or CN,
any one of G 1 , G 2 , and G 3 is O, and the other two of G 1 , G 2 , and G 3 are CH 2 ,
ring A is aryl or nitrogen-containing heteroaryl,
ring B is cyclic amino,
R 3 and R 4 are the same or different and are H, halogen, lower alkyl, -lower alkylene-OH, halo-lower alkyl, —O-lower alkyl, —O-halo-lower alkyl, cycloalkyl, CN, OH, —N(lower alkyl) 2 , or —C(═O)NH 2 ,
R 5 , R 6 , R 7 and R 8 are the same or different and are H, halogen, lower alkyl, halo-lower alkyl, —O-lower alkyl, or CN, or
when R 5 and R 6 are bonded to the same carbon atom, then R 5 and R 6 optionally form cycloalkane or cyclic ether together with the carbon atom, and may form a spiro ring together with Ring B, or
ring B optionally forms 6,7-dihydro[1,3]oxazolo[4,5-c]pyridin-5(4H)-yl together with R 5 and R 6 ,
or a salt thereof.

2. The compound or salt thereof according to claim 1 , wherein:
R 1 is H,
R 2 is H,
G 1 is O,
G 2 and G 3 are CH 2 ,
ring A is phenyl or nitrogen-containing heteroaryl,
ring B is 5- or 6-membered cyclic amino, and
R 5 , R 6 , R 7 and R 8 are the same or different and are H, halogen, lower alkyl, halo-lower alkyl, —O-lower alkyl, or CN.

3. The compound or salt thereof according to claim 2 , wherein:
ring A is nitrogen-containing monocyclic heteroaryl,
R 3 is H or lower alkyl, and
R 4 is H, halogen, lower alkyl, -lower alkylene-OH, halo-lower alkyl, —O-lower alkyl, —O-halo-lower alkyl, cycloalkyl, CN, OH, —N(lower alkyl) 2 , or —C(═O)NH 2 .

4. The compound or salt thereof according to claim 3 , wherein:
ring B, R 5 , R 6 , R 7 , and R 8 together form a group of formula (II):

wherein:
X is CH 2 , O, or a bond,
when X is CH 2 , then R 5 and R 6 are optionally bonded to X, and
R 5 , R 6 , R 7 , and R 8 are the same or different and are H, halogen, lower alkyl, or halo-lower alkyl.

5. The compound or salt thereof according to claim 4 , wherein:
X is CH 2 or O.

6. The compound or salt thereof according to claim 4 , wherein:
X is a bond.

7. The compound or salt thereof according to claim 5 , wherein:
ring A is nitrogen-containing 6-membered heteroaryl having one or two nitrogen atoms as ring atoms,
ring B, R 5 , R 6 , R 7 , and R 8 together form a group of formula (III):

wherein:
R 5 is halogen or lower alkyl,
R 6 is H,
R 7 is H, and
R 8 is H or lower alkyl.

8. The compound or salt thereof according to claim 7 , wherein:
ring A is pyridyl,
X is CH 2 ,
R 5 is halogen, and
R 8 is H.

9. The compound or salt thereof according to claim 7 , wherein:
ring A is pyridyl,
X is O,
R 5 is lower alkyl, and
R 8 is lower alkyl.

10. The compound or salt thereof according to claim 6 , wherein:
ring A is nitrogen-containing 6-membered heteroaryl having two nitrogen atoms as ring atoms,
ring B, R 5 , R 6 , R 7 , and R 8 together form a group of formula (IV):

wherein:
R 5 is halogen or lower alkyl,
R 6 is H,
R 7 is H, and
R 8 is H.

11. A compound or a salt thereof, which is a compound selected from the group consisting of:
N-(5-chloropyridin-2-yl)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
N-(6-methoxypyridazin-3-yl)-2-[(2R)-2-methylpyrrolidin-1-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
N-(6-methylpyrazin-2-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
2-[(2R)-2-ethylmorpholin-4-yl]-N-(6-methylpyridin-3-yl)-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
2-(4-fluoropiperidin-1-yl)-N-(pyridazin-3-yl)-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
N-(5,6-dimethylpyrazin-2-yl)-2-[(2S)-2-methylpyrrolidin-1-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
2-[(2S)-2-methylpiperidin-1-yl]-N-(pyridazin-3-yl)-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
2-[(2S)-2-methylpiperidin-1-yl]-N-(pyrazin-2-yl)-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide, and,
N-(5-chloropyridin-2-yl)-2-[(3S)-3-fluoropiperidin-1-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide,
or a salt of said compound.

12. The compound or salt thereof according to claim 11 , which is N-(5-chloropyridin-2-yl)-2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide or a salt thereof.

13. The compound or salt thereof according to claim 11 , which is N-(6-methoxypyridazin-3-yl)-2-[(2R)-2-methylpyrrolidin-1-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide or a salt thereof.

14. The compound or salt thereof according to claim 11 , which is N-(5-chloropyridin-2-yl)-2-[(3S)-3-fluoropiperidin-1-yl]-5,6,8,9-tetrahydrooxepino[4,5-b]pyridine-4-carboxamide or a salt thereof.

15. A pharmaceutical composition, comprising a compound or a salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

16. A method for treating a disease or condition modulated by the stimulation of the α7 nACh receptor wherein said disease or condition is selected from the group consisting of dementia, cognitive impairment, schizophrenia, Alzheimer's disease, CIAS, negative symptoms of schizophrenia, inflammatory diseases, and pain, said method comprising administering an effective amount of a compound or a salt thereof according to claim 1 to a subject in need thereof.

Assignees

• Astellas Pharma Inc

Inventors

• Koganemaru Yohei
• Miyamoto Satoshi
• Nagashima Shinya
• Kamikawa Akio
• Yonezawa Koichi
• Koizumi Yuka
• Aoki Satoshi
• Ogiyama Takashi
• Kawakami Shimpei
• Kunikawa Shigeki
• Sato Ryo
• Shishikura Junichi
• Kakimoto Shuichirou
• Yamada Hiroshi
• Tamaki Keisuke

Classifications

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• C07D491/044 Primary

  with only one oxygen atom as ring hetero atom in the oxygen-containing ring · CPC title

• A61P43/00

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

• A61K31/4523

  containing further heterocyclic ring systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title