Heterocyclic compound and use thereof

Patent metadata

Field	Value
Publication number	US-10807987-B2
Application number	US-201916366710-A
Country	US
Kind code	B2
Filing date	Mar 27, 2019
Priority date	Mar 28, 2018
Publication date	Oct 20, 2020
Grant date	Oct 20, 2020

Abstract

The present invention provides a heterocyclic compound having an antagonistic action on an NMDA receptor containing the NR2B subunit, and expected to be useful as an agent for the prophylaxis or treatment of major depression, bipolar disorder, migraine, pain, behavioral and psychological symptoms of dementia and the like.
The present invention relates to a compound represented by the formula (I):

wherein each symbol is as described in the description, or a salt thereof.

First claim

The invention claimed is:

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

wherein
the group represented by

is a group represented by

X a1 is CH or a nitrogen atom;
X a2 is
(1) CR a wherein R a is
(a) a hydrogen atom,
(b) a halogen atom, or
(c) a C 1-6 alkyl group, or

(2) a nitrogen atom;
X a3 is
(1) CR a wherein R a is
(a) a hydrogen atom, or
(b) a C 1-6 alkyl group, or

(2) a nitrogen atom;
X a4 is
(1) CR a wherein R a is
(a) a hydrogen atom, or
(b) a C1-6 alkyl group, or

(2) a nitrogen atom; and
X a5 is
(1) CR a wherein R a is
(a) a hydrogen atom,
(b) a C 1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C 1-6 alkoxy group,
(c) a C 1-6 alkoxy group, or
(d) a C 3-10 cycloalkyl group, or

(2) a nitrogen atom;
provided that when X a5 is CR a , then at least one of X a1 , X a2 and X a3 is a nitrogen atom;
X b1 is CH or a nitrogen atom;
X b2 is CR b wherein R b is
(a) a hydrogen atom, or
(b) a C 1-6 alkyl group;

X b3 is a nitrogen atom optionally substituted by a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; and
X b4 is CR b wherein R b is
(a) a hydrogen atom, or
(b) a C 1-6 alkyl group;

R 1 and R 2 are each a hydrogen atom; and
R 3 is a group represented by

R 4 is
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms,
(2) a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms,
(3) a C 3-10 cycloalkyloxy group, or
(4) a halogen atom;
Y is a nitrogen atom or CR 6 wherein R 6 is a hydrogen atom or a halogen atom; and
Ring C 1 is a benzene ring (i.e., Y is CR 6 ) or a pyridine ring (i.e., Y is N), each of which is optionally further substituted by one halogen atom;
R 5 is a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; and
Ring C 2 is a thiophene ring substituted by only R 5 ,
or a salt thereof.

2. The compound or salt according to claim 1 , wherein
the group represented by

is a group represented by

X a1 is CH or a nitrogen atom;
X a2 is CH;
X a3 is CH or a nitrogen atom;
X a4 is CH; and
X a5 is CH or a nitrogen atom;
provided that when X a5 is CH, then at least one of X a1 and X a3 is a nitrogen atom;
X b1 is CH;
X b2 is CH;
X b3 is a nitrogen atom optionally substituted by a C 1-6 alkyl group; and
X b4 is CH;
R 1 and R 2 are both hydrogen atoms; and
R 3 is a group represented by

R 4 is a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
Y is a nitrogen atom or CH; and
Ring C 1 is a benzene ring (i.e., Y is CH) or a pyridine ring (i.e., Y is N), each of which is optionally further substituted by one halogen atom.

3. The compound or salt according to claim 1 , wherein
the group represented by

is a group represented by

X a1 is CH or a nitrogen atom;
X a2 is CH;
X a3 is CH;
X a4 is CH; and
X a5 is CH or a nitrogen atom;
provided that when X a5 is CH, then X a1 is a nitrogen atom;
X b1 is CH;
X b2 is CH;
X b3 is a nitrogen atom optionally substituted by a C 1-6 alkyl group; and
X b4 is CH;
R 1 and R 2 are both hydrogen atoms; and
R 3 is a group represented by

R 4 is a C 1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;
Y is a nitrogen atom or CH; and
Ring C 1 is a benzene ring (i.e., Y is CH) or a pyridine ring (i.e., Y is N), each of which is optionally further substituted by one halogen atom.

4. 6-(Difluoromethoxy)-5-fluoro-N-[(pyrazolo[1,5-b]pyridazin-3-yl)methyl]pyridine-3-carboxamide or a salt thereof.

5. 3-Fluoro-N-[([1,2,3]triazolo[1,5-a]pyridin-3-yl)methyl]-4-(trifluoromethoxy)benzamide or a salt thereof.

6. 6-(Difluoromethoxy)-5-fluoro-N-[(1-methyl-1H-imidazo[1,2-b]pyrazol-7-yl)methyl]pyridine-3-carboxamide or a salt thereof.

7. A pharmaceutical composition comprising the compound or salt according to claim 1 , and a pharmacologically acceptable carrier.

8. A method for the treatment of major depression, bipolar disorder, migraine, pain, or behavioral and psychological symptoms of dementia in a mammal, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Oguro Yuya
• Matsumoto Shigemitsu
• Wakabayashi Takeshi
• Tokunaga Norihito
• Kamei Taku
• Ito Mitsuhiro
• Mikami Satoshi
• Seto Masaki
• Morimoto Shinji
• Nakamura Shinji
• Takashima Sachie
• Murakami Masataka
• Daini Masaki
• Kamata Makoto
• Nakamura Minoru
• Wada Yasufumi
• Kakei Hiroyuki
• Takami Kazuaki
• Tawaraishi Taisuke
• Aida Jumpei
• Iwanaga Kouichi
• Yamamoto Satoshi

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title