Heterocyclic compound

Patent metadata

Field	Value
Publication number	US-11230541-B2
Application number	US-201816634402-A
Country	US
Kind code	B2
Filing date	Jul 26, 2018
Priority date	Jul 28, 2017
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

Provided is a heterocyclic compound that can have an antagonistic action on an NMDA receptor containing the NR2B subunit, and is expected to be useful as a prophylactic or therapeutic agent for major depression, bipolar disorder, migraine, pain, peripheral symptoms of dementia and the like. 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):

or a salt thereof, wherein:
X 1 and X 2 are each a carbon atom or a nitrogen atom;
at least one of X 1 and X 2 is a nitrogen atom;
ring A is an imidazole ring, a pyrazole ring, or a triazole ring, each of which is optionally further substituted with 1 or 2 substituents independently selected from a C1-6 alkyl group and a halogen atom;
ring B is a benzene ring optionally further substituted by 1 to 3 substituents selected from:
(1) a halogen atom;
(2) a C1-6 alkyl group optionally substituted by 1 to 3 substituents selected from a halogen atom and a C1-6 alkoxy group;
(3) a C1-6 alkoxy group; and
(4) a C3-6 cycloalkyl group;

R 1 and R 2 are each independently a hydrogen atom or a C1-6 alkyl group optionally substituted by fluorine atom(s);
R 3 is:

R 4 and R 5 are each a substituent selected from substituent group X;
Y is N or CR 6 ;
R 6 is a hydrogen atom or a substituent selected from substituent group A;
ring C 1 is a benzene ring or a pyridine ring, each of which is optionally further substituted with 1 to 3 substituents independently selected from: a halogen atom; a C1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; and a C1-6 alkoxy group;
ring C 2 is a thiophene ring optionally further substituted by a substituent selected from substituent group X;
L 1 is a methylene group, O, or NH;
L 2 is a bond or a methylene group; and
ring C 3 is a benzene ring, a pyridine ring, or a thiophene ring, each of which is optionally further substituted with 1 to 5 substituents independently selected from: a halogen atom; a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms; and a C1-6 alkoxy group optionally substituted by 1 to 3 halogen atoms;

wherein substituent group X is selected from:
(1) an optionally substituted hydrocarbon group;
(2) an optionally substituted C1-6 alkoxy group;
(3) an optionally substituted C3-10 cycloalkyloxy group;
(4) a halogen atom;
(5) a cyano group;
(6) an optionally substituted amino group;
(7) an optionally substituted C6-14 aryloxy group; and
(8) an optionally substituted C1-6 alkylthio group,
wherein:
each hydrocarbon group, C 1-6 alkoxy group, C3-10 cycloalkyloxy group, C6-14 aryloxy group, and C1-6 alkylthio group is independently optionally substituted with 1 to 3 substituents independently selected from substituent group A; and
each amino group is optionally substituted with 1 or 2 substituents selected from:
a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1-6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1-6 alkyl-carbamoyl group, a mono- or di-C 7-16 aralkyl-carbamoyl group, a C 1-6 alkylsulfonyl group and a C 6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from substituent group A;

wherein substituent group A is selected from:
(1) a halogen atom;
(2) a nitro group;
(3) a cyano group;
(4) a hydroxy group;
(5) an optionally halogenated C 1-6 alkoxy group;
(6) a C 6-14 aryloxy group;
(7) a C 7-16 aralkyloxy group;
(8) a 5- to 14-membered aromatic heterocyclyloxy group;
(9) a 3- to 14-membered non-aromatic heterocyclyloxy group;
(10) a C 1-6 alkyl-carbonyloxy group;
(11) a C 6-14 aryl-carbonyloxy group;
(12) a C 1-6 alkoxy-carbonyloxy group;
(13) a mono- or di-C 1-6 alkyl-carbamoyloxy group;
(14) a C 6-14 aryl-carbamoyloxy group;
(15) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group;
(16) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group;
(17) an optionally halogenated C 1-6 alkylsulfonyloxy group;
(18) a C 6-14 arylsulfonyloxy group optionally substituted by a C 1-6 alkyl group;
(19) an optionally halogenated C 1-6 alkylthio group;
(20) a 5- to 14-membered aromatic heterocyclic group;
(21) a 3- to 14-membered non-aromatic heterocyclic group;
(22) a formyl group;
(23) a carboxy group;
(24) an optionally halogenated C 1-6 alkyl-carbonyl group;
(25) a C 6-14 aryl-carbonyl group;
(26) a 5- to 14-membered aromatic heterocyclylcarbonyl group;
(27) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group;
(28) a C 1-6 alkoxy-carbonyl group;
(29) a C 6-14 aryloxy-carbonyl group;
(30) a C 7-16 aralkyloxy-carbonyl group;
(31) a carbamoyl group;
(32) a thiocarbamoyl group;
(33) a mono- or di-C 1-6 alkyl-carbamoyl group;
(34) a C 6-14 aryl-carbamoyl group;
(35) a 5- to 14-membered aromatic heterocyclylcarbamoyl group;
(36) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group;
(37) an optionally halogenated C 1-6 alkylsulfonyl group;
(38) a C 6-14 arylsulfonyl group;
(39) a 5- to 14-membered aromatic heterocyclylsulfonyl group;
(40) an optionally halogenated C 1-6 alkylsulfinyl group;
(41) a C 6-14 arylsulfinyl group;
(42) a 5- to 14-membered aromatic heterocyclylsulfinyl group;
(43) an amino group;
(44) a mono- or di-C 1-6 alkylamino group;
(45) a mono- or di-C 6-14 arylamino group;
(46) a 5- to 14-membered aromatic heterocyclylamino group;
(47) a C 7-16 aralkylamino group;
(48) a formylamino group;
(49) a C 1-6 alkyl-carbonylamino group;
(50) a (C 1-6 alkyl)(C 1-6 alkyl-carbonyl)amino group;
(51) a C 6-14 aryl-carbonylamino group;
(52) a C 1-6 alkoxy-carbonylamino group;
(53) a C 7-16 aralkyloxy-carbonylamino group;
(54) a C 1-6 alkylsulfonylamino group;
(55) a C 6-14 arylsulfonylamino group optionally substituted by a C 1-6 alkyl group;
(56) an optionally halogenated C 1-6 alkyl group;
(57) a C 2-6 alkenyl group;
(58) a C 2-6 alkynyl group;
(59) a C 3-10 cycloalkyl group;
(60) a C 3-10 cycloalkenyl group; and
(61) a C 6-14 aryl group.

2. The compound according to claim 1 , or a salt thereof, wherein:
ring A is an imidazole ring (that is, X 1 is a carbon atom, and X 2 is a nitrogen atom), a pyrazole ring (that is, X 1 is a nitrogen atom, and X 2 is a carbon atom), or a triazole ring (that is, X 1 and X 2 are both nitrogen atoms), each of which is optionally further substituted by 1 or 2 substituents selected from a C 1-6 alkyl group and a halogen atom;
ring B is a benzene ring optionally further substituted by 1 to 3 substituents selected from:
(1) a halogen atom:
(2) 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;
(3) a C 1-6 alkoxy group; and
(4) a C 3-6 cycloalkyl group;

R 1 and R 2 are both hydrogen atoms;
R 3 is:

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; or
(3) a halogen atom;

R 5 is:
(1) a C 1-6 alkyl group optionally substituted by 1 to 3 halogen atoms;
(2) a C 3-6 cycloalkyl group;
(3) a C 1-6 alkoxy group; or
(4) a halogen atom;

ring C 1 is a benzene ring (that is, Y is CR 6 ) or a pyridine ring (that is, Y is N), each of which is optionally further substituted by 1 to 3 substituents selected from:
(1) a halogen atom;
(2) a C 1-6 alkyl gro

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Kimura Eiji
• Ogino Masaki
• Kohara Yasuhisa
• Ohashi Tomoko
• Kaku Tomohiro
• Oguro Yuya
• Matsumoto Shigemitsu
• Wakabayashi Takeshi
• Tokunaga Norihito
• Kamei Taku
• Ito Mitsuhiro

Classifications

• A61P25/04 Primary

  Centrally acting analgesics, e.g. opioids · CPC title

• C07D235/06

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2 · CPC title

• C07D235/08

  Radicals containing only hydrogen and carbon atoms · CPC title

• A61K9/2095

  Tabletting processes · CPC title

• A61K9/2059

  Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin · CPC title