US 11,230,541 B2Granted

Heterocyclic compound

AssigneeTakeda Pharmaceutical Company Limited

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

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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.

Claims12

Dependent claims

A compound represented by the formula (I):

or a salt thereof, wherein:
X1 and X2 are each a carbon atom or a nitrogen atom;
at least one of X1 and X2 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;
R1 and R2 are each independently a hydrogen atom or a C1-6 alkyl group optionally substituted by fluorine atom(s);
R3 is:
R4 and R5 are each a substituent selected from substituent group X;
Y is N or CR6;
R6 is a hydrogen atom or a substituent selected from substituent group A;
ring C1 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 C2 is a thiophene ring optionally further substituted by a substituent selected from substituent group X;
L1 is a methylene group, O, or NH;
L2 is a bond or a methylene group;
and
ring C3 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 C1-6 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, C1-6 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 C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group, a mono- or di-C7-16 aralkyl-carbamoyl group, a C1-6 alkylsulfonyl group and a C6-14 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 C1-6 alkoxy group;
(6) a C6-14 aryloxy group;
(7) a C7-16 aralkyloxy group;
(8) a 5- to 14-membered aromatic heterocyclyloxy group;
(9) a 3- to 14-membered non-aromatic heterocyclyloxy group;
(10) a C1-6 alkyl-carbonyloxy group;
(11) a C6-14 aryl-carbonyloxy group;
(12) a C1-6 alkoxy-carbonyloxy group;
(13) a mono- or di-C1-6 alkyl-carbamoyloxy group;
(14) a C6-14 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 C1-6 alkylsulfonyloxy group;
(18) a C6-14 arylsulfonyloxy group optionally substituted by a C1-6 alkyl group;
(19) an optionally halogenated C1-6 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 C1-6 alkyl-carbonyl group;
(25) a C6-14 aryl-carbonyl group;
(26) a 5- to 14-membered aromatic heterocyclylcarbonyl group;
(27) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group;
(28) a C1-6 alkoxy-carbonyl group;
(29) a C6-14 aryloxy-carbonyl group;
(30) a C7-16 aralkyloxy-carbonyl group;
(31) a carbamoyl group;
(32) a thiocarbamoyl group;
(33) a mono- or di-C1-6 alkyl-carbamoyl group;
(34) a C6-14 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 C1-6 alkylsulfonyl group;
(38) a C6-14 arylsulfonyl group;
(39) a 5- to 14-membered aromatic heterocyclylsulfonyl group;
(40) an optionally halogenated C1-6 alkylsulfinyl group;
(41) a C6-14 arylsulfinyl group;
(42) a 5- to 14-membered aromatic heterocyclylsulfinyl group;
(43) an amino group;
(44) a mono- or di-C1-6 alkylamino group;
(45) a mono- or di-C6-14 arylamino group;
(46) a 5- to 14-membered aromatic heterocyclylamino group;
(47) a C7-16 aralkylamino group;
(48) a formylamino group;
(49) a C1-6 alkyl-carbonylamino group;
(50) a (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino group;
(51) a C6-14 aryl-carbonylamino group;
(52) a C1-6 alkoxy-carbonylamino group;
(53) a C7-16 aralkyloxy-carbonylamino group;
(54) a C1-6 alkylsulfonylamino group;
(55) a C6-14 arylsulfonylamino group optionally substituted by a C1-6 alkyl group;
(56) an optionally halogenated C1-6 alkyl group;
(57) a C2-6 alkenyl group;
(58) a C2-6 alkynyl group;
(59) a C3-10 cycloalkyl group;
(60) a C3-10 cycloalkenyl group;
and
(61) a C6-14 aryl group.

102 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/634,402Filed 26 Jul 2018
Priority: JP JP2017-14674428 Jul 2017
Published: US 2020/0231579 A123 Jul 2020
Granted: 25 Jan 2022
Term ends: Not estimatedThe source records don’t support an estimate.

Classification27 codes

A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
C07D 409/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 9/2013
Excipients; Inactive ingredients: organic compounds, e.g. phospholipids, fats
A61K 9/2018
Organic compounds, e.g. phospholipids, fats: sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Family

US 2020/0231579 A1Pre-grant publication · published 23 Jul 2020
US 11,230,541 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound represented by the formula (I):

or a salt thereof, wherein:
X1 and X2 are each a carbon atom or a nitrogen atom;
at least one of X1 and X2 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;
R1 and R2 are each independently a hydrogen atom or a C1-6 alkyl group optionally substituted by fluorine atom(s);
R3 is:
R4 and R5 are each a substituent selected from substituent group X;
Y is N or CR6;
R6 is a hydrogen atom or a substituent selected from substituent group A;
ring C1 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 C2 is a thiophene ring optionally further substituted by a substituent selected from substituent group X;
L1 is a methylene group, O, or NH;
L2 is a bond or a methylene group;
and
ring C3 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 C1-6 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, C1-6 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 C1-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-14 aryl group, a C7-16 aralkyl group, a C1-6 alkyl-carbonyl group, a C6-14 aryl-carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C1-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C1-6 alkyl-carbamoyl group, a mono- or di-C7-16 aralkyl-carbamoyl group, a C1-6 alkylsulfonyl group and a C6-14 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 C1-6 alkoxy group;
(6) a C6-14 aryloxy group;
(7) a C7-16 aralkyloxy group;
(8) a 5- to 14-membered aromatic heterocyclyloxy group;
(9) a 3- to 14-membered non-aromatic heterocyclyloxy group;
(10) a C1-6 alkyl-carbonyloxy group;
(11) a C6-14 aryl-carbonyloxy group;
(12) a C1-6 alkoxy-carbonyloxy group;
(13) a mono- or di-C1-6 alkyl-carbamoyloxy group;
(14) a C6-14 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 C1-6 alkylsulfonyloxy group;
(18) a C6-14 arylsulfonyloxy group optionally substituted by a C1-6 alkyl group;
(19) an optionally halogenated C1-6 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 C1-6 alkyl-carbonyl group;
(25) a C6-14 aryl-carbonyl group;
(26) a 5- to 14-membered aromatic heterocyclylcarbonyl group;
(27) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group;
(28) a C1-6 alkoxy-carbonyl group;
(29) a C6-14 aryloxy-carbonyl group;
(30) a C7-16 aralkyloxy-carbonyl group;
(31) a carbamoyl group;
(32) a thiocarbamoyl group;
(33) a mono- or di-C1-6 alkyl-carbamoyl group;
(34) a C6-14 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 C1-6 alkylsulfonyl group;
(38) a C6-14 arylsulfonyl group;
(39) a 5- to 14-membered aromatic heterocyclylsulfonyl group;
(40) an optionally halogenated C1-6 alkylsulfinyl group;
(41) a C6-14 arylsulfinyl group;
(42) a 5- to 14-membered aromatic heterocyclylsulfinyl group;
(43) an amino group;
(44) a mono- or di-C1-6 alkylamino group;
(45) a mono- or di-C6-14 arylamino group;
(46) a 5- to 14-membered aromatic heterocyclylamino group;
(47) a C7-16 aralkylamino group;
(48) a formylamino group;
(49) a C1-6 alkyl-carbonylamino group;
(50) a (C1-6 alkyl)(C1-6 alkyl-carbonyl)amino group;
(51) a C6-14 aryl-carbonylamino group;
(52) a C1-6 alkoxy-carbonylamino group;
(53) a C7-16 aralkyloxy-carbonylamino group;
(54) a C1-6 alkylsulfonylamino group;
(55) a C6-14 arylsulfonylamino group optionally substituted by a C1-6 alkyl group;
(56) an optionally halogenated C1-6 alkyl group;
(57) a C2-6 alkenyl group;
(58) a C2-6 alkynyl group;
(59) a C3-10 cycloalkyl group;
(60) a C3-10 cycloalkenyl group;
and
(61) a C6-14 aryl group.

102 more elements

Facts

Application

16/634,402Filed 26 Jul 2018

Priority

JP JP2017-14674428 Jul 2017

Published

US 2020/0231579 A123 Jul 2020

Granted

25 Jan 2022

Term ends

Not estimatedThe source records don’t support an estimate.

Classification27 codes

A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids
C07D 409/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61K 9/2013
Excipients; Inactive ingredients: organic compounds, e.g. phospholipids, fats
A61K 9/2018
Organic compounds, e.g. phospholipids, fats: sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates