US 2020/0345729 A1Published application

6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZINONE DERIVATIVE AND MEDICAL USE THEREOF

AssigneeSumitomo Dainippon Pharma Co., Ltd.

InventorsYohei IKUMA, Kengo TOJO, Ryo FUKAZAWA, Shuji MASUMOTO

Life of this patent

Estimating the term…

Abstract

Provided are a compound that is useful for the prevention of and/or as a treatment agent for a disease in which a group II mGlu receptor is involved; and a medical application of said compound. Provided is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

Claims75

Dependent claims

A compound of Formula (1):

or a pharmaceutically acceptable salt thereof,
wherein R1 and R2 are each independently hydrogen atom, halogen atom, cyano, C1-4 alkyl, or C3-6 saturated carbocyclyl group, wherein the alkyl and the saturated carbocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy, or
alternatively, R1 and R2 may combine together with the carbon atom to which they attach to form a C3-4 saturated carbocyclyl group, wherein the saturated carbocyclyl group may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy;
Ring A is C6-10 aromatic carbocyclyl group, 4- to 10-membered saturated heterocyclyl group, or 5- to 10-membered aromatic heterocyclyl group;
R3 and R4 are each independently hydrogen atom, halogen atom, cyano, hydroxy, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C2-4 alkenyl, 4- to 6-membered saturated heterocyclyl group, or 5- or 6-membered aromatic heterocyclyl group (wherein the alkyl, the alkoxy, the alkylthio, the saturated heterocyclyl group, and the aromatic heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 halogen atoms), C3-6 saturated carbocyclyl group, or C3-6 cycloalkoxy, wherein the saturated carbocyclyl group and the cycloalkoxy are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom and C1-4 alkyl;
R5 and R6 are each independently hydrogen atom, halogen atom, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, 4- to 6-membered saturated heterocyclyl group (wherein the alkyl, the alkoxy, the alkylthio, and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy optionally substituted with the same or different 1 to 5 halogen atoms), C3-6 cycloalkoxy, C3-6 saturated carbocyclyl group (wherein the cycloalkoxy and the saturated carbocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, C1-4 alkyl, and C1-4 alkoxy optionally substituted with the same or different 1 to 5 halogen atoms), —NaRb, —NRd—C(O)—Rc, —NRd—C(O)—ORc, —NRd—C(O)—NRaRb, —NRd—SO2—Rc, —CH2—C(O)—NRaRb, —C(O)—Rd, —C(O)—ORd, or —C(O)—NRaRb;
Ra and Rb are each independent and Ras or Rbs when NRaRb exists plurally are each independent, and they are hydrogen atom, C1-4 alkyl (wherein the alkyl is each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy), C3-6 saturated carbocyclyl group, or 4- to 6-membered saturated heterocyclyl group, wherein the saturated carbocyclyl group and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, C1-4 alkyl, and C1-4 alkoxy, or
alternatively, Ra and Rb may combine together with the nitrogen atom to which they attach to form a 4- to 6-membered nitrogen-containing saturated heterocyclyl group, wherein the nitrogen-containing saturated heterocyclyl group may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, C1-4 alkyl, and C1-4 alkoxy;
Rc, where Rcs are each independent when existing plurally, is C1-4 alkyl, C3-6 saturated carbocyclyl group, or 4- to 6-membered saturated heterocyclyl group, wherein the alkyl, the saturated carbocyclyl group, and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy;
Rd, where Rds are each independent when existing plurally, is hydrogen atom, C1-4 alkyl, C3-6 saturated carbocyclyl group, or 4- to 6-membered saturated heterocyclyl group, wherein the alkyl, the saturated carbocyclyl group, and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy;
X is nitrogen atom or —CRe—;
and
Re is hydrogen atom, halogen atom, cyano, C1-6 alkyl, or C1-6 alkoxy, wherein the alkyl and the alkoxy may be optionally substituted with the same or different 1 to 5 halogen atoms.

10 more elements

A method of preparing a compound of Formula (1a):

or a pharmaceutically acceptable salt thereof,
wherein R3 and R4 are each independently hydrogen atom, halogen atom, C1-6 alkyl, or C1-4 alkoxy, wherein the alkyl and the alkoxy are each independent and may be optionally substituted with the same or different 1 to 5 halogen atoms;
R5 and R6 are each independently hydrogen atom, halogen atom, C1-6 alkyl, or —NH2;
and
X is nitrogen atom or —CH—,
which comprises the following steps:
(step B1) coupling a compound of Formula (8a):
wherein R3 and R4 are as defined in this claim, and X1 is iodine, bromine, or chlorine, with a compound of Formula (12a):
or a salt thereof,
in the presence of a transition metal catalyst to give a compound of Formula (13a):
or a salt thereof,
wherein R3 and R4 are as defined in this claim;
(step B2) reacting the compound of Formula (13a), or a salt thereof, and a compound of Formula (22):
or a salt thereof,
wherein X is as defined in this claim, and R7 is methyl or ethyl,
under Mitsunobu condition to give a compound of Formula (23a):
or a salt thereof,
wherein R3, R4, R7, and X1 are as defined in this claim;
(step B3) hydrolyzing the compound of Formula (23a), or a salt thereof, in the presence of an acid or base to give a compound of Formula (24a):
or a salt thereof,
wherein R3, R4, and X1 are as defined in this claim;
(step B4) cyclizing the compound of Formula (24a), or a salt thereof, in the presence of an acid or base to give a compound of Formula (15a):
wherein R3, R4, and X1 are as defined in this claim;
and
(step B5) coupling the compound of Formula (15a) and a compound of Formula (16):
or a salt thereof,
wherein R5, R6, and X are as defined in this claim, and RA is boronic acid or boronic acid ester,
in the presence of a transition metal catalyst to give a compound of Formula (1a), or a pharmaceutically acceptable salt thereof;
wherein the step B3 and step B4 may be replaced with one single step of the following step B6:
(step B6) cyclizing the compound of Formula (23a), or a salt thereof, in the presence of an acid or base to give a compound of Formula (15a).

27 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/764,962Filed 22 Nov 2018
Priority: JP 2017-22536424 Nov 2017
Published: 5 Nov 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification18 codes

A61K 31/4985
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrazines or piperazines…
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 45/00
Medicinal preparations containing active ingredients not provided for in groups a61k31/00 -
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

US 11,633,395 B2Related patent
US 2020/0345729 A1This patent

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

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Abstract

A compound of Formula (1):

or a pharmaceutically acceptable salt thereof,
wherein R1 and R2 are each independently hydrogen atom, halogen atom, cyano, C1-4 alkyl, or C3-6 saturated carbocyclyl group, wherein the alkyl and the saturated carbocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy, or
alternatively, R1 and R2 may combine together with the carbon atom to which they attach to form a C3-4 saturated carbocyclyl group, wherein the saturated carbocyclyl group may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy;
Ring A is C6-10 aromatic carbocyclyl group, 4- to 10-membered saturated heterocyclyl group, or 5- to 10-membered aromatic heterocyclyl group;
R3 and R4 are each independently hydrogen atom, halogen atom, cyano, hydroxy, C1-6 alkyl, C1-4 alkoxy, C1-4 alkylthio, C2-4 alkenyl, 4- to 6-membered saturated heterocyclyl group, or 5- or 6-membered aromatic heterocyclyl group (wherein the alkyl, the alkoxy, the alkylthio, the saturated heterocyclyl group, and the aromatic heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 halogen atoms), C3-6 saturated carbocyclyl group, or C3-6 cycloalkoxy, wherein the saturated carbocyclyl group and the cycloalkoxy are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom and C1-4 alkyl;
R5 and R6 are each independently hydrogen atom, halogen atom, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, 4- to 6-membered saturated heterocyclyl group (wherein the alkyl, the alkoxy, the alkylthio, and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy optionally substituted with the same or different 1 to 5 halogen atoms), C3-6 cycloalkoxy, C3-6 saturated carbocyclyl group (wherein the cycloalkoxy and the saturated carbocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, C1-4 alkyl, and C1-4 alkoxy optionally substituted with the same or different 1 to 5 halogen atoms), —NaRb, —NRd—C(O)—Rc, —NRd—C(O)—ORc, —NRd—C(O)—NRaRb, —NRd—SO2—Rc, —CH2—C(O)—NRaRb, —C(O)—Rd, —C(O)—ORd, or —C(O)—NRaRb;
Ra and Rb are each independent and Ras or Rbs when NRaRb exists plurally are each independent, and they are hydrogen atom, C1-4 alkyl (wherein the alkyl is each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy), C3-6 saturated carbocyclyl group, or 4- to 6-membered saturated heterocyclyl group, wherein the saturated carbocyclyl group and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, C1-4 alkyl, and C1-4 alkoxy, or
alternatively, Ra and Rb may combine together with the nitrogen atom to which they attach to form a 4- to 6-membered nitrogen-containing saturated heterocyclyl group, wherein the nitrogen-containing saturated heterocyclyl group may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, C1-4 alkyl, and C1-4 alkoxy;
Rc, where Rcs are each independent when existing plurally, is C1-4 alkyl, C3-6 saturated carbocyclyl group, or 4- to 6-membered saturated heterocyclyl group, wherein the alkyl, the saturated carbocyclyl group, and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy;
Rd, where Rds are each independent when existing plurally, is hydrogen atom, C1-4 alkyl, C3-6 saturated carbocyclyl group, or 4- to 6-membered saturated heterocyclyl group, wherein the alkyl, the saturated carbocyclyl group, and the saturated heterocyclyl group are each independent and may be optionally substituted with the same or different 1 to 5 substituents selected from the group consisting of halogen atom, hydroxy, and C1-4 alkoxy;
X is nitrogen atom or —CRe—;
and
Re is hydrogen atom, halogen atom, cyano, C1-6 alkyl, or C1-6 alkoxy, wherein the alkyl and the alkoxy may be optionally substituted with the same or different 1 to 5 halogen atoms.

10 more elements

Facts

Application

16/764,962Filed 22 Nov 2018

Priority

JP 2017-22536424 Nov 2017

Published

5 Nov 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

A61K 31/4985
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: pyrazines or piperazines…
C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 45/00
Medicinal preparations containing active ingredients not provided for in groups a61k31/00 -
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents