Disubstituted 1, 2, 4-triazine compound

Patent metadata

Field	Value
Publication number	US-10029993-B2
Application number	US-201515305587-A
Country	US
Kind code	B2
Filing date	Apr 23, 2015
Priority date	Apr 24, 2014
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

This invention provides a novel disubstituted 1,2,4-triazine compound or a pharmaceutically acceptable salt thereof, which has an aldosterone synthetase inhibitory activity and is useful for preventing and/or treating various diseases or conditions associated with aldosterone; a method for preparing it; use of it; as well as a pharmaceutical composition comprising it as an active ingredient. A compound of the general formula [I]:

wherein R A is, for example, a group of the following formula (A-1):

wherein ring A 1 is, for example, a cycloalkyl group which may be substituted, and R B is, for example, a monocyclic cycloalkyl group,

or a pharmaceutically acceptable salt thereof.

First claim

The invention claimed is:

1. A compound of the following formula [I]:

wherein
R A is
a group of the following formula (A-1):

wherein ring A 1 represents an aryl group which may be partially hydrogenated and may be substituted,
wherein
a substituent of an aryl group which may be partially hydrogenated and may be substituted represented by ring A 1 in the above formula (A-1) is 1-3 groups selected independently from the group consisting of a halogen atom, a cyano group, an alkyl group, a haloalkyl group, an alkoxyalkyl group, an alkoxy group, and an alkylenedioxy group which may be substituted with 1-2 halogen atoms,
an aryl moiety in the aryl group which may be partially hydrogenated and may be substituted is 6- to 10-membered monocyclic or bicyclic aryl,
R B is

a group of the following formula (B-4):

wherein X a represents CR 3a or N,
(i) when X a represents CR 3a ,
X b represents CHR 3b , X c represents O or NR 4c ,
X b represents O, X c represents NR 4c , or
X b represents NR 4b , X c represents O, NR 4c , or CHR 3c ,
(ii) when X a represents N,
X b represents CHR 3b or C(═O), X c represents NR 4c , or
X b represents NR 4b , X c represents CHR 3c ;
R 3a represents a hydrogen atom, a hydroxyl group, an alkyl group, or an amino group,
each of R 3b and R 3c represents a group selected independently from the group consisting of a hydrogen atom, a hydroxyl group, and an alkyl group,
each of R 4b and R 4c represents a group selected independently from the group consisting of a hydrogen atom, an alkyl group, and a cycloalkyl group;
R B6 represents a hydrogen atom or an alkyl group;
R B7 represents
(i) a cycloalkyl group which may be substituted,
(ii) an aliphatic heterocyclic group which may be substituted, or
(iii) a heteroaryl group which may be partially hydrogenated and may be substituted, or
when X c represents NR 4c , R B7 and R 4c are bound to each other at their terminus to form an aliphatic heterocyclic group, which may be substituted with an alkyl group which may be substituted, together with a nitrogen atom to which they are bound,

wherein
a substituent of (i) the cycloalkyl group which may be substituted, (ii) the aliphatic heterocyclic group which may be substituted, and (iii) the heteroaryl group which may be partially hydrogenated and may be substituted represented by R B7 is 1-4 groups selected independently from the group consisting of a halogen atom; a hydroxyl group; an oxo group; an alkyl group which may be substituted with 1-3 groups selected independently from the group consisting of a hydroxyl group, an alkoxy group, an alkylsulfonyl group, an amino group which may be substituted with 1-2 groups selected independently from the group consisting of an alkoxycarbonyl group and an alkylsulfonyl group, a carbamoyl group which may be substituted with 1-2 alkyl groups, a cycloalkyl group which may be substituted with a hydroxyl group, an aliphatic heterocyclic carbonyl group, and a heteroaryl group which may be substituted with an alkyl group and may be partially hydrogenated; a cycloalkyl group which may be substituted with 1-2 groups selected independently from the group consisting of a hydroxyl group and an alkylsulfonyl group; an aryl group; a heteroaryl group which may be partially hydrogenated; an alkanoyl group which may be substituted with 1-3 groups selected independently from the group consisting of a halogen atom and a hydroxyl group; a cycloalkylcarbonyl group which may be substituted with a hydroxyl group; an aliphatic heterocyclic carbonyl group which may be substituted with an alkyl group; an amino group which may be substituted with 1-2 groups selected independently from the group consisting of an alkyl group which may be substituted with an alkylsulfonyl group, an alkanoyl group, and an alkoxycarbonyl group; a carbamoyl group which may be substituted with 1-2 alkyl groups; an alkylsulfonyl group; an alkoxy group which may be substituted with a carbamoyl group which may be substituted with 1-2 alkyl groups; and an aliphatic heterocyclic group which may be substituted with 1-3 groups selected independently from the group consisting of a hydroxyl group, an oxo group, an alkyl group, an alkanoyl group, and an alkylsulfonyl group, or
when R B7 is (i) a cycloalkyl group which may be substituted, or (ii) an aliphatic heterocyclic group which may be substituted, two substituents on the same ring-constituting carbon atom may be bound to each other at the terminus thereof to form an alkylene group which may be substituted (wherein a substituent of the alkylene group is an oxo group or an alkyl group, and the alkylene group may contain 1-3 heteroatoms selected independently from a sulfur atom, an oxygen atom, and a nitrogen atom),
in R B7 , aryl is 6- to 10-membered monocyclic or bicyclic aryl, heteroaryl is 5- to 10-membered monocyclic or bicyclic heteroaryl which contains 1-4 heteroatoms selected independently from the group consisting of a sulfur atom, an oxygen atom, and a nitrogen atom, an aliphatic heterocyclic ring is a 4- to 9-membered aliphatic heterocyclic ring which contains 1-2 heteroatoms selected independently from the group consisting of an oxygen atom and a nitrogen atom, or
when X c is NR 4c , and R B7 and R 4c are bound to each other at their terminus to form an aliphatic heterocyclic group which may be substituted with an alkyl group which may be substituted, together with a nitrogen atom to which they are bound, a substituent of the alkyl group which may be substituted is a hydroxyl group, and the aliphatic heterocyclic group is a 4- to 9-membered aliphatic heterocyclic ring which may further contain 1 heteroatom selected independently from the group consisting of a sulfur atom, an oxygen atom and a nitrogen atom other than the nitrogen atom to which R B7 and R 4c are bound,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 ,
wherein
in a group represented by the above formula (A-1), ring A 1 is
an aryl group which may be partially hydrogenated and may be substituted,
wherein
a substituent of the aryl group which may be partially hydrogenated and may be substituted is 1-3 groups selected independently from the group consisting of a halogen atom, an alkyl group, a haloalkyl group, an alkoxyalkyl group, an alkoxy group, and an alkylenedioxy group

which may be substituted with 1-2 halogen atoms,
an aryl moiety of the aryl group which may be partially hydrogenated and may be substituted is phenyl or naphthyl,
in a group of the above formula (B-4), R B7 is (i) a cycloalkyl group which may be substituted, (ii) an aliphatic heterocyclic group which may be substituted, or (iii) a heteroaryl group which may be partially hydrogenated and may be substituted, or
when X c is NR 4c , R B7 and R 4c may be bound to each other at their terminus to form an aliphatic heterocyclic group which may be substituted with an alkyl group which may be substituted with a hydroxyl group, together with a nitrogen atom to which they are bound,
wherein
(i) a substituent of the cycloalkyl group which may be substituted is 1-2 groups selected independently from the group consisting of a hydroxyl group; an aliphatic heterocyclic group which may be substituted with 1-3 groups selected independently from the group consisting of a hydroxyl group and an oxo group; an amino group which may be substituted with 1-2 groups selected independently from the group consisting of an alkyl group which may

Assignees

• Mitsubishi Tanabe Pharma Corp

Inventors

• Ushirogochi Hideki
• Sasaki Wataru
• Onda Yuichi
• Sakakibara Ryo
• Akahoshi Fumihiko

Classifications

• A61K31/553

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D498/08

  Bridged systems · CPC title

• A61P13/12

  of the kidneys · CPC title