Pyrimidine derivative

Patent metadata

Field	Value
Publication number	US-11034659-B2
Application number	US-201716473749-A
Country	US
Kind code	B2
Filing date	Dec 26, 2017
Priority date	Dec 27, 2016
Publication date	Jun 15, 2021
Grant date	Jun 15, 2021

Abstract

Cystic fibrosis is developed through mutation of Cystic Fibrosis Transmembrane conductance Regulator (CFTR), which is one type of chloride channel. An object of the present invention is to provide compounds effective in the treatment of cystic fibrosis that open a chloride channel different from CFTR, which is the cause of the disease, and do not depend on CFTR.Compounds of the present invention are compounds or pharmaceutically acceptable salts thereof that open calcium dependent chloride channels (CaCCs) via G-protein coupled receptor 39 (GPR39) agonism to have strong chloride ion-secretory action, and are represented by the following general formula (I):General formula (I):wherein,X represents a carboxyl group or a tetrazolyl group;Q represents a C1-C3 alkylene group, an oxygen atom, a sulfur atom, etc.;G represents a phenyl group where the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C1-C6 alkyl group, etc.;R1 represents a C1-C6 alkyl group, etc.;R2 represents a C1-C6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B:Group A: a phenyl group and a pyridyl group, wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D;Group B: —OH, —O-M, —SH, —S-M, —NH2, —NH-M, and —N-M2, wherein M is a C1-C6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C3-C6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C;Group C: a halogen atom, a cyano group, a phenyl group, a pyridyl group, etc., wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; andGroup D: a halogen atom, a cyano group, a C1-C6 alkyl group, etc.

First claim

The invention claimed is:

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

wherein,
X represents a carboxyl group or a tetrazolyl group;
Q represents a C 1 -C 3 alkylene group, an oxygen atom, a sulfur atom, or R a N, where
R a represents a hydrogen atom or a C 1 -C 3 alkyl group;

G represents a phenyl group, where
the phenyl group may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a cyano group, a C 1 -C 6 alkyl group, a C 1 -C 3 alkoxy group, and a trihalo C 1 -C 6 alkyl group;

R 1 represents a C 1 -C 6 alkyl group, a C 1 -C 3 alkoxy C 1 -C 6 alkyl group, or a C 3 -C 6 cycloalkyl group; and
R 2 represents a C 1 -C 6 alkyl group that may have 1 to 3 substituents independently selected from the following group A, or a group selected from the following group B,
or a pharmaceutically acceptable salt thereof:
Group A: a phenyl group and a pyridyl group,
wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D;
Group B: —O-M, —SH, —S-M, —NH 2 , —NH-M, and —N-M 2 ,
wherein M is a C 1 -C 6 alkyl group that may have 1 or 2 substituents independently selected from the following group C, or a C 3 -C 6 cycloalkyl group that may have 1 or 2 substituents independently selected from the following group C;
Group C: a halogen atom, a hydroxy group, a cyano group, a carbamoyl group, a carboxyl group, a C 1 -C 6 alkoxycarbonyl group, a C 1 -C 3 alkoxy group, a phenyl group, and a pyridyl group,
wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D; and
Group D: a halogen atom, a cyano group, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, and a trihalo C 1 -C 6 alkyl group.

2. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), X represents a carboxyl group.

3. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), Q represents a methylene group, an oxygen atom, or a sulfur atom.

4. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), G is a phenyl group having 1 to 3 substituents independently selected from the group consisting of a chlorine atom, a fluorine atom, a cyano group, a C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group and a trihalomethyl group, or an unsubstituted phenyl group.

5. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), G is a phenyl group having 1 to 2 substituents independently selected from the group consisting of a chlorine atom and a fluorine atom.

6. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), R 1 represents a C 1 -C 6 alkyl group.

7. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), R 2 is a C 1 -C 6 alkyl group that may be substituted with one pyridyl group, or —O-M, —S-M, —NH-M,
wherein M is a C 1 -C 6 alkyl group that may have 1 or 2 substituents independently selected from the following group C 1 , or a C 3 -C 6 cycloalkyl group that may have one substituent independently selected from the following group C 1 :
Group C 1 : a halogen atom, a cyano group, a phenyl group, and a pyridyl group,
wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D 1 ; and
Group D 1 : a halogen atom, a cyano group, a C 1 -C 6 alkyl group.

8. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein, in formula (I), Q represents a methylene group, an oxygen atom, or a sulfur atom;
G is a phenyl group having 1 to 2 substituents independently selected from the group consisting of a chlorine atom and a fluorine atom;
R 1 is a C 1 -C 3 alkyl group; and
R 2 is a C 1 -C 6 alkyl group that may be substituted with one pyridyl group, or —O-M, —S-M, —NH-M, wherein M is a C 1 -C 6 alkyl group that may have 1 or 2 substituents independently selected from the following group C 1 , or a C 3 -C 6 cycloalkyl group that may have one substituent independently selected from the following group C 1 :
Group C 1 : a halogen atom, a cyano group, a phenyl group, and a pyridyl group,
wherein the phenyl group and the pyridyl group may have 1 to 3 substituents independently selected from the following group D 1 ; and
Group D 1 : a halogen atom, a cyano group, a C 1 -C 6 alkyl group.

9. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is any one selected from the following group:
5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid;
5-((2-chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid;
5-(2-chloro-3-fluorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-ethyl-6-(3-fluoropropoxy)pyrimidine-2-carboxylic acid;
5-(2,4-dichlorobenzyl)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid;
4-(benzyloxy)-5-(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-methyl-6-(pyridin-4-ylmethoxy)pyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-methyl-6-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxylic acid;
5-(2,4-dichlorophenoxy)-4-methyl-6-(methylamino)pyrimidine-2-carboxylic acid;
5-(2,4-dichlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid;
5-(2,3-dichlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-ethoxy-6-methylpyrimidine-2-carboxylic acid;
5-(2-chloro-3-fluorobenzyl)-4-ethoxy-6-ethylpyrimidine-2-carboxylic acid;
5-(2,3-dichlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-(cis-3-cyanocyclobutoxy)-6-methylpyrimidine-2-carboxylic acid;
5-(2,4-dichlorobenzyl)-4,6-dimethylpyrimidine-2-carboxylic acid; and
5-(2,4-dichlorobenzyl)-N,6-dimethyl-2-(1H-tetrazol-5-yl)pyrimidine-4-amine.

10. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is any one selected from the following group:
5-(2,4-dichlorobenzyl)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid;
5-((2-chlorophenyl)thio)-4-(ethylamino)-6-methylpyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid;
5-(2-chloro-3-fluorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-ethyl-6-(3-fluoropropoxy)pyrimidine-2-carboxylic acid;
5-(2,4-dichlorobenzyl)-4-methyl-6-(methylthio)pyrimidine-2-carboxylic acid;
4-(benzyloxy)-5-(2-chlorobenzyl)-6-methylpyrimidine-2-carboxylic acid;
5-(2-chlorobenzyl)-4-methyl-6-(pyridin-4-ylmethoxy)pyrimidine-2-carboxylic acid; and
5-(2-chlorobenzyl)-4-methyl-6-(2-(pyridin-4-yl)ethyl)pyrimidine-2-carboxylic acid.

11. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is 5-(2-chlorobenzyl)-4-methoxy-6-methylpyrimidine-2-carboxylic acid.

12. A compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is 5-(2-chlorobenzyl)-4-ethyl-6-methoxypyrimidine-2-carboxylic acid.

13. A compound or a p

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Takeda Yasuyuki
• Suzuki Yamato
• Noji Toshiharu
• Murafuji Hidenobu
• Muneoka Satoshi
• Inoue Hidekazu
• Takahashi Bitoku
• Inaba Rie

Classifications

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D239/34 Primary

  One oxygen atom · CPC title

• C07D239/28 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms · CPC title

• C07D239/52

  Two oxygen atoms · CPC title

• C07D239/56

  One oxygen atom and one sulfur atom · CPC title