Azole derivatives as apelin receptor agonist

Patent metadata

Field	Value
Publication number	US-12071413-B2
Application number	US-202117506497-A
Country	US
Kind code	B2
Filing date	Oct 20, 2021
Priority date	Nov 24, 2015
Publication date	Aug 27, 2024
Grant date	Aug 27, 2024

Abstract

The present invention relates to a novel azole derivative as an apelin receptor agonist and a method for treating cardiovascular disease, diabetic disease, renal disease, hypertension, and arteriosclerosis, etc., using the same. The present invention provides a compound represented by formula (I) or a pharmacologically acceptable salt thereof wherein X 1 represents —N═ or —CH═, X 2 represents —CH═ or —N═, R 1 and R 2 each represent a C 1 to C 6 alkoxy group or the like, R 3 represents a heteroaryl group (the heteroaryl group is optionally substituted by a methyl group or the like) or the like, and R 4 represents a C 1 to C 6 alkylthio group or a C 2 to C 6 alkenyl group (the C 1 to C 6 alkylthio group and the C 2 to C 6 alkenyl group are each optionally substituted by one carboxy group or the like) or the like.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a compound represented by formula (I), or a pharmacologically acceptable salt thereof:

wherein
X 1 is —N═ or —CH═,
X 2 is —CH═ or —N═,
R 1 and R 2 are each independently a C 1 to C 6 alkyl group, a C 1 to C 6 alkoxy group, or a halogeno group, wherein the C 1 to C 6 alkyl group and the C 1 to C 6 alkoxy group are each optionally substituted by 1 to 3 fluoro groups;
R 3 is a furyl group, a thienyl group, a pyridyl group, a phenyl group, a n-butyl group, or a cyclopentyl group (the furyl group, the thienyl group, the pyridyl group, and the phenyl group are each optionally substituted by 1 or 2 identical or different groups selected from a methyl group and a halogeno group); and
R 4 is

an active ingredient.

2. The pharmaceutical composition according to claim 1 , wherein X 1 is —N═; and X 2 is —CH═.

3. The pharmaceutical composition according to claim 1 , wherein R 1 and R 2 are each independently a C 1 to C 6 alkoxy group or a C 1 to C 6 alkyl group.

4. The pharmaceutical composition according to claim 1 , wherein R 3 is a furyl group, a thienyl group, a pyridyl group, a phenyl group, or a cyclopentyl group, wherein the furyl group, the thienyl group, the pyridyl group, and the phenyl group are each optionally substituted by 1 or 2 groups each independently selected from a methyl group and a halogeno group.

5. The pharmaceutical composition according to claim 1 , wherein R 3 is a 5-methylfuran-2-yl group.

6. The pharmaceutical composition according to claim 1 , wherein the compound is represented by formula (II):

or a pharmacologically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6 , wherein the compound is {[4-(2,6-Dimethoxypheny])-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid:

or pharmacologically acceptable salt thereof.

8. The pharmaceutical composition according to claim 1 , wherein R 4 is

9. The pharmaceutical composition according to claim 1 , wherein R 4 is

10. The pharmaceutical composition according to claim 1 , wherein R 4 is

11. The pharmaceutical composition according to claim 1 , wherein R 4 is:

or a pharmacologically acceptable salt thereof.

12. The pharmaceutical composition according to claim 1 , wherein R 4 is

13. The pharmaceutical composition according to claim 1 , wherein R 4 is

14. The pharmaceutical composition according to claim 1 , or a pharmacologically acceptable salt thereof, wherein R 4 is

15. The pharmaceutical composition according to claim 1 , wherein the compound is selected from the group consisting of:
{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid,
4-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}butanoic acid,
{[5-(5-Bromofuran-2-yl)-4-(2,6-dimethoxyphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid,
{[4-(2,6-Diethylphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid,
{[4-(2,4-Dimethoxypyridin-3-yl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid,
{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(phenyl)acetic acid,
2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl] sulfanyl}-2-methylpropanoic acid,
{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}(naphthalen-1-yl)acetic acid,
2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-phenylpropanoic acid,
2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propanoic acid,
2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}pentanoic acid,
2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-3-methylbutanoic acid,
{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]oxy}acetic acid,
2-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-N-(phenylsulfonyl)acetamide,
({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)phosphonic acid,
(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid,
3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]propanoic acid,
3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoic acid,
4-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]benzoic acid,
(2Z)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoic acid,
{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methoxy}acetic acid,
4-(2,6-Dimethoxyphenyl)-3-(5-methylfuran-2-yl)-5-[(4H-1,2,4-triazol-3-ylsulfanyl)methyl]-4H-1,2,4-triazole,
N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl}methanesulfonamide,
N-{[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]methyl-4-methylbenzenesulfonamide,
1-{(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-L-proline,
(4R)-1-{(2E)-3-[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]prop-2-enoyl}-4-hydroxy-L-proline,
6-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyrimidine-2,4(1H,3H)-dione,
5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one,
4-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)pyridin-2(1H)-one,
5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1H-tetrazole,
3-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,2,4-oxadiazol-5(2H)-one,
5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one,
5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-1,3,4-oxadiazol-2(3H)-one, and
5-({[4-(2,6-Dimethoxyphenyl)-5-(5-methylfuran-2-yl)-4H-1,2,4-triazol-3-yl]sulfany

Assignees

• Sanford Burnham Prebys Medical Discovery Inst

Inventors

• Ikeda Takuya
• Kobayashi Yoshiyuki
• Miyoshi Naoki
• Suzuki Osamu
• Nagayama Takahiro
• Tsuji Takashi
• Smith Layton H
• Pinkerton Anthony B

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D409/04

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