Pyridine derivative

Patent metadata

Field	Value
Publication number	US-10059720-B2
Application number	US-201515313712-A
Country	US
Kind code	B2
Filing date	May 28, 2015
Priority date	May 28, 2014
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

The problem to be solved by the present invention is to provide a compound suitable for a pharmaceutical composition, specifically a pharmaceutically composition for treating nocturia.
The inventors have assumed that inhibition of nocturnal activity of placental leucine aminopeptidase (P-LAP), i.e. aminopeptidase that cleaves AVP, would maintain and/or increase an endogenous AVP level to enhance the antidiuretic effect, which would contribute to a decreased number of nocturnal voids, and have extensively studied compounds which inhibit P-LAP.
As a result, the inventors have found that (2R)-3-amino-2-{[4-(substituted pyridine)-2-yl]methyl}-2-hydroxy-propanoic acid derivatives have excellent P-LAP inhibitory activity. The inventors have evaluated antidiuretic effects in water-loaded rats and have found that the compounds increase endogenous AVP levels by inhibiting P-LAP and consequently reduce urine production. The present invention therefore provides compounds expected to be used as an agent for treating nocturia based on P-LAP inhibition.

First claim

The invention claimed is:

1. A compound represented by Formula (I) or a salt thereof:

wherein:
X is O;
R 1 is H; C 1-10 alkyl; -(lower alkylene)-O-(lower alkyl); C 3-12 cycloalkyl which optionally has one to five substituents selected from the group consisting of lower alkyl and halogen; C 5-6 cycloalkenyl condensed with a benzene ring; aryl which optionally has one to five substituents selected from the group consisting of halogen and —O-(lower alkyl); -(lower alkylene)-R 11 ; -(lower alkylene)-O—(C 3-12 cycloalkyl); -(lower alkylene)-O-aryl or -(lower alkylene)-O-(lower alkylene)-aryl;
R 11 is C 3-12 cycloalkyl which is optionally substituted by one to five lower alkyls, or aryl which optionally has one to five substituents selected from the group consisting of halogen, lower halogenoalkyl, —O-(lower alkyl) and —O-(lower halogenoalkyl);
R 2 's are the same or different from each other, and are H, lower alkyl, halogen, -(lower alkylene)-aryl, or -(lower alkylene)-O-(lower alkylene)-aryl;
R 3 is C 1-10 alkyl which is optionally substituted by one to five halogens; -(lower alkylene)-O-(lower alkyl which optionally has one to five substituents selected from the group consisting of halogen and OH); -(lower alkylene)-O-(lower alkenyl); aryl which optionally has one to five substituents selected from the group consisting of halogen, CN, -(lower alkylene)-O-(lower alkyl), C 3-8 cycloalkyl, aryl which is optionally substituted by —S(O) 2 -(lower alkyl), and —S(O) 2 —(C 3-8 cycloalkyl); -(lower alkylene)-(C 3-8 cycloalkyl); -(lower alkylene)-O—(C 3-8 cycloalkyl); -(lower alkylene)-O-{aryl which optionally has one to five substituents selected from the group consisting of halogen, —O-(lower alkyl), CN and -(lower alkylene)-O-(lower alkyl)}; -(lower alkylene)-O-(lower alkylene)-aryl; -(lower alkylene)-O-(lower alkylene)-(C 3-8 cycloalkyl); -(lower alkylene)-S(O)-(lower alkyl), wherein n is 0, 1, or 2; -(lower alkylene)-S—(C 3-8 cycloalkyl); -(lower alkylene)-S-(lower alkylene)-(C 3-8 cycloalkyl); or -(lower alkenylene)-aryl;
RP is H or a lower alkyl; and
R 6 is H.

2. The compound or a salt thereof according to claim 1 , wherein X is O; R 1 is C 1-10 alkyl, C 3-10 cycloalkyl which is optionally substituted by one to three lower alkyls, -(lower alkylene)-(C 3-10 cycloalkyl which is optionally substituted by one to three lower alkyls), or -(lower alkylene)-aryl; R 2 's represent H; R 3 is C 1-10 alkyl, -(lower alkylene)-O-(lower alkenyl), -(lower alkylene)-(C 3-8 cycloalkyl), -(lower alkylene)-O-(lower alkylene)-(C 3-8 cycloalkyl), -(lower alkylene)-S-(lower alkyl), or -(lower alkylene)-S-(lower alkylene)-(C 3-8 cycloalkyl); R P is H; and R 6 is H.

3. The compound or a salt thereof according to claim 2 , wherein X is O; R 1 is C 1-10 alkyl, C 3-10 cycloalkyl which is optionally substituted by lower alkyl, or -(lower alkylene)-(C 3-10 cycloalkyl which is optionally substituted by lower alkyl); and R 3 is C 1-10 alkyl, -(lower alkylene)-(C 3-8 cycloalkyl), -(lower alkylene)-S-(lower alkyl), or -(lower alkylene)-S-(lower alkylene)-(C 3-8 cycloalkyl).

4. The compound or a salt thereof according to claim 1 , which is a compound selected from the group consisting of the following compounds, or a salt thereof:
(2R,3 S)-3-amino-2-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic acid;
(2R,3 S)-3-amino-2-{[4-(cyclohexyloxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic acid;
(2R,3S)-3-amino-2-hydroxy-5-methyl-2-{[4-(spiro[2.5]oct-6-yloxy)pyridin-2-yl]methyl}hexanoic acid;
(2R,3R)-3-amino-4-[(cyclopropylmethyl)sulfanyl]-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)butanoic acid;
(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoic acid;
(2R,3S)-3-amino-5-cyclobutyl-2-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxypentanoic acid;
(2R,3S)-3-amino-2-hydroxy-5-methyl-2-({[4-(2-(1-methylcyclopropyl)ethoxy]pyridin-2-yl}methyl)hexanoic acid;
(2R,3S)-3-amino-2-{[4-(3-cyclopropylpropoxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic acid;
(2R,3S)-3-amino-2-{[4-(cycloheptyloxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic acid;
(2R,3S)-3-amino-2-({4-[(2R)-hexan-2-yloxy]pyridin-2-yl}methyl)-2-hydroxy-5-methylhexanoic acid;
(2R,3R)-3-amino-4-(ethylsulfanyl)-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)butanoic acid; and
(2R,3R)-3-amino-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)-4-(methylsulfanyl)butanoic acid.

5. A pharmaceutical composition, comprising a compound or a salt thereof according to claim 1 and an excipient.

6. The compound or a salt thereof according to claim 4 , wherein the compound is (2R,3S)-3-amino-2-{[4-(2-cyclopropylethoxy)pyridin-2-yl]methyl}-2-hydroxy-5-methylhexanoic acid.

7. The compound or a salt thereof according to claim 4 , wherein the compound is (2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)hexanoic acid.

8. The compound or a salt thereof according to claim 4 , wherein the compound is (2R,3S)-3-amino-2-hydroxy-5-methyl-2-({4-[2-(1-methylcyclopropyl)ethoxy]pyridin-2-yl}methyl)hexanoic acid.

9. The compound or a salt thereof according to claim 4 , wherein the compound is (2R,3 S)-3-amino-2-({4-[(2R)-hexan-2-yloxy]pyridin-2-yl}methyl)-2-hydroxy-5-methylhexanoic acid.

10. The compound or a salt thereof according to claim 4 , wherein the compound is (2R,3R)-3-amino-4-(ethylsulfanyl)-2-hydroxy-2-({4-[(trans-4-methylcyclohexyl)oxy]pyridin-2-yl}methyl)butanoic acid.

11. The pharmaceutical composition according to claim 5 , wherein said compound or a salt thereof is the compound or a salt thereof according to claim 4 .

Assignees

• Astellas Pharma Inc
• Kotobuki Pharmaceutical Co Ltd
• Kotobuki Pharmaceuticals Co Ltd

Inventors

• Kawaguchi Kenichi
• Ishihata Akihiro
• Inagaki Yusuke
• Tsuchiya Kazuyuki
• Hanadate Tadaatsu
• Kanai Akira
• Kaizawa Hiroyuki
• Kazami Junichi
• Morikawa Hiroshi
• Hiramoto Masashi
• Enjo Kentaro
• Takamatsu Hajime

Classifications

• A61P7/12

  Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10) · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P13/00

  Drugs for disorders of the urinary system · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title