Compound having lysophosphatidylserine receptor function modulation activity

Patent metadata

Field	Value
Publication number	US-9469665-B2
Application number	US-201414764808-A
Country	US
Kind code	B2
Filing date	Jan 30, 2014
Priority date	Jan 31, 2013
Publication date	Oct 18, 2016
Grant date	Oct 18, 2016

Abstract

The object of the present invention is to provide a compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof.
A compound having a lysophosphatidylserine receptor function modulation activity or a salt thereof, or a pharmaceutical composition or a lysophosphatidylserine receptor function moderator containing such compound or salt is provided by the present invention.

First claim

The invention claimed is:

1. A compound represented by formula (I):

wherein R 1 is C 1-30 alkyl, C 2-30 alkenyl, C 2-30 alkynyl, or a group represented by formula: —(C 1-15 alkylene)-Q 1 -Z 1 -(C 1-15 alkylene)-Z 2 -Q 2 ;
in which Q 1 is C 3-10 cycloalkylene, 5-10 membered heterocyclylene, C 6-10 arylene, or 5-10 membered heteroarylene,
Q 2 is a hydrogen atom, C 3-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, and Q 2 may be substituted with -Z 3 -Q 3 ,
Q 3 is C 3-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl,
Z 1 , Z 2 , and Z 3 are independently selected from the group consisting of an oxygen atom, a sulfur atom, —NR 9 —, difluoromethylene, and a direct bond,
wherein the alkyl, alkenyl, alkynyl, cycloalkylene, heterocyclylene, arylene, heteroarylene, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be independently substituted with one or more substituents selected from halo and hydroxy;
R 2 is a hydrogen atom, C 1-6 alkyl, C 7-14 aralkyl, or C 1-6 alkoxy C 1-6 alkyl;
R 3 is a hydrogen atom or C 1-6 alkyl;
R 4 and R 5 are independently selected from the group consisting of a hydrogen atom, C 1 - 6 alkyl, C 7 - 14 aralkyl, formyl, C 1-6 alkylcarbonyl, arylcarbonyl, C 1-6 alkoxycarbonyl, C 1-6 alkoxy C 1-6 alkyl, and C 7 - 14 aralkyloxycarbonyl;
R 6 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or C 7-14 aralkyl;
R 7 is a hydrogen atom or C 1-6 alkyl,
R 8 is C 1-6 alkyl, in which the alkyl may be substituted with one or more substituents selected from the group consisting of hydroxy, C 1 - 6 alkoxy, C 3 - 10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C 7 - 14 aralkyloxy, C 6 - 10 aryloxy, and 5-10 membered heteroaryloxy, or
R 7 and R 8 together with the carbon atom which they are attached may form a ring, if and only if X is CH 2 , said ring selected from a C 3 - 10 saturated carbocyclic ring, and 5-10 membered saturated or partially-saturated heterocyclic ring;
R 9 is a hydrogen atom or C 1-6 alkyl;
X is CH 2 or a direct bond, with the proviso that if X is CH 2 , R 7 and R 8 together with a carbon atom which they are attached form a ring; and
Y is CH 2 or a direct bond,
or a salt thereof.

2. The compound according to claim 1 , which is represented by formula (Ia):

wherein R 8 is C 1-6 alkyl, wherein the alkyl may be substituted with hydroxy, C 1-6 alkoxy, C 3-10 cycloalkyloxy, 5-10 membered heterocyclyloxy, C 7-14 aralkyloxy, C 6-10 aryloxy, or 5-10 membered heteroaryloxy; and
R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined in claim 1 , or a salt thereof.

3. The compound according to claim 1 , which is represented by formula (Ib):

wherein A is a ring selected from C 3-10 saturated carbocyclic ring, and 5-10 membered saturated or partially-saturated heterocyclic ring; and
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, and Y are as defined in claim 1 , or a salt thereof.

4. The compound according to claim 3 , which is represented by formula (Ic):

wherein A is a ring selected from the following:

wherein p is 1-5, and
* and ** represent the binding positions of side chains on ring A;
or a salt thereof.

5. The compound according to any one of claims 1 - 4 , wherein R 3 is a hydrogen atom or methyl.

6. The compound according to claim 1 , wherein
R 1 is selected from the following:

wherein n and m are independently 1-12, and Z 1 , Z 2 , and Z 3 are as defined in claim 1 , or a salt thereof.

7. A compound selected from:
(9Z)-octadeca-9-enoic acid (2R)-2-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-propyl ester;
(9Z)-octadeca-9-enoic acid (2S)-2-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-propyl ester;
(2S)-2-amino-3-[hydroxyl-((1R)-1-methyl-2-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxy}-ethoxy)-phosphoryloxy]-propionic acid;
(9Z)-octadeca-9-enoic acid (2R)-2-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-3-methoxy-propyl ester;
(9Z)-octadeca-9-enoic acid (2S)-2-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-3-methoxy-propyl ester;
(9Z)-octadeca-9-enoic acid (2R)-2-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-3-ethoxypropyl ester;
(9Z)-octadeca-9-enoic acid (2R)-2-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-3-benzyloxy-propyl ester;
(2S)-2-amino-3-(hydroxy{(3R,4R)-4-[3-(2-undecyloxy-phenyl)-propionyloxy]-tetrahydro-pyran-3-yloxy} -phosphoryloxy)-propionic acid;
(2S)-2-amino-3-(hydroxy{(3R,4R)-3-[3-(2-undecyloxy-phenyl)-propionyloxy]-tetrahydropyran-4-yloxyl}-phosphoryloxy)-propionic acid;
(2S)-2-amino-3-(hydroxy{(3S,4S)-4-[3-(2-undecyloxy-phenyl)-propionyloxy]-tetrahydro-pyran-3-yloxy}-phosphoryloxy)-propionic acid;
(2S)-2-amino-3-(hydroxy{(3S,4S)-3-[3-(2-undecyloxy-phenyl)-propionyloxy]-tetrahydro-pyran-4-yloxy}-phosphoryloxy)-propionic acid;
(2S)-2-amino-3-({(3S,4S)-3-[3-(5-tert-butyl-2-undecyloxy-phenyl)-propionyloxy]-tetrahydro-pyran-4-yloxy}-hydroxy-phosphoryloxy)-propionic acid;
(2S)-2-amino-3-[hydroxy((2R,3S)-3-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxy}-tetrahydro-pyran-2-ylmethoxy)-phosphoryloxy]-propionic acid;
(2S)-2-amino-3-(hydroxy{(2R,3S)-3-[3-(2-undecyloxy-phenyl)-propionyloxy]-tetrahydro-pyran-2-ylmethoxyl}-phosphoryloxy)-propionic acid;
(9Z)-octadeca-9-enoic acid (2R,3R)-3-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-tetrahydro-pyran-2-ylmethyl ester;
(2S)-2-amino-3-(hydroxy{(2R,3R)-2-[3-(2-undecyloxy-phenyl)-propionylmethoxy]-tetrahydro-pyran-3-yloxy}-phosphoryloxy)-propionic acid;
(2S)-2-amino-3-[hydroxy-((2R,3R)-2-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionylmethoxy}-tetrahydropyran-3-yloxy)-phosphoryloxy]-propionic acid;
(2S)-2-amino-3-[hydroxy-((2R,3R)-3-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxy}-tetrahydropyran-2-ylmethoxy)-phosphoryloxy]-propionic acid;
(2S)-2-amino-3-(hydroxyl-{(2R,3S)-2-[3-(2-undecyloxy-phenyl)-propionyloxymethyl]-3,6-dihydro-2H-pyran-3-yloxy}-phosphoryloxy)-propionic acid;
(9Z)-octadeca-9-enoic acid (2R,3S)-3-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]tetrahydro-pyran-2-ylmethyl ester;
(2S)-2-amino-3-(hydroxy-{(2R,3S)-2-[3-(2-undecyloxy-phenyl)-propionyloxymethyl]-tetrahydro-pyran-3-yloxy}-phosphoryloxy)-propionic acid;
(2S)-2-amino-3-[hydroxy-((2R,3S)-2-{3[2(3-phenoxy-benzyloxy)-phenyl]-propionyloxymethyl}-tetrahydropyran-3-yloxy)-phosphoryloxy]-propionic acid;
(9Z)-octadeca-9-enoic acid (2R,3S)-3-[((2S)-2-amino-2-carboxy-ethoxy)-hydroxy-phosphoryloxy]-3,6-dihydro-2H-pyran-2-ylmethyl ester;
(2S)-2-amino-3-[hydroxy-((2R,3S)-2-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxymethyl}-3,6-dihydro-2H-pyran-3-yloxy)-phosphoryloxy]-propionic acid;
(2S)-2-amino-3-(hydroxy-{(2R,3R)-2[3-(2-undecyloxy-phenyl)-propionyloxymethyl]-3,6-dihydro-2H-pyran-3-yloxyl}-phosphoryloxy)-propionic acid;
(2S)-2-amino-3-[hydroxy-((2R,3R)-2-{3-[2-(3-phenoxy-benzyloxy)-phenyl]-propionyloxymethyl}-3,6-dihydro-2H-pyran-3-yloxy)-

Assignees

• Univ Tokyo
• Univ Tohoku

Inventors

• Ohwada Tomohiko
• Otani Yuko
• Ikubo Masaya
• Nakamura Sho
• Jung Sejin
• Aoki Junken
• Makide Kumiko
• Inoue Asuka

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P43/00

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P21/04

  for myasthenia gravis · CPC title