Lysophosphatidylserine derivative

Patent metadata

Field	Value
Publication number	US-9856278-B2
Application number	US-201515322041-A
Country	US
Kind code	B2
Filing date	Jul 3, 2015
Priority date	Jul 4, 2014
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

An object of the present invention is to provide a lysophosphatidylserine derivative or a salt thereof.
The present invention provides a lysophosphatidylserine derivative or a salt thereof, or a pharmaceutical composition or a lysophosphatidylserine receptor function modulator comprising said compound or a salt thereof.

First claim

The invention claimed is:

1. A compound represented by formula (I):

wherein:
R 1 is represented by the following group:
C 1-30 alkyl optionally substituted by one or more R 8 , C 2-30 alkenyl optionally substituted by one or more R 8 , or C 2-30 alkynyl optionally substituted by one or more R 8 , where R 8 is independently selected from among C 1-6 alkyl, C 1-6 alkoxy, and a halogen atom, or is a group represented by the formula:
—(C 0-15 alkylene)-Q 1 -Z 1 —(C 0-15 alkylene)-Z 2 -Q 2 ,

where Q 1 is a C 3-10 cycloalkylene optionally substituted by one or more R 9 , a 5- to 10-membered heterocyclylene optionally substituted by one or more R 9 , a C 6-10 arylene optionally substituted by one or more R 9 , or a 5- to 10-membered heteroarylene optionally substituted by one or more R 9 , where R 9 is independently selected from among C 1-6 alkyl, C 1-6 alkoxy, and a halogen atom;
Q 2 is a hydrogen atom, a C 3-10 cycloalkyl optionally substituted by one or more R 10 , a 5-to 10-membered heterocyclyl optionally substituted by one or more R 10 , a C 6-10 aryl optionally substituted by one or more R 10 , or a 5- to 10-membered heteroaryl optionally substituted by one or more R 10 , where R 10 is independently selected from among C 1-6 alkyl, C 1-6 alkoxy, a halogen atom, and —Z 3 —(C 0-15 alkylene)-Q 3 ,
Q 3 is a C 3-10 cycloalkyl optionally substituted by one or more R 11 , a 5- to 10-membered heterocyclyl optionally substituted by one or more R 11 , a C 6-10 aryl optionally substituted by one or more R 11 , or a 5- to 10-membered heteroaryl optionally substituted by one or more R 11 , where R 11 is independently selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, hydroxyl C 1-6 alkyl, C 7-14 aralkyl, C 1-6 alkoxy C 1-6 alkyl, C 3-10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, cyano, amino, nitro, trifluoromethyl, halogen atom, and hydroxy;
Z 1 , Z 2 and Z 3 are independently selected from the group consisting of an oxygen atom, a sulfur atom, —NR 7 —, —CO—, —SO 2 —, difluoromethylene, and a direct bond, where R 7 is a hydrogen atom or C 1-6 alkyl, provided that in the case of —Z 1 —(C 0-1 alkylene)-Z 2 —, either one of Z 1 and Z 2 is an oxygen atom and the other is a direct bond or both of them are direct bonds;
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, C 6-10 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;
A is phenylene or ethynylene;
X and Y are independently 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 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X, and Y are as defined above,
or a salt thereof.

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

wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are as defined above,
or a salt thereof.

4. The compound according to claim 1 , wherein R 3 is a hydrogen atom or methyl, or a salt thereof.

5. The compound according to claim 1 , wherein:
R 2 is a hydrogen atom;
R 4 and R 5 are each a hydrogen atom; and
R 6 is a hydrogen atom,

or a salt thereof.

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

wherein:
R 12 and R 13 are independently selected from among C 1-6 alkyl, C 1-6 alkoxy, and a halogen atom,
R 14 is independently selected from among C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylsulfonyl, hydroxyl C 1-6 alkyl, C 7-14 aralkyl, C 1-6 alkoxy C 1-6 alkyl, C 3-10 cycloalkyl, 5- to 10-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, cyano, amino, nitro, trifluoromethyl, a halogen atom, and hydroxy,
R 15 is selected from among C 3-15 alkyl, C 3-10 cycloalkyl, and 5- to 10-membered heterocyclyl,
l and m are independently 0 to 15,
n is 0 to 15,
Z 1 and Z 2 are such that in the case where m is 0 or 1, either one of them is an oxygen atom while the other is a direct bond or both of them are direct bonds, and in the case where m is 2 to 15, Z 1 and Z 2 are independently selected from the group consisting of an oxygen atom and a direct bond,
Z 3 is independently selected from the group consisting of an oxygen atom, a sulfur atom, —NR 7 —, —CO—, —SO 2 —, difluoromethylene, and a direct bond, where R 7 is a hydrogen atom or C 1-6 alkyl,
p and q are independently 0 to 4,
r is 0 to 5 in the case of formulas (IIc) to (IIe), and 0 to 4 in the case of formula (IIf), or a salt thereof.

7. The compound according to claim 6 , wherein R 14 is independently selected from among C 1-6 alkyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryloxy, and a halogen atom, or a salt thereof.

8. A compound selected from:
O-(hydroxy(2-((3-(2-(undecyloxy)phenyl)propanoyl)oxy)phenoxy)phosphoryl)-L-serine;
O-(hydroxy(3-((3-(2-(undecyloxy)phenyl)propanoyl)oxy)phenoxy)phosphoryl)-L-serine;
O-(hydroxy(4-((3-(2-(undecyloxy)phenyl)propanoyl)oxy)phenoxy)phosphoryl)-L-serine;
O-(hydroxy(2-(((3-(2-(undecyloxy)phenyl)propanoyl)oxy)methyl)phenoxy)phosphoryl)-L-serine;
O-(hydroxy(2-(((3-(2-((3-phenoxybenzyl)oxy)phenyl)propanoyl)oxy)methyl)phenoxy)phosphoryl)-L-serine;
O-(hydroxy(3-(((3-(2-(undecyloxy)phenyl)propanoyl)oxy)methyl)phenoxy)phosphoryl)-L-serine;
O-(hydroxy(3-(((3-(2-((3-phenoxybenzyl)oxy)phenyl)propanoyl)oxy)methyl)phenoxy)phosphoryl)-L-serine;
O-(hydroxy(4-(((3-(2-(undecyloxy)phenyl)propanoyl)oxy)methyl)phenoxy)phosphoryl)-L-serine;
O-(hydroxy((3-((3-(2-(undecyloxy)phenyl)propanoyl)oxy)benzyl)oxy)phosphoryl)-L-serine;
O-(hydroxy((3-((3-(2-((3-phenoxybenzyl)oxy)phenyl)propanoyl)oxy)benzyl)oxy)phosphoryl)-L-serine;
O-(hydroxy((4-((3-(2-(undecyloxy)phenyl)propanoyl)oxy)benzyl)oxy)phosphoryl)-L-serine;
O-(hydroxy((4-((3-(2-(undecyloxy)phenyl)propanoyl)oxy)but-2-yn-1-yl)oxy)phosphoryl)-L-serine;
O-(hydroxy(4-(((3-(2-((3-phenoxybenzyl)oxy)phenyl)propanoyl)oxy)methyl)phenoxy)phosphoryl)-L-serine; and
O-(hydroxy((3-(((3-(2-(undecyloxy)phenyl)propanoyl)oxy)methyl)benzyl)oxy)phosphoryl)-L-serine,
or a salt thereof.

9. A pharmaceutical composition, comprising the compound or salt thereof according to claim 1 .

10. A method of modulating a lysophosphatidylserine receptor function, comprising administering an effective amount of a compound or salt thereof according to claim 1 which acts on any one or more lysophosphatidylserine receptors selected from among GPR34, P2Y10, and GPR174.

11. The method according to claim 10 , wherein the compound or salt thereof acts on any two lysophosphatidylserine receptors selected from among GPR34, P2Y10, and GPR174.

12. The method according to claim 10 , wherein the compound or salt thereof selectively acts on P2Y10.

Assignees

• Univ Tokyo

Inventors

• Ohwada Tomohiko
• Nakamura Sho
• Jung Sejin
• Otani Yuko
• Sayama Misa
• Aoki Junken

Classifications

• A61P43/00

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

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P29/00

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