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Novel EP4 agonist

A technology of agonists and pharmaceuticals, applied in the direction of anti-inflammatory agents, non-central analgesics, digestive system, etc., can solve the problems of weak binding affinity and only strong binding affinity

Active Publication Date: 2013-02-06
ASAHI GLASS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, a selective EP4 agonist has not been reported, which is 7,7-difluoroPGI 2 One of the classes, showing weak binding affinities for IP, EP1, EP2 and EP3, and binding only strongly and selectively to EP4

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0238] Synthesis of (2R)-2-(m-tolyl)propionic acid methyl ester

[0239] To (2R)-2-(m-tolyl)propionic acid (12.45 g) were added methanol (14.83 g) and concentrated sulfuric acid (6.46 g), and the mixture was stirred under reflux for 6 hours. Next, the mixture was neutralized with a 10% aqueous sodium carbonate solution, and extracted with hexane. After drying over magnesium sulfate, the residue was concentrated under reduced pressure to obtain the title compound (12.79 g). Its structural properties are described below.

[0240] 1 H-NMR (CDCl 3 ):δ 1.49(d, J=7.0 Hz, 3H), 2.33(s, 3H), 3.64(s, 3H), 3.69(dd, J=14.4, 7.3 Hz, 1H), 7.06-7.22(m, 4H ).

Embodiment 2

[0242] Synthesis of (3R)-2-oxo-3-(m-tolyl)butyl phosphonic acid dimethyl ester

[0243] To dimethyl methylphosphonate (1.97 g) was added tetrahydrofuran (THF) (25 ml), and the mixture was cooled to 78°C. n-Butyllithium (1.5M in hexane) (10 ml) was added, and the mixture was stirred for 1 hour. Then, a THF (3.8 ml) solution of the methyl ester {(2R)-2-(m-tolyl)propionic acid methyl ester} (1.34 g) synthesized in Example 1 was added at -78° C., and the mixture was stirred for 2 Hour. The reaction was quenched with 25 mL of saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate=5:1 to 1:5) to obtain the title compound (1.63 g). Its structural properties are described below.

[0244] 1 H-NMR (CDCl 3 ):δ 1.39(d, J=6.7 Hz, 3H), 2.34(s, 3H), 2.84(ddd, J=22.3, 14.1, 0.6 Hz, 1H),...

Embodiment 3

[0246] (1S,5R,6R,7R)-6-[(1E,4R)-3-oxo-4-(m-tolyl)-1-pentenyl]-7-benzoyloxy-2-oxo Synthesis of Heterobicyclo[3.3.0]octan-3-one

[0247] Sodium hydride (55%) (8.75 g) was dispersed in 1,2-dimethoxyethane (DME) (300 ml), and the mixture was ice-cooled. A DME (50 ml) solution of phosphonate {(3R)-2-oxo-3-(m-tolyl)butyl phosphonic acid dimethyl ester} (54.7 g) synthesized in Example 2 was added, and the mixture was stirred for 1 Hour. To the above solution was added (1S,5R,6R,7R)-6-formyl-7-benzoyloxy-2-oxabicyclo[3.3.0]octan-3-one (50.0 g) in DME (400ml) solution and the mixture was stirred for 1 hour. The reaction was quenched with 350 ml of 10% brine, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the residue was concentrated under reduced pressure. The concentrated crude product was recrystallized from tert-butyl methyl ether to obtain the title compound (64.7 g). Its structural properties are described below.

[0248]...

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Abstract

Disclosed are: a compound which has excellent metabolic stability and selectively binds to EP4 receptor; and a pharmaceutical product which contains the compound. Specifically disclosed is a compound represented by formula (1) (wherein R and R each independently represents a hydrogen atom or a linear alkyl group having 1-3 carbon atoms, and R represents a hydrogen atom, an alkyl group having 1-4 carbon atoms, an alkoxyalkyl group, an aryl group, a halogen atom or a halogenated alkyl group) or a pharmaceutically acceptable salt thereof, which is different from publicly known PGIs and has a selective EP4 agonist action. Consequently, a pharmaceutical product which contains the compound is useful for prophylaxis and / or treatment of immune diseases, cardiovascular diseases, heart diseases, respiratory diseases, eye diseases, kidney diseases, hepatic diseases, bone diseases, digestive tract diseases, neurological diseases, skin diseases and the like.

Description

technical field [0001] The present invention relates to 7,7-difluoroprostaglandin I 2 Derivatives, or pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and pharmaceutical uses thereof, wherein the carboxyl group at C-1 position of prostaglandin (hereinafter referred to as PG) is substituted by tetrazolyl, and two fluorine atoms Bonded to C-7 position of PG. More specifically, the present invention relates to 7,7-difluoroprostaglandin I 2 Derivatives, which are useful EP4 agonists for the prevention or treatment of immune diseases, cardiovascular diseases, heart diseases, respiratory diseases, eye diseases, kidney diseases, liver diseases, bone diseases, digestive tract diseases, neurological diseases, skin diseases and the like. technical background [0002] Natural PGs each bind to their specific receptors and exhibit characteristic effects. PGI 2 , PGE 2 、PGD 2 、PGF 2 alpha and thromboxane A 2 (TXA 2 ) are referred to as IP, EP, DP, ...

Claims

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Application Information

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IPC IPC(8): A61K31/41A61P1/02A61P1/04A61P1/16A61P7/00A61P9/00A61P9/10A61P11/00A61P11/06A61P13/12A61P15/00A61P17/02A61P17/06A61P17/14A61P19/00A61P19/02A61P19/10A61P21/02A61P25/00A61P27/02A61P27/06A61P27/16A61P29/00A61P37/02A61P37/04A61P43/00C07D405/06
CPCC07F9/4006C07D405/06C07F9/6524A61P1/00A61P1/02A61P1/04A61P1/16A61P11/00A61P11/06A61P13/12A61P15/00A61P17/00A61P17/02A61P17/06A61P17/14A61P19/00A61P19/02A61P19/10A61P21/02A61P25/00A61P27/02A61P27/06A61P27/16A61P29/00A61P37/00A61P37/02A61P37/04A61P43/00A61P7/00A61P9/00A61P9/10A61K31/41
Inventor 村田隆彦天川昌洋寺平晋松村靖小西克彦
Owner ASAHI GLASS CO LTD
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