Salts of Halogen Substituted Heterocyclic Compounds

A technology of cyclopropane carboxylic acid and alkali metal, which is applied in the direction of drug combination, organic chemistry, digestive system, etc., and can solve problems such as undisclosed compounds

Active Publication Date: 2019-11-22
UBE IND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] On the other hand, Patent Documents 2 to 23, Non-Patent Documents 5, 7, 8 and 16 disclose ([1,1'-biphenyl]-4-yl)acetic acid derivatives as compounds having LPA receptor antagonistic action , In addition, Patent Document 17 discloses (2'-methoxy-[1,1'-biphenyl]-4-yl) acetic acid derivatives, and Patent Document 19 discloses 3-chloroisothiazole derivatives, but does not disclose Compounds of the invention

Method used

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  • Salts of Halogen Substituted Heterocyclic Compounds
  • Salts of Halogen Substituted Heterocyclic Compounds
  • Salts of Halogen Substituted Heterocyclic Compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0221] (R)-1-[4'-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2'-methoxy-[1,1 Sodium '-biphenyl]-4-yl]cyclopropanecarboxylate (compound number I-2)

[0222]

[0223] (R)-1-[4'-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2 synthesized in the same manner as in Reference Example 29 '-Methoxy-[1,1'-biphenyl]-4-yl]cyclopropanecarboxylic acid 1.10g (2.00mmol) in acetonitrile (80ml) suspension solution, while stirring under ice bath, add 1N After adding 2.00 ml (2.00 mmol) of an aqueous sodium hydroxide solution, ultrapure water (6 ml) was added, and ultrasonic treatment was performed to obtain a homogeneous solution, followed by stirring at room temperature for 3 hours. A small amount of ultrapure water was further added to the reaction mixture, freeze-dried, and then heated and dried under reduced pressure to obtain 1.08 g (1.89 mmol, yield 95%) of the target compound as a white solid.

[0224] Mass spectrometry (ESI + ,m / z): 570[M+1] + .

[0...

Embodiment 2

[0227] (R)-1-[4'-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2'-methoxy-[1,1 Potassium '-biphenyl]-4-yl]cyclopropanecarboxylate (compound number I-4)

[0228]

[0229] (R)-1-[4'-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2 synthesized in the same manner as in Reference Example 29 '-Methoxy-[1,1'-biphenyl]-4-yl]cyclopropanecarboxylic acid 275mg (0.501mmol) in acetonitrile (20ml)-ultrapure water (1.5ml) suspension solution, while stirring 0.500 ml (0.500 mmol) of 1N aqueous potassium hydroxide solution was added to make a uniform solution, and ultrapure water (6 ml) was added thereto, followed by ultrasonic treatment. After allowing the reaction mixture to stand at room temperature for 30 minutes, a small amount of ultrapure water was added, freeze-dried, and then heated and dried under reduced pressure to obtain 235 mg (0.401 mmol, yield 80%) of the target compound as a white solid.

[0230] Mass spectrometry (ESI + ,m / z): 586[M+1] + .

...

Embodiment 3

[0233] (R)-1-[4'-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2'-methoxy-[1,1 '-Biphenyl]-4-yl]cyclopropanecarboxylic acid 1 / 2 calcium (compound number I-6)

[0234]

[0235] (R)-1-[4'-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2'-methanol obtained in Example 1 After adding 0.180ml (0.090mmol) of 0.5M calcium acetate aqueous solution to 101mg (0.177mmol) of sodium oxy-[1,1'-biphenyl]-4-yl]cyclopropanecarboxylate in ultrapure water (25ml) , stirred at room temperature for 2 days. The obtained suspension solution was filtered with a membrane filter (manufactured by Millipore Corporation), washed with ultrapure water, and then heated and dried under reduced pressure to obtain 40.4 mg (0.071 mmol, yield 40%) of the target compound as a white solid. .

[0236] Mass spectrometry (ESI + ,m / z): 1133[2M+1] + .

[0237] 1 H-NMR spectrum (400MHz, DMSO-d 6 )δ: 9.42 (1H, brs), 7.41-7.25 (10H, m), 7.19-7.15 (2H, m), 7.07 (1H, dd, J = 7.9, 1.3Hz), 5...

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Abstract

To provide a salt of a novel α-position halogen-substituted thiophene compound which has potent LPA receptor antagonistic activity and is useful as a drug. A salt shown in general formula (I), wherein, R is a hydrogen atom or a methoxyl group; X is a halogen atom; A is a group selected from the group consisting of the following groups (AA); M is Alkali metal or alkaline earth metal; n represents 1 when M is an alkali metal, and 2 when M is an alkaline earth metal.

Description

technical field [0001] The present invention relates to novel salts of α-position halogen-substituted thiophene compounds useful as medicines. The salt of the α-position halogen-substituted thiophene compound of the present invention is useful for preventing and / or treating diseases caused by LPA because it has lysophosphatidic acid (LPA) receptor antagonistic activity. Background technique [0002] Lysophosphatidic acid (LPA) is a physiologically active phospholipid present in living organisms. LPA binds to specific G protein-conjugated receptors (LPA1, LPA2, LPA3, LPA4, LPA5, LPA6) to transmit signals in cells, thereby regulating cell proliferation, differentiation, survival, migration, adhesion, infiltration, and morphology form. It is also known that LPA intervenes in diseases accompanied by fibrosis in various organs. [0003] Regarding the liver, it has been reported that LPA promotes the proliferation and / or contraction of astrocytes, which play an important role i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D333/36A61K31/381A61P13/00A61P19/04A61P25/00A61P29/00A61P35/00A61P37/02A61P43/00
CPCA61K31/381C07D333/36A61P1/16A61P11/00A61P13/00A61P13/12A61P19/04A61P25/00A61P29/00A61P35/00A61P37/02A61P43/00
Inventor 岩瀬德明西田洋奥土诚伊藤雅章河野繁行的山正明牛山茂冈成荣治松永博文西川显治木村富美夫
Owner UBE IND LTD
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