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Carboxylic acid derivative as lysophosphatidic acid receptor antagonist

A technology for compounds and stereoisomers, applied in the field of carboxylic acid derivatives as lysophosphatidic acid receptor antagonists, can solve the problems of short half-life and troublesome compounds

Inactive Publication Date: 2015-03-18
KBP BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Amira's compound AM-095 (structure as follows) as a selective LPA 1 Receptor antagonists are in the preclinical stage and are active in animal models of pulmonary fibrosis, but the short half-life of the compound presents problems for clinical dosing

Method used

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  • Carboxylic acid derivative as lysophosphatidic acid receptor antagonist
  • Carboxylic acid derivative as lysophosphatidic acid receptor antagonist
  • Carboxylic acid derivative as lysophosphatidic acid receptor antagonist

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0176] Example 1 2-(4'-(3-methyl-4-(((R)-(1-phenylethoxy)carbonylamino)isoxazol-5-yl)biphenyl)-4-yl ) Preparation of spiro[3.3]heptane-2-carboxylic acid (compound 1)

[0177]

[0178] (1) Preparation of cyclobutyl-1,1-dimethanol

[0179]

[0180] In a 500mL reaction flask, cyclobutyl-1,1-dicarboxylic acid (14.4g, 0.1mol) was dissolved in 300mL THF, and LiALH4 (15.2g, 0.4mol) was added in batches under an ice-water bath. After reacting for 2 hours, quenched with ethyl acetate, added 4N hydrochloric acid to dissolve in clarification, separated liquids, dried and concentrated to obtain 11 g of crude product. The yield was 95%, and the product was directly used in the next reaction.

[0181] (2) Preparation of 1,1-bis(methylsulfonylmethylene)cyclobutane

[0182]

[0183] In a 500mL reaction flask, dissolve cyclobutyl-1,1-dimethanol (11g, 95mmol) in 300mL DCM, add methanesulfonyl chloride (22.9g, 0.2mol) dropwise under an ice-water bath, and react at room temperature ...

Embodiment 2

[0201] Example 2 2-(4'-4-((1-(4-fluorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl)-4-yl ) Preparation of spiro[3.3]heptane-2-carboxylic acid (compound 2)

[0202]

[0203] (1) 3-methyl-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoxazole-4 -ylcarbamate-(1-(4-fluorophenyl)ethyl ester)

[0204]

[0205] The operation is the same as in Example 1 (5), and the product is directly used in the next reaction without purification.

[0206] (2) 2-(4'-4-((1-(4-fluorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl)-4-yl ) ethyl spiro[3.3]heptane-2-carboxylate

[0207]

[0208] Operation is the same as in Example 1 (6), and the productive rate is 54%.

[0209] (3) 2-(4'-4-((1-(4-fluorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl)-4-yl ) spiro[3.3]heptane-2-carboxylic acid

[0210]

[0211] Operation is the same as Example 1(7), and the productive rate is 2.5%.

[0212] Mass Spectrum (m / e): 555.2 (M+1)

[0213] ...

Embodiment 3

[0214] Example 3 2-(4'-4-((1-(2-fluorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl)-4-yl ) Preparation of spiro[3.3]heptane-2-carboxylic acid (compound 3)

[0215]

[0216] (1) 2-(4'-4-((1-(2-fluorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl)-4-yl ) ethyl spiro[3.3]heptane-2-carboxylate

[0217]

[0218] Operation is the same as in Example 1 (6), and the productive rate is 62%.

[0219] (2) 2-(4'-4-((1-(2-fluorophenyl)ethoxy)carbonylamino)-3-methylisoxazol-5-yl)biphenyl)-4-yl ) spiro[3.3]heptane-2-carboxylic acid

[0220]

[0221] Operation is the same as in Example 1 (7), and the productive rate is 25%.

[0222] Mass Spectrum (m / e): 555.2 (M+1)

[0223] 1 H-NMR (400MHz, CDCl 3 ,δppm)δ:1.40-1.50(m,3H),1.78-1.93(m,4H),2.10-2.20(m,2H),2.20-2.30(m,3H),2.50-2.60(d,2H), 2.95-3.05(d,2H),6.00-6.20(m,1H),6.90-7.20(m,3H),7.30(m,1H),7.40-7.50(m,2H),7.52-7.64(m,4H ),7.75-7.83(s,2H).

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Abstract

The invention belongs to the technical field of medicine, and particularly relates to a carboxylic acid derivative as a lysophosphatidic acid receptor antagonist as shown in a general formula (I) and a pharmaceutically acceptable salt thereof or an stereomer thereof, wherein A, B, C, D, E, R1, R3, R4, R5, RA, RB, RC, m and p are as defined in the specification. The invention also relates to preparation methods of the compounds, a drug composition or a drug preparation which contains the compounds and an important application of the compounds in preparing a drug for treating and / or preventing LPA-dependence or LPA-mediation diseases.

Description

1. Technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to carboxylic acid derivatives as lysophosphatidic acid receptor antagonists, pharmaceutically acceptable salts or stereoisomers thereof, preparation methods of these compounds, and pharmaceutical compositions containing these compounds Or pharmaceutical preparations, and these compounds play an important role in the treatment and / or prevention of LPA-dependent or LPA-mediated diseases. 2. Background technology [0002] Lysophosphatidic acid (LPA) is a water-soluble glycerophospholipid with a simple structure, which is a membrane-derived bioactive lipid medium. In the past, LPA was considered to be the precursor of lipid synthesis. Later, it was gradually found that LPA has a wide range of biological effects, such as inducing nerve axon retraction, stress fiber formation, promoting cell proliferation / apoptosis, platelet aggregation, and tumor cell infiltration. Its ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D261/14C07D413/10C07D413/04C07D413/14A61K31/42A61K31/4439A61K31/444A61P11/00A61P11/06A61P13/12A61P17/00A61P1/00A61P1/16A61P35/00A61P35/02A61P37/06A61P29/00A61P27/02A61P3/10A61P9/10
CPCC07D261/14C07D413/04C07D413/10C07D413/14
Inventor 张敏王爱臣
Owner KBP BIOSCIENCES CO LTD
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