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Compound with PPAR delta agonistic activity, pharmaceutical composition and medical application

A compound and drug technology, applied in the field of compounds with PPARδ agonistic activity, can solve problems such as increasing the risk of fractures

Active Publication Date: 2021-03-12
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, TZDs can cause adverse events such as fluid retention, weight gain, and edema, and especially increase the risk of congestive heart failure and osteoporotic fractures

Method used

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  • Compound with PPAR delta agonistic activity, pharmaceutical composition and medical application
  • Compound with PPAR delta agonistic activity, pharmaceutical composition and medical application
  • Compound with PPAR delta agonistic activity, pharmaceutical composition and medical application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Ethyl 2-(4-((2-(((N-cyclopropyl-4-(trifluoromethyl)benzamido)methyl)benzyl)oxy)phenyl)acetate (compound 1)

[0063]

[0064] Synthesis of compound I-1

[0065] Under argon protection, 2-cyanobenzyl bromide (300mg, 1.5mmol) was dissolved in anhydrous dichloromethane (5mL), cooled in an ice-water bath, and a 1.5M n-hexane solution of diisobutylaluminum hydride (1.1 mL, 1.6mmol), stirred at 0°C for 4 hours. The reaction solution was poured into cold 48% hydrobromic acid aqueous solution (20 mL), and stirred at room temperature for 1.5 hours. The reaction was monitored by TLC. After the reaction was complete, dichloromethane (20mLx3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (eluent: petroleum ether / ethyl acetate Ester: 30:1) purification to obtain compound I-1 (yellow green liquid, 217mg, yield: 71%).

[0066...

Embodiment 2

[0073] 2-(4-((2-((N-cyclopropyl-4-(trifluoromethyl)benzamido)methyl)benzyl)oxy)phenyl)acetic acid (compound 2)

[0074]

[0075] Compound 1 (78mg, 0.1mmol) was dissolved in ethanol:tetrahydrofuran (1:1) mixed solvent (2mL), 1N lithium hydroxide aqueous solution (0.3mL) was added, and the reaction was stirred at room temperature. The reaction was monitored by TLC. After the reaction was complete, the solvent was evaporated under reduced pressure, water (10mL) and 1N hydrochloric acid were added successively to adjust the pH to 3, a large amount of white solid was precipitated, filtered with suction, the filter cake was washed with water (10mLx3), and dried in vacuo to obtain the compound 2 (white solid, 50mg, yield: 68%): 1 H NMR (300MHz, DMSO-d 6 )δ12.53-11.87(m,1H),7.84-7.67(m,4H),7.56-7.46(m,1H),7.43-7.36(m,2H),7.37-7.28(m,1H),7.23- 7.17(m,1H),7.18-7.12(m,1H),7.03-6.96(m,1H),6.96-6.90(m,1H),5.17(s,2H),4.80(s,2H),3.49( s,2H),2.87-2.67(m,1H),0.59-0.32(m,4H).MS(ESI):m / z[M+N...

Embodiment 3

[0077] Ethyl 2-(4-((2-(((N-cyclopropyl-4-methoxybenzamido)methyl)benzyl)oxy)phenyl)acetate (Compound 3)

[0078] With reference to the method of Example 1, 4-trifluoromethylbenzoic acid was replaced by 4-methoxybenzoic acid to obtain compound 3: 1 H NMR (300MHz, DMSO-d 6 )δ7.59-7.53(m,1H),7.53-7.49(m,1H),7.50-7.45(m,1H),7.43-7.35(m,2H),7.35-7.27(m,1H),7.24- 7.18(m,1H),7.18-7.14(m,1H),7.02-6.95(m,2H),6.95-6.91(m,2H),5.15(s,2H),4.76(s,2H),4.06( q,J=7.1Hz,2H),3.79(s,3H),3.57(s,2H),2.85–2.74(m,1H),1.17(t,J=7.1Hz,3H),0.57-0.48(m ,2H),0.48-0.41(m,2H).MS(ESI):m / z[M+Na] + 496.2.

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Abstract

The invention discloses a compound with PPAR delta agonistic activity, a pharmaceutical composition and medical application, wherein the structure of the compound is shown as a formula I in the specification. The compound shown in the formula I is a novel PPAR delta agonist, so that the compound can be used for preparing medicines for preventing or treating PPAR delta mediated diseases.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to a compound having PPARδ agonistic activity, a pharmaceutical composition and a medical application. Background technique [0002] Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated receptor in the nuclear hormone receptor family. Three mammalian peroxisome proliferator-activated receptors have been isolated, namely PPARα, PPARδ (also known as PPARβ) and PPARγ. After PPAR is activated by ligand binding, it forms a heterodimer with the retinoid X receptor (RXR), and the formed PPAR / RXR heterodimer binds to the PPAR response element (PPRE) upstream of the target gene promoter, and finally Regulates transcription of target genes. [0003] PPARα is expressed in many metabolically active tissues, including liver, kidney, heart, skeletal muscle, and brown fat, and its expression in fat and cartilage is relatively low. PPARδ is widely expressed in vivo, and t...

Claims

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Application Information

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IPC IPC(8): C07C233/74C07C231/12C07C253/30C07C255/57C07C235/48C07C235/84C07D319/18C07D317/68C07D333/24C07D307/54A61K31/216A61K31/192A61K31/277A61K31/357A61K31/341A61K31/381A61P3/10A61P9/12A61P5/48A61P3/04A61P1/16A61P17/00A61P11/06A61P7/06A61P35/00
CPCC07C233/74C07C255/57C07C235/48C07C235/84C07D319/18C07D317/68C07D333/24C07D307/54A61P3/10A61P9/12A61P5/48A61P3/04A61P1/16A61P17/00A61P11/06A61P7/06A61P35/00C07C2601/04C07C2601/02
Inventor 侯东亮亓雪戴量温小安
Owner CHINA PHARM UNIV
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