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GPR120 agonist as well as preparation method and application thereof

An agonist and solvate technology, applied in the field of GPR120 agonists and their preparation, can solve the problems of strong toxicity, poor selectivity, lack of sulfonamide small molecule GPR120 agonists, etc., and achieves strong selectivity, mild conditions and good pharmacological activity Effect

Active Publication Date: 2021-06-01
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The GPR120 small-molecule agonists reported in the prior art are rarely used in clinical research, and some GPR120 small-molecule agonists have strong toxicity, poor selectivity, and lack of sulfonamide small-molecule GPR120 agonists.

Method used

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  • GPR120 agonist as well as preparation method and application thereof
  • GPR120 agonist as well as preparation method and application thereof
  • GPR120 agonist as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0071] Embodiment 1: Preparation of general formula (2) compound (B1-B8; D1-D7)

[0072]

[0073] Prepare the synthetic method of N-m-benzyl-[1,1'-biphenyl]-4-sulfonamide (B1):

[0074] Synthesis of 4-iodo-N-isophthalamide (Intermediate 2):

[0075] Add 2,4,6-trimethylaniline (134.09mg, 991.7μmol) and pyridine (156.89mg, 1.98mmol) into 10mL Sinopharm dichloromethane, then slowly add 4-iodobenzenesulfonate dissolved in dichloromethane dropwise Acyl chloride (200mg, 661.13μmol), the reaction solution was colorless and turned yellow again. After reacting at room temperature for 1-2h, wash twice with 1M hydrochloric acid, twice with saturated sodium bicarbonate, three times with water, and three times with saturated sodium chloride. After drying with anhydrous sodium sulfate for 3 hours, it was filtered, and column chromatography (petroleum ether: ethyl acetate = 5:1) gave 234 mg of a white solid with a yield of 84.8%, mp: 178-179°C. 1 H NMR (400MHz, DMSO-d6) δ9.34(s, 1H), 7....

Embodiment 2

[0127] Embodiment 2: preparation general formula (3) structure compound (C1-C3)

[0128]

[0129] The synthetic method of 4-((3,5-dimethylbenzyl)oxy)-N-m-toluenesulfonamide (C1):

[0130] Synthesis of 4-hydroxy-N-m-benzenemethanesulfonamide (Intermediate 4):

[0131] Add 2,4,6-trimethylaniline (210.59mg, 1.56mmol) and pyridine (246.41mg, 3.12mmol) into 10mL of Sinopharm dichloromethane, then slowly add 4-hydroxybenzenesulfonate dissolved in dichloromethane Acyl chloride (200mg, 1.04mmol), the reaction solution was colorless and turned yellow again. After reacting at room temperature for 1-2h, wash it twice with 1M hydrochloric acid, twice with saturated sodium bicarbonate, three times with water, and three times with saturated sodium chloride. After drying with anhydrous sodium sulfate for 3 hours, it was filtered, and column chromatography (petroleum ether: ethyl acetate = 5:1) gave 256 mg of white solid with a yield of 84.6%, mp: 208-209°C. 1 H NMR (400MHz, DMSO-d6) δ10...

Embodiment 3

[0138] Example 3: Preliminary Screening of Compound Activity

[0139] Using the BRET (Bioluminescence Resonance Energy Transfer) method established by our previously synthesized fluorescent probe N1 for screening, HEK293 cells (stable transfection GPR120-Rluc) that had been passaged three times were planted in a black 96-well plate, and after the cells adhered , suck out the medium in the plate with a sputum aspirator, add fluorescent probe N1 (400nM / well; 50μL / well) and incubate for 30min, then add different compounds (10μM / well) prepared with HBSS buffer, and set 6 for each compound Repeat the well, add the prepared coelenterazine (10μM / well) after incubation for 40min, measure the emitted light values ​​at 550nm and 460nm with a microplate reader after incubation for 10min, the ratio of the two is the BRET value, and treat with Grafpaph Prism 5 data.

[0140] Depend on figure 1 and figure 2 It can be seen that through activity screening experiments, compounds B5, B6, B7...

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Abstract

The invention relates to the technical field of sulfonamide compounds, and particularly provides a GPR120 agonist as well as a preparation method and application thereof. The GPR120 agonist is a compound represented by a formula (1) which is described in the specification, or a pharmaceutically acceptable salt, a stereoisomer, an isotope label, a solvate, a polycrystal or a prodrug thereof. In the formula (1), R is one selected from a group consisting of a 3,5-methoxy group, a 2-fluoro-6-trifluoromethoxy group, a 4-bromooxy group, a 4-trifluoromethoxy group, a naphthalene ring, hydrogen, 4-chlorine, 4-fluorine, 4-bromo-, a 4-methyl group, a 4-trifluoromethoxy group and 4-amino-3-fluorine; and R2 is one selected from a group consisting of a 2,4,6-trimethyl group, a 3,5-dichloro group, a 3,4-methoxyl group, a 3,4,5-methoxyl group, a 4-trifluoromethoxyl group, a 4-phenoxyl group, 4-fluorine and a 4-methoxyl group. The GPR120 agonist overcomes the problems that reported GPR120 small-molecule agonists in the prior art are rarely used for clinical research, a part of the GPR120 small-molecule agonists are high in toxicity and poor in selectivity, and sulfonamide small-molecule GPR120 agonists are lacked.

Description

technical field [0001] The disclosure relates to the technical field of sulfonamide compounds, and specifically provides a GPR120 agonist and its preparation method and application. Background technique [0002] The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art. [0003] G protein-coupled receptors (GPCRs) are the largest type of membrane protein family involved in cell surface signal transduction. They can stimulate signals outside the cell membrane to enter cells through receptors on the cell membrane and are therefore involved in the pathogenesis of many diseases. GPR120 [G protein-coupled receptor 120, also known as free fatty acid receptor 4 (FFA4)] is a GPCR, also known as omega-fat receptor 1. Similar to other GPCRs, it contains an extracellular N-terminal domain, an intracellular C-terminal domain and seven transmembrane domains. GPR120 is expressed differently in different sp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/21C07C311/29C07C303/40C07C303/38A61K31/18A61P3/10A61P1/16A61P9/10A61P29/00A61P5/50A61P3/04
CPCC07C311/21C07C311/29C07C303/40C07C303/38A61P3/10A61P1/16A61P9/10A61P29/00A61P5/50A61P3/04Y02P20/55
Inventor 杜吕佩李敏勇马思月
Owner SHANDONG UNIV