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2-(substituted benzene matrix) aromatic formic acid FTO inhibitor, preparation method and application thereof

An unsubstituted, heterocyclic group technology, applied in the field of pharmaceutical compounds, can solve the problems of multiple deformities, growth retardation, etc.

Pending Publication Date: 2018-09-14
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0002] Fat mass and obesity associated protein (fat mass and obesity associated protein) FTO is the first to be found to have both m 6 A(N 6 -methyl adenosine, N 6 (methylated adenosine) RNA demethylase activity can regulate the metabolic process of the protein in vivo, Fto gene knockout will lead to severe growth retardation and multiple malformations

Method used

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  • 2-(substituted benzene matrix) aromatic formic acid FTO inhibitor, preparation method and application thereof
  • 2-(substituted benzene matrix) aromatic formic acid FTO inhibitor, preparation method and application thereof
  • 2-(substituted benzene matrix) aromatic formic acid FTO inhibitor, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0117] Preparation of 2-(substituted phenylhelicoyl)aromatic formic acids compound 15 and compound 25

[0118] The synthesis of compound 25 starts with o-iodobenzoic acid and 4-bromo-2,6-dichloroaniline, Ullman coupling occurs under the action of anhydrous copper acetate and N-methylmorpholine, undergoes esterification, Suzuki coupling reaction, compound 15 can be obtained by hydrolysis, and compound 25 can be obtained by hydroxamation on this basis, as shown in the figure below:

[0119]

[0120] The first step: 30g (120mmol, 1.2eq) of o-iodobenzoic acid, 24g (100mmol, 1.0eq) of 2,6-dichloro-4-bromoaniline, triethylamine (150mmol, 1.5eq) and anhydrous copper acetate 9g (5.0mmol, 0.5eq) was dissolved in 500mL of DMF, heated to 120°C for 24h under the protection of argon, and the reaction was completed. Cool down to room temperature, add an equal volume of water, extract the mother liquor with DCM 300mL×3, wash the DMF with water, spin the organic phase to dry, pass the col...

Embodiment 2

[0282] The following is the effect of 2-(substituted phenylheteroyl) aromatic formic acid and its derivatives FTO inhibitors shown in general formula (I) on solid tumor human small cell lung cancer cell line (SCLC-21H), human bone marrow rhabdomyocarcinoma cell line (RH30) and pancreatic cancer cell line (KP3) cytotoxicity studies:

[0283] Culture SCLC-21H, RH30, KP3 and other solid tumor cell lines respectively, plant cells in a 96-well plate at a density of 5,000 per well, culture the cells until they adhere to the wall, add different compounds and continue to culture for 72 hours, and directly add 10uL of MTS solution for incubation 4h, the absorbance value at 490nm was detected, and the inhibition rate was calculated with the DMSO group as the control.

[0284] The following is the cytotoxicity of the 2-(substituted phenylhelicoyl) aromatic formic acid compound FTO inhibitor represented by the general formula (I) at a concentration of 50 μM and a time point of 72 hours to...

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PUM

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Abstract

The invention provides a 2-(substituted benzene matrix) aromatic formic acid FTO inhibitor, a preparation method and application thereof. Specifically, the invention discloses a 2-(substituted benzenematrix) aromatic formic acid compound as shown in a general formula (I) and a pharmacologically acceptable salt, a hydrate or a solvate. The 2-(substituted benzene matrix) aromatic formic acid compound can be used as an inhibitor of an FTO target to treat diseases related to the FTO target, such as obesity, metabolic syndrome (MS), Type 2 diabetes (T2D), Alzheimer's disease, breast cancer, smallcell lung cancer, human bone marrow rhabdomyosarcoma, cancer of pancreas, and malignant glioma. The formula is shown in the description.

Description

technical field [0001] The present invention relates to the field of pharmaceutical compounds. Specifically, the present invention discloses 2-(substituted phenylheteroyl)aromatic formic acid compounds represented by the following general formula (I) and their pharmaceutically acceptable salts or pharmaceutically acceptable Solvates, as inhibitors targeting FTO, can treat diseases targeting FTO, such as obesity, metabolic syndrome (metabolic syndrome, MS), type II diabetes (Type 2 diabetes, T2D), Al Alzheimer's disease, breast cancer and other cancers. Background technique [0002] Fat mass and obesity associated protein (fat mass and obesity associated protein) FTO is the first to be found to have both m 6 A(N 6 -methyl adenosine,N 6 Methylated adenosine) RNA demethylase activity can also regulate the protein of metabolic process in vivo, and the knockout of Fto gene will lead to severe growth retardation and multiple deformities. In addition to being directly related t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/58C07C227/16C07D213/38C07D333/20C07D239/26C07D333/38C07D239/42C07D211/70C07D209/08C07D261/08C07D413/12C07D295/135C07D211/26C07D401/12C07D213/80C07D213/803C07D405/12C07D403/12C07D213/82C07C237/34C07C231/12A61K31/196A61K31/415A61K31/4409A61K31/381A61K31/505A61K31/4465A61K31/404A61K31/42A61K31/4164A61K31/41A61K31/422A61K31/5375A61K31/4439A61K31/444A61K31/443A61K31/44A61K31/497A61K31/5377A61K31/496A61P3/04A61P3/00A61P3/10A61P35/00A61P25/28
CPCA61K31/198A61K31/381A61K31/404A61K31/41A61K31/415A61K31/4164A61K31/42A61K31/422A61K31/4245A61K31/4409A61K31/4465A61K31/505C07C229/58C07C237/34C07D209/08C07D211/26C07D211/70C07D213/38C07D213/80C07D213/803C07D213/82C07D239/26C07D239/42C07D261/08C07D295/135C07D333/20C07D333/38C07D401/12C07D403/12C07D405/12C07D413/12A61P3/00A61P3/04A61P3/10A61P9/00A61P25/28A61P35/00A61P35/02C07D231/12C07D231/38C07D233/34A61K45/06A61K31/196A61K31/4418A61K31/4439A61K31/5355C07C227/16C07D209/14C07D233/64C07D257/04C07D333/40C07D407/12
Inventor 杨财广黄悦董泽张涛徐洪蛟
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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