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Isocitrate dehydrogenase (IDH) inhibitors

An unsaturated, free technology that can be used in the field of pharmaceuticals for diseases to solve problems such as damage to catalysis

Pending Publication Date: 2022-05-27
ZHEJIANG METON PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] These aforementioned mutations lead to changes in amino acid residues (R132 on IDH1, R140 or R172 on IDH2) that are critical for enzymatic activity and thus impair the catalysis from isocitrate to α-KG by the IDH enzyme

Method used

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  • Isocitrate dehydrogenase (IDH) inhibitors
  • Isocitrate dehydrogenase (IDH) inhibitors
  • Isocitrate dehydrogenase (IDH) inhibitors

Examples

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preparation example Construction

[0201] The preparation of compounds of the present disclosure can involve the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups can be readily determined by those skilled in the art. The chemistry of protecting groups can be found in, for example, T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley & Sons , Inc.), New York (1999), which is incorporated herein by reference in its entirety.

[0202] The reaction can be monitored according to any suitable method known in the art. For example, by spectroscopic means, such as nuclear magnetic resonance spectroscopy (eg 1 H or 13 C), infrared spectroscopy, spectrophotometry (eg UV-visible light), mass spectrometry, or monitoring of the product by chromatography, eg high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LCMS) or thin layer chromatography (TLC) form....

example

[0244] The general methods of the present disclosure are further elucidated below. The compounds of the present disclosure can be prepared by methods known in the art. The detailed preparation methods of the preferred compounds of the present disclosure are described below. However, these in no way limit the preparation methods of the compounds of the present disclosure.

Synthetic example

[0246] The structures of the compounds in the following examples were characterized by nuclear magnetic resonance (NMR) or / and mass spectrometry (ESI). NMR shifts (δ) are in 10 -6 (ppm) is given in units. 1 H-NMR spectra were recorded in dimethyl sulfoxide-d on a VarianMercury VX 400 spectrometer with tetramethylsilane (TMS) as internal standard 6 (DMSO-d 6 ) or CDCl 3 middle.

[0247] ESI-HRMS measurements were performed using an Agilent 1260-6230TOF LC-MS mass spectrometer.

[0248] High performance liquid chromatography (HPLC) measurements were performed on an Agilent 1200LC using a Phenomen C18 column (4.6 mm x 150 mm, 0.4 μm).

[0249] Thin-layer chromatography was performed using Yantai Huanghai HSGF254 silica gel plates. Silica gel plates for thin layer chromatography (TLC) are 0.15mm to 0.2mm. The silica plates used for separation and purification of the product by TLC were 0.4 mm to 0.5 mm.

[0250] The purified chromatography column used silica gel as a carri...

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Abstract

Disclosed are compounds that inhibit the conversion of alpha-KG to D-2-HG, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof, and pharmaceutical compositions comprising the compounds. The compound and the pharmaceutical composition can effectively treat IDH related diseases, including cancers.

Description

[0001] Field of Invention [0002] The present disclosure relates to compounds that inhibit the conversion of α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) such as D-2-HG, pharmaceutical compositions comprising the compounds as active ingredients, and Use of the compound in the manufacture of a medicament for the treatment of a disease associated with the conversion of alpha-KG to D-2-HG. Background technique [0003] Isocitrate dehydrogenase (IDH) is an essential enzyme for cellular respiration in the tricarboxylic acid (TCA) cycle, which catalyzes the oxidative decarboxylation of isocitrate to produce α-ketoglutarate (α-ketoglutarate, α- KG) and CO 2 . In humans, IDH exists in three isoforms: IDH3 catalyzes the third step of the citric acid cycle, while in mitochondria + Converted to NADH. The isoforms IDH1 and IDH2 catalyze the same reaction except in the context of the citric acid cycle and use NADP+ rather than NAD+ as a cofactor. They localize to the cytosol a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/437A61P35/00
CPCA61P35/00C07D471/04C07D519/00
Inventor 杨继斌严峰朱金龙杨健昕
Owner ZHEJIANG METON PHARM CO LTD
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