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Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof

A technology of phenylglycine and deacetylase, applied in the preparation of sulfonamides, carbamic acid derivatives, urea derivatives, etc., can solve the problems of poor pharmacokinetic properties, poor drug efficacy, and difficult absorption

Inactive Publication Date: 2013-06-26
济南铂卅医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many compounds currently in clinical research are not very effective, although they have shown excellent activity in preclinical studies
Moreover, the marketed HDAC inhibitors (SAHA and FK228) have poor efficacy in the treatment of solid tumors, and they also have the disadvantages of short half-life, poor absorption and poor pharmacokinetic properties

Method used

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  • Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof
  • Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof
  • Phenylglycine histone deacetylase inhibitor as well as preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0130] Embodiment 1. Synthesis of compounds of the present invention

[0131] by( h2 )and( q1 ) as an example:

[0132] 1) (S)-2-((tert-butoxycarbonyl)-amino)-2-phenylacetic acid b

[0133] To a mixed solution of L-phenylglycine (15.1 g, 100 mmol) dissolved in 300 mL of methanol and water (methanol:water=9:1), triethylamine (15.1 g, 150 mmol) was added, and after 30 minutes of ice bathing, carbonic acid was added Di-tert-butyl ester (32.7 g, 150 mmol). After reacting at room temperature for 8 hours, the solvent in the reaction liquid was evaporated, acidified to pH 4-5 with 1 mol / L citric acid solution, then extracted three times with ethyl acetate, the organic phases were combined and washed with saturated brine, anhydrous sulfuric acid Dried over magnesium and evaporated to dryness to obtain a crude product, which was recrystallized from a mixed solvent of ethyl acetate and n-hexane (ethyl acetate:n-hexane=1:8) to obtain 17.2 g of a white solid. Yield: 91.56%, ESI-M...

Embodiment 2

[0162] Example 2 Target compound inhibits histone deacetylase activity test (In vitro)

[0163] The fluorescent analysis method of histone deacetylase (HDACs) activity is mainly divided into two steps: the first step, the fluorescent substrate of lysine HDACs (Boc-Lys(acetyl)-AMC) containing an acetylated side chain, is used Hela cell extract samples of protein deacetylases (including HDAC1, HDAC2, HDAC3 and HDAC8) were incubated to deacetylate and activate substrates. In the second step, trypsin is used to hydrolyze Boc-Lys-AMC to generate AMC, a fluorescent group (ie, a chromophore), and the fluorescence intensity is measured at the emission wavelength / excitation wavelength (390nm / 460nm), so that according to the inhibitor group and control Calculate the inhibition rate from the fluorescence intensity of the group, and calculate the IC 50 value. For the principle of enzyme activity test, please refer to the relevant content of this patent specification. The experimental...

Embodiment 3

[0169] Example 3 The activity test of the target compound in inhibiting cell proliferation (In vitro)

[0170] Select compounds with better enzymatic activity h8, q4, q6 The activity test of inhibiting the proliferation of cancer cells in vitro was carried out, and the results are shown in Table 2.

[0171] Terminology Explanation:

[0172] U937: Human histiocytic lymphoma cell line.

[0173] K562: human erythroleukemia cell line.

[0174] HL60: human acute leukemia cell line.

[0175] SAHA: The product name is Zolinza, and the generic name is Vorinostat. It is a histone deacetylase inhibitor approved by the US Food and Drug Administration (FDA) in 2006.

[0176] DMSO: dimethylsulfoxide.

[0177] IC 50 : half inhibitory concentration.

[0178] 1. [Materials] U937, K562, HL60 cell lines, MTT tetramethylazoblue, 10% fetal bovine serum, 96-well plate

[0179] 2. [Method]

[0180] cell culture U937, K562, and HL60 three tumor cell lines were cultured conventionally....

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a phenylglycine histone deacetylase inhibitor as well as a preparation method and applications thereof. The invention provides a superactive histone deacetylase inhibitor, which relates to a compound with a structure shown in the general formula (I), and also relates to various optical isomers thereof, a pharmaceutically acceptable salt, a solvate and a prodrug. The invention also relates to a pharmaceutical composition containing the compound with a structure shown in the formula (I), and pharmaceutical applications thereof. According to the invention, diseases with abnormal histone deacetylase activity expression can be effectively treated.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a phenylglycine histone deacetylase inhibitor and a preparation method and application thereof. Background technique [0002] Histone deacetylases (HDACs) are a class of hydrolases with complex functions. In the nucleus, nucleosomes, composed of histone octamers wrapped around DNA strands, are the structural units of chromosomes. Histone deacetylases (HDACs) can attach lysine residues in histones to amino groups The acetyl group of the acetyl group is hydrolyzed (such as reaction formula I), which leads to an increase in the positive charge density of histones, which in turn increases the affinity between histones and negatively charged DNA, and inhibits gene transcription, (see Christian, A. H., et al. Curr Biol., 1997, 1, 300; Kouzarides, T., Curr. Opin. Genet. Dev., 1999, 9, 40); Wolffe, A. P. Sci. Washington, 1996, 272, 371. In addition, deacetylatio...

Claims

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Application Information

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IPC IPC(8): C07C271/22C07C269/06C07C259/10C07C311/29C07C303/38C07C311/42C07C273/18C07C275/28C07C275/34C07C275/42C07D307/42A61K31/341A61K31/18A61K31/17A61K31/27A61K31/167A61P35/00A61P25/28A61P31/12A61P29/00A61P35/02A61P33/06A61P3/10
CPCY02A50/30
Inventor 徐文方张磊张英杰侯金宁
Owner 济南铂卅医药科技有限公司
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