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Histone deacetylase subtype inhibitor thioacetyl arylamine compound and application thereof

A technology of acetylase subtype and agent sulfur acetylarylamine, which is applied in the application field of treating tumors or neurodegenerative diseases, and can solve problems such as low bioavailability, genotoxicity, and poor pharmacokinetic properties

Active Publication Date: 2020-11-17
SHANGHAI ZHONGZE THERAPEUTICS CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005](1) Strong side effects, such as nausea, vomiting, bone marrow suppression, etc.;
[0006](2) genotoxicity;
[0007](3) Poor pharmacokinetic properties, low bioavailability, short half-life, etc.
[0022] The inventors previously discovered a class of compounds containing a sulfhydryl group in the zinc ion binding region (patent application number: 201811052776.2). This type of compound exhibited good inhibitory activity on HDAC6 enzymes, and showed good anti-proliferation activity on tumor cells in vitro, and on nerve cells. Metacells have a protective effect, but the Linker region of this compound is a flexible long carbon chain, and its enzyme subtype selectivity and brain permeability need to be further improved

Method used

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  • Histone deacetylase subtype inhibitor thioacetyl arylamine compound and application thereof
  • Histone deacetylase subtype inhibitor thioacetyl arylamine compound and application thereof
  • Histone deacetylase subtype inhibitor thioacetyl arylamine compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1: Preparation of 2-mercapto-N-(2-(methyl(phenyl)amino)pyrimidin-5-yl)acetamide (1)

[0112]

[0113] Prepared according to the general method of synthesis, the synthetic route is as follows:

[0114]

[0115] Reagents and conditions: (a) HBTU, DIPEA, THF, RT, overnight; (b) TFAA, CH2Cl2, RT, 3h; (c) K2CO3, DMF, 120℃, 6h; (d) H2, Pd / C, RT ,6h.

[0116] Synthesis of N-methyl-5-nitro-N-phenylpyrimidin-2-amine (1-2)

[0117] In a 250ml three-necked flask, add 2-chloro-5-nitropyrimidine (8g, 50.15mmol), potassium carbonate (2eq), N-methylanilinamine (1.1eq) successively, DMF is used as solvent, and under nitrogen protection, 140 ℃ reaction 6h. After cooling to room temperature, the mixture was quenched with ice-water, extracted twice with ethyl acetate, and the organic phase was dried and separated by column chromatography to obtain 8.4 g of a yellow solid with a yield of 72.76%. 1H NMR(600MHz,DMSO-d6)δ:3.58(s,3H),7.31–7.37(m,1H),7.37–7.43(m,2H), 7.47(t,J=...

Embodiment 2

[0124] Example 2 Preparation of 2-mercapto-N-(6-(methyl(phenyl)amino)pyridin-3-yl)acetamide (2)

[0125] 2 was prepared according to the general method.

[0126] 1 H NMR (600MHz, Chloroform-d) δ8.68 (d, J = 1.5Hz, 1H), 7.63 (dd, J = 7.4, 1.5Hz, 1H), 7.37–7.30 (m, 2H), 7.26–7.20 ( m,2H),7.12–7.03(m,2H),3.58(d,J=7.0Hz,2H), 3.45(s,2H),2.85(t,J=7.0Hz,1H), MS(ESI)m / z:274.1(M+).

Embodiment 3

[0127] Example 3 Preparation of 2-mercapto-N-(4-(methyl(phenyl)amino)phenyl)acetamide (3)

[0128] 3 was prepared according to the general method.

[0129] 1 H NMR (600MHz, Chloroform-d) δ: 9.88(s,1H), 7.76–7.70(m,2H), 7.28–7.20(m,2H), 7.12–7.04(m,3H), 6.72–6.66(m , 2H), 3.62 (d, J=6.9Hz, 2H), 3.37(s, 2H), 2.85(t, J=6.9Hz, 1H), MS (ESI) m / z: 273.1 (M+).

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Abstract

The invention discloses a histone deacetylase subtype inhibitor, namely a thioacetyl arylamine compound and application thereof. Pharmacological experiments show that the compound has a selective inhibition effect on HDAC6 enzyme, shows high anti-proliferative activity on various tumor cells, and is low in toxicity to normal cells and low in potential cardiotoxicity. Moreover, the compound has a protective effect on nerve cells, is ideal in pharmacokinetic characteristics, and has relatively high blood-brain barrier dredging characteristics. The compound disclosed by the invention has a deep development prospect as a high-efficiency low-toxicity anti-tumor or neurodegenerative disease therapeutic agent. The structural general formula of the histone deacetylase subtype inhibitor, namely thethioacetyl arylamine compound is as shown in the specification.

Description

technical field [0001] The invention relates to a class of histone deacetylase subtype inhibitors containing sulfur structures and their application in treating tumors or neurodegenerative diseases. Background technique [0002] Histone deacetylases (histone deacetylases, HDACs) can catalyze the deacetylation process of histone and non-histone proteins, and histone acetyltransferases (histone acetyltransferases, HATs) jointly regulate the level of acetylation in cells, thereby regulating gene expression. Express. Currently, there are 18 known subtypes of mammalian HDACs, which are divided into four classes: class I (HDAC1, HDAC2, HDAC3, HDAC8); class II is further divided into IIa (HDAC4, HDAC5, HDAC7, HDAC9) and IIb (HDAC6, HDAC10) two subfamilies; class III (Sirt1-Sirt7); class IV (HDAC11). [0003] Currently there are 5 histone deacetylase inhibitors (HDACi) on the market, namely vorinostat, belinostat, panobinostat, romidepsin ( romidepsin) and chidamide (chidamide), ...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D239/42C07D213/75C07D213/76C07D413/12C07D401/12C07D239/94C07C323/52A61P35/00A61P25/00
CPCC07D239/48C07D239/42C07D213/75C07D213/76C07D413/12C07D401/12C07D239/94C07C323/52A61P35/00A61P25/00
Inventor 李建其郭政张庆伟王冠浦强张子学
Owner SHANGHAI ZHONGZE THERAPEUTICS CO LTD
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