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Sulfhydryl compound serving as histone deacetylase inhibitor, and application thereof

A technology of mercapto compounds and compounds, which is applied in the direction of drug combination, organic chemistry, and medical preparations containing active ingredients, etc., can solve the problems of increased Hsp90 acetylation level, strong toxic side effects, poor pharmacokinetic properties, etc., and achieve high Blood-brain barrier permeability, good selective inhibitory activity, ideal effect of pharmacokinetic characteristics

Active Publication Date: 2020-03-17
SHANGHAI ZHONGZE THERAPEUTICS CO LTD
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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.
The mechanism of action of TA may be to increase the acetylation of tubulin by inhibiting HDAC6 activity, thereby making the secondary microtubule structure more stable. On the other hand, it may lead to the increase of Hsp90 acetylation level and increase the degradation of tau protein secondary structure.
[0012]The HDAC6 inhibitors currently reported in the literature are mainly composed of three parts, including the surface recognition region, the linker region and the zinc ion binding region, and most of the zinc ion binding regions contain isohydroxy Xamic acid structure, which has disadvantages such as genotoxicity and poor pharmacokinetic properties

Method used

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  • Sulfhydryl compound serving as histone deacetylase inhibitor, and application thereof
  • Sulfhydryl compound serving as histone deacetylase inhibitor, and application thereof
  • Sulfhydryl compound serving as histone deacetylase inhibitor, and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Example 1: Preparation of 2-(diphenylamino)-N-(5-(2-mercaptoacetamido)pentyl)pyrimidine-5-carboxamide (I-1) and its salts

[0096]

[0097] Prepared according to Synthetic General Method 1, the synthetic route is as follows:

[0098]

[0099] Synthesis of Intermediate 2:

[0100]

[0101] Add aniline (7.58g, 81mmol), ethyl 2-chloropyrimidine-5-carboxylate (13.80g, 74mmol), potassium carbonate (20.44g, 148mmol), and DMF100ml in sequence in a 250ml three-necked flask, and store at 120°C under nitrogen protection Reaction 6h. After cooling to room temperature, the reaction solution was slowly poured into 200ml of ice-water mixture, stirred at room temperature for 30 minutes, filtered to obtain a light yellow solid, and vacuum-dried at 50°C for 12 hours to obtain 17.25g of the product with a yield of 95.88%.

[0102] Synthesis of Intermediate 3:

[0103]

[0104] Add compound 2 (17.00g, 70mmol), iodobenzene (17.11g, 84mmol), cesium carbonate (45.54g, 140mmol)...

Embodiment 2

[0127] Embodiment 2: 2-(diphenylamino)-N-(6-mercaptohexyl) pyrimidine-5-carboxamide (I-2) and its salt preparation

[0128]

[0129] Prepared according to Synthetic General Method 2, the specific synthetic route is as follows:

[0130]

[0131] Synthesis of Intermediate 5

[0132]

[0133] Add compound 4 (1.50g, 5mmol), 6-bromo-1-aminohexane hydrobromide (2.69g, 10mmol), EDC (1.97g, 10mmol), diisopropylethyl Amine (2.02g, 16mmol), THF 30ml. Stir at room temperature for 12 h, add 50 ml of water, extract 3 times with 50 ml of ethyl acetate, combine the organic layers, wash with 100 ml of saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure to dryness to obtain a pale yellow oil, column chromatography (petroleum ether : Ethyl acetate = 2: 1) Purification gave 1.65 g of light yellow oily substance, yield 71.12%.

[0134] Synthesis of Intermediate 6

[0135]

[0136] Compound 5 (1.50 g, 3 mmol), potassium thioacetate (1.51 g, 13 mmo...

Embodiment 3

[0142] Example 3 Preparation of 4-(diphenylamino)-N-(5-(2-mercaptoacetamido)pentyl)benzamide (I-3) and its salts

[0143] Preparation I-3 was carried out according to General Method 1.

[0144] 1 H NMR (400MHz, DMSO-d6) δppm: 1.32 (2H, q, J = 8.1Hz), 1.66 (4H, dp, J = 20.0, 7.8Hz), 1.97 (1H, s), 3.32 (4H, dt, J=15.2,7.7Hz), 3.45(2H,s),6.06(1H,s),6.29(1H,s),6.96 (2H,tt,J=7.4,2.0Hz),7.04–7.11(4H,m ),7.20–7.28(4H,m),7.32–7.37(2H,m),7.63–7.69(2H,m); ESI-MS(+)m / z=448.3[M+H] +

[0145] The preparation of compound 1-3 malate:

[0146] Compound I-1 (0.1 mmol) and malic acid (0.8 mmol) were added to ethanol (10 mL), dissolved under reflux, and a white solid was precipitated by cooling, and filtered to obtain 0.12 g of white I-3 malate solid.

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PUM

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Abstract

The invention discloses a sulfhydryl compound serving as a histone deacetylase inhibitor, and an application thereof. Pharmacological experiment results show that the composition has high anti-proliferative activity on various tumor cells, shows a protective effect on glutamic acid-induced neuronal cell damage on a cell model, has low toxicity to normal cells, low potential cardiotoxicity, ideal pharmacokinetic characteristics and high blood-brain barrier permeability, and has a development prospect as a high-efficiency low-toxicity antitumor or neurodegenerative disease treatment agent. The sulfhydryl compound is a compound with a structural general formula represented by formula (I) shown in the description, or a pharmaceutically acceptable salt, an ester or a prodrug thereof.

Description

technical field [0001] The invention relates to a class of histone deacetylase inhibitors containing a thiol structure 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), the firs...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/42C07C323/42C07D413/04C07D213/81C07D239/69C07D401/04A61K31/505A61K31/506A61K31/166A61K31/4402A61P35/00A61P5/00A61P37/00A61P25/00
CPCC07D239/42C07C323/42C07D413/04C07D213/81C07D239/69C07D401/04A61P35/00A61P5/00A61P37/00A61P25/00Y02P20/55
Inventor 李建其张庆伟郭政浦强曾景钱浩
Owner SHANGHAI ZHONGZE THERAPEUTICS CO LTD
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