A substituted acrylamide compound and its pharmaceutical composition

A compound and composition technology, applied in the field of medicine, can solve problems such as abnormalities in the blood system and prolongation of the QT interval

Active Publication Date: 2020-09-18
SHENZHEN TARGETRX INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Adverse reactions reported by non-specific HDACi in phase I and II clinical trials of tumors include nausea, vomiting, abnormalities in the blood system, and prolongation of the QT interval. Non-specific HDACi such as SAHA, LBH589, and ITF-2357 may cause a transient Thrombocytopenia or bone marrow suppression, and whether specific HDACi will cause corresponding adverse reactions in the study of tumors is still inconclusive, and there are no reports of adverse reactions as low-dose HDACi

Method used

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  • A substituted acrylamide compound and its pharmaceutical composition
  • A substituted acrylamide compound and its pharmaceutical composition
  • A substituted acrylamide compound and its pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 Preparation of N-hydroxyl-3-(3-d5-phenylsulfamoyl-phenyl)-acrylamide (compound 8), using The following route is synthesized:

[0051]

[0052] Step 1 Synthesis of compound 3.

[0053] Dissolve 3-chlorosulfonylbenzoic acid (compound 1, 300 mg) and d7-aniline (compound 2, 0.30 mL) in 10 mL of anhydrous dichloromethane, and stir overnight at room temperature under nitrogen protection. After filtration, the filter cake was washed three times with 10 mL of ice-cold dichloromethane, and the filter cake was collected and dried in vacuo overnight to obtain compound 3 (377 mg) as a white solid product. LC-MS: 281.1 [M-1] - .

[0054] Step 2 Synthesis of compound 4.

[0055] Under the protection of nitrogen, take compound 3 (379 mg) and dissolve it in 10 mL of anhydrous tetrahydrofuran, slowly add BH 3 ·THF (1M, 5.4mL), react overnight at room temperature after the dropwise addition. Add 2 mL of methanol dropwise under cooling in an ice-water bath, stir at ro...

Embodiment 2

[0062] Example 2 Preparation of N-hydroxyl-3-(3-(2,3,5-d3-phenyl)sulfamoyl-phenyl)-acrylamide (compound 15), adopt the following route to synthesize:

[0063]

[0064] Step 1 Synthesis of Compound 10.

[0065] Take aniline (1.023g) and add it to 9mL deuterium water to disperse evenly, add deuterated concentrated hydrochloric acid (1.1mL) to seal, and microwave the reaction at 180°C for 2 hours. Close the microwave reaction device, cool down to room temperature naturally, add solid sodium bicarbonate to adjust the pH to about 8-9, extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, filter and concentrate to obtain a light yellow oily liquid product compound 10 (876 mg). LC-MS: 96.15[M+1] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ7.46 (s, 1H).

[0066] Step 2 Synthesis of Compound 11.

[0067] 3-Chlorosulfonylbenzoic acid (compound 1, 300 mg) and compound 10 (0.30 mL) were dissolved in 10 mL of anhydrous dichloromethane...

Embodiment 3

[0076] Example 3 Preparation of N-hydroxyl-3-(3-phenylsulfamoyl-phenyl)-2-d-acrylamide (compound 21), using The following routes are synthesized:

[0077]

[0078] Step 1 Synthesis of compound 16.

[0079] Take trimethylphosphonoacetate (compound 6, 1.54g) and disperse it in 6mL of deuterium water, add 15mg of potassium carbonate to seal, and react in microwave for 30 minutes at 80 degrees Celsius, close the microwave reactor, cool down to room temperature naturally, ethyl acetate After extraction (10 mL×2), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give compound 16 (1.471 g) as a colorless oily liquid product. 1 H NMR (300MHz, CDCl 3 ) δ 3.82(s, 3H), 3.78(s, 3H), 3.74(s, 3H).

[0080] Step 2 Synthesis of Compound 17.

[0081] 3-Chlorosulfonylbenzoic acid (compound 1, 300 mg) and aniline (0.30 mL) were dissolved in 10 mL of anhydrous dichloromethane, and stirred overnight at room temperature u...

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Abstract

Disclosed are a substituted acrylamide compound and a pharmaceutical composition thereof, the substituted acrylamide compound being a compound of a formula (I), or a crystalline form, pharmaceutically acceptable salt, prodrug, stereoisomer, hydrate, or solvate thereof. The compound of the present invention can inhibit activity of a histone deacetylase (HDAC) and also has improved pharmacodynamic / pharmacokinetic properties; the compound has high applicability, is safe to use, and can be used for the preparation of a pharmaceutical composition for the treatment of HDAC-mediated diseases, thereby having great market potential.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a substituted acrylamide compound and a pharmaceutical composition thereof, which can be used for treating related diseases mediated by HDAC. Background technique [0002] Histone deacetylases (HDACs, HDACs) are a class of proteases that play an important role in the structural modification of chromosomes and the regulation of gene expression. In general, the acetylation of histones is conducive to the dissociation of DNA and histone octamers, and the relaxation of nucleosome structure, so that various transcription factors and co-transcription factors can specifically bind to DNA binding sites and activate genes transcription. In the nucleus, the process of histone acetylation and histone deacetylation is in a dynamic balance, and is jointly regulated by histone acetyltransferase (histone acetyltransferase, HAT) and histone deacetylase. HAT transfers the acetyl gr...

Claims

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Application Information

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IPC IPC(8): C07C311/21A61K31/18A61P35/00A61P17/06A61P19/08A61P11/00A61P9/10
CPCA61K31/18C07C311/21
Inventor 王义汉金剑
Owner SHENZHEN TARGETRX INC
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