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E-configuration benzamide compound and medicinal preparation thereof

一种苯甲酰胺、化合物的技术，应用在化学制药领域，能够解决未获得、未公开、无法获得苯甲酰胺与聚乙烯吡咯烷酮固体分散体等问题，达到提高溶出速率、提高生物利用度的效果

Active Publication Date: 2017-07-04
SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the information disclosed in the application document CN103432077A, what its embodiment 3 is prepared according to the cited literature (US7,244,751B2) is N-(2-amino-4-fluorophenyl)-4-[N-(3-pyridine Acryloyl)aminomethyl]benzamide, N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl was not obtained base] benzamide (i.e. the E-type isomer), therefore, it is impossible to obtain N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine ) acryloyl] aminomethyl] benzamide and polyvinylpyrrolidone solid dispersion, meanwhile, application document CN103432077A also does not disclose N-(2-amino-4-fluorophenyl)-4-[N-[(E )-3-(3-pyridine)acryloyl]aminomethyl]benzamide and any physicochemical parameters of the solid dispersion formed by polyvinylpyrrolidone (such as solubility data, dissolution data or X-ray powder diffraction of solid dispersion picture)

Method used

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  • E-configuration benzamide compound and medicinal preparation thereof
  • E-configuration benzamide compound and medicinal preparation thereof
  • E-configuration benzamide compound and medicinal preparation thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0054] Example 1: Preparation of 4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl]benzoic acid

[0055]

[0056] Add 298g (2.00mol) trans-3-(3-pyridine)acrylic acid, 324g (2.00mol) N,N'-carbonyldiimidazole and 3000mL tetrahydrofuran into a 5-liter three-neck glass flask equipped with mechanical stirring and reflux condenser , react at about 45°C for about 3 hours to prepare (E)-3-(3-pyridine)acryloyl imidazole active intermediate solution.

[0057] Add 302g (2.00mol) p-aminomethylbenzoic acid, 80g (2.00mol) sodium hydroxide and 2000mL water in another 10 liter three-neck glass flask equipped with mechanical stirring, stir at room temperature for about 30 minutes, then dropwise add the above ( E) -3-(3-pyridine) acryloyl imidazole active intermediate solution, react at room temperature for about 8 hours. Concentrate the reaction mixture in vacuo to remove tetrahydrofuran, add 2000 mL of saturated sodium chloride solution, neutralize with concentrated hydrochloric acid until the...

Embodiment 2

[0062] Example 2: Preparation of N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl]benzamide

[0063]

[0064] Add 282g (1.00mol) 4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl]benzoic acid, 162g (1.00mol) N,N'-carbonyldiimidazole and 2820mL tetrahydrofuran were reacted at 45°C for about 3 hours to obtain 4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl] Benzoyl active intermediate solution.

[0065]Add 168g (1.33mol) of 4-fluoro-o-phenylenediamine and 800mL of tetrahydrofuran into another 5-liter three-neck glass flask equipped with mechanical stirring, protect with nitrogen, stir at room temperature for about 10 minutes, add the above 4-[N-[ (E)-3-(3-pyridine)acryloyl]aminomethyl]benzoyl active intermediate solution, react at room temperature for about 24 hours. Filter, rinse the filter cake with 400 mL of tetrahydrofuran, and dry in vacuo to obtain a crude product. Dissolve the crude product in 1200mL 2mol / L hydrochloric acid, add dropwise 960mL 1mol / L...

Embodiment 3

[0071] Example 3: Determination of the inhibitory activity of test compounds on different subtypes of HDAC

[0072] 1. Experimental plan

[0073] Utilizing the purified 11 subtypes (HDAC1-11) of class I, II, and IV HDAC, the sirtuin detection kit produced by BSP Bioscoence was used to measure the inhibitory activity of the test compound on different subtypes of HDAC, and calculated Its half inhibitory concentration of enzyme activity (IC 50 ).

[0074] 2. Experimental materials and reagents

[0075] (1) N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl]benzamide, according to the embodiment of the present invention 2 prepared by dissolving it in DMSO (100 mM).

[0076] (2) N-(2-amino-4-fluorophenyl)-4-[N-(3-pyridineacryloyl)aminomethyl]benzamide, prepared according to Example 2 of US7,244,751B2, dissolved in in DMSO (100 mM).

[0077] (3) Bovine serum albumin (1mg / mL)

[0078] (4) Purified HDAC1-11 subtype protein (0.4ng / μL, N-GST marker, BSP Biosc...

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Abstract

The invention discloses an E-configuration benzamide compound and a medicinal preparation thereof and an application thereof. The E-configuration benzamide compound has a structure shown as a formula (I), a chemical name is N-(2-amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridine)acryloyl]aminomethyl]benzamide, in the structural formula, the configuration of 3-pyridinyl acryl is E configuration. The E-configuration benzamide compound has subtype selective histone deacetylase inhibition activity, which mainly inhibits HDAC1, HDAC2, and HDAC 3 in an I type of HDAC as well as HDAC10 in a IIb type of HDAC. The E-configuration benzamide compound shown in the formula (I) can be used for treating the disease related to histone deacetylase activity abnormity, such as cancer comprising lymphoma, solid tumor and blood hematological malignancy.

Description

[0001] This application is a divisional application with an application date of April 4, 2014, an application number of 201410136761.X, and an invention titled "An E-configuration benzamide compound and its pharmaceutical preparation and application". technical field [0002] The invention belongs to the field of chemical pharmacy, and in particular relates to an E-configuration benzamide compound, a pharmaceutical preparation and application. Background technique [0003] Histone deacetylase (HDAC) is a class of enzymes that catalyze the removal of the acetyl group on lysine of histone, and plays a key role in chromatin condensation and chromatin remodeling and gene regulation. An important component of epigenetic regulation. HDAC includes four categories and 18 different subtypes (Class I: HDAC1, 2, 3, 8; Class II: HDAC4, 5, 6, 7, 9, 10; Class III: Sirt1-7; Class IV: HDAC11) . HDAC and histone acetyltransferase (HAT) jointly regulate the acetylation modification of histo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/56A61K31/4406A61K9/14A61K9/20A61P35/00A61P35/02
CPCA61K9/1635A61K9/1641C07D213/56A61K9/146A61K9/2054A61K9/2059A61K31/4406A61P35/00A61P35/02
Inventor 鲁先平李志斌徐学奎
Owner SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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