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Pyrrolic amide compound and its preparation method and use

A technology for pyrrole amides and compounds is applied in the field of pyrrole amide compounds and their preparation, and can solve the problems of insignificant cancer curative effect, subtype selectivity of anti-cancer activity, toxic and side effects, and the like

Active Publication Date: 2016-07-27
HITGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] At present, SAHA developed by Merck is a histone deacetylase inhibitor already on the market. It is only limited to the treatment of skin T-cell lymphoma, and its effect on many other cancers is not obvious.
Other HDAC inhibitors developed also have certain problems in terms of anticancer activity, toxic side effects, subtype selectivity, etc.

Method used

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  • Pyrrolic amide compound and its preparation method and use
  • Pyrrolic amide compound and its preparation method and use
  • Pyrrolic amide compound and its preparation method and use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0159] Preparation of Example 11-((4-benzonitrile)sulfonyl)-N-hydroxyl-2,5-dihydro-1H-pyrrole-3-carboxamide

[0160] 1. Preparation of 2,5-dihydro-1H-pyrrole-3-carboxylic acid

[0161]

[0162] Dissolve ethyl N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylate (8.5g, 36mmol; manufacturer: Shaoyuan Technology (Shanghai) Co., Ltd.) in 60mL tetrahydrofuran and 30mL water Lithium hydroxide (4.2g, 176mmol) was then added to the mixed solution, and after stirring and reacting at 25°C for 2 hours, the organic solvent was removed in vacuo to obtain a residue; an appropriate amount of water was added to the residue for dilution, and the pH was adjusted to 5 with 1N hydrochloric acid , precipitated a solid, filtered to obtain a solid; the solid was washed with water and dried to obtain a white solid of N-tert-butoxycarbonyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid (7.0 g, 93% yield).

[0163] MS(ESI)m / z214(M+1) + .

[0164] Under ice bath, N-tert-butoxycarbonyl-2,5-dihydro-...

Embodiment 2

[0184] Example 2 Preparation of N-hydroxyl-1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide

[0185]

[0186] With 2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100mg, 0.5mmol) and benzenesulfonyl chloride (100mg, 0.6mmol; manufacturer: Bailingwei Technology Co., Ltd. ) as raw material, according to the similar steps in Example 1, white solid N-hydroxyl-1-(benzenesulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide (18mg, 14% yield ).

[0187] MS(ESI)m / z269(M+1) + .

[0188] 1 HNMR (400MHz, DMSO-d 6 )δ10.80(brs,1H),9.0(brs,1H),7.84-7.82(d,J=7.6Hz,2H),7.74-7.70(m,1H),7.66-7.62(m,2H),6.30 (s,1H), 4.17(s,4H).

Embodiment 3

[0189] Example 3 Preparation of N-hydroxyl-1-((4-phenoxyphenyl)sulfonyl)-2,5-dihydro-1H-pyrrole-3-carboxamide

[0190]

[0191] Take 2,5-dihydro-1H-pyrrole-3-(tetrahydropyran-2-oxo)-carboxamide (100mg, 0.5mmol) and 4-phenoxybenzenesulfonyl chloride (125mg, 0.6mmol; manufacturer: Bailingwei Technology Co., Ltd.) as raw material, according to the similar steps in Example 1, white solid N-hydroxyl-1-((4-(trifluoromethoxy)phenyl)sulfonyl)-2,5-dihydro - 1H-pyrrole-3-carboxamide (26 mg, 16% yield).

[0192] MS(ESI)m / z361(M+1) + .

[0193] 1 HNMR (400MHz, DMSO-d 6 )δ10.82(brs,1H),9.02(brs,1H),7.84-7.82(m,2H),7.50-7.46(m,2H),7.30-7.26(m,1H),7.18-7.12(m, 4H), 6.34(s, 1H), 4.16(s, 4H).

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Abstract

The invention discloses a pyrrolic amide compound shown in the formula I or its crystal form, pharmaceutically acceptable salts, hydrates or solvates. In the formula I, R1 represents hydrogen, hydroxyl, a cyano group, a halogen, carboxyl or C1-C6 alkyl, R2 represents hydrogen, hydroxyl, a cyano group or a halogen, R3 represents hydroxyl, X is a group selected from the structural formulas shown the description, m is 0, 1, 2 or 3 and n is 0, 1 or 2. The invention provides the novel compound shown in the formula I and the novel compound has good histone deacetylase inhibition activity.

Description

technical field [0001] The invention relates to a pyrrole amide compound and its preparation method and use, in particular to a pyrrole amide compound with histone deacetylase inhibitory activity, its preparation method and use. Background technique [0002] Inactivation of genes that control cell growth in the body is a hallmark of tumorigenesis. The epigenetic mechanisms that cause gene inactivation mainly include DNA methylation, histone acetylation, and modifications of other components in the higher-order structure of chromatin. These modifications change the chromatin configuration, resulting in changes in the regulation of gene transcription. Improper cell proliferation, leading to tumors. [0003] More than 40 years ago, Allfrey et al. realized that the acetylation process of histones was closely related to the regulation of eukaryotic gene transcription (AllfreyVG, FaulknerR, MirskyAE. Acetylation and methylation of histones and their possible role inheregulation o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/48C07D405/12C07D401/12A61K31/40A61K31/4025A61K31/4439A61P35/00A61P37/00A61P29/00A61P25/00A61P31/12
CPCA61P25/00A61P29/00A61P31/12A61P35/00A61P37/00A61P37/06A61P43/00A61K31/40C07D207/48C07D401/12C07D405/12
Inventor 李进李雪明窦登峰万金桥高剑穆云李才奎潘飞钟国庆胡晓刘绍军吕鹏
Owner HITGEN INC