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HDAC inhibitor as well as preparation method and application thereof

A CH2, solvate technology, applied in the field of HDAC inhibitors and its preparation and application, can solve the problem of subtype selectivity of anticancer activity toxicity and side effects

Active Publication Date: 2019-05-03
HITGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These five HDAC inhibitors have certain problems in terms of anticancer activity, side effects, and subtype selectivity, and none of the targets of these five HDAC inhibitors has HDAC6

Method used

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  • HDAC inhibitor as well as preparation method and application thereof
  • HDAC inhibitor as well as preparation method and application thereof
  • HDAC inhibitor as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0123] The synthesis of compound among the present invention in embodiment 1

[0124] General Synthetic Route 1

[0125]

[0126] (1.1) Synthesis of intermediate 3a:

[0127]

[0128] 4-Bromo-2-fluorobenzaldehyde (100g, 493mmol) and 2-methyl glycolate (102g, 1.13mol) were dissolved in DMF (1.0L), and sodium hydrogen (59.2g, 1.48mol) was added at 0°C , 60%), stirred for 1 hour, added ice water (2.0 L), extracted 4 times with ethyl acetate (1.0 L), combined the organic layers and washed 1 time with saturated sodium chloride solution. The solvent was evaporated under reduced pressure, and intermediate 3a (22.0 g, 86.3 mmol, yield 18%) was obtained after purification by column chromatography.

[0129] (1.2) Synthesis of intermediate 3b:

[0130] Using 5-bromo-2-fluorobenzaldehyde and methyl 2-hydroxyacetate as raw materials, according to the synthesis method of intermediate 3a, intermediate 3b was obtained (yield 42%).

[0131] (1.3) Synthesis of intermediate 3c:

[013...

Embodiment 2

[0195] Synthesis of compounds in embodiment 2 of the present invention

[0196] General synthetic route 2:

[0197]

[0198] (1.1) Synthesis of Intermediate 9a

[0199]

[0200] 5-Bromobenzo[d]thiazole (2.57g, 12.0mmol) was dissolved in dry tetrahydrofuran (75.0mL), and lithium hexamethyldisilazide (17.0mL) was added dropwise at -78°C. The reaction was stirred at -78°C for 30 minutes. Ethyl cyanoformate (1.80 g, 18.2 mmol) was added dropwise and the reaction was continued to stir at -78°C for 30 minutes. After the reaction was completed, it was quenched by adding saturated ammonium chloride solution (50.0 mL) and warmed to room temperature. Ethyl acetate (30 mL) was extracted three times, the organic layers were combined, the solvent was evaporated under reduced pressure, and the intermediate 9a was purified by column chromatography (660 mg, 2.31 mmol, yield 19%).

[0201] (1.2) Synthesis of Intermediate 9b

[0202] Using 6-bromobenzo[d]thiazole and ethyl cyanoforma...

Embodiment 3

[0226] Embodiment 3, the preparation of compound of the present invention

[0227] General synthetic route 3:

[0228]

[0229] (1.1) Synthesis of intermediate 14a

[0230] Starting from methyl 5-bromo-1H-indole-2-carboxylate, according to the synthesis method of intermediate 4a, intermediate 14a was obtained (60% yield).

[0231] (1.2) Synthesis of intermediate 14b

[0232] Starting from methyl 6-bromo-1H-indole-2-carboxylate, according to the synthesis method of intermediate 4a, intermediate 14b was obtained (yield 72%).

[0233] (1.3) Synthesis of Intermediate 14c

[0234] Starting from ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate, according to the synthesis method of intermediate 4a, intermediate 14c was obtained (yield 71%).

[0235] (1.4) Synthesis of intermediates 15a2-15a24

[0236] The raw materials in the following table were used to obtain intermediates 15a1 to 15a24 according to the synthesis method of intermediate 6a1.

[0237]

[0238]

[0239] ...

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Abstract

The invention discloses a formula (I) compound shown in the specification. The invention also relates to a pharmaceutical composition containing the formula (I) compound and application of the compound in preparation of an HDAC inhibitor drug. The compound or the pharmaceutical composition thereof can be used for treating cell proliferation diseases, autoimmune diseases, inflammation, neurodegenerative diseases or viral diseases.

Description

technical field [0001] The present invention relates to HDAC inhibitor and its preparation method and application. Background technique [0002] Tumor refers to a new organism formed by the body under the action of various tumorigenic factors, the cells of local tissues lose the normal regulation of their growth at the gene level, resulting in clonal abnormal proliferation. 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] Histone acetylation plays a central role in the regulation of transcription in eukaryotic cells. Its action is regulated by a pair of functionally antagonistic proteases histone acetyltransferases (HATs) and histone deacetylases (HDACs). In nor...

Claims

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Application Information

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IPC IPC(8): C07D307/85C07D405/12C07D333/70C07D307/79C07D417/12C07D277/68C07D209/42C07D401/12C07D405/14A61K31/496A61K31/4525A61K31/4025A61K31/343A61K31/4709A61K31/4725A61K31/443A61K31/4545A61P35/00A61P37/00A61P29/00A61P31/12A61P25/00
CPCA61K31/343A61K31/4025A61K31/416A61K31/423A61K31/428A61K31/443A61K31/4525A61K31/4545A61K31/4709A61K31/4725A61K31/496A61P25/00A61P25/28A61P29/00A61P31/12A61P35/00A61P37/00C07D209/42C07D263/58C07D277/68C07D307/79C07D307/85C07D333/70C07D401/12C07D405/12C07D405/14C07D417/12
Inventor 李进吴波张登友尚巳耘楚洪柱王稚京吕开智梁秋香农云宏陈伟
Owner HITGEN INC
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