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Amide small-molecule organic compound taking indole or indole analogue as parent nucleus structure, application and preparation method of amide small-molecule organic compound

A technology of organic compounds and analogs, applied in the field of drug synthesis, can solve problems such as histone hypoacetylation, chromatin dense and coiled, and tumor suppressor genes cannot be expressed normally

Active Publication Date: 2019-06-14
EAST CHINA NORMAL UNIVERSITY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Studies have shown that in tumor cells, histones are mostly hypoacetylated, and the chromatin is dense and coiled, resulting in the abnormal expression of some tumor suppressor genes

Method used

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  • Amide small-molecule organic compound taking indole or indole analogue as parent nucleus structure, application and preparation method of amide small-molecule organic compound
  • Amide small-molecule organic compound taking indole or indole analogue as parent nucleus structure, application and preparation method of amide small-molecule organic compound
  • Amide small-molecule organic compound taking indole or indole analogue as parent nucleus structure, application and preparation method of amide small-molecule organic compound

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Experimental program
Comparison scheme
Effect test

Embodiment 1-1

[0125] 1 H-NMR was measured with a Bruker 500MHz instrument; MS was measured with a Bruker MicroTOF-Q LCMS instrument, and all were ESI methods unless specified; all solvents were re-distilled before use, and the anhydrous solvents used were all according to the standard method obtained by drying; except for the instructions, all reactions were carried out under the protection of argon and followed by TLC, and the post-treatment was washed with saturated brine and dried with anhydrous magnesium sulfate; the purification of the product was performed using silica gel (200 -300 mesh) column chromatography; the silica gel used, including 200-300 mesh and GF 254 Produced for Qingdao Ocean Chemical Factory or Yantai Yuanbo Silicone Company. Example 1-1, Preparation of Compound (7-(3-((1-adamantyl)formyl))-indolyl)heptanyl hydroxylamide (BE001)

[0126]

[0127] Take 3-indolecarboxylic acid (806mg, 5.0mmol) in dimethylformamide (10ml), cool the reaction system with an ice-water ...

Embodiment 1-2 to 1-9

[0130] Preparation of BE series compounds shown in embodiment 1-2 to 1-9, table 1 (see reference below for specific process)

[0131] Table 1

[0132]

[0133]

Embodiment 1-10

[0134] Example 1-10, Preparation of Compound (7-(3-((2-adamantyl)formyl))-indolyl)heptanyl hydroxylamide (BE010)

[0135]

[0136] Take 3-indolecarboxylic acid (323mg, 2.0mmol), 2-adamantanamine hydrochloride (376mg, 2.0mmol), EDC.HCl (384mg, 2.0mmol), HOBt (271mg, 2.0mmol) in dimethyl form Amide (5ml). The intermediate was obtained after 4h of reaction.

[0137] Take the intermediate (135mg, 0.46mmol) in dimethylformamide (5ml), and slowly add sodium hydride (37mg, 0.92mmol) in an ice-water bath until no bubbles are generated, then add methyl 7-bromoheptanoate ( 123 mg, 0.55 mmol). After 30 min the intermediate ester was obtained.

[0138]Add KOH (2.83g, 50.7mmol) to a methanol (10ml) solution of hydroxylamine hydrochloride (3.33g, 50.7mmol) at 40°C, react for 10min and place the reaction system in an ice bath, and suction filter after 30min to obtain the filtrate. Then the above ester (118mg, 0.27mmol) was added to the filtrate, and KOH (333mg, 5.07mmol) was added to ...

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Abstract

The invention discloses an amide small-molecule organic compound shown in formulas (I) and (II) and based on an indole or indole analogue as a parent nucleus structure or a hydrate or pharmaceuticallyacceptable salt of the amide small-molecule organic compound. The invention also discloses application of the compound and a pharmaceutical composition containing the compound or the hydrate or the pharmaceutically acceptable salt thereof in prevention and / or treatment of various tumors and other diseases, and in prevention and treatment of autoimmune diseases, allergy, inflammation and other diseases as a histone deacetylase inhibitor. The invention also provides a preparation method of the compound and derivatives thereof.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and relates to a class of amide small molecular organic compounds based on indole or indole analogs as the core structure, and a synthesis method and application thereof. Background technique [0002] Epigenetic modification is of great significance to the occurrence, diagnosis and treatment of tumors. It mainly includes DNA methylation, histone modification, chromatin remodeling and non-coding RNA regulation. Abnormal epigenetic modification can lead to misexpression of genes, causing metabolic disorders, diseases and even tumors. [0003] Histone modifications mainly include histone methylation, acetylation, phosphorylation, and histone ubiquitination. The most studied of these is the acetylation of histones. Under normal circumstances, the acetylation and deacetylation of histones are in a dynamic balance, which is jointly regulated by histone acetylase (HAT) and histone deacetylase (HDAC). H...

Claims

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Application Information

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IPC IPC(8): C07D209/42C07D471/04C07D235/24C07D231/56A61K31/405A61K31/404A61K31/437A61K31/416A61K31/4184A61P35/00
Inventor 章涵堃逄秀凤刘明耀蒋蓓尔刘志韬于薇薇梁秋雯
Owner EAST CHINA NORMAL UNIVERSITY
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