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A class of hdac inhibitors and uses thereof

A technology of inhibitors and uses, applied in the field of bifendate derivatives and their preparation, can solve the problems of no HDAC inhibitors

Active Publication Date: 2021-07-02
ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, so far, there is no report on the discovery of HDAC inhibitors based on the bifendate core

Method used

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  • A class of hdac inhibitors and uses thereof
  • A class of hdac inhibitors and uses thereof
  • A class of hdac inhibitors and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0060] 8-(4,10-Dimethoxy-6,8-dihydro-7H-[1,3]dioxol[4',5':3,4]benzo[1,2-c][ Synthesis of 1,3]dioxolo[4',5':5,6]benzo[1,2-e]azepine-7-)-N-hydroxyoctylamide (1)

[0061] (1), Synthesis of (7,7'-dimethoxy-[4,4'-dibenzo[d][1,3]dioxol]-5,5'-)dimethanol (23)

[0062]

[0063] Add bifendate (10.0g, 23.9mmol, 1eq) into a round bottom flask, dissolve it with anhydrous THF (150mL), add LiAlH in batches under ice-cooling 4 (2.72g, 71.7mmol, 3eq), after the addition was complete, it was transferred to room temperature for 4h. Under ice bath, add ice water to remove excess LiAlH 4 , suction filtration, DCM rinse, the filtrate was concentrated, followed by saturated NaHCO 3 Solution, water, saturated brine washing, anhydrous Na 2 SO 4 Dry, filter, and concentrate the filtrate under reduced pressure to obtain 8.33 g of white solid.

[0064] (2), (7,7'-dimethoxy-[4,4'-dibenzo[d][1,3]dioxol]-5,5'-)bis(methylene)bis Synthesis of Mesylate (24)

[0065]

[0066] Intermediate 23 (5.5...

Embodiment 2

[0075] 4-((4,10-Dimethoxy-6,8-dihydro-7H-[1,3]dioxol[4',5':3,4]benzo[1,2-c] Synthesis of [1,3]dioxol[4',5':5,6]benzo[1,2-e]azepine-7-)methyl)-N-hydroxybenzamide (2)

[0076] (1), 7-benzyl-4,10-dimethoxy-7,8-dihydro-6H-[1,3]dioxol[4',5':3,4]benzo[1 ,2-c][1,3]Dioxol[4',5':5,6]Benzo[1,2-e]azepine (25) Synthesis

[0077]

[0078] Intermediate 24 (7.57g, 14.6mmol, 1eq), CH 3 CN (50mL), benzylamine (6.38mL, 58.4mmol, 4eq) and TEA (8.12mL, 58.4mmol, 4eq) were reacted at 40°C for 8h. spin off CH 3 CN, followed by saturated NaHCO 3 Solution, water, saturated brine washing, DCM extraction, anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure and recrystallized from ethyl acetate to obtain 5.01 g of white solid.

[0079] (2), 4,10-dimethoxy-7,8-dihydro-6H-[1,3]dioxol[4',5':3,4]benzo[1,2-c] Synthesis of [1,3]dioxin[4',5':5,6]benzo[1,2-e]azepine(26)

[0080]

[0081] Intermediate 25 (5.00g, 11.5mmol, 1eq), HCOONH 4 (4.00g, 63....

Embodiment 3

[0090] 5-(4,10-Dimethoxy-7,8-dihydro-6H-[1,3]dioxol[4',5':3,4]benzo[1,2-c][ Synthesis of 1,3]dioxol[4',5':5,6]benzo[1,2-e]azepine-7-carbonyl)-N-hydroxythiophene-2-carboxamide (9)

[0091] (1), 5-(4,10-dimethoxy-7,8-dihydro-6H-[1,3]dioxol[4',5':3,4]benzo[1,2 -c][1,3]dioxol[4',5':5,6]benzo[1,2-e]azepine-7-carbonyl)thiophene-2-carboxylic acid methyl ester (28) Synthesis

[0092]

[0093] 5-Methoxycarbonylthiophene-2-carboxylic acid (89.5mg, 0.481mmol, 1.1eq), EDC·HCl (92.1mg, 0.481mmol, 1.1eq), HOBt (65.4mg, 0.481mmol , 1.1eq), DIPEA (217μL, 1.31mmol, 3eq) and DCM (2mL), stirred at room temperature for 1h. Intermediate 26 (150mg, 0.437mmol, 1eq) was added, and the reaction was continued at room temperature for 4h. followed by saturated NaHCO 3 Solution, water, saturated brine washing, DCM extraction, anhydrous Na 2 SO 4 After drying and filtering, the filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography to obtain 208 mg of a...

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Abstract

The present invention discloses a class of HDAC inhibitors, which are bifendate derivatives represented by general formulas (I)-(IV) and their pharmaceutically acceptable salts or deuterated products, as well as their containing The pharmaceutical composition is used for preparing medicines for anti-tumor, autoimmune disease, inflammation or Alzheimer's disease. The bifendate derivatives prepared by the invention all have HDAC inhibitory activity, and pharmacodynamic experiments show that the compounds involved in the invention can be used as therapeutic drugs for tumors, autoimmune diseases, inflammation or Alzheimer's disease.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a class of bifendate derivatives with HDAC inhibitory activity and a preparation method and use thereof. Background technique [0002] Histone deacetylases (HDACs) play an important role in epigenetic regulation and can regulate gene expression by catalyzing the deacetylation of histone or non-histone proteins. Among the four subclasses of HDACs, class I HDACs are more closely related to the occurrence and development of tumors, and they widely exist in various organs of the human body. Studies have confirmed that the HDAC1 subtype in class I HDACs is highly expressed in a variety of malignant tumors, such as endometrial cancer, lung cancer, prostate cancer, breast cancer, colon cancer, pancreatic cancer, blood cancer, etc. (Zhu S, et al .Mir-548an,Transcriptionally Downregulated by HIF1α / HDAC1,Suppresses Tumorigenesis of Pancreatic Cancer by Targeting Vimentin Expression.Mol ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/153A61K31/55A61P37/06A61P35/00A61P25/28A61P29/00
CPCA61P25/28A61P29/00A61P35/00A61P37/06C07D491/153
Inventor 马晓东王昊方方陶强强彭成军孙松王虎传胡海霞
Owner ANHUI UNIVERSITY OF TRADITIONAL CHINESE MEDICINE
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