Histone deacetylase inhibitors

A group and aryl technology, applied in the field of histone deacetylase inhibitors, can solve the problem that DNA is difficult to regulate transcription

Inactive Publication Date: 2010-11-24
ORCHID RES LAB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hypoacetylated histones are believed to have a higher affinity for DNA and form tightly bound DNA-histone complexes, making transcriptional regulation of said DNA difficult

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0292] N-cyclopropyl-2-(4-fluorophenyl)-3-(4-((E)-3-(hydroxyamino)-3-oxoprop-1-en-1-yl)phenyl) Synthesis of Acrylamide.

[0293]

[0294] Step-I

[0295] Preparation of (E)-3-(4-formylphenyl)methyl acrylate

[0296]

[0297] A suspension of (E)-3-(4-formylphenyl)acrylic acid (2 g, 10.5 mmol) in methanol (30 mL) was cooled to 5 °C, then concentrated H was added with stirring. 2 SO 4 (3 mL) and heated at 60 °C for 2 hours. The solvent was removed by evaporation and the obtained compound was stirred with water (100 mL) for 15 minutes. The precipitated white solid was filtered, washed with water (300 mL) and dried to obtain pure product (1.9 g, 86% yield).

[0298] Step-II

[0299] Preparation of 2-(4-fluorophenyl)-3-(4-((E)-3-methoxy-3-oxoprop-1-en-1-yl)phenyl)acrylic acid

[0300]

[0301] Under stirring, a mixture of 4-fluorophenylacetic acid (2.5g, 13.2mmol) and methyl (E)-3-(4-formylphenyl)acrylate (2.03g, 13.2mmol) was mixed with acetic anhydride (8mL ) ...

Embodiment 55

[0330] Synthesis of (1E)-3-(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)prop-1-en-1-yl)phenyl)-N-hydroxyacrylamide

[0331]

[0332] Step-I

[0333] Preparation of methyl 3-(1E)-(4-(2-(4-fluorophenyl)-3-hydroxyprop-1-en-1-yl)phenyl)acrylate

[0334]

[0335] Under constant stirring at 5°C, to 2-(4-fluorophenyl)-3-(4-(3-(E)-methoxy-3-oxoprop-1-en-1-yl)benzene To a suspension of acrylic acid (2 g, 6.1 mmol, prepared according to the procedure described in Example 1 step-II) in THF (10 mL), triethylamine (0.85 mL, 6.67 mmol) was added. To this solution was added dropwise methyl chloroformate (0.53 mL, 6.67 mmol) at 5°C over a period of 30 minutes, and stirred at the same temperature for 30 minutes. To the reaction mixture, sodium borohydride (0.9 g, 24.5 mmol) was added in one portion and methanol (5 mL) was added dropwise with stirring, and the reaction mixture was stirred at 30° C. for 2 hours. After the reaction was finished, the reaction mixture was diluted with ethy...

Embodiment 59

[0352] N-cyclopropyl-3-(4-((1E)-3-(2-aminophenylamino)-3-oxoprop-1-en-1-ylphenyl)-2-(4-fluoro Synthesis of phenyl)-acrylamide

[0353]

[0354] Step-I

[0355] Preparation of 3-(1E)-(4-(3-cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)phenyl)acrylic acid

[0356]

[0357] To 3-(1E)-(4-(3-(cyclopropylamino)-2-(4-fluorophenyl)-3-oxoprop-1-en-1-yl)phenyl)methyl acrylate (1 g, 2.7 mmol) in methanol (20 mL) was added a solution of NaOH (0.44 g, 4.4 mmol) in water (1 mL). The reaction mixture was stirred at 70°C for 2 hours. Subsequently, the solvent was completely removed by evaporation, diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The aqueous layer was acidified to pH 2 with diluted aqueous HCl (1 : 1 ) and allowed to stand at 4°C for 30 minutes, the precipitated solid was filtered and dried in vacuo to give the expected product as a white solid (0.67 g, 70 %Yield).

[0358] Step-II

[0359] N-cyclopropyl-3-(4-((1E)-3-(2-aminoph...

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PUM

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Abstract

Novel compounds of the general formula (I), having histone deacetylase (HDAC) inhibiting enzymatic activity, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, intermediates, pharmaceutically acceptable salts, pharmaceutical compositions, metabolites and prodrugs thereof. The present invention more particularly provides novel compounds of the general formula (I). Also included is a method for treatment of cancer, psoriasis, proliferative conditions and conditions mediated by HDAC, in a mammal comprising administering an effective amount of a novel compound of formula (I).

Description

technical field [0001] Compounds of formula (I), their derivatives, analogs, tautomeric forms, stereoisomers, geometric isomers, polymorphs, hydrates, solvates, intermediates, pharmaceutically acceptable Accepted salts, pharmaceutical compositions, metabolites and prodrugs thereof. [0002] [0003] This document describes the preparation of (I) compounds of the above-mentioned stilbenes, their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, drug Methods of compositions, metabolites and prodrugs thereof. [0004] The compounds described herein are inhibitors of histone deacetylase (HDAC) and also prevent cell growth in neoplastic cells, thereby inhibiting proliferation. They can be used as therapeutic agents for diseases involving cell growth, such as malignancies, autoimmune diseases, skin diseases, infections and the like. Background technique [0005] Transcriptional regulation is a major event in cell differen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C259/06C07C259/10C07C235/84
CPCC07D295/185C07C2101/18C07D209/18C07D213/56C07C233/44C07C2101/08C07C237/40C07C2101/02C07D317/60C07D333/24C07C259/06C07C237/38C07C259/10C07C2601/02C07C2601/08C07C2601/18A61P35/00A61P35/04
Inventor 斯里德哈兰·拉加戈帕尔维兰德拉·卡扎迪亚萨纳赛卡兰·庞潘迪安阿卜杜尔·拉黑姆·克里卡纳穆巴拉姆·阿南德汉斯里拉姆·拉加戈帕尔拉贞德兰·普拉维恩普拉布胡·黛瓦斯加玛尼
Owner ORCHID RES LAB
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