Peripheral alkyl and alkenyl chains extended benzene derivatives and pharmaceutical composition including same

A pharmaceutical and alkyl technology, applied in the field of phenyl derivatives with side chain alkyl and alkenyl extensions and pharmaceutical compositions including them, can solve the problem that dual inhibitors are rarely reported

Pending Publication Date: 2021-11-16
TAIWANJ PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, dual inhibitors of HDAC and autotaxin have rarely been reported

Method used

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  • Peripheral alkyl and alkenyl chains extended benzene derivatives and pharmaceutical composition including same
  • Peripheral alkyl and alkenyl chains extended benzene derivatives and pharmaceutical composition including same
  • Peripheral alkyl and alkenyl chains extended benzene derivatives and pharmaceutical composition including same

Examples

Experimental program
Comparison scheme
Effect test

example I

[0083] Example 1: Synthesis of Compound 1 to Compound 83

[0084] To demonstrate that compounds of the present disclosure can be appropriately synthesized and utilized, the synthetic steps of Compounds 1 to 83 depicted in Tables A to F are described in detail below.

[0085] Synthesis of Compound 1 to Compound 3

[0086] Process 01

[0087]

[0088] To compound 1a (6-amino-1-tetralone) (0.50 gram, 3.10 mmol), monomethyl suberate (0.70 gram, 3.72 mmol) and hydroxybenzotriazole at 0 ℃ (HOBt; 0.21 g, 1.55 mmol) in dichloromethane (DCM; 50 mL) were added N,N-diisopropylethylamine (DIPEA; 1.20 g, 9.31 mmol) and 1-ethyl - 3-(3-Dimethylaminopropyl)carbodiimide (EDCI; 0.82 g, 4.65 mmol). After the addition, the reaction mixture was allowed to warm slowly to room temperature (RT) and stirred overnight.

[0089] After the reaction was completed, the solvent was removed under reduced pressure. The residue was diluted with EtOAc and washed with saturated (sat) NH 4 Cl and saturat...

example II

[1232] Example II: Autotaxin / HDAC Inhibition Assay

[1233] In order to confirm that Compound 1 to Compound 83 of the present disclosure have the effect of inhibiting the activity of autotaxin and HDAC (dual ATX / HDAC inhibitor), the following experiments were carried out for evaluation.

[1234] Autotaxin Inhibition Screening Assay

[1235] ATX (autotaxin) activity was measured by choline release from LPC with or without the addition of test compounds (compound 1 to compound 83; concentrations of 4 micromolar, 20 micromolar and 50 micromolar). Mix twenty (20) Nanogram ATX (10803, Cayman, MI, USA) with 100 micromolar 14:0LPC (855575P, Avanti, Alabama, USA) (AL, USA)) were incubated together in a final volume of 100 μl buffer containing: 50 mM Tris pH 8.0, 0.01% Triton X-100, 50 mM CaCl 2 , 1 unit / ml choline oxidase, 2 units / ml horseradish peroxidase (HRP), 2 mmol homovanillic acid (homovanilic acid) (HVA). The relative amount of choline released was measured by HVA fluoresce...

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Abstract

The compounds represented by Formula (I), which are peripheral alkyl and alkenyl chains extended benzene derivatives, are useful as dual autotaxin (ATX) / histone deacetylase (HDAC) inhibitors. These compounds may be included in a pharmaceutical composition along with a pharmaceutically acceptable carrier, and be used in a therapeutically effective amount for prophylaxis or treatment of various diseases and disorders.

Description

technical field [0001] The present disclosure relates to phenyl derivatives having side chain alkyl and alkenyl extensions and pharmaceutical compositions comprising the same. Phenyl derivatives with side chain alkyl and alkenyl extensions are suitable as dual inhibitors of autotaxin (ATX) / histone deacetylase (HDAC). Background technique [0002] Histones are DNA / protein complexes that form the nucleus of the nucleosome and are the subunit of eukaryotic chromatin. The N-terminal "tails" of histones undergo various post-translational modifications, including phosphorylation, methylation, ubiquitination, ADP-ribosylation, and acetylation. Histone deacetylases (HDACs) are responsible for removing these acetyl groups and play an important role in regulating gene expression. Human HDAC1 is the first protein associated with histone deacetylase activity. Aberrant expression of HDACs has been observed in various human cancers. HDAC inhibitors may become useful as therapeutic or ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/165C07C235/28C07C235/32
CPCC07C259/06C07C235/38C07C233/42C07D209/14C07D233/74C07C2602/08C07C2602/10C07C311/20
Inventor 杨笑岚江彦锋刘孟宪张嘉豪刘皓瑄石英珠刘胜纮王琼雯黄婷妮
Owner TAIWANJ PHARMA
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