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Piperazine thiophene bicyclic nitrile compounds, and preparation method and application thereof

A technology of compound and dibromide, applied in organic chemistry, drug combination, antipyretic, etc.

Inactive Publication Date: 2018-05-29
FOSHAN HANFANG CHINESE MEDICINE HOSPITAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The precise physiological role of this abundant enzyme has not been fully determined, but it appears that SSAO and its reaction products may have several functions in cellular signal transduction and regulation

Method used

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  • Piperazine thiophene bicyclic nitrile compounds, and preparation method and application thereof
  • Piperazine thiophene bicyclic nitrile compounds, and preparation method and application thereof
  • Piperazine thiophene bicyclic nitrile compounds, and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] The synthesis of embodiment 1 compound I

[0022]

[0023] Step 1. Synthesis of Compound IV

[0024] Compound II (2.42g, 10mmol), Compound III (1.08g, 10mmol), Pd(OAc) 2 (0.22g, 1mmol), BINAP (2,2'-bisdiphenylphosphino-1,1'-binaphthyl, 0.62g, 1mmol) and t-BuOK (2.24g, 20mmol) were added to 50mL dry 1 , 2-dimethoxyethane (DME), the reaction mixture was stirred overnight under nitrogen atmosphere, TLC detection found that the reaction was complete.

[0025] The reaction mixture was carefully poured into 200mL ice water, stirred, and washed with 50mL×3CH 2 Cl 2 After extraction, the extract phases were combined, washed successively with 1% dilute hydrochloric acid and brine, and dried over anhydrous sodium sulfate. The desiccant was removed by suction filtration, the filtrate was evaporated to dryness on a rotary evaporator, and the residue was purified by silica gel column chromatography to obtain compound IV, 1.88 g (yield 70%). ESI-MS, m / z=270 ([M+H] + ).

[...

Embodiment 2

[0029] Embodiment 2 compound inhibits SSAO analysis in vitro

[0030]All preliminary assays were performed at room temperature using purified recombinantly expressed human SSAO. Enzymes were prepared essentially as described in Ohman et al. (Protein Expression and Purification, 2006, 46, 321-331). In addition, secondary and selectivity assays were performed using SSAO prepared from various tissues or purified rat recombinant SSAO. Enzyme activity was determined by using hydrogen peroxide generation in a horseradish peroxidase (HRP) coupled reaction using benzylamine as a substrate. Briefly, test compounds were dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM. Dose-response measurements were determined by serial dilutions of 1:10 in DMSO to generate 7-point curves or by serial dilutions of 1:3 in DMSO to generate 11-point curves. The highest concentration was adjusted according to the potency of the compound and then diluted in reaction buffer to give a f...

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Abstract

The invention relates to the field of SSAO inhibitors. In particular, the invention relates to bicyclic nitrile compounds containing piperazine thiophene, and a preparation method and an application thereof in preparation of drugs for treating inflammatory diseases, immune diseases, tumor and the like.

Description

technical field [0001] The present invention relates to the field of SSAO inhibitors. Specifically, the present invention relates to an SSAO inhibitor of a bicyclic nitrile compound containing piperazinethiophene, which has a therapeutic effect on inhibiting SSAO, its preparation method, and its use in pharmacy. Background technique [0002] Semicarbazide-sensitive amine oxidase (SSAO) activity is produced by vascular adhesion protein-1 (Vascular Adhesinon Protein-1, VAP-1) or copper-containing amine oxidase (AmoneOxidase, Copper Containing 3, AOC3 ), which belongs to the family of copper-containing amine oxidases (EC.1.4.3.6). Therefore, inhibitors of SSAO enzymes can also regulate the biological functions of VAP-1 protein. Members of this enzyme family are sensitive to inhibition by semicarbazides and use copper ions and the protein-derived hydroxydopaquinine (TPQ) cofactor for the oxidation of primary amines to aldehydes, hydrogen peroxide, and ammonia Deamination. ...

Claims

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Application Information

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IPC IPC(8): C07D409/04A61P29/00A61P35/00A61P37/02
CPCC07D409/04
Inventor 朱斌
Owner FOSHAN HANFANG CHINESE MEDICINE HOSPITAL CO LTD
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