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Adamantane and dimethylamine pyridine structure-containing derivative, preparation method and application of derivative

A kind of technology of amantadine and dibromide, applied in the field of pharmacy, derivatives containing adamantane and dimethylamine pyridine structure

Inactive Publication Date: 2018-06-08
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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  • Adamantane and dimethylamine pyridine structure-containing derivative, preparation method and application of derivative
  • Adamantane and dimethylamine pyridine structure-containing derivative, preparation method and application of derivative
  • Adamantane and dimethylamine pyridine structure-containing derivative, preparation method and application of derivative

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] The synthesis of embodiment 1 compound I-1

[0023]

[0024] Step 1. Synthesis of compound IV-1

[0025] Compound II-1 (2.37g, 10mmol), Compound III (1.07g, 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.

[0026] 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-I, 1.76 g (67% yield). ESI-MS, m / z=264 ([M+H] +...

Embodiment 2

[0030] The synthesis of embodiment 2 compound 1-2

[0031]

[0032] Step 1. Synthesis of Compound IV-2

[0033] Compound II-2 (2.80g, 10mmol), Compound III (1.07g, 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.

[0034] 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-2. ESI-MS, m / z=307 ([M+H] + ).

[0035] Step 2...

Embodiment 3

[0038] Example 3 compound in vitro inhibition of SSAO analysis

[0039] 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 ...

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Abstract

The invention relates to the field of SSAO (semicarbazide-sensitive amine oxidase) inhibitors, in particular to an adamantane and dimethylamine pyridine structure-containing compound with a structuralformula as shown in the specification, a preparation method of the compound, and an application of the compound in preparing drugs for treating inflammatory diseases, immunological diseases, tumors and the like.

Description

technical field [0001] The present invention relates to the field of SSAO inhibitors. Specifically, the present invention relates to a derivative containing adamantane and dimethylaminopyridine structure that 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. [0003] Know...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04A61P29/00A61P35/00A61P37/02
CPCC07D401/04
Inventor 朱斌
Owner FOSHAN HANFANG CHINESE MEDICINE HOSPITAL CO LTD
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