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Methyl adamantane and dimethylamine pyridine structure derivative, preparation method and application thereof

A technology of amantadine and dibromide, applied in drug combinations, antipyretics, antineoplastics, etc.

Inactive Publication Date: 2018-06-22
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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  • Methyl adamantane and dimethylamine pyridine structure derivative, preparation method and application thereof
  • Methyl adamantane and dimethylamine pyridine structure derivative, preparation method and application thereof
  • Methyl adamantane and dimethylamine pyridine structure derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Example 1 Synthesis of 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 (0.22 g, 1 mmol), BINAP (2,2'-bisdiphenylphosphino-1,1'-binaphthyl, 0.62 g, 1 mmol) and t-BuOK (2.24 g, 20 mmol) were added to 50 mL of dry 1 , 2-dimethoxyethane (DME), the reaction mixture was stirred overnight under nitrogen atmosphere, and the reaction was found to be complete by TLC.

[0026] The reaction mixture was carefully poured into 200 mL of ice water, stirred, and washed with 50 mL × 3 CH 2 Cl 2 After extraction, the extract phases were combined, washed with 1% dilute hydrochloric acid and brine successively, 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 (yield 67%). ESI-MS, m / z=264(...

Embodiment 2

[0030] Example 2 Synthesis of compound I-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(0.22 g, 1 mmol), BINAP (2,2'-bisdiphenylphosphino-1,1'-binaphthyl, 0.62 g, 1 mmol) and t-BuOK (2.24 g, 20 mmol) were added to 50 mL of dry 1 , 2-dimethoxyethane (DME), the reaction mixture was stirred overnight under nitrogen atmosphere, and the reaction was found to be complete by TLC.

[0034] The reaction mixture was carefully poured into 200 mL of ice water, stirred, and washed with 50 mL × 3 CH 2 Cl 2 After extraction, the extract phases were combined, washed with 1% dilute hydrochloric acid and brine successively, 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...

Embodiment 3

[0038] Example 3 Analysis of compound inhibiting SSAO in vitro

[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. Enzymatic activity was determined by hydrogen peroxide production in a coupling reaction using horseradish peroxidase (HRP) using benzylamine as 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 giv...

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Abstract

The invention relates to the field of SSAO inhibitors. Specifically, the invention relates to an SSAO inhibitor containing methyl adamantane and dimethylamine pyridine structures, a preparation methodthereof and application of preparing medicine for curing inflammatory diseases, immune diseases, tumors and the like.

Description

technical field [0001] The present invention relates to the field of SSAO inhibitors. In particular, the present invention relates to a new compound containing methyladamantane and lutidine structure, 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 regulated by Vascular Adhesinon Protein-1 (VAP-1) or copper amine oxidase (AmoneOxidase, Copper Containing 3, AOC3). ), which belong to the family of copper-containing amine oxidases (EC.1.4.3.6). Therefore, inhibitors of SSAO enzymes can also modulate the biological function of VAP-1 protein. Members of this family of enzymes are sensitive to inhibition by semicarbazides and use cupric ions and protein-derived hydroxydopa quinine (TPQ) cofactors for the oxidation of primary amines to aldehydes, hydrogen peroxide, and ammonia Deamination. [0003] Known substrates for human SSAO include end...

Claims

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Application Information

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