Tricyclo-pyrazole [1,5-d] [1,4] benzo oxazepine-one derivatives and preparation method and application thereof

A benzoxazepine and tricyclic pyrazole technology, applied in the field of monoamine oxidase inhibitors, can solve the problems of uncommon MAO-B inhibitors and induce hypertensive crisis, and achieve good MAO inhibitory effect

Active Publication Date: 2015-12-16
汤文建
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Irreversible and non-selective MAO inhibitors have the risk of inducing hypertensive crisis, as well as the possibility of interaction with other drugs (Gardner et al., J. Clin. Psychiatry, 1996, 57, 99-104). Uncommon for selective MAO-B inhibitors

Method used

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  • Tricyclo-pyrazole [1,5-d] [1,4] benzo oxazepine-one derivatives and preparation method and application thereof
  • Tricyclo-pyrazole [1,5-d] [1,4] benzo oxazepine-one derivatives and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～ Embodiment 12

[0041] The preparation of derivative 1~derivative 12 (synthetic route such as figure 1 shown)

[0042] Add substituted acetophenone (10mmol), substituted salicylaldehyde (11mmol) and ethanol (10mL) into the reaction flask, stir in an ice-water bath for 30min, add 40% NaOH aqueous solution (2mL) dropwise, and the reaction solution gradually changes from The color changed to red and a solid precipitated out. Slowly raise the temperature to 60oC, stir at 60oC for 4-10h, spot the plate for detection, and stop the reaction after the acetophenone has completely reacted. Pour the reaction solution into ice water, adjust the pH value to 2~3 with 2mol / L HCl, let it stand for 12~24h, filter it with suction, wash the filter cake with water and petroleum ether successively, and dry it under reduced pressure at 60oC to obtain Char ketone;

[0043] Add the obtained chalcone into ethanol (20mL), stir, heat to 60oC, add 5 times the equivalent of hydrazine hydrate dropwise at 60oC, continue...

Embodiment 1

[0048] Derivative 1: white powder, the yield is 41%; mp269?270°C; 1 HNMR (300MHz, DMSO-d 6 )δ(ppm):3.75(dd,1H,J 1 =11.6Hz,J 2 =17.8Hz,1-Ha),3.87(s,1H),3.99(dd,1H,J 1 =8.6Hz,J 2 =17.8Hz,1-Hb),4.44(d,1H,J=16.5Hz,6-Ha),5.02(d,1H,J=16.5Hz,6-Hb),6.02(dd,1H,J 1 =8.8Hz,J 2 =11.3Hz,11b-H),6.92?7.91(6H,Ar-H).MS:m / z[M+H] + calcdforC 18 h 15 Br 2 N 2 o 3 :466.9425;found:466.9426.

Embodiment 2

[0050] Derivative 2: white powder, the yield is 42%; mp191?193°C; 1 HNMR (300MHz, CDCl 3 )δ(ppm):3.69(dd,1H,J 1 =11.5Hz,J 2 =17.4Hz,1-Ha),3.92(dd,1H,J 1 =9.3Hz,J 2 =17.4Hz,1-Hb),4.48(d,1H,J=16.7Hz,6-Ha),5.05(d,1H,J=16.7Hz,6-Hb),6.01(dd,1H,J 1 =8.8Hz,J 2 =11.3Hz,11b-H),7.17?8.03(9H,Ar-H).MS:m / z[M+H] + calcdforC 17 h 15 N 2 o 2 :279.1128;found:279.1127.

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Abstract

The invention discloses tricyclo-pyrazole [1,5-d] [1,4] benzo oxazepine-one derivatives of which the structure is shown in a general formula of a figure in the abstract. The invention simultaneously discloses the preparation method of the tricyclo-pyrazole [1,5-d] [1,4] benzo oxazepine-one derivatives. The invention further discloses the application of the tricyclo-pyrazole [1,5-d] [1,4] benzo oxazepine-one derivatives as a reversible and selective monoamine oxidase inhibitor drug, specifically, the tricyclo-pyrazole [1,5-d] [1,4] benzo oxazepine can be applied to drugs or drug compositions for treating and preventing diseases related to aging, alzheimer's disease and parkinson's disease.

Description

technical field [0001] The present invention relates to a tricyclic pyrazol[1,5-d][1,4]benzoxazepine derivative, its preparation method and its use as a reversible and selective monoamine oxidase inhibitor, belonging to Proposal, preparation and application of new compounds. Background technique [0002] Monoamine oxidase (MAO, EC 1.4.3.4) is a neurotransmitter responsible for endogenous monoamines such as dopamine, serotonin, epinephrine or norepinephrine, and trace amines (such as phenethylamine), and A flavin-containing enzyme for the oxidative deamination of many monoamines. MAO exists on the mitochondrial outer membrane of cells and is widely distributed in the human body, especially in liver, brain and kidney tissue cells with the highest content. There are two isoforms of this enzyme, MAO-A and MAO-B, which are encoded by different genes and have different tissue distribution, structure and substrate specificity (Edmondson, D.E. et al., Biochemistry, 2009, 48, 4220–...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/04A61P25/28A61P25/16
CPCC07D498/04
Inventor 汤文建童旭石静波刘新华
Owner 汤文建
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