CN-119285479-B - Preparation and application of novel MAO-B inhibitor containing tetrahydronaphthalene-1-amine structure

Abstract

The invention provides preparation and application of a novel MAO-B inhibitor containing tetrahydronaphthalene-1-amine structures, and belongs to the field of medicines. The derivative is a compound shown in a formula I, or pharmaceutically acceptable salt or stereoisomer thereof. The compound can be used for inhibiting monoamine oxidase (MAO), particularly selectively inhibiting MAO-B, can be used for treating diseases such as Parkinson's disease, alzheimer's disease, mood disorder and the like, and has good application prospect.

Inventors

• YU YU
• FENG JING
• WANG ZIWEI

Assignees

• 重庆医科大学

Dates

Publication Date

20260505

Application Date

20241008

Claims (8)

1. 1. A compound shown as a formula I or pharmaceutically acceptable salt thereof, I is a kind of Wherein, the R 4 is H, and the R 1 -R 3 substituent is selected as follows: R 1 is formula II, R 2 -R 3 is selected from hydrogen, halogen, hydroxy, nitro, amino, or R 2 is formula II, R 1 、R 3 is selected from hydrogen, halogen, hydroxy, nitro, amino, or R 3 is formula II, R 1 -R 2 is selected from hydrogen, halogen, hydroxy, nitro, amino; II (II) N is selected from integers of 1-2, and the symbol in brackets is' "Represents CH 2 ; Y is selected from O or S; X 1 、X 2 is selected from hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, nitrile; the salified acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid.
2. 2. A process for the preparation of a compound of formula I, or a pharmaceutically acceptable salt thereof, as claimed in claim 1, wherein: Firstly, synthesizing a compound containing tetralone structure by adopting a coupling reaction, and then obtaining a target compound through a reduction reaction and an amino substitution reaction, wherein the reduction reaction is to reduce ketone into amino by using sodium cyanoborohydride and ammonium acetate, and then further obtain the compound by substituting hydrogen on amino by bromopropyne.
3. 3. The method of claim 2, wherein the acceptable salt is synthesized by a general chemical method.
4. 4. A process according to claim 3 wherein the salt is prepared by dissolving the synthesized compound in toluene and passing dry hydrochloric acid gas therethrough to crystallize the hydrochloride salt.
5. 5. The compound of claim 1, wherein the compound is selected from the group consisting of:
6. 6. The use of a compound comprising a tetrahydronaphthalene-1-amine structure, or a pharmaceutically acceptable salt thereof, according to claim 1 or 5, for the preparation of a selective monoamine oxidase B (MAO-B) inhibitor useful for the treatment of MAO-B mediated neurodegenerative diseases including alzheimer's disease, parkinson's disease, schizophrenia, depression.
7. 7. Use of a compound containing a tetrahydronaphthalene-1-amine structure, or a pharmaceutically acceptable salt thereof, according to claim 1 or 5 in the manufacture of a medicament for the treatment of alzheimer's disease, parkinson's disease, schizophrenia, depression.
8. 8. A pharmaceutical composition is characterized in that the pharmaceutical composition is injection, tablet, capsule, powder, granule, suspension or oral liquid prepared by taking the tetrahydronaphthalene-1-amine-containing compound or pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable carrier.

Description

Preparation and application of novel MAO-B inhibitor containing tetrahydronaphthalene-1-amine structure Technical Field The invention belongs to the field of medicines, and mainly relates to preparation of a compound containing tetrahydronaphthalene-1-amine structures and medicinal application of the compound serving as a selective monoamine oxidase B (MAO-B) inhibitor. Background Parkinson's Disease (PD) is a clinically common neurodegenerative disease, and the burden of Parkinson's disease is gradually increased as the population ages and the life expectancy of humans increases. According to 2016 statistics, the number of patients with global parkinsonism reaches 600 ten thousand, and the prevalence, disability rate and death rate of the parkinsonism are the fastest growing in nervous system diseases in a trend of doubling. In fact, china is the most populated country in the world, and more than 300 thousands of parkinsonism patients exist. By 2030, the number of patients in China is expected to reach 500 ten thousand, and the incidence rate of middle-aged and elderly people over 65 years old is 1.7%. The pathological features of parkinson's disease are degeneration of the substantia nigra dopaminergic neurons of the midbrain, leading to pathophysiological changes in the downstream basal loop. This loss of dopaminergic neurons and the resultant deficiency in dopamine transmission ultimately lead to motor and mental dysfunction. Dopamine degradation requires two enzymes, monoamine oxidase (MAO) and catechol-2-oxo-2-methyltransferase (COMT). Dopamine is oxidatively degraded in the brain by MAO-B and generates a large number of oxygen radicals during its metabolism to damage neurons. Monoamine oxidase (Monoamine oxidase, MAO) is a flavin adenine dinucleotide enzyme, mainly located on the outer membrane of mitochondria of tissue cells such as brain, liver and intestinal mucosa. MAO catalyzes and oxidizes endogenous or exogenous monoamine substances to perform deamination reaction to generate hydrogen peroxide, ammonia and aldehyde substances, so that the monoamine substances lose physiological activity in vivo. Unnecessary MAO enzyme activity can cause traumatic disorders of neural demethenes and mitochondrial damage. There are two subtypes of this enzyme, MAO-A and MAO-B. MAO-B is a complex enzyme of the mitochondrial membrane and plays an important role in dopamine metabolism. MAO-B can decompose dopamine into homovanillic acid, and simultaneously generates free radical hydrogen peroxide (H 2O2), and has toxic effect on nerve cells, which results in increased neuronal injury and death. Therefore, inhibiting MAO-B activity can prevent dopamine degradation, increase the concentration of dopamine in brain, inhibit peroxide generated in dopamine oxidative metabolism, reduce the generation of oxygen free radicals, improve the symptom of Parkinson's disease, block MPTP from being converted into MPP +, delay the death process of melanocytes and change the PD process of patients. The nonselective and irreversible nature of the part of the drugs that are marketed (e.g. bensoxazide, selegiline) can lead to a number of serious adverse effects such as orthostatic hypotension, hypertensive crisis, "cheesy reactions", hepatotoxicity etc. In order to overcome the adverse reactions, the design and screening of high-efficiency low-toxicity MAO-B inhibitors are still one of the current research hot spots for relieving PD diseases and improving the physical health and life quality of PD patients. Disclosure of Invention The invention aims to provide an inhibitor with good inhibition effect and high selectivity on MAO-B, or pharmaceutically acceptable salt or stereoisomer thereof, and a synthesis method and application thereof. The invention solves the problems and adopts the following technical scheme: a compound containing tetrahydronaphthalene-1-amine structure, which is shown in a formula I: Wherein, the R 4 is H, R 1-R3 is selected from hydrogen, halogen, hydroxy, nitro, amino, formula II; n is an integer from 1 to 2, and the symbol "Λ" in brackets represents CH 2; Y is selected from O or S; X 1、X2 is selected from hydrogen, halogen, nitro, methyl, methoxy, trifluoromethyl, nitrile; the salified acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, etc. Specifically, the compound containing tetrahydronaphthalene-1-amine structure shown in the formula I, or pharmaceutically acceptable salt or stereoisomer thereof, is specifically selected from the following compounds: the invention also provides a synthesis method of the tetrahydronaphthalene-1-amine structure, which comprises the following steps: Firstly, synthesizing a compound containing tetrahydronaphthalene-1-amine structures by adopting a coupling reaction, and obtaining a target compound through a reduction reaction and an amino substitution reaction; the reduction reaction is to reduce ketone into amino group by using cyano