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CN-121991053-A - Substituted coumarin-benzoxazole derivative and preparation method and application thereof

CN121991053ACN 121991053 ACN121991053 ACN 121991053ACN-121991053-A

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a substituted coumarin-benzoxazole derivative, and a preparation method and application thereof. The derivative has a structure shown in a formula (I) or (II), wherein R 1 is selected from hydrogen, methyl, chlorine and formyloxyethyl, R 2 is selected from hydrogen, methyl, trifluoromethyl and benzene ring, and n is a positive integer of 2-5. The preparation is realized by two-step substitution reaction, the raw materials are cheap, the process is simple and convenient, and the preparation method is suitable for industrial production. The derivative has remarkable multi-target activity, can inhibit monoamine oxidase-B, beta-amyloid aggregation and butyrylcholine esterase simultaneously, has good antioxidation, can effectively improve the related pathological injury of neurodegenerative diseases, and has low biotoxicity and high safety. The invention can be used for preparing medicines for treating diseases such as Alzheimer disease, parkinsonism and the like, provides novel high-efficiency candidate molecules for treating related diseases, and has important medical research value and market application prospect.

Inventors

  • WANG XIAOQIN
  • ZHONG YINGYING
  • ZHANG YAMEI
  • ZHAO ZUGUO
  • LUO DAMIN
  • SHEN YINYING

Assignees

  • 广东医科大学

Dates

Publication Date
20260508
Application Date
20260305

Claims (10)

  1. 1. A substituted coumarin-benzoxazole derivative characterized by having a structure represented by formula (I) or (II): in the formula (I) and the formula (II), R 1 is selected from one or more of hydrogen, methyl, chlorine and formyloxyethyl, R 2 is selected from hydrogen, methyl, trifluoromethyl and benzene ring, and n is a positive integer of 2-5.
  2. 2. The substituted coumarin-benzoxazole derivative according to claim 2, characterized in that said substituted coumarin-benzoxazole derivative has any of the following structures: 。
  3. 3. A process for the preparation of a substituted coumarin-benzoxazole derivative according to any one of claims 1-2, characterized by the following synthetic route: , The method specifically comprises the following steps: S1, carrying out substitution reaction on a compound of the formula (III) or (V) and Br- (CH 2 ) n -Br) in an alkaline environment to obtain a compound of the formula (IV) or (VI); S2, carrying out substitution reaction on the compound of the formula (IV) or (VI) obtained in the step S1 and 4- (benzo [ d ] oxazol-2-yl) phenol under alkaline conditions to obtain a compound of the formula (I) or a compound of the formula (II); Wherein R 1 is selected from one or more of hydrogen, methyl, chlorine and formyloxyethyl, R 2 is selected from hydrogen, methyl, trifluoromethyl and benzene ring, and n is a positive integer of 2-5.
  4. 4. The preparation method according to claim 3, wherein the alkaline environment in the step S1 is formed by one or more of cesium carbonate, potassium carbonate and sodium carbonate, the reaction temperature is 25-60 ℃, the reaction time is 2-8 hours, the alkaline environment in the step S2 is formed by one or more of cesium carbonate and potassium carbonate, the solvent is one or more of N, N-dimethylformamide and acetonitrile, the reaction temperature is 25-100 ℃, the reaction time is 2-8 hours, and the reaction is followed by column chromatography purification.
  5. 5. Use of a substituted coumarin-benzoxazole derivative according to any one of claims 1-2 for the preparation of monoamine oxidase-B inhibitors.
  6. 6. Use of a substituted coumarin-benzoxazole derivative according to any one of claims 1-2 for the preparation of butyrylcholinesterase inhibitors.
  7. 7. Use of a substituted coumarin-benzoxazole derivative according to any one of claims 1-2 for the preparation of an aβ aggregation inhibitor.
  8. 8. Use of a substituted coumarin-benzoxazole derivative according to any one of claims 1-2 for the preparation of an antioxidant.
  9. 9. Use of a substituted coumarin-benzoxazole derivative according to any one of claims 1-2 in the manufacture of a medicament for the treatment of alzheimer's disease, cerebrovascular dementia, myasthenia gravis, parkinson's disease, huntington's disease or amyotrophic lateral sclerosis.
  10. 10. A pharmaceutical formulation comprising a substituted coumarin-benzoxazole derivative according to any of claims 1-2 in a dosage form selected from the group consisting of tablets, pills, capsules, injections, suspensions or emulsions.

Description

Substituted coumarin-benzoxazole derivative and preparation method and application thereof Technical Field The invention belongs to the technical field of biological medicines, and particularly relates to a substituted coumarin-benzoxazole derivative, and a preparation method and application thereof. Background Alzheimer's Disease (AD) is a chronic central nervous system degenerative disease characterized by progressive cognitive decline, memory loss and abnormal neurobehavioral, whose course is irreversible and progressive, and has become a major threat to the health of the world population in elderly. With the aggravation of the global population aging process, the incidence rate of AD is continuously increased, the life quality of patients is seriously damaged, and the family and the society are brought with heavy medical burden and economic pressure, so that the development of the efficient and safe AD-resistant medicament has important clinical value and social significance. The pathogenesis of AD has not been fully elucidated to date, and its pathological process involves multifactorial, multi-target complex network regulation. Existing studies demonstrate that the onset of AD is closely related to a variety of factors including age spots formed by beta-amyloid (aβ) misfolding and aggregation, neuronal Fiber Tangles (NFT) caused by hyperphosphorylation of intracellular tau, cholinergic nervous system dysfunction, oxidative stress damage, neuroinflammatory response, mitochondrial dysfunction, imbalance of metal ion homeostasis in vivo, and abnormal activation of apoptotic pathways. These pathological factors interweave with each other and act synergistically to drive neuronal damage and death together, ultimately leading to cognitive dysfunction. Due to the complexity of the pathogenesis of AD, single-target drugs often have difficulty achieving the desired therapeutic effect. Traditional anti-AD drugs such as cholinesterase inhibitors, NMDA receptor antagonists and the like only play roles aiming at a single pathological link, have limited clinical effects and cannot delay the progress of diseases. Therefore, multi-target drug design for multiple key pathological targets has become a core hotspot and an important direction of current anti-AD drug development. Monoamine oxidase-B (MAO-B) acts as a key enzyme involved in neurotransmitter metabolism in the brain, with its activity increasing significantly with age and with the pathological course of AD, especially in the AD patients with increased concentration around senile plaques in the brain. Abnormal elevation of MAO-B activity leads to exhaustion of neurotransmitters such as dopamine in brain, and simultaneously generates a large amount of active oxygen free radicals with neurotoxicity, exacerbates oxidative stress injury, and further promotes aggregation of Abeta protein and hyperphosphorylation of tau protein to form malignant circulation of pathological injury. A large number of researches prove that the MAO-B inhibitor can play a role in neuroprotection by inhibiting enzyme activity, reducing free radical generation, regulating neurotransmitter balance and other ways, and provides an important target point for AD treatment. Oxidative stress is one of the key pathological links in the pathogenesis of AD. Abnormal substance metabolism and energy metabolism in brain tissues of AD patients cause unbalance of free radical generation and removal, excessive free radicals cause lipid peroxidation, protein oxidation and nucleic acid damage, and then induce apoptosis of nerve cells, thereby exacerbating the characteristic neuropathological changes of AD. Research shows that the antioxidant can play a role in protecting the onset of AD and delaying the progression of the disease through mechanisms of scavenging active oxygen free radicals, inhibiting oxidative stress reaction, relieving nerve cell injury and the like, so that the small molecular compound with antioxidant activity becomes an important direction for developing anti-AD drugs. Amyloid plaques formed by aβ aggregation are one of the most typical pathological features of AD, and the amyloid hypothesis suggests that abnormal production and imbalance in clearance of aβ in the brain is a central initiating factor in the pathogenesis of AD. While in pathological conditions, APP is continuously cleaved by beta-secretase (BACE-1) and gamma-secretase to generate excessive Abeta (mainly Abeta 1-40 and Abeta 1-42 with stronger neurotoxicity), and Abeta degrading enzyme (such as enkephalinase and insulin degrading enzyme) has reduced activity, so that Abeta is aggregated in brain to form insoluble oligomers and senile plaques, neurotoxicity is caused, and neuronal death and cognitive dysfunction are finally caused. Therefore, inhibition of aβ aggregation and promotion of aβ clearance have become key targets for anti-AD drug development. In addition, the decline of cholinergic nervous system functions is