CN-121652104-B - Piperidine derivative, pharmaceutical composition, application and preparation method thereof

Abstract

The application relates to the field of pharmaceutical chemistry, and particularly discloses a piperidine derivative, a pharmaceutical composition, application and a preparation method thereof. The piperidine derivative has the structure of general formula (I): . The piperidine derivative can obviously improve the learning and memory capacity of an Alzheimer disease model rat induced by Abeta, effectively reduce the activity of acetylcholinesterase in brain tissues, and provide a potential candidate for developing a novel Alzheimer disease treatment drug.

Inventors

• WANG XIAOYU
• FU HAIXIA
• ZHANG JIALI

Assignees

• 成都施贝康生物医药科技有限公司

Dates

Publication Date

20260505

Application Date

20260204

Claims (5)

1. 1. A piperidine derivative having the general formula (I), or a pharmaceutically acceptable salt thereof: (I) The piperidine derivative of formula (I) is selected from the following compounds:
2. 2. The piperidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt comprises acetate, ascorbate, benzoate, benzenesulfonate, citrate, fumarate, hydrochloride, hydrobromide, maleate, methanesulfonate, sulfate, bisulfate, nitrate, oxalate, phosphate, succinate, alkali metal salt, ammonium salt, basic amino acid salt, or pyridinium salt.
3. 3. Use of the piperidine derivative or pharmaceutically acceptable salt thereof according to claim 1 or 2 in the manufacture of a medicament for the prevention or treatment of alzheimer's disease.
4. 4. A pharmaceutical composition for preventing or treating neurodegenerative diseases, comprising a therapeutically effective amount of the piperidine derivative of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
5. 5. A process for the preparation of piperidine derivatives of general formula (I) according to claim 1 or 2, characterized in that it comprises: (a) Acylating halogenated acyl halide with a formula of X- (CH 2 ) n -C (O) Cl and methyl phenylacetate in the presence of a Lewis acid catalyst to obtain an intermediate a, wherein X is chlorine or bromine, and n is an integer from 1 to 8; (b) Enabling the intermediate a and 4- (benzhydryl) piperidine to undergo nucleophilic substitution reaction under alkaline conditions to obtain an ester intermediate b; (c) And (3) carrying out hydrolysis reaction on the ester intermediate b under alkaline condition, and converting the terminal methyl ester group into carboxyl to obtain the piperidine derivative with the general formula (I).

Description

Piperidine derivative, pharmaceutical composition, application and preparation method thereof Technical Field The application relates to the field of pharmaceutical chemistry, in particular to a piperidine derivative, a pharmaceutical composition, application and a preparation method thereof. Background Alzheimer's Disease (AD) is a progressive neurodegenerative disease, which is manifested clinically by dysmnesia, cognitive decline and abnormal behavior, severely affecting the quality of life and social function of patients. The pathogenesis is complex, and the pathogenesis of the beta-amyloid (Abeta) is related to various pathological processes such as beta-amyloid deposition, tau protein hyperphosphorylation, cholinergic system hypofunction, oxidative stress, neuroinflammation and the like. Among them, central cholinergic system function decline is closely related to cognitive dysfunction, and abnormal increase of acetylcholinesterase (AChE) activity leads to decrease of acetylcholinesterase level, further impairing learning and memory functions. In the development of the existing medicines, the piperidine compounds can be used in the structural design of the medicines of the central nervous system due to moderate alkalinity, good conformational flexibility and better central nervous system exposure property. However, most of the piperidine derivatives known so far are still not ideal in improving cognitive function and regulating cholinergic system, and particularly it is difficult to achieve a remarkable and stable recovery of cognitive function in animal models. Furthermore, these compounds have limited ability to inhibit AChE activity and are not effective in restoring cholinergic neurotransmission, and thus their use in the treatment of alzheimer's disease is limited. Although structurally similar piperidine derivatives have been reported (e.g., carebastine), they are flat in pharmacological activity and have a clear gap from positive control drugs. Thus, there is an urgent need in the art to develop a novel class of piperidine derivatives that are reasonably optimized in structure, have significant cognitive improvement effects and potent AChE inhibitory activity, to provide more effective alzheimer's disease treatment strategies. Disclosure of Invention In order to solve the technical problems, the application provides a piperidine derivative, a pharmaceutical composition, application and a preparation method thereof. The application can obviously improve learning and memory functions and effectively regulate cholinergic system functions by carrying out specific functional group modification on the piperidine compounds, thereby providing a new drug candidate for clinical treatment of Alzheimer disease. In a first aspect, the present application provides a piperidine derivative of general formula (I), or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof: (I) Wherein, the R 1、R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl or cycloalkyl; R 3 is selected from hydrogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, halogen; n is an integer of 1 to 8, and when n is 3, R 1 and R 2 cannot be methyl at the same time. Further, in the above general formula (I): Each R 1、R2 is independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl; The C 1-6 alkyl or C 3-6 cycloalkyl group may be optionally substituted with one or more substituents selected from deuterium, halogen, hydroxy, cyano, amino or nitro; Further, in the above general formula (I): R 3 is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy. Further, in the above general formula (I): R 1、R2 are each independently selected from hydrogen, substituted or unsubstituted alkyl; R 3 is hydrogen; n is an integer of 1 to 6, and when n is 3, R 1 and R 2 cannot be methyl at the same time. Further, the piperidine derivative is selected from the following compounds: Further, the pharmaceutically acceptable salts include acetate, ascorbate, benzoate, benzenesulfonate, citrate, fumarate, hydrochloride, hydrobromide, maleate, methanesulfonate, sulfate, bisulfate, nitrate, oxalate, phosphate, succinate, alkali metal salt, ammonium salt, basic amino acid salt, or pyridine salt. Further, hydrogen in the above compound structure may be substituted with 1 to more deuterium. In a second aspect, the present application provides the use of a piperidine derivative as described above, or a pharmaceutically acceptable salt, ester, solvate or stereoisomer thereof, in the manufacture of a medicament for the prevention or treatment of a neurodegenerative disease. Further, the above-mentioned prevention of neurodegenerative diseases includes at least one of Alzheimer's disease, parkinson's disease, huntington's disease, amyotrophic lateral sclerosis, forehead leaf dementia, multiple system atrophy, progressive supranuclear palsy, progressive amyotrophic lateral sclerosis and progressive muscular dy