阅读说明：本技术 一种吡喃酮类化合物及其用途 (Pyrone compound and application thereof ) 是由 陈平 唐宇 于 2019-02-21 设计创作，主要内容包括：本发明提供了一种吡喃酮类化合物及其用途,其属于乙酰胆碱酯酶抑制剂,对这类化合物进行乙酰胆碱酯酶抑制实验,实验结果表明化合物Id对乙酰胆碱酯酶抑制效果明显优于阳性对照药物塔克林,有望开发为治疗和预防阿尔茨海默相关疾病的药物或其前体药物。(The invention provides a pyrone compound and application thereof, belonging to acetylcholinesterase inhibitors, and the compounds are subjected to acetylcholinesterase inhibition experiments, and the experimental results show that the acetylcholinesterase inhibition effect of the compound Id is obviously better than that of a positive control medicament, namely tacrine, and the compound Id is expected to be developed into a medicament for treating and preventing Alzheimer related diseases or a prodrug thereof.)

1. A pyrone compound characterized by the following structural formula:

wherein: r¹Hydrogen, alkyl of 1 to 6 carbons, aryl, heterocycle, ester group, etc.; r²、R³、R⁴、R⁵、R⁶(substituents are independent of one another) = hydrogen, mono-or polysubstituted halogen, alkyl of 1 to 6 carbons, electron donating substituents such as: oxygen, sulfur, selenium and the like; electron-withdrawing substituent: such as: ester group, aldehyde, ketone, nitro, trifluoromethyl, cyano and other related substituents.

2. Such compounds according to claim 1 preferably represent the compounds Id, R¹Is benzyl, R²，R³，R⁶The substituents being hydrogen atoms, R⁴And R⁵The substituent is methoxy.

3. The compound of claim 1, wherein the compound has a backbone structure in which each of the A and B rings has an unsaturated double bond, and the double bonds are conjugated.

4. The compound of claim 1 wherein the C-ring is a six-ring unsaturated lactone structure.

5. The compound of claim 1 wherein the D ring is a mono-or poly-substituted aromatic or heteroaromatic ring.

6. The use of the compounds according to claim 1 in the development of medicaments for the prevention and treatment of alzheimer's disease.

Technical Field

The invention relates to a compound and the technical field of medicinal chemistry thereof, in particular to a pyrone compound structure and application thereof in the field of prevention and treatment of Alzheimer's disease.

Background

Alzheimer's Disease (AD) is a neurodegenerative disease that is clinically manifested by progressive deterioration of cognitive and memory functions, progressive decline in daily living abilities, and accompanying various neuropsychiatric symptoms and behavioral disorders. At present, main obstacles of AD drug development are that drugs lack clinical application indexes and are not strong in specificity, and clinical tests fail due to adverse reactions, insufficient curative effects and the like. Nevertheless, there are still 82 AD drugs in clinical stage, 18 of which enter stage III/IV. Currently, about 4000 million patients suffer from alzheimer disease worldwide, and the number of patients will continue to increase in the coming years, the economic burden will further increase, and the number of AD patients will exceed 1 hundred million, that is, 3 times of the current number by 2050 years, which inevitably leads to corresponding increase of economic loss. The difficulty in the AD drug development field has three reasons: 1) the medicine lacks clinical application indexes, such as difficulty in passing through a blood brain barrier, adverse reaction, easy generation of drug resistance and the like; 2) due to the complex pathological mechanism and clinical manifestations of AD, no suitable animal research model exists at present; 3) many of the key mechanisms have not been fully demonstrated by the current hypothesis.

At present, the treatment of AD is mainly symptomatic treatment with AChE inhibitors (achei inhibitors) and N-methyl-D-aspartate (NMDA) receptor antagonists. Among the AChEIs currently used in clinical practice, there are tacrine, donepezil, rivastigmine and galantamine. Donepezil is a reversible inhibitor of AChE, belongs to benzyl piperidine compounds, has a rapid increase of acetylcholine level in brain after oral administration, has no hepatotoxicity, is a chemically specific piperidine-base acetylcholinesterase inhibitor, is a preferred drug for most of light and moderate AD patients, is already marketed in more than 40 countries and regions, and enters the medical insurance catalogue of China in 2009. In recent years, the research of AChEI has mainly focused on plant-derived cholinesterase inhibitors and derivatives thereof, including alkaloids, terpenoids, shikimic acid derivatives, and the like. However, the effect of the synthetic cholinesterase inhibitors extracted directly from them or simulated is not ideal, for example, phase II clinical trials of physostigmine phenylalanine derivatives show that they can improve cognitive performance of AD patients, while phase III clinical trials find that the differences are not statistically significant compared with those of placebo patients. Therefore, the cholinesterase inhibitor with better curative effect is expected to be researched by further carrying out group modification on the plant-derived cholinesterase inhibitor or the derivative thereof

Arisugacin A is a natural product extracted from penicillium Fo-4259, has obvious acetylcholinesterase selective inhibition bioactivity, and has certain potential value for treating Alzheimer disease. The invention combines and optimizes the high-efficiency and low-toxicity donepezil key pharmacodynamic group (benzyl piperidine) and the natural product Arisugacin A with a novel structure through a skillful structure, simplifies the structure of the natural product, and simultaneously introduces the benzyl piperidine structure to ensure that the extending direction of the whole molecule is consistent with that of the natural product and the activity is kept. The compound has a brand-new parent nucleus structure and a novel structure, and is not protected by related compound patents.

The invention synthesizes a series of Arisugacin analogues to carry out biological activity screening so as to seek a chemical entity which has novel structure, better activity and smaller toxicity and is used for preventing and treating the Alzheimer disease. Through screening of acetylcholinesterase inhibition activity, the acetylcholinesterase inhibition activity of the pyranone compound Id is found to be obviously superior to that of the positive control Tacrine.

The innovation point of the invention is that aiming at the defect of the traditional 'one molecule and one target' mode of the traditional pharmaceutical research and development, according to the characteristics of AD pathogenic multifactorial factors, a new drug design strategy needs to be developed, namely, the multiple targets are regulated or the same target is regulated in a coordinated way to increase the success possibility of the result. The invention discloses a chemical entity-based reasonable design, finds a compound with a novel structure, determines the chemical structure of the compound through technologies such as high-resolution mass spectrometry, nuclear magnetic resonance and the like, can effectively inhibit the activity of acetylcholinesterase, and can be applied to research and development of medicaments for preventing and treating Alzheimer's disease.

Disclosure of Invention

The invention aims to provide a compound with a novel structure based on reasonable design of chemical entities, which can effectively inhibit the activity of acetylcholinesterase and research the application of the compound in the development of medicaments for treating Alzheimer's disease.

The pyrone compound provided by the invention is characterized by having the following structural formula I:

wherein: r¹Hydrogen, alkyl of 1 to 6 carbons, aryl, heterocycle, ester group, etc.; r²、R³、R⁴、R⁵、R⁶(substituents are independent of each other) = hydrogen; one or more substituted halogens, alkyl groups of 1 to 6 carbons, electron donating substituents such as: oxygen, sulfur, selenium and the like; electron-withdrawing substituent: such as: ester group, aldehyde, ketone, nitro, trifluoromethyl, cyano and other related substituents.

In the skeleton structure of the compound, both the ring A and the ring B have an unsaturated double bond, and the two double bonds are conjugated structures. In the skeleton structure of the compound, a C ring is a six-ring unsaturated lactone structure; the D ring is a mono-or poly-substituted aromatic, or heteroaromatic ring.

The invention synthesizes the following four representative compounds Ia, Ib, Ic and Id, which comprise the representative compound Id of the invention, and the compounds Ia, Ib and Ic are similar compounds with different structural units of the compounds changed respectively, and are subjected to screening experiment comparison of acetylcholinesterase inhibition activity, so that the key skeleton structure of the activity is shown as a structural formula I, and the activity is reduced or disappeared after the skeleton structure of the compounds is changed.

The structures are all new compounds, are not reported in documents, and are expected to be developed into medicaments for treating the Alzheimer disease by determining the structures through nuclear magnetic resonance and high resolution. In vitro acetylcholinesterase inhibition activity screening experiments prove that the acetylcholinesterase inhibition activity of the compound 4 is obviously superior to that of a positive control Tacrine (Tacrine).

Data representing compound Id are as follows:¹H NMR (500 MHz, CDCl₃) 7.40 (dd,J= 8.5,2.0 Hz, 1H), 7.37 - 7.34 (m, 4H), 7.32 - 7.28 (m, 2H), 6.92 (d,J= 8.5 Hz,1H), 6.39 (s, 1H), 6.20 (s, 1H), 5.13 - 5.09 (m, 1H), 3.95 (s, 3H), 3.94 (s,3H), 3.66 (s, 2H), 3.35 (s, 2H), 3.28 (s, 2H) 。

detailed description of the preferred embodiments

The following examples are helpful in understanding the present invention, but are not intended to limit the scope of the present invention.