阅读说明：本技术 一种酰胺类化合物、制备方法和医药用途 (Amide compound, preparation method and medical application ) 是由 王潘 李军 张丽萍 赵怡楠 娄勇 高改 赵璇 谢治深 张振强 徐江雁 于 2020-07-29 设计创作，主要内容包括：本发明公开了一种酰胺类化合物、制备方法和医药用途。本发明首次从中药华山参中发现一种新式Ⅰ或Ⅱ化合物,提供了该化合物的制备方法,并发现其可以用于制备CREB激活剂药物的医药用途,本领域技术人员知道：CREB与神经元保护息息相关；CREB在神经元的发育、再生、突触形成及修复等中起着关键性的作用,是调节中枢神经系统功能的关键性因子之一；CREB的激活与促进学习记忆有关；CREB的激活与抗焦虑、抗抑郁有关。因此,酰胺类式Ⅰ或Ⅱ化合物具有开发成神经元保护,促进神经元发育、再生、突触形成及修复,促进学习记忆,以及抗焦虑或抗抑郁药物的前景。(The invention discloses an amide compound, a preparation method and medical application. The invention discovers a novel compound I or II from the traditional Chinese medicine radix physochlainae for the first time, provides a preparation method of the compound, and discovers that the compound can be used for preparing the medical application of CREB activator medicines, and the technical personnel in the field know that: CREB is closely related to neuronal protection; CREB plays a key role in the development, regeneration, synapse formation and repair of neurons, and is one of the key factors for regulating central nervous system functions; activation of CREB is associated with promotion of learning and memory; activation of CREB is associated with anxiolytic, antidepressant activity. Therefore, the amide compounds shown in formula I or II have the prospect of being developed into medicaments for protecting neurons, promoting the development, regeneration, synaptogenesis and repair of the neurons, promoting learning and memory, and resisting anxiety or depression.)

1. An amide compound is characterized in that the chemical structure is shown as formula I or II:

2. a process for the preparation of a compound of formula i or ii as defined in claim 1, comprising the steps of:

step S1, crushing Chinese herbal medicine physochlaina root, extracting with an alcohol-water solution, and concentrating an extracting solution to obtain a crude extract;

step S2, suspending the crude extract obtained in the step S1 with a proper amount of water, extracting with n-butanol, collecting n-butanol extract, and concentrating to obtain n-butanol extract;

step S3, separating the n-butanol extract obtained in step S2 by normal phase silica gel column chromatography, and mixing eluates containing the compound of formula I or II to obtain the compound enrichment of formula I or II; and then the enriched substance is subjected to reverse phase silica gel column chromatography, and eluates containing the compound of the formula I or II are respectively combined, concentrated and dried respectively to obtain the compound of the formula I or II.

3. The method of claim 2, wherein: the alcohol aqueous solution in step S1 is 95% ethanol.

4. The method according to claim 2, wherein the elution solvent of the normal phase silica gel column chromatography in step S3 is a dichloromethane-methanol mixed solvent, and the volume ratio and the elution amount of the two mixed solvents are, in order: 20:1, 4 column volumes; 10:1, 4 column volumes.

5. The method of claim 2, wherein the elution solvent of the reversed phase silica gel column chromatography in step S3 is 30% methanol.

6. The use of a compound of formula i or ii as claimed in claim 1 for the preparation of a CREB agonist drug.

7. The use of a compound of formula i or ii as claimed in claim 1 for the preparation of a medicament for neuronal protection.

8. The use of a compound of formula i or ii as claimed in claim 1 for the preparation of a medicament for promoting neuronal development, regeneration, synapse formation and repair.

9. The use of a compound of formula i or ii as claimed in claim 1 for the preparation of a medicament for promoting learning and memory.

10. The use of compounds of formula i or ii according to claim 1 for the preparation of anxiolytic or antidepressant medicaments.

Technical Field

The invention belongs to the field of natural medicinal chemistry, relates to separation, preparation and application of a novel natural compound, and particularly relates to an amide compound, a preparation method and medical application.

Background

The radix physochlainae is a dried root and rhizome of Physochlaina influndibularis Kuang of a plant of ascochyta of solanaceae, is firstly found in supplement of compendium of materia medica of Ministry of Zhao, also named radix physochlainae, radix Ginseng, radix Fraxini, white-haired ginseng, Zhan grass and the like, is a perennial herb, is a special medicinal plant in China, is mainly distributed from the middle part of Qinling of Shaanxi to the east part, the western part and the south part of Henan and the south part of Shanxi, and is classified as a national secondary protective plant. The root of the Chinese medicinal herb is hot in nature, sweet in taste, slightly bitter and astringent, and has the effects of nourishing and strengthening body, relieving asthma and cough, tonifying deficiency and warming middle energizer, tranquilizing and allaying excitement, removing wind-cold, strengthening spleen and stomach and the like. The functions are mainly used for treating cold phlegm cough, palpitation, insomnia, easy fright and other symptoms, and the traditional Chinese medicine is often used as a specific medicine for treating cough, asthma and phthisis in folk.

CREB is an abbreviation for cAMP response element binding protein, which was found in the late 80 s. CREB consists of 341 amino acid residues with a molecular weight of 43000. The molecular structure is divided into two regions, the N-terminal region is involved in the function of regulating transcription, and the C-terminal region is the site where a promoter binds. CREB is an intracellular regulator that regulates transcription through autophosphorylation. The research finds that CREB plays a key role in certain neurophysiologic activities such as development, regeneration, synaptogenesis and repair of neurons, and is one of key factors for regulating the functions of the central nervous system. The concrete functions include:

the relationship between CREB and learning and memory

The initial study of the role of CREB in learning and memory came from sea rabbits. Multiple electrical stimulation to the tail of the sea hare can facilitate the long-term formation of synaptic connection between sensory neurons and motor neurons participating in the tail contraction reflex of the sea hare, and can last for several days; in contrast, the short-term facilitation duration caused by a single stimulus is short. Long-term facilitation mediates CREB phosphorylation by causing cAMP to increase, which in turn induces expression of the relevant genes, ultimately leading to protein synthesis-dependent structural changes in sensory neurons. Later, in the study of learning memory and plasticity molecular mechanisms, the sea hare shows long-term facilitation similar to the sensitization behavior of memory, and the long-term facilitation needs the participation of a cAMP-CREB signal path, so that the mechanism of learning memory activity-dependent gene expression is proposed for the first time. Inhibition of mRNA and protein expression during or after learning and memory in animals will block memory storage and long term memory acquisition. In addition, studies on learning and memory of drosophila, mice, rats, etc., indicate that the formation of long-term memory plays an important role from non-vertebrate to mammalian CREB. In the fruit fly long-term memory research, after a researcher induces the expression of a CREB (growth hormone receptor) arrestin by using a thermal shock condition, the formation of long-term memory is blocked, and on the contrary, the formation of the long-term memory is promoted by inducing the expression of a CREB activator protein. (literature: Yuereyuan, etc., CREB research progress, China journal of bioengineering, 2003; Gejun, etc., CREB transcription factor and phosphorylation signal pathway research progress, Anhui agricultural science, 2010, Song Syngnathus, etc., regulation and function of CREB signal pathway in nervous system, Chinese biochemistry and molecular biology newspaper, 2013), Beijing university Life sciences institute, Pujun, etc.

The relationship between CREB and emotions such as anxiety and depression

Related researches at home and abroad find that CREB plays an important regulation and control role in maintaining normal emotion; animal experiment results also show that the insufficient synthesis or the reduced phosphorylation degree of CREB in hippocampal tissues can cause a series of emotional disorders such as anxiety, depression and the like of animals. Researches show that the function of a cANP signal path in cerebral nerve cells of a depression patient is disordered, the mRNA expression of CREB of frontal lobe cortex of the depression patient is reduced, and an antidepressant plays an antidepressant role by increasing the content of CREB in cells. Through research on pathogenesis of depression, Nakagawa discovers that stress and depression lower a cAMP CREB system, reduces the expression of CREB and p-CREB, and further reduces the expression of brain-derived nerve growth factor and a receptor tyrosine kinase B thereof (reference: CREB has relation with learning, memory and emotion, journal of medical Forum, 2008).

The research on amide compounds in the panax quinquefolius is very little, and the report on CREB activation effect of the amide compounds is not found.

Disclosure of Invention

The invention aims at providing an amide compound, a preparation method of the amide compound and application of the amide compound in preparing CREB agonist drugs.

The above purpose of the invention is realized by the following technical scheme:

an amide compound is characterized in that the chemical structure is shown as formula I or II:

a process for preparing a compound of formula i or ii as described above comprising the steps of:

step S1, crushing Chinese herbal medicine physochlaina root, extracting with an alcohol-water solution, and concentrating an extracting solution to obtain a crude extract;

step S2, suspending the crude extract obtained in the step S1 with a proper amount of water, extracting with n-butanol, collecting n-butanol extract, and concentrating to obtain n-butanol extract;

step S3, separating the n-butanol extract obtained in step S2 by normal phase silica gel column chromatography, and mixing eluates containing the compound of formula I or II to obtain the compound enrichment of formula I or II; and then the enriched substance is subjected to reverse phase silica gel column chromatography, and eluates containing the compound of the formula I or II are respectively combined, concentrated and dried respectively to obtain the compound of the formula I or II.

Further, the alcohol aqueous solution in step S1 is 95% ethanol.

Further, the elution solvent of the normal phase silica gel column chromatography in step S3 is a dichloromethane-methanol mixed solvent, and the volume ratio and the elution amount of the two in the mixed solvent are sequentially: 20:1, 4 column volumes; 10:1, 4 column volumes.

Further, the elution solvent of the reverse phase silica gel column chromatography in step S3 is 30% methanol.

The compound of the formula I or II is used for preparing CREB stimulant medicines.

The medical application of the compound shown in the formula I or II in preparing neuron protective medicines.

The compound of the formula I or II is used for preparing medicines for promoting the development, regeneration, synaptogenesis and repair of neurons.

The medical application of the compound shown in the formula I or II in preparing the medicine for promoting learning and memory.

The compound of the formula I or II is used for preparing anxiolytic or antidepressant medicines.

Has the advantages that:

the invention discovers a novel compound with a structural formula of formula I or II for the first time, provides a preparation method of the compound, discovers that the compound has CREB (CREB agonistic activity), and can be used for preparing CREB agonistic drugs. Those skilled in the art know that: CREB is closely related to neuronal protection; CREB plays a key role in the development, regeneration, synapse formation and repair of neurons, and is one of the key factors for regulating central nervous system functions; activation of CREB is associated with promotion of learning and memory; activation of CREB is associated with anxiolytic, antidepressant activity. Therefore, the novel compound with the structural formula I or II provided by the invention has the prospect of developing a medicament for protecting neurons, promoting the development, regeneration, synapsis formation and repair of the neurons, promoting learning and memory, and resisting anxiety or depression.

Drawings

FIG. 1 is a structural diagram of a compound of formula I or II

FIG. 2 is a nuclear magnetic hydrogen spectrum of compound I;

FIG. 3 is a nuclear magnetic carbon spectrum of compound I;

FIG. 4 is a nuclear magnetic DEPT135 spectrum of compound I;

FIG. 5 is a nuclear magnetic hydrogen spectrum of compound II;

FIG. 6 is a nuclear magnetic carbon spectrum of compound II;

FIG. 7 is a nuclear magnetic DEPT135 spectrum of compound II;

FIG. 8 is the primary HMBC signal of a compound of formula I or II;

fig. 9 is CREB relative fluorescence intensity.

Detailed Description

The following detailed description of the present invention is provided in connection with the accompanying drawings and examples, but not intended to limit the scope of the invention.