阅读说明：本技术 一种具有神经保护作用的药物及其应用 (Medicine with neuroprotective effect and application thereof ) 是由 冯莹 刘颖 于成龙 任春娜 杨雪琦 郭玲 于 2020-04-30 设计创作，主要内容包括：本发明提供了一种具有神经保护作用的药物及其应用,所述药物为茶黄素-3’-没食子酸酯,其结构如式(I)所示。所述的式(I)化合物在抑郁性神经症方面具有明显效果,茶黄素-3’-没食子酸酯的抗抑郁作用主要通过提高脑内5-HT和DA的含量,提高突触间隙神经递质浓度而实现,能够对神经紧张症状有明显的缓解和治疗作用,本发明茶黄素-3’-没食子酸酯在心脏神经症方面同样也具有较好的疗效。(The invention provides a medicine with a neuroprotective effect and application thereof, wherein the medicine is theaflavin-3' -gallate, and the structure of the medicine is shown in a formula (I). The compound of the formula (I) has obvious effect on depressive neurosis, the antidepressant effect of theaflavin-3 '-gallate is realized by mainly improving the content of 5-HT and DA in brain and improving the concentration of synaptic interstitial neurotransmitter, and the compound can obviously relieve and treat nervous tension symptoms, and the theaflavin-3' -gallate also has better curative effect on cardiac neurosis.)

1. A medicine with neuroprotective effect is theaflavin-3 '-gallate or its pharmaceutical derivatives, the structure of the theaflavin-3' -gallate is shown as the following formula (I):

2. the neuroprotective agent according to claim 1, wherein the derivative is a pharmaceutically acceptable acid, ester or salt, and the salt is a potassium, sodium or ammonium salt.

3. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 or 2 and/or a pharmaceutically acceptable derivative thereof.

4. The pharmaceutical composition of claim 3, wherein the pharmaceutical composition is in the form of: tablet, capsule, granule or injection.

5. The pharmaceutical composition according to claim 4, wherein the granules comprise the compound represented by formula (I) and a pharmaceutical adjuvant, and the pharmaceutical adjuvant comprises at least one of beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropylcellulose, and povidone K30.

6. The pharmaceutical composition of claim 4, wherein the injection comprises the compound of formula (I) and an acceptable carrier, and the acceptable carrier is one of water for injection, mannitol, sodium chloride or glucose or any mixture thereof.

7. The pharmaceutical composition according to claim 4, wherein the capsule comprises the compound of formula (I), microcrystalline cellulose, sodium carboxymethyl starch, and sodium lauryl sulfate, magnesium stearate.

8. The pharmaceutical composition of claim 7, wherein the capsule is prepared by the following method: mixing the compound shown in the formula (I), microcrystalline cellulose, sodium carboxymethyl starch and sodium dodecyl sulfate, performing dry granulation by a rolling method, mixing with a proper amount of magnesium stearate, and filling into hollow capsules to prepare the compound.

9. Use of theaflavin-3' -gallate and/or a pharmaceutically acceptable derivative thereof as set forth in claim 1 or 2 in the preparation of a medicament for treating nervous tension.

10. The use according to claim 9, wherein the nervous tone comprises depressive neurosis and cardiac neurosis.

Technical Field

The invention belongs to the technical field of medicines, particularly relates to a medicine with a neuroprotective effect and application thereof, and more particularly relates to theaflavin-3' -gallate or a pharmaceutical derivative thereof and application thereof.

Background

Gallic acid is also called as "Galla chinensisAcid "," gallic acid ". The name is 3,4, 5-trihydroxybenzoic acid. Molecular formula C₇H₆O₅. The polyphenol compound is widely existed in plants such as rhubarb palmate, eucalyptus robusta, dogwood and the like, and is widely applied to the fields of food, biology, medicine, chemical industry and the like. The theaflavin-3' -gallate is a main monomer of theaflavins in black tea and is also one of main indexes of color and flavor of black tea soup. The existing literature shows that theaflavin has various pharmacological and health-care functions, such as blood fat reduction, oxidation resistance, aging resistance and the like.

In terms of biological activity: gallic acid has antiinflammatory, antimutagenic, antioxidant, and free radical scavenging effects; meanwhile, the gallic acid has the anti-tumor effect and can inhibit the metastasis of mast cell tumor, thereby prolonging the life cycle; is also a relatively suitable candidate drug for killing trypanosomes; has protective effect on liver, and can resist carbon tetrachloride-induced physiological and biochemical transformation of liver; vascular endothelium-dependent contraction and endothelium-dependent relaxation can be induced by inhibiting the production of endothelial NO.

In the aspect of medical application: (1) and (3) antibacterial and antiviral: has inhibitory effect on Staphylococcus aureus, Sarcina, alpha-type Streptococcus, Neisseria, Pseudomonas aeruginosa, Shigella flexneri, Salmonella typhi Hd, and Salmonella paratyphi A in vitro, with an inhibitory concentration of 5 mg/mL. In vitro, the compound has bacteriostasis to 17 fungi at a concentration of 3 percent and also has certain bacteriostasis to influenza virus. Can be used for treating bacillary dysentery. Has astringent, hemostatic, and antidiarrheal effects. (2) And (3) tumor resistance: has strong inhibitory effect on mouse lung adenoma caused by morpholine and sodium nitrite.

Neurosis, a general term for a group of mental disorders including neurasthenia, obsessive-compulsive disorders, anxiety disorders, phobias, somatoform disorders, neurotic depression, etc., afflicts patients and interferes with mental or social functioning, but does not have any demonstrable physical basis. The course of the disease is mostly persistent or episodic.

The clinical table has the following components: 1. clinical symptoms of vegetative nerve functional disturbance

(1) Mental fatigue associated with mental excitement is manifested by increased associative memory, decreased mental labor rate, weak physical strength, fatigue feeling, etc.; (2) emotional symptoms are manifested as annoyance, irritability, nervousness, etc.; (3) sleep disorders are mainly manifested as insomnia; (4) discomfort of the head, feeling of tension headache, heavy sensation of the head, tight sensation of the head, etc.; 5) visceral dysfunction, gastrectasia, borborborygmus, constipation or diarrhea; palpitation, chest distress, short breath, limb paralysis, asthenia, and dying sensation; low heat; positive skin scratch; irregular menstruation for female, spermatorrhea and impotence for male.

2. Clinical symptoms of vegetative nerve functional disturbance of heart and stomach and intestine

The functional disorder of vegetative nerve of heart, also called as cardioneurosis, is a syndrome of vegetative nerve of cardiovascular system under the mediation, influenced by mental factors. Clinically, the symptoms of precordial pain, palpitation, shortness of breath, hyperventilation and dying sensation are the main symptoms, and in addition, the symptoms of hypodynamia, dizziness, hyperhidrosis, insomnia and the like are also caused.

In the process of antibacterial and antiviral research on gallic acid derivatives, the inventor of the application unexpectedly discovers that the gallic acid derivatives, especially theaflavin-3' -gallate, have obvious treatment effect on neurosis, especially depressive neurosis and cardiac neurosis. The mechanism and the application of the compounds in the treatment of diseases such as nervous tension and the like are not reported.

Disclosure of Invention

The invention provides a gallic acid derivative and application thereof, and through research and a large number of experiments, the inventor surprisingly discovers theaflavin-3 '-gallate and a pharmaceutical derivative thereof, and the theaflavin-3' -gallate and the pharmaceutical derivative thereof have good curative effect on neurosis as a medicine.

The above object of the present invention is achieved by the following technical solutions:

a medicine with neuroprotective effect is theaflavin-3 '-gallate or its pharmaceutical derivatives, the structure of the theaflavin-3' -gallate is shown as the following formula (I):

the pharmaceutically acceptable derivative is acid, ester or salt, and the salt is sodium salt, potassium salt or ammonium salt.

It is a further object of the present invention to provide pharmaceutical compositions of the compounds of formula (I) as pharmaceutically active ingredients.

The pharmaceutical composition is a pharmaceutical composition which takes the compound of the formula (I) or the pharmaceutically acceptable salt as a pharmaceutical active ingredient; specifically, the pharmaceutical composition refers to that in the medicine, besides the main active ingredients of the theaflavin-3 '-gallate and/or the pharmaceutically acceptable salts of the theaflavin-3' -gallate, the pharmaceutical composition can also contain minor ingredients which do not influence the active ingredients and/or pharmaceutically acceptable carriers and auxiliary materials necessary for various preparations; the dosage forms of the pharmaceutical composition comprise tablets, capsules and granules for oral administration and injection for injection; for example, when the pharmaceutical composition is a tablet for oral administration, it may contain conventional excipients such as binders, fillers, diluents, tabletting agents, lubricants, disintegrants, coloring agents, flavoring agents and wetting agents, and the tablet may be coated if necessary; suitable bulking agents include cellulose, mannitol, lactose and other similar bulking agents; suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives, such as sodium starch glycolate; suitable lubricants include, for example, magnesium stearate; suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.

Specifically, when the dosage form of the pharmaceutical composition is a capsule, the capsule is prepared by the following method: mixing the compound shown in the formula (I), microcrystalline cellulose, sodium carboxymethyl starch and sodium dodecyl sulfate, performing dry granulation by a rolling method, mixing with a proper amount of magnesium stearate, and filling into hollow capsules to prepare the capsule;

specifically, when the dosage form of the pharmaceutical composition is granules, the granules comprise the compound shown in the formula (I) and pharmaceutic adjuvants, wherein the pharmaceutic adjuvants comprise beta-cyclodextrin, gamma-cyclodextrin, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, povidone K30 and water; the preparation method comprises the following steps: mixing beta-cyclodextrin and gamma-cyclodextrin according to the prescription amount, adding water with the weight being 8 times that of the beta-cyclodextrin, grinding into paste, adding the paste into a colloid mill, adding theaflavin-3' -gallate according to the prescription amount, grinding, and carrying out spray drying to obtain cyclodextrin inclusion compound particles;

specifically, when the pharmaceutical composition is an injection, the injection comprises the compound shown in the formula (I) and an acceptable carrier, wherein the acceptable carrier is one or any mixture of water for injection, mannitol, sodium chloride or glucose;

it is a further object of the present invention to provide the use of a compound of formula (I) and/or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of neurological diseases.

The neurological disorders include depressive neurosis and cardiac neurosis.

Compared with the prior art, the invention has the following advantages:

1. the compound has no obvious toxic or side effect after long-term use through toxicological experiments;

2. animal model experiments of the compound show that the medicine has obvious curative effect on neurosis diseases such as depression and the like; specifically shown in the aspect of depressive neurosis, the antidepressant effect of theaflavin-3' -gallate is mainly realized by inhibiting the reabsorption of neurons on 5-HT and NE and improving the concentration of synaptic cleft neurotransmitter; also has better curative effect on the aspect of the cardiac neurosis.

Detailed Description

The selective β 1 adrenergic inhibitors of the invention are further described in the following examples, but it should be understood that the scope of the invention is not limited to the following examples.

Unless otherwise defined, all terms of art used hereinafter have the same meaning as commonly understood by one of ordinary skill in the art. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention.