CN102336795A - Eucommia ulmoides Oliv active monomer compound and preparation method thereof as well as medicament composition and application thereof - Google Patents

Abstract

The invention discloses an active monomer compound of Eucommia ulmoides. The structural formula of the compound is:

, and also discloses a preparation method of the compound, a pharmaceutical composition containing the compound and a pharmaceutical use thereof. The active monomer compound is extracted from Eucommia ulmoides, and can be extracted from eucommia bark, eucommia leaves, eucommia male flowers or whole Eucommia plants. The active monomer compound 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3,4 ,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7-di Oxygen-4'-methoxy isoflavone has been proved by experimental research to have significant nerve excitatory effect, and has less side effects, higher safety and can be taken for a long time. The invention provides an active monomer compound obtained from eucommia ulmoides and the effect of the compound on nerve stimulation, etc., and provides a new natural active substance for the research and development of novel central nervous system stimulation drugs and health food.

Description

Eucommia active monomer compound, preparation method, pharmaceutical composition and use

technical field

The present invention relates to the technical field of traditional Chinese medicine active monomer and its preparation, in particular to an active monomer compound of Eucommia ulmoides, a preparation method, a pharmaceutical composition and its use.

Background technique

Central nervous system (CNS) diseases in a broad sense include a variety of diseases, such as schizophrenia, depression, epilepsy, Alzheimer's disease, Parkinson's disease, neuropathic pain, and multiple sclerosis, among others. So CNS therapeutics are a huge class of drugs. In recent years, under the influence of the world financial crisis, the unemployment rate in various countries has been rising, and people's mental stress has increased, leading to a rapid increase in the incidence of mental diseases such as anxiety and depression. In addition, the global aging of the population has driven the global CNS drugs. Sales grew rapidly. According to a data released by the internationally renowned consulting company Frost & Sullivan, the total sales of central nervous system (CNS) drugs in the world in 2006 was 90 billion U.S. dollars, and in 2008 it had risen to 104.8 billion U.S. dollars, accounting for about 10% of the total sales of the international pharmaceutical market in that year. 1/7. In 2002, World Health Organization (WHO) officials predicted that by 2020, CNS drugs would account for about 14% of the total global pharmaceutical market. In fact, only 6 years later, that is, in 2008, the total global sales of CNS drugs This forecast figure was reached ahead of schedule. According to the analysis of WHO officials, the rapid rise in the incidence of depression in developed and developing countries and the aggravation of population aging are the two main reasons for the sharp increase in global CNS drug sales. Depression has now risen to become the world's largest mental illness, so the number and variety of antidepressant drugs on the market also rank first in CNS drugs. In 2008, the global sales of antidepressant drugs were about 19 billion to 19.1 billion US dollars.

Central nervous system stimulants are drugs that can increase the functional activity of the central nervous system. Various central nervous system stimulants can excite the entire central nervous system, but have a certain degree of selectivity to different parts of the central nervous system. Central stimulants can be divided into awakening drugs, methylxanthines, and psychostimulants. Commonly used resuscitation drugs include nicothamide, dimethylflurine, lobetaine, pentylenetetrazol, gram-brain fans, and cytochrome C. These drugs generally have a short action time, can be absorbed orally, and are mainly metabolized by the liver. They are used to treat respiratory failure and central depression caused by diseases or drugs. Methylxanthines include caffeine, theophylline, theobromine, etc., and their central excitatory effects are generally weak. Psychostimulants include amphetamine, methylphenidate, pemoline, ephedrine, and fenfluramine.

At present, the commonly used central nervous system stimulant drugs at home and abroad have certain side effects and dependence. A small dose can make drowsiness disappear, fatigue is relieved, the spirit is uplifted, and the thinking is quick. With the increase of the drug dose, not only the intensity of action increases, but also the scope of action on the central nervous system is also expanded, causing widespread excitement, and even convulsions. Depletion of energy leads to inhibition. If the dose is too large, it can cause convulsions, central nervous system depression and coma, and severe cases can be fatal. At present, central stimulants are mainly used to combat central respiratory failure caused by central depressant drug poisoning or certain infectious diseases. Their selectivity is generally not high, the safety range is small, the distance between the dose that excites the respiratory center and the dose that causes convulsions is small, and the risk is relatively high. The dose should be strictly controlled during application. Therefore, finding safer and more effective drugs has become a major topic in the field of central nervous system stimulant drug research.

The research results show that many traditional Chinese medicine ingredients have good biological activities and few adverse reactions, which is in line with the development trend of drugs from non-selective to high-efficiency, high-selectivity, and small side effects, and has broad application prospects. However, the composition of traditional Chinese medicine is complex, and the extraction, separation and purification of active compounds are difficult. At the same time, it is necessary to screen highly active compounds. At present, no single compound with neuroexcitatory activity in traditional Chinese medicine has been found in China. Exciting products need to be developed urgently. Extracting the active components of traditional Chinese medicine and proving its curative effect through animal experiments provides an effective way for the modernization of traditional Chinese medicine.

Eucommia ulmoides Oilv. is a unique medicinal plant in my country, accounting for about 95% of the world's total. According to incomplete statistics, the wild and planted Eucommia in the country has reached 10 million mu, and the wild and artificial planting area in Henan Province is more than 100 ten thousand mu. Modern medicine has proved that Eucommia has many functions such as regulating blood pressure, lowering blood sugar, regulating blood lipids, antibacterial and anti-inflammatory, inhibiting the growth of tumor cells, nourishing yin and tonifying kidney, strengthening muscles and bones, and delaying aging. In recent years, studies have shown that Eucommia bark and its seeds, leaves, and flowers all have effects on the central nervous system, but they have always shown sedative and hypnotic effects, and the specific active ingredients and mechanism of action have not yet been identified. Information on the application of active monomeric compounds of Eucommia in the field of central nervous system action.

Contents of the invention

The object of the present invention is to provide an active monomer compound of Eucommia ulmoides.

The purpose of the present invention is also to provide a preparation method of Eucommia active monomer compound.

The object of the present invention is also to provide a pharmaceutical composition containing the active monomer compound of Eucommia ulmoides.

The object of the present invention is also to provide the application of an active monomer compound of Eucommia ulmoides.

In order to achieve the above purpose, the technical solution adopted in the present invention is: an active monomer compound of Eucommia, the name of which is 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxy Methyl-3-((2S,3S,4S,5R)-3,4,5-trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo) - 2-(3,4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone, its structural formula is shown in formula Ⅰ:

Formula Ⅰ .

Enantiomers, tautomers, physiologically functional derivatives or pharmaceutically acceptable salts of the eucommia active monomer compound represented by formula I.

The preparation method of the active monomer compound of eucommia ulmoides shown in formula I, the compound is extracted from the traditional Chinese medicine Eucommia ulmoides, and the preparation process comprises the following steps:

(1) System solvent extraction process

Take Eucommia bark, Eucommia leaves, Eucommia male flowers or Eucommia whole plant to prepare ethanol extract, and then use the system solvent method to extract and separate extracts with different polarities, that is, sequentially use solvent petroleum ether, ethyl acetate and n-butanol at room temperature extracting the ethanol extract, then merging and concentrating extracts from the same solvent to obtain petroleum ether extract, ethyl acetate extract, and n-butanol extract respectively;

(2) Chromatographic separation process

The n-butanol extract is separated by silica gel column chromatography, the filler used in the silica gel column chromatography separation is 100-200 mesh silica gel, and the eluent is a chloroform-methanol mixed solution with a volume ratio of methanol of 20%, which is eluted to obtain The product is concentrated, and then separated by gel column chromatography. The filler of the gel column is Sephadex LH-20, which is eluted with methanol to obtain the active monomer compound of Eucommia ulmoides.

The preparation method of the ethanol extract is as follows: dry the eucommia bark, eucommia leaves, eucommia male flowers or the whole Eucommia ulmoides plant in the shade, pulverize, soak in ethanol with a mass percentage concentration of 70-95% for two weeks, and then recycle and soak at 65°C under vacuum conditions. solution, repeated three times, combined to obtain ethanol extract.

A pharmaceutical composition containing the active monomer compound of Eucommia represented by formula I, consisting of the active monomer compound of Eucommia represented by formula I, a pharmaceutically acceptable carrier and/or excipient, the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. Such as tablets, dispersible tablets, soft capsules, microcapsules, granules, pills, pellets, powders, drop pills, sustained-release preparations, controlled-release preparations, gastrointestinal localized preparations, oral liquid preparations, injections, powder injections, etc. .

Further, the active monomer compound of Eucommia represented by formula I is contained in the pharmaceutical composition in a weight percentage of 1% to 99%. Preferably, the active monomer compound of Eucommia represented by formula I is contained in the pharmaceutical composition in a weight percentage of 20%-80%.

The application of the eucommia active monomer compound represented by formula I in the preparation of central nervous system stimulating drugs and health food.

Application of enantiomers, tautomers, physiological functional derivatives or pharmaceutically acceptable salts of eucommia active monomer compounds represented by formula I in the preparation of central nervous system stimulating drugs and health food.

The eucommia active monomer compound represented by formula 1 provided by the present invention is extracted from eucommia ulmoides, and can be extracted from eucommia ulmoides bark, eucommia ulmoides leaves, eucommia ulmoides male flowers or whole Eucommia ulmoides plants. The active monomer compound 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3,4 ,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7-di Oxygen-4'-methoxy isoflavone has been proved by experimental studies to have significant excitatory effects on the central nervous system, with less side effects and higher safety.

The successful extraction and preparation of the eucommia active monomer compound of the invention ensures the stability of the dosage and reduces the dosage fluctuation caused by the decoction. Traditional Chinese medicine has strict regulations on the origin, planting and collection of medicines. The purpose is to ensure the quality of medicinal materials. In the final analysis, it is the stability of active ingredients. Eucommia also has other functions such as lowering blood pressure and anti-inflammation. The extraction and purification of neuroexcitatory active monomer compounds can avoid interference and antagonism between various drug effects. Therefore, determining and purifying the active ingredients of traditional Chinese medicine can transform the process control of traditional Chinese medicine quality into more convenient and accurate result control, and significantly enhance the efficacy of traditional Chinese medicine, which is conducive to the modernization of traditional Chinese medicine.

The eucommia active monomer compound represented by the formula I provided by the present invention is an active ingredient of a traditional Chinese medicine, has a good stimulating effect on the central nervous system, has no side effects and dependence, and can be taken for a long time. The invention provides an active monomer compound obtained from eucommia ulmoides and the effect of the compound on central nervous system stimulation, and provides new natural active substances for researching and developing new health food and central nervous system stimulating drugs.

The active monomer compound provided by the present invention is used as the active ingredient of the medicine, and can be added with auxiliary agents, and then made into various beverages through modern processes such as sterilization, canning, sealing, etc., or can be evaporated and concentrated into Oral liquid can also be dried with auxiliary materials. The auxiliary materials can be starch, dextrin, etc. After crushing, sugar, fruit juice and other powders can be added to make various granules, or auxiliary agents can be added, sterilized, canned, and sealed to make health nutrition. Meal, or dried into powder form. The active monomer compound provided by the present invention can also be made into pharmaceutical raw materials with excitatory effects on the central nervous system and conventional pharmaceutical dosage forms, such as tablets, capsules, granules, oral liquids and injections.

The Eucommia active monomer compound provided by the present invention is separated from Eucommia ulmoides, and its source is abundant, the extraction and separation process adopted is stable and easy, the quality is controllable, and the drug effect is certain, which can promote the search for new central nervous system excitatory drugs from traditional Chinese medicine It is of great significance to the comprehensive utilization of eucommia resources and the development and growth of eucommia industry.

Description of drawings

Fig. 1 is the mass spectrogram of the Eucommia ulmoides active monomer compound product obtained in the embodiment of the present invention 1;

Fig. 2 is the H-NMR nuclear magnetic spectrogram of the eucommia active monomer compound product obtained in the embodiment of the present invention 1;

Fig. 3 is the C ₁₃ -NMR nuclear magnetic spectrum of the Eucommia active monomer compound product obtained in Example 1 of the present invention.

Detailed ways

Example 1

The preparation method of the eucommia active monomer compound shown in formula I, the steps are as follows:

(1) System solvent extraction process

Eucommia ulmoides leaves were picked and cleaned to remove impurities, dried in the shade and then lightly crushed. Take 2500g of it, soak it in 30L of ethanol with a mass percentage of 75%, soak it for two weeks, recover the soaking solution (65°C, 0.08 mp) in vacuum and low temperature, repeat three times, and combine , to obtain ethanol extract, dry weight 442g, and then use the system solvent method to extract and separate the extracts of different polarities. Each solvent was repeatedly extracted four times, and each extract was concentrated to obtain various solvent extracts, including 29.0 g of petroleum ether extract, 50.7 g of ethyl acetate extract, and 128.2 g of n-butanol extract. The remaining aqueous phase obtained 343.0 g of water extract;

(2) Chromatographic separation process

The active monomer compound of Eucommia ulmoides shown in formula I is developed in a thin layer chromatography experiment with chloroform-methanol volume ratio as chloroform:methanol=7:3 developer, and is a yellow circular point with an Rf value of 3;

Get 66g of the n-butanol extract that step (1) makes, separate through silica gel column chromatography, the filler that adopts is 100～200 mesh silica gel, and eluent is the chloroform-methanol mixed solution that the volume ratio content of methanol is 20%, The eluted product was concentrated, and then separated by gel column chromatography. The filler of the gel column was Sephadex LH-20, and was eluted with methanol to obtain 0.961 g of Eucommia active monomer compound represented by formula I in the form of yellow flakes Crystal, easily soluble in methanol. The mass spectrum is shown in FIG. 1 , the H-NMR nuclear magnetic spectrum is shown in FIG. 2 , and the C ₁₃ -NMR nuclear magnetic spectrum is shown in FIG. 3 . Judging from Figure 1, Figure 2 and Figure 3, the compound is 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S, 5R)-3,4,5-trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl) -5,7-dioxo-4'-methoxyisoflavone, its structural formula is:

Formula Ⅰ .

Test example The biological activity assay of the compound shown in formula I

1. Research on excitatory activity of central nervous system

1.1 Materials and methods

1.1.1 Main materials and reagents

Eucommia, obtained from the Eucommia planting base of Wangping Township, Ruyang County, Luoyang City; nikethami, 0.9% sodium chloride solution, Shanghai Shiyi Chemical Reagent Co., Ltd.;

1.1.2 Main instruments and equipment

GJ-1 photoelectric counter, Tianjin Medical Device Repair Factory;

1.1.3 Experimental animals

Kunming white mice, common grade, 20-30g (male), provided by Animal Experiment Center of Henan University of Science and Technology;

1.1.4 Test method

1.1.4.1 Effects on autonomous activities of mice

Experimental grouping: 60 Kunming mice were randomly divided into 6 groups, 10 in each group; the first group was the negative control group; the second group was the low-dose group of the active compound of formula Ⅰ; The lower dose group; the fourth group is the middle and upper dose group of the active compound of formula I; the fifth group is the high dose group of the active compound of formula I; the sixth group is the positive control nikethamide group. Group 1 was administered with normal saline on an empty stomach, and mice in groups 2, 3, 4, and 5 were given 50 mg·kg ^-1 ·Bw ^-1 , 100 mg·kg ^-1 · Bw ^-1 , 200 mg·kg ^-1 ·Bw ^-1 , 400 mg·kg ^-1 ·Bw ^-1 , and group 6 received intraperitoneal injection of nikethamide at a dose of 50 mg·kg ^-1 ·Bw ^-1 . Afterwards, the mice in each group were placed in the activity box of the GJ-1 photoelectric counter. After 30 minutes of administration, the recorder was started to record the number of activities of the mice within 5 minutes. The recorded results are shown in Table 1.

1.1.4.2 Convulsive effect test on mice

Experimental grouping: 60 Kunming mice were randomly divided into 6 groups, 10 in each group; the first group was the negative control group; the second group was the low-dose group of the active compound of formula Ⅰ; The lower dose group; the fourth group is the middle and upper dose group of the active compound of formula I; the fifth group is the high dose group of the active compound of formula I; the sixth group is the positive control nikethamide group. Group 1 was administered with normal saline on an empty stomach, and mice in groups 2, 3, 4, and 5 were given 50 mg·kg ^-1 ·Bw ^-1 , 100 mg·kg ^-1 · Bw ^-1 , 200 mg·kg ^-1 ·Bw ^-1 , 400 mg·kg ^-1 ·Bw ^-1 , and group 6 received intraperitoneal injection of nikethamide at a dose of 50 mg·kg ^-1 ·Bw ^-1 . The incidence of convulsions in mice within 30 min after administration was observed, and the recorded results are shown in Table 2.

1.2 Results and analysis

The statistical software SPSS 11.0 was used for the statistical analysis of the data. The effect of different dosage groups of Eucommia active monomer compounds on the number of autonomous activities of the mice was analyzed by one-way analysis of variance. The difference between the drug group and the control group was significant. Analysis was performed using paired sample t test.

1.2.1 Effects on autonomous activities of mice

In the test of the influence on the autonomous activities of the mice, the results of the measured autonomous activities of the six groups of mice are shown in Table 1.

Table 1 The number of spontaneous activities of mice in each group recorded in 1.1.4.1 (x±s)

As can be seen from Table 1, the active monomeric compound of Eucommia ulmoides represented by formula I has a significant stimulating effect on the central nervous system. The number of voluntary activities of the mice increased. Compared with the negative control group, the number of autonomous activities of mice in the middle and lower dose groups increased significantly (P<0.05); in the middle and upper dose groups and high dose groups, the number of autonomous activities of mice increased significantly compared with the negative control group (P<0.05). 0.01), statistical analysis results showed that the active monomer compound of Eucommia had a significant dose-related effect on the autonomous activity of mice (P=0.00079), which was comparable to the positive control and had no significant difference. In the range of low dose to upper middle dose, the number of spontaneous activities of mice increased linearly with the increase of dose, from 142±21 to 201±18. The effect of the eucommia active monomer compound is positively correlated with its dose.

1.2.2 Convulsive effect on mice

In the convulsion-inducing effect test on mice, the convulsion incidence rates of the six groups of mice measured are shown in Table 2.

The incidence of convulsions in each group of mice recorded in Table 2 1.1.4.2

It can be seen from Table 2 that the active monomer compound of Eucommia ulmoides represented by formula I has obvious convulsive effect. After intragastric administration of four doses of active monomeric compounds of Eucommia ulmoides in low, middle, upper, and high doses, within 30 minutes, the convulsion rate of active monomeric compounds of Eucommia ulmoides in low doses was 20%, which was significantly higher than that of the negative control group , the incidence of convulsions in mice increased with the increase of the dose. When the active monomer compound of Eucommia was administered to the middle and upper doses, the incidence of convulsions in mice reached 100%, which was equivalent to the positive control of nicothamide. The incidence of convulsions in mice decreased by 40% at high doses. In the low-dose to upper-middle dose range, the incidence of convulsions in mice was positively correlated with the intragastric dose.

Example 2

   The health-care medicinal tea provided by the present embodiment is composed of 3-((2S, 3S, 4S, 5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S, 3S, 4S, 5R)-3 ,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7 -Dioxy-4'-methoxyisoflavones, black tea and compound sweeteners, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3- ((2S,3S,4S,5R)-3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3 , 4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone with a weight percentage of 3%.

The preparation method of the health-care herbal tea provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R )-3,4,5-trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)- 3 grams of 5,7-dioxo-4'-methoxy isoflavone, mixed with 50 grams of black tea leaves evenly, transferred to a pulverizer and crushed to 15-30 mesh, added 47 kg of compound sweetener, mixed thoroughly and put into special Paper bubble bag, outerwear aluminum-plastic compound bag, sealing, every bag 5-8 gram, makes the health-care herbal tea of this embodiment.

Example 3

The health-care granule provided in this embodiment consists of 3-((2S, 3S, 4S, 5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S, 3S, 4S, 5R)-3, 4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7- Dioxy-4'-methoxy isoflavone, fruit juice powder and white sugar, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-(( 2S,3S,4S,5R)-3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4 -Dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone has a weight percentage of 1%.

The preparation method of the health-care granule provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R) -3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5 , 1 gram of 7-dioxo-4'-methoxy isoflavone, mixed with 50 grams of fruit juice powder and 49 grams of white granulated sugar, passed through a 12-mesh sieve, dried at 75°C, packaged into bags, and made into the health care product of this embodiment Granules.

Example 4

The oral solution provided in this embodiment is composed of 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3, 4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7- Dioxy-4'-methoxyisoflavone, water, benzoic acid and flavoring agent, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3- ((2S,3S,4S,5R)-3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3 , 4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone by weight percentage is 20%.

The preparation method of the oral liquid provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R) -3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5 , 20 grams of 7-dioxo-4'-methoxy isoflavone, add 0.5 grams of benzoic acid and 0.5 grams of flavoring agent, then add water to 100 grams, then divide into 5 ml vials, press the caps, and this implementation is obtained Example oral solution.

Example 5

The tablet provided in this example is composed of 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3, 4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7- Dioxy-4'-methoxyisoflavone, starch, powdered sugar, talc, magnesium stearate, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxy Methyl-3-((2S,3S,4S,5R)-3,4,5-trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo) - The weight percentage of 2-(3,4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone is 80%.

The preparation method of the tablet provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R) -3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5 , 4120 grams of 7-dioxo-4'-methoxy isoflavone, mixed with 800 grams of starch, 200 grams of powdered sugar, 20 grams of talcum powder, and 10 grams of magnesium stearate, mixed well and dried, and pressed into the tablet of the cost embodiment agent.

Example 6

The capsule provided in this embodiment is composed of 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3, 4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7- Composed of dioxy-4'-methoxyisoflavone, starch, dextrin, and talc, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3- ((2S,3S,4S,5R)-3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3 , 4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone by weight percentage is 99%.

The preparation method of the capsule provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R) -3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5 , 990 grams of 7-dioxo-4'-methoxyisoflavone, mixed with 4 grams of starch, 4 grams of dextrin and 2 grams of talcum powder, added 70% ethanol as a wetting agent, granulated, dried, and processed Granules are packed into capsules to make the capsules of this embodiment.

Example 7

The injection provided in this example consists of 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3,4 ,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7-di Oxy-4'-methoxyisoflavone, water for injection, benzyl alcohol, Tween-80, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl- 3-((2S,3S,4S,5R)-3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2- The weight percentage of (3,4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone is 5%.

The preparation method of the injection provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)- 3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5, 50 grams of 7-dioxo-4'-methoxyisoflavone, add 500 ml of water for injection, 20 ml of benzyl alcohol, heat treatment with 10 pounds of pressure for half an hour, freeze for 24 hours and filter, then add 10 ml of Tween-80, Add water for injection to a total weight of 1000 grams, stir well, filter, clarify, potting, circulate steam at 100°C, and sterilize for 1 hour to prepare the injection of this embodiment for intravenous infusion.

Example 8

The dropping pill provided in this embodiment is composed of 3-((2S, 3S, 4S, 5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S, 3S, 4S, 5R)-3, 4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7- Composed of dioxy-4'-methoxyisoflavone and polyethylene glycol, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S ,3S,4S,5R)-3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4- The weight percentage of dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone is 10%.

The preparation method of the drop pill provided in this embodiment: take 3-((2S,3S,4S,5S)-4,5-dihydroxyl-6-hydroxymethyl-3-((2S,3S,4S,5R) -3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5 , 50 grams of 7-dioxo-4'-methoxyisoflavone, and then weighed 450 grams of polyethylene glycol 6000 (PEG6000), heated to 100 ° C until melting, at this time, 50 grams of 3-((2S, 3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3,4,5-trihydroxytetrahydro-dihydropyran-2 -Oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone was added to the molten In polyethylene glycol, stir to prepare a uniform molten liquid, pour the molten liquid into the liquid storage tank of the dropping pill machine under constant temperature conditions, drop the liquid into the liquid paraffin, cool and form, wash off the liquid paraffin, and dry to obtain this practice Examples of drop pills.

Example 9

The dispersible tablets provided in this example are composed of 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3, 4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7- Composed of dioxy-4'-methoxyisoflavone, calcium dihydrogen phosphate, lactose, mannitol, cross-linked polyethylpyrrolidone and magnesium stearate, in which 3-((2S,3S,4S,5S)-4, 5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3,4,5-trihydroxytetrahydro-dihydropyran-2-oxy)-4-oxo-di The weight percentage of hydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone is 9%.

The preparation method of the dispersible tablet provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R) -3,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5 , 5 grams of 7-dioxo-4'-methoxyisoflavone, then mixed with 20 grams of calcium dihydrogen phosphate, 5 grams of lactose, 15 grams of mannitol, 10 grams of cross-linked polyethylpyrrolidone and 0.3 grams of magnesium stearate , use 70% ethanol to make soft material, granulate with 20 mesh sieve, dry, granulate with 14 mesh sieve, tabletting, make the dispersible tablet of the present embodiment.

Example 10

The chewable tablet provided in this example is composed of 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R)-3 ,4,5-Trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)-5,7 -Dioxy-4'-methoxyisoflavone, calcium dihydrogen phosphate, lactose, mannitol and magnesium stearate, in which 3-((2S,3S,4S,5S)-4,5-dihydroxy-6 -Hydroxymethyl-3-((2S,3S,4S,5R)-3,4,5-trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2- The weight percent content of oxy)-2-(3,4-dihydroxyphenyl)-5,7-dioxo-4'-methoxyisoflavone is 16.5%.

The preparation method of the chewable tablet provided in this example: take 3-((2S,3S,4S,5S)-4,5-dihydroxy-6-hydroxymethyl-3-((2S,3S,4S,5R )-3,4,5-trihydroxytetrahydro-dihydropyran-2-oxo)-4-oxo-dihydropyran-2-oxo)-2-(3,4-dihydroxyphenyl)- 5 grams of 5,7-dioxo-4'-methoxyisoflavone, mixed with 5 grams of calcium dihydrogen phosphate, 5 grams of lactose, 15 grams of mannitol, and 0.3 grams of magnesium stearate, softened with 70% ethanol material, granulated with a 20-mesh sieve, dried, granulated with a 14-mesh sieve, and tableted to obtain the chewable tablet of this embodiment.

Claims (9)

1. an active monomer compound of eucommia ulmoides, is characterized in that, the structural formula of this compound is as shown in formula I: Formula I. 2. Enantiomers, tautomers, physiologically functional derivatives or pharmaceutically acceptable salts of the active monomer compound of Eucommia ulmoides according to claim 1. 3. a preparation method of Eucommia ulmoides active monomer compound as claimed in claim 1, is characterized in that, this compound is extracted from Chinese medicine Eucommia ulmoides, and its preparation process comprises the following steps: (1) System solvent extraction process Take Eucommia bark, Eucommia leaves, Eucommia male flowers or Eucommia whole plant to prepare ethanol extract, and then use the system solvent method to extract and separate extracts with different polarities, that is, sequentially use solvent petroleum ether, ethyl acetate and n-butanol at room temperature extracting the ethanol extract, then merging and concentrating extracts from the same solvent to obtain petroleum ether extract, ethyl acetate extract, and n-butanol extract respectively; (2) Chromatographic separation process The n-butanol extract is separated by silica gel column chromatography, the filler used in the silica gel column chromatography separation is 100-200 mesh silica gel, and the eluent is a chloroform-methanol mixed solution with a volume ratio of methanol of 20%, which is eluted to obtain The product is concentrated, and then separated by gel column chromatography. The filler of the gel column is Sephadex LH-20, which is eluted with methanol to obtain the active monomer compound of Eucommia ulmoides. 4. the preparation method of eucommia active monomer compound according to claim 3 is characterized in that, the preparation method of ethanol extract is: with eucommia bark, eucommia leaf, eucommia male flower or eucommia whole plant dry in the shade, pulverize, use mass percentage Soak in ethanol with a concentration of 70-95% for two weeks, then recover the soaking solution under vacuum at 65°C, repeat three times, and combine to obtain ethanol extract. 5. A pharmaceutical composition containing the active monomer compound of Eucommia ulmoides according to claim 1, characterized in that, the active monomer compound of Eucommia ulmoides according to claim 1, a pharmaceutically acceptable carrier and/or excipient Composition, the pharmaceutical composition can be made into any pharmaceutically acceptable dosage form. 6. The pharmaceutical composition according to claim 5, characterized in that the active monomer compound of eucommia ulmoides according to claim 1 is present in a weight percentage of 1% to 99% in the pharmaceutical composition. 7. The pharmaceutical composition according to claim 6, characterized in that the active monomer compound of Eucommia ulmoides according to claim 1 is present in a weight percentage of 20% to 80% in the pharmaceutical composition. 8. the application of the Eucommia ulmoides active monomer compound described in claim 1 in the preparation of central nervous system stimulant medicine and health food. 9. The application of the compound described in claim 2 in the preparation of central nervous system stimulant medicine and health food.

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