CN102320928A - Eucommia active monomer compound as well as preparation method, pharmaceutical 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 the preparation method of the compound, the pharmaceutical composition containing the compound and the pharmaceutical use thereof. The active monomer compound is extracted from eucommia ulmoides, and can be extracted from eucommia ulmoides bark, eucommia ulmoides leaves, eucommia ulmoides male flowers, eucommia ulmoides seeds or whole plant of eucommia ulmoides. The extracted active monomer compound 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol has been proved by experiments to have obvious sedative, hypnotic and anticonvulsant effects , and 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 effects of the compound on sedation, hypnosis and anticonvulsion, etc., and provides a new natural active substance for the research and development of new health food and new sedative and hypnotic drugs.

Description

Active monomer compound of Eucommia ulmoides, preparation method, pharmaceutical composition and application thereof

technical field

The invention relates to the technical field of active monomers of traditional Chinese medicine and the preparation thereof, in particular to an active monomer compound of eucommia ulmoides, a preparation method, a pharmaceutical composition and its application.

Background technique

Insomnia is a clinical frequently-occurring disease with complex etiology and easy recurrence. Insomnia seriously affects people's life, work and physical and mental health. The incidence of serious accidents and trauma caused by long-term insomnia is significantly higher than that of normal sleepers. Insomnia, if left untreated, can lead to disturbances in metabolism and systemic function, causing significant changes in mood, behavior, and psychomotor function.

Drug therapy is one of the most important means for the treatment of insomnia. The effect of sedative hypnotics can make the patient's tension, irritability, insomnia and other mental overexcitement be suppressed, so that he can calm down or fall asleep. Sedative-hypnotic drugs can improve the tense and irritated mood and state of patients taking them in small doses, making them in a stable and quiet state, and are used as sedatives; in larger doses, they can make the users fall asleep and be used as hypnotics. The types of hypnotic and sedative drugs commonly used in clinical practice are: barbiturates, benzodiazepines, non-benzodiazepines, cytokines, and melatonin. The sedative-hypnotics commonly used for treatment both at home and abroad have certain side effects and dependence. For example, barbiturates have relatively large toxic and side effects, especially severe liver and kidney toxicity, and chronic use for a long time may easily lead to tolerance and dependence. Benzodiazepines have obvious sedative and hypnotic effects, but they also have a certain degree of drug dependence and hangover symptoms. Most benzodiazepines are non-selective to receptors, and can cause adverse reactions such as daytime dizziness, drowsiness, lack of energy, psychomotor impairment, and residual effects at high doses and long-term use. Therefore, finding safer and more effective drugs has become a major topic in the field of current sedative-hypnotic drug research.

The current research results show that many traditional Chinese medicine ingredients have good sedative and hypnotic effects, and have few adverse reactions, which is in line with the development trend of hypnotic drugs from non-selective to high-efficiency, high-selectivity, and small side effects, and has broad application prospects. The sedative and hypnotic effect of traditional Chinese medicine has become a hot research topic in recent years. However, the difficulty is that the components of traditional Chinese medicine are 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 monomeric compound with sedative and hypnotic activity in traditional Chinese medicine has been found in China. It is highly efficient and highly selective. , Sedative and hypnotic products with little side effects 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 More than 1 million 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 have sedative and hypnotic effects, but the specific active ingredients and mechanism of action in Eucommia are still unclear, and no active monomeric compounds of Eucommia have been seen so far. Information on applications in the field of sedation-hypnosis.

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 object, the technical scheme adopted in the present invention is: an active monomer compound of Eucommia ulmoides, the structural formula of which 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 ulmoides bark, Eucommia leaves, Eucommia male flowers, Eucommia ulmoides seeds or the whole plant of Eucommia ulmoides to obtain ethanol extract, and then use the system solvent method to extract and separate the extracts of different polarities, that is, sequentially use solvent petroleum ether, ethyl acetate Extract the ethanol extract with n-butanol at room temperature, repeat the extraction four times with each solvent, then combine and concentrate the same solvent extracts to obtain petroleum ether extract, ethyl acetate extract, and n-butanol extract respectively;

(2) Chromatographic separation process

The n-butanol extract is separated by column chromatography for 3 to 5 times to obtain the active monomer compound of Eucommia ulmoides, the filler used in column chromatography is 100 to 200 mesh silica gel, and the eluent is chloroform with a volume ratio of methanol of 20%. -Methanol mixture.

Wherein, the preparation method of the ethanol extract is as follows: eucommia bark, eucommia leaves, eucommia male flowers or whole Eucommia ulmoides plants are dried in the shade, crushed, soaked in ethanol with a mass percentage concentration of 70-95% for two weeks, and then recovered under vacuum at 65°C The soaking solution was repeated three times, and combined to obtain ethanol extract.

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

Further, the weight percentage of the compound represented by formula I in the above pharmaceutical composition is 1%-99%. Preferably, the weight percentage of the compound represented by formula I in the above pharmaceutical composition is 20%-80%.

The application of the eucommia active monomer compound represented by formula I in the preparation of sedative, hypnotic and anticonvulsant drugs and health food.

Use of enantiomers, tautomers, physiologically functional derivatives or pharmaceutically acceptable salts of compounds represented by formula I in the preparation of sedative, hypnotic and anticonvulsant 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, eucommia ulmoides seeds or the whole plant of eucommia ulmoides. The extracted active monomer compound 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol (shown in formula I) has been proved by experimental research to have obvious sedative, Hypnotic and anticonvulsant effects. The successful extraction and separation of active monomer compounds in Eucommia ulmoides that have sedative, hypnotic and anticonvulsant effects can ensure the stability of the dosage and reduce 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. At the same time, Eucommia ulmoides also has other active ingredients that can lower blood pressure and reduce inflammation. The extraction and purification of active monomer compounds in the present invention can avoid interference and antagonism among various medicinal effects. Therefore, determining and purifying the active ingredients of traditional Chinese medicine can transform the process control of traditional Chinese medicine quality into a more convenient and accurate result control, and significantly enhance the efficacy of traditional Chinese medicine, which is conducive to the modernization of Chinese medicine.

The eucommia active monomer compound represented by formula I provided by the present invention is an active ingredient of traditional Chinese medicine, has good sedative, hypnotic and anticonvulsant effects, 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 effects of the compound on sedation, hypnosis and anticonvulsion, etc., and provides a new natural active substance for the research and development of new health food and new sedative and hypnotic 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 invention can also be made into pharmaceutical raw materials with sedative, hypnotic and anticonvulsant effects and conventional pharmaceutical dosage forms, such as tablets, capsules, granules, oral liquids and injections.

The eucommia active monomer compound provided by the invention is obtained by separating from eucommia ulmoides, and its source is abundant, the extraction and separation process adopted is stable and easy, the quality is controllable, the drug effect is certain, and it can promote the search for new sedative and hypnotic 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 extracts of different polarities. Each solvent was repeatedly extracted four times, and each extract was concentrated respectively 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 eucommia active monomer compound shown in formula I was developed twice with a developing agent with a volume ratio of chloroform-methanol of 8:2 in the thin-layer chromatography experiment, and it was a purple-black circular spot with an Rf value of 6;

Get the n-butanol extract 66g that step (1) makes, through column chromatographic separation 3 times, obtain the eucommia active monomer compound product 0.167 g shown in formula I, the packing that adopts during column chromatographic separation is 200 mesh silica gel, washing The deliquification is chloroform-methanol mixed solution with a volume ratio content of methanol of 20%.

The eucommia active monomer compound is a colorless viscous syrup-like substance, which is 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 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol ((4-hydroxy-3-(2 -hydroxyethyl) cyclopent-1-ene-1,2 –diyl ) dimethanol, the structural formula of the active monomer compound is:

Formula Ⅰ .

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

1. Research on sedative, hypnotic and anticonvulsant activity

1.1 Materials and methods

1.1.1 Main materials and reagents

Eucommia, obtained from the planting base of Eucommia ulmoides in Wangping Township, Ruyang County, Luoyang City; pentobarbital sodium, a subpackaged product of Sigma Company in Shanghai; nicothamide, 0.9% sodium chloride solution, diazepam, Shanghai Shiyi Chemical Reagent limited company;

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

Animal grouping: Before the experiment, put the mice into the activity box of the GJ-1 photoelectric counter, start the recorder to record the number of activities within 5 minutes, select normal mice with about 150 times of autonomous activities, and then divide them according to the number of autonomous activities. The mice were randomly assigned to each experimental group, and there was no significant difference in the number of autonomous activities of the mice in each group before the experiment;

Experimental grouping: 50 Kunming mice were randomly divided into 5 groups, 10 in each group; the first group was the negative control group; the second group was the large dose group of the active compound of formula I; the third group was the active compound of formula I dose group; the fourth group is the small dose group of the active compound of formula Ⅰ; the fifth group is the positive control diazepam group; the mice in each group are placed in the activity box of the GJ-1 photoelectric counter, and then the recorder is started to record The number of activities within 5 minutes, the negative control group was given normal saline by intragastric administration, the positive control group was given 0.30% diazepam by intraperitoneal injection according to the volume of 5 mg/kg, the active compound of formula Ⅰ in the high-dose group, middle-dose group, and small-dose group The amount of intragastric administration was 50 mg·kg ^-1 ·Bw ^-1 , 100 mg·kg ^-1 ·Bw ^-1 , 200 mg·kg ^-1 ·Bw ^-1 , respectively, according to the weight of the mice, and after 30 minutes, Measure the number of spontaneous activities of the mice, observe the state of the mice at the same time, record the sedation rate of the mice, and the percentage of falling asleep within 30 minutes. Among them, the mouse has a sedative effect if it is lying still for more than 15 seconds, and the righting reflex disappears for more than 1 minute. to fall asleep;

1.1.4.2 Effect on the sedative effect of subthreshold dose pentobarbital sodium

Subthreshold dose experiment: 50 mice were randomly divided into five groups, which were the large, medium and small dose groups of the active compound of formula I, positive control group and negative control group. The negative control group was given normal saline by intragastric administration. The control group was given 0.30% diazepam by intraperitoneal injection at a volume of 5 mg/kg, and the intragastric doses of the active compound of formula Ⅰ were 200 mg·kg -1 ·Bw -1 , 200 mg·kg ^-1 ·Bw ^-1 , respectively 100 mg·kg ^-1 ·Bw ^-1 , 50 mg·kg ^-1 ·Bw ^-1 , orally administered according to the body weight of the mice, each group was injected with a subthreshold dose of pentobarbit according to the body weight of the mice 30 minutes after administration Sodium thalate (25mg/kg ^. Bw), record the percentage of falling asleep within 30 minutes, sleep latency (from the injection of pentobarbital sodium to the loss of righting reflex is the sleep latency) and sleep time, and the person who lost the righting reflex for more than 1 minute was regarded as falling asleep , from the disappearance of the righting reflex to the recovery of the righting reflex as the sleep time;

1.1.4.3 Effect on the sedative effect of suprathreshold dose pentobarbital sodium

Suprathreshold dose experiment: 50 mice were randomly divided into five groups, respectively large, medium and small dose groups of the active compound of formula I, positive control group and negative control group. The negative control group was given normal saline by intragastric administration. The control group was given 0.30% diazepam by intraperitoneal injection according to the volume of 5 mg/kg, and the intragastric administration volume of each dose group of the active compound of formula Ⅰ was 50 mg·kg ^-1 ·Bw ^-1 Inject the mouse with a suprathreshold dose of pentobarbital sodium (40mg/kg ^. Bw) intraperitoneally, and record the percentage of falling asleep and sleep latency within 30 minutes (from the injection of pentobarbital sodium to the disappearance of righting reflex is the sleep latency period) and sleep time, fall asleep when the righting reflex disappears for more than 1 minute, and sleep time is when the righting reflex disappears until the righting reflex recovers;

1.1.4.4 Anticonvulsant effect

Take 50 mice and divide them into five groups at random, which are the large, medium and small dose groups of the active compound of formula Ⅰ, the positive control group and the negative control group respectively. ^-1 ·Bw ^-1 , 60 minutes after administration, each group injected 1.25% nicothamide 0.1ml/10g intraperitoneally according to the weight of the mice, and the mice in the positive control group were intraperitoneally injected with diazepam at a dose of 5mg /kg, according to the body weight of the mice, 1.25% nicothamide 0.1ml/10g was intraperitoneally injected into the mice 60min after administration, and the negative control group was given normal saline by intragastric administration, and 1.25% nicothamide was intraperitoneally injected 60min after administration. Chami 0.1ml/10g; observe for two hours after administration, record the convulsion latency of the mice and the number of convulsed mice (the generalized tonic convulsion in the mice is used as the index).

Statistical analysis

The statistical software SPSS 11.0 was used for statistical analysis of the data, and the sedative effect of the mice induced by gavage treatment of different dosage groups of the active compound of formula 1 was analyzed by one-way analysis of variance. Paired sample t-test was used to analyze the significant difference between the drug group and the control group.

1.3 Results and analysis

1.3.1 The effect of the active compound of formula Ⅰ on the autonomous activity of mice

Table 1 Effect of different doses of formula Ⅰ monomer compound on the number of autonomous activities in mice

Note: 1) Compared with the negative control group, *P<0.05, **P<0.01, compared with the positive control group ^{, △} P<0.05, ^△△ P<0.01.

Experiments have proved that different doses of the compound of formula I can significantly reduce the number of autonomous activities of mice, and with the increase of dose, the number of autonomous activities of mice is significantly reduced, and there is a significant linear positive correlation in statistics. With the increase of dose, the sedation The hypnotic activity gradually increased, and the number of autonomous activities of the mice in the high-dose compound formula I group was similar to that of the positive control group, and there was no statistical difference.

1.3.2 The effect of the active compound of formula Ⅰ on the sedative-hypnotic effect of subthreshold dose pentobarbital sodium

Table 2 The effect of the monomer compound of formula Ⅰ on the sleep effect of mice induced by subthreshold dose of pentobarbital sodium

Note: 1) Compared with the negative control group, *P<0.05, **P<0.01, compared with the positive control group ^{, △} P<0.05, ^△△ P<0.01.

Experiments have proved that the compound of formula I can significantly increase the sleep rate of mice with subthreshold dose of pentobarbital sodium, can make 80% of mice with subthreshold dose enter sleep, can significantly shorten the sleep latency period, and prolong the sleep of mice significantly time, the effect was stronger than that of diazepam in the positive control group.

1.3.3 The effect of the active compound of formula Ⅰ on the sedative-hypnotic effect of suprathreshold dose pentobarbital sodium

Table 3 The effect of active compounds of formula Ⅰ on the sleep effect of mice induced by suprathreshold dose pentobarbital sodium

Note: Compared with the negative control group, *P<0.05, **P<0.01, compared with the positive control group ^{, △} P<0.05, ^△△ P<0.01.

Experiments have proved that the active compound of formula I has a significant effect on the sedative and hypnotic effects of suprathreshold dose pentobarbital sodium mice. The active compound of formula Ⅰ has a good synergistic effect with the suprathreshold dose of pentobarbital sodium, can significantly shorten the sleep latency, and extremely significantly prolong the sleep time up to 90 minutes. Zepam. the

1.3.4 Anticonvulsant effect of the active compound of formula Ⅰ

Table 4 The effect of active compound of formula Ⅰ on convulsion in mice

Note: Compared with the negative control group, *P<0.05, **P<0.01, compared with the positive control group ^{, △} P<0.05, ^△△ P<0.01.

The results prove that the active compound of formula I has a certain anticonvulsant effect, and the high-dose group of the active compound of formula I can significantly prolong the convulsion latency period and significantly reduce the convulsion rate of mice, showing excellent anticonvulsant efficacy.

The results of the above four experiments combined show that the active compound shown in formula I provided by the present invention can significantly inhibit the autonomous activity of mice, has a good synergistic effect with pentobarbital sodium, and has significant sedative, hypnotic and anticonvulsant effects. role.

Example 2

   The health-care herbal tea provided in this example is composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, black tea and compound sweetener, wherein 4-hydroxy- The weight percentage of 3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 3%.

The preparation method of the health-care herbal tea provided in this example: take 3 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, mix it with 50 grams of black tea leaves, Go to the pulverizer and pulverize to 15-30 mesh, add 47 kilograms of compound sweeteners, put into special paper bubble bag after mixing thoroughly, coat aluminum-plastic compound bag, seal, every bag 5-8 gram, make the health care of this embodiment herbal tea.

Example 3

The health-care granule provided in this example is composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, fruit juice powder and white sugar, in which 4-hydroxy-3- The weight percentage of (2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 1%.

The preparation method of the health care granule provided in this example: take 1 gram of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, mix it with 50 grams of fruit juice powder and 49 grams of white Granulated sugar is mixed, passed through a 12-mesh sieve, dried at 75° C., packaged into bags, and made into the health-care granule of this embodiment.

Example 4

The oral solution provided in this example is composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, water, benzoic acid and flavoring agent, wherein 4-hydroxy- The weight percentage of 3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 20%.

The preparation method of the oral liquid provided in this example: take 20 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, add 0.5 grams of benzoic acid and 0.5 grams of seasoning medicament, then add water to 100 grams, then sub-package in 5 milliliter vials, and press the cap to obtain the oral liquid of the present embodiment.

Example 5

The tablet provided in this example is composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, starch, powdered sugar, talcum powder, and magnesium stearate, Wherein the weight percentage of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 80%.

The preparation method of the tablet provided in this example: take 4120 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, mix with 800 grams of starch and 200 grams of powdered sugar , 20 grams of talcum powder, 10 grams of magnesium stearate mix, mix thoroughly and dry, compress the tablet of cost embodiment.

Example 6

The capsules provided in this example are composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, starch, dextrin, and talc, wherein 4-hydroxy- The weight percentage of 3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 99%.

The preparation method of the capsule provided in this example: take 990 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, mix with 4 grams of starch and 4 grams of dextrin Mix with 2 grams of talcum powder, add 70% ethanol as a wetting agent, granulate, dry, granulate, pack into capsules, and make the capsule of this embodiment.

Example 7

The injection provided in this example consists of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, water for injection, benzyl alcohol, and Tween-80, wherein 4- The weight percentage of hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 5%.

The preparation method of the injection provided in this example: take 50 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, add 500 ml of water for injection, and 20 ml of benzyl alcohol , heat treatment with 10 pounds of pressure for half an hour, refrigerated for 24 hours, filtered, then added Tween-80 10 ml, added water for injection to a total weight of 1000 grams, stirred well, filtered, clarified, potted, circulated steam 100 ° C, 1 Sterilized within 1 hour, promptly make the injection of this embodiment, use for intravenous infusion.

Example 8

The drop pill provided in this example is composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol and polyethylene glycol, wherein 4-hydroxy-3-( The weight percentage of 2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 10%.

The preparation method of the drop pill provided in this example: take 50 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, and then weigh polyethylene glycol 6000 (PEG6000) 450 grams, heated to 100 ° C to melt, at this time, 50 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol was added to the molten polyethylene In diol, 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 away the liquid paraffin, and dry to obtain the present embodiment. Pills.

Example 9

The dispersible tablets provided in this example are composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, calcium dihydrogen phosphate, lactose, mannitol, cross-linked polyethylene Composed of pyrrolidone and magnesium stearate, wherein the weight percentage of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 9%.

The preparation method of the dispersible tablet provided in this example: Take 5 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, and then mix it with 20 grams of calcium dihydrogen phosphate, Mix 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 a soft material, granulate with a 20-mesh sieve, dry, granulate with a 14-mesh sieve, and compress into tablets. Dispersible tablets of this example were produced.

Example 10

The chewable tablet provided in this example is composed of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, calcium dihydrogen phosphate, lactose, mannitol and magnesium stearate Composition, wherein the weight percentage of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol is 16.5%.

The preparation method of the chewable tablet provided in this example: Take 5 grams of 4-hydroxy-3-(2-hydroxyethyl)-1-cyclopentene-1,2-dimethanol, and then mix it with 5 grams of calcium dihydrogen phosphate , 5 grams of lactose, 15 grams of mannitol, and 0.3 grams of magnesium stearate are mixed with 70% ethanol to make soft materials, granulated with a 20-mesh sieve, dried, granulated with a 14-mesh sieve, and compressed into tablets to obtain the oral cavity of the present embodiment. chewable tablets.

Claims (9)

1. a bark of eucommia reactive monomer compound is characterized in that, the structural formula of this compound is suc as formula shown in the I:

The formula I.

2. the enantiomorph of the described bark of eucommia reactive monomer of claim 1 compound, tautomer, physiology functional derivatives or pharmacy acceptable salt.

3. the preparation method of the described bark of eucommia reactive monomer of claim 1 compound is characterized in that, this compound extracts from the Chinese medicine bark of eucommia and obtains, and its preparation process may further comprise the steps:

(1) systematic solvent extraction leaching process

Get Cortex Eucommiae, Folium Eucommiae, eucommia Bark male flower, bark of eucommia seed or bark of eucommia complete stool, make ethanol extract, adopt systematic solvent extraction then; Extraction separation is prepared the medicinal extract of opposed polarity; Promptly extract said ethanol extract with solvent sherwood oil, ETHYLE ACETATE and propyl carbinol normal temperature successively, every kind of solvent re-extract four times, the same solvent extract merges afterwards; Concentrate, obtain sherwood oil medicinal extract, ETHYLE ACETATE medicinal extract, propyl carbinol medicinal extract respectively;

(2) chromatographic separation process

Said propyl carbinol medicinal extract obtains bark of eucommia reactive monomer compound through 3～5 column chromatographys separation, and the filler that adopts when column chromatography is separated is 100～200 order silica gel, and elutriant is that the volume ratio content of methyl alcohol is 20% chloroform-methanol mixed solution.

4. the preparation method of bark of eucommia reactive monomer compound according to claim 3; It is characterized in that the preparation method of ethanol extract is: Cortex Eucommiae, Folium Eucommiae, eucommia Bark male flower or bark of eucommia complete stool are dried in the shade, pulverize; The use mass percent concentration is 70～95% two weeks of alcohol immersion; Then under vacuum condition 65 ℃ reclaim soak solutions, triplicate merges and obtains ethanol extract.

5. pharmaceutical composition that contains the described bark of eucommia reactive monomer of claim 1 compound; It is characterized in that; Be made up of the described bark of eucommia reactive monomer of claim 1 compound, pharmaceutically acceptable carrier and/or vehicle, this pharmaceutical composition can be processed acceptable any formulation on the pharmaceutics.

6. pharmaceutical composition according to claim 5 is characterized in that, the weight percentage of the described bark of eucommia reactive monomer of claim 1 compound in this pharmaceutical composition is 1%～99%.

7. pharmaceutical composition according to claim 6 is characterized in that, the weight percentage of the described bark of eucommia reactive monomer of claim 1 compound in this pharmaceutical composition is 20%～80%.

8. the application of the described bark of eucommia reactive monomer of claim 1 compound in preparation calmness, hypnosis and anticonvulsant drug and protective foods.

9. the application of the described compound of claim 2 in preparation calmness, hypnosis and anticonvulsant drug and protective foods.

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