CN102838645A - Polyphenol hydroxy flavone compound with pharmaceutical function and preparation method thereof - Google Patents
Polyphenol hydroxy flavone compound with pharmaceutical function and preparation method thereof Download PDFInfo
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- CN102838645A CN102838645A CN2012103635708A CN201210363570A CN102838645A CN 102838645 A CN102838645 A CN 102838645A CN 2012103635708 A CN2012103635708 A CN 2012103635708A CN 201210363570 A CN201210363570 A CN 201210363570A CN 102838645 A CN102838645 A CN 102838645A
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Abstract
The invention belongs to the field of medicines and particularly discloses a method for preparing a polyphenol hydroxy flavone compound with a pharmaceutical function. According to the invention, the method comprises the steps of: taking scutellarin and methanol as chlorides of a catalyst, and heating and reacting in a solvent to obtain the polyphenol hydroxy flavone compound. The method is moderate in reacting condition, simple in operation and high in product yield, and is convenient to realize industrialized production; and thus the method has a good industrial application prospect.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of preparation method with polyphenol hydroxyl chromocor compound of pharmaceutical use.
Background technology
People's aging is meant that human body grew after the ripening stage, and with advancing age, a series of degeneration that aspect morphological structure and physiological function, occur change, and are the processes of human tissue organ's deterioration and decline.Modern medicine thinks that aging is the general performance of the various biochemical reactions of body.Constantly producing radical in the human organism, but having effective free radical scavenging system (like GSH, SOD) again simultaneously, the two is in equilibrium state, thereby makes interior free yl maintain normal level.But with advancing age, this balance is destroyed gradually, causes radical superfluous.Radical has very strong response capacity, can make the multiple material generation oxidation in the cell, and the infringement microbial film can also make macromolecules cross-linkings such as protein, nucleic acid, causes impaired, the decline of apoptosis and physiological function thereof, thereby causes aging.Aging is the inexorable law of vital process, can divide two big types: the one, and physiological is old and feeble, refers to that human body reaches the physiology degradation phenomena that ripe back is occurred; The 2nd, pathological seaility promptly on the basis of physiological change, because of suffering from some disease or receive the influence of extraneous factor, and quickens old and feeble process.
Studying anti-ageing problem, not still in order to have good health and a long life, also is to improve the human survival quality, prolongs the human effectively needs at " work age ".China has got into aging society, and elderly population increase just at a terrific speed, and the astogeny problem is serious day by day, and how delaying human body caducity has become the problem that presses for solution.
Insomnia is weighed into again and sleeps and keep somnopathy, clinical manifestation be difficulty falling asleep, early awakening and the length of one's sleep deficiency or poor sleeping quality etc.The insomnia sickness rate increased with the age, and insomnia is very common in the elderly, according to statistics, China more than 60 years old crowd's morbidity be 20%～30%, crowd's morbidity is 40%～50% more than 70 years old, the women is higher than the male sex.Insomnia has a strong impact on people's live and work quality, causes the decline of function of human body, brings out the generation of various diseases.International sleep foundation shows to the elderly's enquiry data; Somnopathy with follow the various diseases of human senescence to be proportionate, can increase onset risk such as the chronic disease relevant such as congestive heart failure, renal failure, chronic obstructive pulmonary disease, apoplexy, Parkinson's disease, mellitus with the age.The hypotype of insomnia has difficulty falling asleep type insomnia, sleep to keep difficult type insomnia, Early morning awakening and psychogenic insomnia, and sleep is kept difficult type and Early morning awakening is comparatively common among the elderly.According to the course of disease of somnopathy, insomnia can be divided into acute again or short-term insomnia (course of disease < January), persistence insomnia (course of disease>4 weeks) and chronic insomnia (course of disease>June).The treatment of insomnia is decided according to the pathologic process of patient's insomnia.Primary insomnia is better to the reaction of pharmacological agent, and Secondary cases insomnia can make heal with medicine with (or) psychotherapeutics.Treatment should be directly to each stage of sleep, as sleeping, sleep is kept, the daytime function of sleep quality or second day.
The medicine of insomnia mainly contains benzene phenodiazine leather type (like Decacil and diazepam) and barbiturates (like Sodital, phenylethyl barbituric acid and Amobarbital).Benzene phenodiazine leather type Department of Pharmacy plays a role through the benzene phenodiazine leather receptoroid that suppresses neurone one propalanine (GABA) ability nerve ending; This type of medicine can cause untoward reactions such as dizzy, sleepy, weak, that fine movement is inharmonious when HD; The heavy dose of application then can be caused ataxia, motor capacity obstacle, and long-time use can cause body resistance and drug dependence.But the barbiturate specificity is incorporated into the specific site of GABA acceptor one chloride channel complex surfaces, prolongs the open hour of chloride channel, strengthens the hyperpolarization of postsynaptic membrane, suppresses the neurone discharge, and cns is suppressed.Such medicine is ascending with dosage, can produce calmness, hypnosis, anticonvulsion and anesthetic action to medication person, has wake up aftereffect and tangible Withrawal symptoms (like excitement, insomnia, anxiety and convulsions) such as the back is dizzy, sleepy, lassitude.
In a word, lack at present and a kind ofly can effectively improve sleep quality, that can delay senility, that have no side effect again medicine is studied and new drug development around this theme, is of great practical significance.
5,6,4 '-trihydroxyflavone-7-O-β-D-glucuronic acid methyl ester; Its structure for polyphenol hydroxyl saponins chromocor compound, has multiple pharmacological effect suc as formula shown in the I; As, existing patent (patent No. 201210001974.2) discloses it in the application that improves sleep quality, delays senility.
Yet at present formula I compound is mainly through the plant mode, from plants such as the root of large-flowered skullcap, rough gentian, Herba Erigerontis, sophora flower, extracts to obtain.Only from plant, extract through the plant mode and to obtain a spot of formula I compound, quantity is rare, only is confined to supply small scale experiments institute to need, and price is extremely expensive, and every gram is worth and reaches more than six, 7,000 yuan.Because the content of formula I compound in plant is very low, be merely ppt, even ten thousand/several about, extract, separate comparatively difficulty, cost is very high, is difficult to mass production, can't satisfy current demand.Therefore, how research realizes the batch large-scale production of this compound through the complete synthesis or semisynthetic mode of chemistry, and this application of compound exploitation is had far-reaching and important meaning.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of manual scale preparation method of formula I compound, to satisfy this compound at the needs aspect the medicinal application.
In order to realize the foregoing invention purpose, the present invention provides following technical scheme:
A kind of preparation method of formula I compound is with lamp-dish flower acetic and methyl alcohol and as the muriate of catalyzer reacting by heating and making in specific solvent.
The preparation method of formula I compound provided by the present invention, directly with commercially available Breviscarpine as reaction raw materials.Before feeding intake, the Breviscarpine raw material need not to carry out special purification pre-treatment.The Breviscarpine that preparation method of the present invention adopted is a kind of Flavonoid substances that obtains that from plants such as Herba Erigerontis, extracts, and its staple is a lamp-dish flower acetic.At present, Breviscarpine has been realized scale operation at home, and manufacturer is more than 100 families nearly, and production technology is ripe, and output is big, and the source of goods and steady quality are reliable, can from market, arbitrarily buy with very low price.In the commercially available Breviscarpine, the content of lamp-dish flower acetic is about about 80～85%.In the embodiment of the invention, employed Breviscarpine raw material is directly buied from market, and manufacturer is Yuxi, Yunnan Province biological ltd incomparably, and lot identification mark 070821 detects through performance liquid chromatography (HPLC), and lamp-dish flower acetic content is 82.5%.
Among the preparation method of formula I compound provided by the present invention, lamp-dish flower acetic that is contained in the raw material Breviscarpine and methyl alcohol under the specific catalyst effect, reacting by heating in specific solvent and obtain formula I compound, reaction principle is shown below:
Among the preparation method of formula I compound provided by the invention, catalyzer is absolutely necessary, and the kind of catalyzer and consumption have fundamental influence to reaction.Do not add catalyzer in the reaction, or add catalyzer amount and/or kind be not suitable for, all possibly cause reaction not take place, other side reaction such as oxidation, hydrolysis, alcoholysis etc. perhaps take place, cause title product to generate or yield very low.The inventor has filtered out the efficiently and directionally catalyzer of suitable this response characteristic through a large amount of experimental studies, and has confirmed the suitable amount ranges of catalyzer.
The inventor finds that through a large amount of experimental studies some specific cl ions type compounds have the directional catalyzing effect to the present invention's reaction.As preferably, in the formula I compounds process for production thereof of the present invention, the muriate that uses as catalyzer is selected from NaCl, KCl, HCl, CaCl
2, MgCl
2, ZnCl
2, FeClx or Fe
2Cl
3In one or more mixture.
More preferably, in the formula I compounds process for production thereof of the present invention catalyst system therefor for being selected from CaCl
2Or ZnCl
2In one or more mixture.
In an embodiment of the present invention, the contriver has also studied the influence of catalyst levels to formula I compound productive rate.Experimental result shows, catalyst levels has material impact to formula I compound synthetic.Catalyst levels is low excessively, does not have katalysis, or catalytic effect is poor, and product yield is low.But after catalyst levels surpassed optimum amount, product yield obvious rising can not occur, and too much consumption reagent does not have practical significance, and can cause the rising of cost.
As preferably, in the formula I compounds process for production thereof of the present invention, the molar feed ratio of catalyzer and lamp-dish flower acetic is 0.05～0.5:1.0.
More preferably, in the formula I compounds process for production thereof of the present invention, the molar feed ratio of catalyzer and lamp-dish flower acetic is 0.1～0.2:1.0.
Among the preparation method of formula I compound provided by the invention, the selection of solvent system is the another key factor that can the relation reaction take place smoothly.In an embodiment of the present invention, the contriver is through lot of experiments, comparative study the selection influence synthetic of solvent system to formula I compound.The result shows, choice of Solvent has material impact to formula I compound synthetic.When selecting acetone, ETHYLE ACETATE, benzene, toluene, chloroform etc. as solvent for use, reaction fails normally to take place; And under other condition situation identical, select water, acetonitrile, methyl alcohol, DMSO 99.8MIN. or N for use with operation, when dinethylformamides etc. were solvent, reaction in various degree can take place in the Breviscarpine raw material.In the formula I compounds process for production thereof of the present invention, highly preferred solvent is methyl alcohol or N, the mixture of one or more in the dinethylformamide.When selecting for use methyl alcohol to be solvent, part methyl alcohol is wherein participated in reaction as reaction reagent, and unnecessary methyl alcohol then uses as solvent.
In an embodiment of the present invention, the contriver has also studied the solvent load influence synthetic to formula I compound.The result shows that solvent load has material impact equally to synthesizing of formula I compound.When solvent load was not enough, lamp-dish flower acetic was difficult to whole dissolvings, caused reaction not thorough, and yield is low; On the other hand, if solvent load is too much, can cause reactant concn low excessively, be unfavorable for the carrying out that react equally, yield is lower equally, and can cause the raising of production cost.According to experimental result, it is comparatively suitable that the mass ratio of solvent and lamp-dish flower acetic is controlled at 13.0～22.0:1.0, and the mass ratio of best solvent and lamp-dish flower acetic is 15.0～20.0:1.0.
The present invention has confirmed rationally that through experimental study the present invention reacts suitable temperature of reaction condition and the reaction times.
In an embodiment of the present invention, the contriver has also studied the temperature of reaction influence synthetic to formula I compound.Experimental result shows, temperature of reaction has material impact to formula I compound synthetic.Reaction temperature is spent low, and speed of response is slow, does not even react, and product yield is low; Otherwise, if temperature of reaction is too high, the side reaction aggravation, impurity increases, and the principal product yield descends, and product darkens.
As preferably, temperature of reaction is 45～100 ℃ in the formula I compounds process for production thereof of the present invention.
More preferably, used temperature of reaction is 50～80 ℃ in the formula I compounds process for production thereof of the present invention.
Except that temperature of reaction, there is influence equally in the performance of reaction times to reaction.Generally speaking, temperature of reaction is high more, and the time that completion is reacted required is just short more.In an embodiment of the present invention, the contriver keep temperature of reaction be 50 ℃ with the constant situation of other experiment conditions under, investigated the influence of reaction times to formula I compound yield.Experimental result shows, under the optional test condition, carries out comparatively completely for guaranteeing reaction, and the reaction times generally can be controlled in 1～5 hour, and the preferred reaction times is 1.5～3.0h.Reaction times is long, and formula I compound yield is on a declining curve, possibly be due to side reaction increases.
Major advantage of the present invention:
The preparation method of formula I compound provided by the invention extracts the preparation method with existing plant and compares, and has significant advantage, is mainly reflected in following several aspect:
1. can realize the large-scale batch production of formula I compound.As previously mentioned, at present formula I compound is mainly through the plant mode, from plants such as the root of large-flowered skullcap, Herba Erigerontis, rough gentian, extracts to obtain.Because the content of this compound in plant is very low, be merely about ppt to ten thousand/several, extract comparatively difficulty, output is very low, can't mass production to satisfy current demand.The preparation method of formula I compound provided by the invention is a raw material with common commercially available Breviscarpine, adopts artificial chemical semi-synthetic mode to prepare.Breviscarpine is the Flavonoid substances in the oil lamp plant; The content of its main chemical compositions lamp-dish flower acetic in the oil lamp plant is very high; About 1～10%, be the hundreds of of formula I compounds content generally, therefore be easy to extensive from plant, the low-cost acquisition to thousands of times.At present, Breviscarpine has been realized large-scale batch production, and domestic production producer is numerous to reach family more than 100, and production technology is ripe, and output is big, and the source of goods and steady quality are reliable, can from market, arbitrarily buy with very low price.Therefore, through the preparation method of formula I compound provided by the invention, can realize the large-scale batch production of formula I compound.
2, production cost is low.As previously mentioned, the content of formula I compound in plant is very low, adopts the preparation of plant extracting mode, and yield is low, needs the valuable plant resources of labor.In addition; Plant is extracted the preparation method and is implemented comparatively difficulty, needs to consume a large amount of extraction solvents, and crude extract also needs the comprehensive methods such as polyamide column chromatography, silica gel column chromatography and recrystallization that adopt repeatedly to separate repeatedly and purify; Just can reach medicinal required purity; Therefore, production cost is very expensive, and every gram cost reaches more than more than 6000 yuan.Comparatively speaking, cheap being easy to get of raw material reagent that formula I compounds process for production thereof of the present invention is adopted, technology is brief, and yield is high, and production cost is low, and about about 2000 yuan of production formula I compound per kilogram cost is merely plant and extracts about preparing method's three per milles.Therefore, formula I compounds process for production thereof of the present invention has the white war advantage.
3. reaction conditions is gentle, and is simple to operate, and product yield is high.The maximum innovation point of the present invention is to adopt specific muriate as the efficiently and directionally catalyzer, directly uses Breviscarpine to be raw material, under lower temperature condition, has synthesized formula I compound with high yield.Because the present invention has selected suitable reaction solvent and system; Breviscarpine raw material among the preparation method of the present invention is refinement treatment in advance; Wherein contained impurity component can not disturb main reaction, can successfully realize separating with principal product through simple aftertreatment again after reaction finishes.The preferred catalyzer of preparation method of the present invention is CaCl
2Or ZnCl
2, reaction solvent is methyl alcohol or N, dinethylformamide, and temperature of reaction is 50～80 ℃; Reaction times 1.5～3.0h, with this understanding, formula I compound can reach 95～98%, and it is strong, cheap and easy to get to have catalyzer efficiently and directionally property; Reaction conditions is gentle, and the time is short, and is simple to operate; Therefore distinguishing features such as product yield height are convenient to industrialization production, have very strong practicality.
The formula I compound of the present invention's preparation pharmaceutically has purposes widely.Described purposes comprises and is used for Cure for insomnia, improves sleep quality, prolongs the deep sleep time, improves memory, diseases such as treatment and prevention memory loss, hypomnesis, senile dementia.Described purposes also comprises and is used for delaying human body caducity, the clinical application of aspects such as prolongs life.
The formula I compound of the present invention's preparation can form pharmaceutical prepn with acceptable accessories, is applied to clinical.Described acceptable accessories comprises all kinds of SOLVENTS, thickening material, solubilizing agent, solubility promoter, inclusion agents, filler, sanitas, stablizer, correctives, tinting material and sweetener etc.Particularly; Described acceptable accessories is including, but not limited to starch, Schardinger dextrins, beta-cyclodextrin, Yelkin TTS, wax, VT 18, peanut oil, til, water, alcohol, glucose, N.F,USP MANNITOL, tween, glycerine, sodium-chlor, sal epsom etc.
The formula I compound of the present invention's preparation is applied to clinical with various pharmaceutical prepns.
The formula I compound of the present invention's preparation can be made into oral prepns or injection formulations.Described oral prepns is specially tablet, capsule, mixture, oral liquid, contains agent and dripping pill etc.Described injection formulations is specially injection liquid, infusion solutions or lyophilized injectable powder.
The formula I compound of the present invention's preparation also can be made into external preparation and uses, and described external preparation comprises liniment, patch, cataplasma, sprays, aerosol etc.
The formula I compound of the present invention preparation also can be made into various novel drug-delivery preparations and is applied to clinically, and described novel drug-delivery preparation can be various inclusion preparations, targeting preparation, drug-delivery preparation etc. at regular time and quantity.Described inclusion preparation comprises beta-cyclodextrin inclusion preparation, starch inclusion preparation, protein inclusion preparation, high-fat emulsion inclusion preparation, chitosan inclusion preparation etc.
The formula I compound of the present invention's preparation can also form pharmaceutical composition with other medicines or excipient substance, and is applied to clinical.Described pharmaceutical composition is made up of two or more material that comprises formula I compound.
Embodiment
The invention discloses a kind of compound and preparation method thereof, those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as and are included in the present invention.Method of the present invention and application are described through preferred embodiment; The related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use technology of the present invention.
Below among the synthetic embodiment of said formula I compound; Used Breviscarpine raw material; Directly from market, buied by drug research institute of Kunming pharmacy group, manufacturer is Yuxi, Yunnan Province biological ltd incomparably, lot identification mark 070821; Detect through performance liquid chromatography (HPLC), lamp-dish flower acetic content is 82.5%.Used chemical reagent methyl alcohol, acetonitrile, DMSO 99.8MIN., DMSO 99.8MIN., N, dinethylformamide, acetone, ETHYLE ACETATE, benzene, toluene, chloroform, sherwood oil, NaCl, KCl, HCl, CaCl
2, MgCl
2, ZnCl
2, FeCl
2And Fe
2Cl
3Be CP, available from Shan Yunnan, Kunming chemical industry ltd, water is purified water.
Following examples 1～9 are keeping under the constant situation of other condition and operating method, have contrasted the influence that the selection of different catalysts is synthesized formula I compound, and its result sees table 1.Among each embodiment reaction product formula I compound all pass through HPLC,
1HNMR,
13CNMR, IR and UV identify and check.
(catalyst system therefor is CaCl for embodiment 1 formula I compound synthetic
2)
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.Reaction solution adopts vacuum concentration to reclaim methyl alcohol, when the solution to be concentrated volume is reduced to 1/3 left and right sides of original volume, stops to concentrate, and liquid concentrator leaves standstill and is cooled to room temperature, has a large amount of product crystallizations to separate out.Vacuum filtration divides to take out for three times with the 30mL cold methanol and washes, and drains as far as possible, and products therefrom changes in 250mL ETHYLE ACETATE-sherwood oil (3:1), is heated to the 30min that boils, and puts 0-5 ℃ of refrigerator and cooled but more than the 4h.Take out crystallized product, vacuum filtration, with the 30mL cold ethyl acetate take out give a baby a bath on the third day after its birth inferior; Take out with about 15mL sherwood oil at last and wash once, drain as far as possible, put in 60 ℃ of vacuum drying ovens more than the dry 48h; Promptly get the formula I compound 22.8g of light yellow loose powder shape, yield 95.8%.
(catalyst system therefor is ZnCl for embodiment 2 formula I compounds synthetic
2)
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.68g ZnCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 23.3g of light yellow loose powder shape, yield 97.9% with embodiment 1 operation.
(catalyst system therefor is MgCl for embodiment 3 formula I compounds synthetic
2)
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.48g MgCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get light yellow loose powder shape formula I compound 19.3g, yield 81.1% with embodiment 1 operation.
(catalyst system therefor is FeCl for embodiment 4 formula I compounds synthetic
2)
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.63g FeCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get light yellow loose powder shape formula I compound 17.5g, yield 73.5% with embodiment 1 operation.
(catalyst system therefor is FeCl for embodiment 5 formula I compounds synthetic
3)
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.81g FeCl
3(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get light yellow loose powder shape formula I compound 18.7g, yield 78.6% with embodiment 1 operation.
Synthetic (catalyst system therefor is HCl) of embodiment 6 formula I compounds
(amount to lamp-dish flower acetic 23.1g, 0.05mol), put in the 1000mL round-bottomed flask, adding methyl alcohol 500g, 0.50g concentration are 36% concentrated hydrochloric acid (containing HCl0.005mol), in 50 ℃ of heated and stirred reaction 2h to get Breviscarpine raw material 28.0g.All the other get light yellow loose powder shape formula I compound 13.2g, yield 55.5% with embodiment 1 operation.
Synthetic (catalyst system therefor is NaCl) of embodiment 7 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.29g NaCl (0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get light yellow loose powder shape formula I compound 19.8g, yield 83.2% with embodiment 1 operation.
Synthetic (catalyst system therefor is KCl) of embodiment 8 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.37g KCl (0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get light yellow loose powder shape formula I compound 16.2g, yield 68.1% with embodiment 1 operation.
Not synthetic (not the using catalyzer) of embodiment 9 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, in 50 ℃ of heated and stirred reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.The influence that the selection of table 1 different catalysts is synthetic to formula I compound
Above-mentioned experiment shows that compound has tangible catalysed promoted effect to this reaction, and the selection of different catalysts has material impact to formula I compound synthetic.Muriatic catalysis action is ZnCl in proper order
2＞CaCl
2＞NaCl＞MgCl
2＞FeCl
3＞FeCl
2＞KCl＞HCl, wherein, CaCl especially
2And ZnCl
2Katalysis best.
Following examples 10～14 and embodiment 1 and embodiment 9 are with CaCl
2Be catalyzer, keeping under the constant situation of other condition and operating method that contrasted the influence that catalyst levels synthesizes formula I compound, its result sees table 2.Among each embodiment reaction product all pass through HPLC,
1HNMR,
13CNMR, IR and UV identify and check.
Synthetic (catalyzer and lamp-dish flower acetic mol ratio are 0.05:1.0) of embodiment 10 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.28g CaCl
2(0.0025mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 9.9g of light yellow loose powder shape, yield 41.6% with embodiment 1 operation.
Synthetic (catalyzer and lamp-dish flower acetic mol ratio are 0.08:1.0) of embodiment 11 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.44g CaCl
2(0.0040mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 19.4g of light yellow loose powder shape, yield 81.5% with embodiment 1 operation.
Synthetic (catalyzer and lamp-dish flower acetic mol ratio are 0.15:1.0) of embodiment 12 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 0.83g CaCl
2(0.0075mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 22.9g of light yellow loose powder shape, yield 96.2% with embodiment 1 operation.
Synthetic (catalyzer and lamp-dish flower acetic mol ratio are 0.20:1.0) of embodiment 13 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 1.11g CaCl
2(0.01mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 22.7g of light yellow loose powder shape, yield 95.4% with embodiment 1 operation.
Synthetic (catalyzer and lamp-dish flower acetic mol ratio are 0.50:1.0) of embodiment 14 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 500g, 2.78g CaCl
2(0.025mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 23.0g of light yellow loose powder shape, yield 96.6% with embodiment 1 operation.
The influence that table 2 catalyst levels is synthetic to formula I compound
Can know that by table 2 catalyst levels has material impact to formula I compound synthetic.Catalyst levels is low excessively, does not reach katalysis, or catalytic effect is poor, and product yield is lower.But after catalyst levels surpassed the optimal economic consumption, product yield can not occur with the increase of catalyst levels obviously rising, and too much consumes reagent and does not have practical significance, and can cause the rising of cost.Take all factors into consideration, confirm in this building-up reactions, the optimum mole ratio scope of catalyzer and lamp-dish flower acetic is 0.1～0.2:1.0.
Following examples 15～23 and embodiment 1 are keeping under the constant situation of other condition and operating method, have investigated the influence that choice of Solvent is synthesized formula I compound, and the result sees table 3.Among each embodiment reaction product all pass through HPLC,
1HNMR,
13CNMR, IR and UV identify and detect.
Synthetic (solvent is a water) of embodiment 15 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, water 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 18.1g of light yellow loose powder shape, yield 76.1% with embodiment 1 operation.
Synthetic (solvent is an acetonitrile) of embodiment 16 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, water-acetonitrile 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 12.7g of light yellow loose powder shape, yield 53.4% with embodiment 1 operation.
Synthetic (solvent is a DMSO 99.8MIN.) of embodiment 17 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, DMSO 99.8MIN. 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 19.3g of light yellow loose powder shape, yield 81.1% with embodiment 1 operation.
Synthetic (solvent is N, dinethylformamide) of embodiment 18 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 23.2g of light yellow loose powder shape, yield 97.5% with embodiment 1 operation.
Synthetic (solvent is an acetone) of embodiment 19 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, acetone 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.
Synthetic (solvent is an ETHYLE ACETATE) of embodiment 20 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, ETHYLE ACETATE 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.
Synthetic (solvent is a benzene) of embodiment 21 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, benzene 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.
Synthetic (solvent is a toluene) of embodiment 22 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, toluene 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.
Synthetic (solvent is a chloroform) of embodiment 23 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, chloroform 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.
The influence that table 3 different solvents is synthetic to formula I compound
From the above, choice of Solvent has material impact to formula I compound synthetic.When selecting acetone, ETHYLE ACETATE, benzene, toluene, chloroform etc. for use as reaction solvent, Breviscarpine and the methyl alcohol production I compound that under the chloride catalyst effect, do not react; And under other condition situation identical, select water, acetonitrile, methyl alcohol, DMSO 99.8MIN. or N for use with operation, when dinethylformamide was reaction solvent, different reactions can take place in the Breviscarpine raw material, obtained the formula I compound of different productive rates.From experimental result, this reaction to be selecting methyl alcohol or N, and the yield that dinethylformamide obtains during for solvent is for high.When selecting for use methyl alcohol to be solvent, part methyl alcohol is wherein participated in reaction as reaction reagent, and unnecessary methyl alcohol then uses as solvent.
Following examples 24～30 and embodiment 18, with N, dinethylformamide is a solvent, is keeping under the constant situation of other condition and operating method, has investigated the influence that the consumption of solvent synthesizes formula I compound, the result sees table 4.Among each embodiment reaction product all pass through HPLC,
1HNMR,
13CNMR, IR and UV identify and detect.
Synthetic (mass ratio of solvent and lamp-dish flower acetic is 4.33:1.0) of embodiment 24 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 100g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 4.7g of light yellow loose powder shape, yield 19.7% with embodiment 1 operation.
Synthetic (mass ratio of solvent and lamp-dish flower acetic is 8.66:1.0) of embodiment 25 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 200g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 11.8g of light yellow loose powder shape, yield 49.6% with embodiment 1 operation.
Synthetic (mass ratio of solvent and lamp-dish flower acetic is 12.99:1.0) of embodiment 26 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 300g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 17.8g of light yellow loose powder shape, yield 74.8% with embodiment 1 operation.
Synthetic (mass ratio of solvent and lamp-dish flower acetic is 15.15:1.0) of embodiment 27 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 350g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 22.1g of light yellow loose powder shape, yield 92.9% with embodiment 1 operation.
Synthetic (mass ratio of solvent and lamp-dish flower acetic is 19.48:1.0) of embodiment 28 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 450g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 23.3g of light yellow loose powder shape, yield 97.9% with embodiment 1 operation.
Synthetic (mass ratio of solvent and lamp-dish flower acetic is 21.65:1.0) of embodiment 29 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 500g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 21.3g of light yellow loose powder shape, yield 89.5% with embodiment 1 operation.
Synthetic (mass ratio of solvent and lamp-dish flower acetic is 25.97:1.0) of embodiment 30 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 600g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reaction 2h.All the other get the formula I compound 15.9g of light yellow loose powder shape, yield 66.8% with embodiment 1 operation.
The influence that table 4 solvent load is synthetic to formula I compound
From the above, solvent load has material impact equally to synthesizing of formula I compound.When solvent load was not enough, lamp-dish flower acetic was difficult to whole dissolvings, caused reaction not thorough, and yield is low; On the other hand, if solvent load is too much, can cause reactant concn low excessively, be unfavorable for the carrying out that react equally, yield is lower equally, and can cause the raising of production cost.According to above-mentioned experimental result, it is comparatively suitable that the mass ratio of solvent and lamp-dish flower acetic is controlled at 13.0～22.0:1.0, and the mass ratio of best solvent and lamp-dish flower acetic is 15.0～20.0:1.0.
Following examples 31～38 and embodiment 18 are keeping under the constant situation of other condition and operating method, have investigated the influence that temperature of reaction is synthesized formula I compound, and the result sees table 5.Among each embodiment reaction product all pass through HPLC,
1HNMR,
13CNMR, IR and UV identify and detect.
Synthetic (20 ℃ of the temperature of reaction) of embodiment 31 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 20 ℃ of stirring reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.
Synthetic (30 ℃ of the temperature of reaction) of embodiment 32 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 30 ℃ of stirring reaction 2h.Reactant detects through TLC and HPLC (performance liquid chromatography), proves the Breviscarpine raw material production I compound that do not react.
Synthetic (40 ℃ of the temperature of reaction) of embodiment 33 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 40 ℃ of stirring reaction 2h.All the other get the formula I compound 8.9g of light yellow loose powder shape, yield 37.4% with embodiment 1 operation.
Synthetic (45 ℃ of the temperature of reaction) of embodiment 34 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 45 ℃ of stirring reaction 2h.All the other get the formula I compound 18.8g of light yellow loose powder shape, yield 79.0% with embodiment 1 operation.
Synthetic (60 ℃ of the temperature of reaction) of embodiment 35 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 60 ℃ of stirring reaction 2h.All the other get the formula I compound 23.3g of light yellow loose powder shape, yield 97.9% with embodiment 1 operation.
Synthetic (80 ℃ of the temperature of reaction) of embodiment 36 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 80 ℃ of stirring reaction 2h.All the other get the formula I compound 23.1g of light yellow loose powder shape, yield 97.1% with embodiment 1 operation.
Synthetic (100 ℃ of the temperature of reaction) of embodiment 37 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 100 ℃ of stirring reaction 2h.All the other get the formula I compound 20.0g of light yellow loose powder shape, yield 84.0% with embodiment 1 operation.
Synthetic (120 ℃ of the temperature of reaction) of embodiment 38 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 120 ℃ of stirring reaction 2h.All the other get the formula I compound 15.6g of light yellow loose powder shape, yield 65.5% with embodiment 1 operation.
The influence that table 4 temperature of reaction is synthetic to formula I compound
From the above, temperature of reaction has material impact to formula I compound synthetic.Reaction temperature is spent low, and speed of response is slow, does not even react, and product yield is low; Otherwise, if temperature of reaction is too high, the side reaction aggravation, impurity increases, and the principal product yield descends, and product darkens.According to above-mentioned experimental result, temperature of reaction be controlled at 45～100 ℃ comparatively suitable, preferred range of reaction temperature is 50-80 ℃.
Following examples 39～44 and embodiment 18 keeping under the constant situation of other condition and operating method, investigated the influence that the reaction times synthesizes formula I compound, and the result sees table 5.Among each embodiment reaction product all pass through HPLC,
1HNMR,
13CNMR, IR and UV identify and detect.
Synthetic (the reaction times 0.5h) of embodiment 39 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reactions 0.5h hour.All the other get the formula I compound 11.1g of light yellow loose powder shape, yield 46.6% with embodiment 1 operation.
Synthetic (the reaction times 1.0h) of embodiment 40 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reactions 1.0h hour.All the other get the formula I compound 18.7g of light yellow loose powder shape, yield 78.6% with embodiment 1 operation.
Synthetic (the reaction times 1.5h) of embodiment 41 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reactions 1.5h hour.All the other get the formula I compound 22.9g of light yellow loose powder shape, yield 96.2% with embodiment 1 operation.
Synthetic (the reaction times 3.0h) of embodiment 42 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reactions 3.0h hour.All the other get the formula I compound 23.1g of light yellow loose powder shape, yield 97.1% with embodiment 1 operation.
Synthetic (the reaction times 5.0h) of embodiment 43 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reactions 5.0h hour.All the other get the formula I compound 21.7g of light yellow loose powder shape, yield 91.2% with embodiment 1 operation.
Synthetic (the reaction times 10.0h) of embodiment 44 formula I compounds
Getting Breviscarpine raw material 28.0g (amounts to lamp-dish flower acetic 23.1g, 0.05mol), puts in the 1000mL round-bottomed flask, add methyl alcohol 100g, N, dinethylformamide 400g, 0.56g CaCl
2(0.005mol), in 50 ℃ of heated and stirred reactions 10.0h hour.All the other get the formula I compound 19.3g of light yellow loose powder shape, yield 81.1% with embodiment 1 operation.
The influence that table 6 reaction times is synthetic to formula I compound
From the above, there is certain influence in the reaction times to formula I compound synthetic.Under the optional test condition, to carry out comparatively completely for guaranteeing reaction, the reaction times generally can be controlled in 1～5 hour, and the preferred reaction times is 1.5～3.0h comparatively.Reaction times is long, and formula I compound yield is on a declining curve, possibly be due to side reaction increases.
Embodiment 45 formula I compounds improve the experimental study of sleep
1. reagent, reagent and material
Formula I compound, drug research institute of Kunming Medicine Group Stock Co., Ltd provides.Vetanarcol, the gloomy Bioisystech Co., Ltd in Wal, Xi'an provides.
Kunming mouse, body weight are 18～22g, 180, and male and female half and half, Kunming Medicine Group Stock Co., Ltd's Animal Lab. provides, production licence number SCXK (Yunnan) 2005-0006, occupancy permit SYXK (Yunnan) 2005-0006.
2. TP
2.1 animal divides into groups and administration
Laboratory animal is divided into 3 batches; Be designated as respectively experiment I criticize (to the influence of mouse body weight, directly sleep experiments, prolong the vetanarcol experiment length of one's sleep), experiment II criticizes (vetanarcol sub-threshold dose hypnosis experiment), experiment III criticizes (the vetanarcol sleep is tested latent period), every batch of animal is divided into 4 groups at random according to body weight. 15 every group.If 5,6,4 '-trihydroxyflavone-7-O-β-basic, normal, high dose groups of D-glucuronic acid methyl ester (be respectively 25,50,150mg/kg body weight dose groups), gastric infusion, control group is irritated stomach and is given equivalent zero(ppm) water.Irritate stomach every day 1 time, continuous 30 days.
2.2 directly sleep test
Observation is tried the given the test agent that treated animal gives 3 dosage, after control group is given isopyknic zero(ppm) water, the phenomenon of sleeping whether occurs.Sleep is index with the righting reflex loss.When mouse is placed supine position, can right the body position immediately, can not the person of righting as surpassing 30～60 seconds, promptly think righting reflex loss to get into sleep.Righting reflex recovers to be the animal awakening, and righting reflex loss is the animal sleep time to recovering during this period of time.The record control group is fallen asleep the number of animals and the length of one's sleep with receiving the examination group
2.3 prolong the test length of one's sleep of vetanarcol inductive
Carry out preliminary experiment earlier before doing formal experiment. confirm to make animal 100% sleeping but can not make the long vetanarcol dosage length of one's sleep (40mg/kg body weight), formally test with this dosage.After the animal last is tried thing, the preceding 15min of peak effect occurs, give each treated animal abdominal injection vetanarcol, injection volume is the 40mg/kg body weight, serves as the sleep index with the mouse righting reflex loss.Observation is tried thing to the prolongation effect of the length of one's sleep of vetanarcol inductive.
2.4 vetanarcol sub-threshold dose hypnosis test
Carry out preliminary experiment earlier before doing formal experiment, confirm pentobarbital sodium sub-threshold lull dosage, i.e. the maximum sub-threshold dose (vetanarcol 25mg/kg body weight) of the vetanarcol that 80%～90% mouse righting reflex does not disappear is formally tested with this dosage.After the animal last is tried thing, the preceding 15min of peak effect occurs, give each treated animal abdominal injection vetanarcol, reach more than the 1min as sleeping judgement criteria with the mouse righting reflex loss.Observation gives the number of animals of each treated animal generation sleep in the vetanarcol 30min.
2.5 vetanarcol inducing mouse sleep latency test
Carry out preliminary experiment earlier before doing formal experiment, confirm to make animal 100% sleeping but do not make the long vetanarcol dosage length of one's sleep (300mg/kg body weight), formally test with this dosage.The animal last is tried 15min behind the thing, gives each treated animal abdominal injection vetanarcol, and injection volume is the 300mg/kg body weight, is index with the righting reflex loss, observes and is tried thing to preclinical influence of vetanarcol inducing mouse sleep.
3. experimental result
3.1 formula I compound is to the influence of the weight of animals
Each dose groups of formula I compound and control group are relatively.Experimental session body weight there are no significant difference (P>0.05), point out this test conditions following formula I compound that the mouse body weight is not had obvious influence, see table l.
Table 1 is tried the influence of thing to the experiment mice body weight
3.2 formula I compound is to the direct sleep effect of animal
Each dose groups and control group. the sleep phenomenon does not all appear in mouse behind the gastric infusion, points out under this experiment condition, and formula I compound does not have direct sleep effect to experiment mice.See table 2.
Table 2 is tried the direct sleep effect of thing to experiment mice
3.3 formula I compound is to the influence of vetanarcol inductive mouse sleep time
Table 3 is tried the influence of thing to vetanarcol inductive mouse sleep time
Visible by table 3; Give the mouse various dose receive the reagent thing after; Compare with control group; Basic, normal, high dose groups prolongs 16.2% (P ﹥ 0.05), 65.4% (P ﹤ 0.05) and 111.4% (P ﹤ 0.01) respectively to vetanarcol inductive mouse sleep time, shows that formula I compound has significant prolongation effect to vetanarcol inductive mouse sleep time, and is certain dose-dependence.
3.4 receive of the influence of reagent thing to vetanarcol sub-threshold dose inductive mice sleep incidence
Table 4 is tried the influence of thing to vetanarcol sub-threshold dose inductive mice sleep incidence
Visible by table 4; Give the mouse various dose receive the reagent thing after; Compare with control group; Basic, normal, high dose groups improves 50.4% (P ﹤ 0.05), 150.3% (﹤ 0.01), 351.1% (﹤ 0.01) respectively to vetanarcol inductive mice sleep incidence, shows to receive the reagent thing to the effect of increasing significantly of vetanarcol inductive mice sleep incidence, and is certain dose-dependence.
3.5 receive the reagent thing to preclinical influence of vetanarcol inductive mice sleep
Table 5 is tried thing to preclinical influence of vetanarcol inductive mice sleep
Visible by table 5; Give the mouse various dose receive the reagent thing after; Compare with control group; Basic, normal, high dose groups shortens 1.2% (P ﹥ 0.05), 11.1% (﹥ 0.05), 28.1% (P ﹤ 0.01) respectively to vetanarcol inductive mice sleep latent period, shows to receive the reagent thing that vetanarcol inductive mice sleep is had certain shortening effect latent period, and is certain dose-dependence.
Embodiment 46 formula I compounds are to the influence experiment of life span of drosophila melanogaster
1. reagent, reagent and material
Formula I compound, drug research institute of Kunming Medicine Group Stock Co., Ltd provides.
U.S.'s wild-type drosophila melanogaster, feeding environment: 25 ± 1 ℃ of temperature, relative humidity 60 ± 5%, 12h illumination, the dark alternately cultivation of 12h, the Kunming zooscopy provides.
2. TP
Collect the new fruit bat adult that sprouts wings in the 24h,, distinguish the male and female individuality, after weighing respectively, be divided into 5 groups at random: 1 control group and 4 experimental group that contain different concns formula I compound through etherization.100 of every group of fruit bats, male and female half and half are put respectively in the test tube of 3cm * 10cm that substratum is housed, 25 of every pipes.Control group gives conventional corn powder substratum, and experimental group contains 0.005%, 0.025% respectively; 0.075% and 0.550% 5; 6,4 '-maize powder medium of trihydroxyflavone-7-O-β-D-glucuronic acid methyl ester powder, test tube stands in the incubator and cultivates; Experimental temperature is 25 ± 1 ℃, relative humidity 60 ± 5%.Changed 1 freshly prepared substratum in per 4 days, every day observed and recorded drosophila survival number and death toll, till the whole death of fruit bat.Calculate the dead fate of half, mean lifetime and average maximum life span.
3. experimental result
Table 6 formula I compound is to the influence of life span of drosophila melanogaster
Visible by table 6, to compare with control group, each concentration group has certain prolongation to the half death time of fruit bat.Compare with male control group, the reagent substrate concentration is half death time of male group of 0.005%, 0.025%, 0.075%, 0.550% to have prolonged 1.4%, 8.7%, 16.6%, 14.1% respectively; Compare with female control group, the reagent substrate concentration is half death time of female group of 0.005%, 0.025%, 0.075%, 0.550% to have prolonged 2.5%, 10.5%, 15.8%, 16.4% respectively.
Table 6 shows that also 0.025%, 0.075%, 0.550% reagent substrate concentration is mean lifetime and the average maximum life span of ability significant prolongation fruit bat all.Compare with male control group, the reagent substrate concentration is that 0.005%, 0.025%, 0.075%, 0.550% male group mean lifetime has prolonged 1.4%, 9.0%, 16.7%, 13.3% respectively; Compare with female control group, concentration is that 0.005%, 0.025%, 0.075%, 0.550% female group mean lifetime has prolonged 1.6%, 11.0%, 15.1%, 16.4% respectively.Compare with male control group, the reagent substrate concentration is that 0.005%, 0.025%, 0.075%, 0.550% male group maximum life span has prolonged 0.4%, 5.4%, 11.7%, 12.5% respectively; Compare with female control group, the reagent substrate concentration is that 0.005%, 0.025%, 0.075%, 0.550% female group maximum life span has prolonged 1.4%, 7.1%, 10.8%, 10.1% respectively.This shows, 5,6,4 '-trihydroxyflavone-7-O-β-D-glucuronic acid methyl ester can effectively prolong half death time, mean lifetime and the highest mean lifetime of fruit bat.
The mechanism effect experiment that embodiment 47 formula I compound retards are old and feeble
1. reagent, reagent and material
Formula I compound, drug research institute of Kunming Medicine Group Stock Co., Ltd provides.
Mda (MDA) is measured test kit, and lot number is 20080925; Superoxide-dismutase (SOD) is measured test kit, stipulate in every milliliter of reaction solution that it is 1 nitrite unit (NU) that the SOD inhibiting rate reaches that 50% o'clock pairing SOD measures, and lot number is 20080629; Selenoperoxidase (GSH-PX) is measured test kit, stipulates that per 4 μ l whole bloods at 37 ℃ of reaction 5min, deduct the effect of non-enzymatic reaction, and making in the reaction system GSH concentration reduce by 1 μ mol/L is 1 enzyme activity unit, and lot number is 20080918; Active oxygen (ROS) is measured test kit, stipulates that every milliliter of serum reacts 1min down at 37 ℃, makes H in the reaction system
2O
2It is 1 active oxygen unit that concentration reduces 1mmol/L, and lot number is 20080721.Above test kit builds up bio-engineering research by Nanjing and provides.
Kunming mouse, 15 monthly ages, body weight 50 ± 2g, Kunming Medicine Group Stock Co., Ltd's Animal Lab. provides, production licence number SCXK (Yunnan) 2005-0006, occupancy permit SYXK (Yunnan) 2005-0006.
2. TP
40 of aged kunming mices, male and female half and half are divided into 4 groups at random: normal control group, low dose group (50mg/kg), middle dose groups (100mg/kg) and high dose group (200mg/kg).Each dose groups mouse is irritated stomach with the reagent thing formula I compound that receives of prescribed dose, and normal control group mouse is used with the zero(ppm) water of volume and irritates stomach.Every day 1 time, continuous 30 days.In addition, weighed 1 time in per 10 days.24h after last is irritated stomach plucks the eyeball blood sampling.According to the test kit operation instructions, it is active to measure mouse red blood cell SOD respectively, whole blood GSH-PX activity and red corpuscle MDA content, serum ROS content.
3. experimental result
The old and feeble mechanism effect of table 7 formula I compound retards
Above-mentioned table 7 result shows that formula I compound can significantly improve SOD and GSH-PX activity in the aged mouse body, reduces ROS content and MDA content in the aged mouse body.This possibly be that it has one of dominant mechanism of delaying senility function.
Embodiment 48 pharmaceutical compositions
Grinding and sieving mixes promptly getting.
Embodiment 49 pharmaceutical compositions
Grinding and sieving mixes promptly getting.
Embodiment 50 pharmaceutical compositions
Grinding and sieving mixes promptly getting.
Embodiment 51 pharmaceutical compositions
Grinding and sieving mixes promptly getting.
Embodiment 52 pharmaceutical compositions
Grinding and sieving mixes promptly getting.
Embodiment 53 pharmaceutical compositions
Compound shown in the formula I 3%
Dry starch 85%
Magnesium Stearate 12%
Grinding and sieving mixes promptly getting.
Embodiment 54 pharmaceutical compositions
Compound shown in the formula I 20%
Dry starch 65%
Magnesium Stearate 15%
Grinding and sieving mixes promptly getting.
Embodiment 55 pharmaceutical compositions
Compound shown in the formula I 17%
Dry starch 75%
Magnesium Stearate 8%
Grinding and sieving mixes promptly getting.
Embodiment 56 pharmaceutical compositions
Compound shown in the formula I 10%
Dry starch 85%
Magnesium Stearate 5%
Grinding and sieving mixes promptly getting.
Embodiment 57 pharmaceutical compositions
Compound shown in the formula I 15%
Dry starch 75%
Magnesium Stearate 10%
Grinding and sieving mixes promptly getting.
Embodiment 58 tablets
With compound shown in the formula I, starch, Microcrystalline Cellulose, sodium starch glycolate and Magnesium Stearate, mix back compressing tablet on tabletting machine, promptly get.
Embodiment 59 capsules
Compound shown in the formula I 3%
Dry starch 85%
Magnesium Stearate 12%
With compound shown in the formula I, dry starch and Magnesium Stearate, be packed into after the mixing in the hard gelatin capsule, promptly get.
Embodiment 17 capsules
Compound shown in the formula I 20%
Dry starch 65%
Magnesium Stearate 15%
With compound shown in the formula I, dry starch and Magnesium Stearate, be packed into after the mixing in the hard gelatin capsule, promptly get.
Embodiment 60 injection liquids
Compound shown in the formula I is added the ethanol stirring and dissolving, add sodium-chlor and an amount of water for injection, stir; Add 0.1% pin and use activated carbon, decarburization is filtered in absorption; Add water for injection to specified amount, the millipore filtration membrane filtration props up embedding by 1mL/; 100 ℃ of moist heat sterilization 20min, qualified through the lamp inspection, promptly get.
Embodiment 61 injection liquids
Compound shown in the formula I is added the ethanol stirring and dissolving, add sodium-chlor and an amount of water for injection, stir; Add 0.1% pin and use activated carbon, decarburization is filtered in absorption; Add water for injection to specified amount, the millipore filtration membrane filtration props up embedding by 1mL/; 100 ℃ of moist heat sterilization 20min, qualified through the lamp inspection, promptly get.
Embodiment 62 lyophilized injectable powders
Compound shown in the formula I is added the ethanol stirring and dissolving, add sodium-chlor, N.F,USP MANNITOL and an amount of water for injection, stir, add 0.1% pin and use activated carbon; Decarburization is filtered in absorption, adds water for injection to specified amount; The millipore filtration membrane filtration props up packing by 4mL/, lyophilize; Encapsulation through being up to the standards, promptly gets.
The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.
Claims (8)
1. the preparation method of a formula I compound is characterized in that, with lamp-dish flower acetic and methyl alcohol and as the muriate of catalyzer reacting by heating and making in solvent.
2. preparation method according to claim 1 is characterized in that, described muriate as catalyzer is selected from NaCl, KCl, HCl, CaCl
2, MgCl
2, ZnCl
2, FeCl
2Or FeCl
3In one or more mixture, preferred CaCl
2Or ZnCl
2
3. preparation method according to claim 1 is characterized in that, said is 0.05～0.5:1.0 as the muriate of catalyzer and the mol ratio of lamp-dish flower acetic, and preferred mol ratio is 0.1～0.2:1.0.
4. preparation method according to claim 1 is characterized in that said solvent is selected from water, acetonitrile, methyl alcohol, DMSO 99.8MIN. or N, the mixture of one or more in the dinethylformamide.
5. preparation method according to claim 1 is characterized in that, said solvent is methyl alcohol or N, the mixture of one or more in the dinethylformamide.
6. preparation method according to claim 1 is characterized in that, the mass ratio of said solvent and lamp-dish flower acetic is 10.0～18.0:1.0, and the mass ratio of preferred solvent and lamp-dish flower acetic is 13.0～16.0:1.0.
7. preparation method according to claim 1 is characterized in that, the temperature of said reaction is 40～120 ℃, and preferred temperature of reaction is 45～100 ℃, and more preferred temperature of reaction is 50～80 ℃.
8. preparation method according to claim 1 is characterized in that, the time of said reaction is 1～5 hour, and the preferred reaction time is 1.5～3.0h.
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Cited By (1)
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| CN106581027A (en) * | 2016-11-25 | 2017-04-26 | 昆药集团股份有限公司 | Compound and pharmaceutical purpose, composition and preparation |
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| CN102838645B (en) | 2015-06-17 |
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