CN101591374B - Steroid compound, preparation method thereof, medicinal composition containing compound and application of compounds - Google Patents
Steroid compound, preparation method thereof, medicinal composition containing compound and application of compounds Download PDFInfo
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- CN101591374B CN101591374B CN2009101041900A CN200910104190A CN101591374B CN 101591374 B CN101591374 B CN 101591374B CN 2009101041900 A CN2009101041900 A CN 2009101041900A CN 200910104190 A CN200910104190 A CN 200910104190A CN 101591374 B CN101591374 B CN 101591374B
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Abstract
The invention provides a steroid compound, a preparation method thereof, a medicinal composition containing the compound and application of the compounds, which belong to the technical field of medicaments. The steroid compound is named as 14,16-dihydroxy-diosgenin (14,16-diosgenin), and the invention also provides the preparation method of the compound and application of the compound in preparing medicaments for preventing and/or treating hyperlipemia, adiposis and cerebral apoplexy. The steroid compound has the functions of lowering blood fat, reducing organism total fat, resisting acute cerebral ischemia and the like, and provides the probability of developing a novel medicament for treating the hyperlipemia, adjusting body fat of adiposis patients and resisting the cerebral apoplexy.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of new steroidal compounds.The invention still further relates to the preparation method of this compound, and described compound is used for preventing and/or treating the purposes of the medicine of hyperlipidemia, obesity and cerebral apoplexy in preparation.
Background technology
In the prior art, many parts of documents disclose and have separated the method that obtains saponin(e in the tuber of dwarf lilyturf (Ophiopogon japonicus), and the purposes of described saponin(e.For example, CN 200610014213.5 disclosed " a kind of preparation method of Radix Ophiopogonis total saponins ", CN 200710024566.8 disclosed " application of ophiopogonin D in preparation vascular endothelial cells regulating signal transduction genomic medicine ", CN 200710024568.7 disclosed " application of ophiopogonin D in preparation regulating vascular endothelial cell apoptogene medicine ", CN 200710024567.2 is disclosed " application of ophiopogonin D in preparation regulating vascular endothelial cell functional gene medicine ", CN 200710024569.1 disclosed " application of ophiopogonin D in preparation regulating vascular endothelial cell cycle genes medicine ", CN 200810022093.2 disclosed " ophiopogonin D is as the medicinal use of tissue factor approach restrainer ".But all do not relate to about new steroidal compounds (14,16-dihydroxyl-diosgenin), preparation method that can treat hyperlipidemia and obesity and the drug regimen that obtains with this steroidal compounds, and be applied to treat the patent application formerly of hyperlipidemia and obesity.
Enter 21st century, cardiovascular disorder is brought new severe challenge to the mankind, and the whole world is annual because of about 1,700 ten thousand people of cardiovascular death, becomes the major disease that the world today threatens to human health.Wherein hypercholesterolemia is a major cause.
In China, along with the development of economic level, living standards of the people improve, dietary structure changes and the rapid aging of population, and the hypercholesterolemia sickness rate rises rapidly, become whole world rising country faster, surpass many developed countries." Chinese cardiovascular diseases report 2005 " that NCCD has been issued shows, hyperlipemia has reached 1.6 hundred million people, overweight 200,000,000 people, fat 6,000 ten thousand people, every year are used for the treatment of this sick medical expense rate of growth 2 times near China's GDP growth rate, cause huge economical load to society.
Yet the medicine that can be used for the treatment of hyperlipidemia and adiposis patient is also few.Effectively treat the Statins of one of high blood cholesterol drug, more and more evidences shows that its safety issue also receives publicity.Effectively the medicine phenol fluorine Lamine of treatment obesity is because safety issue is withdrawn from the market, and existing clinical main medicine sibutramine and orlistat also receive publicity because of effect and security.
After the seventies in last century, the report of using treatment by Chinese herbs hyperlipidemia and obesity is increasing, and obtains certain curative effect.Its superiority shows can obviously improve patient's symptom and quality of life, and by many target spots effect performance regulating effect, but composition is unclear, and the mechanism of action is indeterminate, the curative effect instability.
As fully visible, ideal treatment hyperlipidemia and obesity medicine still lack, and therefore, the compound of a kind of new treated hyperlipidemia and obesity is still people's searching direction.
Summary of the invention
Technical problem to be solved by this invention promptly provides a kind of new steroidal compounds for the treatment of hyperlipidemia and obesity and preparation method thereof; Another object of the present invention provides the drug regimen that obtains with this steroidal compounds, and is applied to treat hyperlipidemia and obesity.
The inventor discovers, a kind of had reducing blood-fat, reduced effects such as total fat of body and anti-acute cerebral ischemia by the folk tradition herbal medicine steroidal compounds that separation and Extraction goes out in the tuber of dwarf lilyturf, thereby be a kind of new treatment hyperlipidemia of exploitation, regulate obesity human body fat and anti-cerebral apoplexy medicine possibility is provided, the inventor is accomplished the present invention based on this discovery.
Summary of the invention:
Therefore, first aspect present invention provides the steroidal compounds of a kind of structural formula suc as formula I:
Or its crystal type, unformed, mixed extract.The steroidal compounds of above-mentioned formula I, its name is called 14,16-dihydroxyl-diosgenin (14,16-Diosgenin); Its chemical formula is: C
27H
46O
5
Second aspect present invention provides the method for preparing described formula I steroidal compounds, it is characterized in that, comprises the steps:
(1) get the tuber of dwarf lilyturf, add water boil by 7 times of weight after, kept 2 hours at 80-90 ℃, filter, the dregs of a decoction kept 1.5 hours at 80-90 ℃ after adding water boil by 4 times of weight, filtered, the dregs of a decoction are again by 4 times of weight, keep 1 hour at 80-90 ℃ after adding water boil, filter; Remerge 3 filtrates and obtain extracting solution;
(2) with the extracting solution of step (1) gained by 0.06-0.13BV/ minute by the macroporous adsorptive resins that 100g handles well is housed, absorption finishes, and uses 80% ethanol elution, the ethanol liquid film concentrating under reduced pressure behind the wash-out, to there not being ethanol, refilter, drying obtains dry thing; The concentrating under reduced pressure condition is vacuum tightness 10.7kPa, temperature 80-90 ℃;
(3) get step (2) the dry thing that obtains, be dissolved in water by 1: 10 (weight ratio), adding 36% hydrochloric acid to concentration again is 1.8mol/L, under 85-95 ℃, and hydrolysis time 2-6 hour, filter, collect water-insoluble;
(4) adopt the octadecylsilane chemically bonded silica post, the ratio of moving phase acetonitrile-water is 35-45: 65-55, detects wavelength 208nm, and the water-insoluble that under the room temperature condition step (3) is obtained carries out specimen preparation, collection contains 14, the sample solution of 16-dihydroxyl-diosgenin;
(5) sample solution that step (4) is obtained carries out concentrating under reduced pressure, and the concentrating under reduced pressure condition is vacuum tightness 10.7kPa, temperature 80-90 ℃;
(6) then, to the concentrating under reduced pressure thing of step (5), under 80-90 ℃ of condition, dry 3-5 hour;
(7) last, obtain 14,16-dihydroxyl-diosgenin (14,16-Diosgenin).
Third aspect present invention provides the purposes of described formula I, it is characterized in that, described formula I is used for preparation falls the total cholesterol medicine.Described formula I is used for preparation falls total triglyceride medicine.Described formula I is used for preparation reduces the low density lipoprotein cholesterol medicine.Described formula I is used to prepare the high density lipoprotein increasing cholesterol drugs.Described formula I is used to prepare the medicine that reduces the total fat of body.The medicine that described formula I is used to prepare anti-cerebral ischemia.
Fourth aspect present invention provides the pharmaceutical composition of described formula I, and it comprises each described formula I compound of at least a first aspect present invention and optional pharmaceutically acceptable carrier or the vehicle that prevents and/or treats significant quantity.
According to the described pharmaceutical composition of fourth aspect present invention, it is a unit dosage form.Wherein said unit dosage form is selected from: tablet, capsule, granule, transdermal patch, ointment, gelifying agent, suppository, oral liquid, oral administration mixed suspension, injectable emulsion, Orally taken emulsion etc., slow releasing tablet, controlled release tablet etc.According to the described pharmaceutical composition of fourth aspect present invention, the significant quantity of wherein said formula I steroidal compounds in described unit dosage form is with formula I compound (C
27H
46O
5) meter, be 10～1000mg.According to the described pharmaceutical composition of third aspect present invention, preferably, the significant quantity of wherein said formula I steroidal compounds in described unit dosage form is with formula I compound (C
27H
46O
5) meter, be 20～800mg.According to the described pharmaceutical composition of fourth aspect present invention, further preferably, the significant quantity of wherein said formula I steroidal compounds in described unit dosage form is with formula I compound (C
27H
46O
5) meter, be 25～500mg.According to the described pharmaceutical composition of fourth aspect present invention, more further preferably, the significant quantity of wherein said formula I steroidal compounds in described unit dosage form is with formula I compound (C
27H
46O
5) meter, be 30～250mg.According to the described pharmaceutical composition of fourth aspect present invention, still more preferably, the significant quantity of wherein said formula I steroidal compounds in described unit dosage form is with formula I compound (C
27H
46O
5) meter, be 80～150mg.According to the described pharmaceutical composition of fourth aspect present invention, at last preferably, the significant quantity of wherein said formula I steroidal compounds in described unit dosage form is with formula I compound (C
27H
46O
5) meter, be 30mg.
As used herein, term " treatment " has its general implication, and be meant especially at this paper and adopt formula I compound of the present invention or pharmaceutical composition to handle, in the hope of described hyperlipemic patients is produced effects such as treating, cure, alleviate, alleviate to hyperlipemic patients.Similarly, as used herein, term " prevention " has its general implication, and be meant especially at this paper and adopt formula I compound of the present invention or pharmaceutical composition to handle, prevent in the hope of described hyperlipidemia is produced, prevent, stop, effect such as partition suffering from hyperlipidemia of the present invention or hyperlipidemia of the present invention being had the risk person of suffering from.
As used herein, term " pharmacy is acceptable " typically refers to pharmacy field and can use, and to product or harmless to Mammals, or has rational or acceptable interests/risk ratio.
As used herein, term " carrier " and " vehicle " can be the carrier and the vehicle of any routine in the pharmacy field.The concrete carrier and the selection of vehicle will be depended on administering mode or disease type and the state that is used for the treatment of particular patient.The suitable drug preparation of compositions method that is used for the specific administration pattern is fully in pharmaceutical field technician's ken.For example, can be used as carrier, vehicle, thinner, weighting agent, solvent, balustrade, tackiness agent, wetting agent, disintegrating agent, absorption enhancer, tensio-active agent, absorption carrier and the lubricant etc. that pharmaceutically acceptable carrier or vehicle comprise the pharmaceutical field routine.In case of necessity, can also comprise flavouring agent, sanitas and sweeting agent etc.
As used herein, term " hyperlipidemia ", " obesity " and " cerebral apoplexy " have the general sense of its medical field.
As used herein, term " significant quantity " is meant the amount of active ingredient of the present invention, and this amount can effectively prevent and/or treat hyperlipidemia of the present invention.
As used herein, term " pharmaceutical composition " or " medicine box product " have its general implication, and can refer to narrow sense pharmaceutical preparation or pharmaceutical dosage form in this article, and it can comprise or not comprise pharmaceutical excipient.Can adopt the particularly routine techniques in the formulation art of pharmacy field, prepare the combination of pharmaceutical composition of the present invention or compound medicine.According to pharmaceutical composition of the present invention, it is the pharmaceutical dosage form that goes for oral administration, parenteral admin or topical, topical administration.According to pharmaceutical composition of the present invention, described pharmaceutical dosage form includes but not limited to: tablet, capsule, granule, pulvis, injection liquid, injectable powder, transdermal patch, ointment, gelifying agent, suppository, oral liquid, oral administration mixed suspension, injectable emulsion, Orally taken emulsion etc., slow releasing tablet, controlled release tablet etc.The medicine of above-mentioned various formulations all can be according to the ordinary method preparation of pharmaceutical field.
When pharmaceutical composition of the present invention or medicine box product as medicament administration during in the animal subject patient, they can give with itself, promptly do not add any above-mentioned pharmaceutically acceptable carrier, and pharmaceutical composition of the present invention directly is applied to the patient with original shape; Perhaps can be with the formula I compound that contains 1-99% for example (more preferably for example 10-90%) be combined into pharmaceutical composition with pharmaceutically acceptable carrier after give the human or animal.
Activeconstituents in formula I compound of the present invention or pharmaceutical composition or medicine box product, its actual dosage level and the time-histories of using can change, so that obtain a kind of amount of activeconstituents, this amount is for specific being subjected to tries individuality, composition and application process, can obtain desired therapeutic effectively and reply, and to being tried individual nontoxicity.Certainly, can change the actual dose level of the formula I compound in the present invention or the medicine box product, so that the active compound amount of gained can effectively obtain required therapeutic response at concrete patient, composition and administering mode.Will be appreciated that total daily dosage portion of the formula I compound in formula I compound of the present invention or pharmaceutical composition or the medicine box product must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root of treatment effective dose is decided according to multiple factor, and described factor comprises the severity of the obstacle of being treated and this obstacle; The activity of the particular compound that is adopted; The concrete composition that is adopted; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that is adopted, route of administration and excretion rate; The treatment time length; The medicine that is used in combination or uses simultaneously with the particular compound that is adopted; And the known similar factor of medical field.
Formula I compound in formula I compound of the present invention or pharmaceutical composition or the medicine box product, as indicated above, their concrete dosage can be determined according to existing knowledge by those skilled in the art.If desired, effectively order dosage can be divided into multiple doses for the administration purpose; Therefore, unit-dose composition or pharmaceutical preparation unit can contain this quantity or its divided dose, to constitute per daily dose.For medicine box product of the present invention, formula I compound wherein is applied to according to the regular hour order and is subjected to examination individual, for example the two is used simultaneously, uses with the interval of optional order etc.
Formula I compound in the pharmaceutical composition of the present invention can be mixed with solid or liquid form for oral administration especially specially.
In yet another aspect, formula I compound in pharmaceutical composition of the present invention or the medicine box product can with one or more nontoxic physiology can tolerance or acceptable diluent, carrier, auxiliary material or vehicle (this paper can be referred to as carrier with them) be mixed with composition, with solid or liquid form oral administration or topical or the like.
Formula I compound in pharmaceutical composition of the present invention or the medicine box product also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, for example parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent action of microorganisms.Also expectation comprises isotonic agent, for example carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin.
Remove the active ingredient beyond the region of objective existence in the suspensoid and also can contain suspension agent, for example ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
Formula I compound in pharmaceutical composition of the present invention or the medicine box product can be solid dosage for oral administration, and described solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier such as Trisodium Citrate or Lin Suanergai and/or following material with at least a inert medicine and mix: a) weighting agent or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as hexadecanol and Zerol; H) sorbent material such as kaolin and wilkinite, and lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.Under the situation of capsule, tablet and pill, also can comprise buffer reagent in the described formulation.
Formula I compound in pharmaceutical composition of the present invention or the medicine box product can be liquid dosage form for oral administration, and described liquid dosage form for oral administration comprises the acceptable emulsion of medicine, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent commonly used except that containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.
Formula I compound of the present invention, through physical and chemical property determining, ultraviolet, infrared, mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum are resolved, and finally prove conclusively its structure.
The pharmaceutical composition of formula I compound provided by the invention and medicine box product are through researchs such as pharmacodynamics, toxicology, preparation technology, quality examination and study on the stability.The inventor finds compound shown in the formula I of the present invention and drug regimen thereof and clinical existing main flow medicine relatively through experiment repeatedly, also has following advantage:
1. formula I same dose of the present invention this to hyperlipemic patients, be better than the chemicals statins.
2. formula I same dose of the present invention reduces effect to the weight of animals and body fat, is better than the chemicals sibutramine.
3. formula I of the present invention also has anti-acute cerebral ischemia, antioxygenation.
4. formula I of the present invention is natural product, and security is good, LD
50For feed this product 3 months of, rat, do not see any toxic reaction yet, be expected in preparation has the medicine of treatment hyperlipidemia, fat-reducing and cerebral apoplexy, be applied.
For above-mentioned advantage, the contriver will also will enumerate specific embodiment and experimental data and make an explanation, illustrate and verify in aftermentioned embodiment the inside.
Embodiment
For showing effect of the present invention, further specify the present invention below by specific embodiment or test example.But, should be understood to, these embodiment or test example are only used for the more detailed usefulness that specifically describes, and are used for limiting in any form the present invention and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.Those skilled in the art know that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
Steroidal compounds of the present invention prepares example:
The compounds of this invention is to separate acquisition the tuber of dwarf lilyturf from the folk tradition herbal medicine, through physical and chemical property determining, ultraviolet, infrared, mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum are resolved, final this compound of conclusive evidence is a steroidal compounds, its chemistry is called 14, and 16-dihydroxyl diosgenin has another name called two pure diosgenins (14,16-Dihydrodiogenin), chemical structure is as follows:
Wherein, for how this compound is isolated in kind peaceful palace in the tuber of dwarf lilyturf, specifically may further comprise the steps:
Step 1: get the 1000kg tuber of dwarf lilyturf, put in the extraction kettle, add behind the water boil by 7 times of weight and kept 2 hours, filter at 80-90 ℃, the dregs of a decoction are by 4 times of weight, keep 1.5 hours at 80-90 ℃ after adding water boil, filter, the dregs of a decoction are again by 4 times of weight, keep 1 hour at 80-90 ℃ after adding water boil, filter.Merge 3 times filtrate;
Step 2: with step (1) extracting solution by 0.06-0.13BV/ minute by the macroporous adsorptive resins that 100kg handles well is housed, absorption finishes, with 50 liter of 80% ethanol elution, ethanol liquid film concentrating under reduced pressure (vacuum tightness 10.7kPa behind the wash-out, temperature 80-90 ℃) to there not being ethanol, filter drying;
Step 3: get step (2) the dry thing that obtains, be dissolved in water by 1: 10 (weight ratio), adding 36% hydrochloric acid to concentration again is 1.8mol/L, and under 85-95 ℃, hydrolysis time 3.5 hours filters, and collects water-insoluble;
Step 4: adopt the octadecylsilane chemically bonded silica post, the ratio of mobile phase methanol-water is 35-65: 65-35, detects wavelength 208nm, under the room temperature condition, the water-insoluble that step 3 is obtained carries out specimen preparation, collects to contain 14, the sample solution of 16-dihydroxyl-diosgenin;
Step 5: above-mentioned collection sample solution is carried out concentrating under reduced pressure;
Step 6: under 80-90 ℃ of temperature condition,, carry out drying to sample through concentrating under reduced pressure;
Step 7: obtain at last to be not less than 95% 14,16-dihydroxyl-diosgenin.
The compounds of this invention is to separate acquisition the tuber of dwarf lilyturf from the folk tradition herbal medicine, through physical and chemical property determining, ultraviolet, infrared, mass spectrum and NMR (Nuclear Magnetic Resonance) spectrum are resolved, final this compound of conclusive evidence is a steroidal compounds, its chemistry is called 14, and 16-dihydroxyl diosgenin has another name called two pure diosgenins (14,16-Dihydrodiogenin), chemical structure is as follows:
Two pure diosgenin formulation example 1: the preparation of tablet
With formula I is raw material, the two pure diosgenin tablets of preparation, and the prescription of 1000 tablets is as follows:
| Two pure diosgenin sheets are (with C 27H 46O 5Meter) | Starch |
| 30 | 70 |
Former, auxiliary material are mixed, be ground into fine powder, cross 100 mesh sieves, by the prescription amount of getting, compression molding, packing gets final product.
Two pure diosgenin formulation example 2: the capsular preparation of two pure diosgenins
With formula I is raw material, the two pure diosgenin capsules of preparation, and the prescription of 1000 capsules is as follows:
| Two pure diosgenin capsules are (with C 27H 46O 5Meter) | Starch |
| 30 | 70 |
Former, auxiliary material are mixed, be ground into fine powder, cross 100 mesh sieves, by the prescription amount of getting, granulation, packing get final product.
Two pure diosgenin formulation example 3: two pure diosgenin preparation of soft capsule
With formula I is raw material, the two pure diosgenin soft capsule preparations of preparation, and the prescription of 1000 capsules is as follows:
| Two pure diosgenins are (with C 27H 46O 5Meter) | 30g |
| Polyoxyethylene glycol | 500ml |
Each composition is mixed, be hybridly prepared into soup, other gets gelatin 100g, glycerine 55ml, and water 120ml mixes being made into gelatin solution, and at 28 ± 2 ℃, under relative humidity 40% condition, soup and gelatin are made 1000 with rotating the Zhanang machine automatically; And at 28 ± 2 ℃, under relative humidity 40% condition, with dry 20 hours of capsule, promptly.
Biology embodiment 1: two pure diosgenin reducing blood lipid
Adopt the disorders of lipid metabolism modelling, rat is raised the basal feed observation after 7 days indoor the feeding of SPF level experimentation on animals.Tail hematometry serum total cholesterol (TC), triglyceride level (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C) level were adopted in fasting in 16 hours.According to the TC level animal is divided into four groups at random, 10 every group.3 dosage groups give the thing that tried of various dose when giving high lipid food.Model control group gives high lipid food and distilled water.Give 30 days continuously 1 time every day.Claim body weight weekly 1 time, adjust the stomach amount of irritating.Finish fasting 16 hours in experiment, get the content of determination of serum TC, TG, HDL-C and LDL-C.Positive drug is a Lovastatin.The testing data statistics adopts the SPSS11.0 software package to handle.
Table 1 pair pure diosgenin is to the influence of hyperlipidemia rats blood fat (X ± S)
Annotate: compare * P＜0 01, * P＜0.05 with model group.
Table 1 results suggest, model control group after cholesterol, triglyceride level and the low density lipoprotein cholesterol test after two pure diosgenin group tests more all has utmost point significance to reduce, simultaneously can also improve high density lipoprotein cholesterol (HDL-C) content, and relatively have extremely significantly and raise with model control group after the test.
30 routine hyperlipemic patients, test-meal every day formula I 30mg/ people of the present invention checks after 30 days that all test-meal personnel cholesterol and triglyceride level are all reduced to normal level.
Biology embodiment 2: two pure diosgenins are to simple alimentary obesity the weight of animals and the influence of body fat
Adopt nutritional type rat and mouse model, carry out two pure diosgenins simple alimentary obesity the weight of animals and the influence of body fat are observed, positive drug is a sibutramine.The data statistics of testing data statistical test adopts the SPSS11.0 software package to handle.The two pure diosgenins of results suggest can significantly reduce experimental animal body weight and body fat (table 2, table 3 and table 4).
Table 2 pair pure diosgenin is to the influence of obese rat body weight (X ± S)
Annotate: compare * * * P＜0 001, * * P＜0 01, * P＜0.05 with model group.
Table 3 pair pure diosgenin is to the influence of obesity mice body fat weight (X ± S)
Annotate: compare * * * P＜0 001, * * P＜0 01, * P＜0.05 with model group.
Table 4 pair pure diosgenin is to the influence of obese rat body fat weight (X ± S)
Annotate: compare * * * P＜0 001, * * P＜0 01, * P＜0.05 with model group.
Biology embodiment 3: the anti-acute cerebral ischemia effect of two pure diosgenins
The mouse head-breaking prepares thoroughness global brain ischemia model, 70 of healthy Kunming mouses, and body weight 18～22g, male, divide 4 groups (10/group) at random: model group (give and wait capacity physiological saline), positive controls (Buddhist nun's film Horizon 200mg.kg
-1), gastric infusion, the 30min operation is compared with model group after the administration in the morning in the 7th day, and two pure diosgenins can be dehisced the time of panting (table 5) behind the significant prolongation mouse broken end.
Table 5 pair pure diosgenin is to the influence of the time of panting of dehiscing behind the mouse broken end (X ± s)
Annotate: compare * * P＜0 01, * P＜0.05 with model group.
Ligation rat bilateral common carotid arteries legal system is equipped with dispersivity imperfection global brain ischemia model.Broken end was got full brain after 120min was finished in model preparation, blotted surface-moisture with filter paper, accurately claim weight in wet base after ,-70 ℃ of Ultralow Temperature Freezers are preserved.Sham operated rats exposes not ligation of bilateral common carotid arteries.Two pure diosgenins to rat cerebral ischemia after cerebral index, MDA content, SOD vigor, Glu and GABA content influence measure, with model group relatively, significant difference, the two pure diosgenins of prompting have obvious provide protection (table 6) to ischemic brain injury.
Table 6 pair pure diosgenin is to the influence of rat cerebral ischemia (X ± s)
Annotate: compare * P＜0 01, * P＜0.05 with model group.
The present invention discovers to have reducing blood-fat through testing conclusive evidence formula I repeatedly, fall total fat of obesity body and treating cerebral ischemia in the Chongqing tackle key problems in science and technology scientific research project that the contriver bears.At present, the sick treatment of hyperlipidemia, obesity and cerebral apoplexy lacks active drug always, brings glad tidings for these diseases patient to this compound exploitation, and prospects for commercial application of the present invention is very good.
Claims (1)
1. a method for preparing steroidal compounds is characterized in that, the structure of described steroidal compounds is suc as formula I:
Its name is called 14,16-dihydroxyl-diosgenin, and described preparation method comprises the steps:
(1) get the tuber of dwarf lilyturf, add water boil by 7 times of weight after, kept 2 hours at 80-90 ℃, filter, the dregs of a decoction kept 1.5 hours at 80-90 ℃ after adding water boil by 4 times of weight, filtered, the dregs of a decoction kept 1 hour at 80-90 ℃ after adding water boil by 4 times of weight again, filtered; Remerge three filtrates and obtain extracting solution;
(2) with the extracting solution of step (1) gained by 0.06-0.13BV/ minute by the macroporous adsorptive resins that 100g handles well is housed, absorption finishes, and uses 80% ethanol elution, the ethanol liquid film concentrating under reduced pressure behind the wash-out, to there not being ethanol, refilter, drying obtains dry thing; The concentrating under reduced pressure condition is vacuum tightness 10.7kPa, temperature 80-90 ℃;
(3) get step (2) the dry thing that obtains, be dissolved in water by 1: 10 weight ratio, adding 36% hydrochloric acid to concentration again is 1.8mol/L, under 85-95 ℃, and hydrolysis time 2-6 hour, filter, collect water-insoluble;
(4) adopt the octadecylsilane chemically bonded silica post, the ratio of moving phase acetonitrile-water is 35-45: 65-55, detects wavelength 208nm, and the water-insoluble that under the room temperature condition step (3) is obtained carries out specimen preparation, collection contains 14, the sample solution of 16-dihydroxyl-diosgenin;
(5) sample solution that step (4) is obtained carries out concentrating under reduced pressure, and the concentrating under reduced pressure condition is vacuum tightness 10.7kPa, temperature 80-90 ℃;
(6) then, to the concentrating under reduced pressure thing of step (5), under 80-90 ℃ of condition, dry 3-5 hour;
(7) last, obtain 14,16-dihydroxyl-diosgenin.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101041900A CN101591374B (en) | 2009-06-26 | 2009-06-26 | Steroid compound, preparation method thereof, medicinal composition containing compound and application of compounds |
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| CN2009101041900A CN101591374B (en) | 2009-06-26 | 2009-06-26 | Steroid compound, preparation method thereof, medicinal composition containing compound and application of compounds |
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| CN101591374A CN101591374A (en) | 2009-12-02 |
| CN101591374B true CN101591374B (en) | 2011-06-29 |
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| CN2009101041900A Expired - Fee Related CN101591374B (en) | 2009-06-26 | 2009-06-26 | Steroid compound, preparation method thereof, medicinal composition containing compound and application of compounds |
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| CN102504007B (en) * | 2011-12-15 | 2013-09-25 | 成都普思生物科技有限公司 | Method for separation and purification of ruscogenin monomer |
| CN104614482A (en) * | 2014-12-04 | 2015-05-13 | 天津世纪天龙药业有限公司 | Determination method for content of dioscin in Longjiatongluo capsule |
| CN108042554B (en) * | 2017-10-27 | 2019-08-27 | 陈思禹 | Application of the ophiopogonin D on preparation treatment metabolic syndrome drug |
| CN113336822B (en) * | 2021-05-21 | 2022-04-15 | 沈阳药科大学 | Ophiopogon japonicus-steroid saponin compound and preparation method and application thereof |
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