CN103211822A - Use of sterol derivatives in inhibition of lipase - Google Patents
Use of sterol derivatives in inhibition of lipase Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceutical engineering and relates to a use of sterol derivatives in inhibition of lipase. The sterol derivatives are compounds shown in the formula I or their pharmaceutically acceptable salts, wherein in the formula I, R1 represents -OH, =O, H, and C1-C3 alkyl; R2 represents -OH, H, and C1-C3 alkyl; R3 represents -OH, =O, H, and C1-C3 alkyl; R4 represents -OH, H and C1-C3 alkyl; and any two or three or four of R1, R2, R3 and R4 simultaneously represent -OH. The sterol derivatives provided by the invention can effectively inhibit lipase. The inhibition effects of the sterol derivatives are in a concentration-effect relationship. The sterol derivatives can be used as drugs or fat-reducing drugs for preventing and/or treating and/or assistantly treating obesity or obesity-related diseases.
Description
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of purposes of inhibition lipase of sterols derivant.
Background technology
Monas cuspurpureus Went (Monascus-fermented rice) is to be raw material with the rice, a kind of aubergine rice-koji of making through monascus (Monascus) fermentation.Monas cuspurpureus Went claims red bent ancient times, is to be that main bent mother or distillers yeast are inoculated in the rice top fermentation and form with monascus, and its red complexion is red, thus have another name called red song, red rice, red rice, red wine dregs, again because of main product in Fujian etc. ground. dying has another name called good fortune song, good fortune rice etc.
China utilizes the with a long history of Monascus anka Nakazawa et sato, just uses its yeast production from the Han dynasty.Monas cuspurpureus Went is the Chinese medicine that dietetic therapy is simply had both.Early it has been widely used in food color, wine brewing, fermentation, Chinese medicine aspect in ancient times.Principle of Correct Diet has Monas cuspurpureus Went " sweet in the mouth, flat, nontoxic ", " spleen invigorating, QI invigorating, warming middle-JIAO "; Compendium of Material Medica have " sweet, warm, nontoxic ", " control woman's blood pain and puerperal stagnant blood unclean, it is good to beat beverage "; " Amplification on Materia Medica addendum " has records such as " invigorate blood circulation, help digestion, spleen invigorating warming the stomach, control red white dysentery, traumatic injury ".
The seventies in last century, Japan professor Endo has isolated since the biological active substances Mo Nakelin K (monacolin K) from red monascus (Monascus ruber) first, numerous Chinese scholars are constantly found biological active substances in the monascus metabolite, comprise monacolin compounds, monascorubin, antihypertensive compositions GABA and antioxidant content dimerumic acid and nearest more isolating terpenoids or the like.Along with modern biochemistry and pharmacological development, effects such as the blood fat reducing of Monas cuspurpureus Went, blood pressure lowering, blood sugar lowering, obesity, anticancer, control senile dementia and osteoporosis are constantly excavated.Thereby increased new intension for traditional Monas cuspurpureus Went.
XUEZHIKANG JIAONANG is efficient, the safe homemade modern fat Chinese medicine of transferring that the mould fermentation of purpose-made monascus of the autonomous research in Beijing WBL Peking University Biotech Co., Ltd is made.
Obesity worldwide becomes popular tendency as a kind of general incretion metabolism disease.It not only influences figure and activity, and closely related with diseases such as hyperlipemia, atherosclerosis, coronary heart disease, diabetes.The fat reason that takes place is many-sided, and as inherited genetic factors, environmental factors, dietary habit etc., wherein high fat diet is the major reason that causes fat.In recent years, Drug therapy is one of effective means of treatment of obesity, reaches therapeutic purposes by reducing fat absorption.Pancreas and gastric lipase are that fat digestion absorbs necessary in the intestinal.Fat in the food is absorbed at intestinal after being hydrolyzed to monoacylglycerol and free fatty, and synthctic fat again in vivo causes athero then, finally can cause fat.Use lipase inhibitor and can effectively suppress in the intestinal lipase the decomposition catalytic action of fat, reach the purpose that reduces fat absorption, control and treatment obesity (Chen Jin etc. fat study medication progress. Chinese Chinese medicine academic periodical, 2007,25 (5): 947-948; Wu waits quietly. fat Progress in Medication. and medical science summary, 2006,12 (11): 693-693.)
At present, U.S. FDA has only been ratified 2 kinds of medicines and can be used for bariatrician: sibutramin (sibutramine, nervus centralis effect appetrol) and orlistat (orlistat, gastrointestinal tract lipase inhibitor) for a long time.But these two kinds of medicines all have the side effect of tangible untoward reaction: sibutramin to mainly contain thirsty, constipation, dizziness and insomnia, the untoward reaction of orlistat mainly is a gastrointestinal symptom, common have diarrhoea stomachache, oiliness speckle, a flatulence etc., and its long-term effect also awaits further evaluation.
Therefore, still need at present and will find the new medicine that suppresses the lipase effect that has.
Summary of the invention
The inventor is through deep research and performing creative labour, obtained a kind of sterols derivant, and the inventor is surprised to find, chemical compound of the present invention can suppress the activity of lipase effectively, and conduct prevents and/or treats and/or the potentiality of the medicine of auxiliary treatment obesity or obesity relevant disease thereby have.Following invention is provided thus:
One aspect of the present invention relates to the chemical compound shown in the formula I, or its pharmaceutically acceptable salt,
Wherein,
R
1Be selected from-OH ,=O (carbonyl), H and C
1-C
3Alkyl;
R
2Be selected from-OH, H and C
1-C
3Alkyl;
R
3Be selected from-OH ,=O, H and C
1-C
3Alkyl;
R
4Be selected from-OH, H and C
1-C
3Alkyl;
And R
1, R
2, R
3, and R
4In any 2,3 or 4 be-OH simultaneously.
In one embodiment of the invention, R
1For-OH or=O (carbonyl), R
2, R
3And R
4Be H.
According to each described chemical compound of the present invention or its pharmaceutically acceptable salt, it is the chemical compound shown in the following formula II, or its pharmaceutically acceptable salt,
The chemistry of formula II chemical compound is by name: 16, and 22-epoxy Ergota steroid-5,7-diene-3,20,23,25-tetrol
(16，22-epoxy-ergosta-5，7-dien-3，20，23，25-tetraol)。
The invention still further relates to the hydrate or the solvate of above-mentioned formula I or formula II chemical compound.
Another aspect of the present invention relates to the preparation method of formula I or formula II chemical compound, comprises the steps:
1) gets ethanol extract (the XUEZHIKANG JIAONANG content for example of Monas cuspurpureus Went and/or Monas cuspurpureus Went, it is a dry powder), one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, the ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, remove and desolvate, obtain extract;
Alternatively, described ethanol extract can following method make: 50%-100% ethanol or 50%-100% methanol with 2-6 times of volume extract one or many as solvent supersonic, and each 20-40 minute, merge extractive liquid, removed and desolvates, and obtains ethanol extract.
Being not limited to theoretical restriction, because Xuezhikang itself is the ethanol extract of Monas cuspurpureus Went, can be raw material with Monas cuspurpureus Went directly therefore, and extraction step and XUEZHIKANG JIAONANG content dry powder are basic identical, but the content of this chemical compound in the Monas cuspurpureus Went is low relatively.The concrete bacterial strain of described Monas cuspurpureus Went is not particularly limited, and comprises arbitrary strain or bacterial strain that belongs to Monas cuspurpureus Went.XUEZHIKANG JIAONANG (for example Beijing University's dimension letter is produced) can be bought by hospital or pharmacy and obtain.
2) extract that step 1) is obtained carries out the silica gel column chromatography separation, carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water was followed successively by 10: 90,50: 50-75: 25,100: 0;
4) methanol-water of getting in the step 3) is 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, is mobile phase with acetonitrile-0.2% acetic acid aqueous solution (45: 55), and the C18 semi-preparative column is an immobile phase, collects the chromatographic peak part of 9.2min; With
5) product with step 4) carries out lyophilization, obtains formula I or formula II chemical compound.
According to each described preparation method of the present invention, its satisfy in following (1)-(9) each or multinomial:
(1) in the step 1), described organic solvent is preferably dichloromethane;
(2) in the step 1), described supersound extraction is carried out 3 times;
(3) in the step 1), remove by concentrating under reduced pressure and to desolvate;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) in the step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
The inventor finds that by test petroleum ether-ethyl acetate is 50: 50-25: 75 eluting part all contains chemical compound of the present invention.
(6) in the step 3), the volume ratio of methanol-water was followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) in the step 4), get methanol-water in the step 3) and be the eluting part of 50: 50 or 75: 25;
The inventor finds that by test methanol-water is 50: 50-75: 25 eluting part all contains chemical compound of the present invention.
(8) in the step 4), the chromatographic peak of the 9.2min that collects is partly merged; With
(9) in the step 5), cryodesiccated condition is: condenser temperature-40 is to-85 ℃, vacuum 0-100Pa; Be preferably condenser temperature-50 to-82.7 ℃, vacuum 2-13Pa; Condenser temperature-82.7 ℃ more preferably, vacuum 2Pa, or condenser temperature-50 ℃, vacuum 8.5Pa.
Of the present inventionly relate in one aspect to a kind of extract again, it contains formula II chemical compound of the present invention.
Each described extract according to the present invention, it is the extract of XUEZHIKANG JIAONANG content dry powder or the extract of Monas cuspurpureus Went.
Each described extract according to the present invention, it is in following (1) to (3) each:
(1) petroleum ether-ethyl acetate that makes above-mentioned step 1) to 2) is 50: 50-25: 75 eluting part; Preferred petroleum ether-ethyl acetate is the eluting part of 50: 50 or 25: 75; Further preferred petroleum ether-ethyl acetate is 25: 75 an eluting part.
(2) methanol-water that makes above-mentioned step 1) to 3) is 50: 50-75: 25 eluting part; Particular methanol-water is the eluting part of 50: 50 or 75: 25; Further particular methanol-water is 75: 25 eluting part; With
(3) the chromatographic peak part of the 9.2min that makes above-mentioned step 1) to 4).
Of the present inventionly relate in one aspect to a kind of compositions again, it comprises each described extract among the chemical compound of formula I or formula II or the present invention; Alternatively, also comprise pharmaceutically acceptable carrier or adjuvant.Particularly, described compositions is a pharmaceutical composition.
The chemical compound of the present invention or each described extract of the present invention or compositions of the present invention of relating in one aspect to again of the present invention prevents and/or treats and/or the medicine of auxiliary treatment obesity or obesity relevant disease or the purposes in the slimming medicine in preparation; Particularly, described obesity relevant disease is hyperlipemia, atherosclerosis, coronary heart disease or diabetes.
Usually pharmaceutical composition of the present invention contains formula I or formula II chemical compound and/or its physiologically acceptable salt of 0.1-90 weight %.Pharmaceutical composition can prepare according to methods known in the art.When being used for this purpose, if desired, formula I or formula II chemical compound and/or stereoisomer and one or more solids or liquid medicine excipient and/or adjuvant can be combined, make the suitable administration form or the dosage form that can be used as human.
Formula I of the present invention or formula II chemical compound or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be intestinal or non-intestinal, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc.Form of administration is tablet, capsule, drop pill, aerosol, pill, powder, solution, suspensoid, Emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc. for example.Can be ordinary preparation, slow releasing preparation, controlled release preparation and various particulate delivery system.For the unit form of administration is made tablet, can be extensive use of various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate etc.; Wetting agent and binding agent are as water, glycerol, Polyethylene Glycol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.; Disintegrating agent, for example dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, Sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.; Disintegrate inhibitor, for example sucrose, glyceryl tristearate, cocoa butter, hydrogenation wet goods; Absorption enhancer, for example quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, for example Pulvis Talci, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, Polyethylene Glycol etc.Tablet further can also be made coated tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.For pill is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, Kaolin, Pulvis Talci etc.; Binding agent such as arabic gum, Tragacanth, gelatin, ethanol, Mel, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.For suppository is made in the administration unit, can be extensive use of various carrier well known in the art.Example about carrier is, for example the ester of Polyethylene Glycol, lecithin, cocoa butter, higher alcohol, higher alcohol, gelatin, semi-synthetic glyceride etc.For capsule is made in the administration unit, effective ingredient formula I chemical compound or its stereoisomer are mixed with above-mentioned various carriers, and the mixture that will obtain thus places hard obviously capsule or soft capsule.Also effective ingredient formula I or formula II chemical compound or its stereoisomer can be made microcapsule, be suspended in and form suspensoid in the aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, Emulsion, lyophilized injectable powder and suspensoid, can use this area all diluent commonly used, for example, water, ethanol, Polyethylene Glycol, 1, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, ooze injection, can in injection preparation, add proper amount of sodium chloride, glucose or glycerol, in addition, can also add conventional cosolvent, buffer agent, pH regulator agent etc. in order to prepare etc.
In addition, as needs, also can in pharmaceutical preparation, add coloring agent, antiseptic, spice, correctives, sweeting agent or other material.
Formula I of the present invention or formula II chemical compound, or the dosage of its officinal salt depends on many factors, for example will prevent or treat the character and the order of severity of disease, the sex of patient or animal, age, body weight and individual reaction, used particular compound, route of administration and administration number of times etc.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations.
Term used herein " compositions " means and comprises the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount.
The reactive compound amount of gained can change the actual dose level of each active component in the pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response at concrete patient, compositions and administering mode.The dosage level fibrous root is selected according to activity, route of administration, the order of severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and the medical history of particular compound.But the way of this area is that the dosage of chemical compound increases dosage gradually from being lower than for obtaining the level that required therapeutic effect requires, up to obtaining required effect.
The chemical compound of the present invention or each described extract of the present invention or compositions of the present invention of relating in one aspect to again of the present invention suppresses the medicine of lipase or the purposes in the reagent in preparation.
Of the present inventionly relate in one aspect to a kind of method that suppresses lipase again, comprise the chemical compound of the present invention that uses effective dose or the step of its pharmaceutically acceptable salt or each described extract of the present invention or compositions of the present invention.
The evidence of embodiment 4, chemical compound of the present invention can suppress lipase effectively.
Of the present inventionly relate in one aspect to a kind of preventing and/or treating and/or method or a kind of ways of preventing obesity of auxiliary treatment obesity or obesity relevant disease again, comprise to the chemical compound of the present invention of effective dose or the step of each described extract of the present invention or compositions of the present invention; Particularly, described obesity relevant disease is hyperlipemia, atherosclerosis, coronary heart disease or diabetes.
When being used for above-mentioned treat and/or prevent or during auxiliary treatment, a kind of The compounds of this invention that treats and/or prevents effective dose can be used with pure form, perhaps use with acceptable ester of pharmacy or prodrug forms (under the situation that has these forms).Perhaps, described chemical compound can be accepted the pharmaceutical composition administration of excipient to contain this purpose chemical compound and one or more medicines.Term " effective dose " is meant the dosage that can realize treating, prevent, alleviate and/or alleviating disease of the present invention or disease in the experimenter.But the total consumption per day that it should be understood that The compounds of this invention and compositions 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 order of severity of the obstacle of being treated and this obstacle; The activity of the particular compound that is adopted; The concrete compositions 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 persistent period; 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.For example, the way of this area is that the dosage of chemical compound increases dosage gradually from being lower than for obtaining the level that required therapeutic effect requires, up to obtaining required effect.In general, formula I chemical compound of the present invention is used for mammal particularly people's dosage can be between the 0.001-1000mg/kg body weight/day, for example between the 0.01-100mg/kg body weight/day, for example between the 0.01-10mg/kg body weight/day.
Can effectively prevent and/or treat various diseases of the present invention or disease according to chemical compound of the present invention.
The invention still further relates to following aspect 1-11:
1. each in following (1)-(4) prevents and/or treats and/or the medicine of auxiliary treatment obesity or obesity relevant disease or the purposes in the slimming medicine in preparation; Particularly, described obesity relevant disease is hyperlipemia, atherosclerosis, coronary heart disease or diabetes,
(1) chemical compound shown in the formula I or its pharmaceutically acceptable salt,
Wherein,
R
1Be selected from-OH ,=O, H and C
1-C
3Alkyl;
R
2Be selected from-OH, H and C
1-C
3Alkyl;
R
3Be selected from-OH ,=O, H and C
1-C
3Alkyl;
R
4Be selected from-OH, H and C
1-C
3Alkyl;
And R
1, R
2, R
3, and R
4In any 2,3 or 4 be-OH simultaneously;
(2) chemical compound shown in the formula II or its pharmaceutically acceptable salt,
(3) extract, it contains formula II chemical compound; With
(4) compositions, it contains in above-mentioned (1)-(3) each.
2. each in (1) described in the 1st aspect-(4) preparing in vivo or the medicine of vitro inhibition lipase or the purposes in the reagent.
3. according to the described purposes in the 1st or 2 aspects, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
4. according to the described purposes in the 3rd aspect, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) methanol-water that makes in is 50: 50-75: 25 eluting part; Or following step 1) to 4) the chromatographic peak part of the 9.2min that makes in:
1) gets the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, the ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, remove and desolvate, obtain extract;
2) extract that step 1) is obtained carries out the silica gel column chromatography separation, carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water was followed successively by 10: 90,50: 50-75: 25,100: 0; With
4) methanol-water of getting in the step 3) is 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, is mobile phase with acetonitrile-0.2% acetic acid aqueous solution (45: 55), and the C18 semi-preparative column is an immobile phase, collects the chromatographic peak part of 9.2min.
5. according to the described purposes in the 4th aspect, it is characterized in that (1)-in (8) each or multinomial:
(1) in the step 1), described organic solvent is a dichloromethane;
(2) in the step 1), described supersound extraction is carried out 3 times;
(3) in the step 1), remove by concentrating under reduced pressure and to desolvate;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) in the step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
(6) in the step 3), the volume ratio of methanol-water was followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) in the step 4), get methanol-water in the step 3) and be the eluting part of 50: 50 or 75: 25; With
(8) in the step 4), the chromatographic peak of the 9.2min that collects is partly merged.
6. according to the described purposes in the 1st or 2 aspects, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
One kind in vivo or the method for vitro inhibition lipase, comprise each the step in (1) described in the 1st aspect of using effective dose-(4).
8. according to the described method in the 7th aspect, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
9. according to the described method in the 8th aspect, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) methanol-water that makes in is 50: 50-75: 25 eluting part; Or following step 1) to 4) the chromatographic peak part of the 9.2min that makes in:
1) gets the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, the ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, remove and desolvate, obtain extract;
2) extract that step 1) is obtained carries out the silica gel column chromatography separation, carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water was followed successively by 10: 90,50: 50-75: 25,100: 0; With
4) methanol-water of getting in the step 3) is 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, is mobile phase with acetonitrile-0.2% acetic acid aqueous solution (45: 55), and the C18 semi-preparative column is an immobile phase, collects the chromatographic peak part of 9.2min.
10. according to the described method in the 9th aspect, it is characterized in that (1)-in (8) each or multinomial:
(1) in the step 1), described organic solvent is a dichloromethane;
(2) in the step 1), described supersound extraction is carried out 3 times;
(3) in the step 1), remove by concentrating under reduced pressure and to desolvate;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) in the step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
(6) in the step 3), the volume ratio of methanol-water was followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) in the step 4), get methanol-water in the step 3) and be the eluting part of 50: 50 or 75: 25; With
(8) in the step 4), the chromatographic peak of the 9.2min that collects is partly merged.
11. according to the described method in the 7th aspect, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
Among the present invention,
Term " C
1-C
3Alkyl " comprise methyl, ethyl, propyl group or isopropyl.
The term obesity include but not limited to Simple Obesity (do not have obvious endocrine, the metabolic cause of disease can be sought, relevant with heredity, dietary habit etc.), Secondary Obesity (often be some disease such as hyperinterrenal a kind of, can eliminate) because of the healing of disease.Described obesity can be mammiferous obesity, and described mammal comprises people or pig.
Term " obesity relevant disease " includes but not limited to hyperlipemia, atherosclerosis, coronary heart disease or diabetes or the like.
Term " lipase " (lipase, enzyme classification EC3.1.1.3) includes but not limited to mammiferous lipase, the lipase of people's lipase or pig for example, described people's lipase can be people's pancreatic lipase, and the lipase of described pig can be porcine pancreatic lipase (porcine pancreatic lipase).
The beneficial effect of the invention
Chemical compound of the present invention can suppress the activity of lipase effectively, and inhibitory action and be concentration-effect relation; Thereby have as preventing and/or treating and/or the medicine of auxiliary treatment obesity or obesity relevant disease or the potentiality of slimming medicine.
Description of drawings
Fig. 1: oleic acid absorbance working curve.
The specific embodiment
Below in conjunction with embodiment embodiment of the present invention are described in detail.It will be understood to those of skill in the art that the following examples only are used to illustrate the present invention, and should not be considered as limiting scope of the present invention.Unreceipted concrete technology or condition person among the embodiment, according to the described technology of the document in this area or condition (for example with reference to works such as J. Sa nurse Brookers, " the molecular cloning experiment guide " that Huang Peitang etc. translate, the third edition, Science Press) or carry out according to product description.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment 1: the preparation of formula II chemical compound (1)
Operating procedure:
1) getting XUEZHIKANG JIAONANG (Beijing University dimension letter produce) the about 1kg of content dry powder, is that solvent supersonic extracts 3 times with the dichloromethane of 2-6 times of volume, 20-40 minute at every turn, and merge extractive liquid,, concentrating under reduced pressure also reclaims solvent, obtains dichloromethane extract 91g.
2) get dichloromethane extract 50g, last silica gel column chromatography separates, and carries out gradient elution with petroleum ether and ethyl acetate.The volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25, and 50: 50,25: 75,0: 100.
3) getting petroleum ether-ethyl acetate is 25: 75 part 5.0g, separate through the C18 reversed-phase column chromatography, (10: 90-100: 0) gradient elution obtains 4 part (methanol-waters 10: 90 to methanol-water, 50: 50,75: 25,100: 0), wherein methanol-water (75: 25) eluting part 1.3g is with half preparative high-performance liquid chromatographic purification, with acetonitrile-0.2% acetic acid aqueous solution (45: 55) is mobile phase, flow velocity is 4mL/min, C18 half preparative hplc post (10 * 250mm, 5 μ m) be immobile phase, it is 270nm that the DAD detector detects wavelength, collect the chromatographic peak of 9.2min, the back of repeatedly adding up concentrates, and lyophilization must the about 40mg of this chemical compound.
Embodiment 2: the preparation of formula II chemical compound (2)
Operating procedure:
1) getting Monas cuspurpureus Went 5kg, is that solvent supersonic extracts 3 times with the dichloromethane of 2-6 times of volume, each 20-40 minute, and merge extractive liquid,, concentrating under reduced pressure also reclaims solvent, obtains dichloromethane extract 78g.
2) get dichloromethane extract 30g, last silica gel column chromatography separates, and carries out gradient elution with petroleum ether and ethyl acetate.The volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25, and 50: 50,25: 75,0: 100.
3) getting petroleum ether-ethyl acetate is 25: 75 part 3.0g, separate through the C18 reversed-phase column chromatography, (10: 90-100: 0) gradient elution obtains 4 part (methanol-waters 10: 90 to methanol-water, 50: 50,75: 25,100: 0), wherein methanol-water (75: 25) eluting part 0.8g is with half preparative high-performance liquid chromatographic purification, with acetonitrile-0.2% acetic acid aqueous solution (45: 55) is mobile phase, flow velocity is 4mL/min, C18 half preparative hplc post (10 * 250mm, 5 μ m) be immobile phase, it is 270nm that the DAD detector detects wavelength, collect the chromatographic peak of 9.2min, the back of repeatedly adding up concentrates, and lyophilization must the about 25mg of this chemical compound.
Embodiment 3: the structure of chemical compound is identified
Specimen in use is the chemical compound of embodiment 1 and 2 preparations.
1. the physicochemical data of chemical compound
White powder, optical rotation: [α]
25 D-50.00 (c0.118, CH
2Cl
2: MeOH=1: 1);
Three maximum absorption bands are arranged in the UV spectrum, be respectively λ
Max(CH
2Cl
2: MeOH)=and 271.6nm, 282.2nm, 293.8nm.
FT-IR (KBr, cm
-1) spectrum: 3392 (OH), 2969,2933 (saturated hydrocarbon), 1652,1647 (C=C), 1456,1378 (gem-dimethyls).
2. molecular formula determines
The m/z 483.3104[M+Na that HR-ESI-MS provides]
+(calcd.483.3081, err2.3), the molecular weight that is inferred as this chemical compound is 460.32.
1H-NMR and
13C-NMR shows, has 40 hydrogen signals and 28 carbon signals.Show 6 quaternary carbons are arranged, 10 CH, 6 CH from DEPT
2And 6 CH
3 13Among the C-NMR, 117.2ppm, 119.6ppm, there are 4 olefinic carbon signals at 139.1ppm and 140.6ppm place.With HSQC figure with
13C-NMR figure binding analysis, 70.5ppm, 72.4ppm, 74.5ppm, 80.4ppm, there are 6 carbon that link to each other with oxygen atom in 83.8ppm and 84.4ppm place.The binding molecule amount and
1H,
13C-NMR and DEPT signal graph surpass 460.32 if this chemical compound has 6 oxygen atom molecular weight, infer that thus this chemical compound has 5 oxygen atoms and do not embody 4 hydrogen atoms of hydrogen spectrum signal.Thereby can judge in above-mentioned 5 oxygen atoms that 4 oxygen atom ownership are 4 hydroxyls, other the 5th oxygen atom exists with the form of ether.According to above-mentioned analysis, can determine has 28 carbon atoms in this molecule, 44 hydrogen atoms and 5 oxygen atoms, and molecular formula is C
28H
44O
5
3. structural formula determines
Analyze this chemical compound carbon spectrum (
13C-NMR and DEPT), 28 carbon atoms are arranged, wherein 6 carbon are methyl.Based on 271.6nm in the ultra-violet absorption spectrum, 3 absorption maximum and the ergosterol class at 282.2nm and 293.8nm place are identical substantially, infer that tentatively this chemical compound has the skeleton of ergosterol.Can calculate its degree of unsaturation from molecular formula is 7.Thereby can infer: this chemical compound also has a unsaturated place and can only be a ring herein except 6 unsaturated places of 2 two keys and 4 rings of sterol skeleton, can judge that thus this ring is the epoxide ring that is formed centrally in being by the 5th oxygen atom.HSQC figure analysiss that combine with HMBC coherent signal figure, 6 carbon that link to each other with oxygen atom, respectively ownership be 4 continuous carbon of 4 hydroxyls (70.5,72.4,74.5,80.4ppm) reach with remain 2 carbon that next oxygen atom links to each other (83.8,84.4ppm).Deep HMBC map analysis can infer that the 5th member ring systems is by C-16 (83.8ppm), C-17 (66.9ppm), C-20 (80.4ppm), 5 yuan of rings that C-22 (84.4ppm) and oxygen atom are formed.This not only satisfies degree of unsaturation, but also satisfies the carbon number that links to each other with oxygen atom.Further analyze molecular weight and the molecular formula that mass spectrometry system provides, confirmed above-mentioned analysis.The above analysis can infer that this noval chemical compound is: 16, and 22-epoxy Ergota steroid-5,7-diene-3,20,23,25-tetrol
Promptly (16,22-epoxy-ergosta-5,7-dien-3,20,23,25-tetraol).Structural formula is shown in the following formula II.
4. the NMR data of formula II chemical compound
Shown in following table 1.
Table 1: NMR data (600MHz, the CDCl of formula II chemical compound
3, J in Hz)
Annotate: there is not coherent signal in "-" expression.
Embodiment 4: the lipase inhibiting activity experiment
1 experiment material
1.1 medicine
Formula II chemical compound.
Orlistat (orlistat)---available from the big pharmacy of Golden Elephant.
1.2 enzyme
Porcine pancreatic lipase---available from Sigma company.
1.3 reagent
Oleic acid---available from Sigma company.
Toluene, olive oil, pyridine, Schweinfurt green, NaH
2PO
4, K
2HPO
4Be homemade analytical pure.
2 experimental techniques
Shown in following step, also can be with reference to Jiang Huifang, Wang Yaqin, Liu Chunguo. three kinds of lipase activity assay methods relatively reach improvement. chemistry and biological engineering .2007,24 (8): 72-75; And Zhu Xiaoqing, Lv Jingci, Huo Shixin etc. lotus leaf alkaloid is to the inhibitory action of lipase. Shanghai University's journal (natural science edition), 2007,13 (1): 85-87.
2.1 the drafting of fatty acid absorbance working curve: the oleic acid-toluene solution (0-3.5mmol/L for preparing a series of variable concentrations, be respectively 0,0.225,0.45,0.675,0.9,1.125,1.35,1.8,2.25,2.7 and 3.5mmol/L), get 4mL respectively in conical flask, add the 1mL developer, magnetic agitation 3min, oleic acid molecular and copper ion generate green complex, get upper organic phase at 714nm place mensuration absorbance after centrifugal.
2.2 enzymatic solution is a 0.5mg/mL pancreatic lipase solution; Buffer is 0.07MNaH
2PO
4-K
2HPO
4Phosphate buffered solution (pH 7.0); Developer is 5% Schweinfurt green solution, regulates pH 6.1 with pyridine.
2.3 the mensuration of lipase activity:
Get 3mL 0.07M phosphate buffer and 1mL olive oil, put into 37 ℃ of preheating 5min of constant temperature water bath magnetic stirring apparatus, add 1.3mL enzyme liquid and (do not add the negative contrast of enzyme inhibitor; Add the positive contrast of 0.1mg/mL orlistat solution 100 μ L; 0.6,0.9,1.1,1.3, the 1.8mg/mL compound solution respectively adds 100 μ L), magnetic agitation 10min adds 8mL toluene immediately, continues to stir 2min, cessation reaction, the oleic acid that extraction simultaneously generates.Solution is transferred in the centrifuge tube centrifugal 10min under 4000rpm, organic facies and water layering clarification.Get upper organic phase 4mL in the fine taper bottle, add the 1mL developer, stir 3min on magnetic stirring apparatus, the oleic acid of generation and copper ion generate green complex.The centrifugal 10min of 4000rpm gets the toluene solution that copper oleate is contained on the upper strata, surveys its absorbance with spectrophotometer at 714nm wavelength place.In the same way preparation not the blank solution of fatty enzyme be reference, contrast oleic acid absorbance working curve can be tried to achieve the concentration of fatty acid.
3 enzymes are lived and are defined and computing formula
The lipase enzyme activity unit is defined as: under certain condition, the enzyme amount that per minute discharges 1 μ mol fatty acid is defined as 1 lipase activity unit of force (U).
Being calculated as follows enzyme lives: X=(cV)/(tV ')
In the formula: X is a lipase activity, U/mL; C is a fatty acid concentration, μ mol/mL; V is the volume of adipic acid solution, mL; V ' is the consumption of enzyme liquid, mL; T is action time, min.
Suppression ratio=[(lipase activity-inhibition back lipase activity)/lipase activity] * 100%
4 experimental results
4.1 oleic acid absorbance working curve
As shown in Figure 1.
4.2 inhibitor activity testing result
Wherein enzyme work calculates according to the computing formula in top 3, wherein:
V＝8mL；V’＝1.3mL；t＝10min。
Experimental result shows that chemical compound of the present invention has good inhibitory effect to the activity of lipase, its IC
50Value is about 220 μ g/mL, and inhibitory action is concentration-effect relation.As seen, chemical compound of the present invention has and prevents and/or treats and/or the potentiality of the medicine of auxiliary treatment obesity or obesity relevant disease.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (11)
1. each in following (1)-(4) prevents and/or treats and/or the medicine of auxiliary treatment obesity or obesity relevant disease or the purposes in the slimming medicine in preparation; Particularly, described obesity relevant disease is hyperlipemia, atherosclerosis, coronary heart disease or diabetes,
(1) chemical compound shown in the formula I or its pharmaceutically acceptable salt,
Wherein,
R
1Be selected from-OH ,=O, H and C
1-C
3Alkyl;
R
2Be selected from-OH, H and C
1-C
3Alkyl;
R
3Be selected from-OH ,=O, H and C
1-C
3Alkyl;
R
4Be selected from-OH, H and C
1-C
3Alkyl;
And R
1, R
2, R
3, and R
4In any 2,3 or 4 be-OH simultaneously;
(2) chemical compound shown in the formula II or its pharmaceutically acceptable salt,
(3) extract, it contains formula II chemical compound; With
(4) compositions, it contains in above-mentioned (1)-(3) each.
2. each in (1) described in the claim 1-(4) preparing in vivo or the medicine of vitro inhibition lipase or the purposes in the reagent.
3. purposes according to claim 1 and 2, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
4. purposes according to claim 3, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) methanol-water that makes in is 50: 50-75: 25 eluting part; Or following step 1) to 4) the chromatographic peak part of the 9.2min that makes in:
1) gets the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, the ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, remove and desolvate, obtain extract;
2) extract that step 1) is obtained carries out the silica gel column chromatography separation, carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water was followed successively by 10: 90,50: 50-75: 25,100: 0; With
4) methanol-water of getting in the step 3) is 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, is mobile phase with acetonitrile-0.2% acetic acid aqueous solution (45: 55), and the C18 semi-preparative column is an immobile phase, collects the chromatographic peak part of 9.2min.
5. purposes according to claim 4, it is characterized in that (1)-in (8) each or multinomial:
(1) in the step 1), described organic solvent is a dichloromethane;
(2) in the step 1), described supersound extraction is carried out 3 times;
(3) in the step 1), remove by concentrating under reduced pressure and to desolvate;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) in the step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
(6) in the step 3), the volume ratio of methanol-water was followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) in the step 4), get methanol-water in the step 3) and be the eluting part of 50: 50 or 75: 25; With
(8) in the step 4), the chromatographic peak of the 9.2min that collects is partly merged.
6. purposes according to claim 1 and 2, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
One kind in vivo or the method for vitro inhibition lipase, comprise each the step in (1) described in the claim 1 of using effective dose-(4).
8. method according to claim 7, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
9. method according to claim 8, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) methanol-water that makes in is 50: 50-75: 25 eluting part; Or following step 1) to 4) the chromatographic peak part of the 9.2min that makes in:
1) gets the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, the ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, remove and desolvate, obtain extract;
2) extract that step 1) is obtained carries out the silica gel column chromatography separation, carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water was followed successively by 10: 90,50: 50-75: 25,100: 0; With
4) methanol-water of getting in the step 3) is 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, is mobile phase with acetonitrile-0.2% acetic acid aqueous solution (45: 55), and the C18 semi-preparative column is an immobile phase, collects the chromatographic peak part of 9.2min.
10. method according to claim 9, it is characterized in that (1)-in (8) each or multinomial:
(1) in the step 1), described organic solvent is a dichloromethane;
(2) in the step 1), described supersound extraction is carried out 3 times;
(3) in the step 1), remove by concentrating under reduced pressure and to desolvate;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate was followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) in the step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
(6) in the step 3), the volume ratio of methanol-water was followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) in the step 4), get methanol-water in the step 3) and be the eluting part of 50: 50 or 75: 25; With
(8) in the step 4), the chromatographic peak of the 9.2min that collects is partly merged.
11. method according to claim 7, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
Priority Applications (15)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210015475.9A CN103211822B (en) | 2012-01-18 | 2012-01-18 | A kind of purposes of the suppression lipase of sterol derivative |
| EP12862540.7A EP2799444B1 (en) | 2011-12-26 | 2012-12-25 | Sterols derivative, and preparation method and purpose thereof |
| TW101149915A TWI518094B (en) | 2011-12-26 | 2012-12-25 | One kind of derivatives of sterols, their preparation and use |
| SG11201403618PA SG11201403618PA (en) | 2011-12-26 | 2012-12-25 | A sterol derivative and preparation method and uses thereof |
| CN201280062316.2A CN104024270B (en) | 2011-12-26 | 2012-12-25 | A kind of sterol derivative, Preparation Method And The Use |
| ES12862540.7T ES2666459T3 (en) | 2011-12-26 | 2012-12-25 | Sterol derivative, preparation procedure and purpose thereof |
| MYPI2014001905A MY172011A (en) | 2011-12-26 | 2012-12-25 | Sterols derivative, and preparation method and purpose thereof |
| PCT/CN2012/087360 WO2013097681A1 (en) | 2011-12-26 | 2012-12-25 | Sterols derivative, and preparation method and purpose thereof |
| US14/368,494 US10889612B2 (en) | 2011-12-26 | 2012-12-25 | Sterol derivatives and preparation method and uses thereof |
| HK14112046.3A HK1198539A1 (en) | 2011-12-26 | 2014-11-28 | Sterols derivative, and preparation method and purpose thereof |
| US17/071,958 US20210024570A1 (en) | 2011-12-26 | 2020-10-15 | Sterol derivatives and preparation method and uses thereof |
| US17/071,963 US11634454B2 (en) | 2011-12-26 | 2020-10-15 | Sterol derivatives and preparation method and uses thereof |
| US17/818,302 US11845774B2 (en) | 2011-12-26 | 2022-08-08 | Sterol derivatives and preparation method and uses thereof |
| US17/818,667 US11845775B2 (en) | 2011-12-26 | 2022-08-09 | Sterol derivatives and preparation method and uses thereof |
| US17/820,553 US20220402967A1 (en) | 2011-12-26 | 2022-08-17 | Sterol derivatives and preparation method and uses thereof |
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|---|---|---|---|---|
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101469014A (en) * | 2007-12-27 | 2009-07-01 | 北京北大维信生物科技有限公司 | Novel compound and separation method thereof |
| CN103172693A (en) * | 2011-12-26 | 2013-06-26 | 北京北大维信生物科技有限公司 | Sterol derivative, and preparation method and application thereof |
-
2012
- 2012-01-18 CN CN201210015475.9A patent/CN103211822B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101469014A (en) * | 2007-12-27 | 2009-07-01 | 北京北大维信生物科技有限公司 | Novel compound and separation method thereof |
| CN103172693A (en) * | 2011-12-26 | 2013-06-26 | 北京北大维信生物科技有限公司 | Sterol derivative, and preparation method and application thereof |
Non-Patent Citations (4)
| Title |
|---|
| 李银花等: "血脂康对冠心病合并高脂血症患者疗效的Meta分析", 《中国循证心血管医学杂志》 * |
| 王飞: "血脂康对糖尿病合并高脂血症的疗效及体重指数的影响", 《江苏医药》 * |
| 石湘芸 等: "血脂康对高脂血症的疗效及体重指数的影响", 《首都医药》 * |
| 谢瑞雄等: "血脂康治疗糖尿病并高脂血症60例疗效观察", 《中国热带医学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104024270A (en) * | 2011-12-26 | 2014-09-03 | 北京北大维信生物科技有限公司 | Sterols Derivative, And Preparation Method And Purpose Thereof |
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