CN103211822B - A kind of purposes of the suppression lipase of sterol derivative - Google Patents
A kind of purposes of the suppression lipase of sterol derivative Download PDFInfo
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- CN103211822B CN103211822B CN201210015475.9A CN201210015475A CN103211822B CN 103211822 B CN103211822 B CN 103211822B CN 201210015475 A CN201210015475 A CN 201210015475A CN 103211822 B CN103211822 B CN 103211822B
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- KJPYXKLGHVIRLM-UHFFFAOYSA-N CC(C(C1OC(CC(C2(C)C3)C4=CC=C(CC(CC5)O)C5(C)C4C3=C)C2C1(C)O)O)C(C)(C)O Chemical compound CC(C(C1OC(CC(C2(C)C3)C4=CC=C(CC(CC5)O)C5(C)C4C3=C)C2C1(C)O)O)C(C)(C)O KJPYXKLGHVIRLM-UHFFFAOYSA-N 0.000 description 1
- SYXGKOVNSVLCIP-UHFFFAOYSA-N CC(C(C1OC(CC2C3=CC=C(CC(CC4)O)C4(C)C3CCC22C)C2C1(C)O)O)C(C)(C)O Chemical compound CC(C(C1OC(CC2C3=CC=C(CC(CC4)O)C4(C)C3CCC22C)C2C1(C)O)O)C(C)(C)O SYXGKOVNSVLCIP-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to field of medicine and chemical technology, it is related to a kind of purposes of the suppression lipase of sterol derivative.Wherein, the sterol derivative is the compound shown in Formulas I, or its pharmaceutically acceptable salt, wherein, R1Selected from OH ,=O, H and C1‑C3Alkyl；R2Selected from OH, H and C1‑C3Alkyl；R3Selected from OH ,=O, H and C1‑C3Alkyl；R4Selected from OH, H and C1‑C3Alkyl；And R1、R2、R3And R4In any 2,3 or 4 simultaneously for OH.The compound of the present invention can effectively suppress lipase, and inhibitory action and in concentration effect relation；So as to the potentiality as prevention and/or the medicine or slimming medicine for the treatment of and/or auxiliary treatment obesity or obesity-related disorder.
Description
Technical field
The invention belongs to field of medicine and chemical technology, it is related to a kind of purposes of the suppression lipase of sterol derivative.
Background technology
Red yeast rice (Monascus-fermented rice) is, using rice as raw material, to ferment and make through monascus (Monascus)
Into a kind of aubergine rice it is bent.Red yeast rice ancient times claim red song, are that the song based on monascus is female or distiller's yeast is inoculated in rice top fermentation
Form, its color is crimson, therefore also known as red song, red rice, red rice, red wine dregs, and because main product is in the ground such as Fujian thus also known as good fortune is bent, good fortune rice
Deng.
China is with a long history using Monascus, and just its koji-making is used from Han dynasty.Red yeast rice is the tradition of dietotherapy simply
Chinese medicine.In terms of early it has been widely used in food color, wine brewing, fermentation, traditional Chinese medicine in ancient times.《Yin Shan Zhengyao, Principles of Correct Diet》There is red yeast rice
" sweet, flat, nontoxic ", " invigorating the spleen, QI invigorating, middle benefit gas "；《Compendium of Materia Medica》There is " sweet, warm, nontoxic ", " control woman's blood pain and postpartum dislikes
Blood is not net, beats the good of beverage "；《A supplement to augmented materia medica》Have " invigorate blood circulation, help digestion, invigorating the spleen warm stomach, control red white diarrhea, traumatic injury " etc.
Record.
The seventies in last century, Japanese professor Endo isolates physiology from red monascus (Monascus ruber) first
Since active material Mo Nakelin K (monacolin K), numerous domestic and foreign scholars constantly find life in monascus metabolite
Manage active material, including monacolin classes compound, monascorubin, antihypertensive compositions GABA and antioxidant content dimerumic
Acid and some terpenoids for separating recently etc..With modern biochemistry and pharmacological development, the drop blood of red yeast rice
The effects such as fat, decompression, hypoglycemic, anti-obesity, anticancer, preventing and treating senile dementia and osteoporosis, is constantly mined.So as to be traditional
Red yeast rice adds new intension.
Blood fat recovery capsule is that the mould fermentation of purpose-made monascus that Beijing WBL Peking University Biotech Co., Ltd is independently studied is made
Efficient, safe domestic modern adjust fat Chinese medicine.
Obesity is as a kind of systemic incretion metabolism disease, worldwide into popular tendency.It not only influences
Figure and activity, and it is closely related with the disease such as hyperlipidemia, atherosclerosis, coronary heart disease, diabetes.What obesity occurred
Reason is many, and such as inherent cause, environmental factor, eating habit, wherein high fat diet are to lead obesogenous important original
Cause.In recent years, drug therapy is to treat one of effective means of obesity, and therapeutic purposes are reached by reducing fat absorption.Pancreas
It is necessary to fat digestion absorbs in enteron aisle with gastric lipase.Fat in food is hydrolyzed to monoacylglycerol and free-fat
After acid, absorbed in enteron aisle, fat is then recombined in vivo, cause fat accumulation, can finally cause obesity.Using fat
Enzyme inhibitor can effectively suppress decomposition catalytic action of the lipase to fat in enteron aisle, reach reduction fat absorption, control and control
Treat fat purpose (the Chinese traditional Chinese medicine academic periodicals of study medication progress the fat such as Chen Jin, 2007,25 (5)：947-948；
Wu waits the fat Progress in Medication Medical reviews of, 2006,12 (11) quietly：693-693.)
At present, U.S. FDA, which only have approved 2 kinds of medicines, can be used for bariatrician for a long time：Sibutramin (Xi Buqu
It is bright, nervous centralis effect slimming drugs) and orlistat (orlistat, gastrointestinal lipases inhibitor).But both medicines have
Obvious adverse reaction：Sibutramin side effect mainly has thirsty, constipation, dizziness and insomnia, and orlistat's is bad anti-
Gastrointestinal symptom should be mainly, diarrhoea stomachache, oiliness spot, flatulence etc. is common are, its long-term effect also await into
One step evaluation.
Therefore, the new medicine with the fatty enzyme effect of suppression will be found by still needing at present.
The content of the invention
The present inventor passes through in-depth study and performing creative labour, has obtained a kind of sterol derivative, and this hair
A person of good sense it has surprisingly been found that the present invention compound can effectively suppress the activity of lipase so that with as prevention and/or
The potentiality of the medicine for the treatment of and/or auxiliary treatment obesity or obesity-related disorder.Thus provide following inventions：
One aspect of the present invention is related to the compound shown in Formulas I, or its pharmaceutically acceptable salt,
Wherein,
R1Selected from-OH ,=O (carbonyl), H and C1-C3Alkyl；
R2Selected from-OH, H and C1-C3Alkyl；
R3Selected from-OH ,=O, H and C1-C3Alkyl；
R4Selected from-OH, H and C1-C3Alkyl；
And R1、R2、R3And R4In any 2,3 or 4 simultaneously for-OH.
In one embodiment of the invention, R1For-OH or=O (carbonyl), R2、R3And R4It is H.
Compound or its pharmaceutically acceptable salt according to any one of the present invention, it is shown in following Formula II
Compound, or its pharmaceutically acceptable salt,
Formula II compound it is chemical entitled：16,22- epoxy ergot steroid -5,7- diene -3,20,23,25- tetrols
(16,22-epoxy-ergosta-5,7-dien-3,20,23,25-tetraol).
The invention further relates to the hydrate or solvate of above-mentioned Formulas I or Formula II compound.
Another aspect of the present invention is related to the preparation method of Formulas I or Formula II compound, comprises the steps：
1) alcohol extract (such as blood fat recovery capsule content, it is dry powder) of red yeast rice and/or red yeast rice is taken, with 2-6 times of volume
One or more organic solvents in dichloromethane, ethyl acetate, acetone, methanol, ethanol extracted as solvent supersonic
It is one or many, it is each 20-40 minutes, merge extract solution, remove solvent, obtain extract；
Alternatively, the alcohol extract can be made in the following manner：With the 50%-100% ethanol or 50%- of 2-6 times of volume
100% methanol extracts one or many as solvent supersonic, each 20-40 minutes, merges extract solution, removes solvent, obtain alcohol
Extract.
The limitation of theory is not limited to, because Effects of Xuezhikang is the alcohol extract of red yeast rice in itself, therefore can be former directly with red yeast rice
Material, extraction step and blood fat recovery capsule content dry powder are essentially identical, but the content of the compound in red yeast rice is relatively low.It is described
The specific bacterial strain of red yeast rice is not particularly limited, including any strain or bacterial strain for belonging to red yeast rice.(for example Beijing University ties up blood fat recovery capsule
Letter production) it can be commercially available by hospital or pharmacy.
2) by step 1) obtained extract carries out silica gel column chromatography separation, and carry out gradient with petroleum ether and ethyl acetate and wash
It is de-；The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100；
3) take step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 elution fraction, through C18 reversed-phase column chromatographies
Separated, gradient elution is carried out with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0；
4) take step 3) in methanol-water purified for 50: 50-75: 25 elution fraction with half preparative high-performance liquid chromatographic,
With the acetic acid aqueous solution of acetonitrile -0.2% (45: 55) for mobile phase, C18 semi-preparative columns are stationary phase, collect 9.2min chromatographic peak
Part；With
5) by step 4) product be freeze-dried, obtain Formulas I or Formula II compound.
Preparation method according to any one of the present invention, it meets any one of following (1)-(9) or many
：
(1) step 1) in, the organic solvent is preferably dichloromethane；
(2) step 1) in, the ultrasonic extraction is carried out 3 times；
(3) step 1) in, pass through the removing solvent that is concentrated under reduced pressure；
(4) step 2) in, the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100；
(5) step 3) in, take step 2) in petroleum ether-ethyl acetate be 50: 50 or 25: 75 elution fraction；
The present inventor is found by experiment that the elution fraction that petroleum ether-ethyl acetate is 50: 50-25: 75 all contains this hair
Bright compound.
(6) step 3) in, the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0；
(7) step 4) in, take step 3) in methanol-water be 50: 50 or 75: 25 elution fraction；
The present inventor is found by experiment that the elution fraction that methanol-water is 50: 50-75: 25 is all containing chemical combination of the invention
Thing.
(8) step 4) in, the 9.2min of collection chromatographic peak part is merged；With
(9) step 5) in, the condition of freeze-drying is：- 40 to -85 DEG C of condenser temperature, vacuum 0-100Pa；Preferably
- 50 to -82.7 DEG C of condenser temperature, vacuum 2-13Pa；More preferably -82.7 DEG C of condenser temperature, vacuum 2Pa, or cold-trap temperature
- 50 DEG C of degree, vacuum 8.5Pa.
Another aspect of the invention is related to a kind of extract, and it contains the Formula II compound of the present invention.
Extract according to any one of the present invention, it is the extract or red yeast rice of blood fat recovery capsule content dry powder
Extract.
Extract according to any one of the present invention, it is any one of following (1) to (3)：
(1) above-mentioned step 1) to 2) in obtained petroleum ether-ethyl acetate be 50: 50-25: 75 elution fraction；It is excellent
Select the elution fraction that petroleum ether-ethyl acetate is 50: 50 or 25: 75；Further preferred petroleum ether-ethyl acetate is 25: 75
Elution fraction.
(2) above-mentioned step 1) to 3) in obtained methanol-water be 50: 50-75: 25 elution fraction；It is preferred that methanol-water
For 50: 50 or 75: 25 elution fraction；The elution fraction that further preferred methanol-water is 75: 25；With
(3) above-mentioned step 1) to 4) in obtained 9.2min chromatographic peak part.
Another aspect of the invention is related to a kind of composition, and it is any in compound or the present invention comprising Formulas I or Formula II
Extract described in；Alternatively, in addition to pharmaceutically acceptable carrier or auxiliary material.Specifically, the composition is medicine
Composition.
Another aspect of the invention is related to extract or this hair described in the compound or any one of the present invention of the present invention
Bright composition is preparing the medicine of prevention and/or treatment and/or auxiliary treatment obesity or obesity-related disorder or subtracted
Purposes in fertile medicine；Specifically, the obesity-related disorder is hyperlipidemia, atherosclerosis, coronary heart disease or glycosuria
Disease.
Formulas I or Formula II compound that usual pharmaceutical composition of the present invention contains 0.1-90 weight % and/or its physiologically may be used
The salt of receiving.Pharmaceutical composition can be prepared according to methods known in the art.When for this purpose, if it is desired, can by Formulas I or
Formula II compound and/or stereoisomer are combined with one or more solids or liquid pharmaceutical excipients and/or assistant agent, and being made can
It is used as the appropriate administration form or dosage form of people.
The Formulas I or Formula II compound of the present invention or the pharmaceutical composition containing it can be administered in a unit, be administered
Approach can be enteron aisle or non-bowel, such as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritonaeum or rectum.To medicament
Type such as tablet, capsule, dripping pill, aerosol, pill, pulvis, solution, supensoid agent, emulsion, granule, liposome, transdermal
Agent, buccal tablet, suppository, freeze drying powder injection etc..Can be ordinary preparation, sustained release preparation, controlled release preparation and various particulates administration system
System.In order to which unit dosage forms for administration is made into tablet, various carriers well known in the art can be widely used.Example on carrier
Be, such as diluent and absorbent, such as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea,
Calcium carbonate, white bole, microcrystalline cellulose, alumina silicate etc.；Wetting agent and adhesive, such as water, glycerine, polyethylene glycol, ethanol, third
Alcohol, starch slurry, dextrin, syrup, honey, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethylcellulose, lac, first
Base cellulose, potassium phosphate, polyvinylpyrrolidone etc.；Disintegrant, for example, dry starch, alginate, agar powder, brown alga and form sediment
Powder, sodium acid carbonate and citric acid, calcium carbonate, polyoxyethylene, sorbitan fatty acid ester, dodecyl sodium sulfate, Methyl cellulose
Element, ethyl cellulose etc.；Disintegration inhibitor, such as sucrose, glyceryl tristearate, cocoa butter, hydrogenated oil and fat；Absorption enhancement
Agent, such as quaternary ammonium salt, lauryl sodium sulfate；Lubricant, such as talcum powder, silica, cornstarch, stearate,
Boric acid, atoleine, polyethylene glycol etc..Tablet can also be further made to coating tablet, such as sugar coated tablet, film coating
Piece, enteric coated tablets, or double-layer tablets and multilayer tablet.In order to which administration unit is made into pill, it can widely use known in this field
Various carriers.Example on carrier is, such as diluent and absorbent, such as glucose, lactose, starch, cocoa butter, hydrogenation
Vegetable oil, polyvinylpyrrolidone, Gelucire, kaolin, talcum powder etc.；Adhesive for example Arabic gum, bassora gum, gelatin,
Ethanol, honey, liquid sugar, rice paste or batter etc.；Disintegrant, such as agar powder, dry starch, alginate, dodecyl sodium sulfate,
Methylcellulose, ethyl cellulose etc..In order to which administration unit is made into suppository, various loads well known in the art can be widely used
Body.Example on carrier is, for example polyethylene glycol, lecithin, cocoa butter, higher alcohol, the ester of higher alcohol, gelatin, semi-synthetic
Glyceride etc..In order to which administration unit is made into capsule, by active ingredient compound of formula I or its stereoisomer with it is above-mentioned various
Carrier is mixed, and thus obtained mixture is placed in hard obviously capsule or soft capsule.Also can be by active ingredient Formulas I or formula
Microcapsules is made in II compounds or its stereoisomer, is suspended in aqueous medium formation supensoid agent, can also be fitted into hard shell capsules
Or injection application is made.In order to which administration unit is made into injection preparation, such as solution, emulsion, freeze drying powder injection and suspension
Agent, can use all diluents commonly used in the art, for example, water, ethanol, polyethylene glycol, 1,3-PD, ethoxylation
Isooctadecanol, polyoxygenated isooctadecanol, Polyoxyethylene Sorbitol Fatty Acid Esters etc..In addition, in order to prepare isotonic parenteral solution, can
To add appropriate sodium chloride, glucose or glycerine into injection preparation, further, it is also possible to add conventional cosolvent, delay
Electuary, pH adjusting agent etc..
In addition, if desired, can also be added into pharmaceutical preparation colouring agent, preservative, spices, flavouring, sweetener or
Other materials.
Formula I or Formula II compound, or the dosage of its officinal salt depend on many factors, for example, want pre-
Sex, age, body weight and the individual reaction of anti-or treatment disease property and the order of severity, patient or animal, used is specific
Compound, method of administration and administration number of times etc..Above-mentioned dosage with ingle dose form or can be divided into several, such as two, three or four
Individual dosage forms for administration.
Term " composition " used herein means to include the product of each specified composition comprising specified amount, and directly or
Any product produced indirectly from the combination of each specified composition of specified amount.
The actual dose level of each active component in pharmaceutical composition of the present invention can be changed, so as to the reactive compound of gained
Amount can effectively obtain required therapeutic response for specific patient, composition and administering mode.Dosage level must be according to materialization
The activity of compound, method of administration, the patient's condition and medical history of the order of severity for treating the patient's condition and patient to be treated are selected.
But, the way of this area is that the dosage of compound is since the level required less than therapeutic effect needed for obtaining, gradually
Incremental dose, until obtaining required effect.
Another aspect of the invention is related to extract or this hair described in the compound or any one of the present invention of the present invention
Bright composition is preparing the purposes in suppressing the medicine or reagent of lipase.
Another aspect of the invention is related to a kind of method for suppressing lipase, the chemical combination of the invention including the use of effective dose
The step of composition of extract or the present invention described in thing or its pharmaceutically acceptable salt or any one of the present invention.
The experiment of embodiment 4 proves that compound of the invention can effectively suppress lipase.
Another aspect of the invention is related to a kind of prevention and/or treatment and/or auxiliary treatment obesity or obesity is related
The method of disease or a kind of ways of preventing obesity, including give described in the compound of the invention or any one of the present invention of effective dose
Extract or the present invention composition the step of；Specifically, the obesity-related disorder is that hyperlipidemia, artery are athero-
Hardening, coronary heart disease or diabetes.
When for above-mentioned treatment and/or prevention or auxiliary treatment, a kind of present inventionization for the treatment of and/or prevention effective dose
Compound can be applied in a pure form, or should with pharmaceutically acceptable ester or prodrug forms (in the case where there are these forms)
With.Or, the compound can be with the medicine group containing the purpose compound with the acceptable excipient of one or more medicines
Compound is administered.Term " effective dose " refers to that treatment can be realized in subject, prevents, mitigates and/or alleviate disease of the present invention
The dosage of disease or illness.It is to be understood that total consumption per day of the compounds of this invention and composition must be by attending physician reliable
Maked decision in medical judgment scope.For any specific patient, specific treatment effective dose level must according to it is a variety of because
Depending on element, the factor includes treated obstacle and the order of severity of the obstacle；The activity of the particular compound used；Institute
The concrete composition of use；Age, body weight, general health, sex and the diet of patient；The particular compound used
Administration time, method of administration and excretion rate；Treat the duration；It is applied in combination or while uses with the particular compound that is used
Medicine；And similar factor known to medical field.For example, the way of this area is, the dosage of compound is from less than obtaining
Required therapeutic effect and desired level starts, gradually incremental dose, until obtaining required effect.It is, in general, that of the invention
Compound of formula I be used for mammal particularly people dosage can between 0.001-1000mg/kg body weight/days, for example between
0.01-100mg/kg body weight/days, such as between 0.01-10mg/kg body weight/days.
It can effectively prevent and/or treat various diseases of the present invention or illness according to the compound of the present invention.
The invention further relates to following aspect 1-11：
1. any one of following (1)-(4) are preparing prevention and/or treatment and/or auxiliary treatment obesity or obesity
Purposes in the medicine or slimming medicine of disease relevant disease；Specifically, the obesity-related disorder is hyperlipidemia, artery
Atherosis, coronary heart disease or diabetes,
(1) compound shown in Formulas I or its pharmaceutically acceptable salt,
Wherein,
R1Selected from-OH ,=O, H and C1-C3Alkyl；
R2Selected from-OH, H and C1-C3Alkyl；
R3Selected from-OH ,=O, H and C1-C3Alkyl；
R4Selected from-OH, H and C1-C3Alkyl；
And R1、R2、R3And R4In any 2,3 or 4 simultaneously for-OH；
(2) compound shown in Formula II or its pharmaceutically acceptable salt,
(3) extract, it contains Formula II compound；With
(4) composition, it contains any one of above-mentioned (1)-(3).
2. any one of (1)-(4) described in the 1st aspect suppress the medicine of lipase preparing in vivo or in vitro
Or the purposes in reagent.
3. the purposes according to the 1st or 2 aspects, wherein, extract in described (3) item for Red Yeast Rice P.E and/
Or the extract of red yeast rice alcohol extract (such as blood fat recovery capsule content).
4. the purposes according to the 3rd aspect, wherein, the extract in described (3) item, it is the steps 1) extremely
2) elution fraction that obtained petroleum ether-ethyl acetate is 50: 50-25: 75 in；Or the steps 1) to obtained first in 3)
Alcohol-water is 50: 50-75: 25 elution fraction；Or the steps 1) to the chromatographic peak part of obtained 9.2min in 4)：
1) alcohol extract (such as blood fat recovery capsule content dry powder) of red yeast rice and/or red yeast rice is taken, with being selected from for 2-6 times of volume
One or more organic solvents in dichloromethane, ethyl acetate, acetone, methanol, ethanol as solvent supersonic extract once or
Repeatedly, it is each 20-40 minutes, merge extract solution, remove solvent, obtain extract；
2) by step 1) obtained extract carries out silica gel column chromatography separation, and carry out gradient with petroleum ether and ethyl acetate and wash
It is de-；The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100；
3) take step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 elution fraction, through C18 reversed-phase column chromatographies
Separated, gradient elution is carried out with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0；
With
4) take step 3) in methanol-water purified for 50: 50-75: 25 elution fraction with half preparative high-performance liquid chromatographic,
With the acetic acid aqueous solution of acetonitrile -0.2% (45: 55) for mobile phase, C18 semi-preparative columns are stationary phase, collect 9.2min chromatographic peak
Part.
5. the purposes according to the 4th aspect, it is characterised in that any one of (1)-(8) are multinomial：
(1) step 1) in, the organic solvent is dichloromethane；
(2) step 1) in, the ultrasonic extraction is carried out 3 times；
(3) step 1) in, pass through the removing solvent that is concentrated under reduced pressure；
(4) step 2) in, the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100；
(5) step 3) in, take step 2) in petroleum ether-ethyl acetate be 50: 50 or 25: 75 elution fraction；
(6) step 3) in, the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0；
(7) step 4) in, take step 3) in methanol-water be 50: 50 or 75: 25 elution fraction；With
(8) step 4) in, the 9.2min of collection chromatographic peak part is merged.
6. the purposes according to the 1st or 2 aspects, wherein, the composition in described (4) item also includes pharmaceutically connecing
The carrier or auxiliary material received.
7. a kind of method for suppressing lipase in vivo or in vitro, described in the 1st aspect including the use of effective dose
(1) the step of any one of-(4).
8. the method according to the 7th aspect, wherein, the extract in described (3) item is Red Yeast Rice P.E and/or red
The extract of bent alcohol extract (such as blood fat recovery capsule content).
9. the method according to the 8th aspect, wherein, the extract in described (3) item, it is the steps 1) extremely
2) elution fraction that obtained petroleum ether-ethyl acetate is 50: 50-25: 75 in；Or the steps 1) to obtained first in 3)
Alcohol-water is 50: 50-75: 25 elution fraction；Or the steps 1) to the chromatographic peak part of obtained 9.2min in 4)：
1) alcohol extract (such as blood fat recovery capsule content dry powder) of red yeast rice and/or red yeast rice is taken, with being selected from for 2-6 times of volume
One or more organic solvents in dichloromethane, ethyl acetate, acetone, methanol, ethanol as solvent supersonic extract once or
Repeatedly, it is each 20-40 minutes, merge extract solution, remove solvent, obtain extract；
2) by step 1) obtained extract carries out silica gel column chromatography separation, and carry out gradient with petroleum ether and ethyl acetate and wash
It is de-；The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100；
3) take step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 elution fraction, through C18 reversed-phase column chromatographies
Separated, gradient elution is carried out with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0；
With
4) take step 3) in methanol-water purified for 50: 50-75: 25 elution fraction with half preparative high-performance liquid chromatographic,
With the acetic acid aqueous solution of acetonitrile -0.2% (45: 55) for mobile phase, C18 semi-preparative columns are stationary phase, collect 9.2min chromatographic peak
Part.
10. the method according to the 9th aspect, it is characterised in that any one of (1)-(8) are multinomial：
(1) step 1) in, the organic solvent is dichloromethane；
(2) step 1) in, the ultrasonic extraction is carried out 3 times；
(3) step 1) in, pass through the removing solvent that is concentrated under reduced pressure；
(4) step 2) in, the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100；
(5) step 3) in, take step 2) in petroleum ether-ethyl acetate be 50: 50 or 25: 75 elution fraction；
(6) step 3) in, the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0；
(7) step 4) in, take step 3) in methanol-water be 50: 50 or 75: 25 elution fraction；With
(8) step 4) in, the 9.2min of collection chromatographic peak part is merged.
11. the method according to the 7th aspect, wherein, the composition in described (4) item also includes pharmaceutically acceptable
Carrier or auxiliary material.
In the present invention,
Term " C1-C3Alkyl " includes methyl, ethyl, propyl group or isopropyl.
Term obesity include but is not limited to simple obesity (without obvious endocrine, metabolism the cause of disease can seek, with heredity,
Eating habit etc. is relevant), Secondary Obesity (be often for example hyperinterrenal one kind of some diseases, can be because of disease
Cure and eliminate).The obesity can be the obesity of mammal, and the mammal includes people or pig.
Term " obesity-related disorder " includes but is not limited to hyperlipidemia, atherosclerosis, coronary heart disease or diabetes
Etc..
Term " lipase " (lipase, enzyme classification EC3.1.1.3) includes but is not limited to the lipase of mammal, example
Such as the lipase or the lipase of pig of people, the lipase of the people can be people's pancreatic lipase, and the lipase of the pig can be
Porcine pancreatic lipase (porcine pancreatic lipase).
The beneficial effect of invention
The compound of the present invention can effectively suppress the activity of lipase, and inhibitory action and in concentration-effect relation；
So as to the medicine or slimming drugs as prevention and/or treatment and/or auxiliary treatment obesity or obesity-related disorder
The potentiality of thing.
Brief description of the drawings
Fig. 1：Oleic acid absorbance working curve.
Embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment.Those skilled in the art will manage
Solution, the following examples are merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.It is unreceipted specific in embodiment
Technology or condition person, (write, Huang according to the technology described by document in the art or condition such as with reference to J. Pehanorm Brookers
What training hall etc. was translated《Molecular Cloning:A Laboratory guide》, the third edition, Science Press) or carry out according to product description.Examination used
Agent or the unreceipted production firm person of instrument, being can be by the conventional products of acquisition purchased in market.
Embodiment 1：The preparation (1) of Formula II compound
Operating procedure：
1) blood fat recovery capsule (Beijing University's dimension letter production) content dry powder about 1kg is taken, is molten with the dichloromethane of 2-6 times of volume
Agent ultrasonic extraction 3 times, it is each 20-40 minutes, merge extract solution, be concentrated under reduced pressure and recycling design, obtain dichloromethane extract
91g。
2) dichloromethane extract 50g is taken, upper silica gel column chromatography separation carries out gradient with petroleum ether and ethyl acetate and washed
It is de-.The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100.
3) it is 25: 75 part 5.0g to take petroleum ether-ethyl acetate, is separated through C18 reversed-phase column chromatographies, methanol-water (10
: 90-100: 0) gradient elution obtains 4 parts (methanol-water 10: 90,50: 50,75: 25,100: 0), wherein methanol-water (75:
25) elution fraction 1.3g is purified with half preparative high-performance liquid chromatographic, is flowing with the acetic acid aqueous solution of acetonitrile -0.2% (45: 55)
Phase, flow velocity is 4mL/min, and C18 partly prepares chromatographic column (10 × 250mm, 5 μm) for stationary phase, and DAD detector Detection wavelengths are
270nm, collects 9.2min chromatographic peak, is concentrated after repeatedly adding up, is freeze-dried and obtains the compound about 40mg.
Embodiment 2：The preparation (2) of Formula II compound
Operating procedure：
1) red yeast rice 5kg is taken, the dichloromethane with 2-6 times of volume is that solvent supersonic is extracted 3 times, each 20-40 minutes, is merged
Extract solution, is concentrated under reduced pressure and recycling design, obtains dichloromethane extract 78g.
2) dichloromethane extract 30g is taken, upper silica gel column chromatography separation carries out gradient with petroleum ether and ethyl acetate and washed
It is de-.The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100.
3) it is 25: 75 part 3.0g to take petroleum ether-ethyl acetate, is separated through C18 reversed-phase column chromatographies, methanol-water (10
: 90-100: 0) gradient elution obtains 4 parts (methanol-water 10: 90,50: 50,75: 25,100: 0), wherein methanol-water (75:
25) elution fraction 0.8g is purified with half preparative high-performance liquid chromatographic, is flowing with the acetic acid aqueous solution of acetonitrile -0.2% (45: 55)
Phase, flow velocity is 4mL/min, and C18 partly prepares chromatographic column (10 × 250mm, 5 μm) for stationary phase, and DAD detector Detection wavelengths are
270nm, collects 9.2min chromatographic peak, is concentrated after repeatedly adding up, is freeze-dried and obtains the compound about 25mg.
Embodiment 3：The Structural Identification of compound
Specimen in use is compound prepared by Examples 1 and 2.
1. the physicochemical data of compound
White powder, optical activity：[α]25 D- 50.00 (c0.118, CH2Cl2: MeOH=1: 1)；
There are three maximum absorption bands, respectively λ in UV spectrummax(CH2Cl2: MeOH)=271.6nm, 282.2nm,
293.8nm。
FT-IR (KBr, cm-1) spectrum：3392 (- OH), 2969,2933 (saturation is hydrocarbon), 1652,1647 (C=C),
1456,1378 (gem-dimethyls).
2. the determination of molecular formula
The m/z 483.3104 [M+Na] that HR-ESI-MS is provided+(calcd.483.3081, err2.3), is inferred as the change
The molecular weight of compound is 460.32.1H-NMR and13C-NMR is shown, has 40 hydrogen signals and 28 carbon signals.It is aobvious from DEPT
Show there is 6 quaternary carbons, 10 CH, 6 CH2And 6 CH3.13In C-NMR, 117.2ppm, 119.6ppm, 139.1ppm and
There are 4 olefinic carbon signals at 140.6ppm.With HSQC figure with13C-NMR figure binding analysis, 70.5ppm, 72.4ppm, 74.5ppm,
There are 6 carbon being connected with oxygen atom at 80.4ppm, 83.8ppm and 84.4ppm.Binding molecule amount and1H、13C-NMR and DEPT
Signal graph, molecular weight infers that the compound has 5 more than 460.32, thus if the compound possesses 6 oxygen atoms
Oxygen atom and 4 hydrogen atoms for not embodying hydrogen spectrum signal.So as to judge in above-mentioned 5 oxygen atoms, 4 oxygen atoms are attributed to
4 hydroxyls, in addition the 5th oxygen atom exist in the form of ether.According to above-mentioned analysis, it may be determined that there is 28 carbon originals in the molecule
Son, 44 hydrogen atoms and 5 oxygen atoms, molecular formula is C28H44O5。
3. the determination of structural formula
Analyze the compound carbon spectrum (13C-NMR and DEPT), there are 28 carbon atoms, wherein 6 carbon are methyl.Based on purple
3 absorption maximums in outer absorption spectrum at 271.6nm, 282.2nm and 293.8nm are coincide substantially with ergosterol class, tentatively
Infer that the compound has the skeleton of ergosterol.It is 7 that can calculate its degree of unsaturation from molecular formula.So as to infer：
The compound is outer except 6 of 4 rings of 2 double bonds and sterol backbone unsaturated places, also one it is unsaturated at and also herein
Can be a ring, it is possible thereby to judge that the ring is the epoxide ring formed centered on the 5th oxygen atom.HSQC figures are related to HMBC
Signal graph is combined analysis, 6 be connected with oxygen atom carbon, be attributed to respectively 4 connected carbon of 4 hydroxyls (70.5,72.4,
74.5,80.4ppm) and with remaining 2 carbon (83.8,84.4ppm) that next oxygen atom is connected.Deep HMBC map analysis, can
To infer that the 5th member ring systems are by C-16 (83.8ppm), C-17 (66.9ppm), C-20 (80.4ppm), C-22 (84.4ppm)
And 5 yuan of rings of oxygen atom composition.This not only meets degree of unsaturation, but also meets the carbon number being connected with oxygen atom.Enter one
Molecular weight and molecular formula that step analysis mass spectrometry system is provided, it was confirmed that above-mentioned analysis.The above analysis can speculate that this is new
Compound is：16,22- epoxy ergot steroid -5,7- diene -3,20,23,25- tetrols
That is (16,22-epoxy-ergosta-5,7-dien-3,20,23,25-tetraol).Structural formula is following formula
Shown in II.
4. the NMR data of Formula II compound
As shown in Table 1 below.
Table 1：NMR data (600MHz, the CDCl of Formula II compound3, J in Hz)
Note："-" represents that coherent signal is not present.
Embodiment 4：Lipase inhibiting activity is tested
1 experiment material
1.1 medicine
Formula II compound.
Orlistat (orlistat) --- purchased from the big pharmacy of Golden Elephant.
1.2 enzyme
Porcine pancreatic lipase --- purchased from Sigma companies.
1.3 reagent
Oleic acid --- purchased from Sigma companies.
Toluene, olive oil, pyridine, copper acetate, NaH2PO4、K2HPO4It is that domestic analysis is pure.
2 experimental methods
As shown in following step, Jiang Huifang, Wang Yaqin, tri- kinds of lipase activity measure sides of Liu Chun states can also be referred to
The comparison of method and improvement chemistry and bioengineering .2007,24 (8)：72-75；And the lotus leaves such as Zhu Xiaoqing, Lv Jingci, Huo Shixin
Alkaloid is to the inhibitory action Shanghai University journal (natural science edition) of lipase, 2007,13 (1)：85-87.
The drafting of 2.1 aliphatic acid absorbance working curves：Prepare a series of oleic acid-toluene solution (0- of various concentrations
3.5mmol/L, respectively 0,0.225,0.45,0.675,0.9,1.125,1.35,1.8,2.25,2.7 and 3.5mmol/L),
4mL is taken respectively in conical flask, 1mL developers are added, and magnetic agitation 3min, oleic acid molecular generates the complexing of green with copper ion
Upper organic phase is taken to determine absorbance at 714nm after thing, centrifugation.
2.2 enzyme solutions are 0.5mg/mL pancreatic lipase solution；Buffer solution is 0.07MNaH2PO4-K2HPO4Phosphate-buffered
Solution (pH 7.0)；Developer is 5% acetic acid copper solution, and pH 6.1 is adjusted with pyridine.
The measure of 2.3 lipase activities：
3mL 0.07M phosphate buffers and 1mL olive oil are taken, is put into 37 DEG C of constant temperature water bath magnetic stirring apparatus and preheats
5min, adds 1.3mL enzyme liquids and (is not added with enzyme inhibitor for negative control；Plus the μ L of 0.1mg/mL orlistats solution 100 are positive right
According to；0.6th, 0.9,1.1,1.3,1.8mg/mL compound solutions respectively add 100 μ L), magnetic agitation 10min adds 8mL first immediately
Benzene, continues to stir 2min, terminating reaction, while extracting the oleic acid of generation.Solution is transferred in centrifuge tube, under 4000rpm
Centrifuge 10min, organic phase and aqueous phase layering clarification.Take upper organic phase 4mL in fine taper bottle, 1mL developers are added, in magnetic
3min is stirred on power agitator, oleic acid and the copper ion of generation generate green complex compound.4000rpm centrifuges 10min, takes upper strata to contain
There is the toluene solution of copper oleate, its absorbance is surveyed at 714nm wavelength with spectrophotometer.Prepare in the same way not fatty
The blank solution of enzyme is reference, compares oleic acid absorbance working curve, you can try to achieve the concentration of aliphatic acid.
3 enzyme activity are defined and calculation formula
Lipase activity unit of force is defined as：Under certain condition, the enzyme amount definition per minute for discharging 1 μm of ol aliphatic acid
For 1 lipase activity unit of force (U).
Enzyme activity is calculated as follows：X=(cV)/(tV ')
In formula：X is lipase activity, U/mL；C is fatty acid concentration, μm ol/mL；V is the volume of adipic acid solution, mL；
V ' is the consumption of enzyme liquid, mL；T is action time, min.
Inhibiting rate=[(lipase activity after lipase activity-suppression)/lipase activity] × 100%
4 experimental results
4.1 oleic acid absorbance working curves
As shown in Figure 1.
4.2 inhibitor activity testing results
Wherein enzyme activity is obtained according to the calculation formula calculating in above 3, wherein：
V=8mL；V '=1.3mL；T=10min.
Test result indicates that, the activity of compound on fatty enzyme of the invention has good inhibiting effect, its IC50Value is about
For 220 μ g/mL, and inhibitory action is in concentration-effect relation.It can be seen that, compound of the invention has prevention and/or treated
And/or the potentiality of the medicine of auxiliary treatment obesity or obesity-related disorder.
Although the embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.Root
According to disclosed all teachings, various modifications and replacement can be carried out to those details, these change the guarantor in the present invention
Within the scope of shield.The four corner of the present invention is provided by appended claims and its any equivalent.
Claims (15)
1. purposes of any one of following (1)-(3) in the medicine for preparing prevention and/or treatment obesity：
(1) as the compound shown in the formula II of sole active agent or its pharmaceutically acceptable salt,
(2) extract, it contains the compound of formula II as sole active agent；With
(3) composition, it is as the extraction described in the compound shown in formula II or its pharmaceutically acceptable salt or (2) item
Thing, and pharmaceutically acceptable carrier or auxiliary material composition.
2. purposes according to claim 1, wherein, the treatment is auxiliary treatment.
3. purposes of any one of following (1)-(3) in slimming medicine is prepared：
(1) as the compound shown in the formula II of sole active agent or its pharmaceutically acceptable salt,
(2) extract, it contains the compound of formula II as sole active agent；With
(3) composition, it is as the extraction described in the compound shown in formula II or its pharmaceutically acceptable salt or (2) item
Thing, and pharmaceutically acceptable carrier or auxiliary material composition.
4. any one of (1)-(3) described in claim 1 prepare in vivo or in vitro suppress lipase medicine or
Purposes in reagent.
5. the purposes according to any claim in Claims 1-4, wherein, the extract in described (2) item is red
Bent extract, or red yeast rice alcohol extract extract.
6. purposes according to claim 5, wherein, the red yeast rice alcohol extract is blood fat recovery capsule content.
7. purposes according to claim 5, wherein, the extract in described (2) item, it is the steps 1) to 2)
In obtained petroleum ether-ethyl acetate be 50:50-25:75 elution fraction；Or the steps 1) to obtained first in 3)
Alcohol-water is 50:50-75:25 elution fraction；Or the steps 1) to the chromatographic peak part of obtained 9.2min in 4)：
1) take the alcohol extract of red yeast rice and/or red yeast rice, with 2-6 times of volume selected from dichloromethane, ethyl acetate, acetone, methanol,
One or more organic solvents in ethanol are one or many as solvent supersonic extraction, each 20-40 minutes, merge and extract
Liquid, removes solvent, obtains extract；
2) by step 1) obtained extract carries out silica gel column chromatography separation, and gradient elution is carried out with petroleum ether and ethyl acetate；
The volume ratio of petroleum ether-ethyl acetate is followed successively by 75:25、50:50-25:75、0:100；
3) take step 2) in petroleum ether-ethyl acetate be 50:50-25:75 elution fraction, is carried out through C18 reversed-phase column chromatographies
Separation, gradient elution is carried out with methanol-water, the volume ratio of methanol-water is followed successively by 10:90、50:50-75:25、100:0；With
4) take step 3) in methanol-water be 50:50-75:25 elution fraction is purified with half preparative high-performance liquid chromatographic, with
The acetic acid aqueous solution of acetonitrile -0.2% (45：55) it is mobile phase, C18 semi-preparative columns are stationary phase, collect 9.2min chromatogram valley
Point.
8. purposes according to claim 7, wherein, the alcohol extract of the red yeast rice is blood fat recovery capsule content dry powder.
9. purposes according to claim 7, it is characterised in that any one of following (1)-(8) are multinomial：
(1) step 1) in, the organic solvent is dichloromethane；
(2) step 1) in, the ultrasonic extraction is carried out 3 times；
(3) step 1) in, pass through the removing solvent that is concentrated under reduced pressure；
(4) step 2) in, the volume ratio of petroleum ether-ethyl acetate is followed successively by 75:25、50:50、25:75、0:100；
(5) step 3) in, take step 2) in petroleum ether-ethyl acetate be 50:50 or 25:75 elution fraction；
(6) step 3) in, the volume ratio of methanol-water is followed successively by 10:90、50:50、75:25、100:0；
(7) step 4) in, take step 3) in methanol-water be 50:50 or 75:25 elution fraction；With
(8) step 4) in, the 9.2min of collection chromatographic peak part is merged.
10. in a kind of method for suppressing lipase in vitro, (1)-(3) described in the claim 1 including the use of effective dose
Any one the step of.
11. method according to claim 10, wherein, the extract in described (2) item is Red Yeast Rice P.E, or red yeast rice
The extract of alcohol extract.
12. method according to claim 11, wherein, the red yeast rice alcohol extract is blood fat recovery capsule content.
13. the method according to claim 11 or 12, wherein, the extract in described (2) item, it is the steps
1) it is 50 to obtained petroleum ether-ethyl acetate in 2):50-25:75 elution fraction；Or the steps 1) made to 3) middle
The methanol-water obtained is 50:50-75:25 elution fraction；Or the steps 1) to the chromatographic peak of obtained 9.2min in 4)
Part：
1) take the alcohol extract of red yeast rice and/or red yeast rice, with 2-6 times of volume selected from dichloromethane, ethyl acetate, acetone, methanol,
One or more organic solvents in ethanol are one or many as solvent supersonic extraction, each 20-40 minutes, merge and extract
Liquid, removes solvent, obtains extract；
2) by step 1) obtained extract carries out silica gel column chromatography separation, and gradient elution is carried out with petroleum ether and ethyl acetate；
The volume ratio of petroleum ether-ethyl acetate is followed successively by 75:25、50:50-25:75、0:100；
3) take step 2) in petroleum ether-ethyl acetate be 50:50-25:75 elution fraction, is carried out through C18 reversed-phase column chromatographies
Separation, gradient elution is carried out with methanol-water, the volume ratio of methanol-water is followed successively by 10:90、50:50-75:25、100:0；With
4) take step 3) in methanol-water be 50:50-75:25 elution fraction is purified with half preparative high-performance liquid chromatographic, with
The acetic acid aqueous solution of acetonitrile -0.2% (45：55) it is mobile phase, C18 semi-preparative columns are stationary phase, collect 9.2min chromatogram valley
Point.
14. method according to claim 13, wherein, the alcohol extract of the red yeast rice is blood fat recovery capsule content dry powder.
15. method according to claim 13, it is characterised in that any one of (1)-(8) are multinomial：
(1) step 1) in, the organic solvent is dichloromethane；
(2) step 1) in, the ultrasonic extraction is carried out 3 times；
(3) step 1) in, pass through the removing solvent that is concentrated under reduced pressure；
(4) step 2) in, the volume ratio of petroleum ether-ethyl acetate is followed successively by 75:25、50:50、25:75、0:100；
(5) step 3) in, take step 2) in petroleum ether-ethyl acetate be 50:50 or 25:75 elution fraction；
(6) step 3) in, the volume ratio of methanol-water is followed successively by 10:90、50:50、75:25、100:0；
(7) step 4) in, take step 3) in methanol-water be 50:50 or 75:25 elution fraction；With
(8) step 4) in, the 9.2min of collection chromatographic peak part is merged.
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| 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 |
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| 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 |
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