CN102659905B - Hederagenin derivative, and preparation method and application thereof - Google Patents
Hederagenin derivative, and preparation method and application thereof Download PDFInfo
- Publication number
- CN102659905B CN102659905B CN201210157859.4A CN201210157859A CN102659905B CN 102659905 B CN102659905 B CN 102659905B CN 201210157859 A CN201210157859 A CN 201210157859A CN 102659905 B CN102659905 B CN 102659905B
- Authority
- CN
- China
- Prior art keywords
- hederagenin
- salt
- derivative
- hederagenin derivative
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Psychiatry (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Steroid Compounds (AREA)
Abstract
The invention discloses a hederagenin derivative, and a preparation method and application thereof. The general formula of the derivative is shown in the specifications, and according to the preparation method, the hederagenin derivative is obtained by taking hederagenin as a raw material through acylation reaction, esterification or transesterification; the yield and the purity of the hederagenin derivative which is obtained by semisynthesis of hederagenin are high and can reach over 95 percent; the preparation process is simple; the conversion rate of the raw materials is high; the hederagenin derivative is suitable to be produced industrially and is easy to popularize and apply; and pharmacology experiment shows that the derivative and salt thereof have obvious treatment effects on depression, and a novel medicine source is provided for treating and researching depression.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of hederagenin derivative and its preparation method and application.
Background technology
Hederagenin is a kind of aglycon common in Chinese medicinal materials, is mainly seen in teasel root, Fruit of Threeleaf Akebia, akebi, Japanese Honeysuckle etc.Hederagenin is white powder, and polarity is little, is slightly soluble in methyl alcohol, ethanol, is insoluble in water.There is report hederagenin to there is the effect of Protein-tyrosine-phosphatase PTP1B inhibitor; can form antidiabetic medicine and healthcare products, and can be for prevention, diagnosis, detect, protection, treatment and research dysthymia disorders and directly related disease thereof provide a kind of new medicament sources.
But due to almost insoluble in water of hederagenin, in ethanol, dissolubility solution degree is not high yet, research data shows that this product bioavailability is also lower, and daily dosage is large, and the present invention, by change structure, changes or improve biological activity.
Chinese patent CN200810032325.2 discloses a kind of hederagenin and derivative thereof the purposes for the preparation of antidepressant product, but the hederagenin derivative described in it refers to hederagenin salt derivative (referring to sodium salt or sylvite), its preparation method is that hederagenin is dissolved in ethanolic soln, react with corresponding alkaline solution, obtain its salt carrying out recrystallization.And prove the effect at anti-depression aspect by activity test in vitro.
The derivative obtaining as raw material is semi-synthetic taking hederagenin at present has no report at present, and the salt of derivative also has no report at present.By preparing hederagenin novel derivative, change physico-chemical property, active centre, thereby change biological activity, improve absorption, metabolism, be very important thereby improve drug effect.
Summary of the invention
Primary and foremost purpose of the present invention is to provide a kind of hederagenin derivative.
Another object of the present invention is to provide the preparation method of hederagenin derivative.
The present invention is achieved through the following technical solutions:
A kind of hederagenin derivative, has following general formula:
Wherein:
R
1and R
2identical or different, independent of each other being expressed as-OR ', R ' is-COCH
3,-CO (CH
2)
ncH
3,-SO
3h,
-CO (CH
2)
ncOOH ,-ortho-sulfonic acid benzoyl ,-sulfonic acid a benzoyl ,-p-sulfonic acid benzoyl ,-p-toluenesulfonyl ,-adjacent carboxylbenzoyl ,-a carboxylbenzoyl ,-to carboxylbenzoyl ,-maleoyl ,-fumaroyl ,-methylsulfonyl or H, condition is that both can not be H, wherein n=1-3 simultaneously;
R
3for H, Na, K or NH
3;
Work as R
1, R
2in R ' in while containing carboxyl, this carboxyl can further form one or more salt with alkali reaction.
Preferably, R ' is-COCH
3or-CO (CH
2)
2cOOH.
The preparation method of hederagenin derivative of the present invention is taking hederagenin as raw material, obtains by acylation reaction, esterification or transesterification reaction, and concrete grammar is as follows:
Acylation reaction:
Take appropriate hederagenin, add 20 ~ 50 times of amount solvents, 0.05 ~ 15 times of amount catalyzer, stir the lower toluene solution that contains carboxylic acid halides that drips, 50-70 DEG C of reaction 5-10 hour, reaction 1-3 hour adds water, branch vibration layer, removes solvent under reduced pressure, adds 10-25 doubly to measure 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtains hederagenin derivative.
Esterification:
Take appropriate acid anhydrides or carboxylic acid, add 20 ~ 50 times of amount solvents, 0.05 ~ 15 times of amount catalyzer, stirring heating, adds 0.1 ~ 1 times of amount hederagenin, back flow reaction 5 ~ 10h, remove solvent under reduced pressure, add 10-25 doubly to measure 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtains hederagenin derivative.
Transesterification reaction:
Take appropriate carboxylicesters, add 0.1 ~ 1 times of amount hederagenin, add 20 ~ 50 times of amount solvents, 0.05 ~ 15 times of amount catalyzer, stirring heating, back flow reaction 5 ~ 10h, add 10% sodium carbonate solution reaction, branch vibration layer, organic layer removes solvent under reduced pressure, add 10-25 doubly to measure 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtains hederagenin derivative.
Solvent described in above-mentioned preparation method is for being pyridine or toluene; Described catalyzer is pyridine or triethylamine in acylation reaction, is the vitriol oil or tosic acid in esterification or transesterification reaction.
Hederagenin of the present invention can adopt known preparation method to extract and obtains or directly buy and obtain from market from Chinese medicinal materials.
The present invention is taking hederagenin as raw material, obtains hederagenin derivative by acylation reaction, esterification or transesterification reaction, and this derivative can further obtain its salt with alkali reaction.The method is all high by productive rate and the purity of the semi-synthetic hederagenin derivative obtaining of hederagenin, can reach more than 95%, and preparation technology is simple, and feed stock conversion is high, is suitable for suitability for industrialized production, and easily applies.
The salt of hederagenin derivative of the present invention can be single salt, double salt or many salt.Can prepare by the following method: by hederagenin derivative 95% dissolve with ethanol, add 1-10% alkaline solution to regulate PH to 9-11 at-10 ~ 30 DEG C, the cooling solid of separating out, obtains the salt of hederagenin derivative.The salt of described hederagenin derivative can be hederagenin derivative sodium salt, hederagenin derivative sylvite or hederagenin derivative ammonium salt.Preferably the salt of hederagenin derivative is hederagenin derivative sodium salt or hederagenin derivative sylvite.
The invention allows for hederagenin derivative or its salt in the application of preparing in antidepressant drug.Be taking hederagenin derivative or its salt raw material as main active ingredient, add pharmaceutically acceptable carrier, make the acceptable formulation of pharmacy by conventional production method well known in the art; Described pharmaceutical acceptable carrier comprises Microcrystalline Cellulose, HPMC, gelatin, starch, dextrin, Magnesium Stearate, lactose, glucose, talcum powder, sodium-chlor, phosphate-buffered saline, glycerine, ethanol etc.; Described formulation can be tablet, capsule, granule, oral liquid, injection etc.The dosage of medicine of the present invention can be according to the variation such as type and severity of route of administration, patient's age, body weight, the disease for the treatment of, and its per daily dose can be that 100-600mg is comparatively suitable.
The present invention further verifies the pharmacologically active of hederagenin derivative or its salt, experiment shows, the activity of hederagenin derivative or its salt is higher than the salt of aglycon and aglycon, and its pharmacologically active has had raising clearly, dysthymia disorders is had to obvious therapeutic action, its pharmacological action is remarkable, and stable in properties can be used for preparing antidepressant medicine.
Embodiment
Further illustrate the present invention below by embodiment; following examples are the concrete embodiment of the present invention; but embodiments of the present invention are not subject to the restriction of following embodiment; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.
embodiment 1hederagenin-3, the preparation of 23-disuccinic acid ester
Take 28 grams of succinyl oxides and drop in three-necked bottle, add 1000 milliliters of toluene, 300 milliliters of triethylamines, stirring heating, in the time that temperature approaches backflow, adds 22 grams of hederagenins, back flow reaction 8 hours, removes solvent under reduced pressure, adds 450 milliliters of 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtains hederagenin-3,31 grams of 23-disuccinic acid esters.
embodiment 2hederagenin-3, the preparation of 23-disuccinic acid ester
Take 22 grams of hederagenins and drop in three-necked bottle, add 600 milliliters of pyridines, stir the lower toluene solution that contains 40 grams of succinyl dichlorides that drips, 60 DEG C are reacted 8 hours, the reaction 2 hours that adds water, branch vibration layer, remove solvent under reduced pressure, add 450 milliliters of 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtain hederagenin-3,32 grams of 23-disuccinic acid esters.
embodiment 3hederagenin-3, the preparation of 23-disuccinic acid ester
Take in 34 grams of succsinic acids, 22 grams of input three-necked bottles of hederagenin, add 1000 milliliters of toluene, 12 milliliters of the vitriol oils, stirring heating, in the time that temperature approaches backflow, adds, back flow reaction 8 hours, removes solvent under reduced pressure, adds 450 milliliters of 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtains hederagenin-3,32 grams of 23-disuccinic acid esters.
embodiment 4hederagenin-3, the preparation of 23-disuccinic acid ester
Take in 40 grams of Succinic acid dimethylesters, 22 grams of hederagenins, 2 grams of input three-necked bottles of tosic acid, add 1000 milliliters of toluene, stirring heating, back flow reaction 12 hours, adds 200 milliliters of reactions of 10% sodium carbonate solution 30 minutes, branch vibration layer, organic layer removes solvent under reduced pressure, adds 450 milliliters of 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtain hederagenin-3,25 grams of 23-disuccinic acid esters.
embodiment 5hederagenin-3, the preparation of 23-acetic ester
Take 25 grams of acetic acid chlorine and drop in three-necked bottle, add 1000 milliliters of toluene, 300 milliliters of triethylamines, add 22 grams of hederagenins, stirring heating, back flow reaction 5 hours, remove solvent under reduced pressure, add 450 milliliters of 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtain hederagenin-3,28 grams of 23-acetic ester.
embodiment 6hederagenin-3, the preparation of 23-acetic ester
Take in 18 grams of methyl acetates, 22 grams of input three-necked bottles of hederagenin, add 1000 milliliters of toluene, 2 grams of tosic acid, stirring heating, back flow reaction 12 hours, removes solvent under reduced pressure, add 450 milliliters of 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtains hederagenin-3,21 grams of 23-acetic ester.
embodiment 7prepare hederagenin-3, the disodium salt of 23-disuccinic acid ester
Make hederagenin-3 by embodiment 1,23-disuccinic acid ester, take 10g hederagenin-3,23-disuccinic acid ester is dissolved in 100ml dehydrated alcohol, add 3% sodium hydroxide solution to regulate PH to be about 11 10 DEG C of left and right, the cooling solid of separating out, washes with dehydrated alcohol after filtration, dry and obtain hederagenin-3, the disodium salt of 23-disuccinic acid ester.
Hederagenin-3, the structural confirmation of 23-bis-amber acid esters disodium salts
Its chemical structural formula is as follows:
ESI-MS(m/z):738[M
++Na]
+ ；
1H NMR(400MH
Z,CDCl
3) δ：0.99（s,6H）, 1.04 (s,9H) , 1.30 (s,3H) , 1.38—1.61 (m,16H,CH
2,CH), 1.80 (q,J=7.1, 2H), 2.01—2.04 (m,4H,CH
2), 2.43 (t,J=6.0 H), 2.53 (t,J=7.1 2H), 2.73 (t,J=7.1 2H), 2.83 (t,J=7.1 4H), 3.89 (t, J=7.0 H), 4.13 (s,2H), 5.29 (t,J=6.2 H)；
13C NMR(100MHz,CDCl
3)δ：33.8(C-1), 24.1(C-2), 75.3(C-3), 40.7(C-4), 53.4(C-5), 18.3(C-6), 33.1(C-7), 39.9(C-8), 47.7(C-9), 37.6(C-10), 23.8(C-11), 122.4(C-12), 143.7(C-13), 41.4(C-14), 29.1(C-15), 23.6(C-16), 46.6(C-17), 41.4(C-18), 46.6(C-19), 30.7(C-20), 34.2(C-21), 32.5(C-22), 66.0(C-23), 21.9(C-24), 15.9(C-25), 17.1(C-26), 25.9(C-27), 184.4(C-28), 26.9(C-29,C-30), 171.8(C-31,C-35), 31.0(C-32,C-36), 34.4(C-33,C-37), 178.0(C-34,C-38)。
embodiment 8
Feed intake by 1000 preparation units, get hederagenin-3,23-disuccinic acid ester 60g, Microcrystalline Cellulose 80g, starch 40 g, sodium starch glycolate 15g, micropowder silica gel 5g, make altogether 1000 capsules, specification: every containing main ingredient 60mg, theoretical weight 200mg.
Above-mentioned supplementary material is first crossed respectively 80 mesh sieves, take hederagenin derivative, Microcrystalline Cellulose starch by recipe quantity, sodium starch glycolate, mixes, with 80% medicinal alcohol softwood processed, cross 24 mesh sieves and granulate, under 60 DEG C of conditions, be dried 1 hour, the whole grain of 20 mesh sieves, add micropowder silica gel, filled capsules, obtains hederagenin-3,950,23-disuccinic acid ester gum capsule.
embodiment 9
Feed intake by 1000 preparation units, get hederagenin-3,23-disuccinic acid ester 180g, HPMC 120g, Microcrystalline Cellulose 50g, polyethylene glycol 6000 6g, Magnesium Stearate 4g, make altogether 1000, specification: every containing main ingredient 300mg, theoretical weight 360mg.
Above-mentioned supplementary material is first crossed respectively 100 mesh sieves, take main ingredient, HPMC, Microcrystalline Cellulose, polyoxyethylene glycol by recipe quantity, mix, with 95% medicinal alcohol softwood processed, cross 24 mesh sieves and granulate, under 60 DEG C of conditions, be dried 4 hours, the whole grain of 20 mesh sieves, adds Magnesium Stearate, compressing tablet, obtain hederagenin-3,912 of 23-disuccinic acid ester slow releasing tablet.
embodiment 10the experiment of hederagenin derivative to the therapeutic action of two kinds of depression model mouse
1, test materials
1.1 laboratory animal
Kunming mouse (6 week age, body weight 20 scholar 2g), male, provide (credit number: SCXK (Guangdong) 2003-2002, word 2008A006 checks and affirm in Guangdong) by Guangdong Medical Lab Animal Center.Animal rearing condition: temperature (23 DEG C scholar 2 DEG C).Buy back after rear adaptability is raised 3d and test.
1.2 medicines and reagent
Tested medicine: hederagenin derivative (HEDS), make and provide by Guangzhou rich Ji medicine bioengineering share Technology Co., Ltd., lot number: 20100413; Hederagenin (HED), is made and is provided by Guangzhou rich Ji medicine bioengineering share Technology Co., Ltd., lot number: 20101031; Hederagenin sodium (HEDN), is made and is provided by Guangzhou rich Ji medicine bioengineering share Technology Co., Ltd., lot number: 20100901.
Western medicine contrast medicine: Warner) (source: Pharmaceutical Co Ltd, Changzhou Pharmaceutical Factory No.4, specification: 25mg/ sheet, lot number: 201004083).
Chinese medicine contrast medicine: capsule for reliving liver and reliving upset (source: Chengdu Kanghong Medicine Group Co.ltd; Lot number: 100602; Specification: 0.36g/ grain)
Modeling medicine: serpentine injection liquid (source: Guangdong Bangmin Pharmaceutical Co., Ltd., specification 1mg1ml-1, lot number 090717).
1.3 laboratory apparatus
Electronic clinical thermometer (lot number: 00196505 producer: Babymatee development in science and technology center, Beijing); Multifunctional mouse autonomic activities instrument, mouse swimming device (self-control); Stopwatch, balance, gavage pin, opaque water vat.
reserpinization mouse model
2.1 experiment grouping and administrations
Mouse is divided into 8 groups at random by body weight, and 10 every group, by following method administration, administration volume is 0.2ml/10g, and after administration 1 h, every mouse peritoneal is injected serpentine 2.5mg/kg the last time.
Normal group: normally feed, do not give any medicine.
Model group: gavage gives distilled water, every day 1 time, gives 7d continuously.
Western medicine group: the Warner) solution that gavage gives to prepare in advance, by 10mg/kg dosed administration, every day 1 time, successive administration 7d.
Chinese patent medicine control group: the By Chinese Medicines that gavage gives to prepare in advance, by 296mg/kg dosed administration, every day 1 time, successive administration 7d.
HEDS high dose group: gavage gives HEDS liquid, dosage is 60mg/kg, every day 1 time, successive administration 7d.
HEDS low dose group: gavage gives HEDS liquid, dosage is 30mg/kg, every day 1 time, successive administration 7d.
HEDN group: gavage gives HEDN liquid, dosage is 60mg/kg, every day 1 time, successive administration 7d.
HED group: gavage gives HED liquid, dosage is 60mg/kg, every day 1 time, successive administration 7d.
2.2 index determinings and detection method
2.2.1 the detection abdominal injection serpentine of anus temperature immediately and after 4h, inserts mouse anal by electronic clinical thermometer probe, and the degree of depth enters anus completely with thermometer probe and is as the criterion, maintain at least 10s, record each group of mouse anus temperature, the difference that relatively administration group and control group anus temperature change, the results are shown in Table 1.
2.2.2 after akinetic observation abdominal injection serpentine 1h, it is that the circle of 7.5cm is observed 15s that mouse is put into diameter, calculates the each group of mouse rate that goes too far, and the results are shown in Table 1.
2.2.3 after the observation abdominal injection serpentine 1h of blepharoptosis, observe every group of animal number that mouse catacleisis is over half, the results are shown in Table 1.
2.2.4 mouse anus temperature drop-out value with mean ± standard deviation (
± s)) represent, measurement data is carried out the one-way analysis of variance of completely randomized design, adopts statistic software SPSS 13.0 to carry out statistical analysis.P<0.05 is for there being statistical significance.
2.3 result
As can be seen from Table 1, the anus temperature drop-out value of each administration group mouse and the difference of model group all have statistical significance, and wherein western medicine group and HEDS high dose group difference have highly significant meaning.
The respectively observation of group mouse index of table 1 (
± s, n=10)
| Group | n | Eyelid full cut-off or semi-closure number of animals | Catacleisis number of animals compares % | Number of animals does not go too far | The number of animals that do not go too far compares % | Mouse anus temperature drop-out value (DEG C) |
| Normal group | 10 | 0 | 0 | 0 | 0 | 0.93±0.38** |
| Model group | 10 | 10 | 100 | 10 | 100 | 3.79±1.32 |
| Western medicine group | 10 | 2 | 20 | 1 | 10 | 1.00±1.08** |
| Chinese medicine control group | 10 | 4 | 40 | 3 | 30 | 2.01±0.72* |
| HEDS high dose group | 10 | 3 | 30 | 2 | 20 | 1.46±1.29** |
| HEDS low dose group | 10 | 6 | 60 | 2 | 20 | 2.50±1.31* |
| HEDN group | 10 | 7 | 60 | 4 | 40 | 2.85±1.02* |
| HED group | 10 | 6 | 90 | 7 | 70 | 3.220±1.43 |
Note: with model group comparison, * P<0.05, * * P<0.01.
3, forced swimming Stress Depression Model
3.1 experiment grouping and administrations
Mouse is divided into 8 groups at random by body weight, and 10 every group, by following method administration, administration volume is 0.4ml/10g,
Normal group: normally feed, do not give any medicine.
Model group: gavage gives distilled water, every day 1 time, gives 14d continuously.
Western medicine group: the Warner) solution that gavage gives to prepare in advance, by 10mg/kg dosed administration, every day 1 time, successive administration 14d.
Chinese patent medicine control group: the By Chinese Medicines that gavage gives to prepare in advance, by 296mg/kg dosed administration, every day 1 time, successive administration 14d.
HEDS high dose group: gavage gives HEDS liquid, dosage is 60mg/kg, every day 1 time, successive administration 14d.
HEDS low dose group: gavage gives HEDS liquid, dosage is 30mg/kg, every day 1 time, successive administration 14d.
HEDN group: gavage gives HEDN liquid, dosage is 60mg/kg, every day 1 time, successive administration 14d.
HED group: gavage gives HED liquid, dosage is 60mg/kg, every day 1 time, successive administration 14d.
3.2 index determinings and detection method
3.2.1 autonomic activities is tested each group the last time after administration 1h, and mouse is put to people's autonomic activities instrument, measures immediately the autonomic activities situation of mouse in 10min.The results are shown in Table 2;
3.2.2 mouse forced swimming is except normal group, respectively organize the last time after administration 1h, mouse is put into the opaque glass cylinder of high 20cm, diameter 10cm, depth of water 10cm, 20 DEG C of left and right of water temperature, 8: 00～10: 00 every day time period forced swimming 5min, forced swimming continues 14d.Normal group mouse, except necessary mouse cage is clean, is left intact.Observe each group of non-swimming time (mouse 6 min that swim, the dead time after accumulative total in 4min) at 1d, 7d, 14d.Test result is in table 3.
3.3 data statisticss and processing
Each group data all represent with mean ± standard deviation (± s)), and measurement data is carried out the one-way analysis of variance of completely randomized design, and employing statistic software SPSS 13.0 carries out statistical analysis.P<0.05 is for there being statistical significance.
3.4 experimental result
Shown in table 2 and table 3, respectively organize statistical indicator compared with normal group, the equal not statistically significant of difference.
Table 2 mouse autonomic activities situation (
± s, n=10)
Note: compared with normal group, respectively organize the equal not statistically significant of difference, prompting HEDS to maincenter without excitation.
The table 3 forced swimming mouse dead time (
± s, n=10) unit (second)
Note: with model group comparison, * P<0.05.
interpretation:
Serpentine is a kind of vesica reuptake inhibitor, and it stays outside vesica mediator, is easily degraded by monoamine oxidase, thereby catecholamine (norepinephrine, suprarenin, Dopamine HCL and 5-HT) is exhausted, causes behavior and physiological variation.In this experiment, high and low dose HEDS can significantly reduce the ptotic degree of closing one's eyes of model mice, points out its mechanism of action may be relevant to excited alpha-adrenergic effect.HEDS high and low dose all can reduce the temperature decline amplitude that serpentine causes, points out this medicine also can play a role by excited beta-adrenergic nerve.
Desperate swimming test is that the classical depression model mice that utilizes desperate behavior to set up, for the preliminary assessment of antidepressant drug drug effect according to the pathogenic theory of environmental factors.Our experimental result shows: high and low dose HEDS can obviously reduce forced swimming model mice motionless time length of despair in water, and prompting HEDS has good therapeutic action.
The treatment result of two kinds of depression model mices is shown, under Isodose, HEDS demonstrates stronger antidepressant effect than HEDN and HED, particularly has more obvious advantage with respect to HED.
Claims (9)
1. a hederagenin derivative, has following general formula:
Wherein:
R
1and R
2identical or different, independent of each other being expressed as-OR ', R ' is-CO (CH
2)
ncOOH, wherein n=1-3;
R
3for H, Na or K.
2. hederagenin derivative according to claim 1, is characterized in that, described R ' is-CO (CH
2)
2cOOH.
3. the preparation method of hederagenin derivative claimed in claim 1, it is characterized in that, taking hederagenin as raw material, pass through acylation reaction, esterification or transesterification reaction obtain, concrete grammar is: take appropriate carboxylic acid halides, acid anhydrides, carboxylic acid or carboxylicesters, add 20 ~ 50 times of amount solvents, 0.05 ~ 15 times of amount catalyzer, stirring heating, add 0.1 ~ 1 times of amount hederagenin, back flow reaction 5 ~ 10h, remove solvent under reduced pressure, add 10-25 doubly to measure 95% ethanol, stirring and dissolving, with activated carbon decolorizing, filtered while hot, decompression recycling ethanol, washing, obtain hederagenin derivative.
4. the preparation method of hederagenin derivative according to claim 3, is characterized in that, described solvent is pyridine or toluene.
5. the preparation method of hederagenin derivative according to claim 3, is characterized in that, described catalyzer is pyridine, triethylamine, the vitriol oil or tosic acid.
6. hederagenin derivative according to claim 1 or its salt are in the application of preparing in antidepressant drug.
7. hederagenin derivative according to claim 6 or its salt, in the application of preparing in antidepressant drug, is characterized in that, the salt of described hederagenin derivative is single salt, double salt or many salt.
8. hederagenin derivative according to claim 6 or its salt are in the application of preparing in antidepressant drug, it is characterized in that, the salt of described hederagenin derivative is hederagenin derivative sodium salt, hederagenin derivative sylvite or hederagenin derivative ammonium salt.
9. hederagenin derivative according to claim 8 or its salt, in the application of preparing in antidepressant drug, is characterized in that, the salt of described hederagenin derivative is hederagenin derivative sodium salt or hederagenin derivative sylvite.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210157859.4A CN102659905B (en) | 2012-05-21 | 2012-05-21 | Hederagenin derivative, and preparation method and application thereof |
| PCT/CN2013/075876 WO2013174245A1 (en) | 2012-05-21 | 2013-05-20 | Hederagenin derivative and preparation method and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210157859.4A CN102659905B (en) | 2012-05-21 | 2012-05-21 | Hederagenin derivative, and preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102659905A CN102659905A (en) | 2012-09-12 |
| CN102659905B true CN102659905B (en) | 2014-07-30 |
Family
ID=46769513
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210157859.4A Active CN102659905B (en) | 2012-05-21 | 2012-05-21 | Hederagenin derivative, and preparation method and application thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN102659905B (en) |
| WO (1) | WO2013174245A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102659905B (en) * | 2012-05-21 | 2014-07-30 | 广州博济医药生物技术股份有限公司 | Hederagenin derivative, and preparation method and application thereof |
| WO2016193309A1 (en) * | 2015-06-01 | 2016-12-08 | Dsm Ip Assets B.V. | New bis esters of ivy sapogenins for ruminants |
| CN105481935B (en) * | 2015-11-21 | 2019-06-07 | 吉林省中医药科学院 | Hederagenin derivative and its application in the drug of preparation prevention and treatment senile dementia |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101074259A (en) * | 2007-03-08 | 2007-11-21 | 江苏省中国科学院植物研究所 | Saponin compound, its production and use |
| CN101125880A (en) * | 2007-08-13 | 2008-02-20 | 中国科学院新疆理化技术研究所 | Hedera saponin and its preparation method and use |
| CN101214250A (en) * | 2008-01-07 | 2008-07-09 | 中国人民解放军第二军医大学 | Use of helexin and its derivatives in the preparation of antidepressant products |
| CN102068445A (en) * | 2010-04-30 | 2011-05-25 | 江西中医学院 | Method for preparing pulsatilla chinensis (Bunge) Regel saponin matter and application of pulsatilla chinensis (Bunge) Regel saponin matter in preparation of antischistosomal medicament |
| CN102199184A (en) * | 2011-04-07 | 2011-09-28 | 江西本草天工科技有限责任公司 | Hederasaponin derivative, preparation method of salts thereof and application thereof to resisting tumor |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX9606493A (en) * | 1994-06-24 | 1997-03-29 | Nippon Shinyaku Co Ltd | Triterpene derivative and medicinal composition. |
| CN102659905B (en) * | 2012-05-21 | 2014-07-30 | 广州博济医药生物技术股份有限公司 | Hederagenin derivative, and preparation method and application thereof |
-
2012
- 2012-05-21 CN CN201210157859.4A patent/CN102659905B/en active Active
-
2013
- 2013-05-20 WO PCT/CN2013/075876 patent/WO2013174245A1/en active Application Filing
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101074259A (en) * | 2007-03-08 | 2007-11-21 | 江苏省中国科学院植物研究所 | Saponin compound, its production and use |
| CN101125880A (en) * | 2007-08-13 | 2008-02-20 | 中国科学院新疆理化技术研究所 | Hedera saponin and its preparation method and use |
| CN101214250A (en) * | 2008-01-07 | 2008-07-09 | 中国人民解放军第二军医大学 | Use of helexin and its derivatives in the preparation of antidepressant products |
| CN102068445A (en) * | 2010-04-30 | 2011-05-25 | 江西中医学院 | Method for preparing pulsatilla chinensis (Bunge) Regel saponin matter and application of pulsatilla chinensis (Bunge) Regel saponin matter in preparation of antischistosomal medicament |
| CN102199184A (en) * | 2011-04-07 | 2011-09-28 | 江西本草天工科技有限责任公司 | Hederasaponin derivative, preparation method of salts thereof and application thereof to resisting tumor |
Non-Patent Citations (5)
| Title |
|---|
| 蓣知子的化学成分研究 I.白木通种子中的3位单糖链皂甙化合物;马双成等;《中草药》;19941231;第25卷(第4期);171-174、222 * |
| 蓣知子的化学成分研究 II.白木通种子中的3,38位双糖链皂苷化合物;马双成等;《中草药》;19941231;第25卷(第11期);613、616 * |
| 马双成等.蓣知子的化学成分研究 I.白木通种子中的3位单糖链皂甙化合物.《中草药》.1994,第25卷(第4期),171-174、222. |
| 马双成等.蓣知子的化学成分研究（IV）.《中草药》.1995,第26卷(第3期),122-124、167. * |
| 马双成等.蓣知子的化学成分研究II.白木通种子中的3 38位双糖链皂苷化合物.《中草药》.1994 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102659905A (en) | 2012-09-12 |
| WO2013174245A1 (en) | 2013-11-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103209704B (en) | Organic compound | |
| CN107213466A (en) | A kind of post aromatic hydrocarbons compound, its preparation method, pharmaceutical composition and purposes | |
| CN102274227B (en) | Application of tetrandrine in preparation of drug for prevention and/or treatment of depression | |
| CN101704874A (en) | Pentacyclic triterpene and melbine salt of derivative thereof, preparation method and medical application of pentacyclic triterpene | |
| CN102659905B (en) | Hederagenin derivative, and preparation method and application thereof | |
| CN101823956B (en) | Diisopropylamine fenofibrate, preparation method thereof, pharmaceutical composition and application thereof | |
| CN101817862A (en) | Ursolic acid-3-O-beta-D-pyranglucuronide and derivatives thereof, and preparation method and medicinal application thereof | |
| WO2009067891A1 (en) | Water-soluble triterpenephenol compounds having antitumor activity and the preparation thereof | |
| CN102093462B (en) | Preparation method and application of 1alpha, 2alpha-dyhydroxyl oleanolic acid | |
| CN102875617A (en) | Geniposide derivative, preparation method thereof and application of geniposide derivative to inflammation resistance | |
| CN101773475B (en) | Preparation method of capsicine micro spheres | |
| JP2016508489A (en) | Protopanaxadiol derivative, production method thereof and application thereof | |
| CN101429191B (en) | Use of substituted tetrahydroisoquinoline derivatives | |
| CN102391352B (en) | Amino acid derivatives of rotundic acid and application of derivatives in preparation of antitumor medicines | |
| CN104877000A (en) | Ursolic acid derivative and preparation method and application thereof | |
| JP2022517743A (en) | Acetylsalicylic acid derivatives and their use | |
| CN105859823A (en) | Application of ilicis routundae cortex acid ester derivatives in preparation of anti-tumor drugs | |
| CN105777520A (en) | Novel chalcone compound Chalcone-1203, and composition, preparation method and application thereof | |
| CN102786458B (en) | Pyrrole formamide derivative, and preparation method and application thereof | |
| CN104276960B (en) | Tapentadol hydrochloride and celecoxib eutectic and combinations thereof thing and preparation method | |
| CN105534990A (en) | Application of cardiospermum halicacabum extract in preparation of medicinal preparations for treating diabetes | |
| CN101386617A (en) | Substituted tetrahydroisoquinoline derivatives, their preparation methods and pharmaceutical compositions containing them | |
| CN102793696B (en) | Application of butylphthalide in preparation of medicament for treating bronchial asthma | |
| CN103288821A (en) | Palmatine derivative and preparation method and application thereof | |
| CN104829679A (en) | Water-soluble celastrol derivative and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: 510670 Building 2, 3, 4 and 5, No. 62, Nanxiang 1st Road, Science City, Huangpu District, Guangzhou, Guangdong Province Patentee after: Boji Pharmaceutical Technology Co.,Ltd. Address before: 510635 Guangdong Province, Guangzhou Tianhe North Road, No. 609 Hua Hui Hua s Plaza Pavilion room 1707 Patentee before: GUANGZHOU BOJI MEDICAL BIOTECHNOLOGY Co.,Ltd. |
|
| CP03 | Change of name, title or address |