CN105481935B - Hederagenin derivative and its application in the drug of preparation prevention and treatment senile dementia - Google Patents
Hederagenin derivative and its application in the drug of preparation prevention and treatment senile dementia Download PDFInfo
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- CN105481935B CN105481935B CN201510813484.6A CN201510813484A CN105481935B CN 105481935 B CN105481935 B CN 105481935B CN 201510813484 A CN201510813484 A CN 201510813484A CN 105481935 B CN105481935 B CN 105481935B
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- hederagenin
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- senile dementia
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- 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
Abstract
The invention discloses from the dry root of Dipsacaceae plant teasel (Dipsacus asperoides C.Y.Cheng et T.M.Ai) extraction separation and purification obtain hederagenin as lead compound, chemically reacted be prepared for a series of derivatives accordingly.The derivative is compared with hederagenin parent nucleus, it will be apparent that increases solubility, improves drug dissolution.Animal experiments prove that hederagenin derivative 2- [(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acyl group]-ethylaminoethanol has the function of preventing and treating senile dementia well.
Description
Technical field
The present invention relates to a kind of hederagenin obtained from natural drug, and the preparation method of synthesis of derivatives,
It is specifically a kind of using the chemical component extracted in Chinese medicine as lead compound, prepares 2- [(3 β, 4a) -3,23- diacetyl
Base-olive -12- alkene -28- acyl group]-ethylaminoethanol.Pharmacodynamic experiment proves that the derivative has the work of prevention and treatment senile dementia
With belonging to pharmaceutical technology field.
Background technique
Hederagenin is from Dipsacaceae plant teasel (Dipsacus asperoides C.Y.Cheng et
T.M.Ai extracted in dry root), purifying, separation, alkaline degradation and a kind of pentacyclic triterpenoid obtained.Lou Lili etc.
Research have shown that hederagenin have prevent and treat senile dementia pharmacological activity (Lou Lili etc. resists senile
Dull-witted Natural products research progress, Shenyang Pharmaceutical University's journal, 2010, volume 27, the 1st phase, page 76).Yang Zhonglin also applies
Patent report hederagenin have the function of prevention and senile brain dementia of curing the disease (application number:
201210205561.6, ivy soap former times member is applied in the drug that preparation resists senile brain dementia).But due to ivy soap
Solubility is smaller in water for aglycon, and bioavilability is not high, therefore hederagenin is converted to one kind with stronger life
The compound of object availability has very big Development volue.So we are using hederagenin as lead compound, with acetic acid
Acid anhydride is raw material, intermediate (3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acid is generated in pyridine, then in dichloro
The acyl chlorides of generation 28 is reacted in methane with oxalyl chloride, then reacts production final product 2- with ethylaminoethanol in the presence of triethylamine
[(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acyl group]-ethylaminoethanol.So as to improve the dissolution in water again
Property, dissolution rate is increased, its pharmacological activity is enhanced.
It, which has the work for preventing and treating senile dementia, is shown to the pharmacodynamic study of amino alcohol derivative in the application
With.Have some pentacyclic triterpenoids of document report, such as ursolic acid (make by the pharmacology of Cheng Xiaohua, pentacyclic triterpene saponin
With progress, Chinese herbal medicine, 2007, volume 38,5 phases, page 792), the saponins compound that separates in Radix Polygalae (Ni Jian is new etc.,
Polygala triterpenoid saponin and its bioactivity research progress, Chinese medicine, 2011, volume 37, the 2nd phase, page 317) etc.
With the activity for preventing and treating senile dementia, it is an object of the invention to carry out structure of modification, preparation to hederagenin
Hederagenin acyl amino alcohol derivative, to find the stronger derivative of activity with prevention and treatment senile dementia effect
Object.
Before the present invention completes, there are no the acyl amino alcohol derivatives of document report hederagenin to have in advance
Anti- and treatment senile dementia report does not find application of the derivative in the drug of preparation prevention and treatment senile dementia effect yet
Report.
Summary of the invention
The invention reside in one kind is provided using hederagenin as lead compound, which is Hederagenin
Member and acetic anhydride generate intermediate product (3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acid in pyridine, and is produced from centre
Object reacts the acyl chlorides of generation 28 with oxalyl chloride in methylene chloride again, then reacts production with ethylaminoethanol in the presence of triethylamine
Final product 2- [(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acyl group]-ethylaminoethanol has prevention and treatment old
Dull-witted effect.
The purpose of the present invention is be achieved by the following technical programs:
A kind of hederagenin derivative with prevention and treatment senile dementia effect, structural formula are as follows:
It is as described above that there is the hederagenin derivative for preventing and treating senile dementia effect to be obtained by following methods
It arrives:
1, ethyl alcohol extract Chinese medicine teasel root, it is purified, separation, acid degradation and obtain chemical compounds I [(3 β, 4a) -3,23- dihydroxy
Base olive -12- alkene -28- acid], i.e. hederagenin.
2, hederagenin and acetic anhydride are stirred to react for 80 DEG C of normal pressure in pyridine, after reaction, are recovered under reduced pressure molten
Agent adds water, is 5 with dilute hydrochloric acid tune PH, and filtration, filter cake is washed with water to colourless, is dissolved, is washed with water with ethyl acetate, then uses carbon
The washing of sour sodium, recycling ethyl acetate obtain compound ii [(3 β, 4a) -3,23- diacetyl to dry, then with ethyl alcohol recrystallization, drying
Base-olive -12- alkene -28- acid].
3, ice bath reacts 1 hour compound ii in methylene chloride with oxalyl chloride, then reacts at room temperature, end of reaction
Afterwards, it adds methylene chloride and is recovered under reduced pressure.Then it is dissolved again with methylene chloride, is 9-10 with triethylamine tune PH, adds ethanol amine, room temperature is anti-
It answers 1 hour, adds water, be 3-4 with dilute hydrochloric acid tune PH, recycling design, filtering, filter cake ethyl alcohol recrystallization is dry, with silicagel column point
From obtaining final product compound III { 2- [(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acyl group]-amino second
Alcohol }.
Above-described 2- [(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acyl group]-ethylaminoethanol has
The effect of senile dementia is prevented and treated, can be applied in the drug of preparation treatment senile dementia.
The invention has the characteristics that being chemically modified to natural products hederagenin, parent nucleus and ivy soap are obtained
The similar derivative of aglycone structure, proves through pharmacological evaluation, has the function of preventing and treating senile dementia.Triterpenic acid derivative is filled up
Blank in terms for the treatment of senile dementia.For the derivative compared with parent nucleus hederagenin, solubility in water is big simultaneously
Big enhancing, improves the solubility of hederagenin, and pharmacological activity is significantly improved, and has very high medicinal valence
Value.
Hederagenin derivative has the function of preventing and treating senile dementia, these pharmacological actions, by following
Pharmacodynamics test example is confirmed.Final product compound III { 2- [(3 β, 4a) -3,23- diacetyl-olive -12- alkene -
28- acyl group]-ethylaminoethanol } hereinafter referred to as compound III.
1, compound III is to AlCl3Cause the influence of memory deficits in mice
Mouse 70 are taken, is randomly divided into 7 groups, is grouped by table 1.1st day to the 7th day, physiology was subcutaneously injected in control group daily
Salt water, remaining each group mouse subcutaneous injection AlCl350mg/kg.Medication group is distinguished continuous gavage and is administered 2 weeks.It carries out keeping away dark test,
Mouse enters the errors number in darkroom in record 3min, for 24 hours after Memory result test with errors number and wrong percentage.Experiment
It the results are shown in Table 1.
Table 1, compound III are to AlCl3Cause the influence (n=10, X ± S) of memory deficits in mice
* compared with normal group, P < 0.01 * P < 0.05, * *；△ compared with model group,△P < 0.05,△△P<0.0l
Illustrate the metering of compound III difference to AlCl3It causes memory disorders to have different degrees of confrontation effect, can be reduced small
The wrong frequency and error generation rate of mouse.
2, compound III causes the influence of memory deficits in mice to hyoscine
Mouse 70 are taken, is randomly divided into 7 groups, is grouped by table 2.1st day to the 7th day, control group and model group to distilled water,
Remaining each group is administered by table 2.Once a day, continuous 7 days, after last dose 1h, normal group was given physiological saline 0.1ml/10g,
Remaining each group gives scopolamine hydrobromide 3mg/kg, and Jumping test is carried out after 10min, and training 3min carries out test result afterwards for 24 hours.
It the results are shown in Table 2.
Table 2, compound III cause the influence (n=10, X ± S) of memory deficits in mice to hyoscine
* compared with normal group, P < 0.01 * P < 0.05, * *；△Compared with model group,△P < 0.05,△△P<0.0l
More normal group of scopolamine hydrobromide group mouse wrong times dramatically increase, and medication group considerably reduces the mistake of mouse
Accidentally number, has apparent antagonism to memory deficits in mice caused by scopolamine hydrobromide group, hence it is evident that reduce the mistake of mouse
Accidentally frequency and error generation rate.
3, compound III causes the influence of memory deficits in mice to 30% ethyl alcohol
Mouse 70 are taken, is randomly divided into 7 groups, is grouped by table 3.1st day to the 7th day, control group and model group to distilled water,
Remaining each group is administered by table 3.Once a day, continuous 7 days, after last dose 1h, normal group was given physiological saline 0.1ml/10g,
Remaining each group gives 30% ethyl alcohol, carries out Jumping test after 15min, in test record 5min per mouse errors number.As a result see
Table 3.
Table 3, compound III cause the influence (n=10, X ± S) of memory deficits in mice to 30% ethyl alcohol
* compared with normal group, P < 0.01 * P < 0.05, * *；△Compared with model group,△P < 0.05,△△P<0.0l
30% more normal group of ethanol group mouse wrong times dramatically increase, and for medication group in addition to low dose of general flavone, remaining is each
Group has apparent antagonism to memory deficits in mice caused by 30% ethyl alcohol.
4, compound III and composition are to Senlie dementia model mouse brain mitochondrial superoxide dismutase SOD activity, third
The influence of dialdehyde (MDA) content and brain coefficient.
Mouse 70 are taken, Normal group and model group are randomly divided into.Model group is to A1C13Solution, starts to press for 70 days
2g/L A1C1 is used always in 400mg/kg/d stomach-filling later3Solution is drunk；The distilled water of Normal group stomach-filling equivalent.By model
Group is randomly divided into 6 groups, by shown in table 4, gastric infusion 60 days, and the distilled water that Normal group Model of Dementia group is filled to measure.Entirely
Experimentation avoids contacting with aluminum products.Mouse is put to death, brain tissue is taken out rapidly in ice bath, and accurately weigh, measures respectively
SOD, MDA and calculating brain coefficient.Experimental result is shown in Table 4.
Table 4, compound III influence (n=10, the X of active, MDA content and brain coefficient to Senlie dementia model mouse brain SOD
±S)
* compared with normal group, P < 0.01 * P < 0.05, * *；△ compared with model group,△P < 0.05,△△P<0.0l
Model control group brain SOD activity reduces, and MDA content increases, and brain coefficient reduces (P < 0.05).Compared with model group,
The high, medium and low dosage group SOD activity of compound III increases, and MDA content reduces, and illustrates that there is compound III apparent antioxygen to be turned into
With the excess metabolism of improvement free radical in vivo.Increase SOD content, enhance oxidation resistance, accelerate the removing of free radical, presses down
Peroxidization processed inhibits Peroxidation Product MDA to generate and remove the effect of excessive MDA, to illustrate that compound III has
The effect of stronger anti-encephalatrophy.
5, influence of the compound III to Senlie dementia model acetyl choline content.
Mouse 70 are taken, Normal group and model group are randomly divided into.Model group is to A1C13Solution, starts to press for 70 days
2g/L A1C1 is used always in 400mg/kg/d stomach-filling later3Solution is drunk；The distilled water of the appearances such as Normal group stomach-filling.By model
Group is randomly divided into 6 groups, and by shown in table 5, gastric infusion 60 days, Normal group Model of Dementia group was filled with isometric distilled water.
Whole experiment process avoids contacting with aluminum products.Rat sacrificed by decapitation is opened rapidly cranium removing brain tissue (removal cerebellar tissue), is taken
It is rinsed in the brain tissue physiological saline of part, removes blood, filter paper is wiped dry, and cold saline is added and is put into homogenate tube and fills in ice bath
Divide and grind, 10% brain homogenate is made, is centrifuged, takes supernatant colorimetric method for determining brain tissue enzyme acetylcholine content.Experimental result
It is shown in Table 5.
The influence (n=10, X ± S) of table 5, compound III to Senlie dementia model acetyl choline content
* compared with normal group, P < 0.01 * P < 0.05, * *；△ compared with model group,△P < 0.05,△△P<0.0l
Each treatment group and model group compare, and acetyl choline content reduces, and has significant difference.
The above pharmacodynamics test shows that compound III can improve mouse memory, reduces error generation rate, and SOD can be made living
Property increase, MDA content reduce, reduce acetyl choline content, illustrate compound III have the function of prevention and treatment senile dementia.
In addition, from pharmacodynamic experiment result it is also seen that after structural modification the prevention and treatment of its derivative compound III it is old
Dull-witted activity is apparently higher than its guide's compound hederagenin, illustrates that derivative is not only tied compared with its lead compound
Structure is improved, and improves activity, truly has prominent feature and significant technological progress.
Below with reference to embodiment, invention is further described in detail.But following embodiments is only letter of the invention
Easy example, does not represent or limits the scope of the present invention, and protection scope of the present invention is subject to claims.
Specific embodiment
Example 1
The preparation of (3 β, 4a) -3,23- dihydroxy olive -12- alkene -28- sour (chemical compounds I, hederagenin)
Teasel root medicinal material 1kg is taken, is extracted 3 times with 8 times of 75% alcohol refluxs of amount.3 hours every time, merges extracting solution three times, add
Entering 30g calcium oxide, stir, stand overnight, filters, filtrate is 6-7 with dilute hydrochloric acid acid tune PH, and 200g active carbon is added, it stirs,
Filtration, filtrate recycling ethanol to no alcohol taste add water to 2000ml, by processed macroporous resin column, are first with containing pH value
12 20% ethyl alcohol washes 3 times of column volumes, then is washed to neutrality, finally with 70% ethanol elution, collects 70% eluent, and depressurize
It is concentrated to dryness；It is hydrolyzed 3 hours with 12 times of amounts of 40% ethyl alcohol of 2N hydrochloric acid.Filtration, discards hydrolyzate, filter cake is washed with deionized water
To neutrality；It is heated to boiling with 95% ethyl alcohol again, adds the medicinal carbon of 50g, filter while hot, filtrate decompression concentration and recovery, drying,
Obtain total aglycone of himalayan teasel roots, content 92.8%.Total aglycone of himalayan teasel roots is taken, is dissolved by heating with 90% ethyl alcohol, recrystallizes 3 times, obtains compound
I, hederagenin.Yield 3.3%, content 96.4%.White powder, mp:331~333 DEG C；IR(KBr)νmax: 3453,
3307,2583,3009,2943,2913,2882,2851,1698,1435,13881378,1303,1268,1327,1232,
1163,1143,1207,1189,1037,1012,988,972,960,813,779,730cm-1.HR-ESI-MSm/z:
472.4061(calcd.472.7038,C30H49O4[M+H]+)；Molecular formula is C30H48O4；Elemental analysis: measured value, C are
75.97%, H 10.25%, O 13.78%；Calculated value: C 76.22%, H 10.24%, O 13.54%.
Example 2
(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- sour (compound ii) preparation:
Compound N 1 (RA, 4.72g) 10mmol is taken, adds pyridine 200mL, acetic anhydride 100mL is reacted at 80 DEG C, examined with TLC
It surveys reaction end and solvent is recovered under reduced pressure after completion of the reaction, add water to 250mL, be 5 with dilute hydrochloric acid tune pH, filtration, filter cake water
It is washed till colourless, is dissolved, be washed with water 2 times, each 100mL with ethyl acetate 250mL, then wash 3 times with 10% sodium carbonate, every time
100mL, then washed 1 time with the hydrochloric acid 100mL of 1mol/L, it is finally washed with water 2 times, each 100mL, recycling ethyl acetate is extremely
It is dry, add ethyl alcohol 300mL to recrystallize, dry compound ii (3.88g).Yield 69.9%.White powder；298~299 DEG C of mp；
IR(KBr)νmax:3 597,3 443,2 955,2 873,1 727,1 704,1 472,1 370,1 036,924cm-1；HR-
ESI-MS m/z:557.380 4(calcd.C34H53O6,557.379 1[M+H]+)；Molecular formula is C34H52O6；Elemental analysis: real
Measured value, C 72.99%, H 9.51%, O 17.50%；Calculated value: C 73.34%, H 9.42%, O 17.24%.
Example 3
The system of 2- [(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acyl group]-ethylaminoethanol (compound III)
It is standby
Compound N 2 (0.723g) 1.3mmol is taken, is dissolved with methylene chloride 15mL, oxalyl chloride 1.2mL, ice bath reaction is added
Then 1h reacts at room temperature again, detect reaction end with TLC, after completion of the reaction, 30 DEG C are concentrated to dryness.Add dichloromethane
Alkane is recovered under reduced pressure, and 3 times repeatedly, each 50mL, is dissolved with methylene chloride 8mL, is 9-10 with triethylamine tune pH, adds ethanol amine
0.8mL reacts at room temperature 1.5h, adds water 50mL, is 3-4, recycling design, filtering, filter residue ethyl alcohol 300mL weight with dilute hydrochloric acid tune pH
Crystallization, it is dry, it is separated with silica gel column chromatography, is solvent elution with petroleum ether (60-90 DEG C)-ethyl acetate (1:3), merges phase
Same component, recycling design, dry compound III (0.590g).Yield 75.8%；White powder；Mp201~303 DEG C；IR
(KBr)νmax:3 597,3 443,2 955,2 873,1 727,1 704,1 472,1 370,1 036,924cm-1；HR-ESI-
MS m/z:622.3985(Calcd.622.402 9,C36H57NO7Na[M+Na]+)；Molecular formula is C36H57NO6；Elemental analysis: real
Measured value, C 71.96%, H 9.60%, N 2.35%, O 16.09%；Calculated value: C 72.08%, H 9.58%, N
For 2.34%, O 16.00%.
Claims (2)
1. a kind of hederagenin derivative 2- [(3 β, 4a) -3,23- diacetyl-olive -12- alkene -28- acyl group]-ammonia
Base ethyl alcohol, structure feature are as follows:
2. application of the hederagenin derivative according to claim 1 in the drug of preparation prevention and treatment senile dementia.
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| CN111333694B (en) * | 2020-04-28 | 2022-04-26 | 吉林省中医药科学院（吉林省中医药科学院第一临床医院） | Application of hederagenin derivative in medicine for resisting myocardial anoxia reoxygenation injury |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101157715A (en) * | 2007-11-20 | 2008-04-09 | 沈阳化工学院 | Ursolic acid chemical modified compound amino alcohol having antitumor activity |
| CN102659905A (en) * | 2012-05-21 | 2012-09-12 | 广州博济医药生物技术股份有限公司 | Hederagenin derivative, and preparation method and application thereof |
| CN102697791A (en) * | 2012-06-20 | 2012-10-03 | 杨中林 | Application of hederagenin in preparation of medicine for resisting senile dementia |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101157715A (en) * | 2007-11-20 | 2008-04-09 | 沈阳化工学院 | Ursolic acid chemical modified compound amino alcohol having antitumor activity |
| CN102659905A (en) * | 2012-05-21 | 2012-09-12 | 广州博济医药生物技术股份有限公司 | Hederagenin derivative, and preparation method and application thereof |
| CN102697791A (en) * | 2012-06-20 | 2012-10-03 | 杨中林 | Application of hederagenin in preparation of medicine for resisting senile dementia |
Non-Patent Citations (1)
| Title |
|---|
| 抗老年性痴呆天然产物研究进展;娄丽丽等;《沈阳药科大学学报》;20100131;第27卷(第1期);第76-79 * |
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