CN101486743A - Novel iridoid compound with anti-Alzheimer's disease function - Google Patents
Novel iridoid compound with anti-Alzheimer's disease function Download PDFInfo
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Abstract
The invention discloses a serial of iridoids compounds with the structural formula (I), the application of the compounds in preparing medicaments applied to the prevention or treatment of nervous system degenerative disorders such as senile dementia and the like, the medical compositions containing the compounds and a preparation method of the compounds. The structural formula is as shown above, wherein, various groups are defined in the instruction.
Description
Technical field
The present invention relates to the application of a series of iridoids in preventing nerve degenerative diseases such as senile dementia.Be raw material with cape jasmine and radix scrophulariae respectively, obtain a series of iridoids by multiple separation method, with the transgenic fly is the screening active ingredients that model carries out the anti-senile dementia medicine, the result shows, these compounds can improve the ability of learning and memory of senile dementia transgenic fly effectively, show that these compounds have the effect of nervous system degenerative diseases such as obvious treatment senile dementia and good research and development prospect.
Background of invention
Senile dementia is a kind of central nervous system degenerative disease based on carrying out property cognitive disorder and memory infringement
[1]Patient's quality of life is low, and the course of disease is long and need the special messenger to nurse all the time during one's sickness, adds the ANOMALOUS VARIATIONS of patient's mood and behavior poorness, causes great economy for family members and society and bears at heart
[1]The development of anti-senile dementia disease drug has caused global great attention.Set up now many relevant bioactivity screenings and appraisement system, the fruit bat in the whole animal model is one of model animals of knowing the most of people.The advantage that has other animal models not compare, as: individual space occupy-place minimum (a reagent bottle in can cultivate thousands of fruit bats), low, the easy cultivation of feeding cost, reproduction speed is fast and short (about 50 days of reproductivity strong (screening flux height), sample consumption few (5-50mg), life cycle, the active testing cycle is short), the deterioration of neurons relevant with the age be obvious, is that nerve degenerative diseases such as senile dementia is studied and the ideal model of drug screening
[3]
Iridoid belongs to the monoterpenes compound, is distributed widely in the dicotyledonss such as radix scrophulariae, cape jasmine, the bark of eucommia, psyllium, bark of ash, because its various pharmacologically active enjoys investigator's concern.Bibliographical information, Geniposidic acid has tangible negative inotropic action, negative chronotropic effect and the effect of negativity coronary artery notes rate to rat heart, and the prompting iridoid is the significant effect of performance probably in the treatment of cardiovascular disorder
[4]One new iridoid glycoside compounds gelsemiol-6 '-trans-cageoyl-glucoside is arranged among the verbena Verbenalittoralis, the PC12D cell experiment is shown 30 μ molL
-1This compound to nerve growth factor (2ngmL
-1) the PC12D cell axon growth of mediation has 10% enhancement [5].4 new iridoid glycosides that from the root of Scrophularia buergeriana Miq. Scrophularia buergerianaMiquel, extract: 8-O-E-p-methoxyl group cinnyl Harpagide, 8-O-Z-p-methoxyl group cinnyl Harpagide, 6 '-O-E-p-methoxyl group cinnyl Harpagide and 6 '-O-Z-p-methoxyl group cinnyl Harpagide; all significantly stop the release of serum lactic dehydrogenase (LDH), play neuroprotective
[6]Coastal horsewhip grass seeds has also found to have the active iridoid of promotion nerve growth factor.There is the research report to have the effect of anti-senile dementia with the Rhizoma Coptidis toxic materials clearing away decoction (coptis, golden cypress, the root of large-flowered skullcap, cape jasmine) of cape jasmine prescription in the recent period
[7,8]But the active substance of Rhizoma Coptidis toxic materials clearing away decoction anti-senile dementia it be unclear that, and remains further to be studied.Based on former study and complete screening system, we have carried out the research of active guide of anti-senile dementia or compound to plants such as cape jasmine and radix scrophulariaes, have found a series of iridoids with remarkable activity.
[1] Qi Chen's herbal medicine efficacy research thinking and method Beijing: People's Health Publisher 2005
[2] Han Ji gives birth to Principles of Neural Science Beijing: press of Beijing Medical University 1999
[3] people .Comparative genomics of the eukaryotes.Science2000 such as Rubin GM, 287 (5461), 2204-2215
[4] Dong Juan pretty young woman opens progress Xibei Forest College journal 2004,19 (3) of iridoid in the quiet plant, 131-135
[5] a new iridoid glycosides is suffered from compound and is posted enhanced activity World Notes on Plant Medicine to nerve growth factor, 2004,19 (5): 207 among the Duan Jingyu verbena Verbena littoralis
[6]Kim?S?R，Koo?K?A，Sung?S?H，et?al，Iridoids?from?Scrphulariabuergeriana?attenuate?glutamate-include?neurotoxicity?in?rat?corticalcultures[J].J?Neurosci?Res，2003，74(6)：948-955
[7] lucky senile dementia present Research of Xing Xiu and Chinese traditional treatment countermeasure Colleges Of Traditional Chinese Medicine Of Fujian journal 2002,12 (1), 58-60
[8] Chen Jianhong waits beneficial gas disintoxication to treat the clinical study Colleges Of Traditional Chinese Medicine Of Fujian journal 2006,16 (5) of senile dementia, 7-8
Summary of the invention
The present invention relates to the iridoid shown in the general formula (I)
Or its pharmacologically acceptable salt
Wherein:
3-4,6-7 and 7-8 is two keys or singly-bound.
R
1Be H, OH, OCH
3, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
R
3, R
7And R
8Be H, CH independently
3, CHO, COOCH
3, COOH, CH
2OH, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
R
2, R
4, R
5And R
6Be H, OCH independently
3, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
Perhaps there is ternary oxygen ring with 7 and/or 7 with 8 interdigits at 6,
Condition is that described general formula (I) compound does not comprise following compound:
With
In preferred embodiments, in general formula (I), 3-4 is two keys, R
2, R
3And R
6Be hydrogen, R
4And R
5Be hydroxyl, and R
8Be methyl.
In a preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, in general formula (I), 3-4 and 7-8 are two keys, R
2, R
4, R
5, R
6And R
8Be hydrogen, and R
3Be COOCH
3
In a preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
The invention still further relates to the iridoid shown in the general formula (I) or its pharmacologically acceptable salt and be used for preventing or treating the purposes of the medicine of nerve degenerative diseases in preparation:
Wherein:
3-4,6-7 and 7-8 is two keys or singly-bound.
R
1Be H, OH, OCH
3, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
R
3, R
7And R
8Be H, CH independently
3, CHO, COOCH
3, COOH, CH
2OH, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
R
2, R
4, R
5And R
6Be H, OCH independently
3, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
Perhaps there is ternary oxygen ring with 7 and/or 7 with 8 interdigits at 6.
In a preferred embodiment, described nerve degenerative diseases is vascular dementia, vascular cognitive impairment, senile dementia, hypomnesis, cerebral tissue degeneration syndrome or cholinergic nerve degeneration.
In a preferred embodiment, in general formula (I), 3-4 and 7-8 are two keys, R
2, R
4, R
5, R
6And R
8Be hydrogen, and R
3Be COOCH
3
In a preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
In a preferred embodiment, in general formula (I), 3-4 and 7-8 are two keys, R
2, R
4, R
5, R
6And R
8Be hydrogen, and R
3Be COOCH
3
In a preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another preferred embodiment, described compound is
In another embodiment, described compound is selected from
The invention still further relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises iridoid and pharmaceutically acceptable carrier of aforesaid general formula (I).
The invention still further relates to the method for iridoid of the aforesaid general formula of preparation (I), described method comprises and adopts Chinese medicine radix scrophulariae and cape jasmine as raw material, extracts and separates with solvent.
Described solvent is preferably organic solvent and/or water.Described organic solvent is preferably lower alcohol.Preferably, described lower alcohol is selected from methyl alcohol and ethanol.Described organic solvent also can be selected from acetoneand ethyl acetate.
Described separation is preferably undertaken by chromatography and/or extraction process.
Detailed Description Of The Invention
The present invention relates to a series of iridoids and the wherein application of composition in nervous system degenerative diseases such as antagonism and senile dementia prevention and cure that constitute of any one or more than one compound.
The inventor has obtained a series of iridoids (being represented by following general formula I) by the number of chemical means from Chinese medicine radix scrophulariae and cape jasmine, and has proved the effect of its preventing/treating senile dementia by transgenic fly screening active ingredients system.
Wherein each group is civilian as defined above described.
First group of preferred compound, wherein 3,4 interdigits exist two keys, R
2, R
3, R
6Be hydrogen, R
4, R
5, hydroxyl, R
8Be methyl.
Preferred R
1Be O-β-D-Glu-6-O-caffeoyl, R
7Be OH, chemistry by name 6 "-O-coffee acyl Harpagide (6 "-O-caffeoylharpagide) new compound, be called for short (SN-1).
Preferred R
1Be O-β-D-Glu-6-O-feruloyl, R
7Be OH, chemistry by name 6 "-new compound of O-asafoetide acyl group Harpagide (6 "-O-feruloyl harpagide), be called for short (SN-2).
Preferred R
1Be O-β-D-Glu-6-O-β-D-Glu, R
7Be O-cinnamoyl, chemistry by name 6 "-O-β-D-pyrans grape Ji Hapae glycosides (6 "-new compound of O-β-glucopyranosylharpagoside), be called for short (SN-3).
Preferred R
1Be O-β-D-Glu-6-O-a-D-Glu, R
7Be O-cinnamoyl, chemistry by name 6 "-O-α-D-pyrans grape Ji Hapae glycosides (6 "-new compound of O-α-glucopyranosylharpagoside), be called for short (SN-4).
Second group of preferred compound, wherein 3 and 4,7 and 8 interdigits exist two keys, R
2, R
4, R
5, R
6, R
8Be hydrogen, R
3Be COOCH
3
Preferred R
1Be O-β-D-Glu, R
7Be CH
2OCOCH
2CH
2COOH, the new compound of chemistry Succinic Acid list Geniposide ester (geniposide 10-succinate) by name is called for short (GJ-1).
Preferred R
1Be O-β-D-Glu-6-O-sinapoyl, R
7Be CH
2OH, the new compound of chemistry 6 '-O-mustard acyl Geniposide (6 '-O-sinapoyl geniposide) by name is called for short (GJ-2).
Preferred R
1Be O-β-D-Glu-6-O-p-hydroxy cinnamoyl, R
7Be CH
2OH, chemical name 6 '-O-are called for short (GJ-3) the new compound of hydroxyl cinnamyl Geniposide (6 '-O-p-hydroxy cinnamoyl geniposide).
Preferred R
1Be O-β-D-Glu-6-O-Ac, R
7Be CH
2OH, the new compound of chemical name 6 '-ethanoyl Geniposide (6 '-acetyl geniposide) is called for short (GJ-4).
In addition, the following compound in general formula (I) scope is known:
Be called for short
Structural formula of compound
Compound provided by the present invention, has the significant effect that improves transgenosis senile dementia fruit bat learning and memory, can be used for comprising vascular dementia, vascular cognitive impairment, senile dementia (being called Alzheimer's disease again), cholinergic nerve degenerative lesion, the ability of learning and memory prevention and the treatment of nervous system degenerative disease such as go down.
Above-mentioned iridoid compound general formula I, comprise preferred any one compound be applied to the prevention and the treatment of nerve degenerative diseases such as senile dementia.And available above-mentioned compound is formed composition, any or more than one, with the various auxiliary materials of available on the pharmacy meaning, make various preparations and formulation and be applied to nerve degenerative diseases such as prevention and treatment senile dementia.
Specifically, the iridoid compound that provides among the present invention extraction separation from Chinese medicine radix scrophulariae and cape jasmine obtains.The solvent that is used to extract can adopt the solvent that is generally used for plant extract, for example, can be used alone or in combination organic solvent and water such as lower alcohols such as methyl alcohol, ethanol, acetone, ethyl acetate.The method of extracting can adopt ordinary method, and generally extracting temperature is 20-100 ℃, but total extraction time 1-48 hour, can adopt heat to extract or cold extraction.The extract obtained medicinal extract that arrives through concentrating under reduced pressure.Total medicinal extract can pass through the number of chemical method, obtains total iridoid glycoside as several different methods enrichments such as column chromatography, extraction processs.Subsequently, adopt multiple separation means separation and purification to obtain monomer iridoid compound.
Result of the present invention has provided total iridoid glycoside, monomeric compound and the composition thereof with the neural property carried out disease effects such as preventing/treating senile dementias.
The term that uses in present specification and claims " pharmacologically acceptable salt " is meant that wherein parent compound is by forming the derivative that its acid or alkali salt obtain modifying.The example of pharmacologically acceptable salt includes but not limited to, the inorganic or organic acid salt of alkaline residue (such as amine); The basic metal or the organic salt of acidic residues (such as carboxylic acid); Or the like.Pharmacologically acceptable salt comprises conventional non-toxic salt or the quaternary ammonium salt that parent compound forms, for example, and the salt that forms by nontoxic mineral acid or organic acid.For example, the non-toxic salt of described routine comprises the salt that is obtained by mineral acid, for example hydrochloride, hydrobromate, vitriol, amine sulfonate, phosphoric acid salt and nitrate or the like; And by the salt of organic acid preparation, for example acetate, propionic salt, succinate, glycollate, stearate, lactic acid salt, malate, tartrate, Citrate trianion, ascorbate salt, embonate, maleate, hydroxymaleic acid salt, phenyl maleate, glutaminate, benzoate, salicylate, sulfanilate, 2-acetoxyl group-benzoate, fumarate, tosylate, mesylate, ethylene disulfonic acid salt, oxalate and isethionate or the like.
When The compounds of this invention was alkalescence, described salt can be prepared by pharmaceutically acceptable non-toxic acid, comprises inorganic or organic acid.Described acid comprises acetate, Phenylsulfonic acid, phenylformic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate and tosic acid or the like.In one aspect of the invention, described salt is citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid, fumaric acid and tartrate.Should be appreciated that such as herein application, the reference of mutual-through type (I) compound also means and comprises pharmacologically acceptable salt.
The term alkoxyl group that uses in present specification and claims is the C1-C6 alkoxyl group preferably, for example methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, hexyloxy or the like.
The term that uses in present specification and claims " composition " means the product that comprises the special component that contains specified quantitative, and anyly is designated as branch combination directly or the product that obtains indirectly by specified amount.This term that relates to pharmaceutical composition means the product that comprises the inert fraction that contains activeconstituents and form carrier, and any by combination, cooperate or assemble any two or more compositions, decompose one or more compositions or by other type reaction of one or more compositions or interact directly or the product that obtains indirectly.In view of the above, pharmaceutical composition of the present invention comprises any by mixing the composition that The compounds of this invention and pharmaceutically acceptable carrier prepare." pharmaceutically acceptable " means carrier, thinner or vehicle must be compatible with other preparation composition and harmless to its receptor.
The compounds of this invention can be by oral, parenteral (for example, intramuscular, intraperitoneal, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implantation), by sucking sprays, intranasal, vagina, rectum, hypogloeeis or topical administration, and they can be mixed with the optimal dose unit preparation that contains the conventional nontoxic pharmaceutically acceptable carrier, auxiliary agent and the vehicle that are applicable to various route of administration separately or together.
The pharmaceutical composition that is used for the administration The compounds of this invention can exist with dosage unit form aptly, and can be prepared by any method of knowing of pharmaceutical field.All methods all comprise to be made activeconstituents and comprises one or more pharmaceutically acceptable carrier blended steps.Usually, pharmaceutical composition is prepared in the following manner: make all even close mix and then of activeconstituents and liquid vehicle or solid carrier in small, broken bits or the two, if necessary, with the preparation of product shaping for expectation.In pharmaceutical composition, described activeconstituents is included in wherein with the amount that is enough to lysis or symptom are produced desired result.The term of Shi Yonging " composition " intention comprises the product of the appointment composition that contains specified amount in this article, and anyly is designated as the branch combination directly or the product that obtains indirectly by specified amount.
The pharmaceutical composition that contains activeconstituents can be for being applicable to the form of oral application, for example, be tablet, tablet, lozenge, moisture or contain oil suspension, dispersible powder or granula, emulsion, liquor, hard capsule or soft capsule or syrup or elixir.The composition that is designed for oral application can be prepared according to any method that the manufacturing field of medicinal compositions is known, and for pharmaceutically exquisite and good to eat preparation are provided, described composition can contain one or more reagent that is selected from sweeting agent, sweetener, tinting material and sanitas.Tablet contains and the activeconstituents that is applicable to the nontoxic pharmaceutically acceptable mixed with excipients of making tablet.These vehicle can for, for example, inert diluent is such as lime carbonate, yellow soda ash, lactose, calcium phosphate or sodium phosphate; Granulation and disintegrating agent, for example W-Gum or alginic acid; Tackiness agent, for example starch, gel or gum arabic; And lubricant, for example Magnesium Stearate, stearic acid or talcum.Described tablet can be not coated or they can carry out dressing postponing disintegration and to be absorbed in the gi tract by already known processes, thereby interior continuous action of long period is provided.For example, can use the time-delay material, such as glyceryl monostearate or distearin.They can also carry out dressing, thereby are formed for the osmotic therapeutic tablet of controlled release.The oral tablet preparation quick-release be can also be used for, tablet or wafer, fast dissolving tablet agent or fine and close dissolving film be melted such as densification.
The preparation that is used for oral application can also exist as hard capsule, wherein activeconstituents mixes with inert solid diluent (for example lime carbonate, calcium phosphate or kaolin), perhaps exist as soft capsule, wherein activeconstituents mixes with moisture or oil-containing medium (for example peanut oil, whiteruss or sweet oil).
Aqueous suspensions contains and the active substance that is applicable to the nontoxic pharmaceutically acceptable mixed with excipients of making aqueous suspensions.Described vehicle is a suspending agent, for example Xylo-Mucine, methylcellulose gum, hydroxyl-propyl methocel, sodium alginate, polyvinylpyrrolidone, Tragacanth and Sudan Gum-arabic; Dispersion or wetting agent can be naturally occurring phosphatide (for example Yelkin TTS), the perhaps condensation product of oxyalkylene and lipid acid (for example polyoxyethylene stearic acid ester), the perhaps condensation product of ethylene oxide and long chain aliphatic (for example heptadecane vinyloxy group hexadecanol), perhaps ethylene oxide with come from the condensation product (such as octadecanoic acid ester of polyethylene glycol) or the ethylene oxide of the meta-acid of lipid acid and hexitol and come from the partial ester of lipid acid and the condensation product of hexitol acid anhydrides (for example polyethylene list oleic acid sorbitan ester).Described aqueous suspensions can also contain one or more sanitass (for example ethyl p-hydroxybenzoate or P-hydroxybenzoic acid n-propyl), one or more tinting materials, one or more sweetener and one or more sweeting agents (such as sucrose or asccharin).
Containing oil suspension can be prepared by activeconstituents being suspended in the vegetables oil (for example peanut oil, sweet oil, sesame oil or Oleum Cocois) or being suspended in the mineral oil (such as whiteruss).The described oil suspension that contains can contain thickening material, for example beeswax, paraffinum durum or hexadecanol.Can will add wherein, thereby good to eat oral preparations is provided such as aforesaid those sweeting agents and sweetener.These compositions can be maintained by adding antioxidant (such as xitix).
Be applicable to that preparation dispersible powder of aqueous suspensions and granula by adding entry, provide and dispersion agent or wetting agent, suspending agent and one or more sanitas blended activeconstituentss.Suitable dispersion agent or wetting agent and suspending agent are those reagent of above-mentioned illustrations.Wherein can also there be other vehicle (for example sweeting agent, sweetener and tinting material).
Pharmaceutical composition of the present invention can also be the oil-water emulsifiers form.Described oil phase can be vegetables oil (for example sweet oil or peanut oil) or mineral oil (for example whiteruss) or their mixture.Examples of suitable emulsifiers can and come from the ester of lipid acid and hexitol acid anhydrides or the condensation product (for example polyoxyethylene list oleic acid sorbitan ester) of partial ester (for example single oleic acid sorbitan ester) and described partial ester and ethylene oxide for naturally occurring natural gum (for example Sudan Gum-arabic or Tragacanth), naturally occurring phosphatide (for example soybean, Yelkin TTS).Described emulsion can also contain sweeting agent or sweetener.
Syrup and elixir can utilize sweeting agent (for example, glycerine, propylene glycol, sorbyl alcohol or sucrose) to prepare.Described preparation can also contain wetting agent, sanitas and sweetener and tinting material.
Pharmaceutical composition is can be for sterile injectable moisture or contain the form of oil suspension.Described suspensoid can utilize above-mentioned suitable dispersion agent or wetting agent and suspending agent to prepare according to technology well known in the art.Described injectable sterile preparation can also be at nontoxic parenteral acceptable diluent or injectable sterile solution or the suspension in the solvent, for example is 1,3 butylene glycol solution.In acceptable vehicle and solvent, operable is water, physiological saline and isotonic sodium chlorrde solution.In addition, usually aseptic, fixed oil are used as solvent or suspension medium.Based on above-mentioned purpose, any tasteless fixed oil can be used, and comprises synthetic list or triglyceride.In addition, in injectable formulation, can use such as oleic lipid acid.
The compounds of this invention can also be for being used for the suppository form of rectal administration medicine.Thereby these compositions can by with medicine with at normal temperatures for solid but under rectal temperature for liquid and will in rectum, melt the suitable nonirritant excipient that discharges medicine thus and mix and obtain preparing.Described material is theobroma oil and polyoxyethylene glycol.
For topical application, can use ointment, paste, jelly, liquor or suspensoid of containing The compounds of this invention or the like.Similarly, percutaneous plaster also can be used for topical.
Provide the following example further to illustrate the present invention, but this is not a limitation of the present invention.
Embodiment
Embodiment 1
First part: the extraction separation of iridoid in the radix scrophulariae
Get goatweed radix scrophulariae (Scrophularia ningpoensis Hemsl) dry root 18kg, extract with 60% alcohol heating reflux, concentrated extract, adopt ethyl acetate respectively, propyl carbinol carries out equal-volume extraction 3 times, partly by the D101 macroporous resin column, water, 30% ethanol, 50% ethanol and 95% ethanol carry out gradient elution to n-butanol extraction.50% ethanol elution part 50.2g is through silica gel column chromatography, and chloroform-methanol 95:5-70: 30 gradient elutions obtain SN-9 (14g); With sub-cut Fr.1-Fr.7 (3.9g), through the ODS post, 40: 60 wash-outs of methanol-water, pass through reverse hplc again, methanol-water 35:65 wash-out obtains SN-2 (117.1mg), SN-6 (17.9mg), SN-7 (10.1mg), SN-8 (28.2mg), sub-cut Fr.5 (6.1g) is through reverse hplc, methanol-water 50:50 wash-out, obtain compound S N-3 (237.6mg), SN-4 (110.1mg), SN-5 (13.0mg).30% ethanol elution part 51.4g is through silica gel column chromatography, chloroform-methanol 90:10-60:40 gradient elution, and sub-cut Fr.4 (13g) is through the reverse column chromatography of ODS, methanol-water 20:80-60:40 gradient elution, pass through the HPLC purifying again, methanol-water 25:75 wash-out obtains SN-1 (27.2mg).Sub-cut Fr.6 (5.6g), through the reverse column chromatography of ODS, methanol-water 20:80-60:40 gradient elution passes through the HPLC purifying again, and methanol-water 25:75 wash-out obtains SN-10 (21.7mg).
The purity of each compound that is obtained and measuring shown in the following Table A:
Table A
No. number the purity Weight structure
1
* SN-1 95％ 27.2mg
2
* SN-2 95％ 117.1mg
3
* SN-3 95％ 237.6mg
4
* SN-4 95％ 110.1mg
5 SN-5 95％ 13.0mg
6 SN-6 95％ 17.9mg
7 SN-7 95％ 10.1mg
8 SN-8 95％ 28.2mg
9 SN-9 90％ 14g
10 SN-10 75％ 21.7mg
Annotate: have * person to be new compound
The physicochemical constant of each compound that is obtained is as follows:
Compound S N-1 (6 ＂-O-coffee acyl Harpagide): light brown indefinite form powder,
-37.6 ° (c=1.0, MeOH).Molish and FeCl
3React all positive.UV(MeOH)λ
max?nm(logε)：203(2.56)，227(2.48)，312(2.60)；IR(KBr)cm
-1：3394(OH)，1605，1520(phenyl?nucleus)。HR-ESI-MS:m/z 549.1592[M+Na]
+(Calcd for:549.1584) confirms that the molecular formula of compound S N-1 is C
24H
30O
13 13C reaches
1H NMR data see Table 1.
Compound S N-2 (6 ＂-O-asafoetide acyl group Harpagide): light brown indefinite form powder.Molish and FeCl
3React all positive.
-35.2°(MeOH，c＝1.0)；UV(MeOH)λ
maxnm(log?ε)：204(2.58)，235(2.48)，325(2.61)；IR(KBr)cm
-1：3417(OH)，1601，1516(phenyl?nucleus)。HR-ESI-MS:m/z 563.1752[M+Na]
+(Calcdfor:563.1741), the molecular formula of affirmation compound S N-2 is C
25H
32O
13 13C reaches
1H NMR data see Table 1.
Compound S N-3 (6 ＂-O-β-D-pyrans grape Ji Hapae glycosides): light brown indefinite form powder.The Molish reacting positive.
-81.6°(c＝1.0，MeOH)；UV(MeOH)λ
maxnm(log?ε)：206(2.16)，281(1.50)，325(1.18)；IR(KBr)cm
-1：3337(OH)，1635，1516(phenyl?nucleus)。HR-ESI-MS:m/z 679.2192[M+Na]
+(Calcdfor:679.2214), the molecular formula of affirmation compound S N-3 is C
26H
40O
16 13C reaches
1H NMR data see Table 2.
Compound S N-4 (6 ＂-O-α-D-pyrans grape Ji Hapae glycosides): light brown indefinite form powder.Molish reacts positive type.
-82.3°(c＝1.0，MeOH)；IR(KBr)cm
-1：3421(OH)，1700(-C＝O)，1508，1454(phenyl?nucleus)。HR-ESI-MS:m/z679.2164[M+Na]
+(Calcd for:679.2214) confirms that the molecular formula of compound S N-4 is C
26H
40O
16 13C reaches
1H NMR data see Table 2.
Compound S N-5 (6 ＂-O-α-D-galactopyranose base Harpagide): light brown indefinite form powder.The Molish reacting positive.ESI-MS:m/z 679[M+Na]
+, 655[M-H]
-, the molecular weight of prompting compound S N-5 is 656.
13C reaches
1H NMR data see Table 2.
Compound S N-6 (6 ＂-O-is to hydroxyl cinnamoyl Harpagide): light brown indefinite form powder, Molish and FeCl
3React all positive.ESI-MS:m/z 533[M+Na]
+, 519[M-H]
-, the molecular weight of prompting compound S N-6 is 520.
13C reaches
1H NMR data see Table 3.
Compound S N-7 (8-O-is to hydroxyl meat acyl group Harpagide): light brown indefinite form powder, Molish and FeCl
3React all positive.ESI-MS:m/z 533[M+Na]
+, 519[M-H]
-, the molecular weight of prompting compound S N-7 is 520.
13C reaches
1H NMR data see Table 3.
Compound S N-8 (8-O-asafoetide acyl group Harpagide): light brown indefinite form powder, Molish and FeCl
3React all positive.ESI-MS:m/z 563[M+Na]
+, 539[M-H]
-, the molecular weight of prompting compound S N-8 is 540.
13C reaches
1H NMR data see Table 3.
Compound S N-9 (Harper Russia glycosides): light brown indefinite form powder, Molish and reacting positive.ESI-MS:m/z 517[M+Na]
+, 493[M-H]
-, the molecular weight of prompting compound S N-9 is 494.
13C reaches
1H NMR data see Table 4.
Compound S N-10 (Harpagide): white indefinite form powder, Molish reacting positive.ESI-MS:m/z 387[M+Na]
+, 363[M-H]
-, the molecular weight of prompting compound S N-10 is 364.
13C reaches
1H NMR data see Table
Table 1: the NMR data of compound S N-1 and SN-2 (400 and 100MHz, CD
3OD)
1 2
No.
δ
H，J(Hz) δ
c δ
H，J(Hz) δ
c
1 5.65，d(1.2) 93.1 5.65，d(1.2) 93.1
2
3 6.32，d(6.4) 142.5 6.30，d(6.4) 1425
4 4.93，dd(6.4，1.4) 108.4 4.93，dd(6.4，1.5) 108.4
5 72.8 72.7
6 3.67，t(3.9) 783 3.67，t(3.9) 783
1.85，dd(13.7，4.6)； 1.84，dd(13.7，4.6)
7 46.9 46.9
1.75dd(13.8，3.0) 1.73dd(13.73.2)
8 78.4 78.4
9 254，s 59.5 2.54，s 59.5
10 1.18，s 25.0 1.17，s 25.0
1’ 127.7 127.6
2’ 7.03，d(2.0) 115.2 7.16，d(1.9) 117.7
3’ 146.8 149.3
4’ 149.6 150.6
5’ 6.76，d(8.2) 116.5 6.79，d(8.2) 116.5
6’ 6.93，dd(8.2，2.0) 123.1 7.05，dd(8.2，1.9) 124.2
α 6.28，d(15.9) 114.8 6.38，d(15.9) 115.2
β 7.56，d(15.9) 147.2 7.62，d(15.9) 147.1
-C＝O 169.1 169.1
1” 4.59，d(7.9) 99.2 4.59，d(7.9) 99.2
2” 3.25，t(8.9) 74.4 3.24，t(9.0) 74.4
3” 3.39，t(7.4) 774 3.41，t(6.2) 77.4
4” 3.40，t(7.4) 71.7 3.40，t(6.2) 71.7
5” 3.56，m 75.7 3.55，m 75.6
4.48，dd(12.02.1) 4.48，dd(12.0，2.2)；
6” 64.5 645
4.35，dd(12.0，5.8) 4.36，dd(12.0，5.8)
Table 2: compound S N-3, the NMR data of SN-4 and SN-5 (400 and 100MHz, CD
3OD)
3 4 5
No
δ
H，J(Hz) δ
c δ
H，J(Hz) δ
c δ
H，J(Hz) δ
c
1 6.19，d(1.2) 94.3 6.19，d(1.2) 94.2 6.20，d(1.2) 94.4
2
3 6.39，d(6.4) 143.8 6.39，d(6.4) 143.8 6.40，d(6.4) 143.8
4 4.93，dd(6.4，1.6) 107.0 4.93，dd(6.4，1.6) 107.1 4.93，dd(6.4，2.0)107.1
5 73.6 73.7 73.5
6 3.74，t(34) 77.7 3.75，m 77.8 3.74，m 77.8
7 2.24，d(15.1) 2.24，d(15.1) 2.34，d(15.1)
46.3 46.3 46.3
1.99dd(15.14.4) 1.98dd(15.14.4) 2.00dd(15.14.4)
8 88.5 88.5 88.5
9 2.92，s 55.4 2.92，s 55.5 2.93，s 55.5
10 1.53，s 22.9 1.53，s 22.8 1.53，s 22.8
1’ 136.0 136.0 136.0
2’ 7.58，m 129.2 7.60，m 129.3 7.59，m 129.3
3’ 7.37，m 130.0 7.37，m 130.0 7.38，m 130.0
4’ 7.39，m 131.3 7.39，m 131.3 7.38，m 131.4
5’ 7.37，m 130.0 7.37，m 130.0 7.38，m 130.0
6’ 7.58，m 129.2 7.60，m 129.3 7.59，m 129.3
α 6.50，d(16.0) 120.3 6.49，d(16.0) 120.4 6.49，d(16.0) 120.2
β 7.70，d(16.0) 146.0 7.68，d(16.0) 145.9 7.68，d(16.0) 146.0
-C＝O 168.3 168.2
-OCH
3
1” 4.63，d(7.9) 99.3 4.63，d(7.9) 99.3 4.64，d(7.9) 99.6
2” 3.23，t(9.1) 74.4 3.23，t(8.6) 74.5 3.23，t(8.9) 74.0
3” 3.45，m 77.7 3.45，m 77.8 3.40，m 77.8
4” 3.38，t(7.4) 71.7 3.38，m 71.7
5” 3.55，m 77.7 3.57，m 76.8
6” 4.20，dd(12.0，1.8)；
69.6 3.96，m；3.85，m 67.8
3.89，dd(12.0，6.5)
1” 4.59，d(7.9) 104.6 4.98，d(3.5) 100.3
2” 3.23，t(9.1) 75.4 3.57，m 71.9
3” 3.41，m 77.7 3.40，t(6.2) 72.4
4” 3.38，t(7.4) 71.7 3.36，m 70.6
5” 3.53d(9.1) 77.7 3.95m 71.3
6” 3.90，dd(12.0，2.3)
62.8 3.78，m 63.1
3.68，dd(12.0，5.8)
Table 3: compound S N-6, the NMR data of SN-7 and SN-8 (400 and 100MHz, CD
3OD)
Table 4: the NMR data of compound S N-9 and SN-10 (400 and 100MHz, CD
3OD)
Second section: isolating iridoid anti-senile dementia effect test from radix scrophulariae
The cultivation of senile dementia fruit bat
By parent fruit bat that will carry the elav promotor gene and the parent's drosophila hybrid that carries A β 42 protein genes, obtain to be integrated with the filial generation disease fruit bat of elav promotor gene and A β 42 protein genes.
The administration of senile dementia fruit bat
Test is provided with healthy fly does not have the medicine contrast, the disease fly does not have the medicine contrast and gives different three kinds of combinations of medicine with the disease fly.Every kind of combination (healthy fly does not have the medicine contrast, the disease fly does not have medicine contrast, disease fly hello some medicines) has 250 fruit bats, 2 glass that are placed in refer to (each glass refers to bottled 125 fruit bats) in the bottle, every day, elder generation was 2 hours on an empty stomach, administration 40 μ l under the condition of still isolating food then, force medicine feed 4 hours (this moment, the medicine of 40 μ l was suffered all), the glass that the last fruit bat that will eat up medicine is again transferred to food refers in the bottle.Method of feeding medicine (number of patent application 2005100117054) mandate (patent name: a kind of insect medication and device and the purposes in large-scale medicine screening thereof) that patented.
8 groups of each medicine revision tests, medicine feed were carried out 6 days continuously.
Memory obstruction recovery effect assessment after the fruit bat administration
Fruit bat places automatic instrument for training to undergo training, successively feed smell (1.5 ‰ octanol octanol during training, solvent is a dimethyl silicone oil, the smell that foaming is distributed) follows electric shock (CS+), feed another kind of smell (1 ‰ methyl-cyclohexanol methylcyclohexanol then, solvent is a dimethyl silicone oil), but do not follow electric shock (CS-), after finishing, 1 cycle training detects its memory immediately, place relative fruit bat and two kinds of smells (1.5 ‰ octanol octanol and 1 ‰ methyl-cyclohexanol methylcyclohexanol that blow during detection, the smell that distributes of foaming respectively) central authorities, let alone freely to select 120 seconds, calculate the learning and memory indices P I (Performance Index) of each experiment according to the fruit bat number of selecting every kind of smell, octanol octanol follows smell to stimulate the study index that produces to represent that with PIOCT calculation formula is PI
OCT={ 2[MCH/ (OCT
*+ MCH)]-1}*100
Fruit bat places automatic instrument for training to undergo training, successively feed smell (1 ‰ methyl-cyclohexanol methylcyclohexanol during training, solvent is a dimethyl silicone oil) follow electric shock (CS+), feed another kind of smell (1.5 ‰ octanol octanol then, solvent is a dimethyl silicone oil, the smell that foaming is distributed), but do not follow electric shock (CS-), after finishing, 1 cycle training detects its memory immediately, place relative fruit bat and two kinds of smells (1.5 ‰ octanol octanol and 1 ‰ methyl-cyclohexanol methylcyclohexanol that blow during detection, the smell that distributes of foaming respectively) central authorities, let alone freely to select 120 seconds, calculate the learning and memory indices P I (Performance Index) of each experiment according to the fruit bat number of selecting every kind of smell, methyl-cyclohexanol methylcyclohexanol follows smell to stimulate the study index that produces with PI
MCHExpression, calculation formula is PI
MCH={ 2[OCT/ (MCH
*+ OCT)]-1}*100
Net result is with total learning and memory index (PI
TOTAL) expression, calculation formula is PI
TOTAL=0.5 (PI
MCH+ PI
OCT).
When carrying out active testing, carry out the healthy fly of same genetic background of medicine feed not, the senile dementia disease fly of medicine feed not simultaneously, feed the sense of smell short-term memory defect test of the senile dementia disease fly of test medicine, calculate their total learning and memory index respectively, with the senile dementia disease fly learning and memory index of feeding the test medicine with compare the effect of evaluation test thing anti-senile dementia with genetic background health fly learning and memory index, senile dementia disease fly learning and memory index.The senile dementia disease fly learning and memory index of feeding tester is high relatively more to illustrate that then the effect of tester anti-senile dementia is strong more.
Adopt the T check relatively, the senile dementia disease fly learning and memory index of feeding tester and the senile dementia disease fly learning and memory index of medicine feed (only give not the solvent of pastille sample) not, P less than 0.05 for difference is arranged, P is less than 0.01 for there being marked difference, P less than 0.001 for utmost point marked difference is arranged.
The T of isolating iridoid test result disease not administration of fly and administration check contrast is in the radix scrophulariae: the T check P=0.000010 of SN-1, the T check P=0.000041 of SN-2, the T check P=0.001297 of SN-3, the T check P=0.000777 of SN-4, the T check P=0.000177 of SN-5, the T check P=0.000172 of SN-6, the T check P=0.031647 of SN-7, the T check P=0.000063 of SN-8, the T check P=0.000001 of SN-9, the T check P=0.000000 of SN-10.Show that SN1-10 has in various degree the active effect of blocking-up to fruit bat senile dementia disease short-term memory decline.The testing data of concrete each compound is listed as each correspondence table as follows:
(1) SN-1 active testing result
(1-1) SN-1 background information and test result
(1-2) with the healthy fly study of background index test result
(1-3) not administration of disease fly contrast study index test result
(1-4) the disease fly feeds 0.050 ‰ SN-1 study index test result
(2) SN-2 active testing result
(2-1) SN-2 background information and test result
(2-2) with the healthy fly study of background index test result
(2-3) not administration of disease fly contrast study index test result
(2-4) the disease fly feeds 0.050 ‰ SN-2 study index test result
(3) SN-3 active testing result
(3-1) SN-3 background information and test result
(3-2) with the healthy fly study of background index test result
(3-3) not administration of disease fly contrast study index test result
(3-4) the disease fly feeds 0.050 ‰ SN-3 study index test result
(4) SN-4 active testing result
(4-1) SN-4 background information and test result
(4-2) with the healthy fly study of background index test result
(4-3) not administration of disease fly contrast study index test result
(4-4) the disease fly feeds 0.050 ‰ SN-4 study index test result
(5) SN-5 active testing result
(5-1) SN-5 background information and test result
(5-2) with the healthy fly study of background index test result
(5-3) not administration of disease fly contrast study index test result
(5-4) the disease fly feeds 0.050 ‰ SN-5 study index test result
(6) SN-6 active testing result
(6-1) SN-6 background information and test result
(6-2) with the healthy fly study of background index test result
(6-3) not administration of disease fly contrast study index test result
(6-4) the disease fly feeds 0.050 ‰ SN-6 study index test result
(7) SN-7 active testing result
(7-1) SN-7 background information and test result
(7-2) with the healthy fly study of background index test result
(7-3) not administration of disease fly contrast study index test result
(7-4) the disease fly feeds 0.050 ‰ SN-7 study index test result
(8) SN-8 active testing result
(8-1) SN-8 background information and test result
(8-2) with the healthy fly study of background index test result
(8-3) not administration of disease fly contrast study index test result
(8-4) the disease fly feeds 0.050 ‰ SN-8 study index test result
(9) SN-9 active testing result
(9-1) SN-9 background information and test result
(9-2) with the healthy fly study of background index test result
(9-3) not administration of disease fly contrast study index test result
(9-4) the disease fly feeds 0.050 ‰ SN-9 study index test result
(10) SN-10 active testing result
(10-1) SN-10 background information and test result
(10-2) with the healthy fly study of background index test result
(10-3) not administration of disease fly contrast study index test result
(10-4) the disease fly feeds 0.050 ‰ SN-10 study index test result
Embodiment 2
First part: the extraction separation of iridoid in the cape jasmine
Get Rubiaceae Gardenia Ellis plant cape jasmine (Gardenia jasminoides Ellis) dry fruit 5kg, extract with 60% alcohol heating reflux, concentrated extract is in the extract obtained water in suspension, by the D101 macroporous resin column, water, 30%, 50%, 70% and 95% ethanol gradient elution.50% ethanol elution part, through silica gel column chromatography (200-300 order), with chloroform-methanol-water (100:0:0) to the methyl alcohol gradient elution.Sub-cut Fr7 (9g) is through the ODS column chromatography, methanol-water (10:90-90:10) gradient elution, sub-cut Fr.1 is through Toyopearl HW-40 post, methanol-water (20:80-80:20) gradient elution, again through reverse hplc, methanol-water 40:60 wash-out, purifying obtains GJ-1 (6mg), GJ-4 (28.9mg), GJ-5 (45mg), GJ-6 (22.0mg); Sub-cut Fr.3 is through Toyopearl HW-40 post, and (20: 80-80:20) gradient elution, reverse hplc purifying obtain GJ-2 (35.7mg) to methanol-water; Sub-cut Fr.4 is through Toyopearl HW-40 post, methanol-water (20:80-80:20) gradient elution, and the reverse hplc purifying obtains GJ-3 (28.5mg).
The purity of each compound that is obtained and measuring shown in the following Table A
Table B
No. number the purity Weight structure
1
* GJ-1 90％ 6mg
2
* GJ-2 90％ 35.7mg
3
* GJ-3 95％ 28.5mg
4
* GJ-4 88％ 28.9mg
5 GJ-5 90％ 45mg
6 GJ-6 95％ 22.0mg
Annotate: have * person to be new compound
The physicochemical constant of each compound that is obtained is as follows:
Compound GJ-1 (Succinic Acid list Geniposide ester): faint yellow unformed powder, Molish reacting positive.
+ 15.0 ° (c=0.4, MeOH); UV (MeOH) λ
MaxNm (log ε): 202.0 (3.99), 238.0 (4.01); IR (KBr) cm
-1: 3414 (OH), 1700 (C=O), 2927 (CH
3); HR-ESI-MS:m/z 511.1400[M+Na]
+(calcd for C
21H
28O
13); The molecular formula of confirming compound GJ-1 is C
21H
28O
13 13C reaches
1H NMR data see Table 5.
Compound GJ-2 (6 '-O-mustard acyl Geniposide): yellow oil, Molish reacting positive.
-21.0 ° (c=0.4, MeOH); UV (MeOH) λ
MaxNm (log ε): 203.5 (3.85), 238.0 (3.81), 329 (3.66); IR (KBr) cm
-1: 3425 (OH), 1700 (C=O), 2927 (CH
3); HR-ESI-MS:m/z 617.1829[M+Na]
+(calcd forC
28H
34O
14); Confirm the molecular formula C of compound GJ-2
28H
34O
14 13C reaches
1H NMR data see Table 5.
Compound GJ-3 (6 '-O-is to hydroxyl cinnamyl Geniposide): yellow oil, Molish reacting positive.
-16.0°(c＝0.4，MeOH)；UV(MeOH)λ
max?nm(logε)：203.5(4.06)，238(4.02)，329(3.86)；IR(KBr)cm
-1：3425(OH)，1708(C＝O)，2927(CH
3)。HR-ESI-MS:m/z 557.1641[M+Na]
+(calcd for C
26H
30O
12); The molecular formula of confirming compound GJ-3 is C
26H
30O
12 13C reaches
1H NMR data see Table 5.
Compound GJ-4 (6 '-ethanoyl Geniposide): faint yellow unformed powder, Molish reacting positive.
+ 10.0 ° (c=0.4, MeOH); UV (MeOH) λ
MaxNm (log ε): 203.5 (3.59), 237 (3.70); IR (KBr) cm
-1: 3438 (OH), 1645 (C=C), 2925 (CH
3); HR-ESI-MS:m/z 453.1394[M+Na]
+(calcd for C
19H
26O
11); The molecular formula of confirming compound GJ-4 is C
19H
26O
11 13C reaches
1H NMR data see Table 6.
Compound GJ-5 (Geniposide): white unformed powder, molecular formula are C
17H
24O
10, the Molish reacting positive.ESI-MS:m/z 799 (2M+Na)
+, 411 (M+Na)
+, 775 (2M-H)
-, 387 (M-H)
-, prompting compound molecular weight 388.
13C reaches
1H NMR data see Table 6.
Compound GJ-6 (10-ethanoyl Geniposide): white unformed powder, molecular formula are C
19H
26O
11, the Molish reacting positive.ESI-MS:m/z 453[M+Na]
+, 429[M-H]
-, prompting compound molecular weight 430.
13C and 1H NMR data see Table 6.
Table 5: compound GJ-1, the NMR data of GJ-2 and GJ-3 (400 and 100MHz, CD
3OD)
Table 6: compound GJ-4, the NMR data of GJ-5 and GJ-6 (400 and 100MHz, CD
3OD)
Second section: isolating iridoid anti-senile dementia effect test from cape jasmine
The cultivation of senile dementia fruit bat
By parent fruit bat that will carry the elav promotor gene and the parent's drosophila hybrid that carries A β 42 protein genes, obtain to be integrated with the filial generation disease fruit bat of elav promotor gene and A β 42 protein genes.
The administration of senile dementia fruit bat
Test is provided with healthy fly does not have the medicine contrast, the disease fly does not have the medicine contrast and gives different three kinds of combinations of medicine with the disease fly.Every kind of combination (healthy fly does not have the medicine contrast, the disease fly does not have medicine contrast, disease fly hello some medicines) has 250 fruit bats, 2 glass that are placed in refer to (each glass refers to bottled 125 fruit bats) in the bottle, every day, elder generation was 2 hours on an empty stomach, administration 40 μ l under the condition of still isolating food then, force medicine feed 4 hours (this moment, the medicine of 40 μ l was suffered all), the glass that the last fruit bat that will eat up medicine is again transferred to food refers in the bottle.Method of feeding medicine (number of patent application 2005100117054) mandate (patent name: a kind of insect medication and device and the purposes in large-scale medicine screening thereof) that patented.
8 groups of each medicine revision tests, medicine feed were carried out 6 days continuously.
Memory obstruction recovery effect assessment after the fruit bat administration
Fruit bat places automatic instrument for training to undergo training, successively feed smell (1.5 ‰ octanol octanol during training, solvent is a dimethyl silicone oil, the smell that foaming is distributed) follows electric shock (CS+), feed another kind of smell (1 ‰ methyl-cyclohexanol methylcyclohexanol then, solvent is a dimethyl silicone oil), but do not follow electric shock (CS-), after finishing, 1 cycle training detects its memory immediately, place relative fruit bat and two kinds of smells (1.5 ‰ octanol octanol and 1 ‰ methyl-cyclohexanol methylcyclohexanol that blow during detection, the smell that distributes of foaming respectively) central authorities, let alone freely to select 120 seconds, calculate the learning and memory indices P I (Performance Index) of each experiment according to the fruit bat number of selecting every kind of smell, octanol octanol follows smell to stimulate the study index that produces to represent that with PIOCT calculation formula is PIOCT={2[MCH/ (OCT
*+ MCH)]-1}*100
Fruit bat places automatic instrument for training to undergo training, successively feed smell (1 ‰ methyl-cyclohexanol methylcyclohexanol during training, solvent is a dimethyl silicone oil) follow electric shock (CS+), feed another kind of smell (1.5 ‰ octanol octanol then, solvent is a dimethyl silicone oil, the smell that foaming is distributed), but do not follow electric shock (CS-), after finishing, 1 cycle training detects its memory immediately, place relative fruit bat and two kinds of smells (1.5 ‰ octanol octanol and 1 ‰ methyl-cyclohexanol methylcyclohexanol that blow during detection, the smell that distributes of foaming respectively) central authorities, let alone freely to select 120 seconds, calculate the learning and memory indices P I (Performance Index) of each experiment according to the fruit bat number of selecting every kind of smell, methyl-cyclohexanol methylcyclohexanol follows smell to stimulate the study index that produces with PI
MCHExpression, calculation formula is PI
MCH={ 2[OCT/ (MCH
*+ OCT)]-1}*100
Net result is with total learning and memory index (PI
TOTAL) expression, calculation formula is PI
TOTAL=0.5 (PI
MCH+ PI
OCT).
When carrying out active testing, carry out the healthy fly of same genetic background of medicine feed not, the senile dementia disease fly of medicine feed not simultaneously, feed the sense of smell short-term memory defect test of the senile dementia disease fly of test medicine, calculate their total learning and memory index respectively, with the senile dementia disease fly learning and memory index of feeding the test medicine with compare the effect of evaluation test thing anti-senile dementia with genetic background health fly learning and memory index, senile dementia disease fly learning and memory index.The senile dementia disease fly learning and memory index of feeding tester is high relatively more to illustrate that then the effect of tester anti-senile dementia is strong more.
Adopt the T check relatively, the senile dementia disease fly learning and memory index of feeding tester and the senile dementia disease fly learning and memory index of medicine feed (only give not the solvent of pastille sample) not, P less than 0.05 for difference is arranged, P is less than 0.01 for there being marked difference, P less than 0.001 for utmost point marked difference is arranged.
The T of isolating iridoid test result disease not administration of fly and administration check contrast is in the cape jasmine: the T check P=0.000000 of T check P=0.000289, the GJ-6 of T check P=0.000004, the GJ-5 of T check P=0.000002, the GJ-4 of T check P=0.000031, the GJ-3 of T check P=0.000747, the GJ-2 of GJ-1.Show that GJ1-6 has in various degree the active effect of blocking-up to fruit bat senile dementia disease short-term memory decline.The testing data of concrete each compound is listed as each correspondence table as follows:
(1) GJ-1 active testing result
(1-1) GJ-1 background information and test result
(1-2) with the healthy fly study of background index test result
(1-3) not administration of disease fly contrast study index test result
(1-4) the disease fly feeds 0.050 ‰ GJ-1 study index test result
(2) GJ-2 active testing result
(2-1) GJ-2 background information and test result
(2-2) with the healthy fly study of background index test result
(2-3) not administration of disease fly contrast study index test result
(2-4) the disease fly feeds 0.050 ‰ GJ-2 study index test result
(3) GJ-3 active testing result
(3-1) GJ-3 background information and test result
(3-2) with the healthy fly study of background index test result
(3-3) not administration of disease fly contrast study index test result
(3-4) the disease fly feeds 0.050 ‰ GJ-3 study index test result
(4) GJ-4 active testing result
(4-1) GJ-4 background information and test result
(4-2) with the healthy fly study of background index test result
(4-3) not administration of disease fly contrast study index test result
(4-4) the disease fly feeds 0.050 ‰ GJ-4 study index test result
(5) GJ-5 active testing result
(5-1) GJ-5 background information and test result
(5-2) with the healthy fly study of background index test result
(5-3) not administration of disease fly contrast study index test result
(5-4) the disease fly feeds 0.050 ‰ GJ-5 study index test result
(6) GJ-6 active testing result
(6-1) GJ-6 background information and test result
(6-2) with the healthy fly study of background index test result
(6-3) not administration of disease fly contrast study index test result
(6-4) the disease fly feeds 0.050 ‰ GJ-6 study index test result
Embodiment 3: the preparation of drug combination of tablet form
Form:
Compound S N-1 0.5 gram
Compound S N-2 0.5 gram
Amylum pregelatinisatum 150 grams
17% starch slurry is an amount of
Magnesium Stearate 1.8 grams
Preparation process: SN-1 and SN-2 are mixed with starch, add starch slurry and make softwood, granulation is placed on 80 ℃ of dry down backs in the whole grain of 12 mesh sieves, after the adding Magnesium Stearate mixes, and the Singlepunchtabletpress compressing tablet, promptly.
Embodiment 4: the preparation of drug combination of Capsule form
Form:
Compound S N-9 1 gram
Compound GJ-2 0.5 gram
Starch 150 grams
17% starch slurry is an amount of
Magnesium Stearate 1.8 grams
Preparation process: SN-9 and GJ-2 are mixed with starch, add starch slurry and make softwood, granulating is placed on 80 ℃ of down dry backs in the whole grain of 12 mesh sieves, the can capsule, promptly.Embodiment 5: the preparation of drug combination of injection form
Form:
Compound S N-9 2 grams
Compound S N-10 1 gram
Compound GJ-5 1 gram
Compound GJ-6 1 gram
430 milligrams in sodium-chlor
0.05 milliliter of tween 80
Water for injection adds to 5 milliliters
Preparation process: four kinds of compounds and sodium-chlor are mixed with 80% water for injection and tween 80, make its whole dissolvings, water for injection is added to 5 milliliters again, filter, embedding, 100 ℃ of sterilizations 30 minutes are promptly.
Invention has been described and explanation with reference to some specific embodiment, but those skilled in the art are to be understood that, can carry out multiple modification, change, modification, replacement, deletion or interpolation to described method and scheme, this does not deviate from the spirit and scope of the invention.Scope of the present invention is defined by the claims, and these claims should be interpreted as wide scope rationally.
Claims (32)
1. the iridoid shown in the general formula (I)
Or its pharmacologically acceptable salt
Wherein:
3-4,6-7 and 7-8 is two keys or singly-bound.
R
1Be H, OH, OCH
3, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace [MS3], n=0,1,2,3,4,5 or 6;
R
3, R
7And R
8Be H, CH independently
3, CHO, COOCH
3, COOH, CH
2OH, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
R
2, R
4, R
5And R
6Be H, OCH independently
3, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
Perhaps there is ternary oxygen ring with 7 and/or 7 with 8 interdigits at 6,
Condition is that described general formula (I) compound does not comprise following compound:
2. the compound of claim 1, wherein in general formula (I), 3-4 is two keys, R
2, R
3And R
6Be hydrogen, R
4And R
5Be hydroxyl, and R
8Be methyl.
3. the compound of claim 2, wherein said compound is
4. the compound of claim 2, wherein said compound is
5. the compound of claim 2, wherein said compound is
6. the compound of claim 2, wherein said compound is
7. the compound of claim 1, wherein in general formula (I), 3-4 and 7-8 are two keys, R
2, R
4, R
5, R
6And R
8Be hydrogen, and R
3Be COOCH
3
8. the compound of claim 7, wherein said compound is
9. the compound of claim 7, wherein said compound is
10. the compound of claim 7, wherein said compound is
11. the compound of claim 7, wherein said compound is
12. the iridoid shown in the general formula (I) or its pharmacologically acceptable salt are used for preventing or treating the purposes of the medicine of nerve degenerative diseases in preparation:
General formula (I)
Wherein:
3-4,6-7 and 7-8 is two keys or singly-bound.
R
1Be H, OH, OCH
3, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
R
3, R
7And R
8Be H, CH independently
3, CHO, COOCH
3, COOH, CH
2OH, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
R
2, R
4, R
5And R
6Be H, OCH independently
3, OH, straight chain glycosyl or side chain glycosyl; described glycosyl is selected from glucosyl group, galactosyl, mannose group, Arabic glycosyl, xylosyl, ribosyl, lysol glycosyl and husband's glycosyl, optional following acidylate group acidylate: the CH that is selected from of the hydroxyl in the sugar chain of described glycosyl
3(CH
2)
nCO, HOOC (CH
2)
nCO, benzoyl, phenylacetyl, hydrocinnamoyl, heterocycle formyl, heterocycle ethanoyl and heterocycle propionyl, described heterocycle is selected from pyrans, thiapyran, pyridine, pyrimidine, pyrazine, triazine, pyridazine, oxazine He Yi oxazine, wherein said phenyl ring and heterocycle can be chosen wantonly by one or more substituting groups that are selected from fluorine, chlorine, bromine, iodine, hydroxyl and alkoxyl group and replace n=0,1,2,3,4,5 or 6;
Perhaps there is ternary oxygen ring with 7 and/or 7 with 8 interdigits at 6.
13. the purposes of claim 12, wherein said nerve degenerative diseases are vascular dementia, vascular cognitive impairment, senile dementia, hypomnesis, cerebral tissue degeneration syndrome or cholinergic nerve degeneration.
14. the purposes of claim 12 or 13, wherein in general formula (I), 3-4 and 7-8 are two keys, R
2, R
4, R
5, R
6And R
8Be hydrogen, and R
3Be COOCH
3
15. the purposes of claim 14, wherein said compound is
16. the purposes of claim 14, wherein said compound is
17. the purposes of claim 14, wherein said compound is
18. the purposes of claim 14, wherein said compound is
19. the purposes of claim 12 or 13, wherein in general formula (I), 3-4 and 7-8 are two keys, R
2, R
4, R
5, R
6And R
8Be hydrogen, and R
3Be COOCH
3
20. the purposes of claim 19, wherein said compound is
21. the purposes of claim 19, wherein said compound is
22. the purposes of claim 19, wherein said compound is
23. the purposes of claim 19, wherein said compound is
24. the purposes of claim 12 or 13, wherein said compound is selected from
25. a pharmaceutical composition, described pharmaceutical composition comprise iridoid and the pharmaceutically acceptable carrier of the general formula (I) described in claim 1.
26. prepare the method for the described pharmaceutical composition of claim 25, described method comprises that the iridoid with the general formula described in claim 1 (I) mixes with pharmaceutically acceptable carrier.
27. the method for iridoid of the general formula (I) of preparation as claim 1 described in, described method comprise employing Chinese medicine radix scrophulariae and cape jasmine as raw material, extract and separate with solvent.
28. the method for claim 27, wherein said solvent are organic solvent and/or water.
29. the method for claim 28, wherein said organic solvent are lower alcohol.
30. the method for claim 29, wherein said lower alcohol is selected from methyl alcohol and ethanol.
31. the method for claim 28, wherein said organic solvent is selected from acetoneand ethyl acetate.
32. the method for claim 27, wherein said separation is undertaken by chromatography and/or extraction process.
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