CN103183719B - Saponin derivative and uses thereof - Google Patents
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- CN103183719B CN103183719B CN201210576694.4A CN201210576694A CN103183719B CN 103183719 B CN103183719 B CN 103183719B CN 201210576694 A CN201210576694 A CN 201210576694A CN 103183719 B CN103183719 B CN 103183719B
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Abstract
A kind of saponin derivative, its structure is shown below.Prove through experimentation on animals, this saponin derivative has significant antidepressant pharmacologically active, can be used as activeconstituents and makes medicine, food and healthcare products, is used for prevention and therapy dysthymia disorders separately or with other combinations of substances.
Description
Technical field
The present invention relates to a kind of saponin derivative, particularly relate to a kind of furostan type saponin derivative, and the application of this derivative in prevention and therapy dysthymia disorders.
Background technology
The dry rhizome that the wind-weed (having another name called rabbit oil grass, Dioscorea nipponica Mak. Ningpo Yam Rhizome) is the liliaceous plant wind-weed (Anemarrhena asphodeloides).Record according in " flora ", its property bitter cold, has nourishing Yin and falling fire, to moisturize laxation, sharp stool and urine effect.
The main chemical composition of the Chinese medicinal materials wind-weed has steroidal saponin, diphenyl pyrone class, polyose and lignin etc., as: timosaponin (glucoside) (timosaponin) A-I, A-II, A-III, A-IV, B-I, B-II and B-III, wherein, 1-timosaponin A-1-II, A-IV structure are still not clear.And timosaponin (amemarsaponin) A2, i.e. Ma Erkao sapogenin-3-O-β-D-glucopyranosyl (1 → 2)-β-D-galactopyranoside B(marlogenin-3-O-β-D-glucopyranosy(1 → 2)-β-D-galactopyranoside B), go semi-lactosi to replace to accuse saponin(e (desgalactotigonin), F-water caltrop takes off saponin(e (F-gitonin) and smilonin (smilageninoside) etc.In addition, also containing anemaran (anemaran) A/B/C/D, cis-Japan cypress Syringaresinol (cis-hinokiresinol), monomethyl-cis-Japan cypress Syringaresinol (monomethyl-cis-hinokiresinol), oxidation-cis-Japan cypress Syringaresinol (oxy-cis-himokiresinol), 2, 6, 4'-trihydroxy--4-methoxy benzophenone (2, 6, 4'-trihydroxy-4-methoxy benzophenone), p-hydroxyphenyl crotonol (p-hydroxyphenyl crotonic acid), pentacosoic acid ethene fat (pentacosyl vinyl ester), β-sitosterol (β-sitosterol), Mangiferin (mangiferin), nicotinic acid (nicotinic acid), niacinamide (nicotinamide) and pantothenic acid (pantothenic acid) etc.
Rhizoma Anemarrhenae saponin B-Ⅱ has improvement result (Neuroscience letter., 2007,421,147-151) to the learning memory disorder that cerebral ischemia causes.Timosaponin A-III is mainly through acetylcholine esterase inhibition, and the expression of the inflammation-inhibiting factor and have mitigation (Pharmacol.Biochem.Be., 2009,93,121-127) to lethe.
Existing many research proves, these materials contained by the wind-weed have therapeutic action to various diseases, as: Rhizoma Anemarrhenae total saponins can be used for treatment myocardial ischemia (CN1682873A), has also been used for the treatment of thrombotic diseases (WO2011/026259) with the medicament that timosaponin A-III and B-II make for main component.Timosaponin A-III can bring out human cervical carcinoma cell apoptosis, all prove that it has effect (the Cancer Res. for the treatment of coton and rectal cancer in vivo with in experiment in vitro, 2008,68,10229-10237), and there is the unusual effect suppressing vascular endothelial cell proliferation, for disease such as treatment tumour and rheumatoid arthritis etc., there is therapeutic action (CN102030812A).
Recent correlative study also shows, the total soap of the wind-weed has antidepressant effect on multiple depression model, may relevant with its enhancing norepinephrine energy and serotonin nervous system (new Chinese medicine and clinical pharmacology, 2007,18,29).Verified by experimentation on animals, Sarsasapogenin contained in the wind-weed has certain effect to mouse experiment depression, can affect the activity of Dopamine HCL and monoamine oxidase in mouse brain, and make such sapogenin have antidepressant activity (Biol.Pharm.Bull., 2006,29,2304-2306).The research of the people such as Yi Jia finds, Rhizoma Anemarrhenae saponin B-Ⅱ has antidepressant activity, its mechanism of action may with the relevant (CN101214253A of 5-HT and DA action of nervous system in enhancing brain; Pharmacy practice magazine, 2010,28,283-287).
The traditional Chinese medical science is thought, dysthymia disorders is many because being worried excessively, and internal lesion caused by overexertion heart spleen is disease, and treatment should with tranquillizing by calming the heart, and nourishing the blood and yin is main.Therefore, be used in major part in the prescription of Chinese traditional treatment dysthymia disorders, the wind-weed is also the Chinese medicinal materials comparatively commonly used simply.The antidepressant drug that current application is comparatively commonly used clinically has: three rings and tetracyclic antidepressants, oxidase inhibitor, selectivity 5-HT cell reabsorption inhibitor (SSRI), atypical antidepressants and lithium salts etc.
In recent years, most widely used clinically SSRI class medicine---there is many untoward reactions in fluoxetine, as: whole body or local anaphylaxis, (Chinese Journal of Modern Applied Pharmacy, 2008,25, the 763-765 such as functional gastrointestinal disorder; Chinese Journal of New Drugs, 2001,10,20; Chinese journals of practical medicine, 2004,20,318-319).Have research to point out, young children likely increases introgression after taking fluoxetine, also reports that taking fluoxetine may cause violent tenet to strengthen and congenital cardiovascular inborn defect.
SSRI class medicine---Sertraline (Sertraline) is the antidepressant brand medicine that U.S.'s recipe quantity is larger, but easily cause (the Chinese Journal of New Drugs and Clinical Remedies such as patient's sinus tachycardia and ST-T change, 2002,21,711-713) untoward reaction, can cause maniac access to a certain extent or turn hot-tempered (foreign medical science psychiatry fascicle, 2004 in treatment paralepsy process, 3l, 104).
Though Venlafaxine is the same with clomipramine be easy to tolerance, about there is the medication person of l/3 that reaction of feeling sick can occur, comparatively obvious in several weeks starting medication especially.Untoward reaction caused by the Venlafaxine found has malin syndrome, it is manic to bring out, purpura, illusion, all standing cause illusion, withdrawal symptom, 5-HT syndrome, uncomfortable in chest, dizzy, ypotension, menelipsis and intraocular pressure rising etc., to turn higher (the Clinical Psychological Medicine magazine of hot-tempered rate of children, 2002,12,382).
According to World Health Organization's scholarly forecast, society to the year two thousand twenty dysthymia disorders always bears and will rise to first in all Disease Spectrum, and the bioactive molecule contained by being used for the treatment of in the medicine of dysthymia disorders activity mainly relies on the mode of chemosynthesis to obtain, mostly there is the problems such as toxic side effect is large, antidepressant spectrum is narrow and expensive, our country connects subject patients with depression at present only has 2%, has potential high risks to family and society.Therefore, research and develop safe, effective and inexpensive antidepressant original new drug and seem particularly necessary.
Chinese medicine and natural drug are one of important sources of innovation drug research exploitation.In recent years, international and domestic have the researches on natural drugs of antidepressant effect to Herba Hyperici perforati etc. and exploitation achieves a series of achievement (contemporary Chinese Chinese medicine, 2009,11,6-9; Chinese patent medicine, 2006,28,713-716; Guangdong medical science, 2005,859-860; Nanjing University of Traditional Chinese Medicine's journal, 2001,17,294-298; Liberation office Acta Pharmaceutica Sinica, 2003,19,426-428; Pharmacy practice magazine, 2004,22,104-105; Pharm.Biol., 2006,44,503-510).But the listing of the new Chinese medicine of so far there are no Cure of depression, also rarely has the research of this respect chemical structure and Pharmacodynamical mechanism relation to report.
Summary of the invention
One object of the present invention is to provide a kind of steroidal saponin derivative, has antidepressant pharmacological action, can be used as activeconstituents for the preparation for the treatment of and the medicine of prevention of depression.
Another object of the present invention is to provide a kind of furostan type saponin derivative, has antidepressant pharmacological action, can be used as activeconstituents for the preparation for the treatment of and the medicine of prevention of depression.
Another object of the present invention is to provide a kind of by timosaponin B-III or the furostan type saponin derivative producing from the Chinese medicinal materials wind-weed and obtain, has antidepressant pharmacological action.
Another object of the present invention is to provide a kind of composition, with provided saponin derivative for activeconstituents makes medicine, food and healthcare products, is used for prevention and therapy dysthymia disorders separately or with other combinations of substances.
" saponin derivative " alleged by the present invention refers to saponin derivative and formed pharmacy acceptable salt, as: but be not limited only to hydrochloride, vitriol, carbonate, supercarbonate, acetate, sylvite, sodium salt, calcium salt, magnesium salts, barium salt, manganese salt, zinc salt, molysite and quaternary ammonium salt etc.
" furostan type saponin derivative " alleged by the present invention refers to furostan type saponin derivative and formed pharmacy acceptable salt, as: but be not limited only to hydrochloride, vitriol, carbonate, supercarbonate, acetate, sylvite, sodium salt, calcium salt, magnesium salts, barium salt, manganese salt, zinc salt, molysite and quaternary ammonium salt etc.
" producing from the Chinese medicinal materials wind-weed and the furostan type saponin derivative obtained " alleged by the present invention refers to this derivative and various mineral acid, mineral alkali, compound formed by organic acid or organic bases, comprise in the process producing furostan type saponin derivative from the Chinese medicinal materials wind-weed, furostan type saponin derivative and the direct or indirect precursor compound (as: timosaponin B-III) that generates this derivative thereof with produce pharmacy acceptable salt formed by used all ingredients, as: hydrochloride, vitriol, carbonate, supercarbonate, acetate, sodium salt, sylvite or quaternary ammonium salt etc.
" the Chinese medicinal materials wind-weed " alleged by the present invention refers to the various piece of the liliaceous plant wind-weed (Anemarrhena asphodeloides), as: root, stem, page and fruit etc., due to maximum target saponin derivatives can be produced from the rhizome of this plant, the rhizome of therefore its drying of prioritizing selection of the present invention.These rhizoma ane marrhenaes select materials and whether concocting process meets Chinese medicinal materials complete processing and standard must not limit the present invention.
" dysthymia disorders (depression) " alleged by the present invention belongs to affective disorders disease (mood disorders), is a kind of with the low syndrome for principal character of remarkable and lasting mental state.Usually said dysthymia disorders refers to major depression (major depression) (Chinese experimental pharmacology of traditional Chinese medical formulae magazine, 2005,11,46 clinically; Pharmacy practice magazine, 2008,26,282).The patient of dysthymia disorders is often with anxiety symptom, and anxiety can increase the weight of again depressed development (Chinese Clinical rehabilitation, 2006,10,58).Depressive episode is low based on mental state, unbecoming with its situation, can, from depressed to extremely grieved, even occur numb.The psychotic symptoms such as illusion, vain hope can be there is in severe patient.The anxiety of some case and mobility intense very remarkable.Its Case definition is also low based on mental state, and with having following listed 4 at least: the happy sense of (1) hebetude, nothing; (2) energy goes down or tired sense; (3) psychomotor activity is sluggish or intense; (4) too low, the self-accusation of self-assessment, or has feeling of guilt; (5) association difficulty or conscious elaborative faculty decline; (6) repeatedly there is the thought of wanting to die or have suicide, autolesionism; (7) somnopathy, as insomnia, early awakening, or hypersomnia; (8) appetite reduction or body weight obviously alleviate; And (9) hyposexuality.And social function is impaired, to cause suffering to me or adverse consequences then belongs to the serious standard of PD.With regard to its course of disease angle, patient meets symptom standard and serious standard continues 2 weeks at least; Some fissility symptom can be there is, but do not meet the diagnosis of Split disease.If meet the symptom standard of Split disease simultaneously, after division remission, meet paralepsy standard at least 2 week (Chinese Spirit Obstacles classification and Case definition [M], Jinan: Shandong science tech publishing house, 2001,28-35).
" antidepressant " alleged by the present invention refers to the object that can play treatment to the symptom of patients with depression, improve or cure, and improves so that recover normal to make the state of an illness of patient.
" forced swim test (Forced Swimming Test alleged by the present invention, FST) " or " animal models of depression of forced swimming " refer to by laboratory animal (as: mouse) is placed in one limitation environment (as: water), animal in this context risk one's life struggle make an attempt at escaping and cannot escape, thus provide one without avoidable compressing environment, after the experiment of for some time, namely animal shows typically " motionless state ", in fact animal abandons the hope escaped, reflect one to be referred to as " behavioral despair state ", record is in the series of parameters in the motionless state procedure of the animal generation despair of this environment.This system uses camera to experimentation video recording and carries out trace analysis with corresponding software to image, and reduce manual operation, data have objectivity.The animal models of depression of forced swimming, be research human depression's pharmacology and pathogeny thereof, screening to observe in antidepressant drug research reliably experimental model, its main feature is pharmaceutically-active high degree of specificity, this experiment can be good at antidepressant drug and strong stabilizing to be distinguished with anxiolytic, and the effect that produces of most of thymoleptic and clinical potency significant correlation (Arch.Int.Pharmacodyn.Ther., 1977,229,327-336; Neurosei.Biobehav.Rev., 1995,19,377-395).
" tail-suspention test (Tail Suspension Test, TST) " alleged by the present invention is a kind of method of classics and energy Fast Evaluation antidepressant drug drug effect.Its principle is that after utilizing mouse tail suspension, attempt is escaped but cannot escape, thus abandons struggling, and enter the motionless state of distinctive depression, recording the animal dead time in experimentation reflects depressive state, and antidepressant drug can shorten significantly and change its state.
" organism ", " animal " or " patient " alleged by the present invention refers to people, wildlife and domestic animal (Livestock).Wildlife is the animal without domestication under state of nature.Domestic animal is the animal in order to provide food source and artificial breeding, as: but be not limited only to dog, cat, mouse, rat, hamster, pig, rabbit, milk cow, buffalo, bull, sheep, goat, goose and chicken etc.Give " patient ", " animal " or " organism " prioritizing selection Mammals treated, especially people.
" prevention " alleged by the present invention refers to before the disease do not assert by clinical criteria, various for preventing means or the measure of disease generation or development, comprises the method for medical science, physics or chemistry, to stop and to reduce generation or the development of the various symptom of disease.
" treatment " alleged by the present invention refers to generation or development in order to stop and reduce disease, make the development of disease course or increase the weight of to be suppressed, contain, alleviate, improve, slow down, stop, postponing or reverse, various indexs that are disease when described maintenance and/or medication, disorderly or pathologic state comprise and alleviate or reduces symptom or complication, or cure or eliminate a disease, disorder or situation.
" food " alleged by the present invention refers to that comprising various saponin derivative provided by the invention makes edible single compound or composition.Production and the manufacture of this kind of single compound or composition should meet relevant food safety standards, but these food security standards must not limit the present invention.
" healthcare products " alleged by the present invention refer to and make edible single compound or composition to impose on patient by comprising various saponin derivative provided by the invention, play the object of disease being carried out to prevention and therapy.It belongs to the food alleged by the present invention, but its produce, produce and market also should meet various relevant requirement, standards and norms.
" medicine " alleged by the present invention refers to the composition, Chinese medicinal materials and the extract thereof that may be used for preventing or treat the single compound of certain disease, multiple compounds is formed, or refer to take single compound as composition or the preparation (formulation) of main active ingredient, also refer to be composition or the preparation of activeconstituents by multiple compounds." medicine " is interpreted as not only referring to the legal provisions according to a state, the administrative organization set up by it is examined and grants the product produced, also refer in order to obtain by examining and granting in the process of production, what formed is all kinds of physical forms of activeconstituents containing single compound." formation " is interpreted as being obtained by approach such as chemosynthesis, bio-transformation or purchases.
" preparation " alleged by the present invention refers to the formulation being conducive to administration (drug delivery) containing isoflavonoid of the present invention, as: but be not limited only to, aqueous solution injection, powder injection, pill, powder, tablet, patch, suppository, emulsion, creme, gelifying agent, granule, capsule, aerosol, sprays, powder inhalation, sustained release dosage and control-released agent etc.These pharmaceutical excipients both can be conventional in various preparation uses, as: but be not limited only to, isotonic agent, damping fluid, correctives, vehicle, weighting agent, tackiness agent, disintegrating agent and lubricant etc.; Also can in order to adapt and choice for use with described material, as: emulsifying agent, solubilizing agent, fungistat, pain killer and oxidation inhibitor etc., this kind of auxiliary material effectively can improve the stability of compound contained by composition and the rate of release of solvability or change compound and uptake rate etc., thus improve the compounds of this invention metabolism in vivo, and then strengthen administering effect.In addition, can also for realizing specific administration object or mode, as: sustained-release administration, controlled release drug administration and pulsatile administration etc., and the auxiliary material used, as: but be not limited only to, gelatin, albumin, chitosan, polyethers and polyester macromolecular material, as: but be not limited only to, polyoxyethylene glycol, urethane, polycarbonate and multipolymer thereof etc.The main manifestations of alleged " being conducive to administration " has: but be not limited only to improve result for the treatment of, raising bioavailability, reduce toxic side effect and improve patient's conformability etc.
" dose therapeutically effective " alleged by the present invention refers to the symptom that can slow down in various pathological significance and uses the compounds of this invention as the amount of activeconstituents, the amount given generally is determined according to the body weight of organism, as: every day gives total amount 0.05mg/kg-50mg/kg.According to the practical situation of organism and the state of an illness thereof, amount used and number of times used can also adjust, as: every day gives total amount 0.05-0.5mg/kg, 0.6-1mg/kg, 1-10mg/kg, 11-25mg/kg, 26-40mg/kg or 41-50mg/kg more than 2 times.According to the difference of the formulation of medicine, that gives will also can change, as: conventional tablet needs to give 10mg/kg, and the amount adopting sustained-release preparation then required is lower.The given dose of steroidal saponin derivative of the present invention needs to be determined according to specific circumstances, as the state of patient when the mode of: administration, route of administration, administration and the pathological conditions etc. when treating.
" basic compound " alleged by the present invention is the compound replacing all variable substituting groups on structural formula of compound with " hydrogen " and obtain.For example, " hydrogen " is replaced as shown in the formula the substituent R in structure shown in I simultaneously
1, R
2and R
3the compound obtained, is basic compound.
" substituting group " alleged by the present invention refers to one or more general designations that are inorganic or organic group replacing specific position hydrogen atom on basic compound, and it can be atom, molecule, ion, compound and polymkeric substance etc.
" halogen " alleged by the present invention comprises fluorine, chlorine, bromine and iodine, and with the aggregate manner of-F ,-Cl ,-Br and-I alternatively base be applied to basic compound.
" sulfate group " alleged by the present invention is-OSO
3h ,-OSO
3na ,-OSO
3k and-OSO
3nH
4.
" phosphate-based " alleged by the present invention is-OPO (HO)
2, and on it, hydrogen is substituted formed pharmacy acceptable salt.
" trifluoroacetic acid base " alleged by the present invention is-OCOCF
3.
" amino of replacement " alleged by the present invention is the amino that amino upper hydrogen is partly or entirely replaced by C1-C3 saturated alkane, as: but be not limited only to methylamino-and dimethylamino.
The straight or branched alkane that " C1-C3 saturated alkane " alleged by the present invention is carbonatoms 1-3.Wherein, letter C represents carbon atom, and numeral is positive integer thereafter, as: 1,2 or 3 etc., represent the carbon atom number contained by group, as: methane, ethane and propane etc.
" sugar " alleged by the present invention, also known as " carbohydrate ", for the basic organism of a class in chemistry or biological chemistry, be with elementary composition poly-hydroxy (the being greater than 2) aldehyde of C, H and O, polyhydroxyketone (being greater than 2) and can be hydrolyzed and generate the organic compound of poly-hydroxy aldehyde or polyhydroxyketone." monose ", " disaccharides " and " polysaccharide " can be divided into by its molecular structure.By the organic compound of several monosaccharide molecule via glycosidic link condensation, also known as " sugar chain ".Prioritizing selection monose of the present invention or disaccharides alternatively base are applied to basic compound.
" monose (monosaccharide) " alleged by the present invention refers to the elementary composition a kind of organic compound of C, H and O, is also to form the elementary cell of other glucide, is generally the organism of poly-hydroxy aldehyde containing 3-6 carbon atom or polyhydroxyketone.Prioritizing selection carbon atom is poly-hydroxy aldehyde or the polyhydroxyketone organism of 5 or 6, also claim " pentose " and " sugared " as: but be not limited only to ribose, wood sugar, pectinose, glucose, seminose, semi-lactosi, psicose, fructose, sorbose, tagatose, gulose, she shuts out sugar, talose, allose and altrose etc.In monose structure of the present invention, O element can be S element portions or replacing whole.
" disaccharides (disaccharide) " alleged by the present invention refers to the elementary composition a kind of organic compound of C, H and O, be generally the mode forming glycosidic link by condensation and dehydration by 2 monosaccharide molecule is formed by connecting, the disaccharides known is as sucrose, lactose, cellobiose, trehalose and maltose etc.Between monosaccharide molecule formed glycosidic link as: but be not limited only to α-1,1-, α-1,2-, α-1,3-, α-Isosorbide-5-Nitrae-, several glycosidic link form such as β-Isosorbide-5-Nitrae-and α-1,6-.In disaccharides structure of the present invention, O element can be S element portions or replacing whole.
" polysaccharide (polysaccharide) " alleged by the present invention also comprises oligosaccharides (oligosaccharide), referring to the elementary composition a kind of organic compound of C, H and O, is generally the polymkeric substance of the linear or branch be formed by connecting by the mode that condensation and dehydration form glycosidic link by more than 3 monosaccharide molecule.The polymkeric substance of the linear or branch that a prioritizing selection 3-15 monosaccharide molecule is formed by connecting by glycosidic link, the polysaccharide known is as gentianose, melizitose, acacia trisaccharide, verbascose, stachyose and raffinose etc.Between monosaccharide molecule formed glycosidic link as: but be not limited only to α-Isosorbide-5-Nitrae-, several glycosidic link form such as β-Isosorbide-5-Nitrae-and α-1,6-.In polysaccharide structures of the present invention, O element can be S element portions or replacing whole.
Saturated or the unsaturated hydrocarbons of the straight or branched that " alcohol of C1-C6 " alleged by the present invention replaces for one or more hydroxyl.Wherein, letter C represents carbon atom, and numeral is positive integer thereafter, as: 1,2,3,4 or 5 etc., represent the carbon atom number contained by group, as: methyl alcohol, ethanol, propyl alcohol, Virahol and propyl carbinol etc.
A kind of saponin derivative provided by the invention, is specially furostan type saponin derivative, and its structure is such as formula shown in I.Wherein, R
1represent a kind of substituting group, be selected from a kind of group of the amino that-OH ,-SH, halogen and C1-C3 saturated alkane replace; R
2represent a kind of substituting group, be selected from-OH ,-SH, a kind of group of sugar that amino that halogen, sulfate group, phosphate-based, trifluoroacetic acid base, C1-C3 saturated alkane replace, the sugar that connected by O-glycosides key are connected with by S-glycosides key.
formula I
Another kind of saponin derivative provided by the invention, its structure such as formula shown in I, wherein R
1represent a kind of substituting group, be selected from a kind of group of the amino that-OH ,-SH, halogen and C1-C3 saturated alkane replace; R
2represent a kind of substituting group, be selected from-OH ,-SH, a kind of group of monose that amino that halogen, sulfate group, phosphate-based, trifluoroacetic acid base, C1-C3 saturated alkane replace, the monose that connected by O-glycosides key are connected with by S-glycosides key.
Another kind of saponin derivative provided by the invention, its structure such as formula shown in I, wherein R
1represent a kind of substituting group, be selected from-OH or-SH; R
2represent a kind of substituting group, be selected from-OH ,-SH, a kind of group of monose that amino that halogen, sulfate group, phosphate-based, trifluoroacetic acid base, C1-C3 saturated alkane replace, the monose that connected by O-glycosides key are connected with by S-glycosides key.
Another kind of saponin derivative provided by the invention, its structure such as formula shown in II, wherein R
2represent a kind of substituting group, be selected from-OH ,-SH, a kind of group of monose that amino that halogen, sulfate group, phosphate-based, trifluoroacetic acid base, C1-C3 saturated alkane replace, the monose that connected by O-glycosides key are connected with by S-glycosides key.
formula II
Another kind of saponin derivative provided by the invention, its structure is such as formula shown in III-I.
formula III-I
Another kind of saponin derivative provided by the invention, its structure is such as formula shown in III-II.
formula III-II
Various steroidal saponin derivative provided by the invention; various ways can be adopted to produce and obtain; as timosaponin B-III or timosaponin B-III sapogenin are dissolved in solvent; after adding various necessary reagent; reaction under rare gas element (as: but being not limited only to nitrogen, hydrogen or helium) protection; after reaction terminates, adopt the quencher termination reactions such as Trimethylamine 99, triethylamine, sodium bicarbonate or Sulfothiorine.Products therefrom adopts filler to be the column chromatography for separation of silica gel, aluminum oxide, ODS or macroporous resin etc., be separated solvent used as: but be not limited only to one or more of tetrahydrofuran (THF), sherwood oil, ethyl acetate, DMF, pyridine, methylene dichloride, ethanol, methyl alcohol or water.
One provided by the invention obtains the various saponin derivative of the present invention comparatively direct method, with timosaponin B-III for raw material be hydrolyzed after be isolated, its concrete grammar as: by timosaponin B-III parts by weight and solvent, (solvent can be the aqueous solution of 10v/v%-100v/v%C1-C6 alcohol and the aqueous solution of other common organic solvents, or add solubility promoter in water, as: tensio-active agent) volume ratio 1: 0.2-10, timosaponin B-III is dissolved in container, mineral acid is added by timosaponin B-III parts by weight and mineral acid (as: hydrochloric acid and sulfuric acid etc.) volume ratio 1: 1-4, in 60 DEG C-100 DEG C reaction 1-10 hour, stopped reaction afterwards, add appropriate alkaline liquor (as: sodium bicarbonate and sodium hydroxide) in reaction solution and be neutralized to pH6-8, extract 1-3 time by timosaponin B-III parts by weight and propyl carbinol volume ratio 1: 1-10, merge n-butanol portion, decompression and solvent recovery, obtain solids.The conventional organic solvent (as: acetonitrile and methyl alcohol etc.) of solids dissolves, type, semi-preparative or preparation HPLC or open ODS post are separated and collect main chromatographic peak by analysis, solution containing target product of the present invention is after recycling design, obtain micro-yellow or white product, be furostan type saponin derivative of the present invention.
Multiple direct or indirect method can obtain various saponin derivative provided by the present invention, pharmacy acceptable salt or its composition.Those skilled in the art will envision that, timosaponin B-III (as: CN101307090A) is first extracted from the wind-weed or its extract, various furostan type saponin derivative provided by the invention indirectly can be produced again through above-mentioned disclosed acid hydrolysis process, as: after the timosaponin B-III obtained from the Chinese medicinal materials wind-weed is hydrolyzed, through being separated the furostan type saponin derivative shown in obtained formula I.In addition, also can obtain target derivative of the present invention by timosaponin B-III sapogenin, and other such as: organic synthesis, the complete synthesis and mode such as biocatalysis and conversion of extracting and developing and purifying, chemistry equally also can obtain these derivatives from organism meta-bolites.Necessity that various preparation methods cited by the present invention should be understood to enforcement technical solution of the present invention is carried out discloses.Those skilled in the art according to the instruction of textbook and laboratory manual, and can obtain saponin derivative of the present invention by necessary experiment, and the method for the acquisition saponin derivative described in these must not as limitation of the invention.
Various saponin derivative provided by the invention can as the medicine of unique or main activeconstituents for the preparation of prevention or treatment virus disease, or have the chemical substance of antidepressant effect with other one or more or medicine gives organism in the lump.These chemical substances as: but be not limited only to Rhizoma Anemarrhenae extract, Rhizoma Anemarrhenae total saponins and hydrolyzate thereof, Rhizoma Anemarrhenae saponin B-Ⅱ and hydrolyzate, timosaponin B-III sapogenin, timosaponin B-III and hydrolyzate, three rings and tetracyclic antidepressants, oxidase inhibitor, selectivity 5-HT cell reabsorption inhibitor (SSRI), atypical antidepressants and lithium salts etc.Alleged " giving organism in the lump " refers to that the various saponin derivative of the present invention separately or have with other one or more after compound of antidepressant effect or medicament mixed through single route of administration, as: but be not limited only to, oral (Oral), nasal cavity (Nasal), (face) cheek (Buccal), transdermal (Transdermal), lung (Pulmonal), vagina (Vaginal), subcutaneous (Subcutaneous) or vein (Intravenous) give organism; Or there is with other one or more chemical substance of antidepressant effect or medicine gives organism through multiple route of administration respectively, as: but the oral preparations being not limited only to quick-release coordinates with the implant preparation of slow controlled release.
Prove through forced swim test and tail-suspention test, give organism by the furostan type saponin derivative shown in the formula I of dose therapeutically effective, organism depressive symptom can be made to improve or eliminate.Show thus, furostan type saponin derivative provided by the invention has significant antidepressant activity, with it for activeconstituents makes medicine, food and healthcare products, is applied to the prevention and therapy of dysthymia disorders.
A kind of pharmaceutical composition provided by the invention, with provided various furostan type saponin derivatives for activeconstituents is for prevention and therapy dysthymia disorders.
A kind of food provided by the invention, with provided various furostan type saponin derivatives for activeconstituents is for prevention and therapy dysthymia disorders.
A kind of healthcare products provided by the invention, with provided various furostan type saponin derivatives for activeconstituents is for prevention and therapy dysthymia disorders.
The beneficial effect that technical solution of the present invention realizes:
Furostan type saponin derivative shown in formula I, especially such as formula the furostan type saponin derivative of the structure conformation shown in III-I and III-II, there is significant antidepressant pharmacologically active, can be used as activeconstituents and make medicine, food and healthcare products, be used for the prevention and therapy of dysthymia disorders separately or with other combinations of substances.
Accompanying drawing explanation
Fig. 1 is formula III-I
1h NMR composes (400MHz, Pyr-d
5);
Fig. 2 is formula III-I
13c-NMR spectrum and DEPT135 compose (100MHz, Pyr-d
5);
Fig. 3 is that formula III-II HMBC composes (Pyr-d
5);
Fig. 4 is that formula III-II ROESY composes (Pyr-d
5);
Fig. 5 is formula III-II HMBC correlogram, and in figure, " → " represents the long-range correlationship of hydrogen carbon;
Fig. 6 is formula III-II ROESY correlogram, in figure " ← → " represent hydrogen hydrogen NOE correlationship.
Embodiment
Technical scheme of the present invention is described in detail below in conjunction with accompanying drawing.The embodiment of the present invention is only in order to illustrate technical scheme of the present invention and unrestricted, although with reference to preferred embodiment to invention has been detailed description, those of ordinary skill in the art is to be understood that, can modify to the technical scheme of invention or equivalent replacement, and not departing from the spirit and scope of technical solution of the present invention, it all should be encompassed in right of the present invention.
If the present invention's reagent used does not clearly indicate, then all purchased from Sigma-Aldrich (Sigma-Aldrich).
Producing of embodiment 1 furostan type saponin(e monosaccharide derivatives
With timosaponin B-III for start material produces furostan type saponin(e monosaccharide derivatives, concrete steps are as follows:
(1) 0.05mol timosaponin B-III is dissolved in methanol solution that 300ml volume ratio is 10v/v% (water or 30v/v% ethanolic soln or 1w/v% tween solution), adds the 0.5ml-1ml vitriol oil, 80 DEG C-150 DEG C reactions 1 hour-6 hours.
(2) above-mentioned reaction solution sodium hydroxide is regulated pH=6-7.
(3) divide 3 rear gained solution of extraction step (2) neutralization with 900ml-1200ml propyl carbinol, extraction liquid is evaporated to evaporate to dryness.
(4) with water by above-mentioned dissolution of solid, and after making saponin(e be adsorbed in ODS post, by the methanol-eluted fractions of 40v/v%-60v/v%, collect elutriant.
(5) reclaimed by solution decompression, namely evaporate to dryness obtains furostan type saponin(e monosaccharide derivatives 2(NMR: refer to table 1).
Producing of embodiment 2 furostan type saponin derivative
(1) 0.05mol timosaponin B-III being dissolved in 300mL volume ratio is in the methanol solution (water or 30% ethanolic soln or 1% tween solution) of 10%, adds 2mL-4mL concentrated hydrochloric acid, 80-150 DEG C of reaction 1 hour ~ 6 hours.
(2) above-mentioned reaction solution sodium hydroxide is regulated pH=6-7.
(3) divide 3 rear gained solution of extraction step (2) neutralization with 900mL-1200mL propyl carbinol, extraction liquid is evaporated to evaporate to dryness.
(4) with water by above-mentioned dissolution of solid, and after making saponin(e be adsorbed in ODS post, by the methanol-eluted fractions of 40v/v% ~ 60v/v%, collect elutriant.
(5) reclaimed by solution decompression, namely evaporate to dryness obtains furostan type saponin(e monosaccharide derivatives 2(NMR: refer to table 1).
Producing of embodiment 3 furostan type saponin(e monosaccharide derivatives
With timosaponin B-III for start material produces furostan type saponin(e monosaccharide derivatives, concrete steps are as follows:
(1) 0.1mol timosaponin B-III being dissolved in 600ml volume ratio is in the methanol solution of 10v/v%, adds 30ml-50ml concentrated hydrochloric acid, and 80 DEG C-100 DEG C are reacted 2 hours.
(2) pH=6-7 is adjusted to sodium hydroxide.
(3) divide 3 rear gained solution of extraction step (2) neutralization with 1.8L-2.4L propyl carbinol, extraction liquid is evaporated to evaporate to dryness.
(4) with water by above-mentioned dissolution of solid, and after making saponin(e be adsorbed in ODS post, by the methanol-eluted fractions of 40v/v%-60v/v%, collect elutriant.
(5) reclaimed by solution decompression, namely evaporate to dryness obtains the aglycon 3(NMR:30.63 (1-C) of timosaponin B-III; 27.14 (2-C); 66.07 (3-C); 34.41 (4-C); 37.04 (5-C); 26.97 (6-C); 28.65 (7-C); 35.27 (8-C); 40.02 (9-C); 35.57 (10-C); 21.38 (11-C); 40.15 (12-C); 43.88 (13-C); 54.83 (14-C); 31.39 (15-C); 84.59 (16-C); 64.68 (17-C); 14.45 (18-C); 24.26 (19-C); 103.59 (20-C); 11.83 (21-C); 152.38 (22-C); 34.41 (23-C); 23.62 (24-C); 33.68 (25-C); 68.76 (26-C); 17.16 (27-C)).
(6) aglycon of 0.05mol timosaponin B-III and 0.05mol-0.07mol reagent T1 methylene dichloride are dissolved, cool to-20 DEG C-0 DEG C under nitrogen protection, add 0.91ml-1.4mlCF
3sO
3si (CH
3)
3, react after 40 minutes-1 hour and stop.
(7) add triethylamine cancellation reaction, decompression is spin-dried for solvent.
(8) precipitation joins 200mLCH
2cl
2in-MeOH (2: 1, v/v) solution, then add the methanol solution of sodium methylate 50ml of 1mol/L-1.5mol/L, reaction 3-5 hour, evaporate to dryness reaction solution
(9) with water by above-mentioned dissolution of solid, and after making saponin(e be adsorbed in ODS post, by the methanol-eluted fractions of 40v/v%-60v/v%, collect elutriant.Reclaimed by solution decompression, namely evaporate to dryness obtains furostan type saponin(e monosaccharide derivatives 2.
Producing of embodiment 4 furostan type saponin(e iodo derivative
The aglycon 3 of the timosaponin B-III obtained with embodiment 3 is for start material, and produce furostan type saponin(e iodo derivative, concrete steps are as follows:
(1) the saponin(e aglycon 0.05mol (5) step in embodiment 3 obtained and 0.05mol sodium iodide were dissolved in 150ml-200ml2-butanone, 25 DEG C-50 DEG C reactions 1 hour-3 hours.
(2) after reaction terminates, reaction solution is poured in 1.25L-2L water, filter, and wash twice with water.
(3) by filtration cakes torrefaction, recrystallizing methanol is used.
(4) filter, desciccate, obtains furostan type saponin(e iodo derivative 4(NMR:30.60 (1-C); 27.27 (2-C); 66.05 (3-C); 37.37 (4-C); 40.68 (5-C); 27.22 (6-C); 29.64 (7-C); 34.92 (8-C); 40.02 (9-C); 35.57 (10-C); 21.38 (11-C); 40.15 (12-C); 43.88 (13-C); 54.83 (14-C); 31.39 (15-C); 84.59 (16-C); 64.68 (17-C); 14.45 (18-C); 24.26 (19-C); 103.59 (20-C); 11.83 (21-C); 152.38 (22-C); 17.14 (23-C); 32.62 (24-C); 35.82 (25-C); 32.87 (26-C); 20.23 (27-C)).
Producing of embodiment 5 furostan type saponin(e bromo derivative
The aglycon 3 of the timosaponin B-III obtained with embodiment 3 is for start material, and produce furostan type saponin(e bromo derivative, concrete steps are as follows:
(1) the saponin(e aglycon 0.05mol that (5) step in embodiment 3 obtains is dissolved in 250ml-300mlCH
2cl
2in, add 25ml-30ml Eorontrifluoride etherate complexometric reagent (CAS:109-63-7), drip acetic anhydride 0.05mol-0.1mol, 20 DEG C-60 DEG C are reacted 30 minutes-1 hour, wash reaction solution, then use 750ml-1L washed reaction liquid with saturated NaCl aqueous solution 1L, separate organic phase, use Na
2sO
4dry; Organic phase filtered, be spin-dried for filtrate, use purification by silica gel column chromatography product, developping agent is sherwood oil and the ethyl acetate of volume ratio 6:1.
(2) step (1) products therefrom is dissolved in 250ml-300ml tetrahydrofuran solution, adds 0.05mol-0.1molNBS and 0.005mol-0.01mol (Ph)
3p, normal-temperature reaction 5 hours-7 hours.
(3) filtering reacting liquid, the dry solvent of vacuum rotary steam, adds 200mLCH
2cl
2-MeOH (2: 1, v/v) solution extraction, adds the methanol solution of sodium methylate 50ml-100ml of 1mol/L-1.5mol/L, and 20 DEG C-50 DEG C are reacted 5 hours-8 hours.
(4) underpressure distillation, concentration response, with ethanol and ethyl acetate mixtures recrystallization, obtains end product furostan type saponin(e bromo derivative 7(NMR:31.52 (1-C); 26.44 (2-C); 33.85 (3-C); 38.32 (4-C); 40.68 (5-C); 27.22 (6-C); 29.64 (7-C); 34.92 (8-C); 40.02 (9-C); 35.57 (10-C); 21.38 (11-C); 40.15 (12-C); 43.88 (13-C); 54.83 (14-C); 31.39 (15-C); 84.59 (16-C); 64.68 (17-C); 14.45 (18-C); 24.26 (19-C); 103.59 (20-C); 11.83 (21-C); 152.38 (22-C); 34.41 (23-C); 23.63 (24-C); 35.43 (25-C); 68.07 (26-C); 17.04 (27-C)).
Embodiment 6 furostan type saponin(e phosphoric acid ester producing for derivative
The aglycon 3 of the timosaponin B-III obtained with embodiment 3 is for start material, and produce furostan type saponin(e phosphoric acid ester for derivative, concrete steps are as follows:
(1) the saponin(e aglycon 0.05mol that (5) step in embodiment 3 obtains is dissolved in 200ml tetrahydrofuran (THF) is cooled to--50 DEG C-20 DEG C, slowly add the pyrophosphoryl chloride of 0.25mol-0.3mol wherein, keep temperature-resistant, react l hour-3 hours.
(2) dilute with water reaction solution, is warmed up to 40 DEG C about-60 DEG C, adds a certain amount of Na wherein
2cO
3release to bubble-free, 25 DEG C of-35 DEG C of stirring reactions 0.5 hour-1.5 hours, filter, layering, lower aqueous solution steams to without obvious bubble at 50 DEG C of backspins.Add hydrochloric acid wherein, regulate pH=1-2, separate out white precipitate.
(3) filtering-depositing, precipitates three times with acid elution, dry product furostan type saponin(e phosphoric acid ester for derivative 8(NMR:30.60 (1-C); 27.27 (2-C); 66.05 (3-C); 37.37 (4-C); 40.68 (5-C); 27.22 (6-C); 29.64 (7-C); 34.92 (8-C); 40.02 (9-C); 35.57 (10-C); 21.38 (11-C); 40.15 (12-C); 43.88 (13-C); 54.83 (14-C); 31.39 (15-C); 84.59 (16-C); 64.68 (17-C); 14.45 (18-C); 24.26 (19-C); 103.59 (20-C); 11.83 (21-C); 152.38 (22-C); 33.43 (23-C); 24.12 (24-C); 34.82 (25-C); 71.13 (26-C); 16.21 (27-C)).
Embodiment 7 furostan type saponin(e sulfuric ester producing for derivative
The aglycon 3 of the timosaponin B-III obtained with embodiment 3 is for start material, and produce furostan type saponin(e sulfuric ester for derivative, concrete steps are as follows:
(1) the saponin(e aglycon 0.05mol that (5) step in embodiment 3 obtains is dissolved in 300mLDMF, passes into nitrogen protection, be cooled to-15 DEG C-0 DEG C.By 0.05mol-0.1molEt
3nSO
3add reaction solution with 0.4mol-0.6mol tosic acid, react 3 hours-5 hours.
(2) add 0.05mol-0.07mol triethylamine, add the methyl alcohol with solution 1: 1 volume ratio afterwards.Continue to stir, react 3 hours-5 hours; Be warming up to 20 DEG C-30 DEG C, continue to stir, stir 2 hours-4 hours.
(3) vacuum is spin-dried for solvent, with water by above-mentioned dissolution of solid, and after making saponin(e be adsorbed in ODS post, by the methanol-eluted fractions of 40v/v%-70v/v%, collects elutriant.
(4) reclaimed by solution decompression, evaporate to dryness obtains solid.
(5) by the NaOH solution dissolved solids of the 1mol/L of 50ml-60ml, be heated to 40 DEG C-70 DEG C, stir 1 hour-3 hours.
(6) solvent evaporated, with acetone recrystallization, filters, obtains product furostan type saponin(e sulfuric ester for derivative 9(NMR:30.60 (1-C); 27.27 (2-C); 66.05 (3-C); 37.37 (4-C); 40.68 (5-C); 27.22 (6-C); 29.64 (7-C); 34.92 (8-C); 40.02 (9-C); 35.57 (10-C); 21.38 (11-C); 40.15 (12-C); 43.88 (13-C); 54.83 (14-C); 31.39 (15-C); 84.59 (16-C); 64.68 (17-C); 14.45 (18-C); 24.26 (19-C); 103.59 (20-C); 11.83 (21-C); 152.38 (22-C); 33.43 (23-C); 24.12 (24-C); 32.82 (25-C); 84.13 (26-C); 17.41 (27-C)).
Producing of embodiment 8 furostan type saponin(e trifluoroacetic acid base substitutive derivative
The aglycon 3 of the timosaponin B-III obtained with embodiment 3 is for start material, and produce furostan type saponin(e trifluoroacetic acid base substitutive derivative, concrete steps are as follows:
(1) the saponin(e aglycon 0.05mol that (5) step in embodiment 3 obtains is dissolved in 250mlCH
2cl
2in, add 50ml-60ml Eorontrifluoride etherate complexometric reagent, drip acetic anhydride 0.1mol-0.13mol, 20 DEG C-40 DEG C are reacted 1 hour-2 hours, wash reaction solution, then use 750ml washed reaction liquid, separate organic phase, use Na with saturated NaCl aqueous solution 1L
2sO
4dry; Organic phase filtered, be spin-dried for filtrate, use purification by silica gel column chromatography product, developping agent is sherwood oil and the ethyl acetate of volume ratio 6:1.
(2) product in (1) is dissolved in 250mlCH
2cl
2in, be cooled to-40 DEG C--15 DEG C, add 0.075mol-0.1mol trifluoroacetyl triflate (TFAT), react 2 hours-4 hours.
(3) reaction terminates, and adds sodium bicarbonate cancellation reaction, continues stirring 30 minutes-1 hour, and raised temperature to 20 DEG C-30 DEG C, continues stirring 30 minutes-1 hour.
(4) vacuum is spin-dried for solvent, with water by above-mentioned dissolution of solid, and after making saponin(e be adsorbed in ODS post, by the methanol-eluted fractions of 40v/v%-70v/v%, collects elutriant.
(5) reclaimed by solution decompression, evaporate to dryness obtains furostan type saponin(e trifluoroacetic acid base substitutive derivative 11(NMR:30.60 (1-C); 27.27 (2-C); 66.05 (3-C); 37.37 (4-C); 40.68 (5-C); 27.22 (6-C); 29.64 (7-C); 34.92 (8-C); 40.02 (9-C); 35.57 (10-C); 21.38 (11-C); 40.15 (12-C); 43.88 (13-C); 54.83 (14-C); 31.39 (15-C); 84.59 (16-C); 64.68 (17-C); 14.45 (18-C); 24.26 (19-C); 103.59 (20-C); 11.83 (21-C); 152.38 (22-C); 33.43 (23-C); 24.12 (24-C); 32.82 (25-C); 68.73 (26-C); 17.41 (27-C); 156.60 (28-C); 113.19 (29-C)).
Producing of embodiment 9 furostan type saponin(e alkylamino derivative
The aglycon 3 of the timosaponin B-III obtained with embodiment 3 is for start material, and produce furostan type saponin(e alkylamino substitutive derivative, concrete steps are as follows:
(1) the saponin(e aglycon 0.05mol that (5) step in embodiment 3 obtains is dissolved in 300mL tetrahydrofuran (THF), cools the temperature to-30 DEG C-0 DEG C; By 0.1mol-0.2mol dimethylamine, 0.15mol-0.2mol diethylazodicarboxylate, 0.12mol-0.22mol PPh
3add solution, pass into nitrogen protection, react 2 hours-3 hours.
(2), after reaction terminates, filter, filtrate is spin-dried for.
(3) vacuum is spin-dried for solvent, with water by above-mentioned dissolution of solid, and after making saponin(e be adsorbed in ODS post, by the methanol-eluted fractions of 50v/v%-70v/v%, collects elutriant.
(4) reclaimed by solution decompression, evaporate to dryness obtains furostan type saponin(e alkylamino substitutive derivative 12(NMR:30.60 (1-C); 27.27 (2-C); 66.05 (3-C); 37.37 (4-C); 40.68 (5-C); 27.22 (6-C); 29.64 (7-C); 34.92 (8-C); 40.02 (9-C); 35.57 (10-C); 21.38 (11-C); 40.15 (12-C); 43.88 (13-C); 54.83 (14-C); 31.39 (15-C); 84.59 (16-C); 64.68 (17-C); 14.45 (18-C); 24.26 (19-C); 103.59 (20-C); 11.83 (21-C); 152.38 (22-C); 23.43 (23-C); 28.12 (24-C); 30.82 (25-C); 68.73 (26-C); 18.41 (27-C); 41.49 (3-N-CH
3); 47.13 (26-N-CH
3)).
Embodiment 10 structural confirmation
The solid of embodiment 1 or embodiment 2 gained, be all positive through Molish reaction and Liebermann-Burchard reaction detection, its nmr spectrum (Nuclear Magnetic Resonance, NMR) data are as table 1.Again through the multiple profiling results analysis such as comprehensive HMBC, ROESY, MS and NMR be the derivative shown in formula III-II.
Formula III-II derivative, outward appearance is white amorphous powder, is soluble in pyridine, dissolves in acetone-water, acetonitrile-water and the aqueous solution.Liebermann-Burchard and Molish reaction is positive, and proves that this compound is timosaponin.
（c0.05mg/ml,pyridine）。
HR-ESI-MS(positive ion mode) display [M+Na]
+m/z601.3713(counts C
33h
56o
9na:601.3711), determine that its molecular formula is C
33h
55o
8.
Containing a part glucose in nuclear magnetic resonance spectrum prompting structure, hydrogen spectrum (
1h-MNR, is shown in Fig. 1) middle δ 4.87(d, J=7.7Hz) be glucose anomeric proton signal, be defined as beta comfiguration.Comprehensive analysis
13c-NMR spectrum and DEPT compose (see figure 2), determine to there are 4 methyl carbon signals, 12 mesomethylene carbon signals, 13 methine carbon signals and 4 quaternary carbon signals in the carbon signal on 26 aglycons.The carbon spectrum of this compound aglycon part is all similar to timosaponin B3 with hydrogen modal data, illustrates that it has similar parent nucleus to timosaponin B3.Compose in (see figure 3) at HMBC, H21 and C20 and C22 exists long-range relevant, illustrates that the position of double bond is consistent with timosaponin B3.δ in addition
h4.87(H-1') glucose anomeric proton and δ
c75.22(C-26) there is long-range being correlated with, determine glycosylation position, namely glucose and 26-OH are connected to glycosides.Relative configuration is composed (see figure 4) by ROESY and is determined, namely to there is NOE relevant for H-5 proton and H-19 proton, determines that A ring and B ring are cis-configuration.Other NMR data and correlationship are in table 1, Fig. 5 and Fig. 6.This compound has no bibliographical information, is new compound, called after timosaponinB III-4(or abbreviation: B III-4).
The NMR data of derivative shown in table 1 formula III-II
Embodiment 11 antidepressant activity is verified
FST and TST two kinds of behavioral despair models are responsive to most thymoleptic, simple to operate, quick, be widely used in the screening of such medicine, the present embodiment is also verified with the antidepressant pharmacological action of this model to the derivative obtained by embodiment 1-embodiment 9.
Experiment selects male ICR mouse, body weight (20 ± 2) g, purchased from Shanghai medicine institute of Chinese Academy of Sciences Experimental Animal Center, and drinking-water of freely ingesting, room temperature (23 ± 2) DEG C, natural lighting.All mouse random packet are 10/cage, adapt to start experiment after 3 days in feeding environment, fasting 12 hours before experiment, and drinking-water freely.Concrete medication is: blank group one group, to isopyknic physiological saline.
FST confirmatory experiment
1) concrete operations: successive administration 6 days, test for after last administration 1 hour.First utilize and open the autonomic activities that wild method measures mouse, be placed in separately in cylinder shape glass jar by mouse, timing 4min, the carry arm number of times after record in 2min.Then mouse is put into separately the cylinder shape glass jar of high 20cm, diameter 14cm, depth of water 10cm in cylinder, water temperature 23-25 DEG C.Timing 6min after entering water from mouse, the accumulative dead time (judging motionless standard: mouse stops struggling in water, or in levitated state, only has tiny limb motion to keep afloat to keep head) after record in 4min.Each group of mouse parallel running.
2) Data Processing in Experiment: experimental result represents with mean value ± standard error (x ± SE).Adopt t inspection to carry out statistical study, judge whether that there is significant.First carry out t inspection to its autonomic activities index, its P ﹥ 0.05 illustrates the autonomous rear dynamic not impact of mouse, to avoid the interference of central nervous system stimulants.Then carry out t inspection to forced swim test index, blank group and high, normal, basic dosage three groups of experimental group compare respectively, judge whether the relation with antidepressant effect and antidepressant effect intensity and dosage.
TST confirmatory experiment
1) concrete operations: successive administration 6 days, test for after last administration 1 hour.First utilize and open the autonomic activities that wild method measures mouse, be placed in separately in cylinder shape glass jar by mouse, timing 4min, the carry arm number of times after record in 2min.Then be bonded at whippletree on by mouse tail apart from tail point 2cm place with adhesive tape, surrounding is with plate isolation animal sight line, and whippletree is about 25cm apart from ground, makes mouse be about 10cm, timing 6min apart from ground, accumulative dead time in 4min after record, each group mouse parallel running.
2) Data Processing in Experiment: experimental result represents with mean value ± standard error (x ± SE).Adopt t inspection to carry out statistical study, judge whether that there is significant.First carry out t inspection to its autonomic activities index, its P ﹥ 0.05 illustrates the autonomous rear dynamic not impact of mouse, to avoid the interference of central nervous system stimulants.Then carry out t inspection to tail-suspention test index, blank group and high, normal, basic dosage three groups of experimental group compare respectively, judge whether the relation with antidepressant effect and antidepressant effect intensity and dosage.
Verify that derivative that the present invention produces is to antidepressant effect by experimentation on animals, result and data are in table 2 and table 3.Abdominal injection gives the various compound of mouse 10mg/Kg respectively, separately establishes blank group (physiological saline).T inspection is carried out to the index of mouse autonomic activities, without significant difference, illustrate these compounds all on the autonomic activities of mouse without impact.Respectively t inspection is carried out to the dead time of mouse forced swimming test and the test of outstanding tail, result shows, various derivatives obtained by embodiment 1-embodiment 9 all obviously can shorten the dead time of mouse forced swimming test and outstanding tail, point out them to have significant antidepressant activity.
Table 2 intraperitoneal administration is on the impact of ICR mouse forced swimming test dead time
" * " represents P < 0.05; " * * " represents P < 0.01.
Table 3 intraperitoneal administration is on the impact of ICR mouse tail suspension dead time
" * " represents P < 0.05; " * * " represents P < 0.01.
Claims (4)
1. such as formula the saponin derivative shown in III-I,
2. saponin derivative according to claim 1, is characterized in that the conformation of described formula III-I is for shown in formula III-II
。
3. saponin derivative according to claim 1 and 2 as activeconstituents for the preparation of the medicine of prevention and therapy dysthymia disorders, food or healthcare products.
4., for an antidepressant composition, its activeconstituents contains the saponin derivative described in claim 1 or 2.
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| CN201210576694.4A CN103183719B (en) | 2011-12-30 | 2012-12-26 | Saponin derivative and uses thereof |
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| CN201210576694.4A CN103183719B (en) | 2011-12-30 | 2012-12-26 | Saponin derivative and uses thereof |
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| CN104513289B (en) * | 2015-01-27 | 2017-12-22 | 华东理工大学 | The derivative of Sarsasapogenin structural modification, its pharmaceutical composition and its application |
| CN106146597A (en) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | A kind of saringosterol compound and extracting method, application |
| CN106146596A (en) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | A kind of Sargassum phyllocystum Tseng et Lu,Sargassum horneri (Turn.) C. Ag. (Fucus horneri (Turn.)C.Ag.,Spongocarpus horneri Kutz.) Sitosterolum compound and extracting method, application |
| CN109431968A (en) * | 2018-12-29 | 2019-03-08 | 天津凯茵科技有限公司 | Gynaecology's compound based on clotrimazole |
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| US20080206161A1 (en) * | 2002-10-25 | 2008-08-28 | Dov Tamarkin | Quiescent foamable compositions, steroids, kits and uses thereof |
| CN101214253B (en) * | 2008-01-07 | 2011-09-21 | 中国人民解放军第二军医大学 | Application of anemarrhenasaponin B-II in preparing antidepressant product |
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- 2012-12-26 CN CN201210576694.4A patent/CN103183719B/en active Active
Non-Patent Citations (4)
| Title |
|---|
| HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY OF STEROIDAL SAPOGENINS;JIANN-TSYH LIN, et al.;《Journal of Chromatography》;19841231;第287卷;第105-112页 * |
| Structural characterization of phytotoxic terpenoids from Cestrum parqui;Brigida D’Abrosca, et al.;《Phytochemistry》;20051025;第66卷;第2681-2688页 * |
| The structural elucidation of two new artificial steroidal saponins;Bin Wu, et al.;《Chinese Chemical Letters》;20120126;第23卷;第332-334页 * |
| The Synthesis of Azaoxaspirane Steroid Alkaloids;FREDERICK C. UHLE;《Journal of the American Chemical Society》;19610320;第83卷;第1460-1472页 * |
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| CN103183719A (en) | 2013-07-03 |
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