WO2013097661A1 - Furostanol saponin derivative and use thereof - Google Patents

Abstract

A furostanol saponin derivative; the structure thereof is as represented by formula (I). Experimentation proves that the furostanol saponin derivative is provided with significant antidepressant pharmacological activity, can be used as an active ingredient to be prepared into a medicament, food, and healthcare product, and, either separately or in conjunction with other substances, can be used for preventing and treating depression.

Description

 Furoxan saponin derivative and use thereof

 The present invention relates to a saponin derivative, and more particularly to a furane-type saponin derivative and an epimer thereof, and the use of these derivatives in the prevention and treatment of depression.

Dragon

 Zhimu (also known as rabbit oil grass, wearing dragon) is the dry rhizome of Anemarrhena asphodeloides. According to the "Plants", it is bitter and cold, and it has the effect of nourishing yin and reducing fire, moistening and drying the intestines, and benefiting the urine.

The main chemical components of Chinese herbal medicines are saponins, dibenzopyrones, polysaccharides and lignins, such as: timosaponin A- I, A- IK A-III, A-IV, B-I, Β-Π和口 B-III, wherein the structure of timosaponin-Α and A-IV is unknown. And amemarsaponin A2, ie, Marcos saponin-3-0-pD-glucopyranosyl ( 1 → 2 ) -β-D-pyridinium galactoside B (marlogenin-3-0-PD -glucopyranosy ( 1 ^→ 2) -β-D-galactopyranoside B) Degalactose (desgalactotigonin) F-deglucoside (F-gitonin) and smilageninoside. In addition, it contains anemarone A/B/C/D, cis-hinokiresinol, monomethyl-cis-hinokiresinol, oxidized-cis- Phenolic resin phenol (oxy- cis-himokiresinol), 2,6,4'-trihydroxy-4-methoxybenzophenone (2,6,4'-trihydroxy-4-methoxy benzophenone) p-hydroxybenzene P-hydroxyphenyl crotonic acid, pentacosyl vinyl ester β-sitosterol, mangiferin nicotinic acid, nicotinamide (p-hydroxyphenyl crotonic acid) Nicotinamide) and pantothenic acid.

 Anthraquinone saponin- Π has an improved effect on learning and memory impairment caused by cerebral ischemia (Neuroscience letter., 2007, 421, 147-151 timosaponin-ΠΙ mainly inhibits acetylcholinesterase and inhibits the expression of inflammatory factors. It has a mitigating effect on memory loss (Pharmacol. Biochem. Be., 2009, 93, 121-127).

 Many studies have shown that these substances contained in Zhimu have therapeutic effects on various diseases, such as: Total timosaponin can be used to treat myocardial ischemia (CN1682873A), mainly known as timosaponin-ΠΙ and B-II. Ingredients made from ingredients have also been used to treat thrombotic diseases (WO 2011/026259). Anthraquinone saponin-ΠΙ can induce apoptosis in human cervical cancer cells, and has been shown to have colon and rectal cancer effects in both in vivo and in vitro experiments (Cancer Res., 2008, 68, 10229-10237), and has inhibitory blood vessels. A significant effect of endothelial cell proliferation has therapeutic effects in the treatment of diseases such as tumors and rheumatoid arthritis (CN102030812A).

Recent studies have also shown that Zhimu total soap has antidepressant effects in various depression models, which may be related to the enhancement of noradrenergic and serotonergic nervous system (New Chinese Medicine and Clinical Pharmacology, 2007, 18, 29) . It was confirmed by animal experiments that the saponins contained in Zhimu had a certain effect on experimental depression in mice, which could affect the activity of dopamine and monoamine oxidase in the brain of mice, and make the saponins have antidepressant activity (Biol. Pharm. Bull., 2006, 29, 2304-2306). I Jia et al. found that timosaponin B-II has antidepressant activity, and its mechanism may be related to enhancing the effects of 5-HT and DA nervous system in the brain (CN101214253A; Journal of Pharmaceutical Practice, 2010, 28, 283-287) ).

 Chinese medicine believes that depression is often caused by excessive anxiety, and the heart and the spleen are sick. The treatment should be based on tranquillity, nourishing the blood and nourishing yin. Therefore, in most prescriptions for the treatment of depression in Chinese medicine, Zhimu is also a commonly used Chinese herbal medicine. The most commonly used antidepressants in clinical practice include tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors, selective 5-HT reuptake inhibitors (SSRIs), atypical antidepressants, and lithium salts.

 In recent years, the most widely used SSRI drug, fluoxetine, has many adverse reactions, such as: systemic or local allergies, gastrointestinal dysfunction, etc. (China Modern Applied Pharmacy, 2008, 25, 763-765; China New Drug Journal, 2001, 10, 20; Journal of Practical Medicine, 2004, 20, 318-319). Studies have shown that the use of fluoxetine in young children may increase suicidal tendencies, and there are reports that fluoxetine may cause increased violent tendencies and congenital cardiovascular birth defects.

 Sertraline, a SSRI drug, is an antidepressant brand drug with a large prescription in the United States, but it is easy to cause sinus tachycardia and ST-T changes in China (Chinese Journal of New Drugs and Clinical Medicine, 2002, 21, 711) -713) Adverse reactions, which may cause manic episodes or metastasis to some extent during the treatment of depressive episodes (Forensic Psychiatry, 2004, 31, 104).

 Although venlafaxine and clomipramine are as easy to tolerate, about one-third of the patients will develop nausea, especially in the weeks when the drug is started. Adverse reactions caused by venlafaxine have been found to have malignant syndrome, induced mania, purpura, hallucinations, sudden hallucinations, withdrawal syndrome, 5-HT syndrome, chest tightness, dizziness, hypotension, menopause, and eyes Increased pressure, etc., have a higher rate of conversion in children (Journal of Clinical Psychiatry, 2002, 12, 382).

 According to World Health Organization experts, the total social burden of depression will rise to the top of all disease burdens by 2020, and the active molecules contained in drugs used to treat depression activity are mainly obtained by chemical synthesis. Most of them have problems of toxic side effects, narrow anti-depression spectrum and high price. Only 2% of the patients with depression currently treated in our country have potential harm to families and society. Therefore, it is particularly necessary to develop safe, effective and inexpensive antidepressant innovative drugs.

 Traditional Chinese medicine and natural medicine are one of the important sources of innovative drug research and development. In recent years, international and domestic research and development of natural drugs with antidepressant effects such as St. John's wort have achieved a series of results (Chinese Modern Chinese Medicine, 2009, 11, 6-9; Chinese patent medicine, 2006, 28, 713-716; Guangdong Medicine, 2005, 859-860; Journal of Nanjing University of Traditional Chinese Medicine, 2001, 17, 294-298; Journal of Pharmaceutical Sciences, 2003, 19, 426-428; Journal of Pharmaceutical Practice, 2004, 22, 104-105; Pharm. Biol ., 2006, 44, 503-510). However, no new Chinese medicines for treating depression have been listed, and there are few reports on the relationship between chemical structure and pharmacodynamic mechanisms. Summary of the invention

 SUMMARY OF THE INVENTION An object of the present invention is to provide a saponin derivative which has an antidepressant pharmacological action and can be used as an active ingredient for the preparation of a medicament for the treatment and prevention of depression.

Another object of the present invention is to provide a furane-type saponin derivative or an epimeric composition thereof, Has anti-depressant pharmacological effects.

 Still another object of the present invention is to provide a furazan-type saponin derivative or an epimer thereof obtained from timosaponin-oxime or from a medicinal material of the medicinal material, and having an antidepressant pharmacology effect.

 It is still another object of the present invention to provide a composition for the manufacture of a medicament, a food and a health supplement using various body saponin derivatives or compositions thereof as active ingredients, alone or in combination with other substances for prevention and treatment Depression.

 The term "body saponin derivative" as used in the present invention means a saponin derivative and a pharmaceutically acceptable salt thereof, such as: but not limited to hydrochloride, sulfate, carbonate, hydrogencarbonate, acetic acid Salt, potassium salt, sodium salt, calcium salt, magnesium salt, barium salt, manganese salt, zinc salt, iron salt and quaternary ammonium salt.

 The term "furane-type saponin derivative" as used in the present invention means a furane-type saponin derivative and a pharmaceutically acceptable salt thereof, such as: but not limited to hydrochloride, sulfate, carbonate, hydrogencarbonate Salt, acetate, potassium salt, sodium salt, calcium salt, magnesium salt, barium salt, manganese salt, zinc salt, iron salt and quaternary ammonium salt.

 The "furane-type saponin derivative obtained from the Chinese medicinal material known as the mother" as used in the present invention means a compound formed by the derivative with various inorganic acids, inorganic bases, organic acids or organic bases, including In the process of preparing a furazan-type saponin derivative from the medicinal material of the medicinal material, a furane-type saponin derivative and a direct or indirect precursor compound thereof (such as: timosaponin-oxime) which is produced and prepared The pharmaceutically acceptable salts of the various reagents used are, for example, hydrochlorides, sulfates, carbonates, bicarbonates, acetates, sodium salts, potassium salts or quaternary ammonium salts.

 The "Chinese herbal medicine known as the mother" refers to various parts of the Anemarrhena asphodeloides, such as roots, stems, pages and fruits, because the most targets can be obtained from the roots of the plant. Steroidal saponin derivatives, and thus the present invention prefers dried rhizomes. The selection and processing of these medicinal herbs are not in accordance with the processing techniques and standards of Chinese medicinal materials.

 The term "depression" as used in the present invention is a mood disorder, which is a syndrome characterized by a significant and persistent low mood. The so-called depression refers to clinical major depression (Chinese Journal of Experimental Traditional Chinese Medicine, 2005, 11, 46; Journal of Pharmaceutical Practice, 2008, 26, 282). Patients with depression are often accompanied by anxiety symptoms, which can aggravate the development of depression (China Clinical Rehabilitation, 2006, 10, 58). The episode of depression is dominated by low mood, which is not commensurate with its situation. It can be from sullen and unhappy to grief and even stupor. In severe cases, psychotic symptoms such as hallucinations and delusions may occur. The anxiety and motility agitation in some cases is significant. The diagnostic criteria are also dominated by low mood, accompanied by at least four of the following: (1) loss of interest, no sense of pleasure; (2) lack of energy or fatigue; (3) psychomotor retardation or agitation;

(4) Self-evaluation is too low, self-blame, or guilty; (5) Lenovo's difficulty or conscious thinking decline; (6) Repeated thoughts of wanting to die or suicidal, self-injury; (7) Sleep disorders, Such as insomnia, early waking, or excessive sleep;

(8) decreased appetite or significant weight loss; and (9) loss of libido. The impaired social function and the pain or adverse consequences for me are serious criteria for the development of the disease. From the point of view of the disease, the patient met the symptom criteria and the severity criteria for at least 2 weeks; there may be some schizophrenic symptoms, but not in the diagnosis of schizophrenia. If it meets the symptom criteria of schizophrenia, meet the criteria for depressive episodes at least 2 weeks after the mitotic symptoms are alleviated (Chinese Classification and Diagnostic Criteria for Mental Disorders [M], Jinan: Shandong Science and Technology Press, 2001, 28-35). The term "anti-depression" as used in the present invention refers to the purpose of treating, ameliorating or curing the symptoms of a patient suffering from depression, so that the patient's condition is improved to return to normal.

 The "Forced Swimming Test (FST)" or "forced swimming animal model of depression" referred to in the present invention means that a laboratory animal (e.g., a mouse) is placed in a confined environment (e.g., in water). ), animals struggled in this environment and tried to escape and could not escape, thus providing an unavoidable oppressive environment. After a period of experimentation, the animals showed a typical "immobility state". In fact, the animals gave up and escaped. Hope, reflecting a series of parameters called "behavior desperate state", recording the desperate state of the animal in the environment. The system uses the camera to record the experimental process and track the image with the corresponding software to reduce the human operation and the data is objective. The animal model of forced swimming is a reliable experimental model for studying the pharmacology of human depression and its pathogenesis, screening and observing antidepressant drugs. Its main feature is the high specificity of drug action. The experiment can be very good. Antidepressants are distinguished from strong anti-anxiety and anti-anxiety drugs, and the effects of most antidepressants are significantly associated with clinical potency (Arch. Int. Pharmacodyn. Ther., 1977, 229, 327-336; Neurosei. Biobehav. Rev., 1995, 19, 377-395).

 The "Tail Suspension Test (TST)" referred to in the present invention is a classic and rapid method for evaluating the efficacy of antidepressants. The principle is to use the mouse to suspend the tail and attempt to escape, but can not escape, thus giving up the struggle and entering the unique state of depression and immobility. During the experiment, the animal is not moved to reflect the depression state, and the antidepressant can significantly shorten its change. status.

 The term "organism", "animal" or "patient" as used in the present invention refers to humans, wild animals and livestock (Livestocks are wild animals that are not artificially domesticated in a natural state. Livestock is a human word for providing food sources) Animals such as: but not limited to dogs, cats, rats, rats, hamsters, pigs, rabbits, cows, buffalo, bulls, sheep, goats, geese, chickens, etc. Treating "patients", "animals" or " The organism "preferres to mammals, especially humans.

 The term "prevention" as used in the present invention refers to various means or measures for preventing the occurrence or development of a disease, including medical, physical or chemical means, to prevent and reduce various diseases before the disease is not recognized by clinical standards. The occurrence or development of symptoms.

 The term "treatment" as used in the present invention means to prevent or reduce the occurrence or development of a disease, and to inhibit, suppress, alleviate, ameliorate, slow down, stop, delay or reverse the progression or aggravation of the disease course. / or various indicators of disease, disorder, or pathology at the time of administration include alleviating or reducing symptoms or complications, or curing or eliminating a disease, disorder, or condition.

 The term "food" as used in the present invention refers to a single compound or composition comprising various body saponin derivatives provided by the present invention. The production and manufacture of such a single compound or composition should be in accordance with relevant food safety standards, but such food safety standards must not limit the invention.

 The term "health product" as used in the present invention means that a variety of the saponin derivatives provided by the present invention are prepared into an edible single compound or composition for administration to a patient for the purpose of preventing and treating diseases. It belongs to the food referred to in the present invention, but its production, manufacture and sale should also comply with various relevant requirements, standards and specifications.

The term "drug" as used in the present invention means a single compound which can be used for preventing or treating a certain disease, and a variety of compounds. A composition, a Chinese medicinal material and an extract thereof, or a composition or formulation having a single compound as a main active ingredient, and a composition or preparation comprising a plurality of compounds as an active ingredient. "Drug" should be understood to mean not only the products approved and approved for production by the administrative agencies established by the laws of a country, but also the inclusion of a single compound as the active ingredient in order to obtain approval and approval of production. Various forms of matter. "Formation" is understood to be obtained by means of chemical synthesis, biotransformation or purchase.

 The term "formulation" as used in the present invention means a dosage form containing a drug delivery of an isoflavone compound of the present invention, such as, but not limited to, an aqueous solution injection, a powder injection, a pill, a powder, a tablet, a patch. , suppositories, emulsions, creams, gels, granules, capsules, aerosols, sprays, powders, sustained release agents and controlled release agents. These pharmaceutical excipients may be conventionally used in various preparations, such as, but not limited to, isotonic agents, buffers, flavoring agents, excipients, fillers, binders, disintegrators, lubricants, and the like. Or may be selected for use in accordance with the substance, such as: emulsifiers, solubilizers, bacteriostatic agents, analgesics and antioxidants, etc., such excipients can effectively improve the stability of the compounds contained in the composition And solubility or changing the release rate and absorption rate of the compound, etc., thereby improving the metabolism of the compound of the present invention in the living body, thereby enhancing the administration effect. In addition, excipients such as: sustained release, controlled release, and pulsed administration, such as: but not limited to, gelatin, albumin, chitosan, may also be used for specific purposes or modes of administration. , Polyether and polyester polymer materials, such as: but not limited to, polyethylene glycol, polyurethane, polycarbonate and copolymers thereof. The main manifestations of "good for administration" are: However, it is not limited to improving the therapeutic effect, improving bioavailability, reducing toxic side effects, and improving patient compliance.

The term "effective therapeutic dose" as used in the present invention refers to an amount which can alleviate various pathologically significant symptoms using the compound of the present invention as an active ingredient, and the amount given is generally determined according to the body weight of the living body, such as: 0.05mg/kg-50mg/kg _o According to the actual situation of the organism and its condition, the amount used and the number of times used can also be adjusted, for example, the total amount of 0.05-0.5mg/kg, 0.6_lmg/kg is given twice a day or more. , l_10mg/kg, l l_25mg/kg, 26_40mg/kg or 41_50mg/kg. Depending on the dosage form of the drug, the amount to be given will also vary, such as: 10 mg/kg for regular tablets and lower for slow release formulations. The specific dose of the body saponin derivative of the present invention needs to be determined depending on the specific circumstances, such as the manner of administration, the route of administration, the state of the patient at the time of administration, and the pathological condition at the time of treatment.

The "base compound" referred to in the present invention is a compound obtained by substituting "hydrogen" for all variable substituents of the structural formula of the compound. For example, the substitution of "hydrogen" for the substituents F, R ₂ and the obtained compound in the structure represented by the following formula I is a basic compound.

 The term "substituent" as used in the present invention refers to a general term for one or more inorganic or organic groups which replace a hydrogen atom at a specific position on a base compound.

 The "halogen" referred to in the present invention includes fluorine, chlorine, bromine and iodine, and is applied as a substituent to the base compound in a combination of _F, -Cl, -Br and -I.

 The "oxo group" referred to in the present invention is represented by "=0" in the structural formula of the compound and is covalently bonded to the atom on the base compound. For example, an oxo group is covalently bonded to a C atom to form a carbonyl group (C = 0).

The "sulfate group" referred to in the present invention is _OS0 ₃ H, _OS0 ₃ Na, _OS0 ₃ K and _OS0 ₃ NH ₄ .

The "phosphate group" referred to in the present invention is -OPO(HO) ₂ , and the pharmaceutically acceptable hydrogen group is substituted thereon. The salt that is affected.

The "trifluoroacetate group" referred to in the present invention is _OCOCF ₃ .

 The "substituted amino group" referred to in the present invention is an amino group in which hydrogen on the amino group is partially or wholly substituted by a C1-C3 saturated alkane, such as: but not limited to methylamino and dimethylamino groups.

 The "C1-C3 saturated alkane" referred to in the present invention is an alkane having 1-3 carbon atoms. Wherein, the letter C represents a carbon atom, and the subsequent digits are positive integers, such as: 1, 2 or 3, indicating the number of carbon atoms contained in the group, such as methane, ethane, and propane.

 The term "sugar", also known as "sugar", is a basic organic substance in chemical or biochemistry. It is a polyhydroxy (more than 2) aldehyde, polyhydroxyketone composed of C, H and 0 elements. (greater than 2) and an organic compound capable of hydrolyzing to form a polyhydroxy aldehyde or a polyhydroxy ketone. According to its molecular structure, it can be divided into "monosaccharide", "disaccharide" and "polysaccharide". An organic compound formed by condensation of a plurality of monosaccharide molecules via a glycosidic bond, also known as a "sugar chain." The present invention preferably employs a monosaccharide or a disaccharide as a substituent for the base compound.

 The term "monosaccharide" as used in the present invention refers to an organic compound composed of C, H and 0 elements, and is also a basic unit constituting other saccharide substances, generally a polyhydroxy group having 3 to 6 carbon atoms. An organic substance of an aldehyde or a polyhydroxyketone. Preference is given to polyhydroxy aldehydes or polyhydroxy ketones having 5 or 6 carbon atoms, also known as "pentoses" and "hexoses" such as: but not limited to ribose, xylose, arabinose, glucose, mannose, galactose, Allosterose, fructose, sorbose, tagatose, gulose, idose, tarotose, allose and altrose. In the monosaccharide structure of the present invention, the 0 element may be partially or completely replaced by the S element.

 The term "disaccharide" as used in the present invention means an organic compound composed of C, H and 0 elements, and is generally formed by linking two monosaccharide molecules by condensation and dehydration to form glycosidic bonds. Well known disaccharides such as: sucrose, lactose, cellobiose, trehalose and maltose. Glycosidic bonds formed between monosaccharide molecules such as: but not limited to α-1,1-, α-1,2-, α-1,3-, α-1,4-, β-1,4- and Several glycosidic bond forms such as α-1,6-. In the disaccharide structure of the present invention,

The 0 element can be partially or completely replaced by the S element.

 The term "polysaccharide" as used in the present invention also includes oligosaccharide, which means C,

The H and 0 elements constitute an organic compound, and are generally linear or branched polymers in which three or more monosaccharide molecules are linked by condensation and dehydration to form glycosidic bonds. Preferred are linear or branched polymers in which 3-15 monosaccharide molecules are linked by glycosidic bonds. Well-known polysaccharides such as: gentiotriose, melezitose, acacia, vanilla, stachyose and raffin Wait. The glycosidic bonds formed between the monosaccharide molecules are as follows: but not limited to several glycosidic bond forms such as α-1,4-, β-1,4- and α-1,6-. In the polysaccharide structure of the present invention, the 0 element may be partially or completely replaced by the S element.

 The "C1-C6 alcohol" referred to in the present invention is a linear or branched saturated or unsaturated hydrocarbon substituted with one or more hydroxy groups. Wherein, the letter C represents a carbon atom, and the subsequent digits are positive integers, such as: 1, 2, 3, 4 or 5, etc., indicating the number of carbon atoms contained in the group, such as: methanol, ethanol, propanol, isopropyl Alcohol and n-butanol.

The invention provides a body saponin derivative which is a furan-type saponin derivative having the structure shown in formula I, wherein a substituent is selected from -OH, -SH, halogen, oxo group, sulfuric acid. a group of an ester group, a sugar linked by an O-glycosidic bond, a sugar linked by an S-glycosidic bond, or a C1-C3 saturated alkane; R ₂ represents a substituent selected from -0H, - a group of SH and halogen; R ₃ represents a substituent selected from -OH, -SH, a halogen, an oxo group, a sulfate group, a phosphate group, a trifluoroacetic acid group, a C1-C3 saturated alkane-substituted amino group, a group linked by an O-glycosidic bond. Formula I

Another saponin derivative provided by the present invention is a furane-type saponin derivative having the structure shown in Formula I, wherein a substituent is selected from -OH, -SH, halogen, C1-C3 saturated alkane a group of a substituted amino group; R ₂ represents a substituent selected from a group of -OH, -SH and halogen; and R ₃ represents a substituent selected from -OH, -SH, a halogen, an oxo group, a sulfate group, a phosphate group, a trifluoroacetic acid group, a C1-C3 saturated alkane-substituted amino group, a 0-glycosidically linked monosaccharide, and a group of monosaccharides linked by an S-glycosidic bond group. Formula I

Another saponin derivative provided by the present invention is a furane-type saponin derivative having a structure represented by Formula II, wherein a substituent is selected from -OH, -SH, halogen, C1-C3 saturation. a group of an alkane-substituted amino group; R ₃ represents a substituent selected from -OH, -SH, halogen, oxo, sulfate, phosphate, trifluoroacetate, C1-C3 saturated An alkane-substituted amino group, a monosaccharide linked by an O-glycosidic bond, and a group of a monosaccharide linked by an S-glycosidic bond. Formula II

Another saponin derivative provided by the present invention is a furan-type saponin derivative having a structure represented by Formula III, wherein R ₃ represents a substituent selected from -OH, -SH, halogen, oxo a group of a sulfhydryl group, a phosphate group, a trifluoroacetic acid group, a C1-C3 saturated alkane-substituted amino group, a monosaccharide linked by an O-glycosidic bond, and a monosaccharide linked by an S-glycosidic bond. Formula III

Another saponin derivative provided by the present invention is a furan-type saponin derivative having a structure as shown in Formula IV.

Formula IV

Another saponin derivative provided by the present invention is a furan-type saponin derivative having a structure represented by the formula and the formula ν-π, respectively.

V-I

Another saponin derivative provided by the present invention consists of a furan-type saponin derivative epimer represented by the formula V - I and the formula ν - π.

 The various body saponin derivatives provided by the present invention can be obtained by various methods, such as dissolving timosaponin-III, timosaponin-saponin or timosaponin-saponin in a solvent. After adding various necessary reagents, the reaction is carried out under the protection of an inert gas such as, but not limited to, nitrogen, hydrogen or helium. After the reaction, quenching with trimethylamine, triethylamine, sodium hydrogencarbonate or sodium thiosulfate The quencher terminates the reaction. The obtained product is separated by column chromatography using silica gel, alumina, ODS or macroporous resin, and the solvent used for separation is as follows: but not limited to tetrahydrofuran, petroleum ether, ethyl acetate, DMF, pyridine, dichloromethane, ethanol, One or more of methanol or water.

The invention provides a direct method for obtaining the V saponin of the present invention and the saponin derivative of the formula V - ,, such as: by weight of the timosaponin Β-ΠΙ and the solvent (the solvent can be 10v / _V % - 100W _V %Cl-C6 alcohol aqueous solution and other common organic solvent aqueous solution, or water added cosolvent, such as: surfactant) volume ratio 1: 0.2-10, sow saponin ΠΙ-ΠΙ dissolved in the container, press The weight ratio of the timosaponin Β-ΠΙ to the inorganic acid (such as hydrochloric acid and sulfuric acid) 1: 1-4 is added to the inorganic acid, and the reaction is carried out at 60 ° C -100 ° C for 1-10 hours, after which the reaction is stopped. Adding an appropriate amount of alkali solution (such as sodium bicarbonate or sodium hydroxide) to the solution to pH6_8, extracting 1-3 times according to the weight ratio of timosaponin ΠΙ-ΠΙ to n-butanol 1: 1-10, The n-butanol extraction portion was combined, and the solvent was recovered under reduced pressure to give a solid. The solid substance is dissolved in a common organic solvent (for example, acetonitrile or methanol, etc.), and the main chromatographic peak is separated and collected by an analytical, semi-preparative or preparative HPLC or open ODS column, and the solution containing the target product of the present invention is recovered by a solvent. A yellowish or white product is obtained, i.e., a furane-type saponin derivative of the present invention.

 The various body saponin derivatives, pharmaceutically acceptable salts or combinations thereof provided by the present invention can be obtained by a variety of direct or indirect methods. Those skilled in the art can foresee that the timosaponin B-III (such as CN101307090A) can be firstly extracted from the mother or its extract, and the various furans provided by the present invention can be indirectly obtained by the acid hydrolysis method disclosed above. a saponin derivative, such as: after acid hydrolysis of the timosaponin ΠΙ-ΠΙ obtained from the Chinese medicinal material, the saponin derivative of the formula V - I or the formula V - Π and its Any proportion of the composition. In addition, the target derivatives of the present invention can also be obtained by the timosaponin, saponin, timosaponin or saponin, and other such as: organic synthesis, extraction from biological metabolites These derivatives are also obtained by methods such as separation and purification, chemical total synthesis, and biocatalysis and conversion. The various preparation methods exemplified in the present invention should be understood as necessary disclosures for carrying out the technical solutions of the present invention. Those skilled in the art can obtain the saponin derivatives provided by the present invention according to the teachings of the textbooks and the experimental manuals, and the necessary experiments. The methods for obtaining the saponin derivatives described herein are not intended to limit the present invention.

The various body saponin derivatives provided by the present invention can be used as the sole or main active ingredient for preparing a medicament for preventing or treating a viral disease, or together with other one or more chemicals or drugs having an antidepressant effect. Give the organism. These chemicals are, for example, but not limited to the extract of the mother-in-law, the total saponins of the timid genus and its hydrolysate, the timosaponin Π-Π and its hydrolyzate, the timosaponin ΠΙ-ΠΙ and its hydrolyzate, timosaponin Β-ΠΙ Saponin, timosaponin A-I and its hydrolysate, timosaponin A-I sapogenin, tricyclic and tetracyclic antidepressants, monoamine oxidase inhibitors, selective 5-quinone reuptake inhibitors (SSRI), Atypical antidepressants and lithium salts. The term "given to a living organism" means that the various body saponin derivatives of the present invention are administered alone or in combination with one or more other compounds or drugs having antidepressant effects, such as: but not only Limited to oral (Oral), nasal (Nasal), (face) Buccal, Transdermal, Pulmonal, Vaginal, Subcutaneous, or Intravenous; or with one or more other antidepressant chemicals Or the drug is administered to the organism through a plurality of administration routes, such as: but not limited to, the immediate release oral preparation is combined with the sustained release release implant preparation.

 The forced swimming test and the tail suspension experiment prove that the effective therapeutic dose of various body saponin derivatives (such as: Formula II, Formula III or a combination thereof) provided by the present invention can be used to improve the depressive symptoms of the organism. Or eliminate. Thus, the furoyl saponin derivative provided by the present invention has remarkable antidepressant activity, and is used as an active ingredient to prepare medicines, foods, and health care products for use in the prevention and treatment of depression.

 The present invention provides a pharmaceutical composition for the prevention and treatment of depression by using various body saponin derivatives or compositions thereof as active ingredients.

 The food provided by the present invention is useful for preventing and treating depression by using various body saponin derivatives or compositions thereof as active ingredients.

 The present invention provides a health care product comprising the various body saponin derivatives or compositions thereof as active ingredients for the prevention and treatment of depression.

 The beneficial effects achieved by the technical solution of the invention:

 The invention provides a body saponin derivative, specifically a furan-type saponin derivative represented by the formula I, especially a structure represented by the formula II, the formula III, the formula IV, the formula V-I and the formula V-Π. A furazan-type saponin derivative having significant antidepressant pharmacological activity, can be used as an active ingredient in medicines, foods, and health care products, alone or in combination with other substances, for the prevention and treatment of depression. DRAWINGS

Figure 1 is a formula V - I 1H NMR if (400MHz, Pyr-t ₅ );

Figure 2 is a V-I ¹³ C-NMR spectrum of the formula and a DEPT135 spectrum (100 MHz, Pyr-t ₅ );

Figure 3 is a formula V-I HMBC spectrum (Pyr-d ₅ );

Figure 4 is a V-I ROESY spectrum (Pyr-t ₅ );

 Figure 5 is a correlation diagram of the formula V-I HMBC, which represents the hydrogen-carbon remote correlation;

Figure 6 is a correlation diagram of the formula V-I ROESY, where "一→" represents the hydrogen-hydrogen NOE correlation; Figure 7 is the formula V-II 1H NMR spectrum (400MHz, Vyr-d ₅ );

Figure 8 is a formula V-II ¹³ C-NMR spectrum and DEPT135 spectrum (100MHz, Pyr-t ₅ );

Figure 9 is a formula V-Π HMBC spectrum (Pyr-d ₅ );

Figure 10 is a formula V-II ROESY spectrum (Pyr-t ₅ );

 Figure 11 is a correlation diagram of the formula V-IIHMBC, which represents the hydrogen-carbon remote correlation;

Fig. 12 is a correlation diagram of the formula V-IIROESY, in which "一→" represents a hydrogen-hydrogen NOE correlation. detailed description

 The technical solution of the present invention will be described in detail below with reference to the accompanying drawings. The embodiments of the present invention are only intended to explain the technical solutions of the present invention, and the present invention is not limited thereto. Although the present invention has been described in detail with reference to the preferred embodiments, those skilled in the art The spirit and scope of the technical solutions of the present invention should be included in the scope of the claims of the present invention.

 The reagents used in the present invention were purchased from Sigma-Aldrich if not explicitly indicated.

The furazolidin-type saponin monosaccharide derivative is prepared by using timosaponin-oxime as a reaction starting material, and the specific steps are as follows:

(1) Dissolving 0.05 mol of timosaponin-indene in 300 mL of methanol solution (water or 30 v/v% ethanol solution or lw/v% Tween solution) in a volume ratio of 10 v/v%, and adding 0.5 mL_lmL concentrated sulfuric acid. , 80 ° C _150 ° C reaction 1 hour _ 6 hours.

 (2) The above reaction solution was adjusted to pH 6-7 with sodium hydroxide.

 (3) The solution obtained after neutralization of the extraction step (2) is carried out in three steps of 900 mL to 1200 mL of n-butanol, and the extract is concentrated under reduced pressure to evaporate to obtain a furan-type saponin monosaccharide derivative 2 (NMR: see Table 1 for details) .

(4) The obtained furan-type saponin monosaccharide derivative 2 was dissolved in water and adsorbed on an ODS column, and then eluted with 50 _v / _v %-70 W _V % acetonitrile aqueous solution to collect the derivative of the S configuration. Eluent of derivative 2-2 of 2- 1 and R configurations.

 (5) The solution is recovered under reduced pressure, and evaporated to dryness to obtain furan-type saponin monosaccharide derivatives 2-1 and 2-2, respectively.

Example 2 Preparation of a furan-type saponin monosaccharide derivative

R=OH (S configuration) R=OH (R configuration) The furazolidin-type saponin monosaccharide derivative is prepared by using timosaponin Β-ΠΙ as a reaction starting material, and the specific steps are as follows:

(1) Dissolve 0.05 mol of timosaponin-indene in 300 ml of methanol solution (water or 30 v/v% ethanol solution or lw/v% tween solution) in a volume ratio of 10 v/v%, and add 2 ml of 4 ml thick Hydrochloric acid, reacted at 80 ° C - 150 ° C for 1 hour - 6 hours.

 (2) The above reaction solution was adjusted to pH 6-7 with sodium hydroxide.

 (3) The solution obtained after the neutralization step (2) is extracted in three steps from 900 ml to 1200 ml of n-butanol, and the extract is concentrated under reduced pressure to dryness to obtain a furan-type saponin monosaccharide derivative 2 (NMR: see Table 1 for details) .

(4) Dissolving the obtained furan-type saponin monosaccharide derivative 2 in water and adsorbing the saponin on the ODS column, and eluting with 40 _v / _v %-60 W _V % methanol to collect the derivative of the S configuration. Derivative 2-2 eluate of the 2-1 and R configurations.

 (5) The solution was recovered under reduced pressure, and evaporated to dryness to obtain furan-type saponin monosaccharide derivatives 2-1 and 2-2, respectively.

 The preparation of a furan-type saponin monosaccharide derivative using the timosaponin A I as a reaction starting material is as follows:

(1) Dissolving 0.05 mol of saponin 3 of timosaponin AI and 0.06 mol-0.1 mol of t-butyldimethylchlorosilane in 200 ml-250 ml of DMF, and reacting at 60 ° C - 90 ° C for 8 hours - 10 hours Add 600m of 800ml petroleum ether to the reaction solution, wash twice with 900ml of water, and wash once with 600ml of NaCl solution. The organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure.

(2) Dissolving the product obtained in the step (1) and 0.8 mol l.lmol of NaHC0 ₃ in a mixed solution of 700 ml of a 1:1:1 ratio of dichloromethane, acetone, and 1 mmol/L of Na ₂ EDTA; A 1 mmol/L to 3 mmol/L Na ₂ EDTA solution of potassium peroxodisulfate complex salt is added to the reaction solution, and reacted at 20 ° C to 30 ° C for 10 hours to 16 hours. The organic phase was evaporated under reduced pressure and dichloromethane was evaporated to dryness. The solvent was distilled off under reduced pressure. Compound 4 was isolated using a 20:1 petroleum ether, ethyl acetate developing solvent, and the same compound was combined and recovered.

(3) The product 4 obtained in the step (2) and 0.05 mol-0.07 mol T1 are dissolved in 300 ml of dichloromethane, the temperature of the system is lowered to 0 ° C - 30 ° C, and protected with nitrogen, and 4.7 mmo b 5.5 mmol CF is added. ₃ S0 ₃ Si(CH ₃ ) ₃ , the reaction was carried out for 40 minutes to 1 hour, and the reaction was quenched with triethylamine. Compound 5 was isolated using 20: 1-10:1 petroleum ether, ethyl acetate developing solvent, and the same compound was combined and recovered.

(4) The compound 5 obtained in the third step was dissolved in 200 ml of 300 ml of ethanol, 0.01 mol of 0.015 mol of NaBH _{4 was} added, and the mixture was heated to 60 ° C to 75 ° C for 3 hours.

(5) Spin the solution, add the precipitate to 200mL CH ₂ Cl ₂ -MeOH (2: 1, v / v) solution, then add 1ml / L -1.4mol / L sodium methoxide methanol solution 50ml, reaction for 3 hours _ At 5 hours, the furazan-type saponin monosaccharide derivative 2 was obtained. (6) Drying the solvent in a vacuum, dissolving the solid of the furan-type saponin monosaccharide derivative 2 with water, and adsorbing it on the ODS column, and eluting with a 50 _v / _v %-70 W _V % acetonitrile aqueous solution to collect the S configuration. The derivative 2-1 and the derivative of the R configuration 2-2 eluate.

 (7) The solution was recovered under reduced pressure and evaporated to dryness to give the solids 2-1 and 2-2.

 Example 4 Preparation of furan-type saponin monosaccharide derivatives

R=OH (S configuration) _R = OH (R configuration)

6 Tl 2

 The saponin compound 6 is prepared by using the timosaponin B-III as a reaction starting material, and then the furazan saponin monosaccharide derivative 2 is prepared by adding the reagent T1. The specific steps are as follows:

 (1) O.lmol of timosaponin Β-ΠΙ is dissolved in 600 ml of a methanol solution having a volume ratio of 10%, and 3 OmL - 5 OmL of concentrated hydrochloric acid is added, and the reaction is carried out at 80 ° C - 100 ° C for 2 hours.

 (2) Adjust to pH=6_7 with sodium hydroxide.

 (3) The extraction solution after neutralizing the extraction step with 1.8 L-2.4 L of n-butanol (2), and extracting the extract under reduced pressure until evaporated.

(4) The above solid was dissolved in water, and the saponin was adsorbed on the ODS column, and then the eluate of Compound 6 was collected by elution with 60 _v / _V % - 80 W _V % acetonitrile aqueous solution.

 (5) The solution is recovered under reduced pressure and evaporated to dryness to give the saponin compound 6 (NMR: 30.47 (1-C); 27.12 (2-C); 66.06 (3-C); 36.95 (4-C); 40.00 (5-C); 26.58(6-C); 28.59(7-C); 35.37(8-C); 36.98(9-C); 35.42(10-C); 21.00(11-C); 40.39( 12-C); 44.49(13-C); 53.73(14-C); 34.32(15-C); 75.93(16-C); 63.39(17-C); 13.65(18-C); 24.20(19 -C); 49.34(20-C); 16.78(21-C); 214.86(22-C); 40.21(23-C); 26.88(24-C); 35.47(25-C); 67.87(26- C); 17.16(27-C)).

(6) 0.05 mol of saponin compound 6 and 0.05 mol-0.07 mol of reagent Tl were dissolved in dichloromethane, and the temperature was lowered to -20 ° C -0 ° C under nitrogen protection, and 0.91 ml - 1.4 ml of CF ₃ S0 _{3 was added.} Si(CH ₃ ) ₃ , the reaction was stopped after 40 minutes _ 1 hour.

 (7) The reaction was quenched by the addition of triethylamine, and the solvent was evaporated to dryness.

(8) The precipitate is added to 200 ml of CH ₂ Cl ₂ -MeOH (2:1, v/v) solution, and then 50 ml of 1 mol/L_1.5 mol/L sodium methoxide methanol solution is added, and the reaction is carried out for 3-5 hours to obtain furose. The alkane saponin monosaccharide derivative 2 is evaporated to dryness.

(9) Dissolve the above solids with water and adsorb to the ODS column, using 50v/ _v %-70W _V % acetonitrile aqueous solution

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 10

 The saponin compound 6 prepared in Example 4 is used as a reaction starting material to prepare a furan-type saponin brominated derivative 10, and the specific steps are as follows:

(1) 0.05 mol of the saponin compound 6 obtained in the above step (5) in Example 4 was dissolved in 250 ml of CH ₂ C1 ₂ , and 50 ml of 70 ml of boron trifluoride-diethyl ether complex reagent (CAS: 109-63) was added. -7), add acetic anhydride (0.1 mmol), 2 mol, 20 ° C -60 ° C reaction for 30 minutes -1 hour, wash the reaction solution with 1L of saturated NaCl aqueous solution, then wash the reaction solution with 750ml_lL water, separate the organic phase, use dried over Na ₂ S0 _4; the organic phase was filtered, the filtrate by rotary evaporation, product was purified by silica gel column chromatography, developing solvent volume ratio of 6: 1 of petroleum ether and ethyl acetate.

(2) The product obtained in the step (1) is dissolved in a solution of 250 ml-300 ml of tetrahydrofuran, and 0.05 mol - 0.1 mol of NBS and 0.005 mol of 0.01 mol (Ph) ₃ P are added, and the reaction is carried out at room temperature for 5 hours to 7 hours.

(3) The reaction solution was filtered, and the solvent was evaporated to dryness under reduced pressure. The mixture was extracted with 200 ml of CH ₂ Cl ₂ -MeOH (2:1, v/v) solution, and 50 ml of 1 mol/L to 1.5 mol/L sodium methoxide methanol solution was added. - 100 ml, 20 ° C _50 ° C reaction for 5 hours _ 8 hours.

 (4) Distilling under reduced pressure, concentrating the reaction, and recrystallizing from a mixture of ethanol and ethyl acetate to obtain a furan-type saponin brominated derivative 10 (NMR: 30.47 (1-C); 27.12 (2-C); 66.06 ( 3-C); 36.95(4-C); 40.00(5-C); 26.58(6-C); 28.59(7-C); 35.37(8-C); 36.98(9-C); 35.42(10 -C); 21.00(11-C); 40.39(12-C); 44.49(13-C); 53.73(14-C); 29.78(15-C); 39.98(16-C); 55.89(17- C); 12.61 (18-C); 24.20 (19-C); 49.34 (20-C); 16.78 (21-C); 214.86 (22-C); 38.89 (23-C); 27.92 (24-C) 33.56(25-C); 67.23(26-C); 17.04(27-C)).

(5) Dissolving the furazan-type saponin bromo derivative 10 solid with water, adsorbing it on the ODS column, and eluting with 50W _V %-70W _V % acetonitrile aqueous solution, and collecting the derivative of the compound S configuration 10- Eluent of derivative 10-2 in the 1 and R configurations.

(6) The solution is recovered under reduced pressure, and evaporated to give the furan-type brominated derivatives 10-1 and 10-2, respectively. Example 7 Preparation of a furane-type saponin phosphate derivative

R=OH (S configuration = OH (R configuration; ¹ fJ)

6 11 The saponin compound 6 prepared in Example 4 is a reaction starting material, and a furan-type saponin phosphate derivative is obtained. The specific steps are as follows:

 (1) 0.05 mol of the saponin obtained in the step (5) in Example 4 was dissolved in 200 mL of tetrahydrofuran, and the temperature was lowered to -50 ° C to -20 ° C, and 0.25 mol of 0.3 mol of pyrophosphoryl chloride was gradually added thereto. Keep the temperature constant and react for 1 hour to 3 hours.

(2) Dilute the reaction solution with water, raise the temperature to about 40 ° C -60 ° C, add a certain amount of Na ₂ C0 ₃ to the bubble free release, stir the reaction at 25 ° C -35 ° C for 0.5 hour - 1.5 hours, filter , layering, the lower aqueous solution was steamed at 50 ° C until no obvious bubbles. Hydrochloric acid was added thereto, and pH = 1 - 2 was adjusted to precipitate a white precipitate.

 (3) The precipitate was filtered, and the precipitate was washed three times with hydrochloric acid to obtain a furan-type saponin phosphate derivative 11 (NMR: 30.47 (1-C); 27.12 (2-C); 66.06 (3-C); 36.95 (4-C); 40.00(5-C); 26.58(6-C);

28.59(7-C); 35.37(8-C); 36.98(9-C); 35.42(10-C); 21.00(11-C); 40.39(12-C); 44.49(13-C); 53.73 (14-C); 34.32(15-C); 75.93(16-C); 63.39(17-C); 13.65(18-C); 24.20(19-C); 49.34(20-C); 16.78( 21-C); 214.86(22-C); 38.79(23-C); 27.61(24-C); 32.43(25-C); 71.23(26-C); 16.71(27-C) ) o

(4) Dissolve the solid of the furane-type saponin phosphate derivative 11 with water, and adsorb the saponin to the ODS column, and elute with 20v/ _v %-40W _V % acetonitrile aqueous solution to collect the S configuration. Eluate of derivative 11-1 and derivative 11-2 of the R configuration.

 (5) The solution is recovered under reduced pressure, and evaporated to dryness to obtain furan-type saponin phosphate derivatives 11-1 and 11-2, respectively.

 Preparation of ester-based derivatives

 R=OH (S configuration 3⁄4) = OH (R configuration)

6 12

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 (3) At the end of the reaction, the reaction is quenched by the addition of sodium hydrogencarbonate, stirring is continued for 30 minutes to 1 hour, the temperature is raised to 20 ° C -30 ° C, and stirring is continued for 30 minutes to 1 hour to obtain furazolidin saponin trifluoride. Acetic acid derivative 14 (NMR: 30.47 (1-C); 27.12 (2-C); 66.06 (3-C); 36.95 (4-C); 40.00 (5-C); 26.58 (6-C); 28.59(7-C); 35.37(8-C); 36.98(9-C); 35.42(10-C); 21.00(11-C); 40.39(12-C); 44.49(13-C); 53.73 (14-C); 34.32(15-C); 75.93(16-C); 63.39(17-C); 13.65(18-C); 24.20(19-C); 49.34(20-C); 16.78( 21-C); 214.86(22-C); 38.89(23-C); 27.92(24-C); 33.56(25-C); 68.97(26-C); 17.21(27-C); 159.23(28 -C); 116.32(29-C)).

(4) The solvent is dissolved in a vacuum, and the solid of the furane-type saponin trifluoroacetic acid derivative 14 is dissolved in water, adsorbed on the ODS column, and eluted with 40 _v / _v %-70 W _V % acetonitrile aqueous solution to collect the S structure. An eluate of the derivative 14-1 of the type and the derivative 14-2 of the R configuration.

 (5) The solution is recovered under reduced pressure, and evaporated to dryness to obtain a derivative of the S configuration and a derivative of the R configuration.

14-2.

 The saponin compound 6 prepared in Example 4 was used as a reaction starting material to prepare a furan-type saponin alkylamino derivative, and the specific steps were as follows:

(1) 0.05 mol of the saponin compound 6 obtained in the above step (5) in Example 4 is dissolved in 300 ml of tetrahydrofuran, and the temperature is lowered to -30 ° C - (TC _; O. lmo Bu 0.2 mol of dimethylamine 0.15 mo, 0.2 mol of diethyl azodicarboxylate, 0.12 mol of 0.22 mol of PPh _{3 was} added to the solution, and the mixture was purged with nitrogen for 2 hours to 3 hours.

(2) After completion of the reaction, the mixture was filtered, and the filtrate was spun to give a furan-sodium succinylamino derivative 15 (NMR: 33.37 (1-C); 24.59 (2-C); 71.65 (3-C); 30.46 ( 4-C); 44.65(5-C); 26.58(6-C); 28.59(7-C); 35.37(8-C); 36.98(9-C); 35.42(10-C); 21.00(11 -C); 40.39(12-C); 44.49(13-C); 53.73(14-C); 34.32(15-C); 75.93(16-C); 63.39(17-C); 13.65(18- C); 24.20(19-C); 49.34(20-C); 16.78(21-C); 214.86(22-C); 39.84(23-C); 29.46(24-C); 31.26(25-C 67.82(26-C); 18.25(27-C); 42.31(3-N-CH ₃ ); 48.23(26-N-C3⁄4)).

 (3) Drying the solvent in vacuo, dissolving the solid of the furan-type saponin amino derivative 15 with water, and adsorbing it on the ODS column, and then eluting with 5 (^%_7(^% of acetonitrile aqueous solution) to collect the S configuration. Eluent of derivative 15-1 and derivative 15-2 of the R configuration.

(4) The solution was recovered under reduced pressure, and evaporated to dryness to obtain furane-type saponin amino derivatives 15-1 and 15-2, respectively. Example 11 Structure Confirmation The furfuran-type saponin monosaccharide derivative obtained in Example 1 or Example 2 was positive by Molish reaction and Liebermann-Burchard reaction, and the Nuclear Magnetic Resonance (NMR) data is shown in Table 1. The results of various maps such as HMBC, ROESY and MS were combined and analyzed as derivatives of formula V_I and formula V-II.

 Derivative of formula V - I, appearance as white amorphous powder, soluble in pyridine, soluble in acetone-water, acetonitrile-water and aqueous solution. Liebermann-Burchard and Molish were positive, demonstrating that the compound is a steroidal saponin.

HR-ESI-MS (positive ion mode) showed [M+Na]+w/z 619.3798 (calculated as C ₃₃ H ₅₆ 0 ₉ Na: 619.3817), and its molecular formula was determined to be C ₃₃ H ₅₆ 0 ₉ .

The NMR spectrum suggests that the structure contains one molecule of glucose, and the hydrogen spectrum ^H-MNR, as shown in Fig. 1) shows that δ 4.88 (d, J = 7.7 Hz) is the end-matrix signal of glucose, indicating that the glucose is in the ? configuration. A comprehensive analysis of ¹³ C-NMR spectra and DEPT spectra (see Figure 2) determined that four of the carbon signals on the 26 aglycones were methyl carbon signals, 12 were methylene carbon signals, and 14 were methine carbons. Signal and 3 quarter carbon signals. The carbon and hydrogen spectra of the aglycon moiety of the compound are similar to those of the timosaponin Β-ΠΙ, indicating that it has a similar nucleus to the timosaponin Β-ΠΙ. Compared with the carbon spectrum of the timosaponin-ΠΙ aglycon moiety, the double bond signal disappears and a carbonyl signal appears at 214.63. In the HMBC spectrum (see Figure 3), H-20 ( 2.84), H-21 ( 1.49), and H-23 ( 2.76) are remotely related to 214.63, while H-17 ( 2.23 ) is remotely related to ^75.22. It is indicated that the carbonyl group is at the C-22 position and the hydroxy group is at the C-16 position. The glucose endosome of 4.88 (Η-Γ) is remotely associated with the presence of HMBC in 75.01 (C-26) to determine the position of glycosidation, ie, glucose is linked to 26-OH to form a glycoside. The relative stereo configuration is determined by the ROESY spectrum (see Figure 4), specifically the presence of NOE in H-5 and H-19, indicating that the aglycon A and B rings are in the cis configuration. 3 0.76 (11-18) and 3 4.09 (H-16) There is NOE correlation, indicating that 16-OH is the ^ configuration. Other NMR data and correlations are shown in Table 1, Figure 5 and Figure 6. This compound has not been reported in the literature and is a new compound named timosaponin BlII-1 (or simply ΒΠΙ-1).

Formula ν - π derivative, appearance as white amorphous powder, soluble in pyridine, soluble in acetone-water, acetonitrile-water and aqueous solution. Liebermann-Burchard and Morish react positively, suggesting that the compound is a steroidal saponin. [a] ² _D ^e = -46.0 (c 0.05 mg/ml, pyridine).

HR-ESI-MS (positive ion mode) showed [M+Na] ⁺ w/z 619.3816 (calculated as C ₃₃ H ₅₆ 0 ₉ Na: 619.3817), and its molecular formula was determined to be C ₃₃ H ₅₆ 0 ₉ .

The NMR spectrum suggests that the structure contains one molecule of glucose. In the hydrogen spectrum (1H-MNR, see Figure 7), 3.85 (d, J = 7.7 Hz) is the glucose-end matrix sub-signal and is determined to be the configuration. A comprehensive analysis of ¹³ C-NMR spectra and DEPT spectra (see Figure 8) determined that four of the carbon signals on the 26 aglycones were methyl carbon signals, 12 were methylene carbon signals, and 14 were methine carbons. Signal and 3 quarter carbon signals. The carbon and hydrogen spectra of the aglycon moiety of the compound are similar to those of the timosaponin B3, indicating that it has a similar nucleus to the timosaponin B3. Compared with the carbon spectrum of the aglycone B3 aglycon moiety, the double bond signal disappears and a carbonyl signal appears at 214.86. In the HMBC spectrum (see Figure 9), H-20 (3⁄4 2.80), H-21 (3⁄4 1.23) and H-23 ( 2.93, 2.75 ) are remotely related to 214.86, and -17 ( 1.90) and 75.93 exist remotely. Correlation, indicating that the carbonyl group is at the C-22 position and the hydroxy group is at the C-16 position. In addition, the 4.85 (Η-Γ) grape-end stromate is remotely related to 75.19 (C-26), and the location of glycosidation is determined, that is, glucose is linked to 26-OH to form a glycoside. The relative stereo configuration is determined by the ROESY spectrum (see Figure 10), that is, the 3 0.71 (H-18) proton is associated with the NOE of the 3.29 (H-16) proton, and the 16-OH is determined to be o (configuration). -5 protons are related to H-19 protons, and it is determined that the A and B rings are cis structure. Other NMR data and correlations are shown in Table 1, Figure 11, and Figure 12. This compound has not been reported in the literature and is a new compound named timosaponin BlII-2 (or simply ΒΠΙ-2).

 Table 1 NMR data of derivatives represented by V - I and formula V - II

 Formula V - I V - II

 No.

 3⁄4 (J in Hz) <5H (J in Hz)

 1 1.52 (m), 1.88 (m) 30.52 1.58 (m), 1.93 (m) 30.47

2 1.92 (m), 1.19 (m) 27.19 1.91 (m), 1.33 (m) 27.12

3 4.41 (m) 66.07 4.42 (m) 66.06

4 1.92 (m), 1.75 (m) 37.54 1.84 (m), 1.67 (m) 36.95

5 2.17 (m) 37.08 1.71 (m) 37.00

6 1.39 (m), 1.19 (m) 26.65 1.32 (m), 1.18 (m) 26.58

7 1.78 (m), 1.62 (m) 28.61 1.75 (m), 1.63 (m) 28.59

8 1.38 (m) 35.45 1.36 (m) 35.37

9 1.39 (m) 40.08 1.84 (m) 40.00

10 - 35.49 - 35.42

11 1.35 (m), U5 (m) 20.97 1.39 (m), 1.23 (m) 21.00

12 1.58 (m), 1.30 (m) 39.59 1.38 (m)1.30 (m) 40.39

13 - 44.01 - 44.49

14 1.62 (m) 53.36 1.55 (m) 53.71

15 2.0 (m), 1.60 (m) 34.37 2.01 (m), 1.56 (m) 34.32

16 4.09 (m) 75.22 4.29 (m) 75.93

17 2.23 (dd,6.4, 10.4) 62.17 1.90 (d, 3.2) 63.39

18 0.76 (s) 14.93 0.71 (s) 13.65

19 1.0 l(s) 24.24 1.03 (s) 24.19

20 2.84 (dq, 6.6, 10.4) 47.09 2.80 (m) 49.34

21 1.49 (d, 6.95) 17.28 1.23 (d, 6.7) 16.78

22 - 214.63 - 214.86

23 2.76 (m) 38.91 2.93 (m), 2.75 (m) 38.89

24 2.06 (m), 1.92 (m) 27.92 2.06 (m), 1.91 (m) 27.92

25 2.01 (m) 33.56 2.01 (m) 33.56

26 4.33 (m), 3.56 (dd, 6.3, 9.5) 75.01 4.07 (m, 6.5), 3.52 (dd, 9.4) 75.19

27 1.04 (d, 6.6) 17.41 1.02 (d, 7.4) 17.44

Γ 4.88 (d, 7.75) 105.10 4.85 (d, 7.7) 105.02

2' 4.09(m) 74.95 4.06 (m) 75.21

3' 4.29(m) 78.58 4.28 (m) 78.50

4' 4.28(m) 71.70 4.27 (m) 71.64

5' 4.0 l(m) 78.63 3.98 (m) 78.58

6' 4.61 (brd, 11.6), 4.44 (m) 62.86 4.59 (m), 4.42 (m) 62.75 The structure of the derivative obtained in Example 5 - Example 10 was confirmed in the same manner as above.

 Example 12 Verification of antidepressant activity

Both FST and TST behavioral despair models are sensitive to most antidepressants, simple and fast, and are widely used in the screening of such drugs. This example is also prepared by using this model for Examples 1 to 10. The antidepressant pharmacological effects of various derivatives were verified. Male ICR mice, weighing (20 ± 2 ) g, were purchased from the Experimental Animal Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, free access to drinking water, room temperature (23 ± 2) V, and natural light. All mice were randomly divided into 10/cage, and the experiment was started after 3 days of adaptation in the word culture environment. Fasting for 12 hours before the experiment, drinking water was free. The specific administration method is as follows: a group of blank control groups, giving an equal volume of physiological saline.

 FST verification experiment

 1) Specific operation: Continuous administration for 6 days, and testing 1 hour after the last administration. First, the mouse's autonomic activity was measured by the open field method. The mice were individually placed in a cylindrical glass jar, timed for 4 minutes, and the number of lifts within 2 minutes after recording was recorded. The mice were then individually placed in a cylindrical glass jar 20 cm high and 14 cm in diameter with a water depth of 10 cm and a water temperature of 23 °C -25 °C. The time from the time the mouse enters the water is 6 minutes, and the accumulated immobility time within 4 minutes after recording (determination of the standard: the mouse stops struggling in the water, or is floating, only the small limbs move to keep the head floating on the water) . Each group of mice was operated in parallel.

 2) Experimental data processing: The experimental results are expressed as mean ± standard error (x ± SE). Statistical analysis was performed using the t test to determine whether it was significant. First, the t-test was performed on the indicators of autonomic activity, and 1> > 0.05 indicated that the autonomous post-movement of the mice had no effect, so as to avoid the interference of the central stimulant. Then, t test is performed on the forced swimming test index to judge whether it has antidepressant effect.

 TST verification experiment

 1) Specific operation: Continuous administration for 6 days, and testing 1 hour after the last administration. First, the mouse's autonomic activity was measured by the open field method. The mice were individually placed in a cylindrical glass jar, timed for 4 minutes, and the number of lifts within 2 minutes after recording was recorded. Then use the tape to stick the tail of the mouse to the horizontal bar 2 cm from the tip of the tail, and isolate the animal's line of sight with the plate around. The horizontal bar is about 25 cm from the ground, so that the mouse is about 10 cm from the ground, and the time is 6 min. The accumulated time was accumulated in minutes, and each group of mice was operated in parallel.

 2) Experimental data processing: The experimental results are expressed as mean ± standard error (x ± SE). Statistical analysis was performed using the t test to determine whether it was significant. First, the t-test was performed on the indicators of autonomic activity, and 1> > 0.05 indicated that the autonomous post-movement of the mice had no effect, so as to avoid the interference of the central stimulant. Then, the t-test was performed on the hanging tail experimental index to determine whether it has an anti-depressant effect.

 The effects of the derivatives prepared by the present invention against depression were verified by animal experiments. The results and data are shown in Tables 2 and 3.

 Table 2 Effect of intraperitoneal administration on forced swimming time in ICR mice

 Immobility time ±85 (flat compound dose (mg/Kg) number of animals (only)

Mean, sec) Physiological saline 0.1 ml/10 g 10 182.20 ± 6.82 Example 1 (2-1) 10 10 100.50 ± 6.59 * Example 1 (2-2) 10 10 37.10 ± 5.42** Example 2 (2-1 10 10 109.38±11.35* Example 2(2-2) 10 10 37.68±11.46* Example 3(2-1) 10 10 109.38±11.35* Example 3(2-2) 10 10 39.36±12.23* Implementation Example 4(2-1) 10 10 109.38±11.35* Example 4(2-2) 10 10 40.12±9.68* Example 5 (7-1) 10 10 104.56 ± 9.67 * Example 5 (7-2) 10 10 109.42 ± 10.34 * Example 6 (10-1) 10 10 111.38 ± 7.96 * Example 6 (10-2) 10 10 118.47±9.89* Example 7(11-1) 10 10 103.35±9.81* Example 7(11-2) 10 10 112.21±8.97* Example 8(12-1) 10 10 104.64±9.82* Example 8(12-2) 10 10 114.15±9.73* Example 9(14-1) 10 10 116.28±10.31* Example 9(14-2) 10 10 109.82±11.48* Example 10(15-1) 10 10 105.56±9.98*

 10 10 109.75±10.31*

"*" means P<0.05;"** ^: " means P<0.01.

Table 3 Effect of intraperitoneal administration on the time of suspension of ICR mice. Compound dose _(mg / K _{g )} dynamic touch (only) ^{(Ψ Ψ} physiological saline 0.1ml/10g 10 119.90±5.65 Example 1 (2-1 10 10 59.00±6.33** Example 1 (2-2) 10 10 33.90±5.71* Example 2 (2-1) 10 10 73.68±10.61* Example 2 (2-2) 10 10 75.69±11.36* Example 3 (2-1) 10 10 69.38±12.35* Example 3 (2-2) 10 10 66.53±12.57* Example 4 (2-1) 10 10 69.67±13.62* Example 4 (2-2) 10 10 71.52±12.61* Example 5(7-1) 10 10 74.38±10.79* Example 5(7-2) 10 10 78.34±12.47* Example 6(10-1) 10 10 72.15±10.46* Example 6(10-2) 10 10 68.23±10.82* Example 7(11-1) 10 10 69.47±10.37* Example 7(11-2) 10 10 72.11±9.95* Example 8(12-1) 10 10 78.32±10.85* Example 8(12-2) 10 10 79.46±12.27* Example 9(14-1) 10 10 71.48±11.38* Example 9(14-2) 10 10 62.11±12.45* Example 10 ( 15-1) 10 10 69.37±9.96* Example 10(15-2) 10 10 73.39±10.34*

"*,, means P<0.05; "**,, means P<0.01.

 Mice were given 10 mg/Kg of the above compound by intraperitoneal injection, and a blank control group (normal saline) was additionally provided. There was no significant difference in the t-test of the indicators of spontaneous activity in mice, indicating that these compounds had no effect on the autonomic activity of mice. The t test was performed on the immobility time of forced swimming and tail suspension test in mice. The results showed that the above furan saponin derivatives can significantly shorten the immobility time of forced swimming and tail suspension in mice, suggesting that they have significant resistance. Depressive activity.

Claims

Claim WO 2013/097661 PCT/CN2012/087260

A furane-type saponin derivative having the structure shown in formula I

Formula I;

 Wherein the substituent is selected from the group consisting of -OH, -SH, halogen, oxo, sulfate group, sugar linked by 0-glycosidic bond, sugar linked by S-glycosidic bond, amino group substituted by C1-C3 saturated alkane One type;

The substituent R _{2 is} selected from the group consisting of -OH, -SH and halogen;

The substituent R _{3 is} selected from the group consisting of -OH, -SH, halogen, oxo, sulfate, phosphate, trifluoroacetate, C1-C3 saturated alkane substituted amino, sugar linked by 0-glycosidic linkage and One of the sugars linked by an S-glycosidic bond.

 2. A furane-type saponin derivative having the structure shown in Formula IV

Formula IV.

 The furane-type saponin derivative according to claim 2, wherein the formula IV includes one or more furan-type saponin derivatives represented by the formula V - I and the formula ν - π

V-

 The furazan-type saponin derivative according to any one of claims 1 to 3, which is derived from timosaponin ΠΙ-ΠΙ, timosaponin A-I, timosaponin-saponin or timosaponin A- I sapogenin is prepared.

 The furane-type saponin derivative according to any one of claims 1 to 3, which is obtained from an imaginary parent or an extract thereof.

 The furane-type saponin derivative according to any one of claims 1 to 3 as an active ingredient for the preparation of a medicament, a food or a health supplement for preventing and treating depression.

 An antidepressant administration method for administering a therapeutically effective amount of a furan-type saponin derivative according to any one of claims 1 to 3 to a patient suffering from depression.

 The antidepressant administration method according to claim 7, wherein the effective therapeutic dose is a total amount of 0.05 mg/kg to 50 mg/kg of the furazan-type saponin derivative per day.

 A composition for antidepressant, which comprises the furoyl saponin derivative according to any one of claims 1 to 3.

 10. The anti-depressant composition according to claim 9, wherein a therapeutically effective amount of the furazan-type saponin derivative is administered to a patient suffering from depression.