CN105777837A - Novel Mogrol derivative monomer - Google Patents
Novel Mogrol derivative monomer Download PDFInfo
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- CN105777837A CN105777837A CN201610321210.XA CN201610321210A CN105777837A CN 105777837 A CN105777837 A CN 105777837A CN 201610321210 A CN201610321210 A CN 201610321210A CN 105777837 A CN105777837 A CN 105777837A
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- CHDKKJGVQOJYHM-UHFFFAOYSA-N CCC1N(C)CC2C1C2 Chemical compound CCC1N(C)CC2C1C2 CHDKKJGVQOJYHM-UHFFFAOYSA-N 0.000 description 1
- NGWSAUQBWVWFCU-UHFFFAOYSA-N CCNC(C)(C)C(C)C Chemical compound CCNC(C)(C)C(C)C NGWSAUQBWVWFCU-UHFFFAOYSA-N 0.000 description 1
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
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Abstract
The invention provides a novel Mogrol derivative monomer (4). The novel Mogrol derivative monomer (4) can be prepared into drugs for treating and/or preventing different cancers and/or tumors, can also be prepared into healthy products for regulating immunity and/or improving microcirculation and/or improving quality of life, crucially is applied to the treatment of malignant tumors and has a broad application prospect.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to a kind of novel momordica grosvenori alcohol derivatives monomer.
Background technology
Cancer is the second-biggest-in-the-world disease torturing human life, and mortality rate is only second to cardiovascular and cerebrovascular disease, is one of the main factor of human death.By World Health Organization organize subordinate IARC of cancer mechanism of official (IARC) responsible latest edition " report of world's cancer " prediction, whole world cases of cancer will present rapidly breeds situation, by 14,000,000 people of 2012, fast 19,000,000 people increasing to 2025, were up to 24,000,000 people by 2035 year by year.Report also shows, within 2012, the newly-increased cases of cancer in the whole world has nearly half to occur in Asia, and wherein most is in China, and the newly-increased cases of cancer height of China ranks first.Within 2012, newly-increased 3,070,000 cancer patients of China also cause about 2,200,000 people dead, divide and account for the 21.9% and 26.8% of whole world total amount.The data of WHO are slightly below the statistics of China.2012 annual datas that whole nation tumor Register issues show, the annual newly-increased cases of cancer about 3,500,000 of China, there are about 2,500,000 people therefore dead.
The common method for the treatment of of cancer mainly has Three models now: operation, radiotherapy and Drug therapy, and which Therapeutic Method selected then depends on the position of tumor, grade malignancy, development degree and patient body state.In Three models, the Therapeutic Method of operation, the invasion of Chang Yinwei cancerous cell spreads to adjacent tissue or far-end shifts and limited efficiency；The Therapeutic Method of radiotherapy, then be limited to the injury that other normal structures internal are caused；The Therapeutic Method of medicine, for late period dispersivity and transitivity malignant tumor be most basic Therapeutic Method.In the decades in past, though the chemotherapy being conceived to direct killing tumor cell has obvious development and progress, become the backbone of tumor pharmacother, but the defect breeding solid tumor weak effect slowly, drug selectivity is little, toxicity is many and serious is become the important limiting factor in clinical treatment by this Therapeutic mode.Continue the Biotherapeutics that operation, the 4th kind of pattern after radiation and chemotherapy are tumors, it regulates the biologically of body self mainly by the effect of tumor host defense mechanism or biological preparation, thus suppressing or eliminating tumor；Although Biotherapeutics is too big toxic and side effects not, but owing to technology requires tight, complex process, therefore price is high, and numerous cancer patients and family members are difficult to bear, and affects its popularizing in field of cancer.
Owing to there is above-mentioned various restriction, the research and development of natural antitumor medicine achieve increasing concern.No matter natural anti-cancer drugs is at suppression or killing tumor cell, adjustment body's immunity, improves symptom and feature and alleviate on toxic and side effects of chemoradiotherapy, or in the conditioning after being ill of tumor, is respectively provided with important function.Thus, natural plants new therapy will become the 5th kind of pattern after operation, radiotherapy, chemotherapy and biotherapy.
Fructus Momordicae is a kind of rare medicinal herbs, belongs to the perennial liana of Cucurbitaceae, sweet in the mouth cool in nature.nullContaining the saponin constituent of non-saccharide sweet taste in Fructus Momordicae extract，Also known as momorside，According to wherein sapogenin connect the difference of the number of glycosyl and link position in momorside isolation identification go out Fructus Momordicae bioside、Three glucosides、Four glucosides、Five glucosides、The multiple saponin monomers such as six glucosides，It is respectively designated as mogroside II、III、IV、V、VI(MogrosideII、III、IV、V、VI) etc.，Wherein the sugariness of momordica glycoside V-MogrosideV (1A) (as shown in Figure 1) is 256-344 times of sucrose，Sugariness is sucrose 126 times of mogroside IV-MogrosideIV (1B) (as shown in Figure 1)，Its heat is zero，There is clearing heat and moistening lung antitussive、Effect of loosening bowel to relieve constipation，To obesity、Constipation、Diabetes etc. have preventive and therapeutic effect.
Triterpene glucoside Mogrosides is that two glucoside side chains being made up of less than four glucose units are connected with C-3, C-24 of β-glycosidic bond with sapogenin momordica grosvenori alcohol Mogrol (2), connecting key between pendant glucose is β-1,6 and β-l, 2 glycosidic bonds.
Many studies have shown that, triterpene glucoside can improve glucose and the utilization of fat, increases the sensitivity of insulin, but the effective ingredient of Fructus Momordicae hypoglycemic activity and mechanism of action indefinite.The hypoglycemic activity of Fructus Momordicae has been studied by Hu Lihong seminar of Shanghai institute of materia medica of the Chinese Academy of Sciences and Shen Xu seminar, first in HepG2 cell, the momordica glycoside V (1A) that content in Fructus Momordicae is the highest is tested, it has been found that AMPK is not had activity by it；And momordica grosvenori alcohol Mogrol (2) (as shown in Figure 2) and derivant 3 alpha-hydroxy-2 5-dehydroxylation-24-ketone-momordica grosvenori alcohol (3 α-hydroxy-25-dehydroxy-24-oxomogrol) (3) thereof can activate AMPK (ChenX.B., etal；Bioorganic&MedicinalChemistry2011,19:5776).At present, generate momordica grosvenori alcohol derivatives monomer (3) and momordica grosvenori alcohol derivatives monomer (4) but without any patent and bibliographical information under given conditions by momordica grosvenori alcohol (2), have momordica grosvenori alcohol derivatives monomer (4) also without any patent and bibliographical information.
Summary of the invention
The technical problem to be solved in the present invention there is provided a kind of novel momordica grosvenori alcohol derivatives monomer (4), this momordica grosvenori alcohol derivatives monomer (4) can make pharmaceutical preparation or health product, for treatment and/or the prevention of tumor and/or cancer.
First aspect present invention provides a kind of momordica grosvenori alcohol derivatives monomer (4), is structured with:
Second aspect present invention provides a kind of compositions, comprises following structure
Momordica grosvenori alcohol derivatives monomer (4).
In a preference, described compositions is pharmaceutical preparation, and described pharmaceutical preparation also includes pharmaceutically acceptable diluent, carrier, excipient, adjuvant or vehicle.
In a preference, the dosage form of described pharmaceutical preparation is peroral dosage form, injection type or Topical application forms.
In a preference, described peroral dosage form is tablet, powder, suspension, emulsion, capsule, granule, coated tablet, pill, liquid, spirit, syrup or limonada.
In a preference, described injection type includes water preparation, suspension or solution.
In a preference, described Topical application forms includes ointment, solid, suspension, water preparation, spirit, powder, paste, suppository, aerosol, paste, liniment, lotion, enema or Emulsion.
In a preference, described compositions is used for treatment and/or prophylaxis of tumours and/or cancer；
Wherein said tumor and/or cancer are selected from:
Malignant tumor, including bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate and skin carcinoma；
Lymphoid hematopoetic tumor, including leukemia, acute lymphoblastic leukemia, Acute Lymphoblastic Leukemia, B-cell lymphom, T-cell lymphom, Huo Qijin lymphatic cancer, non-Huo Qijin lymphatic cancer, hairy cell lymphom, mantle cell lymphoma, myeloma and Burkett ' sShi lymphatic cancer；
The hematopoetic tumor of bone marrow system, including acute and chronic myelocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia；
The tumor of the interstitial origin cause of formation, including fibrosarcoma and rhabdomyosarcoma；
The tumor of maincenter and peripheral nervous system, including astrocytoma, becomes neurofibroma, glioma and schwannoma；And
Other tumors, including melanoma, spermocytoma, teratocarcinoma, osteosarcoma, exophytic pigment neck tumor, thyroid filter capsule cancer and Kaposi's sarcoma.
In a preference, described compositions is health product, also includes acceptable carrier in optional health product.
In a preference, described compositions is used for immunomodulating, improves microcirculation and/or improves quality of life.
The term that the present invention uses has defined below, unless otherwise described:
Term used herein " momordica grosvenori alcohol derivatives monomer (3) " means 3 alpha-hydroxy-2 5-dehydroxylation-24-ketone-momordica grosvenori alcohol (3 α-hydroxy-25-Dehydroxy-24-oxomogrol)；Term used herein " novel momordica grosvenori alcohol derivatives monomer (4) " means 3 alpha-hydroxy-2s 2,24-diene-24,25-dehydroxylation-momordica grosvenori alcohol (3 α-hydroxy-22,24-diene-24,25-dehydroxy-mogrol) (4) (structural formula is as shown in Figure 3).
Term used herein " compositions " means to include comprising each product specifying composition of specified amount and any product directly or indirectly produced from each combination specifying composition of specified amount.Described Topical application forms includes ointment, solid, suspension, water preparation, spirit, powder, paste, suppository, aerosol, paste, liniment, lotion, enema or Emulsion..Aseptically by reactive compound and pharmaceutically acceptable carrier and any required preservative, buffer agent or propellants.Ophthalmic preparation, eye ointment, powder and solution are contemplated within the scope of the present invention.
When for above-mentioned treatment or other treatment, a kind of the compounds of this invention for the treatment of and/or prevention effective dose can be applied in a pure form, or with pharmaceutically acceptable salt, ester or prodrug forms (when there are these forms) application.Or, described compound can be administered with the pharmaceutical composition containing this purpose compound with one or more pharmaceutically acceptable excipient.The compounds of this invention of word " treatment and/or prevention effective dose " refers to the compound of the q.s with the reasonable effect/Hazard ratio treatment obstacle suitable in any therapeutic treatment.It is to be understood that total consumption per day of the compounds of this invention and compositions must be maked decision within the scope of reliable medical judgment by attending physician.Must determining according to many factors for any concrete patient, concrete treatment and/or prevention effective dose level, described factor includes the order of severity of obstacle and this obstacle treated；The activity of the particular compound adopted；The concrete compositions adopted；The age of patient, body weight, general health situation, sex and diet；The administration time of the particular compound adopted, route of administration and excretion rate；The treatment persistent period；With the particular compound combination use adopted or the medicine used simultaneously；And the known similar factor of medical field.Such as, the way of this area is, the dosage of compound, from the level being less than obtaining required therapeutic effect and require, is gradually increased dosage, until obtaining required effect.
The present invention also provides for comprising the pharmaceutical preparation of the compounds of this invention optionally formulated together with the acceptable diluent of one or more non-toxic pharmaceutical, carrier, excipient, adjuvant or vehicle.Described pharmaceutical preparation can become for oral administration with solid or liquid form, supply parental injection or for rectally by particular formulation especially.
The pharmaceutical composition of the present invention can by oral, rectum, parenteral, pond, intravaginal, intraperitoneal, locally (as by powder, ointment or drop), buccal gives the mankind and other mammals, or gives as oral spray or nasal mist.Term used herein " parenteral " refers to include intravenous, intramuscular, intraperitoneal, breastbone interior, the administering mode of subcutaneous and intra-articular injection and transfusion.
In yet another aspect, the present invention provides and comprises present component and the pharmaceutical composition of physiologically tolerable diluent.The present invention includes one or more above-claimed cpds, it is configured to compositions together with one or more nontoxic physiologically tolerable or acceptable diluent, carrier, adjuvant or vehicle (herein they being referred to as diluent), for parental injection, nasal delivery, with solid or liquid form oral administration, rectum or topical etc..
The compositions being suitable for parental injection can include physiologically acceptable sterile, aqueous or non-aqueous liquor, dispersant, suspensoid or Emulsion, and for reconstructing the sterile powders of sterile injectable solution agent or dispersant.Suitable moisture or nonaqueous carrier, diluent, solvent or vehicle example includes water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), vegetable oil (such as olive oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositionss also can contain adjuvant, such as preservative, wetting agent, emulsifying agent and dispersant.By various antibacterial agents and antifungal, for instance parabens, chlorobutanol, phenol, sorbic acid etc., it can be ensured that prevent the effect of microorganism.It is also expected to include isotonic agent, for instance saccharide, sodium chloride etc..By using the material that can postpone to absorb, for instance aluminum monostearate and gelatin, the prolongation that can reach injectable drug form absorbs.
Suspensoid also can contain suspending agent in addition to the active compound, for instance the mixture etc. of ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline Cellulose, inclined aluminium hydroxide, bentonite, agar and Tragacanth or these materials.
In some cases, for extending the effect of medicine, it is desirable to the absorption of the subcutaneously or intramuscularly injectable drug of slowing down.This can be realized by the liquid suspension of the crystal of use poorly water-soluble or amorphous substance.So, the infiltration rate of medicine depends on its dissolution velocity, and dissolution velocity can be depending on crystal size and crystal formation.Or, the delay of the medicament forms of parenteral absorb by by this medicine dissolution in or be suspended in oil vehicle and realize.
Injectable depot formulations form can be prepared by the microcapsule matrix of formation medicine in biodegradable polymer such as polylactide-polyglycolide (polylactide-polyglycolide).According to the character of the medicine ratio with polymer and the concrete polymer adopted, drug releasing rate can be controlled by.The example of other biological degradable polymer includes poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations can be prepared in the liposome compatible with bodily tissue or microemulsion also by pharmaceutical pack being embedded in.
Injectable formulation can such as by filtering with bacteria filter or carrying out sterilizing by mixing the biocide of aseptic solid composite form, and described solid composite can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
Solid dosage forms for oral administration includes capsule, tablet, pill, powder and granule.In this type of solid dosage forms, reactive compound can mix with the pharmaceutically acceptable excipient of at least one inertia or carrier such as sodium citrate or dicalcium phosphate and/or following material: a) filler or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid；B) binding agent such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and Radix Acaciae senegalis；C) wetting agent such as glycerol；D) disintegrating agent such as agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some silicate and sodium carbonate；E) solution retarding agents such as paraffin；F) accelerator such as quaternary ammonium compound is absorbed；G) wetting agent such as spermol and glyceryl monostearate；H) adsorbent such as Kaolin and bentonite and i) lubricant such as Pulvis Talci, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.When capsule, tablet and pill, described dosage form also can comprise buffer agent.
The solid composite of similar type uses excipients such as lactose and high molecular weight polyethylene glycol etc., it is possible to as the implant in soft capsule and hard capsule.
Tablet, dragee (dragees), capsule, pill can be prepared with the solid dosage forms of granule together with coating and shell material such as enteric coating material and field of medicine preparations other clothing materials known.These solid dosage formss can optionally contain opacifier, and its composition also can make its simply or preferentially at certain position of intestinal optionally with delayed mode release of active ingredients.The example of operable embedding composition includes polymer substance and wax class.If be suitable for, reactive compound also can be made into microencapsulated form with one or more above-mentioned excipient.
Liquid dosage form for oral administration includes pharmaceutically acceptable Emulsion, solution, suspensoid, syrup and elixir.Liquid dosage form is except also can contain inert diluent commonly used in the art containing active ingredient beyond the region of objective existence, such as water or other solvents, the fatty acid ester of solubilizing agent and emulsifying agent such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethylformamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol (tetrahydrofurfurylalcohol), Polyethylene Glycol and sorbitan and their mixture.Orally administered composition also can comprise adjuvant except comprising inert diluent, for instance wetting agent, emulsifying and suspending agent, sweeting agent, correctives and flavouring agent.
Compositions for rectum or vagina administration is preferably suppository.Suppository can be prepared by being mixed with suitable non-irritating excipient or carrier such as cocoa butter, Polyethylene Glycol or suppository wax by the compounds of this invention, they are at room temperature solid, but it is then liquid under body temperature, therefore can melt in rectal cavity or vaginal canal and discharge reactive compound.
The compounds of this invention can also liposomal form administration.As it is known in the art, liposome prepares typically by phospholipid or other lipid materials.Liposome is formed by the single or multiple lift aquation liquid crystal being scattered in water-bearing media.On any nontoxic, physiology that can form liposome, acceptable and metabolizable lipid all can use.The present composition of liposomal form, except containing the compounds of this invention, also can contain stabilizer, preservative, excipient etc..Preferred lipid is phospholipid that is natural and that synthesize and phosphatidylcholine (lecithin), and they can use individually or together.The method forming liposome is well known in the art.
Term used herein " pharmaceutically acceptable prodrug " represents the prodrug of the compounds of this invention, it is suitable for occurring without excessive toxicity, stimulation, anaphylaxis etc. with the mankind and zootic contact tissue within the scope of reliable medical judgment, match with rational effect/Hazard ratio and its intended purpose is effective, also represent the zwitterionic form of the compounds of this invention in the conceived case.The prodrug of the present invention such as can be rapidly converted into the parent compound of above formula in vivo by being hydrolyzed in blood.
The invention provides a kind of novel momordica grosvenori alcohol derivatives monomer (4), treatment and/or the medicine of prevention various cancers and/or tumor can be made for, and be used for immunomodulating and/or improve microcirculation and/or improve the health product of quality of life, emphasis is applied to the treatment of malignant tumor, has broad application prospects.
Accompanying drawing explanation
Fig. 1 is the schematic arrangement of momordica glycoside V (1A), VI (1B).
Fig. 2 is the schematic arrangement of momordica grosvenori alcohol Mogrol (2).
Fig. 3 is the schematic arrangement of momordica grosvenori alcohol derivatives monomer (4).
Detailed description of the invention
Unless specifically indicated, term used herein has the general sense in art of the present invention.
Below with reference to specific embodiment, the present invention will be described, it is necessary to explanation, and these embodiments are merely illustrative, and are not considered as limiting the invention.Unreceipted concrete technology or condition in embodiment, technology or condition described by the document in this area or carry out according to product description.Agents useful for same or the unreceipted production firm person of instrument, be can pass through city available from conventional products.
Embodiment 1: prepare momordica grosvenori alcohol derivatives monomer (3) and (4) from the extract of momorside 98%
By Fructus Momordicae extract 50g (momorside 98%, containing 55% mogroside V, buy in Guilin Laiyin Biotechnology Co., Ltd.) add the ethanol of 250mL aqueous solution (volume ratio of second alcohol and water is 1:1) (in advance with hydrochloric acid regulate to pH value be 3.0), stirring and dissolving in a kettle., then heat to heat 2 hours at 120 DEG C, after being cooled to room temperature 25 DEG C, it is 7 that the NaOH alkali liquor of reactant liquor 1M is neutralized to pH value, at 90-95 DEG C, ethanol is steamed as far as possible, remaining concentrated solution adds 200mL distilled water, cool down after being sufficiently stirred for, stand, by water layer isolated for disposal above, obtain coffee-like extractum；Use 100mL, 50mL, 50mL extraction into ethyl acetate coffee color extractum 3 times respectively, after merging 3 extracts, concentrate with Rotary Evaporators at 100-120 DEG C, ethyl acetate is evaporated completely, namely obtains the light coffee color solid 18.2g containing momordica grosvenori alcohol derivatives monomer (3) and momordica grosvenori alcohol derivatives monomer (4)；With ethanol, light coffee color solid is loaded into silicagel column, with acetonitrile: water (volume ratio 20:1) gradient elution, collects different effluent sequentially, after concentration, obtain A (6.8g), B (5.6g) two component；First collect A (6.8g) the component recycle silicon glue post obtained and separate (chloroform: ethanol/60:5 eluting), obtain momordica grosvenori alcohol derivatives monomer (3) 4.1g (HPLC > 99%).ESIMSm/z503(458+45)[M+HCOO-]-(calcdforC31H51O5)；13nullC-NMR(600MHz，MeOD)δppm:29.1(C-1),31.7(C-2),79.4(C-3),42.8(C-4),144.1(C-5),120.7(C-6),25.2(C-7),44.8(C-8),41.1(C-9),35.4(C-10),77.7(C-11),30.6(C-12),48.3(C-13),49.6(C-14),34.9(C-15),27.5(C-16),50.7(C-17),17.2(C-18),26.6(C-19),41.1(C-20),19.0(C-21),37.8(C-22),40.3(C-23),218.2(C-24),35.4(C-25),18.8(C-26),18.8(C-27),26.4(C-28),19.9(C-29),19.3(C-30)；Compare with 3a-hydroxyl-25-dehydroxylation-24-carbonyl-momordica grosvenori alcohol (3a-hydroxy-25-Dehydroxy-24-oxomogrol) the carbon modal data of bibliographical information, the two basically identical (ChenX.B., etal；Bioorganic&MedicinalChemistry2011,19:5776).
B (5.6g) the component recycle silicon glue post that rear collection obtains separates (petroleum ether: ethyl acetate/5:2 eluting), obtains momordica grosvenori alcohol derivatives monomer (4).3.2g (HPLC > 99%).ESIMSm/z441[M+H]+(calcdforC30H49O2)；13nullC-NMR(600MHz，MeOD)δppm:23.5(C-1),29.5(C-2),87.8(C-3),44.2(C-4),144.1(C-5),121.8(C-6),25.5(C-7),40.9(C-8),40.8(C-9),51.3(C-10),71.9(C-11),41.5(C-12),48.2(C-13),52.2(C-14),35.3(C-15),24.9(C-16),54.3(C-17),15.2(C-18),18.6(C-19),40.2(C-20),20.3(C-21),137.4(C-22),128.8(C-23),125.4(C-24),143.3(C-25),19.7(C-26),25.7(C-27),21.7(C-28),21.7(C-29),18.6(C-30).
Embodiment 2: prepare momordica grosvenori alcohol derivatives monomer (3) and (4) from the extract of momorside 95%
By Fructus Momordicae extract 50g (momorside 95%, containing 45% mogroside V, from Guilin Laiyin Biotechnology Co., Ltd. buy) add 250mL methanol aqueous solution (volume ratio of first alcohol and water is 3:2) (in advance with sulphuric acid regulate to pH value be 2.8), stirring and dissolving in a kettle., then heat to heat 2 hours at 120 DEG C, after being cooled to room temperature, it is 7 that the KOH alkali liquor of reactant liquor 1M is neutralized to pH value, at 90-95 DEG C, methanol is steamed as far as possible, remaining concentrated solution adds 200mL distilled water, cool down after being sufficiently stirred for, stand, by water layer isolated for disposal above, obtain coffee-like extractum；Use 100mL, 50mL, 50mL extraction into ethyl acetate coffee color extractum 3 times respectively, after merging 3 extracts, concentrate with Rotary Evaporators at 100-120 DEG C, ethyl acetate is evaporated completely, namely obtains the light coffee color solid 15.5g containing momordica grosvenori alcohol derivatives monomer (3) and momordica grosvenori alcohol derivatives monomer (4)；With methanol, light coffee color solid is loaded into silicagel column, with acetonitrile: water (19:1) gradient elution, collects different effluent sequentially, after concentration, obtain A (6.0g), B (5.2g) two component；First collect A (6.0g) the component recycle silicon glue post obtained and separate (chloroform: ethanol/60:5 eluting), obtain momordica grosvenori alcohol derivatives monomer (3) 3.9g (HPLC > 99%)；HPLC、13C-NMR, ESIMS testing result is consistent with the compound (3) in embodiment 1.B (5.2g) the component recycle silicon glue post that rear collection obtains separates (petroleum ether: ethyl acetate/3:1 eluting), obtains momordica grosvenori alcohol derivatives monomer (4).3.0g (HPLC > 99%)；HPLC、13C-NMR, ESIMS testing result is consistent with the momordica grosvenori alcohol derivatives monomer (4) in embodiment 1.
Embodiment 3: prepare momordica grosvenori alcohol derivatives monomer (3) and (4) from the extract of momorside 90%
By Fructus Momordicae extract 50g (momorside 90%, containing 40% mogroside V, from Guilin Laiyin Biotechnology Co., Ltd. buy) add 250mL normal propyl alcohol aqueous solution (volume ratio of normal propyl alcohol and water is 2:3) (in advance with formic acid regulate to pH value be 3.2, stirring and dissolving in a kettle., then heat to heat 2 hours at 120 DEG C, after being cooled to room temperature, it is 7 that the NaOH alkali liquor of reactant liquor 1M is neutralized to pH value, at 90-95 DEG C, normal propyl alcohol is steamed as far as possible, remaining concentrated solution adds 200mL distilled water, cool down after being sufficiently stirred for, stand, by water layer isolated for disposal above, obtain coffee-like extractum；Use 100mL, 50mL, 50mL extraction into ethyl acetate coffee color extractum 3 times respectively, after merging 3 extracts, concentrate with Rotary Evaporators at 100-120 DEG C, ethyl acetate is evaporated completely, namely obtains the light coffee color solid 14.2g containing momordica grosvenori alcohol derivatives monomer (3) and momordica grosvenori alcohol derivatives monomer (4)；With methanol/ethanol, light coffee color solid is loaded into silicagel column, with acetonitrile: water (20:1) gradient elution, collects different effluent sequentially, after concentration, obtain A (5.4g), B (4.3g) two component；First collect A (5.4g) the component recycle silicon glue post obtained and separate (chloroform: ethanol/60:5 eluting), obtain momordica grosvenori alcohol derivatives monomer (3) 3.5g (HPLC > 99%)；HPLC、13C-NMR, ESIMS testing result is consistent with the compound (3) in embodiment 1.B (4.3g) the component recycle silicon glue post that rear collection obtains separates (petroleum ether: ethyl acetate/6:4 eluting), obtains momordica grosvenori alcohol derivatives monomer (4) 2.8g (HPLC > 99%)；HPLC、13C-NMR, ESIMS testing result is consistent with the momordica grosvenori alcohol derivatives monomer (4) in embodiment 1.
Embodiment 4: prepare momordica grosvenori alcohol derivatives monomer (3) and (4) from the extract of momorside 80%
By Fructus Momordicae extract 50g (momorside 80%, containing 20% mogroside V, from Guilin Laiyin Biotechnology Co., Ltd. buy) add 250mL ethanol aqueous solution (volume ratio of second alcohol and water is 1:1) (in advance with ethanedioic acid regulate to pH value be 2.6), stirring and dissolving in a kettle., then heat to heat 2 hours at 120 DEG C, after being cooled to room temperature, the Na of reactant liquor 1M2CO3It is 7 that alkali liquor is neutralized to pH value, is steamed by ethanol at 90-95 DEG C as far as possible, and remaining concentrated solution adds 200mL distilled water, cools down, stands after being sufficiently stirred for, and by water layer isolated for disposal above, obtains coffee-like extractum；Use 100mL, 50mL, 50mL extraction into ethyl acetate coffee color extractum 3 times respectively, after merging 3 extracts, concentrate with Rotary Evaporators at 100-120 DEG C, ethyl acetate is evaporated completely, namely obtains the light coffee color solid 8.8g containing momordica grosvenori alcohol derivatives monomer (3) and momordica grosvenori alcohol derivatives monomer (4)；With methanol/ethanol, light coffee color solid is loaded into silicagel column, with acetonitrile: water (95:5) gradient elution, collects different effluent sequentially, after concentration, obtain A (3.8g), B (3.0g) two component；First collect A (3.8g) the component recycle silicon glue post obtained and separate (chloroform: ethanol/60:5 eluting), obtain momordica grosvenori alcohol derivatives monomer (3) 2.1g (HPLC > 99%)；HPLC、13C-NMR, ESIMS testing result is consistent with the compound (3) in embodiment 1.B (3.0g) the component recycle silicon glue post that rear collection obtains separates (petroleum ether: ethyl acetate/4:1 eluting), obtains momordica grosvenori alcohol derivatives monomer (4) 1.8g (HPLC > 99%)；HPLC、13C-NMR, ESIMS testing result is consistent with the momordica grosvenori alcohol derivatives monomer (4) in embodiment 1.
Embodiment 5: momordica grosvenori alcohol derivatives monomer (4) suppresses cell proliferation experiment
Laboratory sample:
Testing drug: the momordica grosvenori alcohol derivatives monomer (4) that embodiment 1 prepares；
Control drug: paclitaxel (SELLECK；Cat.#S1150)；Ginsenoside monomer Rg3 (buys from Yuan Ye bio tech ltd, Shanghai, commodity article No. is B21059).
Experimental procedure:
With 24 kinds of cell lines (including 23 kinds of tumor cell lines and a kind of Human umbilical vein endothelial cells system) for experiment cell line, take the logarithm trophophase cell (3x104/ mL to 2.5x105/ mL), it is seeded in 96 orifice plates with every hole 100 μ L, each cell line is with 96 orifice plates；Then, except control drug paclitaxel, take 7 logarithmic decrease concentration (each concentration set two multiple holes) with high concentration 150 μMs to low concentration 2 μMs, be separately added into testing drug solution and control drug solution 500nL (testing drug solution or control drug solution preparation: be respectively adopted testing drug or control drug be dissolved in 0.5% DMSO solution).The addition concentration of paclitaxel is by 7 three times of decreasing concentration of high concentration 1 μM to low concentration 0.0014 μM.After after tested/control drug solution effects 72 hours, use CellTiter-(Promega；Cat.#G7573) luminescent cell viability examination method obtains each concentration of every kind of medicine in each cell line to this is the Proliferation Ability percentage rate of cell, and draws dose-effect relationship figure, finally according to curve measuring and calculating IC in figure50The highest inhibition percentage (Emax), as shown in Table 1 and Table 2.
Table 1: momordica grosvenori alcohol derivatives monomer (4) and comparison medicine Rg3 suppress cell-proliferation activity laboratory test results.
Table 2: momordica grosvenori alcohol derivatives monomer (4) and comparison medicine paclitaxel, Rg3 suppress cell proliferation effectiveness laboratory test results.
SPSSStatistics software (supplier: IBMcorporation, software version: XLfit21) is used to provide statistical analysis.
With assuming whether the difference that unequal independent sample inspection (independent-sampleT-test) of variance detects medicine group and matched group meansigma methods presents statistically significant (P < 0.05 or P < 0.01).
Analyze result:
1., when momordica grosvenori alcohol derivatives monomer (4) of the present invention average IC50 in 24 cell line and the control drug ginsenoside monomer Rg3 average IC50 in 24 cell line compares, difference presents statistically significant (P < 0.05 is P < 0.01 simultaneously).
2. the momordica grosvenori alcohol derivatives monomer (4) of the present invention the highest average inhibition percentage in 24 cell line is when the highest average inhibition percentage in 24 cell line compares with control drug paclitaxel and control drug ginsenoside monomer Rg3, and difference presents statistically significant (P < 0.05 is P < 0.01 simultaneously).
Conclusion:
1. the momordica grosvenori alcohol derivatives monomer (4) of the present invention suppression cell-proliferation activity in all 24 kinds of surveyed cell lines is above the similar control drug ginsenoside monomer Rg3 (IC of momordica grosvenori alcohol derivatives monomer (4)50IC less than ginsenoside monomer Rg350)。
2., in all tested cell lines, momordica grosvenori alcohol derivatives monomer (4) of the present invention has the highest suppression cell-proliferation activity (IC in people umbilical blood venous endothelial cell system HUVEC50=10.72 μMs), show its powerful Antineoplastic angiogenesis potentiality；Momordica grosvenori alcohol derivatives monomer (3) suppresses cell-proliferation activity to come secondly (IC in Colon and rectum gland cell system HCT-850=14.83 μMs).
3. momordica grosvenori alcohol derivatives monomer (4) of the present invention is to the highest suppression ratio (effectiveness) of all 24 kinds of tested cell lines all closely 100%；And compare medicine paclitaxel and ginsenoside monomer Rg3 in the 24 kinds of cell lines surveyed, all only 2 kinds of cell lines are had the suppression ratio of nearly 100%.This shows that the effectiveness of momordica grosvenori alcohol derivatives monomer (4) is apparently higher than control drug, and its high anticancer effectiveness is applicable to many carcinoids kind.
Claims (10)
1. a momordica grosvenori alcohol derivatives monomer (4), is structured with:
2. a compositions, it is characterised in that comprise following structureMomordica grosvenori alcohol derivatives monomer (4).
3. compositions according to claim 2, it is characterised in that described compositions is pharmaceutical preparation, and described pharmaceutical preparation also includes pharmaceutically acceptable diluent, carrier, excipient, adjuvant or vehicle.
4. compositions according to claim 3, it is characterised in that the dosage form of described pharmaceutical preparation is peroral dosage form, injection type or Topical application forms.
5. compositions according to claim 4, it is characterised in that described peroral dosage form is tablet, powder, suspension, emulsion, capsule, granule, coated tablet, pill, liquid, spirit, syrup or limonada.
6. compositions according to claim 4, it is characterised in that described injection type includes water preparation, suspension or solution.
7. compositions according to claim 4, it is characterised in that described Topical application forms includes ointment, solid, suspension, water preparation, spirit, powder, paste, suppository, aerosol, paste, liniment, lotion, enema or Emulsion.
8. compositions according to claim 7, it is characterised in that described compositions is used for treatment and/or prophylaxis of tumours and/or cancer；
Wherein said tumor and/or cancer are selected from:
Malignant tumor, including bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, head and neck cancer, the esophageal carcinoma, carcinoma of gallbladder, ovarian cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate and skin carcinoma；
Lymphoid hematopoetic tumor, including leukemia, acute lymphoblastic leukemia, Acute Lymphoblastic Leukemia, B-cell lymphom, T-cell lymphom, Huo Qijin lymphatic cancer, non-Huo Qijin lymphatic cancer, hairy cell lymphom, mantle cell lymphoma, myeloma and Burkett ' sShi lymphatic cancer；
The hematopoetic tumor of bone marrow system, including acute and chronic myelocytic leukemia, myelodysplastic syndrome and promyelocytic leukemia；
The tumor of the interstitial origin cause of formation, including fibrosarcoma and rhabdomyosarcoma；
The tumor of maincenter and peripheral nervous system, including astrocytoma, becomes neurofibroma, glioma and schwannoma；And
Other tumors, including melanoma, spermocytoma, teratocarcinoma, osteosarcoma, exophytic pigment neck tumor, thyroid filter capsule cancer and Kaposi's sarcoma.
9. compositions according to claim 2, it is characterised in that described compositions is health product, also includes acceptable carrier in optional health product.
10. compositions according to claim 9, it is characterised in that described compositions is used for immunomodulating, improves microcirculation and/or improves quality of life.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610321210.XA CN105777837A (en) | 2016-05-06 | 2016-05-06 | Novel Mogrol derivative monomer |
| CN201610522398.4A CN106083972B (en) | 2016-05-06 | 2016-07-04 | A kind of momordica grosvenori alcohol derivatives monomer |
| PCT/CN2016/089207 WO2017190421A1 (en) | 2016-05-06 | 2016-07-07 | Novel mogrol derivative monomer |
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| CN201610321210.XA CN105777837A (en) | 2016-05-06 | 2016-05-06 | Novel Mogrol derivative monomer |
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| CN201610522398.4A Active CN106083972B (en) | 2016-05-06 | 2016-07-04 | A kind of momordica grosvenori alcohol derivatives monomer |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017190420A1 (en) * | 2016-05-06 | 2017-11-09 | 深圳以诺生物制药有限公司 | Uses of mogrol derivative monomer and composition thereof |
| WO2017190422A1 (en) * | 2016-05-06 | 2017-11-09 | 深圳以诺生物制药有限公司 | Method for preparing novel mogrol derivative from total mogroside |
| CN111349133A (en) * | 2020-03-27 | 2020-06-30 | 湖南华诚生物资源股份有限公司 | Acetylated mogrol and preparation method and application thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101033244B (en) * | 2007-04-05 | 2010-05-19 | 上海交通大学 | Method of purifying and preparing momordica grosvenori alcohol |
| EP2929043A1 (en) * | 2012-12-04 | 2015-10-14 | Evolva SA | Methods and materials for biosynthesis of mogroside compounds |
| CN105832748B (en) * | 2016-05-06 | 2019-06-07 | 深圳以诺生物制药有限公司 | A method of preparing momordica grosvenori alcohol derivative from momorside |
| CN106188205B (en) * | 2016-05-06 | 2017-08-25 | 深圳以诺生物制药有限公司 | A kind of purposes of momordica grosvenori alcohol derivatives monomer and combinations thereof |
-
2016
- 2016-05-06 CN CN201610321210.XA patent/CN105777837A/en not_active Withdrawn
- 2016-07-04 CN CN201610522398.4A patent/CN106083972B/en active Active
- 2016-07-07 WO PCT/CN2016/089207 patent/WO2017190421A1/en active Application Filing
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017190420A1 (en) * | 2016-05-06 | 2017-11-09 | 深圳以诺生物制药有限公司 | Uses of mogrol derivative monomer and composition thereof |
| WO2017190422A1 (en) * | 2016-05-06 | 2017-11-09 | 深圳以诺生物制药有限公司 | Method for preparing novel mogrol derivative from total mogroside |
| CN111349133A (en) * | 2020-03-27 | 2020-06-30 | 湖南华诚生物资源股份有限公司 | Acetylated mogrol and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106083972A (en) | 2016-11-09 |
| CN106083972B (en) | 2017-09-01 |
| WO2017190421A1 (en) | 2017-11-09 |
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