WO2013185635A1 - Composés polyoxoprégnanes et leur utilisation - Google Patents

Composés polyoxoprégnanes et leur utilisation Download PDF

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WO2013185635A1
WO2013185635A1 PCT/CN2013/077281 CN2013077281W WO2013185635A1 WO 2013185635 A1 WO2013185635 A1 WO 2013185635A1 CN 2013077281 W CN2013077281 W CN 2013077281W WO 2013185635 A1 WO2013185635 A1 WO 2013185635A1
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Prior art keywords
compound
pop
pharmaceutical composition
compounds
cells
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PCT/CN2013/077281
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English (en)
Chinese (zh)
Inventor
叶阳
林革
姚胜
杜健华
马良
蔡若涓
唐春萍
银春
柯昌强
王亚周
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中国科学院上海药物研究所
香港中文大学
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Priority to CN201380031642.1A priority Critical patent/CN104395318B/zh
Publication of WO2013185635A1 publication Critical patent/WO2013185635A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/0026—Oxygen-containing hetero ring cyclic ketals

Definitions

  • the present application relates to the field of medicinal chemistry, and in particular to a class of polyoxygenated stilbene compounds and their medical use, in particular the use of such compounds in the manufacture of a medicament for reversing or inhibiting multidrug resistance of tumor cells.
  • Background technique
  • MDR Mutidmg Resistance
  • MDR refers to the resistance of tumor cells to an anti-tumor drug, and also to other anti-tumor drugs with different structures and different target targets.
  • MDR is a major obstacle to cancer chemotherapy.
  • MDR is caused by overexpression of ABC transporter in tumor cells and the reverse concentration gradient of antitumor drugs is transferred out of the cells, resulting in a decrease in drug accumulation in tumor cells.
  • the ABC transporter is a large group of membrane-bound proteins consisting of two nucleotide binding domains and two transmembrane regions. The active transport of drug substrates out of cells is mediated by the transmembrane region.
  • ABC transporters identified in the human genome, which are divided into seven subfamilies (A-G) based on sequence similarity.
  • the three major ABC transporters associated with MDR are P-gp encoded by the ABCB1 (or MDR-1) gene, MRP1 encoded by the ABCC1 (or MRP1) gene, and BCRP/ABCG2 encoded by the ABCG2 gene. They have a wide range of substrate specificities and are capable of transporting a wide variety of drugs, poisons, metabolites and endogenous substances. Therefore, their overexpression is common in tumor cell lines and clinical drug resistance screened by chemotherapeutic drugs.
  • P-gp can transport a variety of chemotherapeutic drugs including anthracyclines (vincas), vincas, taxanes, etoposide, and mitoxantrone.
  • P-gp is widely expressed in different tissues in the body, and is significantly more highly expressed in the capillary endothelial cells of the brain and other organs including the intestine, testis and skin.
  • P-gp expression is common in kidney cancer, colon cancer, adrenal cancer, and teratocarcinoma.
  • the P-gp substrate drug can bind to the transporter through one or more binding sites, so the mechanism of its transport has certain adaptability.
  • Verapamil is the first known P-gp inhibitor, and studies have shown that it can increase the concentration of anti-tumor drugs in multidrug-resistant cells by inhibiting P-gp-mediated outward transport. . This finding ignited hopes of reversing the resistance of anti-cancer drugs.
  • some drugs used in clinical practice such as calmodulin blocker, immunosuppressant cyclosporin A and anti-hormone drug tamoxifen, have been found to have strong P-gp inhibitory activity, but these drugs are It has its own other pharmacological activities and cannot be used as a P-gp inhibitor in combination with antineoplastic agents to enhance the sensitivity of antitumor drugs to MDR tumor cells.
  • a second aspect of the invention provides a method of preparing the polyoxopregna compound of the first aspect above, the method comprising the steps of -
  • a third aspect of the invention provides the use of the polyoxopregna compound according to the first aspect above, in the preparation of a medicament for reversing or inhibiting multidrug resistance of a tumor cell, more specifically, the polyoxygenated pregnancy
  • the compound is capable of reversing or inhibiting multidrug resistance mediated by at least one ABC transporter, preferably capable of reversing or inhibiting one, two or three transporters selected from the group consisting of P-gp, MRP 1 and ABCG2
  • the multidrug resistance more preferably, is capable of simultaneously reversing or inhibiting multidrug resistance mediated by two or three transporters selected from the group consisting of P-gp, MRP1 and ABCG2.
  • the tumor cells refer to colon cancer cells, breast cancer cells, liver cancer cells, lung cancer cells, stomach
  • the tumor cell refers to a colon cancer cell or a breast cancer cell, more preferably a human colon cancer drug resistant sub-cell line SW620/Ad300, a human breast cancer resistant sub-cell line MCF-7/VP and MCF-7. FLVlOO0.
  • the tumor cell multidrug resistance reversal agent different from the chemical structure of the known tumor cell multidrug resistance reversal agent, and the antitumor tumor Drugs or other tumor cell multidrug resistance reversal drugs are used together to provide anti-tumor efficacy.
  • compounds POP 52, 86, 87 and 88 are capable of reversing ⁇ / ⁇ mediated by an ABC transporter selected from one or more of P-gp, MRP1 and ABCG2, more preferably compounds POP 86 and 87 are capable of At the same time, MDR mediated by three ABC transporters of gp, MRP1 and ABCG2 was reversed.
  • the polyoxo-pregnane compound may be one selected from the group consisting of alkylating agents, taxanes, antibiotics, anthracyclines, podophyllotoxins, vinblastines, camptothecins, and fentanyls. Use one or more combinations. More specifically, the polygas pretentane compound may be combined with cisplatin, docetaxel, doxorubicin, mitoxantrone, teniposide, long albino, topotecan, gefitinib, etc. use.
  • polyoxotengen compound as a type of polyoxygenated decane compound known to have a structure, such a compound is capable of reversing at least one MBC mediated by an ABC transporter, and Anti-tumor drugs or other tumor cell multi-drug resistance reversal drugs are used together to improve anti-tumor efficacy.
  • POP 53, 55, 63 and 65 are capable of simultaneously reversing MDR mediated by two or more ABC transporters P-gp and MRP1, more preferably POP 65 is capable of simultaneously reversing the three transporters P-gp, MDR mediated by MRP1 and ABCG2.
  • a fourth aspect of the invention provides a method of testing a polyoxopreventane compound for reversing tumor multidrug resistance in an in vitro cell model.
  • the multidrug resistance of the tumor cell is associated with one or more transporters selected from the group consisting of P-gp, MRPI and ABCG2.
  • a pharmaceutical composition comprising: (1) selected from the group consisting of a compound POP52, a compound POP53, a compound POP55, a compound POP56, a compound ⁇ 62, a compound ⁇ 63, a compound ⁇ 65, a compound ⁇ 66, a compound ⁇ 86, Compound ⁇ 87, compound POPS8, compound POP73, compound POP74s compound POP75, compound POP76, compound POP77, one or more compounds of compound POP81; and (2) a pharmaceutically acceptable salt.
  • composition according to the fourth aspect of the invention (a) for use as a medicament for reversing or inhibiting multidrug resistance of tumor cells; and/or (b) Used as an inhibitor of P-gp and / or MRP1 and / or ABCG2.
  • a compound of formula V for the preparation of: (i) a pharmaceutical composition for reversing multidrug resistance of a tumor cell; and/or (ii) a P-gp inhibitor;
  • R a and R b are each independently hydrogen, acetyl (Ac), isopropionyl, benzoyl (Bz), 2-methylbutanoyl (mBu) or crotonyl (Tig); jQ is The integer.
  • ⁇ is an integer from 1 to:.
  • the compound is selected from the group consisting of:
  • the pharmaceutical composition or inhibitor comprises the compounds POP 68, 69, 70s 71, 82, 83, 84 and 85; and the compound POP 68 is based on the total weight of the pharmaceutical composition The sum of the contents of 69, 70 is not less than 50% by weight.
  • the pharmaceutical composition or inhibitor comprises the compounds POP 68, 69, 70, 71, 82, 83, 84 and 85; and the compound POP 68, based on the total weight of the drug The sum of the contents of 69 and 70 is not less than 85% by weight.
  • the pharmaceutical composition or inhibitor comprises the compounds POP 68, 69 and 70; and the sum of the contents of the compound is 100% by weight based on the total weight of the pharmaceutical composition.
  • the compound is for use in the preparation of a pharmaceutical composition for reversing or inhibiting multidrug resistance mediated by a P-gp transporter in a tumor cell,
  • the tumor cells include: colon cancer cells, breast cancer cells, liver cancer cells, lung cancer cells, gastric cancer cells, colon cancer cells, osteosarcoma cells, or cervical cancer cells.
  • the pharmaceutical composition further comprises other therapeutic agents selected from the group consisting of alkylating agents, taxanes, antibiotics, anthracyclines, camptothecins. , one or more of a fentanyl, a podophyllotoxin, and a saponin.
  • the other therapeutic agent is selected from the group consisting of cisplatin, docetaxel, doxorubicin, and mitoxantrone
  • the medicament further comprises a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is an oral preparation.
  • a pharmaceutical composition comprising:
  • ⁇ and R b are each independently hydrogen, acetyl (Ac), isopropionyl, benzoyl (Bz;), 2-methylbutanoyl (mBii) or crotonyl (Tig); n is 1 to 5 Integer
  • the pharmaceutical composition comprises the compounds POP 68, 69, 70, 71, 82, 83.84 and 85; and the compound POP 68. 69 based on the total weight of the pharmaceutical composition The sum of the contents of 70 is not less than 50% by weight.
  • the pharmaceutical composition comprises the compounds POP 68, 69, 70, 71, 82, 83, 84 and 85; and the compound POP 68, 69, based on the total weight of the pharmaceutical composition
  • the sum of the contents of 70 is not less than 85% by weight.
  • the pharmaceutical composition comprises the compounds POP 68, 69 and 70, and the sum of the contents of the compound is 100% by weight based on the total weight of the pharmaceutical composition.
  • the use of the pharmaceutical composition according to the seventh aspect of the invention (a) for use as a medicament for reversing or inhibiting multidrug resistance of a tumor cell; and/or (b) ) Used as a P-gp inhibitor.
  • the pharmaceutical composition is for use as a medicament for reversing or inhibiting multidrug resistance mediated by a P-gp transporter.
  • the tumor cells include: colon cancer cells, breast cancer cells, liver cancer cells, lung cancer cells, gastric cancer cells, large cancer cells, osteosarcoma cells, or cervical cancer cells.
  • the pharmaceutical composition further comprises other therapeutic agents selected from the group consisting of alkylating agents, docetaxel, antibiotics, anthracyclines, and anthraquinones.
  • other therapeutic agents selected from the group consisting of alkylating agents, docetaxel, antibiotics, anthracyclines, and anthraquinones.
  • the other therapeutic agent is selected from the group consisting of cisplatin, docetaxel, doxorubicin, mitoxantrone, teniposide, sorghumin, acetonide, gi
  • cisplatin docetaxel
  • doxorubicin mitoxantrone
  • teniposide teniposide
  • sorghumin sorghumin
  • acetonide gi
  • the pharmaceutical composition is an oral preparation.
  • a kit comprising:
  • 1 ⁇ and 1 ⁇ are each independently nitrogen, acetyl, isopropionyl, benzoyl, 2-methylbutanoyl or crotonyl; and ⁇ is an integer of from 1 to 5.
  • the intestinal bacteria comprises: Bifidobacterium: lactic acid bacteria
  • Figure I shows the activity of two representative POP compounds to reverse the multidrug resistance of doxorubicin on human colon tumor cells.
  • Figure A shows the activity of the active metabolite POP 63 to reverse multidrug resistance.
  • POP63 has no significant effect on the cytotoxicity of doxorubicin on the sensitive parental cell SW620.
  • the multidrug resistance can be reversed in the resistant cell SW620/Ad300, thereby significantly enhancing the cells of doxorubicin.
  • Panel B shows that the prodrug compound POP85 does not reverse the multidrug resistance of tumor cells SW620/Ad300.
  • Figure 2 shows the positive effect of a positive control and two representative POP compounds on reversing the multidrug resistance of paclitaxel on human breast cancer cells.
  • Figure A-C shows the effect of the positive control PSC833, the active metabolite POP63 and the prodrug compound POP68 on reversing multidrug resistance.
  • both POP63 and PSC833 can significantly enhance the cytotoxicity of paclitaxel by reversing multidrug resistance in drug-resistant cell LCC6 MDR, but have no effect on the cytotoxicity of paclitaxel in sensitive mother cell LCC6.
  • the results showed that the prodrug compound POP68 did not reverse the multidrug resistance effect on the drug-resistant cell LCC6 MD 1.
  • Figure 3 shows the intestinal flora conversion of the prodrug composition c, wherein Figure A shows the metabolic rate of the prodrug compound POP 68-70 after intestinal flora treatment, and Figure B shows the prodrug compound POP 68- Conversion rate of active metabolites POP62, 63, 66 after treatment with intestinal flora.
  • Figure 4 is a graph showing the relationship between plasma concentration and time after oral administration of the prodrug composition c, wherein Figure A is the relationship between the plasma concentration of the prodrug compound POP 68-70 and the time after oral administration of the prodrug composition c.
  • Figure B is a graph showing the plasma concentration of the active metabolites POP 62, 63, 66 after oral administration of the prodrug composition c versus time.
  • the present inventors unexpectedly obtained a series of active compounds for reversing or inhibiting MDR of tumor cells from Tongguangsan plants, which are effective for reversing MDR of tumor cell tumor cells.
  • the inventors have also obtained a series of prodrug compounds for reversing or inhibiting MDR of tumor cells, which do not by themselves reverse the activity of tumor cell MDR, but their metabolites in vivo or under the action of intestinal flora have reversal or Inhibits the activity of MDR.
  • the inventors have completed the present invention.
  • active compound as used herein means selected from the group consisting of compound POP52, compound POP53, compound POP55, compound POP56, compound POP62, compound POP63, compound POP65, compound POP66 compound POP86, compound POP87, compound POP88, compound One or more compounds of POP73, compound POP74, compound POP75, compound POP76, compound POP77, compound POP81.
  • prodrug compound refers to a compound of the formula V.
  • prodrug composition refers to a composition comprising a prodrug compound of the invention.
  • Prodrugs also known as prodrugs, prodrugs, prodrugs, etc., refer to compounds that have pharmacological effects after transformation in vivo.
  • the prodrug itself has no biological activity or low activity, and becomes an active substance after metabolism in the body. The purpose of this process is to increase the bioavailability of the drug, enhance the targeting, and reduce the toxicity and side effects of the drug.
  • the pharmaceutical composition of the present invention may comprise the "active compound” and/or "prodrug compound” of the present invention.
  • a pharmaceutical composition containing one or more of the prodrug compounds of the present invention can be used to reverse or inhibit multidrug resistance of tumor cells, thereby increasing the sensitivity of tumor cells to chemotherapeutic drugs.
  • the tumor cells include human colon cancer cells, human breast cancer cells, human liver cancer cells, human lung cancer cell lines, gastric cancer cells, colon cancer cells, osteosarcoma cells or human cervical cancer cells.
  • it is a human colon cancer cell and a human breast cancer cell, more preferably a human colon cancer resistant sub-cell line SW620/Ad300 and a human breast cancer resistant sub-cell line LCC6 MD l o
  • the pharmaceutical composition of the present invention may also be a pharmaceutical composition comprising the active compound of the present invention, which can be used for reversing or inhibiting multidrug resistance of tumor cells, wherein the tumor cells refer to colon cancer cells, breast cancer cells, Hepatoma cells, lung cancer cells, gastric cancer cells, colon cancer cells, osteosarcoma cells, cervical cancer cells. More preferably, the tumor cell refers to a colon cancer cell or a breast cancer cell, more preferably a human colon cancer resistant sub-cell line SW620/Ad300 or a human breast cancer resistant sub-cell line MCF-7/VP and MCF/FLV1000 .
  • compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier.
  • the "safe and effective amount” refers to: The amount of the compound is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention.
  • the "one dose" is a capsule or a tablet.
  • the prodrug composition of the present invention comprises the compounds POP 68, 69, 70, 71, 82, 83, 84 and 85, and the above compound POP 68, 69, 70, based on the total weight of the prior drug composition and the total content of not less than 50 wt. 0/0.
  • the prodrug composition of the present invention comprises the compounds POP 68, 69, 70, 71, 82, 83, 84 and 85, and the above compound POP 68, 69, based on the total weight of the prior drug composition.
  • the sum of the contents of 70 is not less than 85% by weight.
  • the prodrug composition of the present invention comprises the compounds POP 68, 69 and 70, and the sum of the contents of the above compounds is 100% by weight based on the total weight of the prior drug composition.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose).
  • solid lubricants such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as Propylene glycol, glycerin, mannitol, sorbi
  • Representative modes of administration of the compounds or pharmaceutical compositions of the invention include oral, injection, and the like.
  • a representative mode of administration of the prodrug or prodrug composition of the present invention is oral.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the compound of the invention is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with the following ingredients: (a) a filler or compatibilizer, for example , starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants , for example, glycerin; (d) a disintegrant, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; Absorbing accelerators, for example, quaternary amine compounds; (g)
  • Solid dosage forms such as tablets, troches, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the compounds or compounds of the invention in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric materials and waxy materials. The active compound may also form a microcapsule form with one or more of the above excipients as necessary.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain a suspending agent, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these substances, etc. .
  • a suspending agent for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline cellulose, aluminum methoxide and agar or a mixture of these substances, etc.
  • the compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds, for example selected from the group consisting of alkylating agents, taxanes, antibiotics, anthracyclines, camptothecins, teinines, One or more of ghost white toxins and vinblastines, preferably with cisplatin, docetaxel, doxorubicin, mitoxantrone, teniposide, vincristine, topography Kang, gefitinib and other joint use.
  • other pharmaceutically acceptable compounds for example selected from the group consisting of alkylating agents, taxanes, antibiotics, anthracyclines, camptothecins, teinines, One or more of ghost white toxins and vinblastines, preferably with cisplatin, docetaxel, doxorubicin, mitoxantrone, teniposide, vincristine, topography Kang, gefitinib and other joint use.
  • a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the daily dose is usually from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the prodrug compounds of the present invention can be prepared by conventional methods in the prior art.
  • the present invention also provides a preferred method of preparation comprising the steps of:
  • the prodrug compound of the invention is obtained.
  • the prodrug composition of the present invention can be prepared by a conventional method in the prior art, or the pure compound of the present invention can be prepared according to the required weight or volume ratio or according to the proportion ratio naturally occurring in the plant. Prodrug composition.
  • the plant is a light-dispersing scatter, especially a light-transmitting cane portion.
  • the present invention also preferably provides a method of preparing various pharmaceutical compositions of the present invention, for example,
  • prodrug composition a dissolved (such as dissolved in ethyl acetate) and mix with silica gel (such as MCI GEL), column chromatography (such as MCI GEL column), elute with eluent (such as ethanol in sequence) - 10%, 85%, 95% elution of the aqueous solution), collect and concentrate the appropriate fraction (such as 85% of the fraction) to obtain a fraction of A.
  • silica gel such as MCI GEL
  • column chromatography such as MCI GEL column
  • elute with eluent such as ethanol in sequence
  • a preferred embodiment of the present invention is a compound of the present invention which is prepared from a light-dispersing dispersion, and can also be produced from any known plant containing the compound of the present invention.
  • the present invention provides a method for determining whether a compound is a prodrug by determining a metabolite of a test compound in vitro and/or in vivo and its activity, the method preferably comprising the steps of:
  • test compound is cultured in a medium containing a solution of the intestinal flora (such as BHI medium) (eg, anaerobic culture at 37 ° C in a simple anaerobic bag), and is terminated after sampling at different time points. (such as adding methanol) intestinal flora transformation, the sample is centrifuged and the supernatant is collected for analysis and detection (such as HPLC-MS) the metabolic rate of the prodrug compound and the rate of formation of the respective metabolite; and / or (b) The test compound is dissolved in physiological saline, and administered to the rats by oral or intravenous injection. Rat blood samples were taken at different time points, and the blood plasma was collected after centrifugation to analyze the metabolic rate of the prodrug compounds (such as HPLC-MS) and the rate of formation of the respective metabolites;
  • a solution of the intestinal flora such as BHI medium
  • the sample is centrifuged and the supernatant is collected for analysis and detection (such
  • test compound and its respective metabolites are cultured in a culture medium containing doxorubicin (Dox or Doxorubicin), and the cytotoxicity of doxorubicin is determined by the SRB method.
  • doxorubicin Dox or Doxorubicin
  • test compound does not significantly increase the cytotoxicity of doxorubicin to drug-resistant cells; and its metabolites significantly increase the cytotoxicity of doxorubicin to drug-resistant cells; thereby determining that the test compound is a prodrug compound .
  • the invention also provides an in vitro cell model for testing a method of reversing or inhibiting multidrug resistance of a tumor cell of a prodrug compound of the invention.
  • the in vitro cell model includes sensitive parental cell SW620 and resistant subcellular line SW620/Ad300, sensitive parental cell LCC6 and drug resistant subcellular LCC6 MDR1.
  • the invention also provides a method of treating a disease.
  • the method comprises the steps of: administering (e.g., orally) a compound or pharmaceutical composition of the invention prior to, concurrently with, or after administration of a disease therapeutic agent to a subject in need of treatment, such as a mammal.
  • the invention also provides a kit comprising:
  • the kit further comprises instructions for administration, for example, before, simultaneously with or after administration of the disease therapeutic agent to a subject in need of treatment (such as a mammal), the compound or pharmaceutical composition is first digested by the enteric bacteria, and then The digested compound or pharmaceutical composition is administered (either by injection or orally, etc.).
  • the intestinal bacteria of the present invention include: Bifidobacterium, lactic acid bacteria
  • a new use of a class of prodrug compounds of the general formula V for reversing or inhibiting multidrug resistance of tumor cells is also provided.
  • a prodrug composition comprising one or more of the prodrug compounds of Formula I is also provided.
  • the invention will be further elucidated below in conjunction with specific implementations. It is to be understood that the examples are not intended to limit the scope of the invention.
  • the experimental methods in the following examples which do not specify the specific conditions are usually produced according to the conditions described in the conventional conditions, for example, Sambrook et al., Molecular Cloning: Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturing conditions. The conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated. Active compound fraction
  • the dried cane was extracted three times with 40 L of 95% industrial alcohol at room temperature, and each time the ethanol extract was combined for three days, steamed. After removing the solvent, a dark extract of 3.4 kg was obtained. The extract was suspended with 10 L of distilled water, and then extracted three times with 10 L of ethyl acetate and 10 L of n-butanol, and the extracts were combined, and the solvent was evaporated to give 460 g of ethyl acetate extract.
  • n-Butanol extract 500 go 270 g of ethyl acetate extract was separated by silica gel column chromatography, petroleum ether: ethyl acetate 10:3, 2:1, 4:3, 1 : 1 (corresponding to components A, B, C, D), ethyl acetate (corresponding to component E), then ethyl acetate: methanol 20: 1, 20:3, 20: 1 (corresponding components F, G, H) gave eight components AH.
  • the component C was purified by silica gel column chromatography (chloroform: petroleum ether 10:1) to obtain the compound by preparative high performance liquid chromatography (acetonitrile: water 20% ⁇ 50%, 15 ml / min, 0 - 192 min) POP 52 (1 1 mg);
  • Component D was subjected to small-pore resin column chromatography (methanol/water 60%, 70%, 85%, 100%, then acetone), followed by silica gel column chromatography (chloroform: methanol 100) : 1) Compound POP 81 (28 mg) ;
  • component E is first subjected to small-pore resin column chromatography (methanol: 60%, 70%, 85%, 100%, then acetone), and then through preparative high-performance liquid phase Chromatography purification (acetonitrile: water 25% ⁇ 55%, 15 ml / min, 0 - 192 min) gave compound POP 74 (25 mg) and POP 75 (23 mg) ; fraction F was first
  • the dried cane was extracted three times with 40 L of 95% industrial alcohol at room temperature, and each time the ethanol extract was combined for three days, steamed. After removing the solvent, a dark extract of 3.4 kg was obtained. The extract was suspended with 10 L of distilled water, and then extracted three times with 10 L of ethyl acetate and 10 L of n-butanol, and the extracts were combined, and the solvent was evaporated to give 460 g of ethyl acetate extract.
  • N-butanol extract 500 go 270 g of ethyl acetate extract was separated by silica gel column chromatography, petroleum ether: ethyl acetate 10:3, 2:1, 4:3, 1 : 1, ethyl acetate, then Ethyl acetate: methanol 20: 1, 20:3, 20: 1) Eight fractions (AH) were obtained after gradient elution. Component B was recrystallized to give the compound POP 62 (2.5 g).
  • Compound POP 52 a white amorphous powder, showed a yellow spot on the TLC plate under the action of a sulfuric acid-vanillin developer.
  • EI-MS showed a molecular weight of 488, which was determined according to the exact molecular weight of 488.2763, which was determined by high-resolution EI-MS, in combination with its 1H-NMR and 13 C-NMR to determine its molecular formula as C 28 H 4 . 0 7 .
  • the compound was inferred to be a gamma ray having a keto group at the C-3 position.
  • the relevant signal indicates that the substituent 2-methylbutyryl is attached at the C-11 position and the substituent acetyl group is attached at the C-12 position.
  • the structural identification of the remaining compounds can be confirmed by a similar method by analyzing 1H-NMR 13 C-NMR EI-MS HR-EIMS 2D-NMR and comparing with the spectral data of known compounds to confirm the structure. Physical and spectroscopy data for polyoxygenated alkane compounds.
  • POP 56 11a-oxy-crotonyl -12 ⁇ -oxy-acetyl gamma glucoside B, white powder, + 0.5 (c 0.39,
  • Valspodar PSC833
  • fumitremorgin C FTC
  • human breast cancer cell line MK571 Fetal bovine serum, PBS, DMEM and RPMI 1640 were purchased from Gibco Invitrogen (Carlsbad, California, USA). All solvents used in the preparation of polyoxopregnanes were analytically pure and supplied by Shanghai Chemical Plant (Shanghai, China). Doxorubicin (Dox), Mitoxantrone verapamil, sulforhodamine B (SRB) and other chemicals were purchased from Sigma-Aldrich (St Louis, MO, USA). .
  • P-gp, MRP l or ABCG2 overexpressing resistant cell lines were used to test the reversal multidrug resistance activity of the polyoxygenated decane compound.
  • P-gp overexpressing SW620/Ad300, MRP-1 overexpressing MCF-7/VP and ABCG2 overexpressing MCF-7/FLV 1000 were purchased from the National Cancer Institute. They are resistant subcellular lines produced by their parental cells SW620 or MCF-7 in increasing concentrations of selected reagents, and cultured in 300 ⁇ M doxorubicin, 10 ⁇ etoposide and 1000 ⁇ ⁇ ⁇ ⁇ ⁇ Degree (flavopiridol) in the culture solution. The resistant cells will be cultured in a drug-free medium for at least two weeks prior to use.
  • SW620 and SW620/Ad300 were cultured in RPMI 1640 medium containing 10% fetal bovine serum.
  • MCF-7, MCF-7/VP and MCF-7/FLV1000 were cultured in DMEM containing 10% fetal calf serum.
  • Drug-resistant tumor cells SW620/Ad300, MCF-7/VP and MCF-7/FLV1000 were compared by comparing drug resistance to parental cells SW620 or MCF-7 and testing the expression levels of P-gp, MRP1 or ABCG2, respectively. Can be verified. All cells were cultured at 37 ° incubator containing 5% C0 2 saturated humidity.
  • New polyoxyprogestane compounds were screened on highly sensitive MCF-7 human breast cancer cell lines. Cytotoxicity tests based on sulforhodamine B staining for three days were performed using known methods [Leslie E. M, et al. Structural Requirements for functional interaction of glutathione tripeptide analogs with the human multidrug resistance protein 1 (MRP l). J. Pharmacol. Exp. Ther. 2003, 304, 643.]. Signals were acquired by a Benchmark Plus Microplate Spectrophotometer (Bio-Rad, Hercules, CA, US). The IC50 was obtained by comparing the average absorption values of the dosing group and the blank control group.
  • MCF-7 Human Breast Cancer Cells
  • MCF-7 is one of three highly sensitive human tumor cell lines used for tumor drug screening by the National Cancer Center (Bethesda, MD, USA).
  • the polyoxyprogestin compounds referred to in the present invention were initially screened using MCF-7.
  • the polyoxopredomane compounds cause changes in the sensitivity of tumor cells to the drug substrates of the three transporters (P-gp, MRP l or ABCG2) by comparing their presence and absence.
  • IC 5 for antitumor drugs in the presence The value is evaluated and then expressed as a reversal factor and a percent reduction.
  • Reversal factor IC 50 (anti-tumor drug without POP) / IC 5 . (Anti-tumor drugs combined with POP).
  • the compounds POP 86, POP 87, POP 65 were able to reverse the multidrug resistance of tumor cells mediated by three ABC transporters P-gp, MRP l and ABCG2; compounds POP 53 , POP 55 and POP 63 can reverse the multidrug resistance of tumor cells mediated by P-gp and MRP l; compounds POP 52 and POP 88 and POP 56, PO P 62 and POP 66 can reverse the mediated by P-gp Multidrug resistance of tumor cells.
  • b Reversal factor indicates the IC50 value of the cell substrate in the absence of a positive control or the POPs of the polyoxanone saponin compound except in the presence of a positive control or POPs of the polyoxanone saponin compound.
  • PSC833, MK571 and f TC are known P-gp, MRP-1 and ABCG2 inhibitors, respectively.
  • Mitoxol was used as a substrate for MCF-7 and MCF-7ffLV1000 cells ABCG2, and doxorubicin was used as SW620 and SW620/A (substrate for P-gp in OO cells and CF-7 and MCF-7) /FLV1000 cell M P1 substrate.
  • Reversal multiples indicate IC50 values in the absence of a positive control ⁇ cell substrate or POPs in the presence of a positive control or dioxin saponin POPs ⁇ cells
  • PSC833, M 571 and FTC are known P-gp, MRP-1 and ABCG2 inhibitors, respectively.
  • c mitochondrial was used as a substrate for MCF-7 and MCF-7/FLV1000 cells ABCG2, which was used as a substrate for P-gp in SW620 and SW620/Ad300 cells and MCF-7 and MCF-7FLV1000 The substrate of the cell MRP1.
  • h reversal multiple indicates the IC50 value of the cell substrate in the absence of a positive control or the presence of poly-pregnant saponin POPs (fl-to-IM or polyoxo-saponin POPs ⁇ ) IC50 values of cell substrates.
  • PSC833, MK57I and FTC are known P-gp, MRP-I and ABCG2 inhibitors, respectively.
  • Mitoxantrone was used as a substrate for MCF-7 and MCF-7FLV10 cells, ABCG2, which was used as a substrate for SW620 and S ⁇ V62O/Ad30O cells, P-gp, and MCP-7 and MCF-7FLV1000 ⁇ Substrate of cell MRP1.
  • Tongguang is collected from Yunnan; except that the solvent used for plant extraction is industrial ethanol, the other organic solvents used are of analytical grade, of which ethanol is pharmaceutical grade (content is 50% ⁇ 95%); column chromatography packing MCI GEL purchase From Japan Mitsubishi Chemical (CHP20P, 75-150 ⁇ ), column chromatography water is purified water; preparative high performance liquid chromatography water is double distilled water.
  • the content of POP 68-70 in the prodrug composition was determined by high performance liquid chromatography (HPLC).
  • the liquid phase conditions are: Mobile phase: Acetonitrile - Water: 35% ⁇ 65%
  • Evaporative Light Scattering Detector Evaporative Light Scattering Detector
  • test solution Precisely weighed the prodrug composition 20.0 mg, dissolved in methanol, transferred to a 100 ml volumetric flask and dilute to volume, as a test solution;
  • Preparation of the reference substance (or standard) solution Weigh 10 mg of each of the serotonin saponins POP 68, 69, 70, accurately weighed, add methanol to make 1 ml of solution containing 200 ⁇ ⁇ , ie Got it.
  • fraction A3 (1 g) is preliminarily separated by preparative high performance liquid chromatography (CH 3 CN-H 2 0, 25% ⁇ 55%, 192 min, 15 ml/min, 210 nm) Silica gel (200 ⁇ 300 mesh, 50 g, dichloromethane-methanol 4:1 ⁇ 2: 1). Purified by column chromatography, sephadex LH-20 (chloroform-methanol, 1:1) to give POP 84 (9 mg);
  • a A4(lg) Prepared by preparative high performance liquid chromatography (CH 3 CN-H 2 0, 35% ⁇ 65%, 192 min, 15 ml/min, 210 nm) to obtain POP 68 (300 mg ), a mixture of POP 70 (240 mg) and POP 69, 70 220 mg; a mixture of POP 69, 70 100 mg by preparative high performance liquid chromatography (CH 3 CN-H 2 0, 35% to 65%, 192 min) Further purification with 15 ml/min, 210 nm) gave POP 69 (45 mg) and POP 70 (12 mg);
  • the dried cane was extracted three times with 40 L of 95% industrial ethanol at room temperature, and each time the ethanol extract was combined for three days, steamed. After removing the solvent, a dark extract of 3.4 kg was obtained. The extract was suspended with 10 L of distilled water, and then extracted three times with 10 L of ethyl acetate. The extracts were combined, and the solvent was evaporated to obtain a prodrug composition a 460 g, which was determined by high performance liquid chromatography. The content of the compound POP 68, 69, 70 was 21.2%, 15.1%, 16.6%, and the total content was 52.9%, respectively.
  • the dried dried cane was extracted three times, and each time the ethanol extract was combined for three days, and the solvent was distilled off to obtain a dark extract of 3.4 kg.
  • the extract was suspended with 10 L of distilled water, and then extracted three times with 10 L of ethyl acetate. The extracts were separately combined, and the solvent was evaporated to give a prodrug composition a 460.
  • the dried cane was extracted three times with 40 L of 95% industrial ethanol at room temperature, and each time the ethanol extract was combined for three days, steamed. After removing the solvent, a dark extract of 3.4 kg was obtained. The extract was suspended in 10 L of distilled water, and then extracted three times with 10 L of ethyl acetate. The extracts were combined and evaporated to give a prodrug composition a 460
  • the prodrug composition b 2 g was prepared by repeated preparative high performance liquid chromatography (CH 3 CN-H 2 0, 35% to 65%, 192 min, 15 ml/min, 210 nm) to obtain pure compound POP 68. (780 mg), 69 (310 mg), 70 (323 mg). POP 68-70 according to its natural proportion in the plant, the prodrug composition c, determined by high performance liquid chromatography content, by weight percentage, the compound POP 68, 69, 70 content is 40.0 %, 28.6 %, 31.4 %, total content is 100%.
  • Example 9 Polyoxoprednisolone prodrug or prodrug composition reverses tumor multidrug resistance activity test
  • the P-gp overexpressing resistant cell lines used to test the reversal of multidrug resistance of dioxin-containing POPs include human colon tumor cells SW620/Ad300 and human breast cancer cells LCC6 MDR1.
  • the SW620/Ad300 cell line was purchased from the National Cancer Institute (NCI), which is a drug-resistant subcellular line produced by gradually increasing the concentration of doxorubicin through its parent cell SW620. It was cultured in a culture medium containing 300 ⁇ of doxorubicin (Dox or Doxorubicin). The resistant cells will be cultured in a drug-free medium for at least two weeks prior to use.
  • Another drug-resistant subcellular line, LCC6 MD1 was obtained by transfecting DNA carrying P-gp expression into the mother cell LCC6 using a retroviral vector.
  • SW620 and SW620/Ad300 were cultured in RPMI 1640 medium containing 10% fetal bovine serum, while LCC6 and LCC6 MD 1 were cultured in DMEM medium containing 10% fetal bovine serum.
  • Male Sprague-Dawley rats are provided by the Experimental Animal Service Center of the Chinese University of Hong Kong and weigh between 200 g and 230 g. The rats were cultured in a sterile environment at a temperature of 24 ⁇ 2 ° C, 12 h light per day, and 12 h dark. The rats were fasted for 24 h before the experiment. Animal management and all experimental procedures were approved by the Animal Ethics Committee of the Chinese University of Hong Kong.
  • the reverse multidrug resistance activity of the compound POPs was determined in the above two drug resistant subcellular lines.
  • the experiment used sulforhodamine B staining (SRB method) to detect the three-day cytotoxicity of the anticancer drug doxorubicin and paclitaxel in the case of use alone and in combination with different compound POPs. Signals were acquired by a Benchmark Plus Microplate Spectrophotometer (Bio-Rad, Hercules, CA, US). The IC 50 was obtained by comparing the average absorption values of the dosing group and the blank control group.
  • SRB method sulforhodamine B staining
  • the compound makes the change in the activity of the tumor cell sensitive to the drug substrate of P-gp as assessed by comparing the IC 5Q value of the antitumor drug in the presence and absence of the compound, and then expressed as a reversal factor and a percent reduction.
  • the calculation method is the same as that in the fourth embodiment.
  • Human fresh stool samples were taken from 4 healthy volunteers in China (two men and two women, 20-32 years old), and four stool samples (each 5 g) were collected and mixed with 30 ml of medium and placed in petri dishes.
  • the medium was prepared by adding 0.05 mg of vitamin K1, 0.5 mg of beef soup, and 50 mg of L-cystine to 100 ml of brain heart infusion broth (BHI, 0.37 mg/ml).
  • the resulting stool suspension was centrifuged at 200 g for 5 minutes, the supernatant was decanted and centrifuged at 5000 g for 30 minutes, and the resulting pellet was resuspended in 10 ml of BHI medium to produce a gut flora solution. For this experiment.
  • the polyoxopregnene saponin POP 68, 69, 70 biotransformation experiments by human intestinal flora were carried out in a sputum medium incubation system containing 25 gut bacterial solution and 2.5 dimethyl sulfoxide stock solution.
  • the artificially formulated prodrug composition c 50 g/mL was anaerobic cultured in a GsaPak® simple anaerobic bag at 37 °C for 0 h, 0.5 h, 1 h, 2 h, 3 h, 6 h B 8 h.
  • the biotransformation reaction was terminated by the addition of 0.5 ml of ice methanol, and immediately centrifuged at 15,000 g for 10 minutes, and the supernatant was collected for 1 ml and analyzed on HPLC-MS.
  • the polyoxygenated decane compound POP 68, 69, 70 was mixed in a certain weight ratio (1.4:1:1.1) in rats containing 5% Tween-80 in saline orally, orally or intravenously. .
  • Blood samples (200 ⁇ ) were taken at different time points in the experimental design within 0-24 hours.
  • the blood paddles were collected by centrifugation and stored at -20 ° C for analysis. 100 ⁇ of the blood plasma sample was subjected to aliquoting and subjected to HPLC-MS analysis.
  • HPLC-MS analysis was performed on a symmetric 5 m C18 column C4.6 x 150 mm from Agilent Technologies, Inc. and a symmetric 5 ⁇ C18 column (4.6 x 150 mm, purchased from Agilent Technologies, USA); mobile phase It consists of methanol (A) and 2 mM ammonium acetate (B).
  • the mobile phase was A:B 70%: 30%, flow rate 0.70 mL/min; for the analysis of compounds POP 62, 63, 66, the mobile phase was A:B 75%: 25 %, flow rate 0.70 mL/mintician
  • the ESI source was run in positive ion mode and the mass spectrometric conditions were as follows: Electrospray voltage, 5500 V; air curtain gas, 20 psi; atomizing gas, 40 psi; auxiliary gas, 20 psi, ion source temperature, 40 CTC; gas used are nitrogen de-clustered voltage and inlet voltage set to 80 V and 10, respectively V, ⁇ Quantitative analysis using multiple reaction monitoring (MM). MM
  • the prodrug compound of the present invention or a pharmaceutical composition comprising the prodrug compound is orally converted in the intestinal tract or transformed into a respective metabolite by the intestinal flora in vitro.
  • the correspondence between prodrug compounds and metabolites is shown in Table 14.
  • Reversal MDR activity was initially screened by the combined use of the anticancer drug doxorubicin on human colon tumor cells (female cell SW620 and drug resistant cells SW620/Ad300).
  • Test group Compound POP 68-71 > POP 82-85;
  • Metabolite group compound POP 62, 63, 65, 66;
  • the reversal of multidrug resistance of the tested compound POPs can be demonstrated by changes in the cytotoxic effect (IC 5Q value) of doxorubicin in drug-resistant cells.
  • the results of the test are shown in Table 15 and Figure 1 in terms of the reversal factor and the percent reduction. Among them, the results of using doxorubicin alone and doxorubicin in combination with a positive control (PSC833) were also listed for comparison.
  • a prodrug composition c (1.4: l: l. l) consisting of three prodrug compound prodrug compounds POP 68, 69, 70 was taken as an example to examine prodrug compounds POP 68-71, 82- 85. Under the action of the intestinal flora and metabolism in the body, it is clarified that POP 68-71, 82-85 and the pharmaceutical composition comprising POP 68-71, 82-85 are prodrug compounds/compositions.
  • the prodrug composition c (1.4: l: l. l) consisting of three prodrug compounds POP 68, 69, 70, after incubation with the intestinal flora solution, the compounds POP 68, 69, 70 were detected.
  • the metabolite compounds POP 62, 63, 66, are shown in Figure 3.
  • Proportional artificial weight ratio (1.4:1:1.1) of the pharmaceutical composition POP 68, 69, 70 (ie prodrug composition c) SD rats were administered intravenously or orally, and compound POP 62 was detected after oral administration. 63, 66 (as shown in Figure 4), and the above three metabolites were not detected after intravenous administration.
  • the compounds of the present invention do not reverse the multidrug resistance of tumor cells mediated by P-gp by themselves, but in vivo they can be converted into their respective active metabolites by the intestinal flora to exert anti-MDR activity, and thus, the present invention
  • the compounds are prodrug compounds that can be used to reverse or inhibit multidrug resistance of tumor cells.

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Abstract

La présente invention concerne des composés polyoxoprégnanes et l'utilisation de ces composés dans la fabrication de médicaments inversant ou inhibant la résistance pléïotrope de cellules tumorales.
PCT/CN2013/077281 2012-06-14 2013-06-14 Composés polyoxoprégnanes et leur utilisation WO2013185635A1 (fr)

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CN101724008A (zh) * 2008-10-08 2010-06-09 吉林省中医药科学院 通光藤c21甾体苷转化产物及其制备方法和用途
WO2011029639A2 (fr) * 2009-09-08 2011-03-17 Medexis S.A. Composés et procédés pour traitement de la néoplasie

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Publication number Priority date Publication date Assignee Title
CN1508145A (zh) * 2002-12-13 2004-06-30 中国科学院大连化学物理研究所 新型抗肿瘤人参皂苷苷元衍生物
CN1911234A (zh) * 2006-08-15 2007-02-14 广州中医药大学热带医学研究所 肿瘤细胞多药耐药逆转剂
CN101724008A (zh) * 2008-10-08 2010-06-09 吉林省中医药科学院 通光藤c21甾体苷转化产物及其制备方法和用途
WO2011029639A2 (fr) * 2009-09-08 2011-03-17 Medexis S.A. Composés et procédés pour traitement de la néoplasie

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