115 results about "Norcantharidin" patented technology

The invention discloses a pyrazolo N-substituted dehydronorcantharidin imide derivative as well as a synthesis method, an activity test method and application thereof, belonging to the field of cantharidin derivatives. The pyrazolo N-substituted dehydronorcantharidin imide derivative has a structural general formula shown as a formula 1: in the formula 1, R1 is H, C1, F, CH3, OCH3, OH or NO2; and R2 is 2-phenyl-2H-1,2,3-triazole-4-substituent or quinoxaline-2-substituent. The novel N-substituted dehydronorcantharidin imide derivative introduces five-membered heterocyclic pyrazole rings into norcantharidin substituted arylamine and has favorable anti-tumor activity.

The invention provides a norcantharidin monomer-acid monoester derivative and an application thereof. The structural formula of the derivative is shown as the No.3 formula (please see the specification), wherein R is selected from alkyl or benzyl of C1 to C3. An activity test proves that the third designed and synthesized norcantharidin monomer-acid monoester derivative has good inhabitation activity in liver cancer tumor cells, stomach cancer tumor cells and colon cancer tumor cells, and can be expected to be applied to preparing medicine for resisting the three tumors.

A biodegradable slow-release micro-sphere of norcantharidin is prepared from a biodegradable polymer as carrier and norcantharidin as active component through mixing the solution of said polymer in dichloromethane or ethyl acetate with the aqueous solution of norcantharidin containing surfactant, stirring, adding it to the aqueous solution containing polyvinyl alcohol, stirring or evaporation, dialysis and freeze drying.

The invention provides an immunoliposome of a CD19 monoclonal antibody. First, a film dispersion method is adopted to prepare the cubical space stable norcantharidin immunoliposome, wherein the mole ratio of soy bean lecithin, cholesterol, methoxyl-polyethylene glycol 2000-phosphatidyl ethanolamine is 2:1:0.01, the mass ratio of norcantharidin immunoliposome and soy bean lecithin is 1:20, and entrapment efficiency of high-performance liquid detection NCTD is 46.5+ / -2.21%. The research proves that 2E8-SL-PE can be combined with Nalm-6 and Raji cell specifically, the positive rates thereof are respectively 89.44% and 88.73%, the 2E8-SL-PE is almost not combined with Molt-3 and K562 cell with the positive rates being only 1.95% and 1.39%, which shows that the immunoliposome has obvious target recognition effect. The norcantharidin immunoliposome can be applied in preparing specific target killer B lymphocyte leukemia and stem cell drugs thereof.

The invention relates to norcantharidin esterified derivatives and a preparation method thereof. The norcantharidin esterified derivatives are 7-oxabicyclo[2,2,1] heptane-2 carboxylic acid butyl ester-3 carboxylic acid butyl ester, 7-oxabicyclo[2,2,1] heptane-2,3 dicarboxylic acid hexyl ester, 7-oxabicyclo[2,2,1] heptane-2,3 dicarboxylic acid monooctyl ester, 7-oxabicyclo[2,2,1] heptane-2,3 dicarboxylic acid decyl ester, and 7-oxabicyclo[2,2,1] heptane-2,3 dicarboxylic acid dodecyl ester. The preparation method comprises the following steps: adding a corresponding alcohol in a mixing amount, adding norcantharidin and sulfuric acid in a mixing amount, mixing, stirring and heating the mixture, refluxing the mixture at 45 to 100 DEG C for 60 to 300 minutes, and obtaining oily liquid after reactions are finished; and washing the products with cold water, filtering solution obtained to obtain white waxy solid, adding preheated normal hexane in the white waxy solid to dissolve the white waxy solid, freezing obtained solution at the temperature of between 18 DEG C below zero and 4 DEG C for refrigeration and crystallization for 1 to 24 hours, and filtering the solution to obtain crystals, namely the corresponding norcantharidin esterified derivatives.

The invention discloses a bromo-norcantharidin acid-benzyl ester shown as a structural formula I. The bromo-norcantharidin acid-benzyl ester is an open-loop 5,6-dibromo-norcantharidin acid benzyl ester, and an active test proves that the bromo-norcantharidin acid-benzyl ester has a good anti-liver-cancer effect and can be used as a high-efficiency and low-toxicity cantharidin anticancer medicine The synthesis process is excellent in selectivity, raw materials are readily available, the cost is low, the synthetic route is simple, operation is easy, a product obtained by the synthesis has low toxicity, high yield and high purity, and the process is high-efficiency, convenient and low in cost.

The invention belongs to medical domain; it has disclosed a compound medicine that contains cantharidin orits derivates and at least one kind of medicine that can improve the immunity, the preparing method and application is also mentioned in the invention. The medicine that can improve immunity is chosen from one kind or various kinds of lentinan, ganoderma and hoelen. The medicine can be used to treat liver cancer, esophageal cancer, carcinoma of gastric cardia, lung cancer, malignant lymphoma and low blood corpuscle; it can also be used to treat hepatitis, cirrhosis or HB virus; it can be used as preoperative drug for cancer operation or be used in combination chemotherapy with the function of coordinated synergistic action. The product in the invention has good stability and the effects have been greatly improved than the single application of Norcantharidin, lentinan, ganoderma and hoelen. The medicine can be made into any medically acceptable dosage with any medically acceptable accessories so it has wide prospects.

The invention relates to a freeze-dried powder of sodium norcantharidin for injection and a preparation method for the freeze-dried powder: adding the norcantharidin and mannitol into well prepared sodium hydroxide solutions and adjusting the ph; adding activated carbon and removing colors, filtering and removing the carbon and finely filtering through a 0.22Mu m filtering film and making loading separately; cooling the separately loaded medical solution rapidly to minus 60 to minus 55 DEG C with the speed of 15 to 25 DEG C per minute; preserving heat and freezing for 3 hours and pumping the vacuum of 5 to 15 Pa; heating slowly and uniformly to minus 5 to 5 DEG C with the speed of 3 to 3.5 DEG C per hour and preserving the heat for 2 to 5 hours and then heating with a uniform speed to 20 to 30 DEG C with 3 to 6 heating hours; preserving heat and drying for 5 hours and detecting, pressing a whole cover and packaging and warehousing. The freeze-dried powder obtained by the method is high in purity, beautiful in appearance and low in water content and the proportion of the nor cantharidin, the sodium hydroxide and the mannitol is provided as 2 to 1 to 20.

The invention relates to a temperature-controlled sustained-release injection containing an alkylating agent and a preparation method thereof, the temperature-controlled sustained-release injection comprises effective anti-cancer amount of the alkylating agent, an amphiphilic block copolymer, a solvent and a certain amount of drug release regulator, wherein, the mixture of the amphiphilic block copolymer and a solvent without organic solvent has the temperature-sensitive gelatinization feature, which is flowable liquid in the environment that is lower than the body temperature and can be automatically converted to the water-insoluble gel that can not flow and be biodegradable for absorption in an endotherm, and the water-insoluble gel can allow the contained angiogenesis inhibitor to have the local sustained release in a tumor and maintain the effective drug concentration for a plurality of weeks to a plurality of months. The sustained-release gel injection can be injected in the tumor or the tumor periphery or be arranged in the postoperative tumor cavity, thus significantly reducing the systemic reaction of the drug and being used for the treatment of the tumors in different stages. The alkylating agent is selected from cyclophosphamide, melphalan, leukeran, 4H-cyclophosphamide peroxide, norcantharidin, mannosulfan, treosulfan, ritrosulfan, ethoglucid, pipobroman, piposulfan, pumitepa, uredepa, azatepa and so on.

The invention belongs to the technical field of medicine. The invention discloses a norcantharidin liver-targeting liposome, a preparation method thereof and the application of a freeze-dried preparation. The norcantharidin liver-targeting liposome of the present invention is connected with a glycyrrhetic acid derivative on the surface of the liposome, which can be combined with the glycyrrhetic acid receptor on the surface of liver tumor cells and undergo endocytosis, thereby producing a tumor-suppressing effect. ; Norcantharidin is encapsulated in liposomes, which has better drug bioavailability and enhanced curative effect. The norcantharidin liposome freeze-dried preparation prepared by the invention has good stability, safety and reliability, is easy to store, and is beneficial to industrialized production.

The coated norcantharidin tablet has one norcantharidin tablet of 0.5-0.8 cm diameter and one surface coating of 0.3-1.0 mm thickness. It is prepared through preparing norcantharidin tablet and forming moisture-proof coating. The coated norcantharidin tablet has high moisture-proof property, high stability, high medicine leaching rate, high bioavailability and high clinical treating effect. It is used in treating liver cancer, esophageal cancer, leucopenia, hepatitis, etc. and may be also used as pre-operational medicine or in combined chemotherapy.

The present invention discloses a novel cantharidin derivative with selective suppressive activity on tumor cells but low toxicity on human body. The present invention also discloses the preparation method of the cantharidin derivative, in which norcantharidin, glycin, and amantadine are adopted as the raw materials to synthesize the cantharidin through steps, and the preparation method is safe, simple and easily accomplishable. The cantharidin derivative with suppressive activity on tumor cells has smart structure and strong suppressive activity on tumor cells, fills in the gap in the field, makes the solid foundation for the preparation of cantharidin derivative which has selective suppressive activity on tumor cells and minor toxicity on human body, and has both potential significance on the industrialized exploit and great contribution to the research on human anti-tumor drugs.

The invention designs and synthetizes a lead compound by using a glycyrrhetinic acid derivative as a carrier and being connected with norcantharidin and a derivative thereof through ester bonds, the obtained lead compound expects to have the advantages of having liver targeting action, prolonging action time, reducing toxic and side effects and improving the curative effect of resisting liver cancer, and a model compound is provided for the research of a liver targeting medicine for the liver cancer. Firstly, two positions of C11 and C30 in glycyrrhetinic acid molecules are reduced and synthetized respectively, methyl ester is chemically modified into glycyrrhetinic acid (GA) and 18 alpha-glycyrrhetinic acid as well as a derivative thereof, the glycyrrhetinic acid (GA) and 18 alpha-glycyrrhetinic acid as well as the derivative thereof are used as framework molecules, through a series of reactions, the framework molecules and the norcantharidin (NCTD) as well as a derivative thereof are condensed to form ester as a prodrug, a cell activity screening test is performed on 5 object compounds, 13 object compounds in 3 series are synthetized, and structural characterization is performed on a carbon spectrum, a hydrogen spectrum and a mass spectrum; the influence of different concentrations of 5 object compounds on HepG2 cell proliferation of the liver cancer is inspected by a method, results show that inhibitory action presents time-dose dependence, and the suppression ratio of 14 mu g / mL is the highest.

The invention provides a camptothecin-20-position ester derivative having a structural formula shown as the figure 4, a preparation method of the derivative, and an antineoplastic application of the derivative. It is proved through an activity test that the camptothecin-20-position ester derivative designed and synthesized in the invention and shown as the figure 4 is a suitable antineoplastic medical candidate, especially an anti-liver-cancer, anti-stomach-cancer, and anti-colorectal-cancer medical candidate. Compared with camptothecin and cantharidin which are taken as positive-control medicines, the derivative has improved water solubility and stability, is relatively sensitive to acid, and is easy to hydrolyze. Besides, according to a synthetic method of the camptothecin norcantharidin ester derivative, raw materials are easy to get; the synthetic route is high in yield; and the method is very easy to operate and implement.

The invention belongs to the pharmaceutical preparation filed and relates to a tumor interventional embolization agent, which takes norcantharidin as the active ingredient and biodegreadable material aliginate and polyanhydride as the accessories to establish emulsion-chemical crossline preparation method and prepare norcantharidin-alginic acid / poly acid anhydride micro-spheres. The norcantharidin micro spheres are applied for tumor interventional treatment through the hepatic artery. It can keep embolizing the tumor as long as one month and cause the tumor necrosis. At the same time, the microspheres can targetingly disperse in the tumor tissues to release the medicine slowly, prolong the active time of the medicine to the tumor tissues, increase partial medicine density and decrease the tumor toxicity. The invention has the advantages of targeting dispersed microspheres in the tumor tissues, long time for embolization, slow drug release, high anti-cancer effect and security.

The invention discloses bromo-norcantharidin mono-methyl ester with a structural formula as shown in a formula I in the specification. The bromo-norcantharidin mono-methyl ester is ring-opened 5,6-dibromo-norcantharidin mono-methyl ester. Activity tests prove that the bromo-norcantharidin mono-methyl ester has a good liver cancer resistance, and can be used as an efficient low-toxicity cantharidin anti-tumor medicine. The synthesis process has good selectivity, easily available raw materials, low cost and simple synthesizing route, and is convenient to operate and implement; and the synthesized product has small toxicity, high yield and high purity. Therefore, the process has the characteristics of high efficiency, convenience and low cost.

The present invention discloses a norcantharidin derivative and a synthesis method thereof, which belongs to the field of medicine preparation technology. The method utilizes ethylene diamine as a connecting arm to connect norcantharidin with lactobionic acid in order to produce a new compound, and besides anticancer activity, the compound also has good liver-targeting character. The synthesis method is simple, the yield is high, the cost is low, the toxic side effect of the norcantharidin in the treatment of liver cancer can be effectively reduced, the liver is targeted, and the curative effect is improved.

The invention relates to a method for green synthesis of a norcantharidin derivative and aims to solve problems of complexity of reaction steps and raw material types, long reaction time and low yield in existing norcantharidin derivative synthesis and high solvent toxicity in some methods. The method for green synthesis of the norcantharidin derivative includes: subjecting furan and maleic anhydride to Diels-Alder reaction at the room temperature to obtain norcantharidin; then performing addition of bromine pair double bonds; finally, adding 7-oxy-bicyclo[2.2.1]heptanes-5,6-dibromoanhydride and amine compounds into Schlenk filled with acetone, stirring at the room temperature, performing TLC (thin-layer chromatography) monitoring, and after reaction is finished, carrying out filtering, acetonitrile washing and infrared drying to obtain a target compound. The method has advantages of safety, environment friendliness, freeness of generation of waste gas and waste water, simplicity and convenience in operation, high in process stability and yield and realization of reaction at the room temperature.

The invention discloses a norcantharidin derivative and an activity testing method and an application thereof and relates to the field of cantharidin derivatives. The norcantharidin derivative has two kinds, one is a norcantharidin dimer derivative, and the other is a heterocyclic substituted norcantharidin derivative. Cell counting kit-8 is used to analyze the influence of the compound on the activity of human lung adenocarcinoma cells A549. The norcantharidin derivative has good anti-tumor activity.

The present invention relates to a type of norcantharidin analogues and a method to synthesis such norcantharidin analogues by transition metal-catalyzed alkynylation of 7-oxabenzonorbornadienes. The present invention also relates to the use of such norcantharidin analogues in manufacture of a medicament for the treatment of cancer tumors.

The invention relates to norcantharidin derivative lipid microsphere injection and a preparation method thereof. The injection contains norcantharidin imide derivative, oil phase, water and surfactant; and the formula of the injection contains the following components by mass: 5 to 30 percent of oil phase, 0.001 to 1 percent of norcantharidin imide N-alkyl derivative, 0.5 to 7 percent of surfactant, 1 to 5 percent of osmotic pressure regulator, and the balance of injection water. Norcantharidin is connected with a long-chain saturated alkane group through amino, so that the lipid solubility of the injection is greatly improved, and the lipid solubility of the injection is improved together with increase of the chain length of the saturated alkane group. Lipid microspheres can carry medicaments with the granularity of more than 90 percent into lipid cores and (or) an interfacial film, so that the medicament loading capacity and the encapsulation efficiency are greatly improved, the vascular stimulation during injection is reduced, the physical and chemical stability of the medicaments and the lipid microsphere injection is improved, the in-vivo acting time of the medicaments is prolonged, the treatment effect is improved, and the toxic or side effect is reduced.

The invention discloses a pH-sensitive double-drug skeleton polymer prodrug, and relates to the technical field of controllable polymer prodrug preparation. The structural formula of the polymer prodrug is shown as VI. The invention further provides a preparation method and application of the polymer prodrug. The pH-sensitive double-drug skeleton polymer prodrug has the beneficial effects that inthe structure of the polymer prodrug disclosed by the invention, the molar ratio of cis-platinum to norcantharidin is always kept at 1: 2; accurate administration is implemented; and the polymer prodrug can remarkably improve the targeted enrichment, cellular uptake and intracellular rapid drug release capabilities of a drug at a tumor site, so that the effect of completely inhibiting tumor growthis achieved.

The invention belongs to the field of new dosage forms of pharmaceutical tumor drugs, and particularly relates to a preparation method and application of norcantharidin-loaded exosomes. The method specifically comprises the following steps of (1), extracting mesenchymal stem cell exosomes by adopting an ultracentrifugation method; and (2), wrapping norcantharidin in the exosomes through an electroporation method to obtain the drug-loaded exosomes. The prepared drug-loaded exosomes can improve the liver targeting property of the drug and enhance the drug effect of norcantharidin.

The invention provides synthesis and anti-tumor application of norcantharidin carboxylic acid monofluorobenzyl ester with a structural formula shown as I in the specification. The specific structure of the norcantharidin carboxylic acid monofluorobenzyl ester as shown in the formula I is shown in the specification, and activity tests show that the norcantharidin carboxylic acid monofluorobenzyl ester as shown in the formula I, which is designed and synthesized by the invention, is a suitable anti-tumor candidate drug, especially as an anti-liver cancer candidate drug. Compared with a positivecontrol drug norcantharidin, the norcantharidin sodium salt has the advantage that the water solubility, the stability and the anti-tumor activity are improved. In addition, the synthesis method of norcantharidin carboxylic acid monofluorobenzyl ester has the advantages that the raw materials are easy to obtain, and the operation and the implementation are very easy.

The invention discloses a norcantharidin oleanolic acid complex lipidosome. The lipidosome is prepared from the following components in parts by weight: 230-250 parts of lecithin, 35-45 parts of cholesterol, 12-16 parts of norcantharidin and 12-16 parts of oleanolic acid, wherein the pH value of the lipidosome is 7.4. The invention further discloses a method for preparing the norcantharidin oleanolic acid complex lipidosome. The norcantharidin oleanolic acid complex lipidosome has relatively good encapsulation efficiency, has liver targeting property, and is capable of effectively treating liver cancer since the liver targeting property of norcantharidin is enhanced by oleanolic acid.

The invention relates to a folic acid modified norcantharidin stealth niosome and a preparation method thereof. The niosome is a surface hydrophilic and folic acid modified stealth niosome which is formed by entrapping norcantharidin with a poloxamer 407-cholesterol compound and a folic acid-polymer as major carrier materials; and the stealth niosome contains no free cholesterol. The entrapment rate of the niosome is (52.30+ / -2.16)%, the mean grain size of the niosome is (100.87+ / -0.23)nm and the zeta potential of the niosome is -25.96 mV; the drug release rate in vitro of the niosome is obviously lower than that of a crude drug; t1 / 2 released by the niosome in an environment in which the pH of 7.4 of the normal tissue is simulated is 1.98 times of that released by the niosome in an environment in which the pH of 5.0 of the normal tissue is simulated; and the folic acid modified norcantharidin stealth niosome is obvious in slow release effect and advantageous for releasing in target cells. Besides, the niosome is capable of obviously increasing the growth inhibition ratio and drug taking quantity of tumor cells, and generating active targeting effect at molecular level, and therefore, the efficacy of the drug is improved, treatment of cancer at high efficiency and low toxicity is facilitated.

The invention relates to a drug combination with anti-hepatoma activity, and a preparation method and application thereof. The active ingredient of the drug combination is extracted from Panax, astragalus root, Toad Venom and Norcantharidin.

The invention discloses tetrafluorobenzyl norcantharidin carboxylate and a synthesis method thereof. The structural formula is shown as a formula I, the specific structure of tetrafluorobenzyl norcantharidin carboxylate shown in a formula I is shown in the specification and the synthesis method comprises the following steps that side-chain tetrafluorobenzyl alcohol (compound 5) and norcantharidin(compound 4) undergo a reaction in an organic solvent at a certain temperature under the action of an organic alkali to obtain tetrafluorobenzyl norcantharidin carboxylate shown as a formula I. The synthesis route is shown as follows that: carboxyl is introduced into the molecular structure of the compound disclosed by the invention, so that the water solubility and stability are improved, and dueto the introduction of a fluorine-containing group, the physical property, the chemical property and the biological activity of parent molecules can be remarkably changed, so that the pharmacokineticefficacy can be enhanced. In addition, the raw materials of the synthesis method are easy to obtain, and operation and implementation are very easy.

A biodegradable slow-release micro-sphere of norcantharidin is prepared from a biodegradable polymer as carrier and norcantharidin as active component through mixing the solution of said polymer in dichloromethane or ethyl acetate with the aqueous solution of norcantharidin containing surfactant, stirring, adding it to the aqueous solution containing polyvinyl alcohol, stirring or evaporation, dialysis and freeze drying.

The invention provides a norcantharidin monoester salt derivative. A structural formula of the derivative is shown as a formula 4 (shown in the description), wherein R is selected from alkyl or benzyl of C1-C3, M is selected from cations plus one or cations plus two. Active tests prove that the designed and synthesized norcantharidin monoester salt derivative 4 has the good inhibitory activity on liver cancer, gastric cancer, colon cancer and colon cancer and can be expected to be applied to preparation of drugs for resisting the four tumors.