27 results about "Regorafenib" patented technology

The invention discloses an anti-tumor combined pharmaceutical composition and application thereof, and belongs to the technical field of biological medicine. The combined pharmaceutical composition comprises an OTUD4 inhibitor and a ferroptosis inducer or regorafenib which serve as active ingredients, and the OTUD4 inhibitor inhibits expression of OTUD4 in a targeted mode or causes function deficiency of OTUD4 and promotes occurrence of ferroptosis in tumor cells. The combined pharmaceutical composition provided by the invention more effectively inhibits tumor growth by synergistically increasing the oxidative stress level in cells, thereby playing a stronger anti-tumor effect. The combined treatment scheme provided by the invention provides a new thought for tumor treatment, and particularly in patients ineffective or drug-resistant to single-drug treatment, targeted inhibition of OTUD4 and regorafenib can effectively overcome drug resistance and significantly inhibit tumor growth.

The invention discloses a kit for simultaneously determining five liver cancer multi-kinase targeted drugs and active metabolites thereof based on LC-MS / MS. The kit comprises an internal standard solution, a standard substance solution, a protein precipitant and a solution used as a mobile phase, the internal standard solution is a gefitinib solution; the standard substance solution is a solution of sorafenib, sorafenib nitric oxide, lenvatinib, lenvatinib nitric oxide, dorafenib, dorafenib nitric oxide, regorafenib, regorafenib nitric oxide, cabozatinib and cabozatinib nitric oxide; the protein precipitant is an ice acetonitrile solution; the mobile phase comprises a mobile phase A and a mobile phase B, the mobile phase A is an aqueous solution containing formic acid, and the mobile phase B is an acetonitrile solution containing formic acid. The invention also discloses a method for determining the liver cancer multi-kinase targeted drug and the active metabolite thereof. The method can be used for monitoring drug concentration and preparing a drug time monitoring curve, and can simultaneously improve the sensitivity and selectivity of the method and shorten the analysis time so as to improve the analysis flux.

This invention discloses the application of regorafenib in the preparation of drugs to reverse gemcitabine resistance in pancreatic cancer. This invention is the first to discover that the protein FBLN3 plays a key regulatory role in gemcitabine-resistant pancreatic cancer cells; its downregulation significantly reduces the half-maximal inhibitory concentration (IC50) of gemcitabine. Furthermore, this invention clarifies that FBLN3 specifically interacts with EGFR, and identifies the key binding region between the two. This invention is also the first to discover that regorafenib can effectively block the interaction between FBLN3 and EGFR, and that the combination of regorafenib and sativa shows significantly better anti-tumor effects than monotherapy, effectively reversing gemcitabine resistance in pancreatic cancer.

A pharmaceutical composition for prevention or treatment of a disease or disorder characterized by chronic inflammation, associated with angiogenesis and fibrosis. The pharmaceutical composition includes a multi-target inhibitor, multi-phase modulator, or multi-kinase inhibitor, such as axitinib, nintedanib, pirfenidone, riociguat, sorafenib, sunitinib, lenvatinib, regorafenib, ponatinib, or pazopanib.

A process for preparing regorafenib using N,N'-bis[(2R)-1,1,1-trifluoropropan-2-yl] triamidodicarbonic acid diamide hydrochloride.

The invention relates to application of a proteasome inhibitor in preparation of a medicine for treating tumors resistant to a tyrosine kinase inhibitor, and in the application, a plurality of strains of liver cancer cells with drug resistance to lenvatinib or regorafenib are constructed by utilizing a plurality of human liver cancer cell lines with different genetic backgrounds; a high-throughput CRISPR (clustered regularly interspaced short palindromic repeats) gene knockout screening technology and a patent medicine gene CRISPR library are utilized, and gene targets of which the gene knockout or inactivation can better kill drug-resistant cells are specifically identified from thousands of patent medicine genes. Wherein the function inactivation of a plurality of genes in the proteasome family shows more obvious cell killing activity in a plurality of drug-resistant cell models compared with non-drug-resistant cells. The invention discovers and verifies that the proteasome inhibitor has a specific killing effect on tyrosine kinase inhibitor drug-resistant liver cancer for the first time.

The invention is applicable to the technical field of drug synthesis, and provides a preparation method of a regorafenib intermediate, which comprises the following steps: under the protection of nitrogen, adding N-methyl-4-chloro-2-pyridinecarboxamide, 4-amino-3-fluorophenol, N-methyl pyrrolidone and tetrahydrofuran into a reaction device for mixing, dissolving and clarifying, and heating to 80-90 DEG C; the method comprises the following steps: dissolving potassium tert-butoxide by using N-methyl pyrrolidone to obtain a potassium tert-butoxide solution; and when the internal temperature of the reaction device reaches 80-90 DEG C, quickly adding a potassium tert-butoxide solution for full reaction, and cooling and crystallizing to obtain the regorafenib intermediate. According to the method disclosed by the invention, the contents of process impurities I and II are greatly reduced, the conversion rate and the yield are remarkably improved, the dosage of N-methyl pyrrolidone is reduced, the production cost is reduced, the obtained regorafenib intermediate is high in yield and purity, the product quality strictly meets the standard, and the method is suitable for industrial production. And a technical scheme with economical efficiency and reliability is provided for industrial production.

The invention relates to an oligonucleotide lung targeting delivery system and application thereof in treatment of lung diseases, and relates to the technical field of biological medicines and nano-medicines. The invention designs a high-efficiency lung targeting oligonucleotide delivery drug, which comprises lipid nanoparticles, the lipid nanoparticles contain oligonucleotide and lipid components, and the lipid components are composed of 4-(N, N-dimethylamino) butyric acid (dilinoleyl) methyl ester, (2, 4-dimethylamino) butyric acid (dilinoleyl) methyl ester, (2, 4-dimethylamino) butyric acid (2, 4-dimethylamino) butyric acid (2, 4-dimethylamino) butyric acid (2, 4-dimethylamino) butyric acid (2, 4-dimethylamino) butyric acid The composition is composed of 1, 3-dioleoyl-propyl)-trimethylamine, dipalmitoyl phosphatidylcholine and pegylated lipid. A breakthrough of a nucleic acid medicine lung delivery technology is realized, in-vivo experiment verification results show that the lung aggregation efficiency is improved by about 2-4 times compared with that of traditional lipid nanoparticles, the lipid nanoparticles have remarkable lung metastatic tumor resisting activity, in-vivo experiments show that the lipid nanoparticles can inhibit growth of colorectal cancer lung metastatic tumors and prolong the survival time of mice, and the lipid nanoparticles have good application prospects. And the effect is better than that of 5-fluorouracil and regorafenib.

The present application relates to the field of organic electrochemistry and medical synthesis, and particularly relates to a preparation method of electrochemical synthesis of N-substituted pyridine-2-formamide. The method has the following technical advantages: no additional oxidizing agent or reducing agent is needed in the electrochemical synthesis, the environmental pollution and the reaction danger are reduced, the reaction condition is mild, the process flow is short, the reaction selectivity is good, the yield is high, and the method is environment-friendly. Specifically, in the present application, pyridine compounds and N-substituted oxamic acid are used as raw materials, and under the electrochemical reaction condition, the pyridine ring is directly activated on the carbon hydrogen to obtain N-substituted pyridine-2-formamide, wherein 4-chloro-N-methyl pyridine-2-formamide is a key intermediate of the antitumor drugs regorafenib and sorafenib, and the reaction equation is represented as:

The present invention relates to a marker for allowing the identification of patients with glioblastoma who respond positively to the drug Regorafenib.

The application belongs to the field of colorectal cancer treatment, and particularly relates to application of dihydroartemisinin in preparation of colorectal cancer liver metastasis drugs. The application research finds that dihydroartemisinin (DHA) can inhibit expression of mutant KRAS, reshape tumor immune microenvironment, thereby enhancing therapeutic effect of regorafenib combined with PD-1 inhibitor. These findings provide new insights for overcoming drug resistance in KRAS mutant colorectal cancer liver metastasis (CRCLM), and support further development of DHA as an adjuvant drug for combination therapy to improve patient prognosis.

The invention discloses a radiation-activated prodrug as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. The novel radiation-activated prodrugs (RAPs) are prepared by the optimization design of the structures of the sorafenib and the regorafenib (nitrogen-containing heterocyclic rings), so that the novel radiation-activated prodrugs (RAPs) can be used for preparing the novel radiation-activated prodrugs (RAPs) and the novel radiation-activated prodrugs (RAPs). External X-ray irradiation is utilized, the prodrug can be specifically activated in a tumor microenvironment, and a raw drug with strong anti-tumor activity is released, so that precise killing of tumors is realized. Meanwhile, the prodrug keeps relatively low systemic toxicity before being exposed to X-ray irradiation, so that complete compatibility with a radiotherapy scheme is ensured, and the potential of the prodrug serving as a tumor targeted therapy drug is shown. The radiation-activated prodrug has a structure as shown in a general formula I: # imgabs0 #, wherein I1: R = H; i2: R = F.

The invention provides a regorafenib-entrapped albumin preparation, a pharmaceutical composition and a preparation method and application of the regorafenib-entrapped albumin preparation, the regorafenib-entrapped albumin preparation is prepared from regorafenib into an albumin nano preparation, the solubility of REG is enhanced, side effects are relieved, the biological half-life period is prolonged, long-acting circulation is achieved, and the regorafenib-entrapped albumin preparation has a good application prospect. And the curative effect is enhanced by increasing the tumor tissue drug accumulation amount. In addition, according to the pharmaceutical composition, the regorafenib component is added into the albumin paclitaxel preparation, so that the pharmaceutical composition has the capability of synergistically reprogramming macrophages. Cell experiments prove that the combined use of PTX and REG under certain proportion conditions can enhance the M1 type polarization of macrophages.

The invention provides a regorafenib in-situ gel preparation for treating ocular neovascular diseases. The regorafenib in-situ gel preparation comprises regorafenib, a surfactant and an ion-sensitive in-situ gel material. According to the in-situ gel preparation disclosed by the invention, an in-situ gel preparation technology is combined with a particle drug carrier technology, and small molecules TKI are uniformly dispersed in an in-situ gel delivery carrier in the form of suspension particles by using suspension in-situ gel, or the small molecules TKI are encapsulated into nano-micelles and then dispersed in the in-situ gel delivery carrier, so that the in-situ gel preparation is prepared. The prepared particle in-situ gel ophthalmic preparation containing the micromolecule TKI is small in particle size, moderate in viscosity, stable in quality and free of irritation, and after the preparation is administrated in an eye drop mode, the eye tissue concentration and bioavailability of the preparation can be further remarkably improved, so that the intraocular curative effect of the preparation is improved.

The invention discloses a method for comprehensively synthesizing a regorafenib anticancer drug with high efficiency and low cost, which is applied to the field of anticancer drugs and chemical industry. The preparation method comprises the following steps: carrying out amidation reaction on 2-amino-4-chloropyridine and formic acid or carrying out amidation reaction on 4-chloro-2-picolinic acid and ammonia to obtain an intermediate (1), namely 2-formamido-4-chloropyridine; then carrying out N-methylation reaction on the intermediate (1) 2-formamide-4-chloropyridine and a methyl reagent (the methyl reagent comprises dimethyl sulfate, dimethyl carbonate and methyl iodide (or alkali participates in) to obtain an intermediate (2) 4-chlorine N-methylpyridine-2-formamide, and carrying out N-methylation reaction on the intermediate (1) 2-formamide-4-chloropyridine and the methyl reagent (the methyl reagent comprises dimethyl sulfate, dimethyl carbonate and methyl iodide (or alkali participates in) to obtain an intermediate (2) 4-chlorine N-methylpyridine-2-formamide; then, enabling the intermediate (2) 4-chloro-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol, so as to obtain an intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide, and enabling the intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide to react with 4-amino-3-fluorophenol; and then continuously using an intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide and 4-chloro-3-trifluoromethyl phenyl isocyanate to obtain a final product 4-[4-{4-chloro-3-(trifluoromethyl) phenyl} carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-formamide (regorafenib), wherein the final product 4-[4-{4-chloro-3-(trifluoromethyl) phenyl} carbamoyl} amino)-3-fluorophenoxy]-N-methylpyridine-2-formamide (regorafenib) is obtained from the intermediate (3) 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-formamide and 4-chloro-3-trifluoromethyl phenyl isocyanate. Wherein the production and synthesis technologies of the bottom raw materials and the intermediate raw materials are most comprehensive and more practical, the substitution reaction is used, and the used synthesis reaction is more suitable for industrial production and is more friendly to industrial medicine production.

The present invention discloses the application of pitavastatin in the preparation of a drug for reversing tumor multidrug resistance. The present invention finds that pitavastatin can significantly enhance the sensitivity of oxaliplatin-resistant human colorectal cancer cells to multiple tumor chemotherapy drugs (including oxaliplatin, irinotecan and regorafenib), and reverse the multidrug resistance of oxaliplatin-resistant human colorectal cancer. The present invention also finds that pitavastatin can significantly enhance the sensitivity of cisplatin-resistant human non-small cell lung cancer cells to multiple tumor chemotherapy drugs (including cisplatin, oxaliplatin and paclitaxel), and reverse the multidrug resistance of cisplatin-resistant human non-small cell lung cancer. Therefore, pitavastatin has the application prospect of being developed into a drug for reversing tumor multidrug resistance.

To provide combination pharmaceuticals for treating, preventing or managing diseases and conditions including hyperproliferative disorders such as cancer in humans and other mammals.SOLUTION: Disclosed is a combination pharmaceutical comprising regorafenib or its hydrate, solvate, metabolite or pharmaceutically acceptable salt or a polymorph thereof and a PD-1 / PD-L1(2) inhibitor.SELECTED DRAWING: None

The present invention discloses an anti-tumor combination pharmaceutical composition and its application, belonging to the field of biomedicine technology. The combination pharmaceutical composition comprises an OTUD4 inhibitor and a ferroptosis inducer or regorafenib as active ingredients. The OTUD4 inhibitor targets and inhibits OTUD4 expression or causes OTUD4 functional loss, thereby promoting the occurrence of ferroptosis in tumor cells. The combination pharmaceutical composition provided by the present invention more effectively inhibits tumor growth by synergistically increasing the level of intracellular oxidative stress, thereby exerting a stronger anti-tumor effect. The combined treatment regimen provided by the present invention provides a new approach to tumor treatment, especially in patients who are ineffective or resistant to monotherapy. Targeted inhibition of OTUD4 combined with regorafenib can effectively overcome drug resistance and significantly inhibit tumor growth.

The invention relates to the field of organic electrochemistry and medicine synthesis, in particular to a preparation method for electrochemical synthesis of N-substituted pyridine-2-formamide. The method has the following technical advantages that an oxidizing agent or a reducing agent does not need to be additionally used in electrochemical synthesis, environmental pollution and reaction danger are reduced, and the method has the advantages of being mild in reaction condition, short in technological process, good in reaction selectivity, high in yield, environmentally friendly and the like. Specifically, a cheap pyridine compound and N-substituted oxamic acid are taken as raw materials, under the electrochemical reaction condition, formamide is directly activated on a pyridine ring in a hydrocarbon mode, N-substituted pyridine-2-formamide is obtained, 4-chlorine-N-methylpyridine-2-formamide is a key intermediate of anti-tumor drugs regorafenib and sorafenib, and 4-chlorine-N-methylpyridine-2-formamide is a key intermediate of anti-tumor drugs regorafenib and sorafenib. Reaction equation: # imgabs0 #

The invention belongs to the field of colorectal cancer treatment, and particularly relates to application of dihydroartemisinin in preparation of a medicine for treating colorectal cancer liver metastasis. Research finds that dihydroartemisinin (DHA) can inhibit expression of mutant KRAS and remodel a tumor immune microenvironment, so that the treatment effect of regorafenib combined with a PD-1 inhibitor is enhanced. These findings provide a new insight for overcoming drug resistance in KRAS mutant colorectal cancer liver metastasis (CRCLM), and support further development of DHA as an adjuvant drug for combination therapy to improve patient prognosis.

The invention relates to the technical field of tumor treatment, in particular to a VEGFR-2 / BRD4 double-target inhibitor and application thereof. The structural general formula of the VEGFR-2 / BRD4 double-target inhibitor is as shown in a formula I in the specification. The tetrahydropteridine compound containing the aryl amide or aryl urea structure, disclosed by the invention, has relatively strong inhibitory activity on VEGFR-2 / BRD4 activity; according to the present invention, the VEGFR-2 / BRD4 double-target inhibitor has good anti-proliferative activity on tumor cells, the compound I-5 shows the optimal activity, and the activity is far superior to the positive control Sorafenib, ReGrafenib and JQ-1, the effect of the ReGrafenib and the effect of the combination of the Sorafenib and the JQ-1 respectively, and the target treatment drug for leukemia, gastrointestinal stromal tumor, liver cancer, kidney cancer, thyroid cancer, non-small cell lung cancer, colorectal cancer and the like can be prepared, and the compound I-5 can be used for the preparation of the target treatment drug for treating leukemia, gastrointestinal stromal tumor, liver cancer, kidney cancer, thyroid cancer, non-small cell lung cancer, colorectal cancer and the like.

The present invention relates to the field of tumor treatment, and specifically to the use of small molecule compounds in the preparation of drugs for treating hepatocellular carcinoma. For the first time, we used disulfiram to reverse the regorafenib resistance of MHCC-97H / REGO cells. The experimental results showed that after using disulfiram, the same concentration of regorafenib inhibited the proliferation, migration and invasion of MHCC-97H / REGO cells more significantly, and could significantly inhibit the tolerance of hepatocellular carcinoma to regorafenib. Therefore, the disulfiram provided by the present invention can be used to prepare drugs for prolonging the life of patients after hepatocellular carcinoma becomes regorafenib-resistant. The present invention provides disulfiram for the preparation of drugs for treating regorafenib-resistant hepatocellular carcinoma.

The invention discloses a dual-targeting superparamagnetic nano-drug carrier as well as a preparation method and application thereof, and belongs to the technical field of biological medicines. Superparamagnetic Fe3O4 is used as an inner core, PHis and chemotherapeutic drugs are sequentially wrapped, 2-DG and CB-839 are co-modified on the outermost layer, and efficient treatment is realized through a triple synergistic mechanism: (1) dual metabolism targeted blocking: 2-DG competitively inhibits glycolysis, CB-839 specifically blocks glutamine metabolism, and synergistically cuts off energy supply of tumor cells; (2) pH-responsive accurate drug release: protonizing and swelling the PHis in a tumor microenvironment (pH is 6.5-7.0) to trigger rapid release of the regorafenib; and (3) magnetocaloric synergistic interaction: Fe3O4 generates local high temperature (42-45 DEG C) under an external magnetic field, accelerates drug release and directly induces tumor cell apoptosis. The average hydrated particle size of the prepared nano-drug carrier is 42 + / -5nm, the regorafenib encapsulation efficiency is greater than 85%, the drug loading rate is greater than 11%, in vitro experiments and tumor-bearing mouse models prove that the inhibition rate of the nano-drug carrier on liver cancer cell proliferation is obviously superior to that of the traditional therapy, and an innovative technical scheme is provided for precise targeted therapy of liver cancer.

The invention discloses an application of a combination of Venoclam and regorafenib in treatment of acute myelogenous leukemia, provides a pharmaceutical composition and a kit for treating leukemia, and also provides a method for inhibiting leukemia cells or tissues in vitro. The invention provides a brand new combined scheme for treating acute myelogenous leukemia, and provides a new scheme for solving the problems of drug resistance and relapse of AML clinically.

A combination of recombinant methioninase and regorafenib for the treatment of cancer. The combination of recombinant methioninase and regorafenib shows a synergistic effect that allows for a reduction in the dose of regorafenib, and thus decreases the dose-dependent toxicity of regorafenib.

The invention discloses a preparation method of active oxygen response intestinal cancer nanoparticles and radiotherapy combined application of the active oxygen response intestinal cancer nanoparticles. The invention relates to the field of cancers, in particular to a method for treating colorectal cancer by using an active oxygen responsive nanoparticle targeted delivery system. According to the invention, a therapeutic drug is loaded by nano-particles, and an external radiotherapy technology is combined, so that efficient targeted therapy of colorectal cancer is realized. The preparation method comprises the following steps: firstly, carrying out connection reaction on PLGA-PEG-NHS and QRH polypeptide to synthesize PLGA-PEG-QRH, carrying out self-assembly on the PLGA-PEG-QRH and mPEG-TK-PLGA to form nanoparticles QRH-TK (at) NP, then loading regorafenib (RG) into the QRH-TK (at) NP, and carrying out self-assembly to form the nanoparticles QRH-TK (at) RG. The nanoparticles prepared by the preparation method disclosed by the invention have low toxicity and good biocompatibility, are directionally enriched in colorectal cancer tissues and have ROS responsiveness.