81 results about "Regorafenib" patented technology

The invention relates to the field of biological medicine, and in particular relates to liver targeted medicine. The medicine is chemical micromolecular medicine connecting galactosamine. The chemicalmicromolecular medicine is medicine for treating liver diseases or liver-related diseases. The chemical micromolecular medicine is prepared from but not limited to thyroxine T3, sorafenib, taxol, regorafenib, lamivudine, entecavir, telbivudine, statins, fibrates, niacin, bile acid sequestrants, other hepatitis virus DNA (RNA) polymerase inhibition compounds and the like. The galactosamine is tervalent acetylgalactosamine. The connection is the direct connection of the galactosamine and the chemical micromolecular medicine or the connection through linking fragments; the linking fragments comprise but not limited to carbon chains, disulfide bonds, pyrophosphate diester, cysteic acid, polypeptide and thioether or valine-citrulline. The medicine provided by the invention has the advantages that the liver targeted performance is improved; the medicine curative effect is enhanced; the toxic and side reactions on other non-targeted tissues are few.

The invention provides a eutectic complex composed of resveratrol and a protein kinase inhibitor, and a composition comprising the eutectic complex. The eutectic complex is characterized in that the protein kinase inhibitor is selected from one of imatinib, gefitinib, erlotinib, sunitinib, sorafenib, dasatinib, lapatinib, nilotinib, pazopanib, afatinib, crizotinib, axitinib, regorafenib, ibrutinib, lenvatinib, palbociclib, osimertinib and alectinib or pharmaceutically acceptable salt thereof. The eutectic complex provided by the invention can produce synergistic effects of inhibiting histamine release.

The invention discloses a targeting mesoporous polydopamine multi-purpose nanometer diagnosis and treatment preparation as well as a preparation method and applications of the targeting mesoporous polydopamine multi-purpose nanometer diagnosis and treatment preparation. The targeting mesoporous polydopamine multi-purse nanometer diagnosis and treatment preparation is composed of a water-soluble folic-acid-targeting mesoporous polydopamine medicine carrier, hydrophobic regorafenib and manganese sulfate, wherein the mass ratio of regorafenib to the folic-acid-targeting mesoporous polydopamine medicine carrier is (0.5-4): 1, and the mass ratio of manganese sulfate to the folic-acid-targeting mesoporous polydopamine medicine carrier is (1-6):1. The targeting mesoporous polydopamine diagnosis and treatment preparation can recognize positive tumor cells of a folic acid receptor, so that a targeting effect is achieved during treatment. For the diagnosis and treatment preparation, the chemotherapy under the guidance of MRI imaging is realized, the tumor treatment effect is expected to be improved, meanwhile, the biocompatibility is good, and therefore, the targeting mesoporous polydopaminemulti-purpose nanometer diagnosis and treatment preparation has the clinical application potential.

The invention discloses a regorafenib synthesis method by one kettle way, which is characterized in that 4-chlorine-trifluoro- tolyl isocyanate and 3-fluorine-4-aminophenol are added in a solvent, the temperature is controlled, a condensation reaction is carried out to generate a regorafenib intermediate 1-(4-chlorine-3-(trifluoromethyl)phenyl)-3-(2-fluorine-4-hydroxyphenyl)carbamide, then alkali is added in a same reactor for stirring, 4-chlorine-N-methyl-2-pyridine methanamide hydrochloride or 4-chlorine-N-methyl-2-pyridine methanamide are subjected to a replacement reaction, and finally purifying processing is carried out to obtain regorafenib. The method has the advantages of short process flow, simple operation, high utilization rate of raw material, and low generation cost, and has better production and utility value.

The invention relates to a regorafenib tablet pharmaceutical composition and a preparation method thereof and in particular relates to a pharmaceutical composition. The pharmaceutical composition comprises an active pharmaceutical compound, a diluent, a disintegrating agent, an adhesive and a lubricating agent, wherein the active pharmaceutical compound refers to 4-[4-({4-chloro-3-(trifluoromethyl)phenyl]carbamyl}amino)-3-chlorophenoxy]-N-methylpyridine-2-formamide or pharmaceutically acceptable salts, solvates and polymorphism. The pharmaceutical composition has a contact angle of 40-100 degrees, particularly a contact angle of 40-90 degrees, preferably a contact angle of 40-80 degrees, and in particular a contact angle of 40-70 degrees. The pharmaceutical composition disclosed by the invention can be used for treating diseases and disease symptoms mediated by abnormal VEGFR, PDGFR, raf, p38 and/or flt-3 kinase signals. The invention also relates to a method for preparing an anti-tumor pharmaceutical composition. The pharmaceutical composition disclosed by the invention has excellent preparation performance.

The invention discloses a method for preparing a regorafenib intermediate; a compound represented by the formula II and a compound represented by the formula III are subjected to three stages of a step A, a step B and a step C, intermediates of all the stages are not separated, and thus the regorafenib intermediate I is prepared. According to the method, the intermediates of all the steps are not separated, post-treatment procedures are reduced, the process operational flow is saved, the solvent recovery and utilization efficiency is improved, pollution emissions and energy consumption are reduced, the requirements on green chemical process are met, and the method is suitable for industrialized production.

The invention relates to a preparation method for Regorafenib hydrate. The method includes the steps that creatively, 4-chloro-1-trifluoromethyl phenylamine (compound 2) and allyl chloroformate (compound 3) react to generate (4-chloro-3-trifluoromethyl phenylamine)-formic acid allyl ester (compound 4); (4-chloro-3-trifluoromethyl phenylamine)-formic acid allyl ester (compound 4) and 4-(4-amino-3-trifluoromethyl)-N-methylpyridine-2-formamide (compound 9) are subjected to a substitution reaction under the catalysis of N-methyl pyrrolidine or trialkylaluminium to obtain Regorafenib hydrate. According to the method, cost is low, operation is easy, few reaction steps are needed, the period is short, energy consumption is low, the yield is high, purity is high, the process is safe, no high-toxicity reagent is used, and the obtained product has no potential safety problem and is suitable for industrial production.

The invention firstly provides a composition containing a protein kinase inhibitor and resveratrol. The composition is characterized in that the protein kinase inhibitor is one, or its pharmaceutically-acceptable salt or solvate or pharmaceutically-acceptable salt solvate, of sunitinib, lapatinib, pazopanib, afatinib, bosutinib, crizotinib, axitinib, and regorafenib; the molar ratio of resveratrolto the protein kinase inhibitor is (0.01-100):1. It is discovered through in-vitro antibacterial tests that the composition of the protein kinase inhibitor and resveratrol, in the molar ratio of (0.01-100):1, and can provide synergic antibacterial action against Kluyvera cryocrescens and other bacteria (interaction index CI<1 upon 30% of inhibition).

The invention discloses a regorafenib solid dispersion, which comprises regorafenib, a carrier material and a synergistic agent in the mass ratio of 1: (2-20): (0.2-5), the carrier material comprises povidone and sorbitol in the mass ratio of 1: (0.1-0.5), and the synergistic agent comprises silica and Docusate sodium in the mass ratio of 1: (0.5-1). Through a certain process, the regorafenib is prepared into the sorbitol-regorafenib-povidone sandwich structure solid dispersion, dissolution of the regorafenib from inside to outside is promoted, the solubility of the regorafenib is greatly improved, safe, non-toxic and volatile ethanol is used as a solvent in the preparation process, and no security risk is caused by residual solvent. At the same time, the aging phenomenon in the long time storage process of the regorafenib solid dispersion can be avoided, and stability is improved.

The invention relates to a preparation method of regorafenib. The method comprises the following steps: heating and melting 3-fluoro-4-nitrophenol and reacting with 4-chloro-N-methylpyridine-2-formamide under the action of KOH; reducing through hydrazine hydrate to obtain an intermediate I; finally enabling the intermediate I and 3-trifluoromethyl-4-chloroaniline, and ethylene carbonate to be subjected to one-pot reaction under the catalysis of a catalyst; carrying out post-treatment to obtain a regorafenib pure product. The method provided by the invention has the advantages of high conversion rate, safety and no harms, no pollution, moderate reaction conditions, high yield and high product purity, and is applicable to industrial production.

The invention belongs to the technical field of medicines, discloses an new application of sorafenib, and particularly relates to an application of the sorafenib to preparation of medicines for treating myeloproliferative neoplasmas. The myeloproliferative neoplasmas is myeloproliferative neoplasmas with polycythemia vera or drug resistance of ruxolitinib. The sorafenib is used for treating the polycythemia vera, a new treatment way is provided for patients suffering from the polycythemia vera, and more choices are provided for clinicians and patients. For a patient suffering from myeloproliferative neoplasmas with drug resistance of ruxolitinib, the sorafenib can provide continuous oral drug therapy for the patient, and bone marrow transplantation is avoided. The sorafenib can be chemically synthesized, and the cost is lower than that of a biological agent. And the sorafenib is approved by FDA and NMPA to appear on the market and is used for clinical treatment. The side reaction is less and lighter, the tolerance of clinical patients is good, and the burden of the patients is lighter.

The invention discloses a regorafenib preparation method, and belongs to pharmacy field. According to the method, on the basis of a conventional routine, the routine defects are avoided, a raw material 4-amino-3-fluorophenol, which is low in price and easy to obtain or prepare, is employed for replacing 4-chloro-3-(trifluoromethyl)phenyl isocyanate, a protection group for protection is ingeniously employed during reaction and unnecessary impurities are prevented from generating, the whole routine is simple in operation, and the product is high in yield, stable and easy to purify.

The invention relates to the field of drug sustained-release preparations, and in particular, relates to a regorafenib-coated nano-porous hydroxyapatite sustained-release microsphere as well as a preparation method and application thereof. The sustained-release microsphere disclosed by the invention contains 5 to 10 parts of regorafenib and 10 to 20 parts of nano-porous hydroxyapatite; the nano porous hydroxyapatite is modified by polyglutamic acid, polyaspartic acid or polylysine. The nano-porous hydroxyapatite is subjected to polyamino acid modification, so that the release rate of the active ingredient regorafenib can be effectively controlled, the drug release rate and the treatment effect are improved, the side effects of drugs on patients can be remarkably reduced, and the nano-porous hydroxyapatite has wide application prospects in the field of drug sustained-release carriers.

The present invention discloses a regorafenib oral solid pharmaceutical composition preparation method, a binder solution is first prepared by solvent method, then regorafenib is added into the binder solution, and sufficiently stirred to obtain a clear granulating liquid; the clear granulating liquid is then sprayed into other auxiliary material to prepare into a suitable solid dispersion; further the suitable solid dispersion is compressed into the smallest pharmaceutical dosage unit, the tablet may further be coated; the composition contains a binder, a disintegrating agent, a lubricant and a wetting agent. Advantages of the method are that: the method mainly solves the problems of small regorafenib solubility andslow dissolution rate to further improve the bioavailability and enhance the stability of the drug.

The invention discloses a novel regorafenib anti-tumor platinum (II) complex. A chemical structural formula of the platinum (II) complex is as shown in the specification. The platinum (II) complex expresses excellent anti-tumor activity in vitro, has a potential medicinal value and is hopefully used for preparing various anti-tumor drugs. The invention further discloses a preparation method and the application of the platinum (II) complex.

The invention belongs to the field of drug synthesis and particularly relates to a preparation method of regorafenib hydrate. 4-methyl-2-pentanone, 4-amino-3-fluorophenol and N-methyl-4-chloro-2-pyridine carboxamide are condensed to obtain a regorafenib intermediate 1, 4-chloro-3-(trifluoromethyl)isocyanate is added for condensation and salt-forming reactions to produce a regorafenib intermediate2, and finally, free hydration is performed in an alkaline acetone aqueous solution to obtain the regorafenib hydrate. The preparation method of the regorafenib hydrate is simple to operate and easy to monitor, has yield up to 90% or above and high efficiency and is applicable to mass industrial production. The prepared regorafenib hydrate has low impurity content, has no solvent residues basically, significantly shortens purification time, has stable properties, keeps stable in accelerated stability tests and has high safety.

The invention relates to the technical field of medicines, specifically discloses a medical composition of didemethyl tetrandrine dual ethyl formate (W18) and a tyrosine kinase inhibitor and the use of the medical composition for treating medicine-resisting liver cancer. Particularly, a medical composition of didemethyl tetrandrine dual ethyl formate (W18) and sorafenib or regorafenib has the effects of synergistically increasing sensitivity and reversing medicine resistance in the respect of treating drug tolerance liver cancer, and can significantly increase the treatment effects of treatingthe drug tolerance liver cancer.

The invention relates to a pharmaceutical composition for preventing and/or treating cancer and application thereof. The pharmaceutical composition takes regorafenib and wogonin as active ingredients,and the regorafenib and the wogonin exist in the form of eutectic. The compound disclosed by the invention has a good anti-cancer effect, particularly improves the solubility and bioavailability of an insoluble drug regorafenib for cocrystals of colon cancer, regorafenib and wogonin, and has a more remarkable anti-cancer effect compared with a physical mixture of the colon cancer, the regorafeniband wogonin.

The invention provides a novel crystal form of regorafenib. Characteristic peaks occur in the X-ray powder diffraction pattern of the crystal form when 2theta is about 9.25, 12.06, 12.88, 13.23, 14.68, 14.96, 15.76, 17.46, 18.44, 19.02, 21.47, 22.97, 24.69, 25.11, 25.83, 27.12, 27.41 and 29.66. The crystal form of regorafenib has good stability.

The invention relates to a preparation method of regorafenib. The method comprises the following steps: performing reaction on 3-fluoro-4-nitrophenol and 4-chloro-N-methyl pyridine-2-methylformamide under the effects of anhydrous potassium carbonate and PEG-400, and performing hydrazine reduction to generate an intermediate I; then performing one-pot reaction on the intermediate I, 3-trifluoromethyl-4-chlorophenylamine and dimethyl dithiocarboxylate under the effect of a catalyst, then performing post-treatment to obtain a regorafenib crude product, and further purifying the regorafenib crudeproduct to obtain a regorafenib purified product. The method disclosed by the invention has the advantages of high conversion ratio, security, no harm, no pollution, mild reaction conditions, high yield and high purity of the product; moreover, the method is suitable for industrial production.

The invention belongs to the technical field of preparation of antitumor drugs and particularly relates to application of regorafenib and lapatinib in the preparation of an antitumor combination drug. The combination drug of regorafenib and lapatinib is significant in causing tumor cell cycle arresting, thus arresting tumor cells in the stage G0/G1 and inhibiting the development of colon cancer; the ability to kill tumor cells can be effectively improved, and tumor cell apoptosis can be greatly promoted. The regorafenib and lapatinib are significant in synergistic action, effectively improving the curative effect, and has more significant effect than the single effect of a single component or double components, thus improving the ability to kill tumor cells; usage of the regorafenib and lapatinib is effectively reduced, thus reducing toxic or side effect. The combined use of the regorafenib and lapatinib can also save the cost and relieve the economic burden of a patient, a new way to control tumors is provided, and this drug has a promising application prospect in the field of medicine.

The invention discloses an application of combined use of regorafenib and a PD-1/PD-L1 inhibitor in preparation of a medicine for treating liver cancer. The pharmaceutical composition (regorafenib andthe PD-1/PD-L1 inhibitor) provided by the invention can generate a synergistic anti-liver cancer effect; according to the scheme of combined administration of the two, the sensitivity of liver cancercells to the regorafenib can be improved, the inhibition effect on the liver cancer cells is improved, the dosage of the regorafenib can be reduced, the treatment cost of each liver cancer patient isdirectly reduced, and more liver cancer patients are benefited; the pharmaceutical composition is low in price, high in safety and affirmative in curative effect; the pharmaceutical composition disclosed by the invention is convenient to produce, convenient for large-scale production, good in curative effect and low in cost, and is also beneficial to social public interests.