60 results about "Cabozantinib" patented technology

The invention relates to a preparation method for a tyrosine kinase inhibitor and a midbody thereof. According to the method, a compound 1,1-cyclopropane dicarboxylic acid diester is taken as a raw material, and 1-((4-((6,7-dimethoxy quinoline-4-yl) oxy) phenyl) carbamoyl) cyclopropane formic ether is prepared by two ways and reacts with p-fluoro aniline after being hydrolyzed so as to prepare Cabozantinib. The reaction conditions of the preparation method are mild, the synthesis cost is lowered, and the preparation method is simple and convenient to operate and is applicable to industrial production.

This invention relates to a dosage form of cabozantinib and a method of employing the dosage form to treat cancer.

The invention relates to a quinoline multi-target kinase inhibitor with antitumor activity and a preparation method thereof. A general structural formula of the compound is shown in a formula (I) described in the specification. In vitro cell experiments verify that the compound provided by the invention has strong in vitro inhibitory activity on five common tumor cell lines, namely human thyroid carcinoma SW579, human hepatic carcinoma HepG2, human lung adenocarcinoma A549, human colorectal adenocarcinoma HCT116 and human gastric carcinoma MKN45, antitumor activities of most of target compounds are better than or equivalent to that of a positive control drug Cabozantinib, and the in vitro cell experiments verify that the compound provided by the invention has strong inhibitory activity on two kinases KDR and MET, so that the compound provided by the invention has a broad application prospect in preparation of a new antitumor drug.

The invention relates to administration of various pharmaceutical formulations of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (cabozantinib) a c-Met inhibitor, and its metabolites, to achieve desirable pharmacokinetic and pharmacodynamic effects.

The invention relates to administration of various pharmaceutical formulations of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (cabozantinib) a c-Met inhibitor, and its metabolites, to achieve desirable pharmacokinetic and pharmacodynamic effects.

The invention discloses cabozantinib dispersible tablets and a preparation method and application thereof. The cabozantinib dispersible tablets consist of the following components in percent by weight: 10-60 percent of cabozantinib, 10-40 percent of filler, 10-50 percent of disintegrating agent, 10-50 percent of acidifying agent, 0.1-10 percent of adhesive and 0.1-20 percent of lubricating agent and flow aids. Compared with common tablets, the dispersible tablets have the advantages that the cabozantinib dispersible tablets do not contain surfactants, are high in solubleness, dispersing property and disintegration property and can be completely disintegrated within 1 minute. The cabozantinib dispersible tablets prepared by the method are high in dissolution degree, high in bioavailability, rapid in in-vivo distribution, stable in quality, good in taste, simple and feasible in preparation method and suitable for industrial production.

The invention belongs to the field of biological medicines, and discloses a composition for promoting hair cell regeneration and hearing recovery and an application thereof. The composition comprisesa Wnt agonist and one or more of the following reagents: (a) a VEGFR inhibitor; (b) a Tgfbr inhibitor; and (c) an ERG inhibitor. The VEGFR inhibitor comprises regorafenib, apatinib mesylate, cabozantinib, pazopanib hydrochloride and medicinal salts or derivatives of the regorafenib, the apatinib mesylate, the cabozantinib and the pazopanib hydrochloride. An organoid platform verifies that after any inhibitor in a signal axis of EGFR-TGFB1-ERG is combined with the Wnt agonist to prepare the composition, efficient hair cell differentiation, maturation and survival can be realized, and the composition has important value for hearing recovery.

The invention provides a synthetic method for cabozantinib. The method comprises the following steps: 1,1-cyclopropanedicarboxylic acid is used a starting raw material, acylation is performed, condensation is performed on an acylation product and 4-[6,7-dimethoxy-4-quinolinyl]oxy]aniline, condensation is further performed on an obtained product and 4-fluoroaniline under effects of a polypeptide condensing agent, and therefore the cabozantinib is obtained. According to the method, the reaction conditions are mild, a chlorinating reagent is used just in one step, and the method is suitable for industrialized production.

The present invention provides diagnostic methods, therapeutic methods, and compositions for the treatment of cancer (e.g., kidney cancer (e.g., renal cell carcinoma (RCC)), lung cancer (e.g., non-small cell lung cancer (NSCLC)), bladder cancer (e.g., urothelial bladder cancer (UBC)), liver cancer (e.g., hepatocellular carcinoma (HCC)), ovarian cancer, or breast cancer (e.g., triple-negative breast cancer (TNBC))). The invention is based, at least in part, on the discovery that expression levels of one or more biomarkers described herein in a sample from an individual having cancer can be used in methods of predicting the therapeutic efficacy of treatment with a VEGF antagonist (e.g., an anti-VEGF antibody, (e.g., bevacizumab) or a VEGFR inhibitor (e.g., a multi-targeted tyrosine kinase inhibitor (e.g., sunitinib, axitinib, pazopanib, or cabozantinib))) and a PD-L1 axis binding antagonist (e.g., a PD-L1 binding antagonist (e.g., anti-PD-L1 antibody, e.g., atezolizumab (MPDL3280A)) or a PD-1 binding antagonist (e.g., anti-PD-1 antibody)), or with an angiogenesis inhibitor (e.g., a VEGF antagonist (e.g., a VEGFR inhibitor, (e.g., a multi-targeted tyrosine kinase inhibitor (e.g., sunitinib, axitinib, pazopanib, or cabozantinib)))).

The invention relates to a preparation method of Cabozantinib, and belongs to the field of pharmaceutical chemistry. The Cabozantinib compound is prepared through two steps. The preparation method comprises following steps: 1, a compound III and a compound VI are subjected to condensation reaction to prepare a compound V; and 2, the compound V and p-fluoroaniline are subjected to condensation reaction to prepare Cabozantinib. The preparation method possesses following characteristics: operation is simple and convenient; reaction conditions are mild; yield is high; and industrial applications are convenient.

The invention relates to novel crystalline solid forms of the chemical compound N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (Compound 1), and solvates thereof, including hydrates, that are useful for the treatment of cancer. Also disclosed are pharmaceutical compositions comprising the crystalline solid forms and processes for making the crystalline solid forms, as well as methods of using them for the treatment of cancer, particularly thyroid cancer, prostate cancer, hepatocellular cancer, renal cancer, and non-small cell lung carcinoma. The crystalline solid forms can be used to make the L-malate salt of cabozantinib.

The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of Cabozantinib. The preparation method comprises following steps: 4-halogenated-6, 7-dimethoxyquinoline is reacted with 4-aminophenol to prepare a compound represented by formula III; cyclopropane-1, 1-dicarboxylic acid / ester and p-fluoroaniline are reacted to prepare a compound represented by formula V; and then condensation reaction is carried out to obtain the Cabozantinib compound. The preparation method is simple and convenient in operation, high in yield, low in cost, and promising in industrialization prospect.

The invention discloses a cabozantinib preparation method. The target product cabozantinib is prepared by performing five-step reaction on diethyl malonate, 4-fluoroaniline, 4-chloro-6,7-dimethoxyquinoline, 4-aminophenol, 1,2-dibromoethane and the like used as raw materials. The preparation method is simple to operate and friendly to environment; the comprehensive yield is more than 50% and is obviously increased in comparison with the yield of 20% in the prior art; and the preparation method greatly lowers the existing medicine production cost, and is suitable for industrial large-scale production.

Pharmaceutical compositions are provided, which comprise cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, wherein the inventive compositions exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations. The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof. The present invention relates to oral pharmaceutical compositions of cabozantinib, methods for their administration, processes for their production, and use of these compositions for treatment of diseases treatable by cabozantinib.

The invention provides a cabozantinib intermediate 4-hydroxy-6,7-dimethoxyquinoline and a preparation method thereof. According to the method, ortho-formate, isopropylidene malonate and 3,4-dimethoxyaniline used as raw materials are subjected to condensation and cyclization reaction to obtain the 4-hydroxy-6,7-dimethoxyquinoline. The chemical reaction conditions are milder; the yield for each reaction is up to 90% or so; and the total product yield is 71.3-79.3%. The method has the advantages of cheap and accessible raw materials, high safety, low toxicity, environment friendliness and simple preparation technique, and is suitable for industrial production.

The invention discloses a method for preparing an antitumor drug cabozantinib and belongs to the field of biological pharmacy. The method disclosed by the invention is realized through the following steps: taking 1,1-cyclopropanedicarboxylic acid and a chlorinating agent to react to generate 1,1-cyclopropyl diacyl chloride (an intermediate 1); and taking the 1,1-cyclopropyl diacyl chloride to react with 4-[(6,7-dimethoxy-4-quinolyl)oxyl]aniline and para-fluoroaniline in sequence to prepare the cabozantinib. Three-step reactions are carried out in the same reactor and an intermediate product does not need to be separated. Compared with the prior art, the method has the characteristics of few reaction steps, few byproducts, simplicity and convenience for operation, high yield and the like.

The invention relates to mucate of N-(4-{[6,7-bis(methoxy)quinoline-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dimethanamide and a crystal form thereof, and a preparation method thereof. The solubility of the mucate of a compound as shown in a formula (I) which is described in the specification is higher than the solubility of malate of the compound, which is of important significance to improvement of bioavailability, curative effect and security of the compound.

The invention relates to the technical field of organic synthesis and preparation of bulk drug intermediates, particularly a preparation method of 4-chloro-6,7-dimethoxyquinoline. The compound is used as an intermediate for preparing antineoplastic drugs cabozantinib and tivozanib. The method comprises the following steps: (1) nitrification: by using 3,4-dimethoxyacetophenone as a raw material, carrying out nitrification to obtain 2-nitro-4,5-dimethoxyacetophenone; (2) condensation: carrying out condensation on the 2-nitro-4,5-dimethoxyacetophenone and N,N-dimethylformamide dimethyl acetal to obtain 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino)propenyl-1-one; (3) reduction cyclization: carrying out hydrogenation reaction on the 1-(4,5-dimethoxy-2-nitrophenyl)-3-(dimethylamino)propenyl-1-oneto obtain 4-hydroxy-6,7-dimethoxyquinoline through reduction cyclization of the molecules; and (4) chlorination: carrying out chlorination on the 4-hydroxy-6,7-dimethoxyquinoline to obtain the 4-chloro-6,7-dimethoxyquinoline. The synthesis route has the advantages of accessible raw materials, mild reaction conditions, simple and convenient after-treatment and high yield, and is suitable for scale-up preparation.

Pharmaceutical compositions are provided, which comprise cabozantinib or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, wherein the inventive compositions exhibit enhanced bioavailability compared to the currently marketed or commercially available formulations. The present invention also provides manufacturing processes thereof and use of the said inventive compositions for the prevention, treatment or prophylaxis of disorders in human patients in need thereof. The present invention relates to oral pharmaceutical compositions of cabozantinib, methods for their administration, processes for their production, and use of these compositions for treatment of diseases treatable by cabozantinib.

The invention belongs to the technical field of catalytic materials, and in particular relates to a method for preparing an antitumor drug cabozantinib intermediate by solid base catalysis. Accordingto the method provided by the invention, Zr is used as a third metal element to modify Mg / Al bimetal, a Zr-doped Mg / Al composite metal hydroxide is prepared by a co-precipitation method, then ion exchange is carried out through potassium carbonate, high-temperature calcination is carried out, and finally reforming is carried out in water to finally prepare a Zr-doped Mg / Al composite metal oxide solid base with a three-dimensional structure. The solid base prepared by the method provided by the invention can replace sodium hydroxide to catalyze the preparation of 4-chloro-6,7-dimethoxyquinolinewhich is condensed with 4-aminophenol to prepare 4-(4-aminophenoxy)-6,7-dimethoxyquinoline, an antitumor drug cabozantinib intermediate. The catalytic system provided by the invention is green and pollution-free, avoids the generation of alkaline waste water and has a high yield and meets the requirements of green chemical industry.

The invention discloses an antitumor drug cabozantinib impurity, a preparation method and application thereof and belongs to the technical field of biological medicine. The structural formula of the anti-tumor drug cabozantinib impurity is shown in the specification. Meanwhile, the invention also provides a synthesis method of a compound. The method comprises the following synthesis steps: (1) dissolving cyclopropane-carboxylic acid and an acid-binding agent in a solvent, activating by a condensing agent, adding p-aminophenol, and carrying out a condensation reaction to obtain a compound c; and (2) dissolving the compound c in the solvent, adding alkali to form a salt with the compound c, adding a compound d, and carrying out a substitution reaction to obtain a target compound II.

The invention belongs to the technical field of pharmaceutical chemistry, and discloses a deuterated cabozantinib derivative, a preparation method and an application thereof, and an intermediate of the deuterated cabozantinib derivative. The deuterated cabozantinib derivative is a compound represented by formula I and may be a pharmaceutically acceptable salt, a crystalline hydrate, a solvate, a prodrug, or a monocrystalline of polymorphic substance. The decomposition speed of the deuterated cabozantinib derivative in vivo is slow, so that the poor metabolism of the medicine is reduced; the half life of the medicine is prolonged; the blood concentration of the medicine is increased; and a better therapeutic effect is achieved. Furthermore, the dosage of the medicine is decreased while keeping the therapeutic effect, and the toxic and side effect of the medicine is further reduced.

The invention discloses a high performance liquid chromatography analysis method for simultaneously determining cabozantinib analogues and related substances thereof, and the chromatographic conditions are as follows: a chromatographic column is an octadecyl silane bonded silica gel column, acetate buffer solution-acetonitrile (70: 30) is used as a mobile phase A, acetonitrile is used as a mobile phase B, gradient elution is performed, the concentration of the acetate buffer solution is 0.005-0.01 mol / L, the pH value is 8.5-9.5, the column temperature is 25-35 DEG C, the flow velocity is 0.9-1.1 ml / min, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, the column temperature is 25-35 DEG C, and the column temperature is the detection wavelength is 254 nm, the temperature of a sample injector is 2-20 DEG C, and the sample injection amount is 10 microliters. The determination method provided by the invention can rapidly and accurately detect the cabozantinib analogue and the related substances thereof, is simple to operate, good in reproducibility and high in sensitivity, can better control the quality of a cabozantinib analogue bulk drug product, and provides a guarantee for optimization of a synthesis process.

The invention relates to a preparation method of cabozantinib. The method comprises the following steps: taking 5,6-dimethoxy-4-hydroxyquinoline, TsCl, fluoronitrobenzene, and 1-(4-fluorophenyl)amino-carbonyl cyclopropane carboxylic acid as raw materials, and performing steps of a hydroxy protection reaction, a coupling reaction, a reduction reaction, and a condensation reaction to obtain the cabozantinib. The preparation method of cabozantinib has the advantages of high yield, low cost, less three wastes, easy operation, and safety, and is suitable for industrialization.

This invention relates to a liquid pharmaceutical composition comprising cabozantinib to treat locally advanced or metastatic solid tumors, particularly advanced urothelial cancer or renal cell carcinoma in patients in need thereof.

The invention relates to a preparation method of cabozantinib. The method includes: taking 4-chloro-6, 7-dimethoxyquinoline (I) as the starting raw material, and conducting substitution and condensation to obtain cabozantinib. Compared with other preparation methods, the preparation method provided by the invention has the advantages of cheap and easily available raw materials, mild reaction conditions, high total yield and high product purity, at the same time avoids high temperature production, reduces risk, simplifies operation, and is more beneficial to industrial production.