20 results about "Cabozantinib" patented technology

Disclosed herein are novel polymorphs of Cabozantinib salts and to the process for preparation thereof.

The present invention relates to oral compositions comprising cabozantinib salts and at least one pharmaceutically acceptable excipient and methods of using the oral compositions to increase the oral bioavailability of the cabozantinib and reduce the adverse events associate with the oral administration of cabozantinib. The invention also relates to methods for preparing cabozantinib lauryl sulfate salts.

The present invention provides a pharmaceutical composition that can suppress the crystallization of amorphous active ingredients, improve storage stability, and suppress the formation of related substances. [Solution] A pharmaceutical composition is prepared by combining an amorphous active ingredient with a pharmaceutically acceptable carrier and a pharmaceutically acceptable acidic additive. The carrier comprises at least one water-insoluble polymer selected from the group consisting of (meth)acrylic polymers and cellulose derivatives. The active ingredient may be cabozantinib or a pharmaceutically acceptable salt thereof. The (meth)acrylic polymer may include a (meth)acrylic polymer having aminoalkyl methacrylate units. The cellulose derivative may include cellulose carboxyalkyl alkyl ethers (in particular carboxymethyl ethyl cellulose). The acidic additive may include an organic acid.

Amorphous solid dispersions of the protein kinase inhibitor cabozantinib. The amorphous solid dispersions exhibit chemical and physical stability under stressed conditions. The amorphous solid dispersions may be suitable for use in pharmaceutical compositions for administration to human subjects or patients.

The invention belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of a cabozantinib intermediate. The invention provides a novel preparation method of a cabozantinib intermediate 6.7-dimethoxy-4-(4-nitrophenoxy) quinoline, which comprises the following steps: by taking 6.7-dimethoxyquinoline-4-alcohol as a starting material, carrying out hydroxyl protection on the 6.7-dimethoxyquinoline-4-alcohol and tert-butyldimethylsilyl chloride, and then reacting with p-fluoronitrobenzene to obtain 6.7-dimethoxy-4-(4-nitrophenoxy) quinoline; the method avoids the problems of serious environmental pollution and strong corrosion to equipment due to the use of highly toxic reagents such as phosphorus oxychloride, sulfonyl chloride and oxalyl chloride in the traditional hydroxyl chlorination, and is suitable for large-scale process production.

The present invention relates to oral compositions comprising cabozantinib salts and at least one pharmaceutically acceptable excipient and methods of using the oral compositions to increase the oral bioavailability of the cabozantinib and reduce the adverse events associated with the oral administration of cabozantinib. The invention also relates to methods for preparing cabozantinib lauryl sulfate salts. The present invention further relates to polymorphic forms of cabozantinib lauryl sulfate salts, methods for preparing the polymorphic forms and uses thereof.

The invention belongs to the technical field of medicine synthesis, and particularly relates to a method for synthesizing a cabozantinib intermediate. According to the method, 6, 7-dimethoxyquinoline-4-alcohol is taken as a starting material and reacts with tert-butyl 4-hydroxyphenylcarbamate, then deprotection is carried out, and 6, 7-dimethoxy-4-(4-nitrophenoxy) quinoline is obtained, so that the method avoids the problems that reagents such as highly toxic phosphorus oxychloride, sulfonyl chloride and oxalyl chloride are used during traditional hydroxyl chlorination, the environment is seriously polluted, the cost is low, and the like. And the method is suitable for large-scale production.

The present invention refers to an amorphous form of cabozantinib sulphate monohydrate and a process for its preparation, a pharmaceutical composition comprising it, and its use for the the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy treatment of cancer.

The present invention refers to a novel crystalline polymorphic form of cabozantinib hemifumarate sesquihydrate designated as Form A, a novel crystalline polymorphic form of cabozantinib hemifumarate hemipentahydrate designated as Form B and a process for their preparation, a pharmaceutical composition comprising Form A or Form B, and their use for the the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy treatment of cancer.

The invention particularly relates to a cabozantinib and osimertinib co-loaded targeting liposome and application thereof in overcoming EGFR-TKI drug resistance, and belongs to the technical field of biological medicine. The co-drug-loaded targeting liposome disclosed by the invention is coated with osimertinib and cabozantinib at the same time, and a GE11 peptide targeting ligand is connected to a membrane material of the co-drug-loaded targeting liposome; wherein the mass ratio of osimertinib to cabozantinib is 1: (0.5-2), preferably 1: 1; the membrane material comprises hydrogenated soybean phosphatidylcholine, cholesterol and DSPE-PEG2000, and the mass ratio of the hydrogenated soybean phosphatidylcholine to the cholesterol to the DSPE-PEG2000 is (2.5-3.5): 1: 1. According to the co-drug-loading targeting liposome disclosed by the invention, a drug can be synergistically delivered to a tumor site through active targeting mediated by GE11 peptide, an EGFR main pathway and key drug-resistant bypasses such as MET are efficiently inhibited, and the co-drug-loading targeting liposome shows a remarkable synergistic interaction effect in the aspect of reversing acquired drug resistance of osimertinib.

The present invention refers to a crystalline form of cabozantinib hemi-(S)-malate designated as Form A and a process for its preparation, a pharmaceutical composition comprising it, and its use for the the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC) and for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy treatment of cancer.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a novel crystal form of cabozantinib-saccharin and a preparation method thereof. The cabozantinib-saccharin new crystal form provided by the invention contains basic units of one molecule of cabozantinib and one molecule of saccharin, so that the stability, solubility and the like are greatly improved, and the preparation method is simple to operate, good in reproducibility and suitable for industrial production.

The invention discloses a cabozantinib liver-targeting lipid nanoparticle injection as well as a preparation method and application thereof, and belongs to the technical field of pharmaceutical preparations. The cabozantinib injection is prepared from the following components in percentage by mass: 0.8 to 1.5 percent of cabozantinib, 2.5 to 4.0 percent of DSPE-PEG2000-galactose, 35.0 to 42.0 percent of dipalmitoyl phosphatidylcholine, 6.0 to 8.0 percent of sitosterol, 3.0 to 5.0 percent of composite freeze-drying protective additive and the balance of citric acid-sodium citrate buffer solution with the pH value of 4.0, and the composite freeze-drying protective additive is a mixture of hydroxypropyl-cyclodextrin and mannitol in a mass ratio of 2 to 1. The preparation provided by the invention reduces systemic toxicity, significantly improves the drug concentration of liver and tumor parts, has better tumor inhibition effect than clinical positive drug adriamycin, is suitable for treatment of liver cancer and hepatic metastatic tumor, and has a relatively high application prospect.

The invention discloses a synthesis method of cabozantinib, which comprises the following steps: reacting methoxyquinoline, 4-aminophenylboronic acid pinacol ester, boric acid B (OH) 3, a catalyst copper salt and a molecular sieve in a solvent to prepare 6, 7-dimethoxy-4-(4-aminophenoxy) quinoline, dissolving the 6, 7-dimethoxy-4-(4-aminophenoxy) quinoline in a tetrafluoroboric acid aqueous solution, and carrying out a reaction to obtain the cabozantinib. The preparation method comprises the following steps: adding a sodium nitrite aqueous solution under an ice-water bath condition to react to prepare a compound 4, putting the compound 4, 1, 1-dicyanocyclopropane and potassium phosphate into a mixed solvent of water and ethyl acetate, and reacting at 60-90 DEG C under the protection of oxygen-free gas to prepare a compound 5; and putting the compound 5, p-fluorobenzene diazonium tetrafluoroborate and potassium phosphate into a mixed solvent of ethyl acetate and water, and reacting at 60-90 DEG C under the protection of oxygen-free gas to prepare the target product cabozantinib. The method is mild in reaction condition, simple and convenient to operate, high in product yield, high in purity, low in production cost and suitable for industrial production of cabozantinib.

Amorphous solid dispersions of the protein kinase inhibitor cabozantinib. The amorphous solid dispersions exhibit chemical and physical stability under stressed conditions. The amorphous solid dispersions may be suitable for use in pharmaceutical compositions for administration to human subjects or patients.

The invention discloses a photoelectric synthesis method of a cabozantinib intermediate, which avoids using highly toxic chemicals and precious metals, and is low in cost and wide in application prospect. And the photoelectric condition is mild, the selectivity is high, and the photoelectric synergistic effect can accurately control the reaction process.

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a new crystal form of cabozantinib, a preparation method and application thereof. The new crystal form provided by the application is a cabozantinib-amino sulfonic acid-methanol co-crystal, wherein one molecule of cabozantinib, one molecule of amino sulfonic acid and one molecule of methanol form a basic unit of the crystal form, and great improvement is achieved in stability, solubility and the like, the preparation method is simple in operation, good in reproducibility and suitable for industrialized production.

The presented invention relates to a process for preparation of Cabozantinib, compound of formula (1), or Tivozanib, compound of formula (10) or a salr or a solvate thereof: Formula (1); Formula (10).

The present invention relates to oral compositions comprising cabozantinib salts and at least one pharmaceutically acceptable excipient and methods of using the oral compositions to increase the oral bioavailability of the cabozantinib and reduce the adverse events associate with the oral administration of cabozantinib. The invention also relates to methods for preparing cabozantinib lauryl sulfate salts.

The invention discloses a preparation method of an antitumor drug cabozantinib, which comprises the following steps: carrying out substitution reaction on a compound 2 and 4-chloro-6, 7-dimethoxyquinoline to prepare a compound 3, and carrying out fluorination reaction on the compound 3 to prepare a target product cabozantinib. The specific synthesis route is as follows: the synthesis method can effectively avoid the use of highly corrosive reagents, high temperature and other relatively harsh conditions, and is mild in reaction condition, easy to operate, high in yield and more suitable for industrial production.