19 results about "Crizotinib" patented technology

The invention discloses a PROTAC compound targeting ALK protein and an anti-tumor application of the PROTAC compound. The structure of the compound is as shown in formula (I) or pharmaceutically acceptable salt thereof, X is an aliphatic chain with 2-7 carbon atoms, Y is NH, O or C = C, and Z is CH2 or C = O. The compound provided by the invention can effectively inhibit the growth of ALK positive tumors, can inhibit the proliferation of ALK drug-resistant mutation cell strains, and overcomes the drug resistance problem generated by crizotinib. The invention also discloses application of the compound or the pharmaceutically acceptable salt thereof in preparation of drugs for treating ALK positive tumors.

Disclosed herein are methods for identifying a subject as having NSCLC that is predicted or is likely to respond to treatment with an ALK inhibitor, for example crizotinib. The methods include identifying a sample including NSCLC tumor cells as ALK-positive or ALK-negative using immunohistochemistry (IHC) and scoring methods disclosed herein. A subject is identified as having NSCLC likely to respond to treatment with an ALK inhibitor if the sample is identified as ALK-positive and is identified as having NSCLC not likely to respond to treatment with an ALK inhibitor if the sample is identified as ALK-negative. According to certain embodiments of the methods, subjects predicted to respond to an ALK inhibitor may then be treated with an ALK inhibitor such as crizotinib.

The invention belongs to the field of biological medicines, and particularly relates to application of a compound to preparation of a medicine for treating papilloma of the upper respiratory tract. The invention provides an application of a compound in preparation of a medicine for treating and / or preventing papilloma of the upper respiratory tract, and is characterized in that the compound comprises one or more of asperisib, crizotinib, lapatinib, osimertinib and bortezomib. Experimental results show that the asperisib, crizotinib, lapatinib, osimertinib and bortezomib can realize long-term control on the papilloma of the upper respiratory tract and reduce the recurrence risk of the papilloma of the upper respiratory tract to a certain extent, so that the life quality of patients with the papilloma of the upper respiratory tract can be improved; the invention has important scientific value and clinical application prospect in the field of upper respiratory papilloma treatment.

The invention discloses an analysis and detection method for determining the content of a cesium element in a crizotinib starting material based on graphite furnace atomic absorption spectrometry without adding a matrix modifier. 2% nitric acid aqueous solution is used as a solvent, is economical, practical and environment-friendly, shortens experimental time and improves efficiency; a sample is dissolved, substrate interference is reduced, and the service life of an atomic absorption instrument is prolonged; the use of high-precision instruments is more efficient and environment-friendly; in the subsequent method development, the method can be used for reference for detection items with low limit and high concentration of a test solution.

Described herein are methods useful for the treatment of cancers in a canine subject with a pharmaceutical compositions comprising HDAC inhibitors, Rapamycin, Dasatinib, Lapatinib, Trametinib, Vorinostat, Imatinib, Crizotinib, Sorafenib, and combinations thereof. Also described herein are methods for identification of subjects with cancers that will benefit from administration of the pharmaceutical compositions comprising HIDAC inhibitors, Rapamycin, Dasatinib, Lapatinib, Trametinib, Vorinostat, Imatinib, Crizotinib, Sorafenib, and combinations thereof. In certain aspects, the methods described herein further comprise administering a therapeutically effective amount of at least one additional anti-cancer agent.

The invention belongs to the technical field of biological medicines, and particularly relates to application of crizotinib in induction of tolerant dendritic cells (tDCs). The invention provides an application of crizotinib in induction of tolerant dendritic cells. It is found that crizotinib can serve as an efficient inducer of tDCs, the activation state of DCs can be remarkably inhibited, the maturation function of DCs can be inhibited, the immune stimulation capacity of DCs can be reduced, then activation of T cells is inhibited, and therefore the crizotinib plays a role in treating immune diseases such as GVHD. In the invention, the inhibition of crizotinib on DCs comprises reduction of expression of maturation indexes CD80, CD40 and CD86. The crizotinib used in the invention is an ALK / ROS1 inhibitor approved by FDA and is mainly used for treating non-small cell lung cancer, the application of the crizotinib in immunotherapy is found, new use of old medicines is realized, and the crizotinib has great economic value.

The application discloses a kind of PROTAC molecules with crizotinib as target head, preparation method and application, belong to the field of biological medicine;Preparation method includes: chloro carboxylic acid, thionyl chloride and anhydrous DMF are mixed, after heating reflux reaction, remove thionyl chloride, obtain acyl chloride;Pomalidomide, acyl chloride, organic solvent are mixed and reacted, then filtered to obtain intermediate M;Intermediate M, crizotinib, Na2CO3 are mixed and reacted, then filtered to obtain the PROTAC molecule with crizotinib as target head.The in vitro biological evaluation shows that the new PROTAC molecule can efficiently and selectively induce ubiquitination and degradation of target protein, and exhibits significant antiproliferative activity in drug-resistant tumor cell models and animal models;The application proves that the PROTAC molecule has great potential in overcoming drug resistance of traditional inhibitors, and provides a promising lead compound for developing new therapies for treating refractory diseases such as cancer.

The invention discloses a method for determining crisaborole in plasma and application. The extracted sample is easy to store and relatively pure, the analysis speed is relatively high, and the method is suitable for large-scale clinical research sample analysis; in addition, the detection sensitivity is relatively high, the specificity is high, the sample pretreatment is relatively simple, the quantitative lower limit of the crisaborole is 0.30 ng / mL, and the determination requirement of the blood concentration is met; the method is good in accuracy, high in precision and good in reproducibility.

This invention belongs to the field of biomedical technology, specifically relating to the application of crizotinib in inducing tolerant dendritic cells (tDCs). This invention provides the application of crizotinib in inducing tolerant dendritic cells. This invention discovers that crizotinib can act as a highly effective inducer of tDCs, significantly inhibiting the activated state of DCs, suppressing their maturation function, reducing their immunostimulatory capacity, and thus inhibiting T cell activation, thereby exerting a therapeutic effect in immune diseases such as GVHD. The inhibitory effects of crizotinib on DCs in this invention include reducing the expression of maturation markers CD80, CD40, and CD86. The crizotinib used in this invention is an FDA-approved ALK / ROS1 inhibitor, primarily used for the treatment of non-small cell lung cancer. This invention discovers its application in immunotherapy, realizing the repurposing of an existing drug, and has significant economic value.

A method for preparing crisaborole through in-situ cyanation relates to the field of chemical synthesis, and adopts a cyano-free compound A and a cyano-free compound B as initial raw materials, and crisaborole is prepared through the reaction steps of nucleophilic coupling reaction, carbonyl protection, hydroxyl protection, borylation, deprotection, cyanation and the like. According to the preparation method, the traditional synthesis mode is changed, and the construction of cyano groups is finally carried out, so that the problem of side reaction caused by cyano groups in the borylation process is avoided. The preparation method is simple and convenient to operate, mild in reaction condition and relatively high in overall yield, avoids the use of a transition metal catalyst, is very suitable for being applied to medicine production, and has a relatively good application prospect.

The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of crizanlizumab, which comprises three steps: S1, preparing compound III; S2, preparing compound V; and S3, preparing crizanlizumab. The application not only solves the side reaction, atom waste and yield loss caused by the protecting group, and improves the atom economy and reaction selectivity, but also realizes high-selectivity C-H bond boronation, completely discards the noble metal palladium catalyst, and eliminates heavy metal pollution from the source, conforms to the development trend of green pharmacy, and further solves the bottleneck problems of high cost, high risk and long steps in the industrial production of crizanlizumab, and provides strong safety guarantee for industrial production.

The present invention discloses a drug for treating crizotinib-induced liver toxicity by targeting the SQLE gene or protein, belonging to the field of pharmaceutical technology. The drug reverses crizotinib-induced liver toxicity by downregulating the expression of the SQLE gene or the accumulation of SQLE protein. By downregulating SQLE, the present invention can effectively reverse crizotinib-induced apoptosis of hepatocytes, revealing that the SQLE gene is a key gene for crizotinib-induced liver injury and providing a new preventive and therapeutic target for intervening in crizotinib-induced hepatotoxicity. The present invention proposes that SQLE can be degraded through the autophagy pathway, providing a new direction for currently searching for intervention strategies for drug-induced hepatotoxicity and to a certain extent solving the current situation of few clinically available intervention drugs and single mechanisms. The intervention drug reverses crizotinib-induced liver toxicity by downregulating SQLE, expanding the clinical application value of crizotinib.

The application discloses a carbonyl reductase BsCR mutant, an engineering bacterium and application of the carbonyl reductase BsCR mutant in synthesis of a chiral intermediate of crizotinib. M2 The specific activity of the mutant is 87.7 times that of the wild-type BsCR, and the highest substrate feeding amount can reach 100 g / L 2,6-dichloro-3-fluoroacetophenone (CFA); the product concentration gradually increases with the prolongation of the reaction time; most of the substrate can be converted (the substrate conversion rate is 92.06%) within 6 h; the e.e. value of the product is always kept above 99.5%; and the space-time yield is 368.24 g / L / d.

The invention provides a preparation method of crizotinib, and belongs to the technical field of medicine synthesis. 5-bromo-2-nitropyridine-3-alcohol is adopted as a raw material to prepare an intermediate 4-(4-(5-hydroxy-6-nitropyridine-3-yl) 1H-pyrazol-1-yl) piperidine-1-carboxylic acid tert-butyl ester, namely a compound III, and then the compound III reacts with (S)-1-(2, 6-dichloro-3-fluorophenyl) ethanol to obtain a key intermediate (R)-4-[4-[6-nitro-5-[1-(2, 6-dichloro-3-fluorophenyl) ethyl]-4-[4-[6-nitro-5-[1-(2, 6-dichloro-3-fluorophenyl)-4-(4-(5-hydroxy-6-nitropyridine-3-yl) piperidine-1-carboxylic acid tert-butyl ester]. The preparation method comprises the following steps: carrying out catalytic reduction and deprotection reaction on a key intermediate to obtain a target product compound VII, namely crizotinib, by taking 2, 6-dichloro-3-fluorophenyl) ethyoxyl] pyridine-3-yl]-1H-pyrazol-1-yl] piperidine-1-carboxylic acid tert-butyl ester as a compound V, and carrying out catalytic reduction and deprotection reaction on the key intermediate. The crizotinib synthesis method provided by the invention is short in step, simple and easy to control, time cost and material cost are saved, and the crizotinib synthesis method has remarkable advantages and industrial practical value.

To provide a pharmaceutical composition for treating acute megakaryoblastic leukemia and primary myelofibrosis.SOLUTION: The present invention provides a pharmaceutical composition for treating a disease selected from acute megakaryoblastic leukemia and primary myelofibrosis, the pharmaceutical composition comprising an active ingredient selected from the group consisting of crizotinib, derivatives thereof, and pharmaceutically acceptable salts thereof.SELECTED DRAWING: Figure 1

The present invention discloses a human primary lung cancer cell line resistant to crizotinib, which is derived from a surgically resected sample of clinical lung adenocarcinoma. The human primary lung cancer cell line is named Lu-01-1443, and its preservation number is CCTCC NO: C2022166. The preservation date is August 25, 2022, and the preservation unit is the China Center for Type Culture Collection. Lu-01-1443 has an EML4-ALK fusion mutation, can be cultured in vitro in a medium, and has rapid and stable growth in vitro and can be continuously passaged, thus facilitating the establishment of an in vivo model of human lung cancer; it has good subcutaneous tumorigenicity in immunodeficient mice, providing an important guarantee for in vivo experiments of drugs, and thus providing a basis for the preparation, screening, and evaluation of anti-tumor drugs.

A near-infrared fluorescent probe, a preparation method therefor, and a use thereof. The preparation method comprises: mixing 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, an alkali, and a polar solvent, and adding crizotinib and a linker molecule for a reaction to obtain a product a; dropwise adding the product a to water to form a suspension, adding an organic solvent for extraction, drying an extract, then concentrating the extract, then adding trifluoroacetic acid, and after the reaction is complete, performing column chromatography to obtain an intermediate b; and adding 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate, an alkali, a dye molecule, and a polar solvent for a reaction to obtain a mixture c, and purifying the mixture c to obtain the near-infrared fluorescent probe. The provided probe can actively target a cellular mesenchymal-epithelial transition factor, can be quickly removed in normal tissues, and can be retained for a long time at a tumor site, thereby achieving the effect of in vivo diagnosis.

The invention belongs to the technical field of pharmaceutical analysis, and particularly relates to a method for separating and detecting a crizotinib starting material SM1a and impurities thereof. The impurities comprise any one or more of an impurity SM < 1a-b >, an impurity SM < 1a-c >, an impurity SM < 1a-e >, an impurity SM < 1a-f >, an impurity SM < 1a-g >, an impurity SM < 1a-h >, an impurity SM < 1a-i >, an impurity SM < 1a-j > and an impurity SM < 1a-k >. According to the method, high performance liquid chromatography is adopted for detection, specifically, water is used as a mobile phase A, and acetonitrile is used as a mobile phase B; octadecylsilane chemically bonded silica is adopted as a chromatographic column filler, and linear gradient elution is carried out; and then calculating the content of each impurity by adopting a limit method according to a chromatogram. The method has the characteristics of good separation degree, good durability, high sensitivity and good reproducibility.