37 results about "Venetoclax" patented technology

The invention discloses a preparation method of a Venetoclax intermediate. 5-bromine-7-azaindole (II) is used as a raw material; an upper protecting group generates 5-bromine-1-(Triisopropyl silicyl)-1H-pyrrolo[2,3-b]pyridine (III); a compound (III) and Triisopropyl borate react and then are oxidized to obtain 1-(Triisopropyl silicyl)-1H-pyrrolo[2,3-b]pyridine-5-alcohol (IV); and a compounds (IV)and 2,4-difluoro methylbenzoate react to generate 2-(1H-pyrrolo[2,3-b]pyridine-5-yloxy)-4-methyl 2-fluorobenzoate (I). According to the preparation method, lithium bisamide is replaced with tertiary butanol sodium / potassium, thus the production cost is lowered, trimethyl borate is replaced with the Triisopropyl borate, equipment input is less in the synthesis process, and the operation flow is simplified; and most of all, reacting under the ultra-low temperature is not needed, the reaction temperature can be minus 20-minus 10 DEG C, general equipment can all meet the requirements, energy consumption is lowered, operation is convenient, and the preparation method is suitable for industrial production.

Aspects of the present application relate to solid forms of Venetoclax and preparative processes thereof. Specific aspects relate to an amorphous form of Venetoclax, its solid dispersion and crystalline forms of Venetoclax or salts thereof. Further aspects of the present application relate to processes for the preparation of Venetoclax.

The invention provides an application of C188-9, Venetoclax and Bumetanide in drugs for fibrotic diseases from perspective of clinic practice. A RNA recognition sequence (RNA recognition motif, RRM) region of LARP6 protein is taken as a docking target, and subject to computer virtual docking and simulated screening. Finally it is found by cellular and animal experiments that C188-9, Venetoclax andBumetanide (a potent quick-acting diuretic commonly used in clinic practice) combine with the RRM region of LARP6 protein to inhibit stability of collagen mRNA, thereby inhibiting collagen productionand further inhibiting fibrosis-related diseases in the process of occurrence and development of injury-induced fibrosis. The study of the invention enriches basic research on the pathogenesis of fibrosis-related diseases, and provides a new idea for deep exploration of essential causes of the fibrotic diseases. Meanwhile, the C188-9, Venetoclax and Bumetanide can be considered as a new potentialdrug for clinical treatment of the fibrotic diseases.

The invention relates to a united medicine composition for resisting double-hit lymphomas and application of the united medicine composition for resisting double-hit lymphomas. The united medicine composition comprises a medicine Venetoclax and a medicine Chiauranib. According to the united medicine composition disclosed by the invention, the medicine Venetoclax and the medicine Chiauranib are creatively united to be used as the united medicine composition for resisting double-hit lymphomas; the inventor finds that the united medicine composition for resisting double-hit lymphomas has significant killing effects on varied DHL cell strains, and presents concentration dependence and time dependence; the research result of in vitro tumor formation experiment also proves that the united medicine composition for resisting double-hit lymphomas can restrain the growth of DHL cells in vivo, alleviates tumor load and immersion degree, and does not have obvious toxic and side effects; and the united medicine composition for resisting double-hit lymphomas has higher activity for resisting double-hit lymphomas than single Venetoclax or single Chiauranib, and can more effectively restrain the growth of in vivo tumors, and a new strategy and thought are provided for the treatment of the resisting double-hit lymphomas.

The invention relates to a venetoclaxnanocrystal oral solid medicinal composition and a preparation method and application thereof. The inventor applies a nanotechnology to a venetoclax raw material to prepare a venetoclaxnanocrystal so as to prepare an oral solid preparation. Ultimately, a preparation technology of the venetoclaxnanocrystal is obtained and a venetoclaxnanocrystal raw material with high water solubility is obtained. The venetoclaxnanocrystal raw material is further prepared into an ordinary oral solid preparation. Tests prove that the dissolution behavior of the venetoclax oral solid preparation prepared by the technology is significantly improved, so that the bioavailability is also improved. The preparation technology is simple, the quality is controllable, and the preparation technology is suitable for industrial production.

The present invention relates to combinations of at least two components, component A and component B, component A being an inhibitor of PI3K kinase, and component B being venetoclax or palbociclib. Another aspect of the present invention relates to the use of such combinations as described herein for the preparation of a medicament for the treatment or prophylaxis of a disease, particurlarly for the treatment or prophylaxis of non-Hodgkin's lymphoma (hereinafter abbreviated to “NHL”), particularly 1st line, 2nd line, relapsed, refractory, indolent or aggressive non-Hodgkin's lymphoma (NHL), in particular follicular lymphoma (hereinafter abbreviated to “FL”), chronic lymphocytic leukaemia (hereinafter abbreviated to “CLL”), marginal zone lymphoma (hereinafter abbreviated to “MZL”), splenic marginal zone lymphoma (hereinafter abbreviated to “SMZL”), diffuse large B-cell lymphoma (hereinafter abbreviated to “DLBCL”), mantle cell lymphoma (MCL), transformed lymphoma (hereinafter abbreviated to “TL”), or peripheral T-cell lymphoma (hereinafter abbreviated to “PTCL”).

This invention relates to deuterated forms of venetoclax, and pharmaceutically acceptable salts thereof. Certain aspects of this invention also provide pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier. Certain aspects of the present invention also provide the use of such compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering an inhibitor of the anti-apoptotic activity of the B-cell lymphoma 2 (Bcl-2) protein.

The present disclosure provides anti-CD19 antibodies and venetoclax for use in the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and / or small lymphocytic lymphoma. The anti-CD19 antibodies, in particular MOR00208, and venetoclax are administered to patients suffering non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL) and / or small lymphocytic lymphoma (SLL) according to a specific treatment paradigm to mitigate therapy associated tumor lysis syndrome.

The invention belongs to the technical field of biological medicines, and relates to a pharmaceutical composition containing homoharringtonine (HHT) and an application of the pharmaceutical composition, in particular to the pharmaceutical composition containing the homoharringtonine and an application of the pharmaceutical composition to preparation of a medicine for treating leukemia. The invention particularly relates to an application of a pharmaceutical composition of HHT and a Bcl-2 inhibitor Venetoclax to treatment of AML or an application of the pharmaceutical composition of HHT and an FLT3 inhibitor (midostaurin, sorafenib, gilteritinib, crenolanib or quizartinib) to preparation of a medicine for treating AML of FLT3-ITD mutation. The molar ratio of the homoharringtonine to the venetoclax serving as the Bcl-2 inhibitor ranges from (1: 5) to (4: 1), and the molar ratio of the homoharringtonine to the FLT3-ITD ranges from (1: 5) to (5: 1). The components of the composition can be used at the same time or in any sequence.

Therapeutic combinations of immunoconjugates that bind to CD123 (e.g., IMGN632) with BCL-2 inhibitors (e.g., venetoclax), and / or a hypomethylating agent (e.g., azacitidine or decitabine) are provided. Methods of administering the combinations to treat hematological malignancies with clinical efficacy and / or decreased toxicity are also provided. Methods of treating hematological malignances present as minimal residual disease using immunoconjugates that bind to CD123 (e.g., IMGN632) are also provided.

The invention discloses a preparation method of a venetoclax key intermediate, belonging to the technical field of pharmaceutical synthesis. The method comprises the steps of enabling deprotonated 3,3'-dimethylcyclohexanone to react with dimethyl carbonate so as to obtain methyl 4,4-dimethyl-2-cyclohexanonecarboxylate; then, enabling the product to react with para chlorobromobenzene, inorganic base, aryl sulfonyl hydrazide and the like by using a one-pot method under the condition of palladium catalysis so as to obtain the product methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-ene-1-carboxylate. The preparation method provided by the invention is simple, convenient and stable in technological operation, high in yield and environmentally-friendly; compared with the existing process, themethod is low in price of raw materials and easy in obtaining of raw materials, greatly lowers the production cost of the existing venetoclax intermediate, and is beneficial to the industrial large-scale production.

An object of the present invention is to provide a new means for treating or ameliorating a blood cancer patient, wherein the new means has high effect and few side effects. The present invention relates to a combined medicine for use in a method for treating or ameliorating a blood cancer patient, comprising 4-amino-1-(2-cyano-2-deoxy-β-D-arabinofuranosyl)-2(1H)-pyrimidinone or a salt thereof and venetoclax or a salt thereof.

Methods and compositions for treating acute myeloid leukemia and diffuse large B-cell lymphoma using combinations of venetora and indolinone derivatives are provided.

Solid state forms of Venetoclax, pharmaceutical compositions thereof, and uses thereof are disclosed. Also disclosed are processes for the preparation of Venetoclax.

The present invention relates to the combination of the HDM2-p53 interaction inhibitor drug (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one [HDM201] and the BCL2 inhibitor 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(oxan-4yl)methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide [venetoclax]. The present invention further relates to the use of said combination in the treatment of cancer, in particular hematological tumors. The present invention further relates to dose and dosing regimen related to this combination cancer treatment.

The instant invention describes pharmaceutical compositions and dosing regimens comprising seviteronel and / or dexamethasone, and methods of treating diseases, disorders or symptoms thereof.

The invention discloses a preparation method of a venetoclax key intermediate, belonging to the technical field of pharmaceutical synthesis. The method comprises the steps of enabling deprotonated 3,3'-dimethylcyclohexanone to react with dimethyl carbonate so as to obtain methyl 4,4-dimethyl-2-cyclohexanonecarboxylate; then, enabling the product to react with para chlorobromobenzene, inorganic base, aryl sulfonyl hydrazide and the like by using a one-pot method under the condition of palladium catalysis so as to obtain the product methyl 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-ene-1-carboxylate. The preparation method provided by the invention is simple, convenient and stable in technological operation, high in yield and environmentally-friendly; compared with the existing process, themethod is low in price of raw materials and easy in obtaining of raw materials, greatly lowers the production cost of the existing venetoclax intermediate, and is beneficial to the industrial large-scale production.

Methods of treating cancer and prolonging survival of a subject having cancer, such as acute myeloid leukemia, via administration of therapeutically effective amounts of agents that depletes plasma glutamine and agents that inhibit BCL-2 activity are detailed herein. Suitable agents that depletes plasma glutamine include asparaginase Suitable agents that inhibit BCL-2 activity include Venetoclax.

A preparation method of venetoclax comprises the following steps: dissolving 2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]-4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl]methyl]piperazin-1-yl]benzoicacid and 4-fluoro-3-nitrobenzenesulfonamide / 4-chloro-3-nitrobenzenesulfonamide in a solvent, and performing a condensation reaction and separation to obtain 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-1-yl]methyl]piperazin-1-yl])-N-[(3-nitro-4-fluoro(or chloro)phenyl) sulfonyl)]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) benzamide; performing a substitution reaction on 4-(4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl-1-yl]methyl]piperazin-1-yl])-N-[(3-nitro-4-fluoro(or chloro)phenyl) sulfonyl)]-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy) benzamide and 4-(aminomethyl)tetrahydro-2H-pyran, and performing separation and refining to obtain venetoclax.

The invention relates to the technical field of medicine synthesis, in particular to a method for synthesizing a key intermediate of venetoclax. The method comprises the following steps: with 4-bromo-2-fluorobenzoic acid (I) as a raw material, carrying out esterification to obtain 4-bromo-2-fluorobenzoic acid tert-butyl ester (II); and subjecting 4-bromo-2-fluorobenzoic acid tert-butyl ester (II)to a substitution reaction with 5-hydroxy-7-azaindole (III) so as to obtain the intermediate of venetoclax, namely 4-bromo-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzoic acid tert-butyl ester (IV). Compared with a traditional Grignard reagent method, the method of the invention has the advantages that operation is simple, the rigorous conditions of no water and no oxygen are avoided, yield and purity are higher after the improvement, and the yield of a substitution reaction in the next step can be obviously improved.

The invention belongs to the technical field of medicines, and relates to a Venetoclax and dihydroartemisinin compound, pharmaceutically acceptable salts, hydrates and optical isomers thereof, a pharmaceutical composition taking the compound as an active component, and an application of the compound in preparation of medicines for treating cancers. The structure of the Venetoclax and dihydroartemisinin compound is as shown in a general formula I in the specification, wherein L is as described in the claims and the specification.

The present disclosure relates to methods of identifying AML patients who will be resistant to venetoclax therapy and methods of treating venetoclax-resistant patients with myeloid leukemia cell differentiation protein (MCL-1) inhibitors.

Therapeutic combinations of immunoconjugates that bind to CD123 (e.g., IMGN632) with BCL-2 inhibitors (e.g., venetoclax), and / or a hypomethylating agent (e.g., azacitidine or decitabine) are provided. Methods of administering the combinations to treat hematological malignancies with clinical efficacy and / or decreased toxicity are also provided. Methods of treating hematological malignances present as minimal residual disease using immunoconjugates that bind to CD123 (e.g., IMGN632) are also provided.

The present invention relates to the combination of the HDM2-p53 interaction inhibitor drug (S)-5-(5-Chloro-1-methyl-2-oxo-1,2-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-d]imidazol-4-one [HDM201] and the BCL2 inhibitor 4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(oxan-4yl)methyl]amino}phenyl)sulfonyl]-2-[(1H-pyrrolo[2,3-b]pyridin-5-yl)oxy]benzamide [venetoclax]. The present invention further relates to the use of said combination in the treament of cancer, in particular hematological tumors. The present invention further relates to dose and dosing regimen related to this combination cancer treatment.

The present invention relates to a process for the preparation of 4-(4-{[2-(4-chlorophenyl)-4,4dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b] pyridin-5-yloxy)benzamide) compound of formula-1 which is represented by the following structural formula:

The invention discloses a method for synthesizing Venetoclax key intermediates. The method includes steps of (1), carrying out coupling reaction on 5-bromine-7-azaindole and bisdiboron in solvents under the effects of organic palladium catalysts and alkali, and carrying out after-treatment after the reaction is completely carried out so as to obtain 7-azaindole-5-pinacol borate; (2), carrying out hydrolysis reaction on the 7-azaindole-5-pinacol borate obtained at the step (1) under the effect of sodium perborate, and carrying out after-treatment after the reaction is completely carried out so as to obtain the Venetoclax key intermediates. The method has the advantages that the method is easy to implement, highly toxic reagents can be omitted, and the HPLC (high-performance liquid chromatography) purity of the Venetoclax key intermediates which are products obtained by the aid of the method is higher than 99%.

The present invention relates to an anti-double hit lymphoma combined pharmaceutical composition and application thereof, the combined pharmaceutical composition comprises medicine Venetoclax and medicine Chiauranib. The present invention creatively uses the drug Venetoclax and the drug Chiauranib in combination as a combined pharmaceutical composition against double-hit lymphoma, and finds that it has a significant killing effect on a variety of DHL cell lines in a concentration- and time-dependent manner, and can form tumors in vivo The experimental results also proved that it can inhibit the growth of DHL cells in vivo, reduce the tumor burden and infiltration degree, and has no obvious toxic and side effects. Compared with single venetoclax or chiauranib, the combined pharmaceutical composition has stronger anti-double hit lymphoma activity, can more effectively inhibit the growth of tumors in vivo, and provides new strategies and ideas for the treatment of double hit lymphoma.

The present invention concerns novel methods of treatment for venetoclax-resistant acute myeloid leukemia, particularly in subjects with a low expression of TP53 protein or expression of TP53 protein associated with a mutation of the TP53 gene, the methods comprising administering to the subject in need thereof a therapeutically effective amount of a NTRK / ALK / ROS1 inhibitor, or a pharmaceutically acceptable salt thereof.