60 results about "Vorinostat" patented technology

The present invention relates to an improved process for the preparation of the active pharmaceutical ingredient, vorinostat. In particular it relates to an efficient process for the preparation of vorinostat of high purity without the requirement to isolate any synthetic intermediate compounds.

A pharmaceutical composition for induction therapy which has a hypomethylating agent and a histone deacetylase inhibitor (“HDAC inhibitor”); wherein the hypomethylating agent is a DNA and histone methylation inhibitor such as cladribine and the HDAC inhibitor is, for example, entinostat, panobinostat, vorinostat, and / or romedepsin; further wherein the hypomethylating agent and the HDAC inhibitor are combined in formulations for various administrations including e.g., a continuous delivery system such as a transdermal patch of at least one reservoir or a plurality of reservoirs, oral, a fixed-dose oral combination, intravenous, and combinations thereof. This pharmaceutical composition for induction therapy is used with a monoclonal antibody in the treatment of various cancers, sarcomas, and other malignancies.

Here, the inventors disclose the treatment of imatinib mesylate resistant chronic myelogenous leukemia cells with a cotreatment of vorinostat (SAHA, suberoylanilide hydroxamic acid) and dasatinib, a dual Abl / Src kinase (TK) inhibitor. Combined treatment of cultured human CML and BaF3 cells with vorinostat and dasatinib induced more apoptosis than either agent alone, as well as synergistically induced loss of clonogenic survival, which was associated with greater depletion of Bcr-Abl, p-CrkL and p-STAT5 levels. Co-treatment with dasatinib and vorinostat also attenuated the levels of Bcr-AblE255K and Bcr-AblT315I and induced apoptosis of BaF3 cells with ectopic expression of the mutant forms of Bcr-Abl. Finally, co-treatment of the primary CML cells with vorinostat and dasatinib induced more loss of cell viability and depleted Bcr-Abl or Bcr-AblT315I, p-STAT5 and p-CrkL levels than either agent alone.

The invention relates to a crystal form of vorinostat as an active pharmaceutical ingredient, a preparation method thereof and an application in a pharmaceutical composition.

The present invention relates to an improved process for the preparation of the active pharmaceutical ingredient vorinostat. In particular it relates to a process for preparing vorinostat substantially free from impurities, involving suberic acid, aniline and hydroxylamine as starting materials.

The invention discloses a novel c-Met / HDAC double-target inhibitor, and a synthetic method and an application thereof. The inhibitor provided by the invention has the following advantages: with a c-Met inhibitor namely Crizotinib and an HDAC inhibitor namely Vorinostat as precursor structures, a double-target inhibitor with a single structure is designed; the Crizotinib is used to remove the structure except a piperidine ring as a cap-like structure of the HDAC inhibitor to replace an aniline acyl group in a Vorinostat structure; a hydroxamic acid structure in the Vorinostat is retained as a chelating group of a metal zinc ion; linking groups with different structures are introduced between the Crizotinib and the Vorinostat; by utilization of the principle of pharmacophore combination, thedouble-target inhibitor with the single structure is designed; and the obtained double-target inhibitor has good inhibitory effect on c-Met and HDAC, and can synergistically inhibit c-Met and HDAC.

The invention provides an application of vorinostat to preparation of a lung cancer treatment drug. The drug is applied to treatment of non-small cell lung cancer, and can directly activate expression of MHCI-associated protein MICA on surfaces of tumor cells, improve killing abilities of NK cells for lung cancer cell strains and inhibit growth of tumor cells. Compared with the chemotherapeutic drugs extensively used in lung cancer treatment, the drug has small side effects; the drug is easy to quantify and standardize, safety, effectiveness, bioactive constituents and the like can be analyzed with conventional detection means, supervision is facilitated, high product cost caused by high detection cost is avoided, and good development prospect is realized.

Here, the inventors disclose the treatment of imatinib mesylate resistant chronic myelogenous leukemia cells with a cotreatment of vorinostat (SAHA, suberoylanilide hydroxamic acid) and dasatinib, a dual Abl / Src kinase (TK) inhibitor. Combined treatment of cultured human CML and BaF3 cells with vorinostat and dasatinib induced more apoptosis than either agent alone, as well as synergistically induced loss of clonogenic survival, which was associated with greater depletion of Bcr-Abl, p-CrkL and p-STAT5 levels. Co-treatment with dasatinib and vorinostat also attenuated the levels of Bcr-AblE255K and Bcr-AblT315I and induced apoptosis of BaF3 cells with ectopic expression of the mutant forms of Bcr-Abl. Finally, co-treatment of the primary CML cells with vorinostat and dasatinib induced more loss of cell viability and depleted Bcr-Abl or Bcr-AblT315I, p-STAT5 and p-CrkL levels than either agent alone.

The invention discloses a method for preparing anticarcinogen vorinostat. The method includes: (1) subjecting suberic anhydride and aniline to contact reaction in water and 1,4-dioxane at the temperature of 5-10 DEG C in the presence of CuI, performing filtering after reaction is finished, regulating the pH of filtrate to 5-6, performing suction filtration, washing filter cake obtained after suction filtration, and drying to obtain 7-phenylcarbamoylheptanoic acid; (2) dissolving the 7-phenylcarbamoylheptanoic acid in methanol, adding cation exchange resin and ZnCl2, heating to 50-55 DEG C for reaction for 3 hours, concentrating, extracting with ethyl acetate, concentrating, washing with petroleum ether, and drying to obtain suberanilic acid methyl ester; (3) subjecting hydroxylamine hydrochloride and sodium methoxide to stirring reaction in absolute methanol for 0.5-1h, filtering prior to adding the suberanilic acid methyl ester into filtrate for reaction at the temperature of 40 DEG C for 3-5 hours, cooling to room temperature, regulating the pH to 7, performing suction filtration, washing filter cake, and performing recrystallization with ethyl alcohol to obtain the vorinostat. The method is high in yield, quick in reaction and simple to operate.

The invention discloses a c-Met / HDAC double-target inhibitor as well as a synthesis method and application thereof. A c-Met inhibitor crizotinib and an HDAC inhibitor vorinostat are used as lead structures; a single-structure double-target inhibitor is designed, the structure of the crizotinib is used as a cap-shaped structure of an HDAC inhibitor, so that an aniline acyl group in a vorinostat structure is replaced, and a hydroximic acid structure in the vorinostat is reserved as a chelating group of metal zinc ions; the single-structure double-target inhibitor is designed by introducing linking groups with different structures between the two inhibitors and utilizing the principle of pharmacophore splicing. The obtained double-target inhibitor has a good inhibition effect on both c-Met and HDAC, and can synergistically inhibit c-Met and HDAC. The preparation method disclosed by the invention is simple, mild in condition and high in yield.

The invention discloses a c-Met / histone deacetylase (HDAC) double-target inhibitor based on a crizotinib structure, and a synthesis method and application of the double-target inhibitor. According tothe inhibitor disclosed by the invention, c-Met inhibitor crizotinib and HDAC inhibitor vorinostat are taken as a lead structure to design a double-target inhibitor with a single structure; the crizotinib structure is used as a hat-shaped structure of the HDAC inhibitor to replace aniline acyl in a vorinostat structure; a hydroximic acid structure in the vorinostat is retained as a chelating groupof metal zinc ions; connecting groups with different structures are introduced between the the crizotinib structure and the hydroximic acid structure; and the double-target inhibitor with a single structure is designed through the principle of pharmacophores combination, so that the obtained double-target inhibitor has good inhibition effects on c-Met and HDAC, and can be used for synergisticallyinhibiting the c-Met and HDAC.

The invention provides a vorinostat derivative based on lithium hydroxide, and a preparation method and application thereof. The vorinostat derivative based on lithium hydroxide uses vorinostat as a parent drug, and a water-soluble group is connected to the hydroxamic acid position of the mother nucleus of vorinostat to realize modification; thus, the water-solubility of the vorinostat parent drugis effectively improved, and the occurrence of adverse reactions can be effectively prevented. Meanwhile, the vorinostat derivative of the invention has good tumor inhibition effect and can be further used for preparing tumor-treating drugs. Furthermore, the invention also provides the preparation method for the lithium hydroxide-based vorinostat derivative. The preparation method has the advantages of few preparation procedures, simple operation, etc.

The invention discloses application of Vorinostat in preparation of soft-resistant Eimeria drugs; powder is formed by the Vorinostat and an acceptable auxiliary material, and then is added into a feed to mix uniformly so as to feed chicken by a daily feed amount; or a Vorinostat water-soluble powder is prepared by the Vorinostat, and is dissolved in water to feed chicken by a daily feed amount. Animal infection experiments confirm an anticoccidia index (ACI) of the Vorinostat is more than 175, and the Vorinostat has function of resisting soft-resistant Eimeria.