26 results about "Vortioxetine" patented technology

The invention relates to the field of biological medicine, in particular to vortioxetine and application of pharmaceutically acceptable salts, solvates, crystal forms and prodrugs of vortioxetine to preparation of drugs for preventing or treating pathogenic fungal infection. The application reveals that the antidepressant vortioxetine (vortioxetine) and hydrobromide thereof (vortioxetine. HBr) which are sold on the market have measurable in-vitro inhibitory activity on various clinical common pathogenic fungi for the first time, so that the pharmacological action spectrum of the compound is expanded, and a new candidate direction is provided for research and development of antifungal drugs; the application not only overcomes the defects of existing antifungal drugs in the aspects of drug resistance, biological membranes and safety, but also opens up a brand new application direction of mental small molecule drugs in the anti-infection field, and has remarkable technical innovation, social value and industrial popularization prospect. The application also provides a theoretical basis for establishing a'multi-modal micromolecular antifungal library ', and can promote the development of pharmacological mechanism research and fungal infection precise treatment.

The invention belongs to the technical field of biological medicines, and particularly relates to a group of synergists for anti-tuberculosis infection medicines and application of the synergists. In the invention, Vortioxetine (Vor) shows obvious activity for enhancing mycobacterium infection resistance: under the concentration of 2 mu g / mL, the MIC (minimal inhibitory concentration) of Bedaquiline to H37Rv can be reduced by about 64 times (from 0.06 mu g / mL to 0.0009375 mu g / mL), and the MIC of Bedaquiline to an Rv0678 mutant strain can be reduced by about 64 times (from 1 mu g / mL to 0.0156 mu g / mL). And the content of sertraline hydrochloride (STL) can be reduced by about 16 times and 8 times respectively. The synergistic effect of fluoxetine (FXT) is weakest and is only reduced by two times. The synergist disclosed by the invention is a drug which has been sold on the market, so that the synergist has safety and complete medication guidance. The preparation process and the production process are both perfect, the product can be quickly sold on the market, the selling price is reasonable, the market acceptability is good, and the patient compliance is high. The votioxetine or the sertraline can be used as a synergist of a medicine for resisting mycobacterium tuberculosis infection.

The present invention discloses a method for preparing a vortioxetine metabolite, comprising the following steps: dissolving compound I (vortioxetine) in an organic solvent, adding a hydroxylamine compound, and reacting at 20-25° C. to obtain compound II. The preparation method has strong operability and reasonable process design, and can realize industrial production. In addition, the reagents used in the synthesis method are simple and easily available, and there are fewer by-products. The prepared vortioxetine metabolite has a purity of over 99%.

The invention discloses a synthesis method of hydrogen isotope labeled vortioxetine. The synthesis method comprises four steps of reaction: construction of diaryl sulfide, selective deuteration of methyl, selective reduction of cyano and coupling reaction of carbon-nitrogen bonds. According to the key step, deuterated dimethyl sulfoxide is used as a deuterium source under the catalysis of a methyl selective deuterated alkali metal catalyst, and methyl deuterated dimethyl sulfoxide and a methyl benzene intermediate are selectively subjected to a methyl deuterated reaction. The method effectively avoids the harsh condition of low temperature for introducing a deuterated methyl scheme after aryl halogenated hydrocarbon lithium halide exchange and deuterated iodomethane reaction, avoids the generation of dehalogenation byproducts, and overcomes the defects that the product is difficult to purify, the reaction is difficult to amplify and produce and the like. The key step of the invention adopts a specific alkali metal salt as a catalyst to carry out methyl deuteration reaction, and combines cyanobenzene to selectively reduce and construct another methyl, so the method has the remarkable advantages of low cost, environmental protection, simple process and suitability for industrial production.

Disclosed is a vortioxetine nitrosamine impurity SJ003-139, which is present in both the vortioxetine active pharmaceutical ingredient and pharmaceutical compositions. The content of the impurity increases during the preparation and storage of the vortioxetine active pharmaceutical ingredient and pharmaceutical compositions. Therefore, a pharmaceutical composition (I) with a low content of nitrosamine impurities, a preparation method therefor, and use thereof are disclosed in the present invention. The pharmaceutical composition of the present invention has the advantage that the content of nitrosamine impurities is low, ensuring the safety of medication in patients.

The invention provides a vothioxetine boron trifluoride complex impurity and a preparation method thereof, and the vothioxetine boron trifluoride complex impurity is obtained by separation and purification through liquid chromatography by taking an octadecyl bonded silica gel chromatographic column as a stationary phase and taking an acetonitrile-ammonium formate buffer solution as a mobile phase. The impurity provided by the invention is of great significance to quality control of a vothioxetine raw material medicine and a vothioxetine preparation.

The invention provides a preparation method of a hydrobromic acid vortioxetine intermediate based on continuous flow hydrogenation, and belongs to the technical field of chemical synthesis. The method provided by the invention comprises the following steps: introducing a reducing gas and a (2, 4-dimethylphenyl) (2-nitrophenyl) sulfane solution into a reaction column of a continuous flow hydrogenation reaction device, and carrying out a reduction reaction to obtain a hydrobromic acid vortioxetine intermediate; a reaction column of the continuous flow hydrogenation reaction device is filled with a nitro reduction catalyst. According to the method, nitryl of (2, 4-dimethylphenyl) (2-nitrophenyl) sulfanyl is reduced through continuous flow hydrogenation equipment, the hydrobromic acid intermediate 2-[(2, 4-dimethylphenyl) sulfanyl] aniline is obtained, the continuous flow equipment is adopted for reduction, the use amount of reducing gas can be reduced, and high safety is achieved; moreover, the product obtained by the method is high in yield and purity, the post-treatment steps are simple, and the method is more beneficial to industrial production.

The invention provides a suspension composition. The suspension composition is prepared from vothioxetine hemipamoate, a wetting agent, a suspending aid, a pH (Potential of Hydrogen) regulator and a solvent. The votioxetine semipamoate suspension composition and the preparation method thereof provided by the invention have the advantages of small burst release of drugs, slow and stable release in vivo, high safety, good resuspension property and the like, and can greatly improve the compliance of patients.

The invention belongs to the technical field of compound synthesis, and particularly discloses a synthesis method of 1-(2-bromophenyl)-4-(2-((2, 4-dimethylphenyl) sulfenyl) phenyl) piperazine. The synthesis method comprises the following steps: in an inert atmosphere, performing a coupling reaction on votioxetine and o-bromo iodobenzene in a system containing a cuprous catalyst, ethylene glycol, inorganic alkali and an alcohol solvent to obtain 1-(2-bromophenyl)-4-(2-((2, 4-dimethylphenyl) sulfenyl) phenyl) piperazine. According to the synthesis method provided by the invention, a cuprous substance is taken as a catalyst, ethylene glycol is taken as a specific ligand, inorganic base is taken as an acid-binding agent, and an alcohol solvent is taken as an organic solvent, so that the coupling reaction can be fully carried out on the vothioxetine and the o-bromoiodobenzene in a reaction system, and the yield of the 1-(2-bromophenyl)-4-(2-((2, 2-dibromophenyl)-4-(2-((2, 2-dibromophenyl)-2-bromophenyl)-2-(2, 2-dibromophenyl)-2 the purity and the yield of the (2, 4-dimethylphenyl) sulfenyl) phenyl) piperazine are improved.

The invention provides a novel crystal form of votioxetine pamoate, and in addition, the invention also relates to application of the crystal form of votioxetine pamoate in treatment and / or prevention of nervous system diseases. According to the crystal form of the vosulfur oxetine pamoate, the action time of vosulfur oxetine in vivo is greatly prolonged, the release rate of vosulfur oxetine is delayed, and the vosulfur oxetine pamoate is more stable in release and better in safety.

The application discloses a vortioxetine impurity, a preparation method and application thereof, and adopts vortioxetine or a pharmaceutically acceptable salt form thereof as raw material, the raw material is easy to obtain and simple to operate, and the reaction condition is mild. The synthesized impurity is characterized by nuclear magnetic resonance, high-resolution mass spectrometry and X-ray single crystal diffraction, and liver toxicity research shows that the compound disclosed by the application has important significance for researching adverse reactions of vortioxetine. The control sample obtained by the method provided by the application can be used for qualitative and quantitative analysis of the vortioxetine impurity, so that the drug safety of vortioxetine is improved.

The invention relates to a pharmaceutical composition. The pharmaceutical composition comprises two active ingredients: (1) votioxetine or a pharmaceutically acceptable salt thereof; and (2) olanzapine, the weight ratio of the vothioxetine or the pharmaceutically acceptable salt thereof to the olanzapine is (6-50): (3-6), preferably (9-50): 6, and the weight of the two active ingredients is calculated in a free form. The invention further relates to a pharmaceutical preparation prepared from the composition and application of the pharmaceutical composition and the pharmaceutical preparation in prevention and / or treatment of depression and other diseases, and the application comprises the step of applying an effective amount of the pharmaceutical composition or the pharmaceutical preparation to a patient in need. The pharmaceutical composition disclosed by the invention can be used for treating bipolar affective disorder, refractory depression and anxiety and improving cognition, and also has the advantages of small side effect and good patient compliance.

The present invention relates to a process for the synthesis of Vortioxetine (I) or a pharmaceutically acceptable salt thereof. This process is accomplished by using a catalytic system consisting of a copper salt and an organic ligand, which can promote the formation of both C—N and C—S bond in one-pot, giving rise to an efficient, simple and industrially viable synthetic route for Vortioxetine.

The present application provides a new crystal form of fluvoxetine pamoate, and the present application also relates to the use of the crystal form of fluvoxetine pamoate in treating and / or preventing nervous system diseases. The crystal form of fluvoxetine pamoate of the present application greatly prolongs the in-vivo action time of fluvoxetine, delays the release rate of fluvoxetine, and releases more smoothly and safely.

The invention discloses a vortioxetine nitrosamine impurity SJ003-139, the vortioxetine nitrosamine impurity SJ003-139 exists in a vortioxetine raw material medicine and a pharmaceutical composition, and the content of the impurity is increased in the preparation and storage processes of the vortioxetine raw material medicine and the pharmaceutical composition. Therefore, the invention discloses a pharmaceutical composition (I) with low content of nitrosamine impurities as well as a preparation method and application of the pharmaceutical composition. The pharmaceutical composition has the advantages that the content of nitrosamine impurities is low, and the medication safety of patients is guaranteed. SJ003-139

1. The name of the design product: medicine box (hydrobromic acid fluvoxamine tablet). 2. The use of the design product: used for the outer package of medicine. 3. The design points of the design product: lies in the pattern. 4. The picture or photo that best indicates the design points: front view.

The invention discloses a method for analyzing related substances of hydrobromic acid vortioxetine, and belongs to the technical field of medicine analys.The related substances are detected through high performance liquid chromatography, and octadecylsilane chemically bonded silica serves as a filling agent; 0.05% trifluoroacetic acid is used as a mobile phase A, and acetonitrile is used as a mobile phase B. The related substances of the hydrobromic acid potioxetine are well separated, the specificity is high, the precision of the method is good, and the durability is high. The established method is sensitive and rapid, the result is accurate and reliable, and the method can be used as a method for detecting the related substances of the hydrobromic acid vortioxetine.

The invention belongs to the technical field of biological medicine, and particularly relates to a hydrobromic acid potioxetine sustained-release microsphere, a preparation thereof, a preparation method and application thereof. Compared with the prior art, the preparation method provided by the invention has the advantages that the drug loading capacity can be improved, the drug encapsulation efficiency can be improved, and the dosage of auxiliary materials is obviously reduced.

The application discloses a method for preparing a vortioxetine drug precursor by a mechanical grinding method catalyzed C-S coupling reaction. The technical scheme is as follows: 2,2'-diamino diphenyl disulfide and 2,4-dimethyl bromobenzene are used as raw materials, a C-S coupling reaction is carried out by using a Ni catalysis and a trace liquid assisted mechanical grinding method under a normal temperature and a solvent-free condition to prepare 2,4-dimethyl phenyl-2-piperazine phenyl sulfide, and the coupling product is obtained in a green and safe manner. The C-S coupling reaction is carried out by using the mechanical force method to prepare the vortioxetine drug precursor, the operation and treatment are simple, the raw materials are green and safe, the method is environment-friendly, a metal Ni is used for catalysis, the reaction condition is mild, and the reaction can be completed in 99 minutes.

The application discloses application of a vortioxetine and gemcitabine composition in preparation of a drug for resisting pancreatic cancer, and the composition is composed of vortioxetine and gemcitabine. The composition of the application can reduce the expression amount of MAOB protein, promote the apoptosis of pancreatic cancer cells, and synergistically increase the sensitivity of pancreatic cancer cell lines in vitro and pancreatic cancer mice in vivo to gemcitabine, so that the chemotherapy effect of pancreatic cancer cells which are resistant to gemcitabine is significantly improved after treatment by the composition. The composition of the application provides a new chemotherapy drug for pancreatic cancer cells which are resistant to gemcitabine treatment.

The present disclosure relates to methods of transitioning patients or obese patients being treated with vortioxetine to treatment with a monoamine oxidase inhibitor (MAOI). The methods provided include delaying administration of the MAOI for certain time periods after stopping administration of vortioxetine. The patients or obese patients possess various capabilities of metabolizing vortioxetine. The current disclosure also includes methods of switching patients to a MAOI intended to treat psychiatric disorders while being treated with vortioxetine. The methods disclosed further comprise determining vortioxetine plasma clearance and washout time for patients with different body fat status and / or different CYP2D6 metabolizer status.

This invention provides a stable solid pharmaceutical composition comprising at least one of vortioxetine or a pharmaceutically acceptable salt thereof, an antioxidant, and / or a basic agent, optionally further comprising one or more pharmaceutically acceptable excipients. The pharmaceutical composition provided by this invention effectively inhibits the increase of nitrosamine impurities in solid dosage forms during storage, while also exhibiting advantages such as minimal impact on related substances, good product storage stability, and similar dissolution characteristics to the reference formulation. This invention also provides a method for preparing the solid dosage form, which is simple to operate and suitable for industrial application.

The present application relates to a kind of pharmaceutical composition comprising vortioxetine prodrug or its salt;Particularly related to a kind of solid dispersion comprising vortioxetine prodrug compound A or its pharmaceutically acceptable salt, and its preparation method and application.The solid dispersion comprises the compound shown in formula A, surfactant and water-soluble carrier material;The solid dispersion has improved solubility and dissolution rate, can significantly improve the brain blood ratio compared with the compound shown in formula A, improve the bioavailability of active ingredient, and has good stability,

The invention relates to the technical field of medicines, in particular to a vothioxetine ester pharmaceutical composition as well as a preparation method and application thereof. The pharmaceutical composition disclosed by the invention has the characteristic of high drug loading capacity, and the drug loading capacity is as high as 100 mg / mL to 400 mg / mL. The pharmaceutical composition disclosed by the invention has the characteristic of high stability, can be prepared by various methods, and is easy to realize industrial production. After intramuscular injection, about 50-1300mg of a drug reservoir can be formed at an injection site, slow and continuous release can be realized in the drug reservoir, the fluctuation of blood concentration is small, continuous and effective drug release as long as 2-24 weeks can be realized, frequent administration is reduced, and the pharmaceutical composition is used for treating adult depression and increasing the compliance of drug use.

The present invention relates to polymorph I of a compound (1) as shown below, its preparation method and application. The polymorph I of the compound (1) obtained in the present invention has good crystal form stability and chemical stability, and can be better used for clinical treatment, #imgabs0#

The present invention belongs to the field of pharmaceutical technology, and particularly relates to a long-acting prodrug derivative of vilazodone, its pharmaceutical composition and uses. The long-acting prodrug derivative of vilazodone includes a compound having the structure shown in formula (I). The long-acting prodrug derivative of vilazodone of the present invention is metabolized by enzymes in vivo to produce vilazodone, so that the fluctuation of the blood drug concentration of vilazodone is small, the effective blood drug concentration is maintained for a long time, the administration frequency can be reduced, and the compliance of patients and the therapeutic effect of diseases can be improved.