72 results about "Pitavastatine" patented technology

The invention discloses a quinolinic compound showed in the formula A and pharmacy acceptable solvate, optical isomers or polymorphic substance and a reaction intermediate compound showed in the formula D; wherein, R1, R2 and R3 are respective and independent H, halogen or group showed in the formula H; wherein, the R is H, the halogen, alkyl of C1-C4 or alkoxide of C1-C4. The invention further discloses a preparation method thereof and application for preparing medicines for inhibiting HMG CoA reductase and treating hyperlipemia related diseases. Compared with the existing fuvastatin, rosuvastatin and pitavastatin in the prior art, the quinolinic compound of the invention can better inhibiting the activity of the HMG CoA reductase and can be used for treating hyperlipemia related diseases.

The invention relates to the field of medicinal preparations, and in particular relates to a novel pitavastatin calcium oral disintegrating tablet composition and a preparation method thereof. The composition is mainly formed by combining soluble auxiliary materials and insoluble auxiliary materials in a certain proportion. The pitavastatin calcium composition has the characteristic of being rapidly disintegrated in the oral cavity to release medicines so as to promote effects of absorption and utilization.

The invention relates to a preparation method of a cholesterol reduction drug, particularly relates to a preparation method of pitavastatin calcium as a crude drug of the cholesterol reduction drug, and aims at the problems that the pitavastatin calcium synthetic technology in the prior art is long in steps and complicated in operation, and uses strongly corrosive reagents which is environmentally unfriendly, causes serious corrosion to equipment, and may not facilitate industrial production. The invention provides the new preparation method of the pitavastatin calcium, the new preparation method is as follows: 3-bromomethyl-2-cyclopropyl-4-(4-fluorophenyl)quinoline is prepared from 2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinecarboxaldehyde by a one step reaction, and then reacts with an organophosphorus reagent to obtain pitavastatin calcium intermediate phosphorus ylide, on the basis of improving of the yield to 80%, the reaction steps are reduced, and the reaction difficulty is reduced, and hydroxylamine hydrochloride is selected as a deprotection reagent, so that the new preparation method is mild in reaction conditions, environmentally friendly, high in yield, and beneficial to industrial production.

The present invention relates to a medicine composition conlaining resulvatatine or pivatatine compound and vitamins B, in which the resulvatatine or pivatatine content is 1-40 mg and vitamins B content is 0.1-50 mg. Said invention also provides the application of said medicine composition in preparation of medicine for preventing and curing the diseases of atherosclerosis, angiocardiopathy and cerebrovascular disease.

The invention relates to a new method of biologically synthesizing (R)-3-hydroxylglutarate monoester and more particularly provides a method of preparing the (R)-3-hydroxylglutarate monoester from (S)-4-chloro-3-hydroxybutyrate through halogenohydrin dehalogenase recombinant bacteria and nitrilase recombinant bacteria, or double-enzyme co-expression recombinant bacteria, in a one-pot manner. The (R)-3-hydroxylglutarate monoester is a key intermediate of statin medicines such as fluvastatin, rosuvastatin, pitavastatin and the like. The method is mild in reaction conditions, is free of pollution and is simple in process route.

The invention relates to a preparation method of a pitavastatin calcium intermediate compound which has a chemical name of 2-cyclopropyl-3-hydroxymethyl-4-(4-fluorophenyl)-quinoline and is shown in Formula (I). The pitavastatin calcium intermediate compound is prepared by hydrolyzing and reducing an ester compound shown in Formula (II) under specific conditions.

The invention discloses miazine compounds as shown in a formula A which is disclosed in the specification and reaction intermediate compounds as shown in formulas B, C and D, wherein X is O or S, R is H,F,C1-C3 alkyl or C1-C3 alkoxy. The invention also discloses preparation methods of the intermediates and miazine compounds and an application of the miazine compounds in preparing medicaments for inhibiting HMG-CoA reductase and / or treating hyperlipidemia diseases. Compared with the pitavastatin, osuvastatin and atorvastatin in the prior art, the 6-isopropyl-2-(N-methyl-N-sulfonyl) amino-4-substituted phenoxy (or thiphenyl) miazine compounds have better or at least comparative activity for inhibiting the HMG-CoA reductase, and can be used for treating the hyperlipidemia diseases.

The invention discloses a synthesis method of pitavastatin tert-butyl ester, which comprises the following steps: carrying out a reaction on (4R-Cis)-6-chloromethyl-2,2-dimethyl-1,3-dioxolane-4-tert-butyl acetate with a substance A under the action of a first base catalyst to obtain a substance B; oxidizing the substance B with an oxidizing agent to obtain a substance C; carrying out a reaction with 2-Cyclopropyl-4-(4-fluorophenyl)-quinoline-3-formaldehyde under the action of a second base catalyst to obtain a substance D; and finally, performing acid deprotection to obtain the pitavastatin tert-butyl ester. The method has the advantages of mild and controllable reaction conditions, wherein the reaction conditions of Julia olefination are free of requirement of ultralow-temperature reaction, so that the synthesis method has advantages of convenience and simplicity in operation, good stereoselectivity and high yield, and the synthesized pitavastatin tert-butyl ester is completely free of cis-isomer and high in purity.

The invention relates to the field of medicine quality detection, in particular to a method for detecting potential mutagenic impurities in pitavastatin calcium tablets. The method comprises the following steps: dissolving a to-be-detected sample by adopting a solvent, and detecting by adopting a high performance liquid chromatography under the chromatographic conditions that a mobile phase comprises an organic acid salt buffer solution and acetonitrile; the flow rate is 1.0 mL / min; the column temperature is 25-40 DEG C; a chromatographic column: octadecylsilane chemically bonded silica is used as a filler; the sample injection volume is 50 [mu] L; the detection wavelength ranges from 270 nm to 280 nm; an elution mode is gradient elution; the potential mutagenic impurities are an impurity1 and an impurity 2. According to the method disclosed by the invention, the pitavastatin calcium, the impurity 1 and the impurity 2 can be effectively separated; meanwhile, interference of other related impurities of pitavastatin calcium on detection of the impurity 1 and the impurity 2 is avoided, the content of potential mutagenic impurities 1 and 2 of the pitavastatin calcium tablets can be accurately detected, the quality of the pitavastatin calcium tablets is effectively monitored, and the medication safety is improved.

The present invention provides a pharmaceutical product which includes a solid preparation comprising pitavastatin or a salt thereof, in which production of a lactone form thereof is suppressed.The pharmaceutical product is characterized by including a solid preparation comprising the following ingredients (A) and (B): (A) pitavastatin or a salt thereof; and (B) at least one member selected from the group consisting of carmellose and a salt thereof, crospovidone, and microcrystalline cellulose, and the solid preparation having a water content of 2.9 mass % or less, wherein the solid preparation is stored in a tight package.

The invention relates to a method for synthesizing a pitavastatin calcium intermediate in a microchannel reactor. Fluorobenzene and phthalic anhydride are used as raw materials, a target product 2-(4-fluoro-benzoyl)-benzoic acid is synthesized through the microchannel reactor, and in the reaction process, and a carbonate compound is used for replacing aluminum trichloride in the prior art to serve as a catalyst, so the catalyst treatment before industrial production is avoided, meanwhile, a large amount of aluminum-containing wastewater is not generated in the reaction process, the method is green and environment-friendly, the reaction condition is mild, the reaction time is short, the product yield is high and reaches 92% or above, the purity is high and reaches 99% or above, the product post-treatment is simple, the cost is reduced, and the method is suitable for industrial production.

The invention discloses an alpha-glycosidase inhibitor and hydroxymethyl glutaryl coenzyme A reductase inhibitor composition for treating diabetes and complications. The medicinal composition consists of an alpha-glycosidase inhibitor or a pharmaceutically acceptable salt thereof, a hydroxymethyl glutaryl coenzyme A reductase inhibitor or a pharmaceutically acceptable salt thereof and a medicinal carrier or an excipient, wherein the alpha-glycosidase inhibitor is acarbose, voglibose or miglitol; and the hydroxymethyl glutaryl coenzyme A reductase inhibitor is simvastatin, lovastatin, fluvastatin, pravastatin, pitavastatin, rosuvastatin, atorvastatin, cerivastatin, mevastatin or rosuvastatin. The invention also relates to application of the medicinal composition in treatment of diabetes and prevention and treatment of diabetic complications such as diabetic nephropathy, diabetic hypertension, hyperlipidemia and dyslipidemia.

The invention discloses a pitavastatin calcium lipid solid preparation and a preparation method thereof. The preparation method comprises the following steps: preparing pitavastatin calcium lipid with excellent quality from pitavastatin calcium, DPPC (dipalmitoyl phosphatidylcholine), stearamide, octadecylamine and Tween 80 in a specific weight proportion; and preparing the pitavastatin calcium lipid into a solid preparation by a conventional preparation method. Compared with the existing preparation, the preparation disclosed by the invention has the advantages of greatly improved stability and bioavailability, enhanced quality, reduced toxic and side effects, smooth and stable drug release, and remarkable curative effect.

The present invention provides a therapeutic agent for hyperlipidemia having an excellent effect of lowering the cholesterol and triglyceride level in blood plasma.The present invention relates to a prophylactic and / or therapeutic agent for hyperlipidemia, a prophylactic and / or therapeutic agent for obesity or diabetes mellitus, and a prophylactic and / or therapeutic agent for metabolic syndrome, each agent including a compound represented by the formula (1), or a salt thereof, and a statin, particularly pitavastatin, in combination.

The invention discloses a pitavastatin calcium tablet which comprises a tablet core and a coating layer coated outside the tablet core, and the tablet core is prepared from the following components in parts by weight: 1-3 parts of pitavastatin calcium; 90 to 100 parts of a filling agent; 2-3 parts of a protection agent; the total amount of 15-20 parts of an internally added disintegrating agent and an externally added disintegrating agent; 150 to 200 parts of an adhesive; and 2-3 parts of a lubricant. The content uniformity of the tablet can be improved, the stability and the dissolution rate of the pitavastatin calcium tablet are effectively improved, and long-term storage is facilitated.

Statin compositions are disclosed for stimulating neurite growth from spiral ganglion neurons in the inner ear, as well as methods and kits for preventing damage to or treating damage of auditory neurons and / or hair cells of the cochlea following acoustic or toxic insult. An exemplary statin for these methods and kits includes Pitavastatin having the compound formula (VIII):

The invention discloses a method for synthesizing a pitavastatin calcium intermediate through a micro-channel reactor. The pitavastatin calcium intermediate is ethyl 7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolinyl]-3,5-dyhydroxyl-6-heptylate. The preparation method comprises the following steps: dissolving hydroxylamine hydrochloride into a mixed solution of water, alcohol and acetone; then, adding tert-butyl 6-[[(1E)-2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-vinyl]-2,2-dimethyl-1,3-dioxane-4-acetate, dissolving the added substance, filtering the obtained solution, feeding the solution toa micro-channel reactor preheating module, introducing the preheated reaction liquid into a reaction module, collecting the reaction liquid flowing out of a cooling module, and performing extraction and purification to obtain pitavastatin tert-butyl ester. The method provided by the invention has the advantages of small organic reagent dosage and high yield.

The invention relates to a preparation method of a pitavastatin calcium intermediate, which comprises the following steps: (1) under the protection of nitrogen, carrying out chemical reaction on compounds N7 and NBS and a solvent at 30-80 DEG C to prepare an intermediate product compound N8.1, and (2) adding triphenylphosphine into the reaction solution obtained in the step (1), heating to 60-120DEG C for reaction, cooling to 0-20 DEG C for stirring crystallization after the reaction is finished, and filtering to obtain a compound N8.2, wherein the specific synthetic route is as follows. Thepreparation method has the advantages of mild reaction conditions, no generation of a large amount of bromine-containing and phosphorus-containing wastewater in the reaction process, no influences ofacids and bases on the intermediate product compound N8.1, and difficult decomposition, so the yield of the target product is high and reaches 90% or above, the purity is high and reaches 99% or above, and the product has the advantages of simple post-treatment, greenness and environmental protection, and suitableness for industrial production.

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a preparation method of a pitavastatin calcium key intermediate. The method comprises a step of preparing an organic zinc reagent by using high-activity zinc and 2-cyclopropyl-4-(4-fluorophenyl)-3-quinoline methylene bromide. The organic zinc reagent generates a Witting reaction with (3R, 5S)-6-oxo-3,5-dihydroxyl-3,5-O-isopropylidene tert-butyl caproate to generate (3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolone-3-yl]-3,5-dihydroxyl-3,5- O-isopropylidene-6-tert-butyl heptenate which is recrystallized to obtain the pitavastatin calcium key intermediate. The synthesis method provided by the invention has the characteristics of high purity of E construction, simple process, high yield and the like.

The invention discloses an analysis method for quantitatively detecting nitrogen and oxygen impurities in pitavastatin calcium. The analysis method adopts a high performance liquid chromatography, and performs qualitative and quantitative analysis on the nitrogen and oxygen impurities in the pitavastatin calcium by screening the detection wavelength, the mobile phase pH, a buffer salt type, gradient elution conditions, the sample injector temperature, the column temperature and the sample injection amount, and methodological verification is carried out. According to the method, nitrogen and oxygen impurities in the pitavastatin calcium can be effectively separated, qualitatively and quantitatively detected, and the analysis method is high in specificity and sensitivity, has a good linear curve in a low concentration range, is not influenced by personnel and instruments, has high repeatability and accuracy, and is stable and reliable.

The invention provides a hypolipidemic medicament and a preparation method thereof. The hypolipidemic medicament comprises the following components in parts by mass: 2 parts of pitavastatin calcium, 2-2.4 parts of magnesium aluminum silicate, 0-0.5 part of montmorillonite, 90-100 parts of lactose, 16-20 parts of low-substituted hydroxypropyl cellulose, 1-3 parts of hydroxypropyl methylcellulose, 0.4-0.8 part of magnesium stearate, 0-1 part of copovidone S630 and 4-5 parts of a film coating premix (stomach-soluble type). According to the invention, montmorillonite and covidone S630 are added into auxiliary materials of pitavastatin calcium tablets, so that stability of the pitavastatin calcium tablets in a storage process is effectively improved, and medication safety is ensured. A simple mixing-tabletting-coating process is adopted, so that the defects of complex procedures and long time consumption caused by a conventional mixing mode of equal-amount progressive addition are avoided.The process is beneficial to improving production efficiency, and is convenient for commercial production.

The invention relates to a preparation method of pitavastatin calcium oxide impurities, which comprises the following steps: by taking pitavastatin ester as a raw material, reacting with an oxidizing agent in an organic solvent to obtain an oxide of the pitavastatin ester, reacting with an inorganic alkali aqueous solution, and further hydrolyzing to obtain a salt of the oxide. The method can be used for qualitative and quantitative detection of impurities, and is beneficial to quality control and medication safety of pitavastatin.

The invention provides a method for detecting pitavastatin calcium intermediates and impurities, which adopts high performance liquid chromatography to detect and analyze the pitavastatin calcium intermediates and impurities 1, 2, 3, 4 and 5, adopts octaalkylsilane bonded silica gel as a chromatographic column of a filling agent, adopts an ammonium acetate buffer solution as a mobile phase A, and adopts a mobile phase B to detect the pitavastatin calcium intermediates. Acetonitrile is used as a mobile phase B, and gradient elution is carried out. According to the method, known impurities can be accurately detected, the main peak of the intermediate and the peak of the known impurities can be effectively separated, and the method is a brand-new detection and analysis method beneficial to quality control of the pitavastatin calcium intermediate.

The present invention provides a pharmaceutical product which includes a solid preparation comprising pitavastatin or a salt thereof, in which production of a lactone form thereof is suppressed.The pharmaceutical product is characterized by including a solid preparation comprising the following ingredients (A) and (B): (A) pitavastatin or a salt thereof; and (B) at least one member selected from the group consisting of carmellose and a salt thereof, crospovidone, and microcrystalline cellulose, and the solid preparation having a water content of 2.9 mass % or less, wherein the solid preparation is stored in a tight package.

The invention discloses a refining method of pitavastatin tert-butyl ester, which comprises the following steps: cooling and crystallizing a mixed solvent in which pitavastatin tert-butyl ester raw materials are dissolved, filtering, and drying; wherein, the mixed solvent It is a mixture of methyl tert-butyl ether and non-polar organic solvent; the non-polar organic solvent is n-hexane, n-heptane, cyclohexane, n-pentane, cyclopentane, octane or isooctane. According to the refining method of the present invention, the isomer content in the obtained pitavastatin tert-butyl ester is low, and the refining effect is good. Epimer impurity 1, epimer impurity 2 and enantiomer impurity The contents are all below 0.05%. Moreover, the refining method of the present invention has high yield, low uncontrollability, simple operation, is suitable for large-scale industrial production, and can prepare high-purity pitavastatin calcium.

A solid oral pharmaceutical composition is disclosed, which comprises: a first active ingredient, which is pitavastatin or a pharmaceutically acceptable salt thereof; a second active ingredient, which is ezetimibe or a pharmaceutically acceptable salt thereof; and at least one excipient, including a diluent, a stabilizing agent, a disintegrant, a binding agent, a sweetener, a lubricant, a glidant, a flavor, a coloring agent or a combination thereof.