55 results about "Sacubitril" patented technology

The invention relates to the technical field of medicines, and particularly discloses a compound antihypertensive pharmaceutical composition. The pharmaceutical composition provided by the invention selects sacubitril valsartan sodium and indapamide as active ingredients, and within a prescription dosage range limited by the application, the two medicines can fully realize an antihypertensive effect through a synergistic effect, and the renal function of a patient is effectively improved. Through cooperation of the two components, the hypertension symptom of a patient can be effectively controlled, the adverse reaction is not obvious, and the compliance of the patient can be improved by adopting the compound preparation, so that the control on the blood pressure of the patient is enhanced.

The invention discloses a chemical enzyme cascade synthesis method of a sacubitril intermediate. An enzyme catalysis reaction is used as a core basic reaction, an intermediate compound VII # imgabs2 # is obtained from a compound V # imgabs0 # and a compound VI # imgabs1 # under the action of olefin reductase by using two schemes, and meanwhile, the synthesis method of the compound V and the compound VI is optimized. The method is short in route and high in efficiency, an intermediate with high chiral purity is efficiently obtained through enzyme catalysis, the process cost is reduced, and the purity of a finished product is improved. The whole process is low in experimental condition requirement, simple to operate, high in yield and suitable for process amplification.

The invention relates to the technical field of medicines, and particularly discloses sacubitril / valsartan sodium hydrochlorothiazide tablets and a preparation method of the sacubitril / valsartan sodium hydrochlorothiazide tablets. According to the application, the prescription dosage range of sacubitril valsartan sodium and hydrochlorothiazide is limited. Under the preferable proportion, the dissolution and disintegration characteristics of sacubitril sodium and hydrochlorothiazide can be balanced, the interference between the sacubitril sodium and hydrochlorothiazide is less, the whole sacubitril sodium and hydrochlorothiazide can be disintegrated and released at a relatively high speed, the sacubitril sodium and hydrochlorothiazide can be completely disintegrated within 5 minutes, the dissolution rate of 75% or above can be realized within 60 minutes, and the preparation method is simple and convenient. The traditional Chinese medicine has a good treatment effect on hypertension.

The invention discloses a composition containing sacubitril-valsartan sodium and fineglitazone and a preparation method thereof, and relates to the technical field of medicines, the composition is composed of sacubitril-valsartan sodium, fineglitazone, a flavoring agent, a taste masking agent, a liposome carrier, a blood vessel protective agent, a synergist, a filler, a disintegrating agent, a lubricant and an adhesive; according to the sacubitril-valsartan sodium tablet and the preparation method thereof, active ingredients of sacubitril sodium and fineglitazone are accurately proportioned, various auxiliary materials such as the flavoring agent, the taste masking agent and the liposome carrier are introduced, the curative effect of the medicine and the medication experience of a patient are greatly improved, sacubitril-valsartan sodium serving as a compound preparation has strong blood pressure lowering and cardiovascular protection effects, and the sacubitril-valsartan sodium tablet is suitable for clinical application. The composition can further improve the cardiovascular function, and the composition and the fipronil have a synergistic effect, so that the composition has excellent performance in the aspect of treating cardiovascular diseases.

The invention discloses a preparation method of a sacubitril intermediate, which comprises the following steps: adding a metal nickel salt and a chiral diphosphine ligand into a solvent in a nitrogen atmosphere at room temperature, and stirring to react for 0.5-6 hours to prepare a nickel catalyst solution; and under the nitrogen atmosphere, sequentially adding a compound (II), the prepared nickel catalyst solution, a solvent and an additive into a high-pressure kettle, reacting for 6-30 hours at the temperature of 20-100 DEG C and the hydrogen pressure of 1.0-6.0 MPa, after the reaction is finished, carrying out vacuum concentration to remove the solvent, and recrystallizing and purifying residues to obtain the sacubitril intermediate (I), the dr value of the sacubitril intermediate can reach 99 / 1, and the stereoselectivity can reach 99% ee. Compared with the prior art, the method provided by the invention has higher implementation value and social and economic benefits, and has the characteristics of high atom economy, small green pollution, easiness in industrialization and the like.

The application relates to application of a transaminase mutant in synthesis of a key chiral intermediate D-4,4'-diphenylalanine of sacubitril valsartan sodium salt (LCZ696), and belongs to the technical field of biocatalytic synthesis.The mutant is a quadruple mutant of the amino acid sequence shown in SEQ ID NO:1, the amino acid sequence of the transaminase mutant is shown in SEQ ID NO:3, and the corresponding amino acid sequence is shown in SEQ ID NO:4.Compared with a wild-type transaminase parent, the unit enzyme activity is increased by about 30 times under the condition of ensuring the chiral purity of a product, the transaminase has very high stereoselectivity and conversion rate, the industrial production cost of sacubitril and LCZ696 can be further reduced, and the transaminase has good industrial application value.

The invention belongs to the field of drug synthesis, and particularly relates to a method for preparing a sacubitril intermediate, which is characterized in that an intermediate compound 3 and an organic ammonium salt are used as raw materials and react in the presence of an iridium catalyst and a ligand to generate the sacubitril intermediate. According to the method, the yield and the chiral purity are high, the e.e value is as high as 99.7%, the reaction conditions are mild, and dangerous raw materials such as hydrogen and sodium borohydride are avoided.

The invention relates to a coated compound tablet, in particular to a quick-release composition, which comprises a first active layer, a second active layer and a coating layer, the first active layer comprises sacubitril valsartan or a salt thereof and a pharmaceutically acceptable additive, the second active layer comprises amlodipine or a salt thereof and a pharmaceutically acceptable additive, and the coating layer is coated on the first active layer. The coating layer contains a coating material that is mainly composed of a cellulose derivative, a polyvinyl alcohol, and an aqueous acrylic resin, and the immediate release composition is capable of achieving a desired elution.

The invention provides a preparation method of a sacubitril intermediate, relates to the technical field of medical chemical synthesis, and particularly relates to a method for synthesizing a key material of sacubitril by taking a compound 4 as a raw material and chiral substituted glycine as a chiral auxiliary agent through the steps of cyclization, deprotection, ring opening, amidation and the like. Aiming at the current situation that a chiral raw material 8 is difficult to obtain, a brand new route from a compound 1 to a compound 8 is designed, the route totally comprises seven steps of chemical reactions, the average yield of each step of chemical reaction is 84%, a target product is successfully obtained, and the chemical purity of the product is 99% or above. The problems that in an existing process route, the optical purity of products is not high, materials are expensive and not easy to obtain, dangerous chemical reactions are not suitable for amplified production, cryogenic reactions do not conform to green chemistry and the like are solved, detailed process optimization is carried out on key steps of the route, and the optimal process conditions of the reactions of all the steps are determined.

The invention provides a preparation method of a sacubitril valsartan key intermediate, which comprises the following steps of: reacting (R)-1-(1-([1, 1 '-biphenyl]-4-yl)-3-chloropropane-2-yl) pyrrolidine-2, 5-diketone and trialkyl phosphite under the action of a catalyst to generate a Witting-Horner reagent, then reacting with ethyl pyruvate under an alkaline condition to generate a double-bond product, and reacting with ethyl pyruvate under an alkaline condition to generate the sacubitril valsartan key intermediate. Hydrolyzing the double bond product to generate (R, E)-5-((1, 1 '-biphenyl)-4-yl)-4-amino-2-methyl-2-ethyl pentenoate; the preparation method comprises the following steps: firstly, taking 4-methyl-2-pentenoic acid as a raw material, then protecting the 4-methyl-2-pentenoic acid through BOC anhydride under the action of an acid-binding agent, and finally hydrolyzing under an alkaline condition to obtain (R, E)-5-([1, 1 '-biphenyl]-4-yl)-4-((t-butyloxycarboryl) amino)-2-methyl-2-pentenoic acid. The preparation method has the advantages of simple process steps, convenient operation, easily available raw materials, and easy industrial production.

A sacubitril intermediate, a preparation method therefor, and use thereof. A key intermediate N-Boc amino alcohol represented by formula (10) or formula (10-a) can be efficiently prepared. The intermediate can be used to prepare a neutral endopeptidase (NEP) inhibitor or a prodrug thereof, particularly a NEP inhibitor comprising a skeleton of γ-amino-δ-biphenyl-α-methylalkanoic acid or ester, such as sacubitril. Also provided are intermediates for preparing formula (10) or formula (10-a). Raw materials of the process route are cheap, the operation is simple and convenient, the production cost is low, and the method is suitable for industrial production

The invention discloses a pharmaceutical composition containing propranolol and a neutral endo-peptidase inhibitor, the pharmaceutical composition comprises propranolol and a neutral endo-peptidase inhibitor, and the propranolol and the neutral endo-peptidase inhibitor are combined and connected through a non-covalent bond. According to the invention, sacubitril and propranolol are combined into a dual-effect salt, so that the two active pharmaceutical ingredients are synchronously released, the drug effect is favorably improved, the synergistic effect is favorably generated in the treatment process, the side effect of propranolol is effectively reduced, and the clinical use values of sacubitril and propranolol are potentially improved; on the premise of ensuring the antihypertensive effect, the occurrence probability of side effects is effectively reduced, and the medication safety is improved.

The present disclosure relates to co-crystals of sacubitril (or a salt of sacubitril, in particular an alkaline earth metal salt or alkali metal salt) and melsartan (or a salt of melsartan, in particular an alkaline earth metal salt or alkali metal salt) and methods of preparation thereof, pharmaceutical compositions containing the co-crystals and uses of the co-crystals, in particular for the treatment of cardiovascular system diseases.

The present invention relates to methods and pharmaceutical compositions for treating heart failure in a pediatric human patient comprising administration to said patient of a therapeutically effective amount or a prophylactically effective amount of a combination of a therapeutic agent blocking the angiotensin receptor and a therapeutic agent inhibiting the NEP enzyme, in particular of a combination of sacubitril and valsartan in a pharmaceutically acceptable form and in a 1:1 molar ratio.

The invention relates to a detection method of sacubitril valsartan sodium related substances and a quality control standard of the sacubitril valsartan sodium related substances, and belongs to the technical field of pharmaceutical analysis. In order to accurately reflect the amount of related substances in sacubitril-valsartan sodium, a reasonable basis can be provided for formulating a quality standard, so that the product quality can be better controlled and mastered, and the safety and effectiveness of clinical medication are improved. The invention provides a method for detecting related substances in sacubitril valsartan sodium and a quality control standard of the related substances in sacubitril valsartan sodium. The detection method has high accuracy and precision and strong durability, and is suitable for industrial inspection and quality control of related substances in sacubitril valsartan sodium.

The present invention provides a method for preparing a sacubitril intermediate, which relates to the technical field of pharmaceutical chemical synthesis. Using compound 4 as a raw material and chiral substituted glycine as a chiral auxiliary, a method for synthesizing the key material of sacubitril is carried out through steps such as cyclization, deprotection, ring opening, and amidation. In view of the current situation that it is difficult to obtain the chiral raw material 8, the present invention designs a new route from compound 1 to compound 8. This route involves a total of 7 chemical reactions, and the average yield of each chemical reaction is 84%. The target product is successfully obtained, and the chemical purity of the product is over 99%. It solves the problems existing in the existing process route, such as low optical purity of the product, expensive and difficult-to-obtain materials, dangerous chemical reactions not suitable for scale-up production, and cryogenic reactions not meeting the requirements of green chemistry. And the key steps of this route are optimized in detail, and the optimal process conditions for each step of the reaction are determined.

The present invention belongs to the field of organic synthesis, particularly relates to the field of organic drug synthesis technology, and more specifically relates to a method for synthesizing a sacubitril drug intermediate. Using compound V and compound VI as raw materials, compound IV is obtained by reacting compound V and compound VI in the presence of a base and a phase transfer catalyst. Then, in the presence of a catalyst, compound IV is oxidized with an oxidant to obtain compound III. Finally, in the presence of a base, compound II and compound III are reacted at low temperature to obtain the target product compound I. This method not only has mild reaction conditions, high safety, and simple preparation process, but also has a high yield and high purity of the target compound, and is suitable for large-scale industrial production.

The application discloses a chiral ligand S , S p t A practical synthesis method of Bu-FOXAP is disclosed. By improving the synthesis process in the literature, the production operation is more simple. Compared with the column chromatography purification method used in each step in the literature, the new process does not need column chromatography purification, the product can be purified by beating or recrystallization, the purity of the final product can reach more than 97.0 %, the ee value is greater than 99.0 %, the d.r. value is greater than 20:1, the purification is simple and the cost is greatly reduced. The chiral ligand prepared by the new process can be used as a catalyst for asymmetric hydrogenation reaction after in-situ complexing with ruthenium metal, and can be used for catalytic synthesis of a key intermediate of a best-selling drug, sacubitril / valsartan.​

This invention provides a method for preparing a sacubitril intermediate, relating to the field of pharmaceutical synthesis technology. Using (2R)-4-nitro-2-methyl-butyrate ethyl ester and 4-bromomethylbiphenyl as initial raw materials, the method involves condensation reaction, hydrogenation reduction reaction, acidification, amino protection reaction with BOC anhydride, hydrolysis, salt formation and resolution reaction with R(+)-α-methylbenzylamine, and acidification to liberate the sacubitril intermediate. The preparation method provided by this invention is simple, easy to operate, has a high yield of the target product (36.5% overall yield in Example 1), high purity, low raw material cost, low production cost, and generates minimal waste, making it suitable for industrial production.

The present invention discloses a preparation method of sacubitril calcium. The preparation method comprises the following steps: adding compound 1 into a pre-prepared mixed solution for esterification and deprotection reactions; after the esterification and deprotection reactions are completed, concentrating under reduced pressure to dryness, adding a non-polar solvent and stirring to dissolve, then adding succinic anhydride and triethylamine for acylation reaction; after the acylation reaction ends, adding water for quenching, acid washing, and water washing in sequence, and standing to collect the organic layer; adding an aqueous solution of alkali metal weak acid salt to the obtained organic layer for sodium salt formation reaction, separating the organic layer, adding a co-crystallization solvent to the aqueous layer and then dropping an aqueous calcium chloride solution, and centrifuging, washing, and drying to obtain sacubitril calcium. The preparation method of the present invention can effectively avoid the generation of amide impurities and disodium salt impurities, effectively improve the difficulties of centrifugation and drying caused by the too fine crystallization of sacubitril calcium salt, and has the characteristics of simple process, low production cost, controllable quality, and suitability for industrial scale production.

The invention relates to a preparation method of sacubitril, which comprises the following steps: (1) reacting (S)-1-([1, 1 '-biphenyl]-4-yl)-3-chloropropane-2-ol with succinimide under the condition of triphenylphosphine and DEAD (Diethylaminoethyl Adenine) to obtain (R)-1-(1-([1, 1'-biphenyl]-4-yl)-3-chloropropane-2-yl) pyrrolidine-2, 5-diketone; (2) adding water and an alkaline reagent into the product in the step (1) to obtain (R)-4-(([1, 1 '-biphenyl]-4-yl)-3-hydroxypropyl-2-yl)-amino-4-oxobutyric acid; (3) carrying out oxidation and wittig reaction on the product obtained in the step (2) to prepare (4R)-5-[1, 1 '-biphenyl]-4-yl-4-[(3-carboxyl-1-oxopropyl) amino]-2-methyl-2-pentenoic acid-1-ethyl ester; (4) performing palladium-carbon catalytic reaction on the product obtained in the step (3) for alkali adjustment to prepare a sacubitril sodium salt aqueous solution; and (5) performing free extraction on the sacubitril sodium salt, concentrating, adding acetone and isopropanol to prepare a mixed solution, and reacting with valsartan and sodium hydroxide to prepare the sacubitril valsartan sodium. The method is simple and convenient to operate, can obtain the product with high purity and high yield, and is suitable for industrial production.

The invention discloses a detection method of sacubitril valsartan sodium tablet isomer impurities, and belongs to the technical field of pharmaceutical analysis. According to the method, sacubitril enantiomer and diastereoisomer impurities and valsartan optical isomer impurities in sacubitril and valsartan sodium tablets are detected by adopting HPLC (High Performance Liquid Chromatography), and under chromatographic conditions, a chromatographic column is a polysaccharide derivative reverse-phase coating type chiral chromatographic column, and the surface of silica gel is coated with cellulose-tri (4-methyl benzoate); a mobile phase is composed of a mobile phase A and a mobile phase B, the mobile phase A comprises water, acetonitrile and trifluoroacetic acid, and the volume ratio of the water to the acetonitrile to the trifluoroacetic acid is (790-810): (190-210): (0.9-1.1); a mobile phase B: methanol-acetonitrile, wherein the volume ratio of methanol to acetonitrile is (500-600): (500-400); a gradient elution mode is adopted. The method uses a reversed-phase system, is simple and convenient to operate, and can effectively realize separation and detection of sacubitril, valsartan and various isomer impurities, thereby realizing the purpose of controlling the quality of sacubitril and valsartan sodium tablets.

The invention discloses a preparation process of a sacubitril intermediate. The process comprises the following steps: using 4-halobiphenyl and (R)-epoxyhalopropane as raw materials, docking them, inserting an ester group, causing an Appel reaction to halogenate a hydroxyl group, and then performing ammonia treatment, inserting a Boc protecting group, and finally synthesizing the sacubitril intermediate. Compared with the existing method, the preparation method of the invention has simpler procedures, easier reactions, and reduced raw material costs.

The invention discloses a Sacubitril-based compound as well as a pharmaceutically acceptable salt, an ester, a solvate, a pharmaceutical composition and a preparation method of the Sacubitril-based compound and the pharmaceutically acceptable salt, the ester, the solvate, the pharmaceutical composition and the preparation method of the Sacubitril-based compound. The sacubitril-based compound is a monoester compound or a monoamide compound, which can be obtained by reacting sacubitril with panoxadiol or 1, 3-diaminoadamantane. The pharmaceutically acceptable salts, esters, solvates, and pharmaceutical compositions include a sacubitril-based compound. All the components can be used for treating cardiovascular diseases including heart failure and hyperlipidemia.

The present invention relates to a pharmaceutical compound formulation that contains sacubitril-valsartan and an SGLT-2 inhibitor as active ingredients, thereby having a synergistic effect in the treatment of heart failure, while minimizing the effects of drug dissolution between each drug to ensure bioequivalence, suppressing the generation of related substances, and exhibiting excellent stability of the active ingredients.

The invention provides a sacubitril and valsartan sodium tablet and a preparation process thereof. The sacubitril valsartan sodium tablet contains sacubitril valsartan sodium, hydrogenated palm oil, trehalose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and a film coating premix, wherein the raw material medicines are subjected to moisture-proof treatment by adopting a co-grinding technology. The preparation process is simple, no organic solvent is used, the requirement for environment humidity is lower, the temporary storage time limit of an intermediate product is longer, and industrialization is facilitated.

The application provides a saccubatr sodium spherical crystal and a preparation method thereof. The saccubatr sodium spherical crystal has excellent fluidity and filterability, and has no obvious solvent residue. The saccubatr sodium spherical crystal has uniform particle size distribution, is beneficial to improving product quality, is suitable for being made into various preparations, and has a simple and easy preparation process and is suitable for industrialized production.

This invention discloses a compound tablet containing sacubitril / valsartan and rosuvastatin calcium, and its preparation method, belonging to the field of pharmaceutical preparation technology. The technical solution comprises: an active ingredient and pharmaceutical excipients; the active ingredient includes sacubitril / valsartan sodium and rosuvastatin calcium; the pharmaceutical excipients include fillers, binders, disintegrants, stabilizers, glidants, lubricants, and a gastrointestinal film-coating premix; the tablets are prepared using a dry granulation process. This invention solves the problems of poor adherence to single-drug use, asynchronous dissolution, and insufficient stability, achieving a synergistic effect of lowering blood pressure and lipids. Furthermore, the preparation process is simple, efficient, and suitable for industrial production.

The application provides a refining method of a sacubitril valsartan sodium intermediate, and relates to the field of drug intermediate synthesis. The sacubitril valsartan sodium intermediate compound is (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methylvalerate ethyl ester hydrochloride. The application also relates to a control method of specific impurities in the refining process of the compound, which comprises the following steps: mixing the sacubitril valsartan sodium intermediate crude product with ethyl acetate or isopropyl acetate, then heating to a reflux state, keeping the reflux state for 1-2 hours, and then performing slow cooling, pressure filtration, vacuum drying and other process procedures to obtain the sacubitril valsartan sodium intermediate (2R, 4S)-4-amino-5-(diphenyl-4-yl)-2-methylvalerate ethyl ester hydrochloride. The sacubitril valsartan sodium intermediate obtained by the refining method has high purity, no solvent residue, mild reaction conditions and is easy to be industrialized.

The invention provides a method for detecting the content of stereoisomer impurities in sacubitril-valsartan sodium tablets by adopting a high performance liquid chromatography. Chromatographic conditions are as follows: Chiralcel OJ-RH, 150 * 4.6 mm, 5 [mu] m chromatographic columns and an ultraviolet detector are adopted, the detection wavelength is 254 nm, the column temperature is 35 DEG C, the flow rate is 0.75 ml / min, and the sample injection volume is 20 [mu] l. Gradient elution is adopted, and a mobile phase A is a mixed solution of water, acetonitrile and trifluoroacetic acid in a ratio of 800: 200: 1; and the mobile phase B is a mixed solution of acetonitrile and methanol in a ratio of 450: 550.