69 results about "Nebivolol" patented technology

The present invention relates to compositions and methods of treating human subjects with a beta-adrenergic receptor blocking agent (“beta-blocker”) provided in a time-sustained-release delivery system. The time-sustained-release drug delivery systems includes at least three populations of beads, where each population of beads includes a beta-blocker. The beads may be selected from immediate-release beads, enteric-release beads, sustained-release beads, and time-sustained-release beads. The beta-blocker may be selected from acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol, butoxamine, carteolol, carvedilol, labetalol, nadolol, oxprenolol, penbutolol, propranolol, pindolol, sotalol, and timolol. According to presently preferred embodiments, the beta-blocker is propranolol. The dosage forms of the present invention are useful for treating conditions including hypertension, angina pectoris due to coronary atherosclerosis, hypertrophic subaortic stenosis, congestive heart failure, arrhythmias, angina, anxiety, glaucoma, migraines, esophageal varices, alcohol withdrawal syndrome, irregular heartbeat, tachycardia, tremor, and neuroleptic-induced akathisia. They are also useful in the prophylaxis of migraine headaches.

The invention discloses a method for preparing a mixture of a RRRS nebivolol intermediate and a SSSR nebivolol intermediate respectively shown in formula II and formula III. The method is characterized by optionally adopting one of the following two manners: (1) adding a precipitation solvent to an alcohol solvent of the mixture containing RRRS, SSSR, RRSR and SSRS nebivolol intermediates as shown in formula I, heating, cooling to separate out crystal, and filtering; and (2) adding the mixture of the RRRS, SSSR, RRSR and SSRS nebivolol intermediates of the formula I to a mixed solvent of the alcohol solvent and the precipitation solvent, heating to dissolve, cooling to separate out crystal, and filtering, wherein, X is H, or C1-C6 alkyl or C1-C6 alkoxyl, and n is 1-5. The method has the advantages of simple and convenient operation, and high separation efficiency, and is available for industrialized production.

Hydroxylated nebivolol metabolites increase NO release in human endothelial cell preparations in a concentration-dependent manner after acute administration. In addition, hydroxylated nebivolol metabolites (including but not limited to 4-hydroxy-6,6'difluoro) have the ability to increase NO release in human endothelial cells after chronic administration. The present invention provides hydroxylated nebivolol metabolites for use in the treatment of cardiovascular diseases. Furthermore, the present invention provides methods of treating and/or preventing vascular diseases by administering at least one hydroxylated metabolite of nebivolol capable of releasing a therapeutically effective amount of nebivolol to targets affected by vascular diseases. Nitric oxide.

The invention discloses a method for preparing nebivolol racemate hydrochloride and belongs to the technical field of pharmaceutical synthesis. The method includes that a formula I compound and a formula II compound are used as raw materials to be subjected to an acyloin condensation to prepare a formula III compound, the formula III compound is subjected to an epimerization reaction to increase the ratio between III a and III b from 1:1 to 9:1, the formula III compound is subjected to a recrystallization purification to obtain a high purity III a, the III a is subjected to a carbonyl reduction to generate a formula IV compound, the formula IV compound is directly subjected to a catalytic hydrogenation to remove a benzyl protecting group to obtain a nebivolol racemate crude product, the nebivolol racemate crude product is directly salified by hydrogen chloride, and the recrystallization is performed to obtain the high purity nebivolol racemate hydrochloride. According to the method, the reaction is easy to control, the postprocessing is easy, and the production efficiency is high.

The present invention relates to a synthesis method and an intermediate compound of nebivolol. Specifically the invention relates to the method for synthesizing the nebivolol, the intermediate compound of the nebivolol, and a method for preparing the intermediate compound.

Nebivolol has been shown to be beneficial in the treatment of cardiovascular diseases such hypertension, congestive heart failure, arterial stiffness and endothelial dysfunction. The present invention features a pharmaceutical composition comprising nebivolol and at least one other active agent, wherein the at least one other active agent is a cardiovascular agent.

The invention discloses a synthetic method of nebivolol. The synthetic method comprises the following steps: by taking a 2-amino-1-(-6-fluoro-2-chromanyl) ethanol diastereomer mixture as an initial raw material, firstly, recrystallizing and separating the 2-amino-1-(-6-fluoro-2-chromanyl) ethanol diastereomer mixture to respectively obtain corresponding diastereomers A and B; carrying out reactions such as diazotization, halogenation and cyclization on the diastereomer B to synthesize an epoxy compound; and then, carrying out a reaction on the obtained epoxy compound and the diastereomer A to obtain nebivolol. The method disclosed by the invention is mild in reaction condition, simple and convenient to operate and short in synthetic line, and is suitable for industrialized batch production of nebivolol.

The invention discloses a Nebivolol HCL orally disintegrating tablet, which comprises the following components by weight: 3.7-7.5 percent of Nebivolol HCL, 75.0-85.0 percent of water-solubility bulking agent, 6.0-15.5 percent of disintegrant, 2.0-3.5 percent of disguising odor and 0.7-1.5 percent of lubricant.

The invention describes novel compositions comprising nebivolol and/or at least one metabolite of nebivolol and at least one nitric oxide donor, and, optionally, at least one antioxidant or a pharmaceutically acceptable salt thereof, and/or at least one compound used to treat cardiovascular diseases or a pharmaceutically acceptable salt thereof, and/or at least one nitrosated compound used to treat cardiovascular diseases. The compounds and compositions of the invention can also be bound to a matrix. The nitric oxide donor is a compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and may preferably be isosorbide dinitrate and/or isosorbide mononitrate. The antioxidant may preferably be a hydralazine compound or a pharmaceutically acceptable salt thereof. The invention also provides methods for treating and/or preventing vascular diseases characterized by nitric oxide insufficiency; and for treating and/or preventing Raynaud's syndrome; and for treating and/or preventing cardiovascular diseases or disorders.

The invention relates to an improvement method for preparing a nebivolol key intermediate, namely 6-fluorin-3,4-dihydro-2H-1-benzopyranyl-2-epoxy ethane. The method comprises the following steps of: (a) condensing a compound (IV) and dihalogenated methane in the presence of an organic metal lithium compound to obtain a compound (II); (b) reducing the compound (II) to obtain a compound (III); and (c) performing cyclization on the compound (III) under alkaline condition to obtain a compound (I). The scheme of the invention has the advantages of readily available raw materials, easiness in operating, greatly increased reaction yield and purity and high contribution to industrial mass production.

The invention relates to a method for preparing and purifying a nebivolol intermediate and in particular relates to an improved method for preparing and purifying 2-chloro-1-(6-fluro-3,4-dihydro-2H-1-benzopyran-2-yl) acetone shown in a formula (I) as shown in the specification. The 2-chloro-1-(6-fluro-3,4-dihydro-2H-1-benzopyran-2-yl) acetone compound is a key intermediate for synthesizing nebivolol. By adopting the method provided by the invention, a high-purity solid of the key intermediate is obtained with high yield (more than 85%) and high purity (more than 99%), operation is easy, and industrial production can be easily realized.

The invention relates to a method for preparing a nebivolol midbody, which belongs to the technical field of medicament synthesis, for solving the problems that the conventional raw material is high in cost, long in route and low in yield. The method comprises the following steps: enabling 6-fluorine chroman-2-formic acid as a raw material to react with chloro-carbonic ester with the presence of a deacid reagent, then adding diazomethane after the reaction is accomplished, so as to enable the midbody to react with the diazomethane to generate a reaction liquid of an intermediate product, and then adding a hydrogen halide gas or a hydrogen halide solution into the reaction liquid to perform halogenating reaction so as to obtain a compound of formula IV, namely, (6-(fluorine-3,4-dihydro-2H-benzopyran-2-methanol-2-yl) ethanone halogenate. The method provided by the invention has the advantages that the reaction route is short, the yield is high, and the used material is low in price and easy to purchase.

The present invention is directed to stable chemical compositions and dosage forms that comprise nebivolol and valsartan and which achieve therapeutically effective plasma levels of both actives in hypertensive patients following administration, as well as to methods of lowering blood pressure and treating hypertension using such compositions and dosage forms.

The present invention relates to a simple and commercially viable process for separation of desired isomers of nebivolol intermediates from a mixture containing undesired isomers of nebivolol intermediates. Thus, (+)-[2R*[1S*,5S*(S*)]]+[2R*[1S*,5R*(R*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] is dissolved in diisopropyl ether at reflux temperature and cooled to below about 30° C. to obtain the desired (+)-[2R*[1S*,5S*(S*)]]-α,α′-[phenylmethyliminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol].

A composition comprising specific beta-blockers such as bisoprolol and nebivolol for the treatment of insomnia and/or another sleep disorder. The composition should be given in such an amount that it causes a less than 40% decrease in the amount of aMT6s in complete nocturnal urin. The composition can be a combination treatment comprising a specific beta-blocker in combination with another known drug e.g., melatonin with similar effect for treatment of insomnia.

The present invention relates to a novel process for the synthesis of the Nebivolol product depicted in Scheme 1, comprised of a reduced number of high-yield steps, and characterized by the enzymatic resolution of the chroman ester precursor.

The invention discloses a preparation method of nebivolol used for preparing medicines for treating hypertension of slight or medium degrees, and an intermediate compound. The preparation method comprises the following steps: taking 6-fluoro-2-(1-hydroxy-2-paratoluensulfonyl oxygroup-ethyl)-3,4-dihydrobenzopyrans as an initial raw material, introducing amino, then coupling with 6- fluoro-3,4-dihydro-2-epoxy ethyl-2H-1-benzopyran, and preparing (S,R,R,R) and (R,S,S,S)-nebivolol. Compared with a prior art, the preparation method has the advantages of novel design, simple operation and high yield, the usage of hazardous reagent such as ssodium azide and sodium hydride can be avoided, a column chromatography purifying method is avoided, so that the preparation method conforms to industrial production.