69 results about "Finerenone" patented technology

The present application belongs to the field of medicines, and particularly relates to a pharmaceutical cocrystal of finerenone and maleic acid, and a preparation method therefor. The pharmaceutical cocrystal of finerenone and maleic acid prepared in the present application has the advantages of high purity, suitable solubility, good stability, etc. and is suitable for new drug development and industrial production. The method for preparing the pharmaceutical cocrystal of finerenone and maleic acid provided in the present application has the advantages of simple process route and low cost, and is suitable for industrial production.

The invention relates to a synthetic method of a finelrenone racemate, which comprises the following steps: carrying out Knoevenagel condensation, Hantzsch dihydropyridine synthesis, O-ethylation and deprotection four-step reaction, selecting a compound shown as a formula (2) and a compound shown as a formula (3) as initial raw materials, and carrying out Knoevenagel condensation reaction under the combined action of organic alkali and organic acid to synthesize a compound shown as a formula (4); carrying out Hantzsch reaction on the compound in the formula (4) and a compound in a formula (5) to synthesize a compound in a formula (6); carrying out O-ethylation reaction on the compound shown in the formula (6) and an ethylation reagent under the catalysis of acid to synthesize a compound shown in a formula (7); finally, 2, 4-dimethoxybenzyl is removed from the compound shown in the formula (7) under the promotion of acid to synthesize the finerenone racemate, the method is high in selectivity and simple in post-treatment, the yield and purity of the product are high, the HPLC purity can reach 99% or above, a new synthesis route and method are developed for synthesizing the finerenone racemate, and the method has good application potential and research value.

The invention belongs to the technical field of medicines, and particularly relates to a fenerenone orally disintegrating tablet and a preparation method thereof. The active component of the fenerenone orally disintegrating tablet is fenerenone, and the fenerenone orally disintegrating tablet comprises the following components in percentage by weight: 10-15% of fenerenone, 10-15% of magnesium stearate, 10-15% of magnesium stearate and the balance of 70-80% of a filler; 5.5-10% of a disintegrating agent; 1-4% of a flow aid; and 1-4% of a lubricant. The finerenone orally disintegrating tablet disclosed by the invention is suitable for being taken by diabetics, and has the advantages of high disintegration and dissolution speed, stable finished product quality, no need of being taken with water and strong patient compliance; in addition, the finerenone orally disintegrating tablet disclosed by the invention is simple in preparation process, low in cost and suitable for large-scale production.

The application provides a preparation method of finerenone and intermediates thereof. The application discloses a preparation method of a finerenone intermediate 5, which comprises the following steps: step 1: in an organic solvent, a resolution reaction is carried out between a finerenone intermediate 2 and D-tartaric acid diphenyl ester to obtain a resolution salt, then an acid-base reaction is carried out between the resolution salt and a base to obtain the finerenone intermediate 3; step 2: in an organic solvent, a nucleophilic substitution reaction is carried out between the finerenone intermediate 3 and triethyl orthoformate in the presence of an acid to obtain a finerenone intermediate 4; step 3: in a solvent, a hydrolysis reaction is carried out between the finerenone intermediate 4 to obtain the finerenone intermediate 5. The preparation method has the advantages of short reaction steps, high total reaction yield, simple and safe operation, simple post-treatment steps, high product purity, low production cost and suitability for industrial production.

The present invention relates to the field of pharmaceutical technologies, and specifically, to a preparation method of finerenone and its key intermediate. The present invention uses enzymatic resolution to prepare the key chiral intermediate (S)-compound of formula I of finerenone. The present invention has the advantages of high chiral selectivity in the reaction, being green and environmentally friendly, high yield, and not requiring the use of chromatographic separation technology, and is suitable for industrial production, etc.

The present invention relates to the technical field of pharmaceuticals. Particularly, disclosed is use of finerenone in the preparation of a drug for treating and / or preventing ovarian dysfunction diseases. Provided is a novel, safe, and effective composition for treating ovarian dysfunction diseases. Finerenone, as a main component in the preparation of the drug for treating and / or preventing the ovarian dysfunction diseases, can be applied orally, which reduces the pain and injury to patients and is more convenient, thereby providing a safe and effective new choice for the use in the preparation of the drug for treating and / or preventing the ovarian dysfunction diseases.

The present invention relates to an improved process for the preparation of (4S)­4-(4- cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3- carboxamide represented by the following structural formula-1, which is referred to as Finerenone. Formula­1 The present invention also relates to a process for the preparation of crystalline form of Finerenone.

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 application discloses a method for asymmetrically catalytically synthesizing naphthyridine carboxamide drug finerenone, and belongs to the technical field of organic synthesis. In the first step, compound 1 is reacted with S-1-phenylethanol in an organic solvent to generate intermediate 2; in the second step, compound 2 is reacted with 4-cyano-2-methoxybenzaldehyde in an organic solvent to generate intermediate 3; in the third step, compound 3 is reacted with 4-amino-5-methylpyridin-2-ol in the presence of a chiral catalyst in an organic solvent to generate crude intermediate 4, the crude intermediate 4 is then salified by adding a resolving agent, and after being freed, the intermediate 4 is obtained; in the fourth step, compound 4 is reacted with triethyl orthoformate in an organic solvent under the catalysis of an acid to generate intermediate 5; in the fifth step, compound 5 is catalytically hydrogenated in the presence of a palladium catalyst to generate intermediate 6; and in the sixth step, compound 6 is reacted with hexamethyldisilazane in the presence of a condensing agent, and after treatment, the product I is obtained. The application provides an improved preparation method for finerenone and has the prospect of industrial production.

This invention belongs to the field of organic synthesis technology and relates to an improved synthetic method for phenelzine. Starting with 4-cyano-2-methoxybenzaldehyde, it reacts with 1-(1H-imidazol-1-yl)butane-1,3-dione, then with 4-amino-5-methyl-2-methoxypyridine to generate 4-(3-(1H-imidazol-1-carbonyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthid-4-yl)-3-methoxybenzonitrile. Under the action of a resolving agent, (4S)-4-(3-(1H-imidazol-1-carbonyl)-2,8-dimethyl-5-oxo-1,4,5,6-tetrahydro-1,6-naphthid-4-yl)-3-methoxybenzonitrile is generated. Finally, phenelzine is obtained through ammonolysis. This preparation method has few steps, is simple to operate, has low cost, and high yield, making it suitable for industrial production.

The application discloses a preparation method of a non-nelirige intermediate 3, which comprises the following steps: carrying out a resolution reaction on non-nelirige intermediate 2 and D-tartaric acid diphenyl ester in an organic solvent to obtain a resolution salt, and then carrying out an acid-base reaction on the resolution salt and a base to obtain the non-nelirige intermediate 3. The preparation method has the advantages of short reaction steps, high total reaction yield, simple and safe operation, simple post-treatment steps, high product purity, low production cost and suitability for industrial production.

The invention discloses a quality control method of fenerenone, which is characterized in that specific fenerenone impurities are subjected to gradient elution by adopting a high performance liquid chromatography, and the quality condition of the fenerenone can be accurately and effectively reflected. The method is simple and convenient to operate, meets the quality control requirement, and can be used for the whole process of finerenone preparation and quality control of raw material medicines and preparation products thereof.

The invention belongs to the field of pharmaceutical preparations, and discloses a pharmaceutical composition of fenerenone, which is prepared from the following components in percentage by weight: 4 to 10 percent of fenerenone, 2 to 15 percent of emulsifier, 60 to 90 percent of filler, 2 to 15 percent of disintegrating agent and 0.5 to 1.5 percent of lubricant. The invention discloses a preparation method of the pharmaceutical composition of the fenerenone, which comprises the following steps: dispersing the fenerenone in a solvent, adding an emulsifier, stirring to obtain a fenerenone dispersion liquid, mixing the fenerenone dispersion liquid with purified water, homogenizing to obtain a nano liquid crystal suspension, dispersing the suspension on a filler and a disintegrating agent, and drying to obtain the pharmaceutical composition of the fenerenone. And carrying out wet granulation to obtain particles, and drying to obtain granulated particles. According to the invention, the fenerenone is dispersed in the emulsifier, so that the raw materials are prevented from being clustered, the solubility of the fenerenone is improved, the fenerenone in the prepared composition is uniformly dispersed and has better stability, and the preparation process is simple and easy for industrial production.

The present application relates to a kind of preparation of finerenone and its preparation method, belong to the technical field of pharmaceutical preparation.The present application adds disintegrant and filler in the form of inside and outside, improves the disintegrant disintegration performance, so as to improve the dissolution effect of finerenone preparation;In addition, the present application adjusts the mass ratio of first filler and second filler, reduces the mass of inside material, reduces the liquid spraying time in preparation process and expands production batch, so as to shorten production time and reduce production cost.The preparation method of the present application is short in preparation time, the finerenone preparation obtained by the preparation method of the present application is uniform and has good dissolution effect, has good industrial application value.

The invention belongs to the technical field of medicines, and particularly relates to a fenerenone orally disintegrating tablet and a preparation method thereof. The active component of the fenerenone orally disintegrating tablet is fenerenone, and the fenerenone orally disintegrating tablet comprises the following components in percentage by weight: 3-45% of fenerenone, 1-5% of magnesium stearate, 1-5% of magnesium stearate, 1-5% of 48-70% of a filler; 0.5-2% of an adhesive; 1-4% of a flow aid; 1-4% of a lubricant; the composition comprises the following components in percentage by weight: 0-15% of a first disintegrating agent, 2-6% of a second disintegrating agent and 2-6% of a third disintegrating agent, the first disintegrating agent, the second disintegrating agent and the third disintegrating agent are the same or at least two of the first disintegrating agent, the second disintegrating agent and the third disintegrating agent are different, preferably, the weight content of the fenerenone is 10-15%, and / or the weight content of the filling agent is 59-70%. The finerenone orally disintegrating tablet disclosed by the invention is suitable for being taken by diabetics, and has the advantages of high disintegration and dissolution speed, stable finished product quality, no need of being taken with water and strong patient compliance; in addition, the finerenone orally disintegrating tablet disclosed by the invention is simple in preparation process, low in cost and suitable for large-scale production.

The present application relates to the technical field of medicine, in particular to a solid preparation containing a solid dispersion of finerenone and a preparation method thereof, which comprises a solid dispersion of finerenone and at least one pharmaceutically acceptable excipient; the solid dispersion of finerenone is prepared by using a hot melt extrusion method with finerenone and a matrix. In the hot melt extrusion method, polyethylene glycol and copolymerized povidone are used as solubilizers and plasticizers, so that the hot melt temperature can be reduced to below 160 DEG C, which not only reduces energy consumption, but also ensures the stability of the drug.

The present invention relates to the technical field of analysis and detection, and specifically discloses a method for detecting impurities in a finerenone intermediate. The present invention uses high performance liquid chromatography to detect the impurity 4-dimethylaminopyridine in the finerenone intermediate, and the detection conditions are as follows: the chromatographic column is a C18 chromatographic column; mobile phase A: an aqueous solution containing phosphoric acid; mobile phase B: methanol; elution is performed in an isocratic elution mode, and the detection wavelength is 273-283nm. The detection method provided by the present invention has the advantages of strong specificity, high sensitivity, rapid detection, accurate and reliable test results, and good precision, stability and durability. The present invention effectively solves the problems of short elution time, interference by solvent peaks, poor peak shape, and even tailing in the detection method for 4-dimethylaminopyridine in the prior art, and there is no problem of the method for detecting 4-dimethylaminopyridine in the finerenone intermediate, which can be used as the basis for quality monitoring of finerenone.

An object of the present invention is to improve the treatment and / or prevention of cardiovascular and renal diseases compared to already known monotherapies. A further object of the present invention is to provide a combination of pharmaceutical active ingredients for treating cardiovascular diseases, particularly cardiac and renal failure, characterized by chronic sodium retention, which reduces patient mortality and / or morbidity. Another object of the present invention is to improve the treatment and / or prevention of cardiovascular and renal diseases by administering a combination comprising finerenone and an SGLT2 inhibitor. [Solution] The present invention relates to pharmaceutical compositions and combinations comprising finerenone or its hydrate, solvate, or pharmaceutically acceptable salt or polymorph thereof, and an SGLT2 inhibitor or its hydrate, solvate, or pharmaceutically acceptable salt or polymorph thereof. The combinations can be used for the treatment and / or prevention of cardiovascular and / or renal diseases in humans and other mammals.

The present invention provides a novel, efficient and industrially advantageous process for the preparation of Finerenone of Formula I. The present invention also provides a process for preparation of Finerenone intermediates of Formula II and Formula V, and their use for the preparation of Finerenone of Formula I. wherein, R1 and R2 each independently selected from hydrogen, C1 to C6 substituted or unsubstituted alkyl, SO3Na or SO3K.

The application discloses a chiral preparation method of finerenone, and a reaction route is shown in the specification, and the preparation method comprises the following steps: (1) reacting compound I with a chiral compound II to obtain compound III; (2) reacting the compound III with a compound IV to obtain a compound V; (3) reacting the compound V with an ethylating agent to obtain a compound VI; and (4) removing a protecting group or ammonolysis of the compound VI to obtain a compound VII. Through asymmetric synthesis induced by a chiral compound raw material, more than 95% of a product with a required configuration is obtained, yield is improved, and waste is reduced. The method has mild reaction conditions, low cost and is suitable for industrial production.

The present application belongs to the technical field of preparation and processing of drugs, and particularly relates to finerenone, a preparation method therefor and a finerenone intermediate. In the preparation method provided by the present application, a compound with a diester structure as represented by formula 2 is used as a reaction raw material to carry out a series of reactions, a chiral catalyst is used in the reaction to obtain a product with an S / R configuration ratio of up to 85:15, and the product is resolved by means of using a tartaric acid derivative, so as to prepare a compound with a structure as represented by formula 7, and then the resulting compound is subjected to hydrolysis and amidation reactions to obtain finerenone. A finerenone drug substance with an ee value of >99.9% and a purity of up to 99.9% can be obtained by means of the preparation method of the present application. Moreover, the reactions during the preparation method provided by the present application are all common reactions, not involving dangerous reaction steps such as hydrogenolysis and high-pressure processes. The method has mild reaction conditions, generates no highly toxic by-products, has low requirements for reaction equipment, has low operational costs, and is simple and convenient to operate. Therefore, the method is suitable for industrial production, and has good market prospects.

The present invention also refers to finerenone or a hydrate, solvate, pharmaceutically acceptable salt or polymorph thereof for use in the prevention or treatment of chronic kidney disease in patients with type 1 diabetes, wherein the prevention or treatment comprises administering to the patient a therapeutically effective amount of finerenone or a hydrate, solvate, pharmaceutically acceptable salt or polymorph thereof.

The present application belongs to the technical field of preparation and processing of drugs, and particularly relates to finerenone, a preparation method therefor and a finerenone intermediate. In the preparation method provided by the present application, a compound with a diester structure as represented by formula 2 is used as a reaction raw material to carry out a series of reactions, a chiral catalyst is used in the reaction to obtain a product with an S / R configuration ratio of up to 85:15, and the product is resolved by means of using a tartaric acid derivative, so as to prepare a compound with a structure as represented by formula 7, and then the resulting compound is subjected to hydrolysis and amidation reactions to obtain Finerenone. A finerenone drug substance with an ee value of ＞99.9% and a purity of up to 99.9% can be obtained by means of the preparation method of the present application. Moreover, the reactions during the preparation method provided by the present application are all common reactions, not involving dangerous reaction steps such as hydrogenolysis and high-pressure processes. The method has mild reaction conditions, generates no highly toxic by-products, has low requirements for reaction equipment, has low operational costs, and is simple and convenient to operate. Therefore, the method is suitable for industrial production, and has good market prospects.

The present application belongs to the technical field of drug synthesis, and particularly relates to a finerenone intermediate compound IV or compound V, a preparation method therefor and a preparation method for finerenone.

The application provides a pharmaceutical composition of finerenone and a preparation method and use thereof. The pharmaceutical composition of the application has good dissolution in various media, and has good uniformity, tolerance and particle size after being prepared into a preparation, and is consistent with the in-vitro release effect of a reference preparation.

The invention discloses a preparation method of a fenerenone intermediate 3, which comprises the following steps: in an organic solvent, carrying out resolution reaction on a fenerenone intermediate 2 and D-diphenyl tartrate to obtain a resolution salt, and then carrying out acid-base reaction on the resolution salt and alkali to obtain the fenerenone intermediate 3. The preparation method provided by the invention has the advantages of short reaction steps, high reaction total yield, simple and safe operation, simple post-treatment steps, high purity of the prepared product, low production cost and suitability for industrial production.

The invention discloses a method for preparing fenerenone from a fenerenone raceme and refining and crystallizing an intermediate. Chirally substituted tartaric acid ester is adopted to prepare an intermediate, namely, a non-nepetenone diastereomer salt III, and then the non-nepetenone diastereomer salt III is subjected to alkali dissociation to prepare the non-nepetenone (IIa). According to the invention, by adding a refining and crystallizing method of the intermediate fenerenone diastereomer salt (III), the ee value obtained by the prepared intermediate fenerenone diastereomer salt (III) is higher than 99.5%, and the e.e value in a fenerenone bulk drug further prepared on the basis is basically 100%; a resolving agent tartrate is not detected in the free fenerenone enantiomer, product loss and three-waste generation caused by multiple dissociation are avoided, the production and manufacturing cost is greatly reduced, the product prepared by the method is high in yield and low in three-waste pollution, the preparation process is extremely simple to operate, the reaction condition is mild, the production cost is saved, and the method is suitable for industrial production. The method is suitable for industrial production.

The present invention provides a method for preparing finerenone by means of resolving a racemate with a diastereomeric tartaric ester, and also relates to diastereomer salts (VIIa), (VIIb), (VIIc) and / or (VIId). The resolving method uses a chiral substituted tartaric ester represented by general formula (VIa) or (VIb) as a resolving agent to resolve a racemate represented by formula (V) to obtain a compound represented by formula (Va) and / or (Vb). The racemate is firstly added into a solvent mixture to be heated until completely dissolved; then the resolving agent is added to obtain a homogeneous system; and resolution is performed by stirring for crystallization.

The invention belongs to the technical field of biological medicines, and particularly relates to application of fenerenone in preparation of a medicine for treating polycystic ovarian syndrome. According to the invention, the fenerenone is used as a high-selectivity non-steroidal salt corticoid receptor antagonist to regulate and control local and systemic inflammatory response of ovary, oxidative stress state, insulin signal pathway and serum hormone level, so that the core pathological mechanism of polycystic ovarian syndrome is intervened.