- GLUCOCORTICOID RECEPTOR AGONIST AND IMMUNOCONJUGATES THEREOF
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Provided herein are glucocorticoid receptor agonist immunoconjugates, glucocorticoid receptor agonists, pharmaceutical compositiosn including the same, and methods of using the same.
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Paragraph 0102-0103
(2021/08/20)
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- Fluticasone propionate synthesis method
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The embodiments of the invention provide a fluticasone propionate synthesis method, which comprises: a thioesterification reaction: adding a first intermediate, an first organic alkali, dimethylaminothioformyl chloride, sodium iodide and a first organic solvent into a reaction kettle, carrying out a reaction, adding a polar aprotic solvent and water after the reaction, carrying out cooling crystallizing, filtering, washing, and drying to obtain a second intermediate; an alcoholysis reaction: adding the second intermediate, a first inorganic alkali and a second organic solvent into a reaction kettle, carrying out a reaction, adding water or water and an extracting agent after the reaction, extracting, taking the water phase, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain a third intermediate; and a substitution esterification reaction: adding the third intermediate, a second inorganic alkali and a third organic solvent into a reaction kettle, adding fluorobromomethane, adding hydrochloric acid in a dropwise manner, crystallizing, filtering, washing, and drying to obtain fluticasone propionate. According to the embodiments of the invention, the low-cost production can be realized, and the reaction yield and the purity are high.
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Page/Page column 7-15
(2020/02/10)
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- Preparation method of fluticasone propionate intermediate
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The invention discloses a preparation method of a fluticasone propionate intermediate. The preparation method comprises the following steps: firstly, preparing silica gel loaded sodium periodate, andthen oxidizing flumetasone by utilizing the silica gel loaded sodium periodate so as to obtain a fluticasone propionate intermediate 6alpha, 9alpha-difluoro-11beta, 17alpha-dyhydroxy-16alpha-methyl-3-oxoandrostane-1, 4-diene-17beta-carboxylic acid. The method has the advantages of readily available reaction raw materials, simple operation, good selectivity, no by-product, stable process, low price, safety, high reaction yield and the like and is beneficial to reduction of the production cost of enterprises and subsequent commercial production and batch supply.
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Paragraph 0036-0081
(2020/07/13)
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- Synthesis method of fluticasone propionate impurities
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The invention provides a synthesis method of fluticasone propionate impurities. The method specifically includes the step of preparing fluticasone propionate impurities EP-ZB and impurities EP-ZG. Flumethasone serves as the raw material, and a compound I is synthesized; the compound I reacts with a sulfur agent, and reaction products are subjected to postprocessing and silica gel column purifyingto obtain the impurities EP-ZB; the compound I serves as the raw material and reacts with an acylation agent to generate a compound II, and the compound II and the impurities EP-ZB are condensed to generate a compound IV; the compound IV and a sulfur agent react in an organic solvent and are catalyzed by a catalyst to generate a compound V; the compound V and an added acid-binding agent react to generate a compound VI; finally, the compound VI and bromofluoromethane react to generate the impurities EP-ZG. The synthesis method is simple in process route, convenient to operate, high in selectivity and high in yield.
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Paragraph 0035-0038; 0042-0045
(2019/10/01)
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- STRUCTURES AND MECHANISM FOR THE DESIGN OF HIGHLY POTENT GLUCOCORTICOIDS
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The present invention relates to novel glucocorticoid compounds. The invention also relates to methods of using these compounds, the synthesis of these compounds, and to compositions and formulations comprising the glucocorticoid compounds, and uses thereof.
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Paragraph 0150-0151
(2018/04/27)
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- POTENT SOFT ANTI-INFLAMMATORY CORTICOSTEROID COMPOUNDS AND USES THEROF
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Potent soft corticosteroid pharmaceutical compositions comprising them and method for use as anti-inflammatory agents. Also, a method for softening fluticasone propionate and similar corticosteroids to arrive at potent but safer alternatives. The compound S-fluoromethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16a- methyl-3-oxoandrosta-1,4-diene-17β-carbothioate, which is equally potent to but safer than fluticasone, is among those provided. Another compound of particular interest is 2-hydroxyethyl 17α-dichloroacetoxy-6α,9α-difluoro-11β-hydroxy-16β- methyl-3-oxoandrosta-1,4-diene-17β-carboxylate.
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Paragraph 0070; 0081; 0082
(2019/01/08)
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- METHODS OF PREPARING INTERMEDIATE OF FLUTICASONE PROPIONATE
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A method of preparing a thioic acid intermediate of fluticasone propionate includes: treating a 17β-[(N,N-dimethyl carbamoyl)thio]carbonyl compound in a solution including an alcohol and an alkali metal hydroxide, an alkaline-earth metal hydroxide, or a mixture thereof to cleave an amide from the 17β-[(N,N-dimethyl carbamoyl)thio]carbonyl compound; treating the solution to separate an aqueous portion; and adding an acid to the aqueous portion to obtain the thioic acid intermediate of fluticasone propionate. A method of preparing fluticasone propionate includes preparing the thioic acid intermediate of fluticasone propionate, and alkylating the thioic acid intermediate of fluticasone propionate to prepare the fluticasone propionate.
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Paragraph 0044; 0048; 0049
(2016/04/26)
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- HIGHLY POTENT GLUCOCORTICOIDS
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The present invention relates to novel glucocorticoid compounds. The invention also relates to methods of using these compounds, the synthesis of these compounds, and to compositions and formulations comprising the glucocorticoid compounds, and uses thereof.
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Paragraph 0225; 0226
(2015/04/15)
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- SELECTIVE GLUCOCORTICOID RECEPTOR LIGANDS
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Described herein are certain steroid derivative compounds, for example of formula (I): wherein X1, X2, X3 L, and Ar are as defined herein, pharmaceutical compositions comprising such compounds, the use of such compounds and compositions to specifically target glucocorticoid action, and the use of such compounds and compositions in the treatment of acute and chronic inflammatory conditions, in particular rheumatoid arthritis, haematological and other malignancies, and for causing immunosuppression in the prevention or treatment of transplant rejection, as well as methods of preparing such compounds.
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Page/Page column 34; 37; 38
(2015/06/03)
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- Improved synthesis of fluticasone propionate
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A novel process for the preparation of fluticasone propionate (1), a corticosteroid, is reported. In this paper, compound 2 was used as starting material to prepare 6 by using NaClO or NaBrO which was much cheaper than H 5IO6 as an oxidizing agent. Furthermore, toxic, expensive, and pollutive BrCH2F was replaced by AgNO3 and Selectfluor in decarboxylative fluorination.
- Zhou, Jiadi,Jin, Can,Su, Weike
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supporting information
p. 928 - 933
(2014/10/16)
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- PROCESS FOR PREPARING FLUTICASONE PROPIONATE/FUROATE
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The present invention relates to an improved process for the preparation of substituted Fluticasone derivatives. The invention also reveals the processes for the purification of Fluticasones and related intermediates to provide the highly pure product.
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Paragraph 0048
(2014/06/11)
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- Macrolactonolides: A novel class of anti-inflammatory compounds
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A new concept in design of safe glucocorticoid therapy was introduced by conjugating potent glucocorticoid steroids with macrolides (macrolactonolides). These compounds were synthesized from various steroid 17β-carboxylic acids and 9a-N-(3-aminoalkyl) derivatives of 9-deokso-9a-aza-9a-homoeritromicin A and 3-descladinosyl-9-deokso-9a-aza-9a-homoeritromicin A using stable alkyl chain. Combining property of macrolides to preferentially accumulate in immune cells, especially in phagocyte cells, with anti-inflammatory activity of classic steroids, we designed molecules which showed good anti-inflammatory activity in ovalbumin (OVA) induced asthma in rats. The synthesis, in vitro and in vivo anti-inflammatory activity of this novel class of compounds are described.
- Toma?kovi?, Linda,Komac, Marijana,Makaruha Stegi?, Oresta,Muni?, Vesna,Rali?, Jovica,Stani?, Barbara,Banjanac, Mihailo,Markovi?, Stribor,Hrva?i?, Bo?ka,?ip?i? Paljetak, Hana,Padovan, Jasna,Glojnari?, Ines,Erakovi? Haber, Vesna,Mesi?, Milan,Mer?ep, Mladen
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p. 321 - 332
(2013/02/23)
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- FATTY ACID ESTERS OF GLUCOCORTICOIDS AS ANTI-INFLAMMATORY AND ANTI-CANCER AGENTS
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The present invention relates to certain unsaturated fatty acid derivatives of therapeutically active glucocorticoides-fatty acid esters of glucocorticoids as anti-inflammatory and anti-cancer agents and pharmaceutical formulations containing them.
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Page/Page column 5
(2010/05/13)
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- METHOD FOR PREPARATION OF FLUTICASONE PROPIONATE
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Taught is a method for preparing S-fluoromethyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (fluticasone propionate). The present method is simple, convenient, and mild, yields highly pure product, and is suitable for use commercially on a large scale.
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Page/Page column 2
(2008/12/05)
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- METHOD FOR THE PREPARATION OF FLUTICASONE PROPIONATE
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Taught is a method for preparing S-fluoromethyl-6α,9α- difluroro-11β-hydroxy-16α-methyl-17α- propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate (fluticasone propionate). The present method is simple, convenient, and mild, yields highly pure product, and is suitable for use commercially on a large scale.
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Page/Page column 5
(2010/11/30)
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- Convenient synthesis of s-fluoromethyl 6alpha, 9alpha-difluoro-11beta-hydroxy-16alpha-methyl-17alpha-propionyloxy-3-oxoandrosta-1,4-diene-17beta-carbothioate
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The present invention provides a convenient process for the preparation of S-fluoromethyl 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioate, a compound of formula 1, comprising (a) treating 17β-[(N,N-dimethylcarbamoyl)thio]carbonyl-6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene, a compound of formula 3 with alkali metal carbonate-alcohol system to obtain 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-propionyloxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid, a compound of formula 4; (b) reacting the compound of formula 4 with bromofluoromethane to yield the compound of formula 1. The present invention also provides an improved process for preparation of compound of formula 1 comprising (a) reacting 6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17-(propionyloxy)androsta-1,4-dien-17β-carboxylic acid, a compound of formula 2, with N,N-dimethylthiocarbamoyl chloride in an inert aprotic solvent in the presence of an iodide catalyst and a base to give a compound of formula 3, (b) reacting the compound of formula 3 with a hydrosulfide reagent and bromofluromethane to obtain a compound of formula 1.
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Page/Page column 8
(2010/02/14)
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- Method for the isolation of 6alpha, 9alpha-difluoro-11beta, 17alpha-dihydroxy-16alpha-methylpregna-3-oxo-1,4-diene-17beta-carboxylic acid
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The invention provides a process for the preparation and isolation of compound of formula 2, comprising the following steps: oxidizing Flumethasone dissolved in a tetrahydrofuran-water mixture with periodic acid at a temperature lower than 30° C.; cooling the reaction mixture to a temperature lower than 10° C.; adding an antisolvent precooled to a temperature lower than 10° C.; and separating the precipitated crystal by filtration, whereby there is obtained a compound of formula 2 in a yield of at least 98% and of a chromatographic purity of at least 99%.
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- Process for the preparation of steroidal 17 beta-carbothioates
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A novel method for the conversion of steroidal 17β-carboxylic acids to carbothioates such as fluticasone propionate via novel in situ generated 17β-carboxy imidazolyl- or succinimidyl esters.
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- Process of preparation of flumethasone 21-acetate, or flumethasone and its 17-carboxyl androsten analogue
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A process for the preparation of high purity flumethasone in high yield involves C3 protecting 9,11β-epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione,21-acetate, fluorinating at 6α, removing the C3 protecting group, fluorinating the 9,11-epoxy group. The resulting flumethasone 21-acetate is treated with the methanolic potassium hydroxide in the presence of an oxidation agent, causing a simultaneous hydrolyzation and degradative oxidation, resulting in the formation of 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-17β-carboxy-androsta-1,4-diene-3-one in high yield. Flumethasone 21-acetate is alternatively hydrolyzed to yield flumethasone free alcohol.
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- Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods
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This invention discloses a novel method for the conversion of carboxylic acids to carbothioic acids and application of the method to the preparation of androstane carbothiolates, such as fluticasone propionate, which avoids column chromatography.
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- Thiol Esters from Steroid 17β-Carboxylic Acids: Carboxylate Activation and Internal Participation by 17α-Acylates
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The chemistry of the steroid 17β-carboxylic acids derived from 16,17α-disubstituted corticosteroids was investigated with respect to thiol ester formation.Major quantities of 17-spiro byproducts were observed in the reactions of 16-methyl-17α-acyloxy acids, and the degree of 17-ester participation leading to these structures was dependent on the carboxylate activating group used and stereochemistry at C-16.Diethyl phosphate mixed anhydrides of these acids reacted with mercaptide salts to give mixtures of thiol esters with 17-spiro acylthio ortho esters, which predominated and were particularly stable in the case of 16β-methyl substrates; in addition, considerable reversion of 16α-methyl phosphate intermediates to starting acid was experienced.The use of diphenyl chlorophosphate as the activating agent greatly improved yields of thiol esters.Methanolysis of the phosphate adducts derived from 17α-acyloxy acids gave 17-spiro acyl ortho esters as the exclusive products.The reactions of 17α-acetoxy acids with 2-fluoro-N-methylpyridinium tosylate (FMPT) gave novel 17-spiro acyl fluoro ketals 32-35, whereas similar treatment of 17-hydroxy acids led to products of dehydration or of 18-methyl migration, including the novel 13,17-β-lactones 39 and 41.Activation with carbonyldiimidazole followed by addition of mercaptans allowed the preparation of thiol ester products from 17-hydroxy acids, but the method was restricted to use with these substrates.Neighbouring-group participation was not possible for the 16,17-acetonide acid 10, and activation with either cllorophosphate diesters or FMPT followed by reaction with methanethiolate gave high yields of methylthio ester 17.
- Kertesz, Denis J.,Marx, Michael
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p. 2315 - 2328
(2007/10/02)
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