- Preformulation studies of spironolactone: Effect of pH, two buffer species, ionic strength, and temperature on stability
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Using a stability-indicating HPLC assay method, the effect of pH, two buffer species (citrate and phosphate), ionic strength, and temperature on the stability of spironolactone in 20% solution of ethyl alcohol in water has been studied. The optimum pH of stability appears to be ~4.5. On increasing the buffer concentration, both species hastened the decomposition of spironolactone. The ionic strength did not affect the stability of the drug. The energy of activation has been estimated to be ~78.8 kJ/mol at pH 4.3. The un-ionized spironolactone is subject to general acid-base catalysis. The K(h) and K(oh) values at 40 °C have been estimated to be 1.63 and 2.8 x 105 day-1, respectively. The HPO4-2 ion had ~10 times more catalytic effect than the H2PO4-1 ion. This data will be used to develop a stable oral liquid dosage form of the drug.
- Pramar,Gupta
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- The nitration of canrenone with acetic anhydride/nitric acid
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3-Oxo-17α-pregna-4,6-diene-21,17-carbolactone (canrenone, II) is produced from the potassium salt of 17-hydroxy-3-oxo-17α-pregna-4,6-diene- 21-carboxylic acid (I) by acid catalyzed lactonization. II reacts with acetic anhydride/nitric acid to give one main product (III) and some minor products. The structure of III was determined by chemical and spectral analysis to be the 4-nitro derivative of canrenone. This result is in contrast to the known reactions of H with most other reagents that were found to add at Δ6, and also in contrast to the reactions of acetic anhydride/nitric acid with alkenes. Electrophilic substitution at the ambident C4 is discussed as the reaction path. The 4-nitro group enhances the inhibitor), activity of II against Na+/K+-ATPase, the target enzyme of the cardioactive digitalis glycosides, which appears to indicate increased cardioactivity.
- Megges, Rudolf,Weiland, Juergen,Undeutsch, Bernd,Buechting, Horst,Schoen, Rudolf
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- Synthesis and reactions of 2-methylene-canrenone
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Starting from the Mannich salt 1 of the aldosterone antagonist canrenone or from 2-methylene-canrenone (2) the A-ring annulated hetero- and carbocycles 5, 6, 8-13 were prepared. Receptor (estradiol, progesterone, androgen, gluco- and mineralocorticoid) binding studies and competition studies with the serum proteins SHBG and CBG were carried out using the compounds 2, 3, 4b, 5, 6b, 8 and 12. The relative binding affinities with CBG are below 1%, in all other cases lower than 0.01%.
- Gorlitzer,Moormann,Pollow,Schaffrath
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- Synthesis method of canrenone
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The invention provides a synthesis method of canrenone, and relates to the technical field of chemical synthesis. The synthesis method of canrenone comprises the following steps: (a) adding a compound in a formula 1 into an organic solvent to obtain a solution containing the compound in the formula 1; and (b) introducing the solution in the step (a) into a micro-channel reactor, and carrying out a decarboxylation reaction to obtain canrenone. The method can completely react within a short time, reduces side reactions caused by long-time high temperature, can continuously react in the microchannel reactor, has the advantages of high mass transfer efficiency, fast reaction, short time and less side reactions, greatly improves the experiment operability, has the yield equivalent to that of the original process, and solves the problems of slow reaction and dangerous and tedious operation, and improves the production applicability of the reaction.
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Paragraph 0047-0190
(2021/10/05)
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- One-Pot γ-Lactonization of Homopropargyl Alcohols via Intramolecular Ketene Trapping
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A one-pot γ-lactonization of homopropargyl alcohols via an alkyne deprotonation/boronation/oxidation sequence has been developed. Oxidation of the generated alkynyl boronate affords the corresponding ketene intermediate, which is trapped by the adjacent hydroxy group to furnish the γ-lactone. We have optimized the conditions as well as examined the substrate scope and synthetic applications of this efficient one-pot lactonization.
- Yamane, Daichi,Tanaka, Haruna,Hirata, Akihiro,Tamura, Yumiko,Takahashi, Daichi,Takahashi, Yusuke,Nagamitsu, Tohru,Ohtawa, Masaki
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supporting information
p. 2831 - 2835
(2021/05/05)
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- Method for preparing spirolactone intermediate canrenone
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The invention provides a method for preparing spirolactone intermediate canrenone. The method comprises the following operation steps: a lactone substance (I) is dissolved in an organic solvent, a catalyst and an auxiliary agent are added, and the mixture is stirred at 50-80 DEG C to prepare the canrenone (II), wherein the organic solvent is at least one of cyclohexane, toluene or methyl tetrahydrofuran; the auxiliary agent is at least one of dimethyl formamide, N,N - dimethyl acetamide and N-methyl pyrrolidone; and the catalyst is poly-4-vinylpyridine. The reaction route is shown in the specification. Compared with the prior art, the method has the advantages that the reaction temperature is low, pressurization is not needed, the quality of canrenone can be improved, the energy consumption can be effectively reduced, and the production cost can be reduced.
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Paragraph 0019-0033
(2021/10/20)
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- Synthesis process of steroid compound, canrenone and spirolactone
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The invention relates to the technical field of medicine synthesis, in particular to a synthesis process of a steroid compound, canrenone and spirolactone. An embodiment of the invention provides thesteroid compound. The steroid compound has a structural formula as shown in the specification. In the structural formula, R is selected from H or an alkyl group. The steroid compound can be used for synthesizing canrenone and spirolactone, synthesis conditions are mild, synthesis efficiency is high, the amount of wastewater is small, the quality of the formed products is high, and production costcan be effectively reduced.
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Paragraph 0126-0127; 0129-0140; 0142-0144; 0146
(2020/11/23)
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- Method for preparing canrenone as spironolactone intermediate
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The invention relates to the technical field of canrenone preparation, and particularly discloses a method for preparing canrenone as a spironolactone intermediate. The method for preparing the canrenone as the spironolactone intermediate specifically comprises the steps that a biological fermentation product 7alpha-hydroxylactone is used as a raw material, a 6,7-site double-bond is formed, and the canrenone as the spironolactone intermediate is obtained. The method for preparing the canrenone as the spironolactone intermediate is simple and efficient and low in the production cost, suitable for large-scale industrial production and convenient for people to use.
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Paragraph 0017-0028
(2020/01/03)
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- Preparation method of canrenone
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The invention provides a preparation method of canrenone. The preparation method comprises the following steps: synthesizing canrenone by using a dehydrogenation product compound I as a substrate, adding a catalyst, carrying out an internal esterification reaction, and optimizing a reaction line. After the reaction is completed, the product is adjusted to be neutral and is directly concentrated, and a high pressure reaction is carried out directly after a dry solvent is recycled by using methylbenzene with ethyl alcohol, so that the aftertreatment reaction steps are reduced, the hydrolysis ofan E-ring ethyl formate group is avoided, and the high-pressure reaction difficulty is greatly lowered. The operability of the reaction is greatly improved, the production cost is reduced, the side reactions are greatly reduced, the reaction of each step is relatively easy to realize, the yield is greatly improved, the production is more economical and safer, and the preparation method is more applicable for industrial production.
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Paragraph 0035; 0037-0040; 0044; 0048; 0050
(2018/05/30)
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- Method for preparing spirolactone
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The invention discloses a method for preparing spirolactone. The method comprises the following steps: 1, performing a reaction on a compound shown as a formula (II) and acrolein under the action of a catalyst, alkali and Lewis acid to obtain a compound shown as a formula (III); 2, performing a reaction on the compound shown as the formula (III) and chloranil to obtain a compound shown as a formula (IV); 3, performing an addition reaction on the compound shown as the formula (IV) and thioacetic acid to obtain the spirolactone. The preparation method of the spirolactone, provided by the invention, has the advantages of a short synthetic route, cheapness and easy obtainment of used reagents, simple operation, high total yield rate, and suitability for industrial production; a novel way for preparing the spirolactone is provided.
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Paragraph 0029; 0030
(2017/11/30)
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- Fungal biotransformation of diuretic and antihypertensive drug spironolactone with Gibberella fujikuroi, Curvularia lunata, Fusarium lini, and Aspergillus alliaceus
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Derivatives of spironolactone (1), a diuretic and antihypertensive drug, were synthesized by using fungal cells for the first time. Ten different fungi were screened for their ability to biotransform 1, four of which were able to produce metabolites 2–8. Gibberella fujikuroi produced canrenone (2), 1-dehydrocanrenone (3), Curvularia lunuta provided compound 2, and 7α-thio-spironolactone (4), Fusarium lini yielded compounds 2, 3, 1β-hydroxycanrenone (5), 1α-hydroxycanrenone (6), 1-dehydro-15α-hydroxycanrenone (7), and 15α-hydroxycanrenone (8), while Aspergillus alliaceus was able to produce all the seven metabolites. Metabolites 5, 6, and 7 were identified as new compounds. Their structures were elucidated by using different spectroscopic techniques. Substrate 1 and its metabolites 2, 3, and 5–8 were also evaluated for α-glucosidase inhibitory activity in vitro. Substrate 1 was found to be strongly active with IC50 = 335 ± 4.3 μM as compared to the standard drug acarbose IC50 = 840 ± 1.73 μM, whereas all of resulting metabolites were found to be inactive.
- Al-Aboudi, Amal,Kana'an, Belal Muneeb,Zarga, Musa Abu,Bano, Saira,Atia-tul-Wahab,Javed, Kulsoom,Choudhary, M. Iqbal
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- Having a method for the synthesis of intermediates spirondactone
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The invention relates to a synthesis method of a chemical medicine, and concretely relates to a synthesis method of a spironolactone intermediate canrenone. The method comprises the following steps: carrying out an ethynylation reaction on a compound I 4-androstenedione (4AD), hydrogenating, carrying out an oxidation cyclization reaction, and carrying out a bromization and debromination reaction to obtain the compound V canrenone, and the above reaction route is shown in the specification. A synthesis method of the structure of an important 21,17-carboxy lactone spiro ring adopted in the invention is different from previous process modes, and is concise and efficient. The method has the characteristics of high yield, good selectivity, low cost, mild reactions, suitableness for industrialization, stability and easy realization.
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- Method for preparing canrenone
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The invention discloses a method for preparing canrenone. The method comprises the following steps of step one, reacting a compound shown in formula (II) with acraldehyde under the action of a catalyst to obtain a compound shown in formula (III); step two, reacting the compound shown in the formula (III) with chloranil to dehydrogenize, thus obtaining the canrenone. The method for preparing the canrenone, provided by the invention, has the advantages of short steps, simplicity and convenience in operation, high synthesis efficiency and suitability for industrial production; a new path is provided for preparing the canrenone.
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Paragraph 0021
(2016/12/22)
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- EX VIVO METHODS FOR PREDICTING AND CONFIRMING IN VIVO METABOLISM OF PHARMACEUTICALLY ACTIVE COMPOUNDS
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Methods and compositions for the catalytic oxidation of pharmaceutically active compounds, and more particularly to ex vivo methods for predicting in vivo metabolism of pharmaceutically active compounds, including predicting in vivo interaction between two or more pharmaceutically active compounds.
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Page/Page column 36; 37; 38
(2015/06/25)
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- A safe and practical method for the preparation of 7α-Thioether and thioester derivatives of spironolactone
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Spironolactone is a renal competitive aldosterone antagonist. One of its most important metabolite is the 7α-methylthio spironolactone: thus it is very important to have an efficient and safe access to this compound, for pharmacokinetic studies. In this context, we synthesized this metabolite by thioalkylation of 7α-Thio spironolactone using Hu?nig's base with a very good yield. We also used our procedure to prepare, with an easy work-up and high yields, 7α-Thioether and thioester derivatives of spironolactone, that could be useful for further Structure-Activity Relationships studies.
- Agusti, Géraldine,Bourgeois, Sandrine,Cartiser, Nathalie,Fessi, Hatem,Le Borgne, Marc,Lomberget, Thierry
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supporting information
p. 102 - 107
(2013/02/22)
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- Spironolactone-related inhibitors of type II 17β-hydroxysteroid dehydrogenase: Chemical synthesis, receptor binding affinities, and proliferative/antiproliferative activities
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The family of 17β-hydroxysteroid dehydrogenases (17β-HSDs) catalyzes the formation and inactivation of testosterone (T), dihydrotestosterone (DHT), and estradiol (E2), thus playing a crucial role in the regulation of active steroid hormones in target tissues. Among the five known 17β-HSD enzymes, type II catalyzes the oxidation of E2 into estrone (E1), T into androstenedione, DHT into androstanedione, and 20α-dihydroprogesterone into progesterone. Specific inhibitors are thus an interesting means to study the regulation and to probe the structure of type II 17β-HSD. In this context, we have efficiently synthesized a series of 7α-thioalkyl and 7α-thioaryl derivatives of spironolactone that inhibit type II 17β-HSD. These new C19-steroidal inhibitors possess two important pharmacophores, namely 17-spiro-γ-lactone and a bulky side-chain at the 7α-position. It was found that a para-substituted benzylthio group at the 7α-position enhances the inhibitory potency of spironolactone derivatives on type II 17β-HSD. In fact, the compound with a para-hydroxy-benzylthio group showed an IC50 value of 0.5μM against type II 17β-HSD, whereas the compound with a para-[2-(1-piperidinyl)-ethoxy]-benzylthio group inhibited this enzyme with an IC50 value of 0.7μM. The latter inhibitor is more selective than the former because it did not show any inhibitory potency against P450 aromatase as well as any affinity towards four steroid receptors (AR, PR, GR, ER). As a result, this inhibitor did not show any proliferative effect on androgen-sensitive Shionogi cells and estrogen-sensitive ZR-75-1 cells. These findings contribute to a better knowledge of the structure of type II 17β-HSD and offer an interesting tool to study the regulation of this enzyme in several biological systems. Copyright (C) 1999 Elsevier Science Ltd.
- Tremblay, Martin R.,Luu-The, Van,Leblanc, Gilles,Noel, Patricia,Breton, Esther,Labrie, Fernand,Poirier, Donald
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p. 1013 - 1023
(2007/10/03)
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- 6,7-DIHYDROXY-6,7-DIHYDROCANRENONE ISOMERS: IMPROVED SYNTHESIS AND PROTON NMR STUDY
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The synthesis in improved yields of one 6,7-epoxide and three 6,7-dihydroxycanrenone derivatives is described.Canrenone was the starting material for all derivatives and was obtained by acid-catalyzed lactonization of potassium canrenoate.The epoxidation of canrenone to 6α,7α-epoxycanrenone by m-chloroperbenzoic acid was improved by addition of a free radical inhibitor.This epoxide was efficiently cleaved to 6β,7α-dihydroxy-6,7-dihydrocanrenone by perchloric acid in a dioxane-water mixture; 6β,7β- and 6α,7α-dihydroxy-6,7-dihydrocanrenone were obtained by OsO4 oxidation of canrenone in ether-pyridine and subsequent reduction of the osmates by hydrogen sulfide.The stereochemistry of the products obtained from the reaction of osmium tetroxide with the 6,7-double bond of steroidal 4,6-dien-3-ones has been a controversial issue for some time.A detailed proton-NMR study of the three diol derivatives unequivocally confirmed the proposed stereochemical structure.
- Tal, Daniel M.
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p. 113 - 122
(2007/10/02)
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- Bioavailability studies of two spironolactone-preparations (author's transl)
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In a preliminary open bioequivalence investigation of orientating character (n =4) a single 100 mg dose of spironolactone (study I) led to maximum canrenone plasma levels (determined by HPLC) of 126.5 +/- 28.4 ng/ml (standard formulation 1) and 130 +/- 13.1 ng/ml (test formulation 2). The corresponding values for the sum of the fluorogenic metabolites were 418.9 +/- 43.5 ng (eq)/ml formulation 1 and 469.9 +/- 80.3 ng (eq)/ml formulation 2. A comparison of AUCs for both total fluorogenic metabolites and canrenone showed no marked differences. In a 2nd cross-over bioequivalence study with multiple dosing, mean minimum steady-state levels of 102.5 +/- 14 ng/ml (formulation 1) and 98.1 +/- 14.1 ng/ml (formulation 2) were obtained for canrenone, and 389 +/- 35.8 ng (eq)/ml (formulation 1) and 391.4 +/- 18.9 ng (eq)/ml (formulation 2) for total fluorescence. The AUCs for post-steady-state elimination, starting with the final spironolactone dose on day 10, were comparable. They were calculated to be 13226 +/-828 ng (eq)/ml . h (formulation 1) and 13858 +/- 651 ng (eq)/ml . h (formulation 2) for total fluorescence, and 3222 +/- 217 ng/ml (formulation 1) and 3167 +/- 195 ng/ml (formulation 2) for canrenone. Both spironolactone formulations can be considered as bioequivalent. The elimination half-lives (t 1/2) after a single 100 mg dose of spironolactone are (Study I) 16.4--19.1 h for canrenone and 13.6--14.0 h for the sum of the active (i.e., antagonistic to aldosterone) metabolites. Certain therapeutic conditions (e.g. multiple dosing of 100 mg spironolactone with tau = 12 h, Study II) can lead to slightly increased t 1/2 values for both canrenone (18.6--21.4 (h)) and total fluorogenic metabolites (15.8--16.9 (h)). The steady-state level for both formulations is reached by the third day of treatment.
- Vergin,Nuss,Schwarzlaender,Strobel,Weigand,Hitzenberger
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p. 1498 - 1503
(2007/10/02)
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- Spironolactone process
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Spironolactone (VIII) is produced from ethisterone (I) by formation of the lactone (IV), a halo lactone (VI) and a Δ4,6-lactone (VII).
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