EP0000368A1 - D-Homosteroids and preparations containing them, processes for the production of such d-homosteroids - Google Patents
D-Homosteroids and preparations containing them, processes for the production of such d-homosteroids Download PDFInfo
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- EP0000368A1 EP0000368A1 EP78100302A EP78100302A EP0000368A1 EP 0000368 A1 EP0000368 A1 EP 0000368A1 EP 78100302 A EP78100302 A EP 78100302A EP 78100302 A EP78100302 A EP 78100302A EP 0000368 A1 EP0000368 A1 EP 0000368A1
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- homosteroid
- homosteroids
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- 0 CC(C)(C(*)C(C(CC1)C2(C)CC3)C4C1(*)[C@](*)(CCC(*)=*)C=CC4)C2=CC3=O Chemical compound CC(C)(C(*)C(C(CC1)C2(C)CC3)C4C1(*)[C@](*)(CCC(*)=*)C=CC4)C2=CC3=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
Definitions
- the invention relates to new D-homosteroids of the formula wherein the dotted line in the A ring is an optional CC bond; X and Y together are an OC bond or X is hydrogen and Y is hydroxy; R 6 is hydrogen and R 7 is hydrogen or acylthio or R 6 and R 7 together represent a CC bond, and physiologically acceptable salts thereof.
- the invention further relates to a process for the preparation of the compounds I and pharmaceutical preparations which contain a compound of the formula I.
- acyl refers to the remainder of a saturated or unsaturated aliphatic carboxylic acid, a cycloaliphatic, an araliphatic or aromatic carboxylic acid with preferably up to 15 carbon atoms.
- acids are formic, acetic, pivalic, propionic, butter, capronic, oenanthic, undecylene, oil, cyclohexylpropionic, cyclopentylpropionic, phenylacetic and benzoic acid.
- Particularly preferred acyl groups are C 1-7 alkanoyl groups, especially acetyl.
- physiologically acceptable salts of the acids of formula I come in particular alkali metal salts, e.g. the Na and K salts and the ammonium salts; and alkaline earth metal salts, e.g. the calcium salts.
- alkali metal salts e.g. the Na and K salts and the ammonium salts
- alkaline earth metal salts e.g. the calcium salts.
- the potassium salts are preferred.
- the methyl group in the 6-position can be in the a- or ⁇ -position; the 6a-methyl isomers are preferred.
- a preferred group of compounds of the formula I are those compounds in which R 7 is acylthio, in particular C 1-7 alkanoylthio.
- the lactones of the formula I are also preferred.
- the hydrogenation of the 6-methylene group in a D-homosteroid of formula II according to process variant a) can be carried out in a manner known per se by means of hydrogenation catalysts, e.g. Precious metal catalysts, such as palladium, can be carried out.
- hydrogenation catalysts e.g. Precious metal catalysts, such as palladium, can be carried out.
- the isomerization of the 6-methylene group to form a 6-methyl-A group can also be carried out in a manner known per se, e.g. be carried out catalytically.
- Suitable isomerization catalysts are e.g. Metal catalysts as used for example in hydrogenations, especially palladium in ethanol.
- a hydrogen donor, such as cyclohexene, is expediently added as an activator for the catalyst. Undesired side reactions, such as hydrogenations by means of the hydrogen donor, can be avoided by buffering the reaction mixture.
- 1,2-saturated compounds of formula I are obtained in which R and R 7 represent hydrogen or together a C-C bond.
- An acylthio substituent R 7 can be introduced into a D-homosteroid of the formula III (process variant b) in a manner known per se by treating the steroid with an appropriate thiocarboxylic acid.
- the reaction can be carried out in an inert solvent, such as an ether, for example dioxane or tetrahydrofuran, or an alcohol, such as methanol or ethanol, or in a chlorinated hydrocarbon, such as chloroform; the reagent, for example the thiocarboxylic acid, is expediently used in excess and can serve as a solvent.
- Process variant b) gives 1,2-saturated D-homosteroids of the formula I in which R 6 is hydrogen and R 7 is acylthio.
- the 1,2-dehydrogenation of a D-homosteroid of the formula IV can be carried out in a manner known per se, for example by microbiological means or by means of dehydrogenating agents such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranil, thallium triacetate or lead tetraacetate be made.
- Suitable microorganisms for 1,2-dehydrogenation are, for example, schizomycetes, in particular those of the genera Arthrobacter, e.g. A. simplex ATCC 6946; Bacillus, e.g. B. lentus ATCC 13805 and B.
- sphaericus ATCC 7055 Pseudomonas, e.g. P. aeruginosa IFO 3505
- Flavobacterium e.g. F. flavescens IFO 3058
- Lactobacillus e.g. L. brevis IFO 3345
- Nocardia e.g. N. opaca ATCC 4276.
- an A 6_ double bond can, for example, with a substituted benzoquinone, such as chloranil [cf. J. Am. Chem. Soc. 82, 4293 (1960); 81, 5951 (1959)] or with 2,3-dichloro-5,6-dicyanobenzoquinone or with manganese dioxide [cf. J. Am. Chem. Soc. 75, 5932 (1953)].
- a substituted benzoquinone such as chloranil [cf. J. Am. Chem. Soc. 82, 4293 (1960); 81, 5951 (1959)] or with 2,3-dichloro-5,6-dicyanobenzoquinone or with manganese dioxide [cf. J. Am. Chem. Soc. 75, 5932 (1953)].
- the 2,3,6-trisdehydro compound can also be obtained directly with 2,3-dichloro-5,6-dicyanobenzoquinone or chloranil.
- Process variant c) leads to 4,6-diene, 1,4-diene and 1,4,6-triene-D homosteroids of the formula I.
- the lactone ring can be split according to process variant d) in a manner known per se, e.g. by means of a base such as potassium or sodium hydroxide in a solvent, e.g. an alcohol such as methanol, ethanol or isopropanol, at a temperature between about 0 ° C and the reflux temperature of the reaction mixture, advantageously at about 50 ° C.
- a base such as potassium or sodium hydroxide
- a solvent e.g. an alcohol such as methanol, ethanol or isopropanol
- the salts thus obtained, corresponding to the base used can be acidified, e.g. using hydrochloric acid to be converted into the free acids.
- the latter can be converted into salts by reaction with suitable bases.
- Process variant d) provides compounds of the formula I in which X is hydrogen and Y is hydroxy and their salts.
- lactonization of a compound of formula VI (variant e) or a salt thereof can be carried out in a manner known per se, for example using a strong acid, such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, in a solvent, for example water, an alcohol, such as methanol, or mixtures thereof, at a temperature between about -50 ° and 100 ° C, suitably at room temperature.
- a strong acid such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid
- the oxidation of a compound of the formula VII can be carried out according to Oppenauer, for example using aluminum isopropylate, or with oxidizing agents such as chromium trioxide (for example Jones' reagent), or according to Pfitzner-Moffatt using dimethyl sulfoxide / dicyclohexylcarbodiimide (the A 5 - 3- Ketone must then be isomerized to the ⁇ 4 -3-reton), or be carried out using pyridine / SO 3 .
- oxidizing agents such as chromium trioxide (for example Jones' reagent)
- Pfitzner-Moffatt using dimethyl sulfoxide / dicyclohexylcarbodiimide (the A 5 - 3- Ketone must then be isomerized to the ⁇ 4 -3-reton)
- oxidizing agents such as Br 2 / LiBr / Li 2 CO 3 in dimethylformamide or in the Oppenauer oxidation in the presence of benzoquinone
- the oxidation gives a 3-keto- ⁇ 4,6 grouping.
- 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) is suitable for the oxidation to a 3-keto- ⁇ 1,4,6 steroid.
- the D-homosteroids of formula I and the salts thereof show pharmacological activity.
- they are diuretically active and are suitable for blocking the action of aldosterone or deoxycorticosterone acetate and can therefore be used, for example, as potassium-sparing diuretics or for washing out edema.
- About 0.1 to 10 mg / kg per day can be used as a dosage guideline.
- the compounds of formula I and the salts thereof can be used as medicaments e.g. in the form of pharmaceutical preparations which they or their salts are mixed with an organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.
- an organic or inorganic inert carrier material suitable for enteral or parenteral administration such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc.
- the pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions.
- auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.
- the pharmaceuticals can be prepared in a manner known per se by combining the compound of the formula I with non-toxic, inert solid and / or liquid carrier materials which are customary in such preparations, such as e.g. the above, mixed and optionally brought into the desired shape.
- This compound can also be obtained by acidifying a solution of potassium 17a-hydroxy-6-methyl-3-oxo-D-homo-17aa-pregna-4,6,16-triene-21-carboxylate with dilute hydrochloric acid.
- the solution obtained is mixed with 6 ml of glacial acetic acid, poured onto 1000 ml of water and extracted with 3 ⁇ 400 ml of ether-methylene chloride (4: 1). The organic phases are saturated. Washed sodium chloride solution until neutral, dried with magnesium sulfate and evaporated to dryness.
- the crude product is purified by chromatography on 100 times the amount of silica gel with methylene chloride-acetone (98: 2). The fractions containing the product are pooled and recrystallized from acetone-hexane.
- the starting material can be prepared as follows: Dimethylsulfoxonium methylide is converted into 3-hydroxy-6-methyl-androst-5-en-17- one in dimethyl sulfoxide to give 17.20-epoxy-3ß- hydroxy-6-methyl-21-norpregn-5-en implemented. The latter is opened with ammonia under pressure to give 20-amino-3 ⁇ , 17-dihydroxy-6-methyl-21-norpregn-5-ene.
- Demjanov ring expansion is 3 beta-hydroxy-6-methyl-D-homoandrost-5-en-17-one was obtained, which by bromination with copper II bromide in boiling methanol and subsequent elimination of hydrogen bromide with calcium carbonate in boiling dimethylacetamide via 17a-bromo -3 ß- hydroxy-6-methyl-D-homoandrost-5-en-17a-one is converted into 3 ß -hydroxy-6-methyl-D-homoandrosta-5,16-dien-17a-one.
- a lithium Grignard reaction with 3-Brompropionaldehyddimethylacetal and subsequent acetylation with acetic anhydride-pyridine deliver ß 3-acetoxy-21-dimethyl-17a-hydroxy-6-methyl-D-homo-l7aa-pregna-5,16-diene.
- This acetal is split with an aqueous 70% acetic acid solution to the corresponding aldehyde.
- This cyclizes spontaneously to 3ß-acetoxy-6-methyl-D-homo-17aa-pregna-5,16-diene-21,17a-carbolactol.
- Jones oxidation provides the corresponding 21,17a-carbolactone, which is saponified with 3-hydroxy-6-methyl-D-homo-17aa-pregna-5,16-diene-21,17a-carbolactone with potassium carbonate in methanol.
- a tablet for oral administration can have the following composition:
- a capsule for oral administration can have the following composition:
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Abstract
Die Erfindung betrifft neue D-Homosteroide der Formel <IMAGE> worin die punktierte Linie im A-Ring eine fakultative C-C-Bindung; X und Y zusammen eine O-C-Bindung oder X Wasserstoff und Y Hydroxy; R<6> Wasserstoff und R<7> Wasserstoff oder Acylthio oder R<6> und R<7> zusammen eine C-C-Bindung darstellen, und physiologisch verträgliche Salze hiervon. Diese Verbindungen sind diuretisch wirksam. Sie können in an sich bekannter Weise hergestellt werden.The invention relates to new D-homosteroids of the formula <IMAGE> wherein the dotted line in the A-ring is an optional C-C bond; X and Y together are an O-C bond or X is hydrogen and Y is hydroxy; R 6 and R 7 or hydrogen or acylthio or R 6 and R 7 together represent a C-C bond, and physiologically tolerable salts thereof. These compounds are diuretically active. They can be produced in a manner known per se.
Description
Die Erfindung betrifft neue D-Homosteroide der Formel
Die Erfindung betrifft weiterhin ein Verfahren zur Herstellung der Verbindungen I sowie pharmazeutische Präparate, welche eine Verbindung der Formel I enthalten.The invention further relates to a process for the preparation of the compounds I and pharmaceutical preparations which contain a compound of the formula I.
Der Ausdruck "Acyl" bezieht sich auf den Rest einer gesättigten oder ungesättigten aliphatischen Carbonsäure, einer cycloaliphatischen, einer araliphatischen oder aromatischen Carbonsäure mit vorzugsweise bis zu 15 C-Atomen. Beispiele solcher Säuren sind Ameisen-, Essig-, Pivalin-, Propion-, Butter-, Capron-, Oenanth-, Undecylen-, Oel-, Cyclohexylpropion-, Cyclopentylpropion-, Phenylessig- und Benzoesäure. Besonders bevorzugte Acylgruppen sind C1-7-Alkanoylgruppen, insbesondere Acetyl.The term "acyl" refers to the remainder of a saturated or unsaturated aliphatic carboxylic acid, a cycloaliphatic, an araliphatic or aromatic carboxylic acid with preferably up to 15 carbon atoms. Examples of such acids are formic, acetic, pivalic, propionic, butter, capronic, oenanthic, undecylene, oil, cyclohexylpropionic, cyclopentylpropionic, phenylacetic and benzoic acid. Particularly preferred acyl groups are C 1-7 alkanoyl groups, especially acetyl.
Als physiologisch verträgliche Salze der Säuren der Formel I kommen insbesondere Alkalimetallsalze, z.B. die Na-und K-Salze sowie die Ammoniumsalze; und Erdalkalimetallsalze, z.B. die Calciumsalze in Betracht. Von den Salzen sind die Kaliumsalze bevorzugt.As physiologically acceptable salts of the acids of formula I come in particular alkali metal salts, e.g. the Na and K salts and the ammonium salts; and alkaline earth metal salts, e.g. the calcium salts. Of the salts, the potassium salts are preferred.
Die Methylgruppe in 6-Stellung kann a- oder ß-ständig sein, bevorzugt sind die 6a-Methyl-Isomeren.The methyl group in the 6-position can be in the a- or β-position; the 6a-methyl isomers are preferred.
Eine bevorzugte Gruppe von Verbindungen der Formel I sind diejenigen Verbindungen, in denen R7 Acylthio, insbesondere C1-7-Alkanoylthio ist. Weiterhin sind die Lactone der Formel I bevorzugt.A preferred group of compounds of the formula I are those compounds in which R 7 is acylthio, in particular C 1-7 alkanoylthio. The lactones of the formula I are also preferred.
Die Verbindungen der Formel I können erfindungsgemäss dadurch hergestellt werden, dass man
- a) ein D-Homosteroid der Formel
- b) ein D-Homosteroid der Formel
- c) ein D-Homosteroid der Formel
- d) in einem D-Homosteroid der Formel
- e) ein D-Homosteroid der Formel
- f) ein D-Homosteroid der Formel
- a) a D-homosteroid of the formula
- b) a D-homosteroid of the formula
- c) a D-homosteroid of the formula
- d) in a D-homosteroid of the formula
- e) a D-homosteroid of the formula
- f) a D-homosteroid of the formula
Die Hydrierung der 6-Methylengruppe in einem D-Homosteroid der Formel II gemäss Verfahrensvariante a) kann in an sich bekannter Weise mittels Hydrierkatalysatoren, z.B. Edelmetallkatalysatoren, wie Palladium, durchgeführt werden.The hydrogenation of the 6-methylene group in a D-homosteroid of formula II according to process variant a) can be carried out in a manner known per se by means of hydrogenation catalysts, e.g. Precious metal catalysts, such as palladium, can be carried out.
Die Isomerisierung der 6-Methylengruppe unter Ausbildung einer 6-Methyl-A -Gruppierung kann ebenfalls in an sich bekannter Weise, z.B. katalytisch durchgeführt werden. Als Isomerisierungskatalysatoren eignen sich z.B. Metallkatalysatoren wie sie beispielsweise auch bei Hydrierungen verwendet werden, insbesondere Palladium in Aethanol. Zweckmässig setzt man noch einen Wasserstoffdonator, wie Cyclohexen, als Aktivator für den Katalysator zu. Unerwünschte Nebenreaktionen, wie Hydrierungen durch den Wasserstoffdonator, können durch Pufferung des Reaktionsgemisches vermieden werden.The isomerization of the 6-methylene group to form a 6-methyl-A group can also be carried out in a manner known per se, e.g. be carried out catalytically. Suitable isomerization catalysts are e.g. Metal catalysts as used for example in hydrogenations, especially palladium in ethanol. A hydrogen donor, such as cyclohexene, is expediently added as an activator for the catalyst. Undesired side reactions, such as hydrogenations by means of the hydrogen donor, can be avoided by buffering the reaction mixture.
Nach der Verfahrensvariante a) werden 1,2-gesättigte Verbindungen der Formel I erhalten, in denen R und R 7 Wasserstoff oder zusammen eine C-C-Bindung darstellen.According to process variant a), 1,2-saturated compounds of formula I are obtained in which R and R 7 represent hydrogen or together a C-C bond.
Die Einführung eines Acylthio-Substituenten R7 in ein D-Homosteroid der Formel III (Verfahrensvariante b) kann in an sich bekannter Weise durch Behandlung des Steroids mit einer entsprechenden Thiocarbonsäure erfolgen. Die Reaktion kann in einem inerten Lösungsmittel wie einem Aether, z.B. Dioxan oder Tetrahydrofuran, oder einem Alkohol, wie Methanol oder Aethanol, oder in einem Chlorkohlenwasserstoff, wie Chloroform durchgeführt werden; das Reagens, z.B. die Thiocarbonsäure wird zweckmässigerweise im Ueberschuss eingesetzt und kann dabei als Lösungsmittel dienen.An acylthio substituent R 7 can be introduced into a D-homosteroid of the formula III (process variant b) in a manner known per se by treating the steroid with an appropriate thiocarboxylic acid. The reaction can be carried out in an inert solvent, such as an ether, for example dioxane or tetrahydrofuran, or an alcohol, such as methanol or ethanol, or in a chlorinated hydrocarbon, such as chloroform; the reagent, for example the thiocarboxylic acid, is expediently used in excess and can serve as a solvent.
Mittels der Verfahrensvariante b) erhält man 1,2-gesättigte D-Homosteroide der Formel I, in denen R6 Wasserstoff und R7 Acylthio darstellen.Process variant b) gives 1,2-saturated D-homosteroids of the formula I in which R 6 is hydrogen and R 7 is acylthio.
Die 1,2-Dehydrierung eines D-Homosteroids der Formel IV (Verfahrensvariante c) kann in an sich bekannter Weise z.B. auf mikrobiologischem Wege oder mittels Dehydrierungsmitteln wie Selendioxyd, 2,3-Dichlor-5,6-dicyanobenzochinon, Chloranil, Thalliumtriacetat oder Bleitetraacetat vorgenommen werden. Geeignete Mikroorganismen für die 1,2-Dehydrierung sind beispielsweise Schizomyceten, insbesondere solche der Genera Arthrobacter, z.B. A. simplex ATCC 6946; Bacillus, z.B. B. lentus ATCC 13805 und B. sphaericus ATCC 7055; Pseudomonas, z.B. P. aeruginosa IFO 3505; Flavobacterium, z.B. F. flavescens IFO 3058; Lactobacillus, z.B. L. brevis IFO 3345 und Nocardia, z.B. N. opaca ATCC 4276.The 1,2-dehydrogenation of a D-homosteroid of the formula IV (process variant c) can be carried out in a manner known per se, for example by microbiological means or by means of dehydrogenating agents such as selenium dioxide, 2,3-dichloro-5,6-dicyanobenzoquinone, chloranil, thallium triacetate or lead tetraacetate be made. Suitable microorganisms for 1,2-dehydrogenation are, for example, schizomycetes, in particular those of the genera Arthrobacter, e.g. A. simplex ATCC 6946; Bacillus, e.g. B. lentus ATCC 13805 and B. sphaericus ATCC 7055; Pseudomonas, e.g. P. aeruginosa IFO 3505; Flavobacterium, e.g. F. flavescens IFO 3058; Lactobacillus, e.g. L. brevis IFO 3345 and Nocardia, e.g. N. opaca ATCC 4276.
Die Einführung einer A6_Doppelbindung kann z.B. mit einem substituierten Benzochinon, wie Chloranil [vgl. J. Am. Chem. Soc. 82, 4293 (1960); 81, 5951 (1959)] oder mit 2,3-Dichlor-5,6-dicyanobenzochinon oder mit Mangandioxid [vgl. J. Am. Chem. Soc. 75, 5932 (1953)] erfolgen.The introduction of an A 6_ double bond can, for example, with a substituted benzoquinone, such as chloranil [cf. J. Am. Chem. Soc. 82, 4293 (1960); 81, 5951 (1959)] or with 2,3-dichloro-5,6-dicyanobenzoquinone or with manganese dioxide [cf. J. Am. Chem. Soc. 75, 5932 (1953)].
Mit 2,3-Dichlor-5,6-dicyanobenzochinon oder Chloranil kann auch direkt die 1,4,6-Trisdehydro-Verbindung erhalten werden.The 2,3,6-trisdehydro compound can also be obtained directly with 2,3-dichloro-5,6-dicyanobenzoquinone or chloranil.
Die Verfahrensvariante c) führt zu 4,6-Dien-, 1,4-Dien-und 1,4,6-Trien-D-Homosteroiden der Formel I.Process variant c) leads to 4,6-diene, 1,4-diene and 1,4,6-triene-D homosteroids of the formula I.
Die Aufspaltung des Lactonrings gemäss Verfahrensvariante d) kann in an sich bekannter Weise durchgeführt werden, z.B. mittels einer Base, wie Kalium- oder Natriumhydroxyd, in einem Lösungsmittel, z.B. einem Alkohol wie Methanol, Aethanol oder Isopropanol, bei einer Temperatur zwischen etwa 0°C und Rückflusstemperatur des Reaktionsgemisches, zweckmässig bei etwa 50°C. Die so erhaltenen, der verwendeten Base entsprechenden Salze können durch Ansäuern, z.B. mittels Chlorwasserstoffsäure, in die freien Säuren übergeführt werden. Letztere können durch Umsetzung mit geeigneten Basen in Salze übergeführt werden.The lactone ring can be split according to process variant d) in a manner known per se, e.g. by means of a base such as potassium or sodium hydroxide in a solvent, e.g. an alcohol such as methanol, ethanol or isopropanol, at a temperature between about 0 ° C and the reflux temperature of the reaction mixture, advantageously at about 50 ° C. The salts thus obtained, corresponding to the base used, can be acidified, e.g. using hydrochloric acid to be converted into the free acids. The latter can be converted into salts by reaction with suitable bases.
Die Verfahrensvariante d) liefert Verbindungen der Formel I, in denen X Wasserstoff und Y Hydroxy darstellen, und deren Salze.Process variant d) provides compounds of the formula I in which X is hydrogen and Y is hydroxy and their salts.
Die Lactonisierung einer Verbindung der Formel VI (Variante e) oder eines Salzes hiervon kann in an sich bekannter Weise durchgeführt werden, z.B. mittels einer starken Säure, wie Chlorwasserstoffsäure, Schwefelsäure oder p-Toluolsulfonsäure, in einem Lösungsmittel, z.B. Wasser, einem Alkohol, wie Methanol, oder Gemischen hiervon, bei einer Temperatur zwischen etwa -50° und 100°C, zweckmässig bei Zimmertemperatur.The lactonization of a compound of formula VI (variant e) or a salt thereof can be carried out in a manner known per se, for example using a strong acid, such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, in a solvent, for example water, an alcohol, such as methanol, or mixtures thereof, at a temperature between about -50 ° and 100 ° C, suitably at room temperature.
Die Oxydation einer Verbindung der Formel VII (Verfahrensvariante f) kann nach Oppenauer, z.B. mittels Aluminiumisopropylat, oder mit Oxydationsmitteln wie Chromtrioxid (z.B. Jones'Reagens), oder nach Pfitzner-Moffatt mittels Dimethylsulfoxid/Dicyclohexylcarbodiimid (wobei das primär erhaltene A 5 -3-Keton anschliessend zum Δ4-3-Reton isomerisiert werden muss), oder mittels Pyridin/SO3 vorgenommen werden. Bei Anwendung der vorstehend genannten Oxydationsmittel wie Br2/LiBr/Li2C03 in Dimethylformamid oder bei der Oxydation nach Oppenauer in Gegenwart von Benzochinon liefert die Oxydation eine 3-Keto-Δ4,6-Gruppierung. Für die Oxydation zu einem 3-Keto-Δ1,4,6-steroid ist beispielsweise 2,3-Dichlor-5,6- dicyano-benzochinon (DDQ) geeignet.The oxidation of a compound of the formula VII (process variant f) can be carried out according to Oppenauer, for example using aluminum isopropylate, or with oxidizing agents such as chromium trioxide (for example Jones' reagent), or according to Pfitzner-Moffatt using dimethyl sulfoxide / dicyclohexylcarbodiimide (the A 5 - 3- Ketone must then be isomerized to the Δ 4 -3-reton), or be carried out using pyridine / SO 3 . When using the above-mentioned oxidizing agents such as Br 2 / LiBr / Li 2 CO 3 in dimethylformamide or in the Oppenauer oxidation in the presence of benzoquinone, the oxidation gives a 3-keto-Δ 4,6 grouping. For example, 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) is suitable for the oxidation to a 3-keto-Δ 1,4,6 steroid.
Die Ausgangsverbindungen der Formeln II-VII können, sofern ihre Herstellung nicht bereits bekannt oder nachstehend beschrieben ist, in Analogie zu bekannten bzw. den nachstehend beschriebenen Methoden hergestellt werden.Unless their preparation is already known or described below, the starting compounds of the formulas II-VII can be prepared analogously to known methods or the methods described below.
Die D-Homosteroide der Formel I und die Salze hiervon zeigen pharmakologische Wirkung. Unter anderem sind sie diuretisch wirksam und geeignet, die Wirkung von Aldosteron oder von Desoxycorticosteron-acetat zu blockieren und können somit beispielsweise als kaliumsparende Diuretika oder zur Ausschwemmung von Oedemen Anwendung finden. Als Dosierungsrichtlinie kommen etwa O,1 bis lO mg/kg pro Tag in Betracht.The D-homosteroids of formula I and the salts thereof show pharmacological activity. Among other things, they are diuretically active and are suitable for blocking the action of aldosterone or deoxycorticosterone acetate and can therefore be used, for example, as potassium-sparing diuretics or for washing out edema. About 0.1 to 10 mg / kg per day can be used as a dosage guideline.
Die Wirksamkeit der D-Homosteroide der Formel I und der Salze hiervon kann wie folgt festgestellt werden:
- Die Testsubstanz wird episiotamizierten und catheterizierten Hunden in einer Gelatinekapsel peroral verabreicht. Unmittelbar danach werden den Tieren 0,5 pg/kg Aldosteron subcutan injiziert. Der Harn der Tiere wird über eine Periode von 6 Stunden gesammelt. Das aus der Gesamtausscheidung errechnete Na+/K+ Verhältnis wird als Mass für den Aldosteron-Antagonismus gewonnen. Bei Durchführung des Versuchs mit 7a-Acetylthio-6a-methyl-3-oxo-D-homo-17ao-pregna-4,16-dien-21,17a-carbolacton (Verbindung A) und 7a-Acetylthio-6a-methyl-3-oxo-D-homo-17aa-pregna-l,4,16-trien-21,17a-carbolacton (Verbindung B) wurden folgende Ergebnisse erhalten:
- The test substance is administered orally to episiotamized and catheterized dogs in a gelatin capsule. Immediately afterwards, 0.5 pg / kg aldosterone is injected subcutaneously into the animals. The animals' urine is passed over a period of 6 hours collected. The calculated from the total excretion of Na + / K + ratio is obtained as a measure of the A ldosteron antagonism. When carrying out the experiment with 7a-acetylthio-6a-methyl-3-oxo-D-homo-17ao-pregna-4,16-diene-21,17a-carbolactone (compound A) and 7a-acetylthio-6a-methyl-3 -oxo-D-homo-17aa-pregna-l, 4,16-triene-21,17a-carbolactone (compound B) the following results were obtained:
Die Verbindungen der Formel I und die Salze hiervon können als Heilmittel z.B. in Form pharmazeutischer Präparate Verwendung finden, welche sie oder ihre Salze in Mischung mit einem für die enterale oder parenterale Applikation geeigneten organischen oder anorganischen inerten Trägermaterial, wie z.B. Wasser, Gelatine, Gummi arabicum, Milchzucker, Stärke, Magnesiumstearat, Talk, pflanzliche Oele, Polyalkylenglykole, Vaseline, usw. enthalten. Die pharmazeutischen Präparate können in fester Form, z.B. als Tabletten, Dragees, Suppositorien, Kapseln; oder in flüssiger Form, z.B. als Lösungen, Suspensionen oder Emulsionen, vorliegen. Gegebenenfalls sind sie sterilisiert und bzw. oder enthalten Hilfsstoffe, wie Konservierungs-, Stabilisierungs-, Netz- oder Emulgiermittel, Salze zur Veränderung des osmotischen Druckes oder Puffer. Sie können auch noch andere therapeutisch wertvolle Stoffe enthalten.The compounds of formula I and the salts thereof can be used as medicaments e.g. in the form of pharmaceutical preparations which they or their salts are mixed with an organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragees, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure or buffers. They can also contain other therapeutically valuable substances.
Die Herstellung der Arzneimittel kann in an sich bekannter Weise erfolgen, indem man die Verbindung der Formel I mit zur therapeutischen Verabreichung geeigneten, nicht-toxischen, inerten, an sich in solchen Präparaten üblichen festen und/oder flüssigen Trägermaterialien, wie z.B. den vorstehend genannten, vermischt und gegebenenfalls in die gewünschte Form bringt.The pharmaceuticals can be prepared in a manner known per se by combining the compound of the formula I with non-toxic, inert solid and / or liquid carrier materials which are customary in such preparations, such as e.g. the above, mixed and optionally brought into the desired shape.
Eine Mischung von 1,0 g 6-Methylen-3-oxo-D-homo-17aa- pregna-4,16-dien-21,17a-carbolacton, 0,5 g Natriumacetat, 50 mg 5% Palladium/Kohle und 35 ml Aethanol wurde 15 Stunden unter Rückfluss erhitzt. Gleichzeitig wurden pro Stunde 2 ml einer 0,5%igen Lösung von Cyclohexen in Aethanol zugetropft. Zur Aufarbeitung wurde der Katalysator abfiltriert und das Filtrat im Vakuum eingedampft. Der Rückstand wurde auf 55 g Silicagel chromatographiert. Mit Methylenchlorid-Aceton (98:2) konnten 820 mg reines 6-Methyl-3-oxo-D-homo-17aa-pregna-4,6,16- trien-21,17a-carbolacton eluiert werden. Smp. 197-198° (aus Aceton-Hexan).
Diese Verbindung kann auch durch Ansäuern einer Lösung des Kalium-17a-hydroxy-6-methyl-3-oxo-D-homo-17aa-pregna-4,6,16-trien-21-carboxylats mit verdünnter Salzsäure erhalten werden.This compound can also be obtained by acidifying a solution of potassium 17a-hydroxy-6-methyl-3-oxo-D-homo-17aa-pregna-4,6,16-triene-21-carboxylate with dilute hydrochloric acid.
Das Ausgangsmaterial wurde wie folgt hergestellt:
- 3-Oxo-D-homo-17aa-pregna-4,16-dien-21,17a-carbolacton wurde mit Pyrrolidin in Methanol in das Enamin 3-(1-Pyrrolidinyl)-D-homo-17aa-pregna-3,5,16-trien-21,17a-carbolacton übergeführt. Durch Reaktion dieser Verbindung mit Formaldehyd in Benzol-Methanol-Wasser erhielt man 6ß-Hydroxymethyl-3-oxo-D-homo-17aa- pregna-4,16-dien-21,17a-carbolacton, Smp. 246-249°,
- 3-Oxo-D-homo-17aa-pregna-4,16-diene-21,17a-carbolactone was converted into the enamine 3- (1-pyrrolidinyl) -D-homo-17aa-pregna-3,5 with pyrrolidine in methanol , 16-triene-21,17a-carbolactone. Reaction of this compound with formaldehyde in benzene-methanol-water gave 6β-hydroxymethyl-3-oxo-D-homo-17a-pregna-4,16-diene-21,17a-carbolactone, mp. 246-249 °,
Eine Lösung von 1,0 g 6-Methyl-3-oxo-D-homo-17aa-pregna-4,6,16-trien-21,17a-carbolacton in 10 ml Thioessigsäure wurde 6 Stunden zum Rückfluss erhitzt. Die überschüssige Thioessigsäure wurde im Vakuum abgedampft und der Rückstand auf 100 g Silicagel chromatographiert. Mit Hexan-Aceton konnten 0,9 g reines 7a-Acetylthio-6a-methyl-3-oxo-D-homo-17aa-pregna-4,16-dien-21,17a-carbolacton eluiert werden. Smp. 215-217° (aus Aceton-Hexan).
Eine Lösung von 1,0 g 7a-Acetylthio-6a-methyl-3-oxo-D-homo-17aa-pregna-4,16-dien-21,17a-carbolacton und 0,9 g DDQ in 50 ml Dioxan wurde 48 Stunden unter Rückfluss gekocht. Die abgekühlte Lösung wurde durch 20 g Alox Akt. II filtriert und das Produkt mit 300 ml Essigester vollständig eluiert. Das Eluat ergab nach Abdampfen des Lösungsmittels 1,0 g Rohprodukt, das auf 50 g Silicagel chromatographiert wurde. Mit Hexan-Aceton (6:1) konnten 730 mg reines 7a-Acetylthio-6a-methyl-3-oxo-D-homo-17aa-pregna-1,4,16-trien-21,17a-carbolacton eluiert werden. Smp. 160-1620.
Zu einer Lösung von 700 mg 6-Methyl-3-oxo-D-homo-17aa- pregna-4,6,16-trien-21,17a-carbolacton in 7 ml 2-Propanol gab man eine Lösung von 126 mg KOH (85%) in 0,68 ml Wasser und erhitzte die Mischung 30 Minuten zum Rückfluss. Die Lösung wurde im Vakuum zur Trockene verdampft, der Rückstand durch Zugabe und Abdampfen von abs. Alkohol wasserfrei gemacht. Den Rückstand suspendiert man in 30 ml Essigester und nutschte das Produkt ab. Nach Trocknen über Nacht im Vakuum bei 60° erhielt man 800 mg reines 17a-Hydroxy-6-methyl-3-oxo-D-homo-17aa-pregna-4,6,16-trien-21-carbonsäure-Kaliumsalz.
Eine Mischung von 1,0 g 6-Methylen-3-oxo-D-homo-17aa- pregna-4,16-dien-21,17a-carbolacton, 200 mg 5% Pd/C, 5 ml Benzol und 5 ml Cyclohexen wurde 12 Stunden unter Argon am Rückfluss erhitzt. Die abgekühlte Mischung wurde filtriert und das Filtrat im Vakuum eingedampft. Durch Umkristallisieren des Rohproduktes aus Alkohol und Aceton erhielt man reines 6ß-Methyl-3-oxo-D-homo-17aa-pregna-4,16-dien-21,17a-carbolacton, Smp. 238-240°.
2,5 g 3ß-Hydroxy-6-methyl-D-homo-l7aa-pregna-5,16-dien-21,17a-carbolacton werden in 67 ml Dimethylformamid gelöst. Dem Gemisch werden 3,1 g Lithiumbromid und 3,1 g Lithiumcarbonat zugegeben. Die weisse Suspension wird unter Rühren und Argonbegasung auf 80°C erwärmt. Bei dieser Temperatur wird innert 80 Minuten eine Lösung von 2,62 g Brom in 21 ml Dioxan zugetropft. Nach beendigter Zugabe wird die gelb-orange Suspension noch weitere 30 Minuten bei 80°C gerührt. Zur Aufarbeitung wird die erhaltene Lösung mit 6 ml Eisessig versetzt, auf 1000 ml Wasser gegossen und mit 3 x 400 ml Aether-Methylenchlorid (4:1) extrahiert. Die organischen Phasen werden mit ges. Natriumchloridlösung neutral gewaschen, mit Magnesiumsulfat getrocknet und zur Trockene eingeengt. Das Rohprodukt wird durch Chromatographie an der 100-fachen Menge Kieselgel mit Methylenchlorid-Aceton (98:2) gereinigt. Die das Produkt enthaltenden Fraktionen werden zusammengenommen und aus Aceton-Hexan umkristallisiert. Man erhält so 3-Oxo-6-methyl-D-homo-17aα-pregna-4,6,16-trien-21,17a-carbolacton in Form von farblosen Kristallen vom Schmelzpunkt 197-198°, [a]D = +41° (Dioxan c = 0,1)2.5 g of 3β-hydroxy-6-methyl-D-homo-17aa-pregna-5,16-diene-21,17a-carbolactone are dissolved in 67 ml of dimethylformamide. 3.1 g of lithium bromide and 3.1 g of lithium carbonate are added to the mixture. The white suspension is heated to 80 ° C. with stirring and gassing with argon. A solution of 2.62 g of bromine in 21 ml of dioxane is added dropwise at this temperature within 80 minutes. After the addition has ended, the yellow-orange suspension is stirred for a further 30 minutes at 80.degree. For working up, the solution obtained is mixed with 6 ml of glacial acetic acid, poured onto 1000 ml of water and extracted with 3 × 400 ml of ether-methylene chloride (4: 1). The organic phases are saturated. Washed sodium chloride solution until neutral, dried with magnesium sulfate and evaporated to dryness. The crude product is purified by chromatography on 100 times the amount of silica gel with methylene chloride-acetone (98: 2). The fractions containing the product are pooled and recrystallized from acetone-hexane. M an thus receives 3-oxo-6-methyl-D-homo-17aα-pregna-4,6,16-triene-21,17a-carbolactone in the form of colorless crystals of melting point 197-198 °, [a] D = + 41 ° (dioxane c = 0.1)
Das Ausgangsmaterial kann wie folgt hergestellt werden: Dimethylsulfoxoniummethylid wird mit 3ß-Hydroxy-6-methyl- androst-5-en-17-on in Dimethylsulfoxid zu 17,20-Epoxy-3ß- hydroxy-6-methyl-21-norpregn-5-en umgesetzt. Letzteres wird mit Ammoniak unter Druck zu 20-Amino-3ß,17-dihydroxy-6-methyl-21-norpregn-5-en geöffnet. Durch Demjanov-Ringerweiterung wird 3ß-Hydroxy-6-methyl-D-homoandrost-5-en-17a-on erhalten, welches durch Bromierung mit Kupfer II-bromid in siedendem Methanol und nachfolgende Bromwasserstoffabspaltung mit Calciumcarbonat in siedendem Dimethylacetamid über 17a-Brom-3ß-hydroxy-6-methyl-D-homoandrost-5-en-17a-on in 3ß-Hydroxy-6-methyl-D-homoandrosta-5,16-dien-17a-on übergeführt wird. Eine Lithium-Grignard-Reaktion mit 3-Brompropionaldehyddimethylacetal und nachfolgende Acetylierung mit Acetanhydrid-Pyridin liefern 3ß-Acetoxy-21-dimethylacetal-17a-hydroxy-6-methyl-D-homo-l7aa-pregna-5,16-dien. Dieses Acetal wird mit einer wässrigen 70%igen Essigsäurelösung zum entsprechenden Aldehyd gespalten. Dieser cyclisiert spontan zu 3ß-Acetoxy-6-methyl-D-homo-17aa-pregna-5,16-dien-21,17a-carbolactol. Jones-Oxidation liefert das entsprechende 21,17a-carbolacton, das mit Kaliumcarbonat in Methanol zu 3ß-Hydroxy-6-methyl-D-homo-17aa-pregna-5,16-dien-21,17a-carbolacton verseift wird.The starting material can be prepared as follows: Dimethylsulfoxonium methylide is converted into 3-hydroxy-6-methyl-androst-5-en-17- one in dimethyl sulfoxide to give 17.20-epoxy-3ß- hydroxy-6-methyl-21-norpregn-5-en implemented. The latter is opened with ammonia under pressure to give 20-amino-3β, 17-dihydroxy-6-methyl-21-norpregn-5-ene. By Demjanov ring expansion is 3 beta-hydroxy-6-methyl-D-homoandrost-5-en-17-one was obtained, which by bromination with copper II bromide in boiling methanol and subsequent elimination of hydrogen bromide with calcium carbonate in boiling dimethylacetamide via 17a-bromo -3 ß- hydroxy-6-methyl-D-homoandrost-5-en-17a-one is converted into 3 ß -hydroxy-6-methyl-D-homoandrosta-5,16-dien-17a-one. A lithium Grignard reaction with 3-Brompropionaldehyddimethylacetal and subsequent acetylation with acetic anhydride-pyridine deliver ß 3-acetoxy-21-dimethyl-17a-hydroxy-6-methyl-D-homo-l7aa-pregna-5,16-diene. This acetal is split with an aqueous 70% acetic acid solution to the corresponding aldehyde. This cyclizes spontaneously to 3ß-acetoxy-6-methyl-D-homo-17aa-pregna-5,16-diene-21,17a-carbolactol. Jones oxidation provides the corresponding 21,17a-carbolactone, which is saponified with 3-hydroxy-6-methyl-D-homo-17aa-pregna-5,16-diene-21,17a-carbolactone with potassium carbonate in methanol.
Eine Tablette zur oralen Verabreichung kann folgende Zusammensetzung aufweisen:
Eine Kapsel zur oralen Verabreichung kann folgende Zusammensetzung aufweisen:
Claims (14)
und physiologisch verträgliche Salze hiervon, dadurch gekennzeichnet, dass man
and physiologically acceptable salts thereof, characterized in that
und physiologisch verträgliche Salze hiervon.8. D-homosteroids of the formula
and physiologically acceptable salts thereof.
und physiologisch verträgliche Salze hiervon, wenn hergestellt nach dem Verfahren der Ansprüche 1-5.13. D-homosteroids of the formula I
and physiologically acceptable salts thereof, when prepared by the process of claims 1-5.
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LU77699 | 1977-07-06 | ||
LU77699A LU77699A1 (en) | 1977-07-06 | 1977-07-06 | METHOD FOR PRODUCING NEW D-HOMOSTEROIDS |
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EP0000368A1 true EP0000368A1 (en) | 1979-01-24 |
EP0000368B1 EP0000368B1 (en) | 1981-04-29 |
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Application Number | Title | Priority Date | Filing Date |
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EP78100302A Expired EP0000368B1 (en) | 1977-07-06 | 1978-07-04 | D-homosteroids and preparations containing them, processes for the production of such d-homosteroids |
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US (2) | US4202823A (en) |
EP (1) | EP0000368B1 (en) |
JP (1) | JPS5414959A (en) |
AU (1) | AU3760378A (en) |
DE (2) | DE2860642D1 (en) |
DK (1) | DK304778A (en) |
ES (1) | ES471470A1 (en) |
FI (1) | FI782137A (en) |
FR (1) | FR2396767A1 (en) |
GB (1) | GB2000781A (en) |
IL (1) | IL55049A0 (en) |
IT (1) | IT1096965B (en) |
LU (1) | LU77699A1 (en) |
NL (1) | NL7805939A (en) |
NO (1) | NO782349L (en) |
PT (1) | PT68254A (en) |
SE (1) | SE7807586L (en) |
ZA (1) | ZA783731B (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2244497A1 (en) * | 1973-09-26 | 1975-04-18 | Hoffmann La Roche | |
DE2424752A1 (en) * | 1974-05-22 | 1975-12-04 | Schering Ag | Steroid 17-spirolactones prepn. - by treating corresponding gamma-hydroxy-propionic acid dimethylamide cpds. with acidic cation exchangers |
NL7713229A (en) * | 1976-12-20 | 1978-06-22 | Hoffmann La Roche | NEW D-HOMOSTEROIDS. |
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US3766213A (en) * | 1966-04-19 | 1973-10-16 | Hoffmann La Roche | Retrosteroid a ring formation |
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1977
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-
1978
- 1978-05-31 NL NL7805939A patent/NL7805939A/en not_active Application Discontinuation
- 1978-06-29 ZA ZA00783731A patent/ZA783731B/en unknown
- 1978-06-29 AU AU37603/78A patent/AU3760378A/en active Pending
- 1978-06-30 IL IL7855049A patent/IL55049A0/en unknown
- 1978-06-30 US US05/921,036 patent/US4202823A/en not_active Expired - Lifetime
- 1978-07-03 FI FI782137A patent/FI782137A/en not_active Application Discontinuation
- 1978-07-04 DE DE7878100302T patent/DE2860642D1/en not_active Expired
- 1978-07-04 DE DE19782829403 patent/DE2829403A1/en not_active Withdrawn
- 1978-07-04 JP JP8060578A patent/JPS5414959A/en active Granted
- 1978-07-04 FR FR7819872A patent/FR2396767A1/en active Granted
- 1978-07-04 IT IT25305/78A patent/IT1096965B/en active
- 1978-07-04 EP EP78100302A patent/EP0000368B1/en not_active Expired
- 1978-07-05 SE SE7807586A patent/SE7807586L/en unknown
- 1978-07-05 ES ES471470A patent/ES471470A1/en not_active Expired
- 1978-07-05 DK DK783047A patent/DK304778A/en unknown
- 1978-07-05 NO NO782349A patent/NO782349L/en unknown
- 1978-07-05 GB GB7828869A patent/GB2000781A/en not_active Withdrawn
- 1978-07-05 PT PT68254A patent/PT68254A/en unknown
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1979
- 1979-10-05 US US06/082,269 patent/US4285880A/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2244497A1 (en) * | 1973-09-26 | 1975-04-18 | Hoffmann La Roche | |
DE2424752A1 (en) * | 1974-05-22 | 1975-12-04 | Schering Ag | Steroid 17-spirolactones prepn. - by treating corresponding gamma-hydroxy-propionic acid dimethylamide cpds. with acidic cation exchangers |
NL7713229A (en) * | 1976-12-20 | 1978-06-22 | Hoffmann La Roche | NEW D-HOMOSTEROIDS. |
Also Published As
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GB2000781A (en) | 1979-01-17 |
FI782137A (en) | 1979-01-07 |
DE2829403A1 (en) | 1979-01-25 |
DE2860642D1 (en) | 1981-08-06 |
US4202823A (en) | 1980-05-13 |
FR2396767A1 (en) | 1979-02-02 |
IT7825305A0 (en) | 1978-07-04 |
EP0000368B1 (en) | 1981-04-29 |
SE7807586L (en) | 1979-01-07 |
ZA783731B (en) | 1979-07-25 |
AU3760378A (en) | 1980-01-03 |
DK304778A (en) | 1979-01-07 |
JPS5414959A (en) | 1979-02-03 |
JPS6160839B2 (en) | 1986-12-23 |
FR2396767B1 (en) | 1980-07-18 |
PT68254A (en) | 1978-08-01 |
NO782349L (en) | 1979-01-09 |
IT1096965B (en) | 1985-08-26 |
IL55049A0 (en) | 1978-08-31 |
US4285880A (en) | 1981-08-25 |
LU77699A1 (en) | 1979-03-26 |
ES471470A1 (en) | 1979-09-16 |
NL7805939A (en) | 1979-01-09 |
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