EP0245276A1 - 1$g(a).7$g(a)-DITHIO SUBSTITUTED SPIROLACTONE, PREPARATION PROCESS THEREOF AND UTILIZATION THEREOF AS DRUG - Google Patents

1$g(a).7$g(a)-DITHIO SUBSTITUTED SPIROLACTONE, PREPARATION PROCESS THEREOF AND UTILIZATION THEREOF AS DRUG

Info

Publication number
EP0245276A1
EP0245276A1 EP86901339A EP86901339A EP0245276A1 EP 0245276 A1 EP0245276 A1 EP 0245276A1 EP 86901339 A EP86901339 A EP 86901339A EP 86901339 A EP86901339 A EP 86901339A EP 0245276 A1 EP0245276 A1 EP 0245276A1
Authority
EP
European Patent Office
Prior art keywords
methylene
carbolactone
oxo
pregn
dithio
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP86901339A
Other languages
German (de)
French (fr)
Inventor
Klaus Nickisch
Henry Laurent
Dieter Bittler
Rudolf Wiechert
Wolfgang Losert
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0245276A1 publication Critical patent/EP0245276A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • C07J53/002—Carbocyclic rings fused
    • C07J53/004—3 membered carbocyclic rings
    • C07J53/008—3 membered carbocyclic rings in position 15/16

Definitions

  • the invention relates to new 1 ⁇ .7 ⁇ -disubstituted spirolactones, processes for their preparation and pharmaceutical preparations containing them according to the claims.
  • R 1 in formula I as an alkyl radical having 1 to 3 carbon atoms represents, for example, a methyl, ethyl, propyl or isopropyl group.
  • 1 to 3 carbon atoms represents, for example, the formyl
  • the new compounds of general formula I have the property of canceling or reversing the effect of aldosterone or deoxycorticosterone on the sodium and potassium salt excretion.
  • the compounds according to the invention are therefore suitable for the treatment of certain forms of hypertension, of edema, for example in the case of heart failure, in liver cirrhosis and nephrotic syndrome, primary and secondary aldosteronism and other endocrinological disorders caused by aldosterone. They can also be used as diuretics.
  • the active compounds according to the invention Compared to the commercially available spironolactone and its metabolites, which contain a mercapto or methylthio group instead of the acetylthio group in the 7 ⁇ position (Steroids 20 (1972) 41), the active compounds according to the invention have the advantage of higher activity and a prolonged duration of action, the effect also occurring is delayed.
  • This activity profile indicates that the compounds according to the invention are biologically active compounds which are metabolic only in the organism be activated to so-called pro-drugs.
  • such compounds have the advantage that the content of active substance in the blood plasma is less exposed to fluctuations.
  • the compounds according to the invention are further characterized in that they are endocrinologically ineffective. You bind e.g. practically not at all on the androgen receptor.
  • the compounds according to the invention which contain a thio group in both the 1 ⁇ and 7 ⁇ positions, have been shown to be superior to the known spironolactone in their antialdosterone activity in the test model by Hollmann (Naunyn-Schmiedebergs Arch. Exp. Path. Pharmak. 247 (1964) 419) and are distinguished from spironolactone by a later onset of action.
  • the new active ingredients can be used in the same way as for spironolactone.
  • the dosage of the active ingredients is below that of spironolactone. Due to the longer lasting effect, however, the new active ingredients usually only need to be applied once a day.
  • the active ingredients can be processed into pharmaceutical preparations, preferably for enteral application, according to methods of galenics known per se.
  • enteral application can be considered in particular tablets, coated tablets or capsules which contain about 25 to 200 mg of active ingredient per dose unit in an inert carrier material.
  • the ⁇ 1.4.6 -unsaturated 3-ketopregnatriene of the formula II is expediently dissolved in a suitable protic solvent or in a mixture thereof, the desired thioalkanoic acid is added and warms the reaction mixture to temperatures above room temperature up to the boiling point of the solvent.
  • suitable solvents or mixtures thereof are methanol, acetone and tetrahydrofuran.
  • solubilizers such as diisopropyl ether, benzene and heptane do not disturb the course of the reaction.
  • the starting material of the formula II is reacted with the corresponding alkyl mercaptan in a suitable solvent.
  • suitable solvents are in particular organic bases such as pyridine, piperidine, collidine and lutidine.
  • the reaction mixture can be warmed to temperatures above room temperature if extremely long reaction times are undesirable.
  • alkali metal alcoholate e.g. Potassium methylate
  • Any subsequent esterification of the mercapto group is carried out according to the steroid chemistry methods for the esterification of sterols.
  • the esterification is preferably carried out with an activated derivative of a lower aliphatic carboxylic acid in the presence of pyridine and / or 4-dimethylaminopyridine.
  • Suitable derivatives are, in particular, the anhydrides and halides of lower carboxylic acids, in particular acetic and propionic acids.
  • reaction products according to the invention are separated off by methods known per se, such as precipitation, filtration or extraction, and are purified, for example, by chromatography and / or recrystallization.
  • UV: ⁇ 236 16,000 (in methanol).
  • Example 3a an ice-cooled solution of 6.0 g of 15 ⁇ .16ß-methylene-1 ⁇ .7 ⁇ -dimethylthio-3-oxo-17 ⁇ -pregn-4-en-21.17-carbolactone in 187 ml of ethanol is mixed with 2.27 g of potassium ethylate added and stirred for 45 minutes while cooling and passing argon. For working up, it is poured into ice water. The precipitate is filtered off, washed with water and dried.
  • UV: ⁇ 236 11 600 (in methanol).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouvelles spirolactones 1alpha.7alpha-dithio substituées de formule générale (I) dans laquelle R1 représente alkyl C1-3 et alcyl C1-3 et R2 représente l'hydrogène, alkyl C1-3 et acyl C1-3, leur préparation et leur utilisation comme médicament. Les composés possèdent une activité antialdostérone et présentent le profil d'activité d'un pro-médicament (''pro-drugs'').New substituted 1alpha.7alpha-dithio spirolactones of general formula (I) in which R1 represents alkyl C1-3 and alkyl C1-3 and R2 represents hydrogen, alkyl C1-3 and acyl C1-3, their preparation and their use as medication. The compounds possess antialdosterone activity and exhibit the activity profile of a pro-drug.

Description

1α.7α-Dithiosubstituierte Spirolactone, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel 1α.7α-Dithio-substituted spirolactones, process for their preparation and their use as medicaments
Die Erfindung betrifft neue 1α.7α-disubstituierte Spirolactone, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Präparate gemäß den Patentansprüchen.The invention relates to new 1α.7α-disubstituted spirolactones, processes for their preparation and pharmaceutical preparations containing them according to the claims.
R1 in Formel I in der Bedeutung eines Alkylrestes mit 1 bis 3 Kohlenstoffatomen stellt zum Beispiel eine Methyl-, Ethyl-, Propyl- oder Isopropylgruppe dar.R 1 in formula I as an alkyl radical having 1 to 3 carbon atoms represents, for example, a methyl, ethyl, propyl or isopropyl group.
R1 in Formel I in der Bedeutung eines Acylrestes mitR 1 in formula I with the meaning of an acyl radical
1 bis 3 Kohlenstoffatomen stellt zum Beispiel die Formyl-,1 to 3 carbon atoms represents, for example, the formyl,
Acetyl- und Propionylgruppe dar.Acetyl and propionyl group.
Die neuen Verbindungen der allgemeinen Formel I haben die Eigenschaft, die Wirkung von Aldosteron oder Desoxycorticosteron auf die Natrium- und Kaliumsalzausscheidung aufzuheben bzw. umzukehren. Die erfindungsgemäßen Verbindungen sind damit geeignet zur Behandlung von bestimmten Formen der Hypertonie, von Ödemen, zum Beispiel bei Herzinsuffizienz, bei Leberzirrhose und nephrotischem Syndrom, des primären und sekundären Aldosteronismus und anderer durch Aldosteron bedingter endokrinologischer Störungen. Sie können außerdem als Diuretika eingesetzt werden.The new compounds of general formula I have the property of canceling or reversing the effect of aldosterone or deoxycorticosterone on the sodium and potassium salt excretion. The compounds according to the invention are therefore suitable for the treatment of certain forms of hypertension, of edema, for example in the case of heart failure, in liver cirrhosis and nephrotic syndrome, primary and secondary aldosteronism and other endocrinological disorders caused by aldosterone. They can also be used as diuretics.
Die erfindungsgemäßen Wirkstoffe besitzen gegenüber dem handelsüblichen Spironolacton und seinen Metaboliten, die in 7α-Stellung statt der Acetylthio- eine Mercapto- oder Methylthiogruppe enthalten (Steroids 20 (1972) 41), den Vorteil der höheren Aktivität und der verlängerten Wirkungsdauer, wobei auch der Wirkungseintritt verzögert ist. Dieses Wirkungsprofil deutet darauf, daß es sich bei den erfindunsgemäßen Verbindungen um biologisch aktive Verbindungen handelt, die erst im Organismus metabolisch aktiviert werden, um sogenannte pro-drugs.Compared to the commercially available spironolactone and its metabolites, which contain a mercapto or methylthio group instead of the acetylthio group in the 7α position (Steroids 20 (1972) 41), the active compounds according to the invention have the advantage of higher activity and a prolonged duration of action, the effect also occurring is delayed. This activity profile indicates that the compounds according to the invention are biologically active compounds which are metabolic only in the organism be activated to so-called pro-drugs.
Derartige Verbindungen haben in ihrer medizinischen Anwendung den Vorteil, daß der Gehalt an Wirkstoff im Blutplasma weniger großen Schwankungen ausgesetzt ist.In their medical application, such compounds have the advantage that the content of active substance in the blood plasma is less exposed to fluctuations.
Die erfindungsgemäßen Verbindungen zeichnen sich des weiteren dadurch aus, daß sie endokrinologisch unwirksam sind. Sie binden z.B. am Androgenrezeptor praktisch überhaupt nicht.The compounds according to the invention are further characterized in that they are endocrinologically ineffective. You bind e.g. practically not at all on the androgen receptor.
Die erfindungsgemäßen Verbindungen, die sowohl in 1α-wie auch in 7α-Stellung eine Thiogruppe enthalten, erweisen sich im Testmodell von Hollmann (Naunyn-Schmiedebergs Arch. Exp. Path. Pharmak. 247 (1964) 419) dem bekannten Spironolacton in ihrer Antialdosteronwirkung überlegen und zeichnen sich gegenüber Spironolacton durch einen späteren Wirkungseintritt aus.The compounds according to the invention, which contain a thio group in both the 1α and 7α positions, have been shown to be superior to the known spironolactone in their antialdosterone activity in the test model by Hollmann (Naunyn-Schmiedebergs Arch. Exp. Path. Pharmak. 247 (1964) 419) and are distinguished from spironolactone by a later onset of action.
Als besonders pharmakologisch wertvoll hat sich das 1α.7α-Diacetylthio-15ß.16ß-methylen-3-oxo-17α--pregn-4-en-21.17-carbolacton erwiesen.The 1α.7α-diacetylthio-15ß.16ß-methylene-3-oxo-17α - pregn-4-en-21.17-carbolactone has proven to be particularly pharmacologically valuable.
Die Anwendung der neuen Wirkstoffe kann an sich in der gleichen Weise wie beim Spironolacton erfolgen. Die Dosierung der Wirkstoffe liegt unterhalb der von Spironolacton. Aufgrund der länger anhaltenden Wirkung brauchen die neuen Wirkstoffe jedoch in der Regel nur einmal am Tag appliziert zu werden.The new active ingredients can be used in the same way as for spironolactone. The dosage of the active ingredients is below that of spironolactone. Due to the longer lasting effect, however, the new active ingredients usually only need to be applied once a day.
Die Wirkstoffe können nach an sich bekannten Methoden der Galenik zu pharmazeutischen Präparaten, vorzugsweise für die enterale Applikation, verarbeitet werden. Für die enterale Applikation kommen insbesondere Tabletten, Dragees oder Kapseln in Frage, die pro Dosiseinheit etwa 25 bis 200 mg Wirkstoff in einem inerten Trägermaterial enthalten.The active ingredients can be processed into pharmaceutical preparations, preferably for enteral application, according to methods of galenics known per se. For the enteral application can be considered in particular tablets, coated tablets or capsules which contain about 25 to 200 mg of active ingredient per dose unit in an inert carrier material.
Die Herstellung der erfindungsgemäßen Verbindungen der allgemeinen Formel I erfolgt gemäß Anspruch nach an sich bekannten Methoden.The compounds of general formula I according to the invention are prepared according to claim by methods known per se.
Zur Herstellung der erfindungsgemäßen Verbindungen, die in 1α- und 7α-Stellung eine Acylthiogruppe enthalten, löst man das Δ 1.4.6-ungesättigte 3-Ketopregnatrien der Formel II zweckmäßigerweise in einem geeigneten protischen Lösungsmittel oder in einem Gemisch davon, gibt die gewünschte Thioalkansäure hinzu und erwärmt das Reaktionsgemisch auf Temperaturen oberhalb Raumtemperatur bis zur Siedetemperatur des Lösungsmittels. Geeignete Lösungsmittel bzw. Gemische davon sind Methanol, Aceton und Tetrahydrofuran. Gegebenenfalls verwendete Lösungsvermittler wie Diisopropyläther, Benzol und Heptan stören den Reaktionsverlauf nicht.To prepare the compounds according to the invention which contain an acylthio group in the 1α- and 7α-positions, the Δ 1.4.6 -unsaturated 3-ketopregnatriene of the formula II is expediently dissolved in a suitable protic solvent or in a mixture thereof, the desired thioalkanoic acid is added and warms the reaction mixture to temperatures above room temperature up to the boiling point of the solvent. Suitable solvents or mixtures thereof are methanol, acetone and tetrahydrofuran. Optionally used solubilizers such as diisopropyl ether, benzene and heptane do not disturb the course of the reaction.
Zur Herstellung von Verbindungen der Formel I, die in 1α- und in 7α-Stellung eine Alkylthiogruppe aufweisen, wird das Ausgangsmaterial der Formel II in einem geeigneten Lösungsmittel mit dem entsprechenden Alkylmercaptan umgesetzt. Geeignete Lösungsmittel sind insbesondere organische Basen wie Pyridin, Piperidin, Collidin und Lutidin. Das Reaktionsgemisch kann auf Temperaturen oberhalb Raumtemperatur erwärmt werden, wenn extrem lange Reaktionszeiten unerwünscht sind. Zur Herstellung von Verbindungen der Formel I, die in der 1α- und in der 7α-Stellung nicht identische Substituenten R 1 und R2 aufweisen, geht man so vor, daß man entweder von den 1α.7α-disubstituierten Verbindungen der Formel I ausgeht und diese partiell zu den entsprechenden Δ1-ungesättigten Verbindungen der Formel II spaltet oder daß man gleich von einer Verbindung der Formel II ausgeht, die in 1.2-Stellung ungesättigt und in 7 α-Stellung mit einer Mercapto-, Acethylthio- oder Methylthiogruppe substituiert ist.To prepare compounds of the formula I which have an alkylthio group in the 1α- and 7α-position, the starting material of the formula II is reacted with the corresponding alkyl mercaptan in a suitable solvent. Suitable solvents are in particular organic bases such as pyridine, piperidine, collidine and lutidine. The reaction mixture can be warmed to temperatures above room temperature if extremely long reaction times are undesirable. To prepare compounds of the formula I which have non-identical substituents R 1 and R 2 in the 1α and 7α positions, the procedure is either to start with the 1α.7α-disubstituted compounds of the formula I and this partially cleaves to the corresponding Δ 1 -unsaturated compounds of the formula II or that one starts from a compound of the formula II which is unsaturated in the 1,2-position and substituted in the 7 α-position with a mercapto, acethylthio or methylthio group.
Die partielle Abspaltung einer Alkylthiogruppe erfolgt mit einem Alkalimetallalkoholat, wie z.B. Kaliummethylat, bei Temperaturen unter Raumtemperatur.The partial cleavage of an alkylthio group takes place with an alkali metal alcoholate, e.g. Potassium methylate, at temperatures below room temperature.
Die sich gegebenenfalls anschließende Veresterung der Mercaptogruppe wird nach den in der Steroidchemie üblichen Verfahren für die Veresterungen von Sterolen durchgeführt. Die Veresterung erfolgt vorzugsweise mit einem aktivierten Derivat einer niederen aliphatischen Carbonsäure in Gegenwart von Pyridin und/oder 4-Dimethylaminopyridin. Als Derivate kommen insbesondere die Anhydride und Halogenide von niederen Carbonsäuren, insbesondere Essig- und Propionsäure, in Frage.Any subsequent esterification of the mercapto group is carried out according to the steroid chemistry methods for the esterification of sterols. The esterification is preferably carried out with an activated derivative of a lower aliphatic carboxylic acid in the presence of pyridine and / or 4-dimethylaminopyridine. Suitable derivatives are, in particular, the anhydrides and halides of lower carboxylic acids, in particular acetic and propionic acids.
Die erfindungägemäßen Reaktionsprodukte werden nach an sich bekannten Methoden wie Fällung, Filtration oder Extraktion abgetrennt und beispielsweise durch Chromatographie und/oder Umkristallisation gereinigt.The reaction products according to the invention are separated off by methods known per se, such as precipitation, filtration or extraction, and are purified, for example, by chromatography and / or recrystallization.
Sowgit die zur Durchführung des erfindungsgemäßen Verfahrens benötigten Ausgangsverbindungen nicht bekannt sind, wird ihre Darstellung beschrieben. Herstellung des AusgangsmaterialsTo the extent that the starting compounds required for carrying out the process according to the invention are not known, their presentation is described. Production of the starting material
A. 15ß.16ß-Methylen-7α-methylthio-3-oxo-17α-pregna- 1.4-dien-21.17-carbolactonA. 15ß.16ß-methylene-7α-methylthio-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone
4,0 g 15ß.16ß-Methylen-3-oxo-17α-pregna-4.6-dien- 21.17-carbolacton werden in 40 ml Methanol und 4 ml Piperxdin gelöst. In die Lösung wird unter Eiskühlung aus einer Stahlflasche Methanthiol über einen Zeitraum von 30 Minuten eingeleitet. Anschließend läßt man 15 Stunden bei Raumtemperatur stehen und gießt die Mischung danach in Eiswasser. Das ausgefällte Produkt wird abfiltriert, mit Wasser gewaschen, getrocknet und an Kieselgel chromatographiert. Mit 8,8-10,3 % Aceton-Dichlormethan eluiert man 2,99 g, die aus Hexan-Dichlormethan-Diisoprbpylether umkristallisiert werden. Ausbeute: 1,80 g 15ß.16ß- Methylen-7α-methylthio-3-oxo-17α-pregn-4-en-24.17- carbolacton vom Schmelzpunkt 269 ºC.4.0 g of 15β.16ß-methylene-3-oxo-17α-pregna-4.6-diene-21.17-carbolactone are dissolved in 40 ml of methanol and 4 ml of piperxdin. Methane thiol is introduced into the solution from a steel bottle with ice cooling over a period of 30 minutes. The mixture is then left to stand at room temperature for 15 hours and the mixture is then poured into ice water. The precipitated product is filtered off, washed with water, dried and chromatographed on silica gel. 2.99 g are eluted with 8.8-10.3% acetone-dichloromethane and are recrystallized from hexane-dichloromethane-diisopryl ether. Yield: 1.80 g of 15β.16ß-methylene-7α-methylthio-3-oxo-17α-pregn-4-en-24.17-carbolactone melting at 269 ° C.
UV: ε236 = 16 000 (in Methanol).UV: ε 236 = 16,000 (in methanol).
Eine Lösung von 600 mg 15ß.16ß-Methylen-7α-methylthio- 3-oxo-17α-pregn-4-en-21.17-carbolacton in 12 ml Dioxan wird mit 660 mg 2.3-Dichlor-5.6-dicyan-1.4-benzochinon versetzt und 17 Stunden bei 100 ºC gerührt. Die Reaktionsmischung wird mit Dethylether verdünnt, mit Natriumhydrogencarbonatlösung und Wasser gewaschen, getrocknet und eingedampft. Der Rückstand wird an Kieselgel chromatographiert. Nach dem Verreiben mit Diisopropylether erhält man 145 mg 15ß.16ß-Methylen- 7α-methylthio-3-oxo-17α-pregna-1.4-dien-21.17-carbolacton. Schmelzpunkt : 265.3 ºC. UV: ɛ244 = 15 400 (in Methanol). B. 7α-Mercapto-15ß.16ß-methylen-3-oxo-17g-pregna- 1.4-dien-21.17-carbolactonA solution of 600 mg of 15ß.16ß-methylene-7α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone in 12 ml of dioxane is mixed with 660 mg of 2,3-dichloro-5.6-dicyan-1.4-benzoquinone and stirred at 100 ° C for 17 hours. The reaction mixture is diluted with ethyl ether, washed with sodium hydrogen carbonate solution and water, dried and evaporated. The residue is chromatographed on silica gel. After trituration with diisopropyl ether, 145 mg of 15β.16ß-methylene-7α-methylthio-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone are obtained. Melting point: 265.3 ° C. UV: ɛ 244 = 15 400 (in methanol). B. 7α-Mercapto-15ß.16ß-methylene-3-oxo-17g-pregna-1.4-diene-21.17-carbolactone
Zu einer auf 0 ºC gekühlten Suspension von 640 mg 7α-Acetylthio-15ß.16ß-methylen-3-oxo-17α-pregna- 1.4-dien-21.17-carbolacton (EPO 099 853) in 5 ml Methanol und 8 ml Tetrahydrofuran tropft man 277 mg Kaliumethylat in 7 ml Methanol und rührt eine Stunde nach. Zur Aufarbeitung verdünnt man mit Dichlormethan, wäscht mit verdünnter Schwefelsäure und Wasser, trocknet über Magnesiumsulfat und engt im Vakuum ein. Das erhaltene Rohprodukt wird durch Säulenchromatographie gereinigt. Man erhält 296 mg 7α-Mercapto- 15ß.16ß-methylen-3-oxo-17α-pregna-1.4-dien-21.17- carbolacton. Schmelzpunkt: 258,7 °C. [α]D = +17 ° (in Chloroform).To a suspension cooled to 0 ° C of 640 mg of 7α-acetylthio-15ß.16ß-methylene-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone (EPO 099 853) in 5 ml of methanol and 8 ml of tetrahydrofuran is added dropwise 277 mg of potassium ethylate in 7 ml of methanol and stirred for an hour. For working up, dilute with dichloromethane, wash with dilute sulfuric acid and water, dry over magnesium sulfate and concentrate in vacuo. The crude product obtained is purified by column chromatography. 296 mg of 7α-mercapto-15β.16ß-methylene-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone are obtained. Melting point: 258.7 ° C. [α] D = +17 ° (in chloroform).
Die nachfolgenden Beispiele sollen die Erfindung erläutern. The following examples are intended to explain the invention.
Beispiel 1example 1
Eine Lösung von 1,5 g 15ß.16ß-Methylen-3-oxo-17α-pregna-1.4.6-trien-21.17-carbolacton in 30 ml Methanol und 6 ml Wasser wird mit 2,1 ml Thioessigsäure versetzt und 16 Stunden bei Raumtemperatur stehengelassen. Zur Aufarbeitung verdünnt man mit Diethylether, wäscht mit Natriumhydrogencarbonatlösung und Wasser, trocknet über Natriumsulfat und dampft im Vakuum ein. Der Rückstand wird an Kieselgel chromatographiert. Man eluiert 570 mg 1α.7α-Diacetylthio-15ß.16ß-methylen-3-oxo-17α-pregn-4-en-21.17-carbolacton.A solution of 1.5 g of 15β.16ß-methylene-3-oxo-17α-pregna-1.4.6-triene-21.17-carbolactone in 30 ml of methanol and 6 ml of water is mixed with 2.1 ml of thioacetic acid and 16 hours at Leave room temperature. For working up, diluted with diethyl ether, washed with sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. 570 mg of 1α.7α-diacetylthio-15ß.16ß-methylene-3-oxo-17α-pregn-4-en-21.17-carbolactone is eluted.
UV: ɛ234 = 16 400 (in Methanol). [α]D = -28 ° (in Chloroform).UV: ɛ 234 = 16 400 (in methanol). [α] D = -28 ° (in chloroform).
Beispiel 2Example 2
In eine Lösung von 8,6 g 15ß.16ß-Methylen-3-oxo-17α--pregna-1.4.6-trien-21.17-carbolacton in 86 ml Methanol und 1,72 ml Piperidin wird Methanthiol bis fast zur Sättigung eingeleitet. Anschließend läßt man das Reaktionsgemisch 16 Stunden bei Raumtemperatur stehen. Zur Aufarbeitung verdünnt man mit Methylenchlorid, wäscht mit Wasser, trocknet über Natriumsulfat und dampft im Vakuum ein. Der Rückstand wird an Kieselgel chromatographiert. Nach dem Verreiben mit Diisopropylether werden 6.9 g 15ß.16ß-Methylen-1α.7α-dimethylthio-3-oxo-17α-pregn-4-en-21.17-carbolacton vom Schmelzpunkt 129,1 ºC erhalten. UV: ε240 = 12 000 (in Methanol). [α]D = +12 ° (in Chloroform). Beispiel 3 a) eine eisgekühlte Lösung von 6,0 g 15ß.16ß-Methylen- 1α.7α-dimethylthio-3-oxo-17α-pregn-4-en-21.17-carbolacton in 187 ml Ethanol wird mit 2,27 g Kaliumethylat versetzt und 45 Minuten unter Kühlung und überleiten von Argon gerührt. Zur Aufarbeitung wird in Eiswasser eingegossen. Der ausgefallene Niederschlag wird abgesaugt, mit Wasser gewaschen und getrocknet. Nach Chromatographie an Kieselgel und Kristallisation a us Aceton werden 3,1 g 15ß.16ß- Methylen-7α-methylthio-3-oxo-17α-pregna-1.4-dien- 21.17-carbolacton vom Schmelzpunkt 267,4 ºC erhalten.In a solution of 8.6 g of 15ß.16ß-methylene-3-oxo-17α-pregna-1.4.6-triene-21.17-carbolactone in 86 ml of methanol and 1.72 ml of piperidine, methanethiol is introduced almost to saturation. The reaction mixture is then left to stand at room temperature for 16 hours. For working up, it is diluted with methylene chloride, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel. After trituration with diisopropyl ether, 6.9 g of 15β.16ß-methylene-1α.7α-dimethylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone with a melting point of 129.1 ° C. are obtained. UV: ε 240 = 12,000 (in methanol). [α] D = +12 ° (in chloroform). Example 3a) an ice-cooled solution of 6.0 g of 15β.16ß-methylene-1α.7α-dimethylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone in 187 ml of ethanol is mixed with 2.27 g of potassium ethylate added and stirred for 45 minutes while cooling and passing argon. For working up, it is poured into ice water. The precipitate is filtered off, washed with water and dried. After chromatography on silica gel and crystallization from acetone, 3.1 g of 15β.16β-methylene-7α-methylthio-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone with a melting point of 267.4 ° C. are obtained.
b) 1,0 g 15ß.16ß-Methylen-7α-methylthio-3-oxo-17α-pregna- 1.4-dien-21.17-carbolacton werden unter den im Beispiel 1 beschriebenen Bedingungen umgesetzt und aufgearbeitet. Nach Chromatographie an Kieselgel und Verreiben mit Diisopropylether werden 960 mg 1α-Acetylthio-15ß.16ß- methylen-7α-methylthio-3-oxo-17α-pregn-4-en-21.17- carbolacton vom Schmelzpunkt 192,3 ºC erhalten.b) 1.0 g of 15β.16ß-methylene-7α-methylthio-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone are reacted and worked up under the conditions described in Example 1. After chromatography on silica gel and trituration with diisopropyl ether, 960 mg of 1α-acetylthio-15β.16ß-methylene-7α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone of melting point 192.3 ° C. are obtained.
UV: ε239 = 15 950 (in Methanol). [α]D - +15 (in Chloroform).UV: ε 239 = 15 950 (in methanol). [α] D - +15 (in chloroform).
Beispiel 4Example 4
50 mg 7α-Mercapto-15ß.16ß-methylen-3-oxo-17α-pregna-1.4-dien-21.17-carbolacton werden tinter den im Beispiel 1 beschriebenen Bedingungen umgesetzt und aufgearbeitet. Nach Schichtchromatographie werden 45 mg 1α-Acetylthio- 7α-mercapto-15ß.16ß-methylen-3-oxo-17α-pregn-4-en- 21.17-carbolacton erhalten.50 mg of 7α-mercapto-15ß.16ß-methylene-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone are reacted and worked up under the conditions described in Example 1. After layer chromatography, 45 mg of 1α-acetylthio-7α-mercapto-15ß.16ß-methylene-3-oxo-17α-pregn-4-en-21.17-carbolactone are obtained.
UV: ε236 = 11 600 (in Methanol).UV: ε 236 = 11 600 (in methanol).
[α]D = +36.5 ° ( in Chloroform) .[α] D = +36.5 ° (in chloroform).
Beispiel 5Example 5
In eine auf -20 ºC gekühlte Lösung von 720 mg 7α-Mercapto-15ß.16ß-methylen-3-oxo-17α-pregna-1.4-dien-21.17-carbolacton in 28 ml Tetrahydrofuran wird Methanthiol bis fast zur Sättigung eingeleitet. Dann wird das Reaktionsgemisch mit 192 mg Kalium-tert.butylat versetzt und 30 Minuten bei obiger Temperatur gerührt. Zur Aufarbeitung wird in Eiswasser eingegossen und mit Essigsäure neutralisiert. Der ausgefallene Niederschlag wird abgesaugt, mit Wasser gewaschen und getrocknet. Nach Verreiben mit Diisopropylether werden 760 mg 7α-Mercapto-15ß.16ß-methylen-1α-methylthio-3-oxo-17α- pregn-4-en-21.17-carbolacton vom Schmelzpunkt 252,3 ºC erhalten.In a solution of 720 mg of 7α-mercapto-15β.16ß-methylene-3-oxo-17α-pregna-1.4-diene-21.17-carbolactone in 28 ml of tetrahydrofuran, cooled to -20 ° C., methanethiol is introduced to almost saturation. Then the reaction mixture is mixed with 192 mg of potassium tert-butoxide and stirred at the above temperature for 30 minutes. For working up, it is poured into ice water and neutralized with acetic acid. The precipitate is filtered off, washed with water and dried. After trituration with diisopropyl ether, 760 mg of 7α-mercapto-15β.16ß-methylene-1α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone with a melting point of 252.3 ° C. are obtained.
UV: ε237 = 11 100 (in Methanol). [α]D = +62 ° (in Chloroform).UV: ε 237 = 11 100 (in methanol). [α] D = +62 ° (in chloroform).
Beispiel 6Example 6
Eine Lösung von 500 mg 7α-Mercapto-15ß.16ß-methylen-1α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolacton in 2 ml Pyridin wird mit 1 ml Acetanhydrid versetzt und 3 Stunden bei Raumtemperatur stehengelassen. Nach Eiswasserfällung wird der abfiltrierte und getrocknete Niederschlag aus Diisopropylether/Aceton umkristallisiert.Man erhält 440 mg 7α-Acetylthio-15ß.16ß-methylen-1α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolacton vom Schmelzpunkt 251,8 ºC. UV: ε236 = 16 100 (in Methanol). [α]D = -19 ° (in Chloroform). A solution of 500 mg of 7α-mercapto-15ß.16ß-methylene-1α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone in 2 ml of pyridine is mixed with 1 ml of acetic anhydride and left to stand for 3 hours at room temperature . After ice water precipitation, the filtered and dried Precipitation recrystallized from diisopropyl ether / acetone. 440 mg of 7α-acetylthio-15β.16ß-methylene-1α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone of melting point 251.8 ° C. are obtained. UV: ε 236 = 16 100 (in methanol). [α] D = -19 ° (in chloroform).

Claims

Patentansprüche Claims
1. 1α.7α-Dithiosubstituierte Spirolactone der allgemeinen Formel I1. 1α.7α-dithio-substituted spirolactones of the general formula I
worin R 1 C1-3-Alkyl und C1-3-Acyl und wherein R 1 is C 1-3 alkyl and C 1-3 acyl and
R2 Wasserstoff, C1-3-Alkyl und C1-3-Acyl bedeuten.R 2 is hydrogen, C 1-3 alkyl and C 1-3 acyl.
2. 1α.7α-Diacetylthio-15ß.16ß-methylen-3-oxo-17α- pregn-4-en-21.17-carbolacton.2. 1α.7α-diacetylthio-15ß.16ß-methylene-3-oxo-17α-pregn-4-en-21.17-carbolactone.
3. 1α-Acethylthio-15ß.16ß-methylen-7α-methylthio-3-oxo- 17α-pregn-4-en-21.17-carbolacton.3. 1α-Acethylthio-15ß.16ß-methylene-7α-methylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone.
4. 15ß.16ß-Methylen-1α.7α-dimethylthio-3-oxo-17α-pregn- 4-en-21.17-carbolacton.4. 15ß.16ß-methylene-1α.7α-dimethylthio-3-oxo-17α-pregn-4-en-21.17-carbolactone.
5. Verfahren zur Herstellung von 1α.7α-dithiosubstituierten Verbindungen der Formel I, dadurch gekennzeichnet, daß man ein 1.2-ungesättigtes Spirolacton der Formel II5. A process for the preparation of 1α.7α-dithio-substituted compounds of the formula I, characterized in that a 1.2-unsaturated spirolactone of the formula II
worin wherein
-A-B- für die -CH=CH-Gruppierung , oder steht, in an sich bekannter Weise-AB- for the -CH = CH grouping, or stands in a manner known per se
a) mit einer Thioalkansäure in einem protischen Lösungsmittel umsetzt odera) reacted with a thioalkanoic acid in a protic solvent or
b) mit einem Alkanthiol in einem protischen Lösungsmittel in Gegenwart einer Base umsetzt und gegebenenfalls eine freie Mercaptogruppe mit einem aktiven Säurederivat verestert.b) reacted with an alkane thiol in a protic solvent in the presence of a base and, if appropriate, esterified a free mercapto group with an active acid derivative.
6. Arzneimittel auf Basis der Verbindungen gemäß Anspruch 1. 6. Medicament based on the compounds according to claim 1.
EP86901339A 1985-02-18 1986-02-13 1$g(a).7$g(a)-DITHIO SUBSTITUTED SPIROLACTONE, PREPARATION PROCESS THEREOF AND UTILIZATION THEREOF AS DRUG Withdrawn EP0245276A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19853506100 DE3506100A1 (en) 1985-02-18 1985-02-18 1 (ALPHA) .7 (ALPHA) -DITHIO-SUBSTITUTED SPIROLACTONE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT
DE3506100 1985-02-18

Publications (1)

Publication Number Publication Date
EP0245276A1 true EP0245276A1 (en) 1987-11-19

Family

ID=6263198

Family Applications (1)

Application Number Title Priority Date Filing Date
EP86901339A Withdrawn EP0245276A1 (en) 1985-02-18 1986-02-13 1$g(a).7$g(a)-DITHIO SUBSTITUTED SPIROLACTONE, PREPARATION PROCESS THEREOF AND UTILIZATION THEREOF AS DRUG

Country Status (5)

Country Link
US (1) US4789668A (en)
EP (1) EP0245276A1 (en)
JP (1) JPS62501844A (en)
DE (1) DE3506100A1 (en)
WO (1) WO1986004900A1 (en)

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2224222A1 (en) * 1995-06-07 1996-12-19 G.D. Searle & Co. Spironolactone and angiotensin ii antagonist combination therapy for treatment of congestive heart failure
US6410524B1 (en) 1998-11-06 2002-06-25 G. D. Searle & Co. Combination therapy of angiotensin converting enzyme inhibitor and aldosterone antagonist for reducing morbidity and mortality from cardiovascular disease
US6716829B2 (en) 2000-07-27 2004-04-06 Pharmacia Corporation Aldosterone antagonist and cyclooxygenase-2 inhibitor combination therapy to prevent or treat inflammation-related cardiovascular disorders
AU2001285318A1 (en) * 2000-08-28 2002-03-13 Pharmacia Corporation Use of an aldosterone receptor antagonist to improve cognitive function
AU2003222010A1 (en) * 2002-03-18 2003-10-08 Pharmacia Corporation Combination of an aldosterone receptor antagonist and a bile acid sequestering agent
JP6148175B2 (en) 2010-05-10 2017-06-14 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル Methods and compositions for the treatment of fluid retention in and / or under the retina
JP6180930B2 (en) 2010-06-16 2017-08-16 アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル Methods and compositions for stimulating reepithelialization during wound healing processes
WO2017055248A1 (en) 2015-09-28 2017-04-06 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of heart failure
WO2017064121A1 (en) 2015-10-13 2017-04-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods and pharmaceutical compositions for the treatment of choroidal neovascularisation
WO2018019843A1 (en) 2016-07-26 2018-02-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonist of mineralocorticoid receptor for the treatment of osteoarthritis
WO2023031277A1 (en) 2021-08-31 2023-03-09 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of ocular rosacea
CN116925170A (en) * 2023-07-20 2023-10-24 浙江朗华制药有限公司 Spirolactone dithio impurity compound and preparation method and application thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3013012A (en) * 1960-12-22 1961-12-12 Searle & Co Alkanoylthio-17alpha-carboxyethyl-17beta-hydroxyandrosten-3-one lactones
DE3227598A1 (en) * 1982-07-22 1984-01-26 Schering AG, 1000 Berlin und 4709 Bergkamen 7 (ALPHA) -ACYLTHIO-15.16-METHYLENE-3-OXO-17 (ALPHA) -PREGNA-1.4-DIEN-21,17-CARBOLACTONE, METHOD FOR THE PRODUCTION AND USE THEREOF AS A MEDICINAL PRODUCT
DE3240510A1 (en) * 1982-10-29 1984-05-03 Schering AG, 1000 Berlin und 4709 Bergkamen NEW 7 (ALPHA) -ACYLTHIO-1 (ALPHA), 2 (ALPHA) -METHYLEN-3-OXO-17 (ALPHA) -PREGN-4-EN-21,17-CARBOLACTONE, THEIR PRODUCTION AND THE MEDICINAL PRODUCTS CONTAINING THEM

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8604900A1 *

Also Published As

Publication number Publication date
JPS62501844A (en) 1987-07-23
US4789668A (en) 1988-12-06
DE3506100A1 (en) 1986-08-21
WO1986004900A1 (en) 1986-08-28

Similar Documents

Publication Publication Date Title
CELLA et al. Steroidal aldosterone blockers. II1
US4921848A (en) Biliary acid derivatives, processes for the preparation thereof and pharmaceutical compositions containing them
US4545938A (en) Chemical synthesis
EP0245276A1 (en) 1$g(a).7$g(a)-DITHIO SUBSTITUTED SPIROLACTONE, PREPARATION PROCESS THEREOF AND UTILIZATION THEREOF AS DRUG
IE851284L (en) 1,24-dihydroxy-delta(22)-vitamin d3
DE2907539A1 (en) 17-ALKYLTHIO- (AND ARYLTHIO) -ANDROSTENO SQUARE BRACKETS ON 17 ALPHA, 16 ALPHA -B SQUARE BRACKETS FOR BENZOPYRAN- 3-ONE AND - SQUARE BRACKETS ON 16 ALPHA, 17 ALPHA-SQUARE BRACKETS FOR NAPHTHOPYRAN-3-ONE AND THE NAPHTHOPYRAN-3-ONE USE AS AN INFLAMMATORY INGREDIENTS
CH631462A5 (en) METHOD FOR PRODUCING NEW STEROIDS OF THE ANDROSTANE OR OESTRANE SERIES.
EP0642529B1 (en) 11beta-substituted 14,17-ethanoestratrienes, process for preparing these compounds and their use for preparing medicaments
SU852176A3 (en) Method of preparing derivatives of steroidspiroxyzolidinone
US4331663A (en) 4α,5α-Epoxy-3,20-dioxopregnane-2α,16α-dicarbonitrile and intermediates and process for preparation, method of use and compositions thereof
US4011316A (en) Cyclohexa-2,5-diene-1-thiones
EP0134529B1 (en) 7-alpha-substituted 3-oxo-17-alpha-pregn-4-ene 21-17 carbolactones, process for their preparation and pharmaceutical compositions containing them
EP0051247B1 (en) 4-thia and 4-sulfinyl pgi1 derivatives, their preparation and pharmaceutical compositions
US3231588A (en) 3-substituted-16-mercapto-pregnan-20-ones
US3294822A (en) 3-unsubstituted delta4, 9(10)-19-norsteroids and process for their manufacture
US2854463A (en) Conversion of 7,11-diketo steroids to 11-keto steroids
EP0034114A1 (en) 3-Desoxy-delta-15 steroids, process for their preparation and pharmaceutical compositions containing them
DE1568013C3 (en) 17 alpha - square bracket on 3'-furyl square bracket on steroids, process for their manufacture and medicinal products containing them
US2897212A (en) 3-hydroxy-11-keto-bisnorallocholenic acid and the esters thereof
US3462467A (en) 17alpha-phenylalkyl/phenylethynyl/phenylvinyl-13beta-alkylgona - 1,3,5(10)-triene-3,17beta-diols and esters thereof
DE2441647A1 (en) 17BETA-AETHINYL-3,17ALPHA-OESTRADIOL COMPOUNDS, METHOD OF MANUFACTURING THEREOF, MEDICINAL PRODUCTS AND 17BETA-AETHINYL-16ALPHA, 17ALPHA-EPOXYOESTRAN-3-OL COMPOUNDS
DE1593448C (en) 13beta-ethyl-gon-4-en-3-one-thioketals, their preparation and agents containing them
DE3330086A1 (en) 7 alpha -Mercapto- and 7 alpha -alkylthio-3-oxo-17 alpha -pregn-4-ene-21,17-carbolactones, process for the preparation thereof, and pharmaceutical products containing these
AT300842B (en) Process for the preparation of compounds which contain two carbonyl groups or two nitrile groups or one nitrile and one carbonyl group
WO1994004555A1 (en) Anti-androgene steroids with an annulated five-membered ring

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19870812

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE FR GB IT LI LU NL SE

17Q First examination report despatched

Effective date: 19880810

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19890221

RIN1 Information on inventor provided before grant (corrected)

Inventor name: WIECHERT, RUDOLF

Inventor name: NICKISCH, KLAUS

Inventor name: BITTLER, DIETER

Inventor name: LAURENT, HENRY

Inventor name: LOSERT, WOLFGANG