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DE1668400A1 - 3-methyl-19-nor-3,5-androstadien-17ss-ols and process for their preparation - Google Patents

3-methyl-19-nor-3,5-androstadien-17ss-ols and process for their preparation

Info

Publication number
DE1668400A1
DE1668400A1 DE19621668400 DE1668400A DE1668400A1 DE 1668400 A1 DE1668400 A1 DE 1668400A1 DE 19621668400 DE19621668400 DE 19621668400 DE 1668400 A DE1668400 A DE 1668400A DE 1668400 A1 DE1668400 A1 DE 1668400A1
Authority
DE
Germany
Prior art keywords
androstadien
allyl
ols
general formula
ethynyl
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.)
Pending
Application number
DE19621668400
Other languages
German (de)
Other versions
DE1668400B2 (en
Inventor
Klaus Dipl-Chem Dr Brueckner
Klaus Dipl-Chem Dr Irmscher
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.)
Merck Patent GmbH
Original Assignee
Merck Patent GmbH
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 Merck Patent GmbH filed Critical Merck Patent GmbH
Priority claimed from DEM51763A external-priority patent/DE1254148B/en
Publication of DE1668400A1 publication Critical patent/DE1668400A1/en
Publication of DE1668400B2 publication Critical patent/DE1668400B2/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J75/00—Processes for the preparation of steroids in general

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)

Description

3-Ilethyl-19-no:c-3,5-androstadieii-17ß-ole und Verfahren zu deren Herstell*.mg. - Die Erfindung betrifft 3-liethyl-19-nor-3#5-androstadien-17P-ole der allgemeinen Formel 1 OH R worin R# Allyl oder Aethinyl bedeutet h -L3 sowie ein 'Verftü=en zu deren Herstellung.3-Ilethyl-19-no: c-3,5-androstadieii-17ß-ole and process for their production * .mg. - The invention relates to 3-diethyl-19-nor-3 # 5-androstadien-17P-ols of the general formula 1 OH R wherein R # allyl or ethynyl means H -L3 as well as an understanding of their production.

Die neuen Verbindungen der Pormeln'I besitzen wertvolle pharmakologische Eigenschaften. Insbesondere sind ihre guten ovulationsher.menden und Antifertilitätswirkungen bemerkwiswert.The new compounds of the Pormeln'I have valuable pharmacological properties Properties. In particular, their good ovulatory and anti-fertility effects are good remarkable.

Gegenstand der Erfindung sind 3-1-Iathyl-19-nor-3,5-androstadien-17P-ole der allgemeinen Formel 1 sowie ein Verfahren zu deren Herstellung, das darin besteht,-dap man naoh an sich bekannten Methoden ein entsprechendes 3-1-lethylen-19-nor-4-androsten-17ß-ol-derivat der allgemein#en Yormel II worin OH UR R die angegebene Bedeutung hat.. ff 20 mit einem Isomerisierungsmittelg wie einer i;inerals2.ure, behandelt.The invention relates to 3-1-ethyl-19-nor-3,5-androstadien-17P-ols of the general formula 1 and a process for their preparation, which consists in using a corresponding 3- 1-Lethylene-19-nor-4-androsten-17ß-ol derivative of the general Yormel II wherein OH UR R has the meaning given .. ff 20 treated with an isomerizing agent such as an i; inerals2.ure.

Als Isomerisierungsmittel können beispielsweise Mineralsäuren, wie Salzsäuret Schwefelsäureg Perohlorsäure, starke organische Säureng wie Oxalsäureg p-Toluolrulfonsäure, Ansolvosäuren, wie Bortrifluorid oder Zinkohlorid, oder auch saure Ionenaustauscher oder Adsorbentien, wie saures AluminiumoXidv saure Silikate oder saures Zieselgelg verwendet werden. As isomerization, for example, mineral acids such as Salzsäuret Schwefelsäureg Perohlorsäure, strong organic Säureng as Oxalsäureg p-Toluolrulfonsäure, Ansolvosäuren such as boron trifluoride or Zinkohlorid, or acid ion exchangers or adsorbents, such as acid AluminiumoXidv acidic silicates or acidic Zieselgelg can be used.

Vorteilhaft führt man die Isomerisierung in Gegenwart eines inerten Lösung ,smittele, wie ZUBO 0 ines Alkoholog der auch mit Wasser gemischt sein kann, sowie zweckmäßig unter Er-.. wärmen durch. Diese Isomerielerung Ist in der Regel nach 095 bIE 6 Stunden beendet, Der Verlauf der Isomerisierung kann dünnschichtchromatographisohoder UV-spektroskopisch verfolgt werden. bie neuen Verbindungen können im GemIsch mit üblichen Arzneimittelträgern in der Human- oder Veterinärmedizin eingesetzt werden, Als Trägersubstanzen kommen solche organischen oder anorganischen Stoffe in Prageg die für die parenterale oder enterale Applikation Seeiipiet sind und die mit den neuen Verbindungen nicht in Reaktion treten, wie beispielsweise Wasser, pflanzliche Oele, Polyäthylenglykoleg Gelatine, hilchzucker, Stärke, 1--lagnesiumstearat, Talk, Vaseline, Cholesterin usw. Zur parenteralen-Applikation dienen insbesondere Lösungen, vorzugsweise ölige oder C> wäßrige Lösungen, sowie Suspensionen, Emulei.o11.ep a. , oder Im- plantate. FUr die enterale Applikation eignen /ferner 52ab- letten oder Drageesq diA gegebenenfalls sterilisiert oder mit Hilfsstoffen, wie Konservierungs-q Stabilisierungs- oder lietzmitteln oder Salzen zur Beeinflussung des osmotischen Druckes oder mit 2uffersubstanzen versetzt sindv angewendet werden.The isomerization is advantageously carried out in the presence of an inert solution, such as ZUBO 0 ines alcohol, which can also be mixed with water, and expediently with heating. This isomerization is generally complete after 095 to 6 hours. The course of the isomerization can be followed by thin-layer chromatography or UV spectroscopy. The new compounds can be used in combination with conventional drug carriers in human or veterinary medicine, organic or inorganic substances that are suitable for parenteral or enteral administration and which do not react with the new compounds, such as, for example , are used as carrier substances Water, vegetable oils, polyethylene glycol gelatin, aloh sugar, starch, 1-lagnesium stearate, talc, petrolatum, cholesterol, etc. For parenteral administration, solutions, preferably oily or C>, are used in particular aqueous solutions and suspensions, Emulei.o11.ep a. , or Im- plants. Suitable for enteral application / furthermore 52 tablets or drageesq diA, if necessary, sterilized or used with auxiliary substances such as preservatives, stabilizers or lubricants or salts to influence the osmotic pressure or with buffer substances.

.beispiel 1 48 g 3-1--,ethylen-17a-äthinyl-19-nor-4-anclrosten-17ß-ol werden In 96 ml-Aethanol gelöst und mit 3 ml konzentrierter Salzsäure versetzt. han läßt über Aacht verschlossen steheri, rührt in 800 ml Wasser ein, filtriert das entstandene 3-I#iethyl-17a-äthinyl-19'-nor-395-androstadien-178-01 ab, wäscht mit Wasser nachg troelmet und krie - tallisiert aus Aoeton um. 2. 196-1990 (eintert bei 1900); g724-2900 D .(in Chloroforn); UV-Spektrtun (in Aethanol):> max 233 und 239 nu (L# l% 734 und 758) , Schulter be 1 248 nm..Example 1 48 g of 3-1 -, ethylene-17a-äthinyl-19-nor-4-anclrosten-17ß-ol are dissolved in 96 ml of ethanol and treated with 3 ml of concentrated hydrochloric acid. han can be closed over Aacht steheri, stirred into 800 ml water, filtered, the resulting 3-I # iethyl-17a-ethynyl-19'-nor-395-androstadien-178-01, washed with water and nachg troelmet Crawling - tallisiert from Aoeton around. 2. 196-1990 (ends at 1900); g724-2900 D. (in chloroform); UV spectra (in ethanol):> max 233 and 239 nu (L # 1% 734 and 758), shoulder at 1 248 nm.

1 cm Das Ausgangsmaterial wird wie folgt erhalten: 5902 g 1,lethyltriphenylphoophoniumbromid werden in 70 r1.1 ab- solutem Aether auspendiert. Unter lltühren und Stickstoffein- leitung werden 11p6 ml ätherische lithiuraphonyllösung (193 n) zugefügt. Das Gemisch wird unter Stickstoff 2 Stunden bei Raumtemperatur gerührt. Zu dieser hellgelben Yildlösun- werden 1,1 g 17a-Aethinyl-19-nor-testosteron in 120 ml absolutem Tetrahydrofuran gegebeng der Kolbeninhalt 4 Stunden bei',Raumtemperatur unter Stickstoff gerührtt dmn über Nacht Atehengelassen. Anschliessend wird der Aether heraus- destilliert und durch absolutes 'Letrahydrofuran ersetzt. liun wird das Gemisch noc-h 6 Stunden unter Stickstoff ain Rückfluß gekocht, nach dem Abkühlen mit Wasser verdüxu-itg mit Aether ausgeschüttelt, der Aether mit 1.-fasser gewascheng mit Hatriumsulfat getroc#met.'filtriert und das Lösungs- mittel unter Vakuum bei 500 abdestilliert. Das erhaltene Oel wird über 30 g alkalisches Aluminiumoxid, Aktivitätsstufe II, mit Benzol ehromatographiert. Aus den vorderen Praktionen kristallisiereh mit 70#-C'igem Methanol 0,7 g 3-Hethylen- 17a-äthinyl-19-nor-4-androsten-17ß-01. Nach dem Umkristalli- sieren aus Petroläther erhält man die Substanz mit einem Schmelzpunkt von 107-110"; _724 +490 (Chloroform). D Beispiel 2 Analog Beispiel 1 wird 3-1;Iethylen-17a-allyl-19-nor-4-androsteii- ja»724+86o in Chloroform; erhalten durch 17P-01 (F. 71 - 730; D Umsetzung von 17a-Allyl-19-nor-testosteron mit Triphenyl- phosplainmethylen analog Beispiel 1) zu 3-lIethyl-17a-allyl- 19-nor-395-androstadien-17ß-01 umgesetzt. 11. 92 - 9611 (aus Nethanol); C«j24_186o (Chloroform); UV-Spektrum (in Achanol).- D -1 t'/ 233-234 und 239 nm*(B' #» 654 und 675), Schulter bei max 1 cm 248 i=. 1 cm The starting material is obtained as follows: 5902 g of 1, lethyltriphenylphoophonium bromide are removed in 70 r1.1 solid ether. While stirring oil and introducing nitrogen line will 11p6 ml of essential lithiuraphonyl solution (193 n) added. The mixture is under nitrogen for 2 hours Room temperature stirred. To this light yellow Yild solution 1.1 g of 17a-ethynyl-19-nor-testosterone in 120 ml given absolute tetrahydrofuran the contents of the flask for 4 hours stirred dmn over at ', room temperature under nitrogen Night let alone. Then the ether is extracted distilled and replaced by absolute letrahydrofuran. The mixture is then cleaned for 6 hours under nitrogen Boiled under reflux, diluted with water after cooling shaken out with ether, washed the ether with 1st barrel filtered with sodium sulfate getroc # met. 'and the solution medium distilled off under vacuum at 500. The oil obtained is about 30 g of alkaline aluminum oxide, activity level II, Ehromatographed with benzene. From the previous internships crystallize with 70 # -C'igem methanol 0.7 g of 3-ethylene 17a-ethinyl-19-nor-4-androsten-17ß-01. After the recrystalline sizing from petroleum ether you get the substance with a Melting point of 107-110 "; _724 +490 (chloroform). D. Example 2 Analogously to Example 1 , 3-1; Iethylene-17a-allyl-19-nor-4-androsteii- yes »724 + 86o in chloroform; received by 17P-01 (F. 71-730; D. Implementation of 17a-allyl-19-nor-testosterone with triphenyl phosplainmethylene analogous to Example 1) to 3-LIethyl-17a-allyl- 19-nor-395-androstadien-17ß-01 implemented. 11. 92 - 9611 (from Nethanol); C «j24-186o (chloroform); UV spectrum (in achanol). D -1 t '/ 233-234 and 239 nm * (B '# » 654 and 675), shoulder at max 1 cm 248 i =.

Claims (1)

Patentansprüche 1, 3-1--lethyl-19-nor-395-aildrdstadien#.17P-Ole der allgemeinen Formel 1
HA worin R Allyl oder Aethinyl bedeutet. H 3 0."
2, 3-1-IethY1-17a-allyl-19-nor-395-androstadien-17P-01. 3, 3-1.let11y1-17a-äthinyl-19-nor-3,5-androstadien-17P-01. 4. Verfahren zur Herstellung von 3-'r.'tethyl-19-nov-395-androsta- dien--17P-olen der allgemeinen Formell
OH R worin H R Allyl oder Aethinyl bedeutet# H 3 0,
dadurch gekennzeichnetg daß man nach an sich bekannten Ilethoden ein entsprechenden 3-liethylen-19-no'r-4-androsten-M-ol der allgemeinen Yormel 11 OH R worin R die angegebene Bedeutung hat, 1120
mit einem Isomerisierungomittelg wie einer klineralsäure, behandelt. Claims 1, 3-1-ethyl-19-nor-395-aildrdstadien # .17P-Ole of the general Formula 1
HA in what R allyl or ethynyl means. H 3 0. "
2,3-1-EthY1-17a-allyl-19-nor-395-androstadien-17P-01. 3, 3-1.let11y1-17a-ethinyl-19-nor-3,5-androstadien-17P-01. 4. Process for the production of 3-'r.'tethyl-19-nov-395-androsta- dien - 17P-ols of the general formula
OH R wherein HR allyl or ethynyl means# H 3 0,
characterized in that a corresponding 3-liethylen-19-no'r-4-androstene-M-ol of the general formula 11 is obtained by methods known per se OH R wherein R has the meaning given, 1120
treated with an isomerization agent such as a clinical mineral acid.
DE19621668400 1962-02-10 1962-02-10 3-METHYL-17ALPHA-AETHINYL-19-NOR3,5- ANDROSTADIEN-17BETA-OL AND THE METHOD FOR PRODUCING IT Pending DE1668400B2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEM51763A DE1254148B (en) 1962-02-10 1962-02-10 Process for the production of 1-dehydro-3-methylene-steroids of the androstane series
DEM0074767 1967-07-15

Publications (2)

Publication Number Publication Date
DE1668400A1 true DE1668400A1 (en) 1971-02-18
DE1668400B2 DE1668400B2 (en) 1973-05-10

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Application Number Title Priority Date Filing Date
DE19621668400 Pending DE1668400B2 (en) 1962-02-10 1962-02-10 3-METHYL-17ALPHA-AETHINYL-19-NOR3,5- ANDROSTADIEN-17BETA-OL AND THE METHOD FOR PRODUCING IT

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Publication number Publication date
DE1668400B2 (en) 1973-05-10

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