CH437277A - Process for the preparation of a new A-nor-B-homo-steroid - Google Patents

Process for the preparation of a new A-nor-B-homo-steroid

Info

Publication number
CH437277A
CH437277A CH901863A CH901863A CH437277A CH 437277 A CH437277 A CH 437277A CH 901863 A CH901863 A CH 901863A CH 901863 A CH901863 A CH 901863A CH 437277 A CH437277 A CH 437277A
Authority
CH
Switzerland
Prior art keywords
homo
compound
new
steroid
preparation
Prior art date
Application number
CH901863A
Other languages
German (de)
Inventor
Jeger Oskar Dr Prof
Kurt Dr Schaffner
Original Assignee
Ciba Geigy
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
Priority to BE650730D priority Critical patent/BE650730A/xx
Priority to BE650731D priority patent/BE650731A/xx
Priority claimed from CH353362A external-priority patent/CH412876A/en
Application filed by Ciba Geigy filed Critical Ciba Geigy
Priority to CH901863A priority patent/CH437277A/en
Priority to CH606367A priority patent/CH445482A/en
Priority to US382643A priority patent/US3504003A/en
Priority to DE19641443651 priority patent/DE1443651A1/en
Priority to DE19641443650 priority patent/DE1443650A1/en
Priority to FR981803A priority patent/FR87457E/en
Priority to FR981804A priority patent/FR87458E/en
Priority to SE876564A priority patent/SE335121B/xx
Priority to AT616464A priority patent/AT282837B/en
Priority to NL6408226A priority patent/NL6408226A/xx
Priority to SE876664A priority patent/SE338044B/xx
Priority to ES0302202A priority patent/ES302202A2/en
Priority to BR16093964A priority patent/BR6460939D0/en
Priority to NL6408227A priority patent/NL6408227A/xx
Priority to ES0302201A priority patent/ES302201A2/en
Priority to DK358964A priority patent/DK120188B/en
Priority to GB30589/64A priority patent/GB1067517A/en
Priority to FR991497A priority patent/FR4002M/fr
Publication of CH437277A publication Critical patent/CH437277A/en
Priority to US840053A priority patent/US3522157A/en

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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/567—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 position 17 alpha, e.g. mestranol, norethandrolone
    • 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
    • C07J69/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom
    • 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)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Steroid Compounds (AREA)

Description

  

  Verfahren zur Darstellung eines neuen     A-Nor-B-homo-steroids       Die vorliegende Erfindung betrifft ein Verfahren  zur Herstellung eines neuen pharmakologisch wirksamen       A-Nor-B-homo-steroids    des     45-3-Oxo-6,17/3-dihydroxy-          7aa,17a-dimethyl-A-nor-B-homo-östrens    der folgenden  Formel  
EMI0001.0005     
    Für die Verbindung kommt auch die     tautomere     Formel  
EMI0001.0007     
    in Betracht, das heisst, die Verbindung kann auch als       3,6-Dioxo-17ss'-hydroxy-7aa,17a-dimethyl-A-nor-          B        homo-östran     aufgefasst werden und sie reagiert zum Teil auch als  solches.

   Die     eingangs    angegebene Formel     stellt    die       Enolform    der neuen Verbindung dar, und diese     liegt     auch zum     überwiegenden.        Teil    in dieser Form vor.

      Die neue     Verbindung    besitzt im Versuchstier eine  gute     anabole    Wirksamkeit bei nur sehr     geringer,    prak  tisch zu     vernachlässigender        androgener    Komponente  und ist daher als Medikament für die Behandlung all  jener Zustände geeignet, welche einen erhöhten Protein  aufbau erfordern, wie Magersucht, postoperative und       postinfektiöse        Zustände,        Anorexie    und Osteoporose,  besonders in der     Geriatrie.    Ferner kann sie auch in der       Veterinärmedizin.    und als Zusatz zu     Futtermitteln    ver  wendet werden.

   Die     Verbindung    zeigt bei subkutaner       Applikation    eine sehr ausgesprochene Dissoziation zwi  schen der optimalen     androgenen    Wirkung und der     opti-          malen        anabolen    Wirkung.  



  Die     anabole        Wirkung        kann.    pharmakologisch an er  wachsenen     männlichen,        kastrierten    Ratten mittels des  sogenannten      levator        an! -Tests        ermittelt    werden. Man  verabreicht den Tieren steigende Dosen der zu prüfen  den Substanz und verfolgt die Gewichtszunahme des  atrophierten      levator        ani -Muskels.    Als optimale Wir  kung kann die Gewichtszunahme bis zum Gewicht des  Muskels     in    den normalen     Kontrolltieren        angesehen,    wer  den.

   Eine solche     vollständige    Wiederherstellung des nor  malen Muskelgewichtes     wird    bei der Verbindung der  vorliegenden Erfindung unter den     erwähnten        experimen-          tellen    Bedingungen bei -einer Dosis von 0,03 mg/kg  Körpergewicht, bei täglicher     subkutaner    Verabreichung  während 15 Tage, erlangt. Bei oraler Verabreichung be  trägt die     entsprechenden,        Dosis    1,0     mg/kg    täglich wäh  rend 15 Tage.  



  Die     androgene        Wirkung        einer        anabolen        Substanz     kann durch die     Gewichtszunahme    der ebenfalls     atro-          phierten    Samenblasen der für die Bestimmung der       anabolen    Wirkung     verwendeten    Tiere     ermittelt    werden.

    Zum Vergleich     mit    der     anabolen    Wirkung wird die       optimale        androgene    Dosis gemessen,     nämlich    diejenige,  welche eine Gewichtszunahme -bis zur Erreichung des  Gewichts der entsprechenden Organe in den normalen       Kontrolltieren    bewirkt.

   Diese     liegt    bei der     Verbindung     der     vorliegenden    Anmeldung unter den     geschilderten         experimentellen Verhältnissen bei subkutaner Gabe bei  3     mg/kg    und ist somit 100mal grösser als die Dosis,  welche den optimalen     anabolen    Effekt erzeugt. Bei  oraler Gabe ist das     entsprechende    Verhältnis auch noch  sehr gut, indem die optimale     androgene    Dosis etwa     30-          bis    70mal so hoch ist wie die optimale     anabole    Dosis.  



  Das     erfindungsgemässe    Verfahren zur     Darstellung     der neuen Verbindung der vorliegenden Anmeldung     ist     dadurch gekennzeichnet, dass man eine Verbindung der       Formel     
EMI0002.0012     
    mit ultraviolettem Licht bestrahlt. Dieses Verfahren  ist generell im Hauptpatent Nr. 412 876 unter Schute  gestellt.  



  Die Bestrahlung wird     vorteilhaft    in organischen  Lösungsmitteln, z. B. in     aliphatischen    und     cycloalipha-          tischen        Kohlenwasserstoffen,    wie     Pentan,        Hexan,        Cyclo-          hexan    und     Methylcyclohexan    ausgeführt.

   Besonders ge  eignet sind     aliphatische    und     cyclische    Äther, wie z.     B,          Diäthyläther    und     Dioxan.        Als    Lichtquelle eignen sich  künstliches oder starkes natürliches Licht; vorzugsweise  wird das     Ultraviolettlicht    von     Quecksilberniederdruck-          und        -hochdruckbrennern    erzeugt, oder es wird starke  Sonnenlicht verwendet. Die Bestrahlung     erfolgt    vor  zugsweise bei Temperaturen zwischen 0 und 80 .  



  Die erhaltene Verbindung kann in an sich bekann  ter Weise     in    ihre sich von der     Enolform    ableitenden  Ester übergeführt werden. So erhält man z. B. durch       Acylierung,    z. B. durch Behandlung mit     Carbonsäure-          anhydriden,    wie     Acetanhydrid    oder     Propionsäure-          anhydrid,    die entsprechenden     Enolester.     



  <I>Beispiel</I>  500 mg 3 -     Oxo-    4,5 -     oxido-17ss-hydroxy-7a,17a-di-          methyl-östran    (F. 138-140 , aus Äther) werden in  120 ml     Dioxan    13 Stunden mit einem Quecksilber  Hochdruckbrenner     belichtet.    Darauf wird die Lösung  im Vakuum eingedampft und der Rückstand in     Benzol-          Äther-(4:        1)-Lösung    durch neutrales     Silicagel        filtriert.     Es werden dabei 400 mg       3,6-Dioxo-17ss-hydroxy-7aa,17a-dirnethyl-A-nor-          B-homo-östran    bzw.  



       d5-3-Oxo-6,17ss-dihydroxy-7aa,17a-dimethyl-A-nor-          B        homo-östren          eluiert,    das nach einmaligem     Umlösen    aus     Methanol-          Wasser    bei     168-1691        schmilzt.            [a]D    =     +    83  (c = 0,67 in     Chloroform).          IR-Spektrum:        v.",    = 3550, 1640, 1595 cm-'  (Chloroform).  



       UV-Spektrum:        Am"    = 293 mg     (E   <I>=</I> 9380).



  Process for the preparation of a new A-nor-B-homo-steroid The present invention relates to a process for the preparation of a new pharmacologically active A-nor-B-homo-steroid of 45-3-oxo-6,17 / 3-dihydroxy 7aa, 17a-dimethyl-A-nor-B-homo-estrous of the following formula
EMI0001.0005
    The tautomeric formula also comes for the compound
EMI0001.0007
    into consideration, that is, the compound can also be understood as 3,6-dioxo-17ss'-hydroxy-7aa, 17a-dimethyl-A-nor-B homo-oestrane and some of it also reacts as such.

   The formula given at the beginning represents the enol form of the new compound, and this is also the predominant one. Part in this form.

      The new compound has good anabolic efficacy in test animals with only a very low, practically negligible androgenic component and is therefore suitable as a drug for the treatment of all those conditions which require increased protein build-up, such as anorexia, postoperative and postinfectious conditions, anorexia and osteoporosis, especially in geriatrics. It can also be used in veterinary medicine. and used as an additive to animal feed.

   When administered subcutaneously, the compound shows a very pronounced dissociation between the optimal androgenic effect and the optimal anabolic effect.



  The anabolic effects can. pharmacologically on adult male, castrated rats using the so-called levator! -Tests are determined. The animals are administered increasing doses of the substance to be tested and the increase in weight of the atrophied levator ani muscle is monitored. The weight gain up to the weight of the muscle in the normal control animals can be regarded as the optimal effect.

   Such a complete restoration of the normal muscle weight is achieved with the compound of the present invention under the mentioned experimental conditions at a dose of 0.03 mg / kg body weight, with daily subcutaneous administration for 15 days. For oral administration, the corresponding dose is 1.0 mg / kg daily for 15 days.



  The androgenic effect of an anabolic substance can be determined by the weight gain of the seminal vesicles, which are also atrophied, of the animals used to determine the anabolic effect.

    For comparison with the anabolic effect, the optimal androgenic dose is measured, namely that which brings about an increase in weight - until the weight of the corresponding organs is reached in the normal control animals.

   In the case of the compound of the present application, this is 3 mg / kg under the experimental conditions described for subcutaneous administration and is thus 100 times greater than the dose which produces the optimal anabolic effect. In the case of oral administration, the corresponding ratio is also very good, in that the optimal androgenic dose is about 30 to 70 times as high as the optimal anabolic dose.



  The process according to the invention for preparing the new compound of the present application is characterized in that a compound of the formula
EMI0002.0012
    irradiated with ultraviolet light. This process is generally covered by main patent no. 412 876.



  The irradiation is advantageously carried out in organic solvents, e.g. B. in aliphatic and cycloaliphatic hydrocarbons such as pentane, hexane, cyclohexane and methylcyclohexane.

   Particularly ge are aliphatic and cyclic ethers, such as. B, diethyl ether and dioxane. Artificial or strong natural light are suitable as the light source; preferably the ultraviolet light is generated by low and high pressure mercury burners, or strong sunlight is used. The irradiation takes place preferably at temperatures between 0 and 80.



  The compound obtained can be converted into its ester derived from the enol form in a manner known per se. So you get z. By acylation, e.g. B. by treatment with carboxylic anhydrides, such as acetic anhydride or propionic anhydride, the corresponding enol esters.



  <I> Example </I> 500 mg of 3-oxo-4,5-oxido-17ss-hydroxy-7a, 17a-dimethyl-estran (F. 138-140, from ether) are in 120 ml of dioxane for 13 hours exposed with a high pressure mercury torch. The solution is then evaporated in vacuo and the residue in benzene-ether (4: 1) solution is filtered through neutral silica gel. There are 400 mg of 3,6-dioxo-17ss-hydroxy-7aa, 17a-dirnethyl-A-nor-B-homo-oestran or



       d5-3-Oxo-6,17ss-dihydroxy-7aa, 17a-dimethyl-A-nor-B homo-oestrene eluted, which melts at 168-1691 after being redissolved once from methanol-water. [a] D = + 83 (c = 0.67 in chloroform). IR spectrum: v. ", = 3550, 1640, 1595 cm- '(chloroform).



       UV spectrum: Am "= 293 mg (E <I> = </I> 9380).

Claims (1)

PATENTANSPRUCH Verfahren zur Herstellung eines 3-Ox0-A-nor-B- homo-osteroids des östranreihe der Formel EMI0002.0076 dadurch gekennzeichnet, dass man eine Verbindung der Formel EMI0002.0077 mit ultraviolettem Licht bestrahlt. PATENT CLAIM Process for the production of a 3-Ox0-A-nor-B-homo-osteroid of the estran series of the formula EMI0002.0076 characterized in that a compound of the formula EMI0002.0077 irradiated with ultraviolet light. UNTERANSPRÜCHE 1. Verfahren gemäss Patentanspruch, dadurch ge- kennzeichnet, dass man die erhaltene Verbindung mit einem Acyherungsmittel zu den 6-Monoacylderivaten acyliert. 2. Verfahren gemäss Patentanspruch und Unteran spruch 1, dadurch gekennzeichnet, dass man die Be strahlung in einem cyclischen Äther ausführt. 3. SUBClaims 1. Process according to claim, characterized in that the compound obtained is acylated with an acylating agent to give the 6-monoacyl derivatives. 2. The method according to claim and sub-claim 1, characterized in that the radiation is carried out in a cyclic ether. 3. Verfahren gemäss Patentanspruch und den Unter ansprüchen 1 und 2, dadurch gekennzeichnet, dass man das 3 - Oxo - 4,5 - oxido-17fl-hydroxy-7a,17a-dimethyl- östran in Dioxan bei Zimmertemperatur bestrahlt. Process according to patent claim and sub-claims 1 and 2, characterized in that the 3-oxo-4,5-oxido-17fl-hydroxy-7a, 17a-dimethyl estran in dioxane is irradiated at room temperature.
CH901863A 1962-03-23 1963-07-19 Process for the preparation of a new A-nor-B-homo-steroid CH437277A (en)

Priority Applications (21)

Application Number Priority Date Filing Date Title
BE650730D BE650730A (en) 1963-07-19
BE650731D BE650731A (en) 1963-07-19
CH901863A CH437277A (en) 1962-03-23 1963-07-19 Process for the preparation of a new A-nor-B-homo-steroid
CH606367A CH445482A (en) 1963-07-19 1963-07-19 Process for the preparation of new A-nor-B homosteroids
US382643A US3504003A (en) 1963-07-19 1964-07-14 A-nor-b-homosteroids
DE19641443651 DE1443651A1 (en) 1963-07-19 1964-07-14 New A-Nor-B homosteroids and pharmaceutical preparations for their use as drugs
DE19641443650 DE1443650A1 (en) 1963-07-19 1964-07-14 Process for the preparation of a new A-nor-B-homo-steroid
FR981803A FR87457E (en) 1963-07-19 1964-07-16 Process for the preparation of new alpha-nor-beta-homo-steroids
FR981804A FR87458E (en) 1963-07-19 1964-07-16 Process for the preparation of new alpha-nor-beta-homo-steroids
ES0302201A ES302201A2 (en) 1963-07-19 1964-07-17 Procedure for obtaining a-nor-b-homosteroids. (Machine-translation by Google Translate, not legally binding)
AT616464A AT282837B (en) 1963-07-19 1964-07-17 Process for the production of new 3-oxo-A-nor-B-homo-steroids of the estran series
SE876564A SE335121B (en) 1963-07-19 1964-07-17
NL6408226A NL6408226A (en) 1962-03-23 1964-07-17
SE876664A SE338044B (en) 1963-07-19 1964-07-17
ES0302202A ES302202A2 (en) 1963-07-19 1964-07-17 Procedure for obtaining a-nor-b-homosteroids. (Machine-translation by Google Translate, not legally binding)
BR16093964A BR6460939D0 (en) 1963-07-19 1964-07-17 PROCESS FOR THE MANUFACTURE OF NEW A-NOR-B-HOMO-STEROIDS FROM THE PREGNANE SERIES
NL6408227A NL6408227A (en) 1963-07-19 1964-07-17
DK358964A DK120188B (en) 1963-07-19 1964-07-18 Process for the preparation of 3-oxo-17α-methyl-17β-hydroxy-A-nor-B-homo-estranes or esters or ethers thereof or 1-dehydro derivatives thereof.
GB30589/64A GB1067517A (en) 1963-07-19 1964-08-04 New a-nor-b-homo-steroid and process for its manufacture
FR991497A FR4002M (en) 1963-07-19 1964-10-15
US840053A US3522157A (en) 1962-03-23 1969-07-08 Process for the manufacture of a-nor-b-homo-steroids

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CH353362A CH412876A (en) 1962-03-23 1962-03-23 Process for the production of new 3,6-Dioxo-A-nor-B-homo-steroids
CH984462 1962-08-17
CH1442262 1962-12-07
CH288063 1963-03-07
CH901863A CH437277A (en) 1962-03-23 1963-07-19 Process for the preparation of a new A-nor-B-homo-steroid

Publications (1)

Publication Number Publication Date
CH437277A true CH437277A (en) 1967-06-15

Family

ID=27509092

Family Applications (1)

Application Number Title Priority Date Filing Date
CH901863A CH437277A (en) 1962-03-23 1963-07-19 Process for the preparation of a new A-nor-B-homo-steroid

Country Status (1)

Country Link
CH (1) CH437277A (en)

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