NO140825B

NO140825B - ANALOGICAL PROCEDURES FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PREGNAN-21 ACID DERIVATIVES

Info

Publication number: NO140825B
Application number: NO491873A
Authority: NO
Inventors: Henry Laurent; Rudolf Wiechert; Helmut Hofmeister; Klaus Mengel; Hans Wendt; Klaus Annen
Original assignee: Schering Ag
Priority date: 1972-12-22
Filing date: 1973-12-21
Publication date: 1979-08-13
Also published as: NO140825C; BE808985A; DE2264003C2; RO71549A; CS168467B2; RO75386A; PH10908A; DE2264003A1; SU555856A3; SU615863A3; HU171521B; ZA739656B; RO72490A

Description

Foreliggende oppfinnelse angår en analogifremgangsmåte The present invention relates to an analog method

for fremstilling av terapeutisk aktive pregnan-21-syrederivater av den generelle formel I for the preparation of therapeutically active pregnan-21-acid derivatives of the general formula I

hvori X betegner et hydrogenatom, et fluoratom eller en methyl- in which X denotes a hydrogen atom, a fluorine atom or a methyl-

gruppe, Y betegner et hydrogenatom, et fluoratom eller et klor- group, Y denotes a hydrogen atom, a fluorine atom or a chlorine

atom, Z betegner en hydroxygruppe eller, såfremt Y er et kloratom, atom, Z denotes a hydroxy group or, provided Y is a chlorine atom,

et fluor- eller kloratom, R 1 og R 2betegner en alkylgruppe med 1-4 carbonatomer eller en fenylgruppe, og R 3 betegner et hydro- a fluorine or chlorine atom, R 1 and R 2 denote an alkyl group with 1-4 carbon atoms or a phenyl group, and R 3 denotes a hydro-

genatom, et natriumatom eller en alkylgruppe med 1-8 carbonato- gene atom, a sodium atom or an alkyl group with 1-8 carbonato-

mer, hvilken fremgangsmåte er kjennetegnet ved at more, which method is characterized by that

a) en forbindelse av generell formel II a) a compound of general formula II

hvori X, Y, Z, R 1 og R 2 har de samme betydninger som angitt for wherein X, Y, Z, R 1 and R 2 have the same meanings as indicated for

formel I, eller hydrater eller hemiacetaler av denne forbindelse oxyderes med oxyderende tungmetalloxyder i nærvær av alkoholer, eller formula I, or hydrates or hemiacetals of this compound are oxidized with oxidizing heavy metal oxides in the presence of alcohols, or

b) en forbindelse av generell formel III b) a compound of general formula III

12 3 12 3

hvori X, Y, Z, R , R og R har de samme betydninger som formel I, og hvori 20-hydroxygruppen kan være a- eller 3-stillet, oxyderes i et inert oppløsningsmiddel med oxyderende metall-oxyder eller metallsalter., in which X, Y, Z, R, R and R have the same meanings as formula I, and in which the 20-hydroxy group can be a- or 3-positioned, oxidized in an inert solvent with oxidizing metal oxides or metal salts.,

og om ønsket at estere med den generelle formel I omsettes med den til den ønskede ester svarende alkohol i nærvær av basiske katalysatorer, eller hydrolyserer og om ønsket forestrer påny. and if desired, esters of the general formula I are reacted with the alcohol corresponding to the desired ester in the presence of basic catalysts, or hydrolyzed and, if desired, re-esterified.

For fremgangsmåten ifølge alternativ a) kan der som oxyderende tungmetalloxyd eksempelvis anvendes sølv, bly(IV)-oxyd, møn-je, vanadium(V)-oxyd, mangan(IV)-oxyd eller krom(VI)-oxyd, det si-ste imidlertid bare når forbindelsene av generell formel II ikke inneholder en 11-hydroxygruppe. Reaksjonen utføres ved at der fortrinnsvis anvendes 0,5 g til 50 g, fortrinnsvis 1 g til 10 g tungmetalloxyd pr. gram forbindelse II. For the method according to alternative a), silver, lead (IV) oxide, lead, vanadium (V) oxide, manganese (IV) oxide or chromium (VI) oxide can be used as oxidizing heavy metal oxide, i.e. however, only when the compounds of general formula II do not contain an 11-hydroxy group. The reaction is carried out by preferably using 0.5 g to 50 g, preferably 1 g to 10 g of heavy metal oxide per gram compound II.

For dette fremgangsmåtealternativ anvendes det som alkohol fortrinnsvis lavere eller midlere, primære eller sekundære alkoholer med 1-8 carbonatomer. Som alkoholer kan eksempelvis nevnes: methanol , ethanol , propanol , isopropanol , butanol , isobutanol , sek.-butanol, amylalkohol, isoamylalkohol , hexanol, heptanol eller octanol. Disse alkoholer kan også samtidig anvendes som løsnings-middel. Selvsagt er det også mulig i tillegg til alkoholen å til-sette reaksjonsblandingen ytterligere inerte løsningsmidler. Slike inerte løsningsmidler er eksempelvis: hydrocarboner slik som benzen, cyclohexan eller toluen, klorerte hydrocarboner slik som methylenklorid, kloroform eller tetraklorethan, ether, slik som diethyl-ether , diisopropylether, dibutylether, glycoldimethylether, dioxan eller tetrahydrofuran, eller dipolare, aprotiske løsningsmidler slik som dimethylformamid, N-methylacetamid eller N-methylpyrrolidon. Ved gjennomføring av fremgangsmåten ifølge alternativ a) opp-nåes det ganske overraskende en betydelig økning i reaksjonshastig-heten og en betydelig økning av utbyttet når denne reaksjon ut-føres under tilsats av cyanidioner som katalysator. Som cyanidion-givende reagenser anvendes fortrinnsvis alkalicyanider slik som natrium- eller ka 1 iumcyanid. Fortrinnsvis anvendes det 0,01 mol - 10 mol, fortrinnsvis 0,1 - 1,0 mol cyanid pr. mol forbindelse av formel II. Anvendes det alkalicyanider som cyanidion-givende reagenser, utføres reaksjonen fortrinnsvis slik at reaksjonsblandingen ytterligere tilsettes bare den for nøytralisering av alkalicyanidet nødvendige mengde mineralsyrer (slik som f.eks. svovelsyre, fosfor-syre eller saltsyre), sulfonsyre (som p-toluensulfonsyre) eller carbonsyre (som maursyre eller eddiksyre). For this method alternative, preferably lower or medium, primary or secondary alcohols with 1-8 carbon atoms are used as alcohol. Alcohols can be mentioned, for example: methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec.-butanol, amyl alcohol, isoamyl alcohol, hexanol, heptanol or octanol. These alcohols can also be used as a solvent at the same time. Of course, it is also possible, in addition to the alcohol, to add further inert solvents to the reaction mixture. Such inert solvents are, for example: hydrocarbons such as benzene, cyclohexane or toluene, chlorinated hydrocarbons such as methylene chloride, chloroform or tetrachloroethane, ethers such as diethyl ether, diisopropyl ether, dibutyl ether, glycol dimethyl ether, dioxane or tetrahydrofuran, or dipolar, aprotic solvents such as dimethylformamide, N-methylacetamide or N-methylpyrrolidone. When carrying out the method according to alternative a) quite surprisingly, a significant increase in the reaction speed and a significant increase in the yield is achieved when this reaction is carried out with the addition of cyanide ions as a catalyst. Alkali cyanides such as sodium or potassium cyanide are preferably used as cyanide ion-yielding reagents. Preferably, 0.01 mol - 10 mol, preferably 0.1 - 1.0 mol of cyanide are used per mol of compound of formula II. If alkali cyanides are used as cyanidion-yielding reagents, the reaction is preferably carried out so that only the amount of mineral acids necessary to neutralize the alkali cyanide (such as sulfuric acid, phosphoric acid or hydrochloric acid), sulphonic acid (such as p-toluenesulphonic acid) or carbonic acid (such as formic or acetic acid).

Den foretrukne utførelsesform av fremgangsmåtealternativ a) utføres hensiktsmessig ved en reaksjonstemperatur mellom -20° og +100°C, og fortrinnsvis ved en reaksjonstemperatur mellom 0° og +50°C. Reaksjonstiden er avhengig av reaksjonstemperatur og valget av reaksjonspartner, og utgjør ved den foretrukne utførelsesform av fremgangsmåtealternativ a) gjennomsnittlig 5 - 120 minutter. The preferred embodiment of process alternative a) is conveniently carried out at a reaction temperature between -20° and +100°C, and preferably at a reaction temperature between 0° and +50°C. The reaction time depends on the reaction temperature and the choice of reaction partner, and in the preferred embodiment of method alternative a) averages 5 - 120 minutes.

Utgangsmaterialer for fremgangsmåtealternativ a) kan fremstilles på enkel måte fra det tilsvarende 21-hydroxysteroid, Starting materials for process alternative a) can be prepared in a simple way from the corresponding 21-hydroxysteroid,

idet dette omsettes med lavere alkoholer slik som methanol, ethan- as this reacts with lower alcohols such as methanol, ethane

ol eller butanol, i nærvær av kobber(II)-acetat i 10 - 120 minut- ol or butanol, in the presence of copper(II) acetate for 10 - 120 min-

ter ved romtemperatur. Efter opparbeidelse av reaksjonsblandingen kan de erholdte forbindelser anvendes direkte som utgangsmateria- ter at room temperature. After working up the reaction mixture, the obtained compounds can be used directly as starting materials

ler ved den nye fremgangsmåte. laughs at the new procedure.

Forbindeslene av generell formel I kan også fremstilles ifølge alternativ b). The compounds of general formula I can also be prepared according to alternative b).

Fremgangsmåten ifølge alternativ b) kan utføres i slike inerte oppløsningsmidler som vanligvis anvendes innen steroidkjemien ved oxydasjoner. Egnede oppløsningsmidler er eksempelvis: Hydrocarboner, slik som cyclohexan, benzen, toluen eller xylen, klorerte hydrocarboner slik som methylenklorid, kloroform, tetra-klorcarbon, tetraklorethylen eller klorbenzen, ether slik som di-ethylether, diisopropylether, dibutylether, tetrahydrofuran, dioxan, glycoldimethylether eller anisol, ketoner slik som aceton, methylethylketon, methylisobutylketon eller acetofenon eller alkoholer slik som methanol, ethanol, isopropanol eller t-butanol. The method according to alternative b) can be carried out in such inert solvents as are usually used in steroid chemistry for oxidations. Suitable solvents are, for example: Hydrocarbons, such as cyclohexane, benzene, toluene or xylene, chlorinated hydrocarbons such as methylene chloride, chloroform, tetrachlorocarbon, tetrachloroethylene or chlorobenzene, ethers such as diethylether, diisopropylether, dibutylether, tetrahydrofuran, dioxane, glycoldimethylether or anisole, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone or acetophenone or alcohols such as methanol, ethanol, isopropanol or t-butanol.

Den nye fremgangsmåte kan også utføres i blandinger av de ovenfor angitte oppløsningsmidler. The new method can also be carried out in mixtures of the above-mentioned solvents.

Fremgangsmåten ifølge alternativ b) kan utføres under anvendelse av mangan(IV)-oxyd eller bly(IV)-oxyd. For denne fremgangsmåtevariant anvendes der for å oppnå høyere utbytter fortrinnsvis aktivt mangan(VI)-oxyd, hvilket er funnet vanlig ved oxydasjons-reaksjoner innen steroidkjemien. The method according to alternative b) can be carried out using manganese (IV) oxide or lead (IV) oxide. For this process variant, in order to achieve higher yields, preferably active manganese (VI) oxide is used, which is found to be common in oxidation reactions within steroid chemistry.

Gjennomføring av reaksjonen ifølge variant b) skjer fortrinnsvis ved en reaksjonstemperatur mellom 0° og 150°C. Således er det eksempelvis mulig å oxydere forbindelsene av generell for-mell III ved romtemperatur eller ved koketemperaturen til det an-vendte oppløsningsmiddel. Carrying out the reaction according to variant b) preferably takes place at a reaction temperature between 0° and 150°C. Thus, for example, it is possible to oxidize the compounds of general formula III at room temperature or at the boiling temperature of the solvent used.

Konfigurasjonen av 20-hydroxylgruppen i utgangsmaterialet av generell formel III er uten betydning ved anvendelse av foreliggende fremgangsmåte. Derfor kan 20a-hydroxysteroidet av generell formel III, 203-hydroxysteroidet av generell formel III og også blandingen av disse omdannes til pregnansyrederivatet av generell formel III ifølge fremgangsmåten. The configuration of the 20-hydroxyl group in the starting material of general formula III is of no importance when using the present method. Therefore, the 20α-hydroxysteroid of general formula III, the 203-hydroxysteroid of general formula III and also the mixture of these can be converted into the pregnanic acid derivative of general formula III according to the method.

Utgangsmaterialet for fremgangsmåtevariant b) kan fremstilles fra de tilsvarende 21-hydroxy-20-oxo-pregnan-derivater. Disse forbindelser oppløses i en alkohol, oppløsningen tilsettes kobber(II)-acetat og omrøres flere dager ved romtemperatur. Derefter tilsettes blandingen vandig ammoniakk, hvorefter man ekstra-herer eksempelvis med methylenklorid, vasker den organiske fase med vann, tørker denne og inndamper den i vakuum. Der erholdes et urent produkt som består av en blanding av 20a-hydroxysteroidet. Denne blanding kan uten videre rensning anvendes som utgangsmate-riale ved fremgangsmåtevariant b). The starting material for process variant b) can be prepared from the corresponding 21-hydroxy-20-oxo-pregnan derivatives. These compounds are dissolved in an alcohol, copper (II) acetate is added to the solution and stirred for several days at room temperature. Aqueous ammonia is then added to the mixture, after which extraction is carried out, for example with methylene chloride, the organic phase is washed with water, dried and evaporated in a vacuum. An impure product consisting of a mixture of the 20a-hydroxysteroid is obtained. This mixture can be used without further purification as starting material in method variant b).

Den eventuelle etterfølgende hydrolyse av 21-esteren skjer efter kjente metoder. Eksempelvis kan nevnes hydrolyse av esteren i vann eller vandig alkohol i nærvær av sure katalysatorer, slik som saltsyre, svovelsyre, p-toluensulfonsyre eller av basiske katalysatorer, som kaliumhydroencarbonat, kaliumcarbonat, natriumhydroxyd eller kaliumhydroxyd. Any subsequent hydrolysis of the 21-ester takes place according to known methods. Examples include hydrolysis of the ester in water or aqueous alcohol in the presence of acidic catalysts, such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or of basic catalysts, such as potassium hydrogencarbonate, potassium carbonate, sodium hydroxide or potassium hydroxide.

Den eventuelt efterfølgende forestring av den frie syre skjer efter kjente metoder. Således kan syren eksempelvis omsettes med diazomethan eller diazoethan, hvorved der erholdes den tilsvarende methyl- eller ethylester. En generelt anvendbar metode er omsetning av syren med alkoholen i nærvær av carbonyldi-imidazol, dicyclohexylcarbodiimid eller trifluoreddiksyreanhydrid. Ennvidere er det eksempelvis mulig å omsette syren med alkylhalo-genider i nærvær av kobber(I)-oxyd eller sølvoxyd. Any subsequent esterification of the free acid takes place according to known methods. Thus, for example, the acid can be reacted with diazomethane or diazoethane, whereby the corresponding methyl or ethyl ester is obtained. A generally applicable method is reaction of the acid with the alcohol in the presence of carbonyldiimidazole, dicyclohexylcarbodiimide or trifluoroacetic anhydride. Furthermore, it is for example possible to react the acid with alkyl halides in the presence of copper (I) oxide or silver oxide.

En ytterligere metode består i at den frie syre overfø-res med det tilsvarende dimethylformamidalkylacetal til den tilsvarende syrealkylester. Videre kan syren i nærvær av sterkt A further method consists in the free acid being transferred with the corresponding dimethylformamide alkyl acetal to the corresponding acid alkyl ester. Furthermore, the acid in the presence of strong

sure katalysatorer slik som klorhydrogen, svovelsyre, perklorsyre, trifluormethylsulfonsyre eller p-toluensulfonsyre omsettes med alkoholen eller med den lavere alkancarboxylsyre av alkoholen. Det er imidlertid også mulig å overføre carbonsyren til syrekloridet eller syreanhydridet og omsette dette i nærvær av basiske katalysatorer med alkoholen. acid catalysts such as hydrogen chloride, sulfuric acid, perchloric acid, trifluoromethylsulfonic acid or p-toluenesulfonic acid are reacted with the alcohol or with the lower alkanecarboxylic acid of the alcohol. However, it is also possible to transfer the carbonic acid to the acid chloride or acid anhydride and react this in the presence of basic catalysts with the alcohol.

Saltene av carboxylsyrene fåes eksempelvis ved forsåp-ning av esteren ved hjelp av basiske katalysatorer eller ved nøy-tralisasjon av syren ved hjelp av alkalicarbonater eller alkali-hydroxyder, slik som f.eks. natriumcarbonat, natriumhydrogencarb-onat, natriumhydroxyd, kaliumcarbonat, kaliumhydrogencarbonat eller kaliumhydroxyd. The salts of the carboxylic acids are obtained, for example, by saponification of the ester with the aid of basic catalysts or by neutralization of the acid with the aid of alkali carbonates or alkali hydroxides, such as e.g. sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, potassium hydrogen carbonate or potassium hydroxide.

Ennvidere er det mulig å omsette esteren av generell Furthermore, it is possible to convert the ester of general

formel I i nærvær av basiske katalysatorer med den endelig ønskede alkohol. Herved anvendes der som basiske katalysatorer fortrinnsvis alkali-, jordalkali- eller aluminiumalkoholater. Denne reaksjon utføres fortrinnsvis ved en reaksjonstemperatur mellom 0 og 180°C. Ved denne reaksjon anvendes den endelig ønskede alkohol i overskudd, der anvendes fortrinnsvis 10 - 1000 mol alkohol pr. mol steroid. Alkoholen kan eventuelt fortynnes med ytterligere oppløsningsmidler, slik som f.eks. ether, di-n-butylether, tetrahydrofuran, dioxan, glycoldimethylether, eller dipolare aprotiske oppløsningsmidler slik som dimethylformamid, N-methylacetamid, dimethylsulfoxyd, N-methylpyrrolidon eller acetonitril. Denne reaksjonsvariant utføres på slik måte at der pr. mol steroid fortrinnsvis anvendes mindre enn 1 mol basisk katalysator. Særlig anvendes der ved utførelse av reaksjonen 0,0001 - 0,5 mol basisk katalysator pr. mol steroid. formula I in the presence of basic catalysts with the final desired alcohol. Hereby, alkali, alkaline earth or aluminum alcoholates are preferably used as basic catalysts. This reaction is preferably carried out at a reaction temperature between 0 and 180°C. In this reaction, the finally desired alcohol is used in excess, where preferably 10 - 1000 mol of alcohol are used per moles of steroid. The alcohol can optionally be diluted with further solvents, such as e.g. ether, di-n-butyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, or dipolar aprotic solvents such as dimethylformamide, N-methylacetamide, dimethylsulfoxide, N-methylpyrrolidone or acetonitrile. This reaction variant is carried out in such a way that per mol of steroid preferably less than 1 mol of basic catalyst is used. In particular, when carrying out the reaction, 0.0001 - 0.5 mol of basic catalyst is used per moles of steroid.

Forbindelsene av generell formel I er verdifulle terapeutisk aktive forbindelser eller verdifulle utgangsmaterialer ved fremstilling av terapeutisk aktive forbindelser. The compounds of general formula I are valuable therapeutically active compounds or valuable starting materials in the preparation of therapeutically active compounds.

De farmakologisk virksomme forbindelser av generell for-mell I utviser ved lokal anvendelse en utmerket antiinflammatorisk aktivitet og medfører den fordel at de ved systemisk anvendelse praktisk talt er uvirksomme. The pharmacologically active compounds of general formula I exhibit excellent anti-inflammatory activity when applied locally and have the advantage that they are practically inactive when applied systemically.

Vasokonstriksjonsforsøk Vasoconstriction test

På menneskehud ble der på følgende måte frembragt en hyperemi. A hyperemia was produced on human skin in the following manner.

På ryggen av frivillige mannlige og kvinnelige forsøks-personer ble hudens hornlag fjernet ved hjelp av 20 ganger over hverandre utførte avrivninger med en 2 cm bred "Tesa"-film, og der ble således frembragt en utpreget hyperemi. On the backs of voluntary male and female test subjects, the stratum corneum of the skin was removed by means of 20 overlapping tearings with a 2 cm wide "Tesa" film, and a marked hyperemia was thus produced there.

På merkede 4 cm store felter innenfor det avrevne område ble der påført ca. 50 mg av salvepreparatene. Salvegrunnlaget (uten aktivt stoff) tjente som blindverdi. On marked 4 cm large fields within the torn area, approx. 50 mg of the ointment preparations. The ointment base (without active substance) served as a blank value.

Foruten iakttagelsen ble ryggene 1, 4, 6 og 8 timer efter påføring fotografert med en "Kodak" farvefilm. In addition to the observation, the backs were photographed 1, 4, 6 and 8 hours after application with a "Kodak" color film.

Til bedømmelsen av hyperemi og vasokonstriksjon ble farven av de enkelte hudfelt omsatt til lyshetsverdier på farvefilmen. De fra farvefilmen gjennom en hullblender på et interferensfilter projiserte partier adskiller seg ved sin lyshet. Som lyshetsindi-kator ble anvendt en sekundærelektromultiplikator av typen FS 9A. Til bestemmelsen av farveverdien ble sekundærelektronmultiplikato-rens anodestrøm målt. For the assessment of hyperemia and vasoconstriction, the color of the individual skin areas was converted to lightness values on the color film. The parts projected from the color film through a pinhole mixer onto an interference filter are distinguished by their brightness. A secondary electromultiplier of the type FS 9A was used as a brightness indicator. To determine the color value, the anode current of the secondary electron multiplier was measured.

For å oppnå sammenlignelige utgangsverdier ble der anvendt forholdstall, da farven på den ubehandlede hud såvel som de hyperemiske områders rødmen er individuelt forskjellige. In order to achieve comparable starting values, ratios were used, as the color of the untreated skin as well as the redness of the hyperemic areas are individually different.

Den ubehandlede huds farveverdi ble anslått til 100, og av den avstrimlede hud til 0. The color value of the untreated skin was estimated at 100, and of the stripped skin at 0.

Hudfarveverdien av den i vasokonstriksjon værende hud (<100>) ble oppnådd ved en forholdstallsdannelse. The skin color value of the skin in vasoconstriction (<100>) was obtained by a ratio formation.

Dårlig, middelstor og kraftig vasokonstriksjon ble tilsvarende vurdert mellom 0 og 100. Bad, medium and severe vasoconstriction were correspondingly rated between 0 and 100.

I den etterfølgende tabell er anført middelverdiene som skriver seg fra undersøkelser av de forskjellige observasjonspa-sienter og av forskjellige ryggregioner. In the following table, the mean values obtained from examinations of the different observation patients and of different back regions are listed.

Vasokonstriksjon på den eksperimentelt hypermiserte hud. Vasokonstriksjonsvirkningen (hudfarveverdi) er angitt i forholdstall. Den ubehandlede huds farveverdi ble anslått til 100, mens hyperemien i hudens avstrimlede område ble anslått til 0. n angir antallet enkeltiakttagelser. Vasoconstriction on the experimentally hypermicized skin. The vasoconstriction effect (skin color value) is indicated in ratios. The color value of the untreated skin was estimated at 100, while the hyperemia in the stripped area of the skin was estimated at 0. n indicates the number of individual observations.

Av tabellen vil det fremgå at den ved fremgangsmåten ifølge oppfinnelsen fremstillede methylester III har en signifi-kant kraftigere antiinflammatorisk virkning enn den tidligere kjente methylester I (beskrivelsen i norsk patentsøknad 581 / 72) . Likeledes utviser de ifølge oppfinnelsen fremstillede butylestere IV-VI en kraftigere virkning enn den tidligere kjente butylester It will appear from the table that the methyl ester III produced by the method according to the invention has a significantly stronger anti-inflammatory effect than the previously known methyl ester I (description in Norwegian patent application 581/72). Likewise, the butyl esters IV-VI prepared according to the invention exhibit a stronger effect than the previously known butyl ester

II (likeledes kjent fra beskrivelsen i norsk patentsøknad 581/ 72). II (also known from the description in Norwegian patent application 581/72).

De nye forbindelser egner seg i kombinasjon med de innen den galeniske farmasi vanlige bærere til lokal behandling av kon-taktdermatitis, eksemer av forskjellig art, neurodermatoser, ery-throdermie, forbrenninger, Pruritis vulvae et ani, rosacea, Ery-thematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus og lignende hudsykdommer. The new compounds are suitable in combination with the usual carriers in galenic pharmacy for the local treatment of contact dermatitis, eczema of various kinds, neurodermatoses, erythroderma, burns, Pruritis vulvae et ani, rosacea, Erythematodes cutaneus, psoriasis, Lichen ruber planus et verrucosus and similar skin diseases.

Fremstillingen av legemidlene foregår efter kjente metoder, idet den aktive bestanddel med egnede tilsetningsstoffer overføres til den ønskede administreringsform, slik som f.eks. oppløsninger, lotions, salver, kremer eller plastere. I de således formulerte legemidler er konsentrasjonen av aktiv bestanddel avhengig av administreringsformen. I lotions og salver anvendes fortrinnsvis en konsentrasjon av den aktive bestanddel på 0,001 - 1 %. The preparation of the medicines takes place according to known methods, with the active ingredient being transferred with suitable additives to the desired administration form, such as e.g. solutions, lotions, ointments, creams or plasters. In the medicines formulated in this way, the concentration of active ingredient depends on the form of administration. In lotions and ointments, a concentration of the active ingredient of 0.001 - 1% is preferably used.

De etterfølgende eksempler illustrerer oppfinnelsen ytterligere. The following examples further illustrate the invention.

Eksempel 1 Example 1

a) En oppløsning av 2,0 g 9a-fluor-llp,21-dihydroxy-16a, a) A solution of 2.0 g of 9a-fluoro-llp,21-dihydroxy-16a,

17a-isopropylidendioxy-l,4-pregnadien-3,20-dion i 250 ml methanol 17α-isopropylidenedioxy-1,4-pregnadiene-3,20-dione in 250 ml methanol

ble tilsatt 500 mg kobber(II)-acetat i 250 ml methanol, og blandingen ble omrørt 30 minutter under gjennomblåsning av luft. Re-aks jonsblnadingen ble fortynnet med diklormethan, vasket med fortynnet ammoniumkloridoppløsning og vann, tørket med natriumsulfat og inndampet i vakuum. Utbyttet var 2,1 g 9a-fluor-113-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-al som 500 mg of copper (II) acetate in 250 ml of methanol was added, and the mixture was stirred for 30 minutes while blowing air through. The reaction mixture was diluted with dichloromethane, washed with dilute ammonium chloride solution and water, dried with sodium sulfate and evaporated in vacuo. The yield was 2.1 g of 9α-fluoro-113-hydroxy-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadien-21-al as

urent produkt. impure product.

b) 1,0 g av det således erholdte aldehyd ble løst i 50 ml methanol og 10 ml diklormethan, og løsningen ble etter tilsats av l60 mg b) 1.0 g of the aldehyde thus obtained was dissolved in 50 ml of methanol and 10 ml of dichloromethane, and the solution became after the addition of 160 mg

kaliumcyanid, 1,0 ml eddiksyre og 2,0 g mangan(IV)-oxyd omrørt i 5 minutter. Mangan(IV)-oxydet ble filtrert fra, filtratet ble fortynnet med diklormethan, vasket med vann, tørket og inndampet i vakuum. Residuet ble kromatografert på kiselgel med en methylenklorid-aceton-gradient (0 - 30% aceton). Utbytte: 578 mg 9n-fluor-11 (3-hydroxy -16c. , 17a -isopropyl idendioxy -3 ,20 -dioxo -1 , 4-pregnadien -21 - syre-methylester. Smeltepunkt 325°C (under spaltning). potassium cyanide, 1.0 ml acetic acid and 2.0 g manganese(IV) oxide stirred for 5 minutes. The manganese(IV) oxide was filtered off, the filtrate was diluted with dichloromethane, washed with water, dried and evaporated in vacuo. The residue was chromatographed on silica gel with a methylene chloride-acetone gradient (0-30% acetone). Yield: 578 mg 9n-fluoro-11 (3-hydroxy -16c. , 17a -isopropyl idendioxy -3 ,20 -dioxo -1 , 4-pregnadiene -21 - acid methyl ester. Melting point 325°C (under decomposition).

[a]p<5>: +55° (kloroform). UV:£23g = 15600 (methanol). [a]p<5>: +55° (chloroform). UV: £23g = 15600 (methanol).

Eksempel 2 Example 2

En løsning av 10 g 9a-fluor-lip,21-dihydroxy46a,17a-isopropy1-idendioxy-1,4-pregnadien-3,20-dion i lOOO ml methanol ble tilsatt 5 g kopper(II)-acetat, og blandingen ble omrørt i 120 timer ved romtemperatur. Løsningen ble inndampet i vakuum, og residuet ble tatt opp i diklormethan. Løsningen ble vasket med 10%-ig ammoniumhydroxyd-løsning og vann, tørket og inndampet. Den således erholdte blanding av 9a-fluor-llp,20a-dihydroxy-l6a,l7a-isopropylidendioxy-3-oxo-l,4-pregnadien-21-syre-methylester og 9a-f luor-ll(3,206-dihydroxy-l6a,17a-isopropylidendioxy-3-oxo-1,4-pregnadien-21-syre-methylest er ble løst i 500 ml diklormethan, tilsatt 500 g mangan(IV)-oxyd og omrørt i 24 timer ved romtemperatur. Etter filtrering ble filtratet inndampet og residuet kromatografert på kiselgel. Med 8 - 12% aceton-methylenklorid ble det etter omkrystallisasjon fra aceton-hexan, erholdt 1,73 g 9a-fluor-lip-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-syre-methylester. Smeltepunkt 324°C (under spaltning). [a]D : +53° (kloroform). UV : £238 = l6l0° (methanol). A solution of 10 g of 9α-fluoro-lip,21-dihydroxy46α,17α-isopropylidenedioxy-1,4-pregnadiene-3,20-dione in 1000 ml of methanol was added with 5 g of copper(II) acetate, and the mixture was stirred for 120 hours at room temperature. The solution was evaporated in vacuo, and the residue was taken up in dichloromethane. The solution was washed with 10% ammonium hydroxide solution and water, dried and evaporated. The thus obtained mixture of 9a-fluoro-11p,20a-dihydroxy-16a,17a-isopropylidenedioxy-3-oxo-1,4-pregnadiene-21-acid methyl ester and 9a-fluoro-11(3,206-dihydroxy-16a, 17α-isopropylidenedioxy-3-oxo-1,4-pregnadiene-21-acid methyl ester was dissolved in 500 ml of dichloromethane, 500 g of manganese(IV) oxide was added and stirred for 24 hours at room temperature. After filtration, the filtrate was evaporated and the residue chromatographed on silica gel. With 8 - 12% acetone-methylene chloride, after recrystallization from acetone-hexane, 1.73 g of 9a-fluoro-lip-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4 were obtained -pregnadiene-21-acid methyl ester. Melting point 324°C (under decomposition). [a]D : +53° (chloroform). UV : £238 = 16l0° (methanol).

Eksempel 3 Example 3

2,1 g 9a-fluor-lip-hydroxy-l6a,17a-isopropylidendioxy-3,20-di-oxo-1 ,Zf-pregnadien-21-al ble omsatt under de i eksempel lb beskrevne betingelser, imidlertid i butanol. Utbytte 585 mg 9a-fluor-lip-hydroxy-l6a , 17a.-isopropylidendioxy-3 ,20-dioxo-1 ,4-pregnadien-21 -syre-but yle st er med smeltepunkt 281°C (under spaltning). ["•<->Iq"' +^7° 2.1 g of 9a-fluoro-lip-hydroxy-16a,17a-isopropylidenedioxy-3,20-di-oxo-1,Zf-pregnadien-21-al were reacted under the conditions described in example 1b, however in butanol. Yield 585 mg of 9a-fluoro-lip-hydroxy-16a, 17a.-isopropylidenedioxy-3,20-dioxo-1,4-pregnadien-21-acid-butyl st is with a melting point of 281°C (under decomposition). ["•<->Iq"' +^7°

(kloroform). UV "-£238 = 16000 (methanol). (chloroform). UV "-£238 = 16000 (methanol).

Eksempel 4 Example 4

5, 0 g 9a-f luor-ll(3-hydroxy-l6a,17a-isopropylidendioxy-3 ,20-dioxo-l ,4-pregnadien-21-al ble i pentanol omsatt under de i eksempel lb beskrevne betingelser. Utbytte 2,58 g 9a- fluor-lip-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-syre - pentylest er med smeltepunkt 247°C. [a]^ : +45° (kloroform). 5.0 g of 9a-fluoro-11(3-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadien-21-al were reacted in pentanol under the conditions described in example 1b. Yield 2 ( chloroform).

UV: 6238 = 15900 (methanol). UV: 6238 = 15900 (methanol).

Eksempel 5 Example 5

En løsning av 500 mg 9a-fluor-118-hydroxy-16a,17a-isopropyl-idendioxy-3,20-dioxo-l,4-pregnadien-21-syre-pentylester i 80 ml propanol ble tilsatt lOO mg kalium-t-butylat og omrørt i 5 timer ved romtemperatur under nitrogenatmosfære. Løsningen ble fortynnet med diklormethan, vasket med fortynnet eddiksyre, natriumhydrogencarbonat-løsning og vann, tørket over natriumsulfat og inndampet i vakuum. A solution of 500 mg of 9a-fluoro-118-hydroxy-16a,17a-isopropyl-idenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid pentyl ester in 80 ml of propanol was added lOO mg of potassium-t- butylate and stirred for 5 hours at room temperature under a nitrogen atmosphere. The solution was diluted with dichloromethane, washed with dilute acetic acid, sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo.

Det urene produkt ble omkrystallisert fra aceton-hexan. Utbytte The crude product was recrystallized from acetone-hexane. Dividend

230 mg 9a-fluor-118-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-syre-propylester med smeltepunkt 285°C (under spaltning). [a]^<5> : +49° (kloroform). UV: 23$ = l5900.230 mg of 9a-fluoro-118-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid propyl ester with melting point 285°C (under decomposition). [a]^<5> : +49° (chloroform). UV: 23$ = l5900.

Eksempel 6 Example 6

Under de i eksempel 5 angitte betingelser ble 500 mg -9a-fluor-11P-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21 - syre-pentylester overført til 9a-fluor-118-hydroxy-l6a,17a-isopropyl-idendioxy-3,20-dioxo-1,4-pregnadien-21-syre-isopropylester med iso-propylalkohol. Utbytte 291 mg med smeltepunkt 286°C (under spaltning), [a]^ : +51° (kloroform). UV:^ 238 = 1^900 (methanol). Under the conditions stated in Example 5, 500 mg of -9a-fluoro-11P-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid pentyl ester was transferred to 9a-fluoro-118- hydroxy-16α,17α-isopropyl-idenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid isopropyl ester with isopropyl alcohol. Yield 291 mg with melting point 286°C (under cleavage), [a]^ : +51° (chloroform). UV: ^ 238 = 1^900 (methanol).

Eksempel 7 Example 7

Under de i eksempel 5 angitte betingelser ble 350 mg 9a-fluor-118-hydroxy-16a ,17'i-isopropyl idendioxy-3 ,20-dioxo-l ,4-pregnadien-21 - syre-pentylester overført til 9a-fluor-118-hydroxy-l6a,1 7a-isopropyl-idendioxy-3,20-dioxo-l,4-pregnadien-21-syre-ethylester med ethanol. Under the conditions stated in Example 5, 350 mg of 9a-fluoro-118-hydroxy-16a,17'i-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid pentyl ester was transferred to 9a-fluoro- 118-hydroxy-16a,17a-isopropyl-idenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid ethyl ester with ethanol.

Utbytte 119 mg med smeltepunkt 288°C (under spaltning). Yield 119 mg with melting point 288°C (during cleavage).

[a]^<5> : +46° (kloroform). UV; 23g <=> 15700 (methanol). [a]^<5> : +46° (chloroform). UV; 23g <=> 15700 (methanol).

Eksempel 8 Example 8

En oppløsning av 810 mg 9a-f luor-ll|3-hydroxy-16a, 17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-syre-pentylester i 50 ml diklormethan og 60 ml methanol ble tilsatt en oppløsnign av 960 mg kaliumhydroxyd i 5 ml vann, og blandingen ble omrørt 30 minutter under nitrogenatmosfære ved romtemperatur. Den alkaliske reaksjonsblanding ble derefter tilsatt vann og ekstrahert med diklormethan. Den vandige fase ble surgjort med 2n-saltsyre og ekstrahert med diklormethan. Den annen diklormethanfase ble vasket med vann, tørket og inndampet i vakuum ved 30°C. Residuet ble tatt opp med lite tetrahydrofuran og tilsatt eddikester til begyn-nende krystallisasjon. Der ble erholdt 490 mg 9a-fluor-lip-hydroxy-16a,17a-isopropyliden-dioxy-3,20-dioxo-l,4-pregnadien-21-syre med smeltepunkt 293°C (under spaltning). A solution of 810 mg of 9a-fluoro-11|3-hydroxy-16a, 17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid pentyl ester in 50 ml of dichloromethane and 60 ml of methanol was added to a solution of 960 mg of potassium hydroxide in 5 ml of water, and the mixture was stirred for 30 minutes under a nitrogen atmosphere at room temperature. The alkaline reaction mixture was then added to water and extracted with dichloromethane. The aqueous phase was acidified with 2n-hydrochloric acid and extracted with dichloromethane. The second dichloromethane phase was washed with water, dried and evaporated in vacuo at 30°C. The residue was taken up with a little tetrahydrofuran and acetic acid was added until crystallization began. 490 mg of 9a-fluoro-lip-hydroxy-16a,17a-isopropylidene-dioxy-3,20-dioxo-1,4-pregnadiene-21-acid with a melting point of 293°C (under decomposition) was obtained.

[a]^<5>: +57° (pyridin). UV: £ 238 = 15300 (methanol). [a]^<5>: +57° (pyridine). UV: £238 = 15300 (methanol).

Eksempel 9 Example 9

100 mg 9a-fluor-llB--hydroxy-16a, 17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-syre ble oppløst i 15 ml methanol og tilsatt2,23 ml av en n/10-oppløsning av kaliumhydroxyd i methanol. 100 mg of 9α-fluoro-11B-hydroxy-16α, 17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid was dissolved in 15 ml of methanol and 2.23 ml of an n/10 solution was added of potassium hydroxide in methanol.

Oppløsningsmidlet ble avdampet i vakuum, og residuet ble tilsatt 25 ml ether. Det utfeldte natriumsalt av 9a-fluor-113-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-syre ble fraskilt og tørket i vakuum. Utbytte 93 mg. The solvent was evaporated in vacuo, and 25 ml of ether was added to the residue. The precipitated sodium salt of 9α-fluoro-113-hydroxy-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid was separated and dried in vacuo. Yield 93 mg.

Eksempel IQ Example IQ

1,0 g 6a,9a-difluor-118,21-dihydroxy-l6a,17a-isopropyliden-dioxy-1,4-pregnadien-3,20-dion ble under de i eksempel la beskrevne betingelser oxydert til 6a , 9a-difluor-l 18 -hydroxy -l6a, 17a-isopropyl - idendioxy-3,20-dioxo-l ,4~pregnadien-21-al. 500 mg av det således erholdte produkt ble under anvendelse av de i eksempel lb beskrevne betingelser overført til 6a ,9a-dif luor-116-hydroxy-16a ,l7a-isopropyl-idendioxy-3,20-dioxo-l,4-pregnadien-21-syre-methylester. Utbytte 277 mg med smeltepunkt 3l4°C (under spaltning). [a]^ : +43° (kloroform). UV:É 238 = 16500 (methanol). 1.0 g of 6a,9a-difluoro-118,21-dihydroxy-16a,17a-isopropylidene-dioxy-1,4-pregnadiene-3,20-dione was oxidized to 6a,9a-difluoro under the conditions described in example la -1 18 -hydroxy -16a,17a-isopropyl-idenedioxy-3,20-dioxo-1,4-pregnadien-21-al. Using the conditions described in example 1b, 500 mg of the product thus obtained was transferred to 6a,9a-difluoro-116-hydroxy-16a,17a-isopropyl-idenedioxy-3,20-dioxo-1,4-pregnadiene- 21-acid methyl ester. Yield 277 mg with melting point 314°C (under cleavage). [a]^ : +43° (chloroform). UV: É 238 = 16500 (methanol).

Eksempel 11 Example 11

500 mg 6a ,9a-dif luor-118-hydroxy-l6a , 17a.-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-al ble under anvendelse av de i eksempel lb beskrevne betingelser i butanol overført til 6a,9a-difluor-116-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-syre-butylester med vanadium(V)-oxyd. Utbytte 364 mg med smeltepunkt 248°C (under spaltning). [a]D : +55° (pyridin). UV: £238 = 16400 (methanol). 500 mg of 6a,9a-difluoro-118-hydroxy-16a,17a.-isopropylidenedioxy-3,20-dioxo-1,4-pregnadien-21-al was transferred to 6a using the conditions described in example 1b in butanol ,9a-difluoro-116-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester with vanadium(V)-oxidn. Yield 364 mg with melting point 248°C (under cleavage). [a]D : +55° (pyridine). UV: £238 = 16400 (methanol).

Eksempel 12 Example 12

Under anvendelse av de i eksempel la beskrevne betingelser ble 500 mg 6a-fluor-9a-klor-118,21-dihydroxy-l6a,17a-isopropylidendioxy-1,4-pregnadien-3,20-dion oxydert til 21-aldehydet, og dette ble under anvendelse av de i eksempel lb beskrevne betingelser- overført til 6a-fluor-9a-klor-118-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxo-l ,4-pregnadien-21-syre-butylester med butanol. Utbytte 336 mg med smeltepunkt 296 C (under spaltning). [a]^ : +68° (kloroform). UV: £238 = 16100 (methanol). Using the conditions described in Example 1a, 500 mg of 6a-fluoro-9a-chloro-118,21-dihydroxy-16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione was oxidized to the 21-aldehyde, and using the conditions described in example 1b, this was transferred to 6a-fluoro-9a-chloro-118-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester with butanol. Yield 336 mg with melting point 296 C (under cleavage). [a]^ : +68° (chloroform). UV: £238 = 16100 (methanol).

Eksempel 13 Example 13

150 mg 6a-fluor-9a-klor-118-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-syre-butylester ble under anvendelse av de i eksempel 5 angitte betingelser i methanol overført til 6a-fluor-9a-klor-118-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregna-dien-21-syre-methylester. Utbytte 98 mg med smeltepunkt 329 C 150 mg of 6α-fluoro-9α-chloro-118-hydroxy-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester was transferred into methanol using the conditions stated in Example 5 to 6α-fluoro-9α-chloro-118-hydroxy-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregna-diene-21-acid methyl ester. Yield 98 mg with melting point 329 C

. (under spaltning). [a]£5 : +74° (kloroform). UV: 238 <=><16>200. (under cleavage). [a]£5 : +74° (chloroform). UV: 238 <=><16>200

(methanol). (methanol).

Eksempel Example

Under anvendelse av de i eksempel 1 angitte betingelser ble Using the conditions stated in example 1 was

3,0 g 6a-fluor-118 ,21-dihydroxy-l6a , 17a-isopropyl idendioxy-1 ,4- '. pregnadien-3,20-dion oxydert til aldehydet, og dette ble med ethanol overført t il 6a-fluor-118-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-l ,4-pregnadien-21-syre-ethylester. Utbytte 1,56 g med smeltepunkt 279°C (under spaltning). iaJp^ : +51° (kloroform). 3.0 g of 6a-fluoro-118,21-dihydroxy-16a,17a-isopropylidenedioxy-1,4-'. pregnadiene-3,20-dione oxidized to the aldehyde, and this was transferred with ethanol to 6a-fluoro-118-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid ethyl ester . Yield 1.56 g with melting point 279°C (under cleavage). iaJp^ : +51° (chloroform).

uv. g2^2 = 16300 (methanol). UV g2^2 = 16300 (methanol).

Eksempel 15 Example 15

Under de i eksempel 5 angitte betingelser ble 750 mg 6a-fluor-118 -hydroxy -l6a , 17a.-isopropyl idendioxy -3 ,20-dioxo -1 , 4-pr egn a dien -21 - syre-ethylester med butanol overført til 6a-fluor-118-hydroxy-l6a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-syre-buty1-ester. Utbytte 451 mg med smeltepunkt 294°C (under spaltning). Under the conditions stated in Example 5, 750 mg of 6α-fluoro-118-hydroxy-16α, 17α-isopropyl idendioxy-3,20-dioxo-1, 4-pregna diene-21-acid ethyl ester with butanol was transferred to 6α-Fluoro-118-hydroxy-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid buty1-ester. Yield 451 mg with melting point 294°C (under cleavage).

[a]p5 :+54° (kloroform). UV:£242 = 16600 (methanol). [a]p5 :+54° (chloroform). UV: £242 = 16600 (methanol).

Eksempel 16 Example 16

150 mg 6a-fluor-9a,1IB-diklor-l6a,17a-isopropylidendioxy-1,4-pregna - dien-3,20-dion ble under anvendelse av de i eksempel 1 beskrevne betingelser over det tilsvarende 21-aldehyd overført til 6a-fluor-9a,118-diklor-l6a,17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-syre-methylester. Utbytte 86 mg med smeltepunkt 330°C (under spaltning), [ajp^ : +86° (kloroform). UV: 6237 <=> !5900 (methanol). 150 mg of 6a-fluoro-9a,1IB-dichloro-16a,17a-isopropylidenedioxy-1,4-pregna-diene-3,20-dione was transferred using the conditions described in example 1 over the corresponding 21-aldehyde to 6a -fluoro-9α,118-dichloro-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid methyl ester. Yield 86 mg with melting point 330°C (under cleavage), [ajp^ : +86° (chloroform). UV: 6237 <=> !5900 (methanol).

Eksempel 17 Example 17

Under de i eksempel la beskrevne betingelser ble 75 mg 6a-fluor-9a,118-diklor-l6a,17a-isopropylidendioxy-1,4-pregnadien-3,20-dion oxydert til 21-aldehyd, og dette ble under anvendelse av de i eksempel lb beskrevne betingelser med butanol overført til 6a-fluor-9a,118-diklor-16a,17a-isopropylidendioxy-3,20-dioxo-1.4-pregnadien-21-syre-butylester. Utbytte 37 mg med smeltepunkt 246°C. Under the conditions described in example 1a, 75 mg of 6a-fluoro-9a,118-dichloro-16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione were oxidized to 21-aldehyde, and this was, using the conditions described in example 1b with butanol transferred to 6α-fluoro-9α,118-dichloro-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester. Yield 37 mg with melting point 246°C.

[a_jp<5><:><+>84° (kloroform). UV:£ 237 = 16100 (methanol). [a_jp<5><:><+>84° (chloroform). UV: £ 237 = 16100 (methanol).

Eksempel 18 Example 18

Under anvendelse av de i eksempel la beskrevne betingelser ble 500 mg 6a,116-difluor-l6a,17a-isopropylidendioxy-1,4-pregnadien-3,20-dion oxydert til 21-aldehyd, og dette ble under anvendelse av de i eksempel lb beskrevne betingelser med butanol overført til 6c. ,118-difluor-9a-klor-16a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregna-dien-21-syre-butylester. Utbytte 416 mg med smeltepunkt over 330°C. Using the conditions described in example 1a, 500 mg of 6a,116-difluoro-16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione was oxidized to 21-aldehyde, and this was, using the conditions in example lb described conditions with butanol transferred to 6c. ,118-difluoro-9a-chloro-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregna-diene-21-acid butyl ester. Yield 416 mg with melting point above 330°C.

[a]^<5> : +55° (kloroform). UV: £ 236 = 15800 (methanol). [a]^<5> : +55° (chloroform). UV: £236 = 15800 (methanol).

E ksempel 19 Example 19

Under de i eksempel 1 beskrevne betingelser ble 5,0 g 113,21-dihydroxy-16a,17a-isopropylidendioxy-1,4-pregnadien-3,20-dion over 21-aldehydet overført til 116-hydroxy-16a,17a-isopropyl-idendioxy-3,20-dioxo-l,4-pregnadien-21-syre-methylester. Utbytte 3,8 g. Under the conditions described in example 1, 5.0 g of 113,21-dihydroxy-16a,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione was transferred over the 21-aldehyde to 116-hydroxy-16a,17a-isopropyl -idenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid methyl ester. Yield 3.8 g.

Eksempel 20 Example 20

1,0 g 113_hydroxy-16a,17a-isopropylidendioxy-3,20-dioxo-1,4-pregnadien-21-syre-methylester ble under de i eksempel 5 beskrevne betingelser omestret i butanol. Utbytte 633 mg 113-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-syre-butylester. Smeltepunkt 253°C; 1.0 g of 113_hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid methyl ester was transesterified in butanol under the conditions described in example 5. Yield 633 mg of 113-hydroxy-16α,17α-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester. Melting point 253°C;

[a]^<5> = +53° (kloroform). [a]^<5> = +53° (chloroform).

Eksempel 21 Example 21

500 mg 113-hydroxy-16a,17a-(1-fenylethylidendioxy)-1,4-pregnadien-3,20-dion ble under de i eksempel 1 angitte betingelser over 21,aldehydet overført til 113~hydroxy-16a,17a-(1-fen-ylethylidendioxy ) -3,20-dioxo-l,4-pregnadien-21-syre-methylester. Utbytte 210 mg. Smeltepunkt 228°C; 500 mg of 113-hydroxy-16a,17a-(1-phenylethylidenedioxy)-1,4-pregnadiene-3,20-dione was transferred under the conditions stated in Example 1 over the 21,aldehyde to 113-hydroxy-16a,17a-( 1-phenylethylidenedioxy)-3,20-dioxo-1,4-pregnadiene-21-acid methyl ester. Yield 210 mg. Melting point 228°C;

[a]£<5> -19° (kloroform). [a]£<5> -19° (chloroform).

Eksempel 22 Example 22

750 mg 113,21-dihydroxy-16a,17a-isopropylidendioxy-6a-methyl-l,4-pregnadien-3,20-dion ble under anvendelse av de i eksempel la angitte betingelser oxydert til 21-aldehydet, og dette ble under anvendelse av de i eksempel lb beskrevne betingelser med butanol overført til 113-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxy-6a-methyl-l,4-pregnadien-21-syre-butylester. Utbytte 320 mg. 750 mg of 113,21-dihydroxy-16a,17a-isopropylidenedioxy-6a-methyl-1,4-pregnadiene-3,20-dione was oxidized to the 21-aldehyde using the conditions stated in example la, and this was of the conditions described in example 1b with butanol transferred to 113-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxy-6a-methyl-1,4-pregnadiene-21-acid butyl ester. Yield 320 mg.

Eksempel 23 Example 23

Under de i eksempel la beskrevne betingelser ble 700 mg 113,21-dihydroxy-16ct,17a-isopropylidendioxy-l,4-pregnadien-3,20-dion oxydert til 21-aldehyd. Dette ble i methanol omsatt som beskrevet i eksempel lb til 113-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxy-l,4-pregnadien-21-syre-ethylester. Utbytte 331 mg. Smp. 260 - 261°C. r„i25 ... - . _ , 1C,«« Smp. 2<60><-> [a]D = +53 (kloroform). UV: £ 242 = 15300 (methanol). Under the conditions described in example 1a, 700 mg of 113,21-dihydroxy-16ct,17a-isopropylidenedioxy-1,4-pregnadiene-3,20-dione was oxidized to 21-aldehyde. This was reacted in methanol as described in example 1b to 113-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxy-1,4-pregnadiene-21-acid ethyl ester. Yield 331 mg. Temp. 260 - 261°C. r„i25 ... - . _ , 1C,«« Temp. 2<60><-> [a]D = +53 (chloroform). UV: £242 = 15300 (methanol).

Eksempel 24 Example 24

Under de i eksempel la beskrevne betingelser ble 500 mg 9a-klor-113,21-dihydroxy-16a,17ct-isopropylidendioxy-l,4-pregnadi-en-3,20-dion oxydert til 21-aldehyd, og dette ble under de i eksempel lb beskrevne betingelser med butanol overført til 9a-klor-113-hydroxy-16a,17a-isopropylidendioxy-3,20-dioxo-l,4-pregnadien-21-syre-butylester. Utbytte 185 mg. Smp. 247,5 - 248,5°C (under spaltning. Under the conditions described in example 1a, 500 mg of 9a-chloro-113,21-dihydroxy-16a,17ct-isopropylidenedioxy-1,4-pregnadi-ene-3,20-dione was oxidized to 21-aldehyde, and this was conditions described in example 1b with butanol transferred to 9a-chloro-113-hydroxy-16a,17a-isopropylidenedioxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester. Yield 185 mg. Temp. 247.5 - 248.5°C (under decomposition.

[a]^<5> = +75° (pyridin). UV: Z 23g = 15300 (methanol). [a]^<5> = +75° (pyridine). UV: Z 23g = 15300 (methanol).

Eksempel 25 Example 25

750 mg 9a,113-diklor-21-hydroxy-16a,17a-isopropyliden-dioxy-1,4-pregnadien-3,20-dion ble under anvendelse av de i eksempel la beskrevne betingelser oxydert til 21-aldehyd. Dette ble med butanol overført til 9a,113-diklor-16a,17a-isopropyliden-dioxy-3,20-dioxo-l,4-pregnadien-21-syre-butylester som beskrevet i eksempel lb. Utbytte 300 mg. Smp. 242 - 243°C (under spaltning) . [<i]q<5> = +101° (kloroform). UV: £ 237 = 15500 (methanol). 750 mg of 9a,113-dichloro-21-hydroxy-16a,17a-isopropylidene-dioxy-1,4-pregnadiene-3,20-dione were oxidized to 21-aldehyde using the conditions described in example la. This was transferred with butanol to 9a,113-dichloro-16a,17a-isopropylidene-dioxy-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester as described in example 1b. Yield 300 mg. Temp. 242 - 243°C (under decomposition) . [<i]q<5> = +101° (chloroform). UV: £237 = 15500 (methanol).

Eksempel 26 Example 26

1,0 g 9a-fluor-113-21-dihydroxy-16a,17a-(1-fenylethyl-idendioxy ) -1 , 4-pregnadien-3 , 20-dion ble under de i eksempel la beskrevne betingelser oxydert til aldehyd. Dette ble i butanol overført til 9a-fluor-113-hydroxy-16a,17a-(1-fenylethylendioxy)-3,20-dioxo-l,4-pregnadien-21-syre-butylester som beskrevet i eksempel lb. Utbytte 570 mg. Smp. 217°C. 1.0 g of 9a-fluoro-113-21-dihydroxy-16a,17a-(1-phenylethyl-idenedioxy)-1,4-pregnadiene-3,20-dione was oxidized to aldehyde under the conditions described in example la. This was transferred in butanol to 9a-fluoro-113-hydroxy-16a,17a-(1-phenylethylenedioxy)-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester as described in example 1b. Yield 570 mg. Temp. 217°C.

[a]g5 = -32° (kloroform). UV: £239 = 15300 (methanol). [a]g5 = -32° (chloroform). UV: £239 = 15300 (methanol).

Eksempel 27 Example 27

590 mg 113,21-dihydroxy-16a,17a-(1'-fenylethylidendi-oxy)-l,4-pregnadien-3,20-dion ble som beskrevet i eksempel la oxydert til 21-aldehyd. Det erholdte aldehyd ble i butanol overført til 113-hydroxy-16a,17a-(1'-fenylethylidendioxy)-3,20-dioxo-l,4-pregnadien-21-syre-butylester som beskrevet i eksempel lb. utbytte 261 mg. Smp. 211°C. ta]^5 = -26° (kloroform). UV:£ 23g <= >15700 (methanol). 590 mg of 113,21-dihydroxy-16a,17a-(1'-phenylethylidenedioxy)-1,4-pregnadiene-3,20-dione was oxidized to 21-aldehyde as described in example 1a. The aldehyde obtained was converted in butanol to 113-hydroxy-16a,17a-(1'-phenylethylidenedioxy)-3,20-dioxo-1,4-pregnadiene-21-acid butyl ester as described in example 1b. yield 261 mg. Temp. 211°C. ta]^5 = -26° (chloroform). UV: £ 23g <= >15700 (methanol).

Claims

Analogous process for the preparation of therapeutically active pregnan-21-acid derivatives of the general formula I

in which X denotes a hydrogen atom, a fluorine atom or a methyl group, Y denotes a hydrogen atom, a fluorine atom or a chlorine atom, Z denotes a hydroxy group or, if Y is a chlorine atom, a fluorine or chlorine atom, R 1 and R 2 denote a alkyl group with 1-4 carbon atoms or a phenyl group, and R 3 denotes a hydrogen atom, a sodium atom or an alkyl group with 1-8 carbon atoms, characterized in that a) a compound of general formula II 1 2 wherein X, Y, Z, R and R have the same meanings as given for formula I, or hydrates or hemiacetals of this compound are oxidized with oxidizing heavy metal oxides in the presence of alcohols, or b) a compound of general formula III in which X, Y, Z, R 1, R 2 and R 3 have the same meanings as formula I, and in which the 20-hydroxy group can be a- or B-positioned, oxidized in an inert solvent with oxidizing metal oxides or metal salts, and if desired, esters of the general formula I are reacted with the alcohol corresponding to the desired ester in the presence of basic catalysts, or hydrolyzed and, if desired, re-esterified.