NO128492B

NO128492B -

Info

Publication number: NO128492B
Application number: NO03203/68A
Authority: NO
Inventors: H Laurent; U Kerb; K Kolb; R Wiechert; E Gerhards
Original assignee: Schering Ag
Priority date: 1967-08-16
Filing date: 1968-08-15
Publication date: 1973-11-26
Also published as: PL71425B1; IL30547A; CH512458A; IL30547A0

Description

Analogifremgangsmåte ved fremstilling av terapeutisk Analogy procedure in the preparation of therapeutic

virksomme 6a- fluor-9a,118-dihalogen-16a-methyl-l,4-pregnadien-21-ol-3,25-dioner eller estere derav. active 6α-fluoro-9α,118-dihalo-16α-methyl-1,4-pregnadien-21-ol-3,25-diones or esters thereof.

Analogifremgangsmåte ved fremstilling av terapeutisk virksomme 6q- fluor- 9a, lip- dihalogen- l6a- methyl- l. 1+- pregnadien- 21- ol-^ t2?- dioner eller estere derav Analogous method for the production of therapeutically effective 6q- fluoro- 9a, lipid- dihalogen- 16a- methyl- 1. 1+- pregnadiene- 21- ol-^ t2?- diones or esters thereof

Foreliggende oppfinnelse angår en analogifremgangsmåte ved fremstilling av terapeutisk virksomme lip-halogen-steroider av den generelle formel CH OR The present invention relates to an analogous method for the production of therapeutically effective lip-halogen steroids of the general formula CH OR

I 2 In 2

hvor R betegner hydrogen, alkanoyl med 1-15 carbonatomer som eventuelt kan være. substituert med klor eller en carboxylgruppe, en where R denotes hydrogen, alkanoyl with 1-15 carbon atoms which may optionally be. substituted with chlorine or a carboxyl group, a

nitrosylrest eller natriumsulfatrest, og X og Y betegner halogen, idet molekylvekten av Y er lik eller storre enn raolekylvekten av X. nitrosyl residue or sodium sulphate residue, and X and Y denote halogen, the molecular weight of Y being equal to or greater than the molecular weight of X.

Fremgangsmåten ifolge oppfinnelsen for fremstilling av lip-halogensteroidene av den generelle formel A utmerker seg ved at man til A-^<H>^-dobbeltbindingen i et tilsvarende steroid på i og for seg kjent måte adderer halogen og deretter eventuelt, alt etter den onskede betydning av R i sluttproduktet, forsåper og/eller forestrer molekylets 21-stilling. The method according to the invention for the production of the lip-halogen steroids of the general formula A is distinguished by the fact that halogen is added to the A-^<H>^ double bond in a corresponding steroid in a manner known per se and then optionally, depending on the desired meaning of R in the final product, saponifies and/or esterifies the molecule's 21-position.

Eksempler på alkanoyl R med 1-15 carbonatomer er fysiologisk henseende akseptable syrer, spesielt lavere og midlere alifatiske carboxylsyrer. Dessuten kan syrene være forgrenede, eller substituert med klor eller en carboxylgruppe. Slike syrer er f.eks. maursyre, eddiksyre, propionsyre, smorsyre, valeriansyre, capronsyre, enanth-syre, undecylsyre, trimethyleddiksyre, diethyleddiksyre, p.butyl-eddlksyre, oljesyre, melkesyre, mono-, di- og trikloreddiksyre, Examples of alkanoyl R with 1-15 carbon atoms are physiologically acceptable acids, especially lower and medium aliphatic carboxylic acids. Furthermore, the acids may be branched, or substituted with chlorine or a carboxyl group. Such acids are e.g. formic acid, acetic acid, propionic acid, butyric acid, valerian acid, caproic acid, enanthic acid, undecyl acid, trimethylacetic acid, diethylacetic acid, p.butylacetic acid, oleic acid, lactic acid, mono-, di- and trichloroacetic acid,

ravsyre, adipinsyre. Dessuten kan man anvende de vanlige anorganiske syrer, såsom f.eks. svovelsyre og salpetersyre. succinic acid, adipic acid. You can also use the usual inorganic acids, such as e.g. sulfuric acid and nitric acid.

De som utgangsmateriale anvendte A^"^^-steroider kan frem-stilles ved dehydratisering av de tilsvarende 11-hydroxyforbindelser. The A^"^^-steroids used as starting material can be produced by dehydration of the corresponding 11-hydroxy compounds.

En mulighet for dehydratisering består deri at man behandler 11-hydroxy-21-acyloxy-steroidet med methansulfoklorid i pyridin og dimethylformamid. 6a-fluor-21-hydroxy-l6a-methyl-l9(11)-pregnatrien-3,20-dion fåes på meget enkel måte ved forsåpning av den tilsvarende 21-ester. One possibility for dehydration consists in treating the 11-hydroxy-21-acyloxy steroid with methanesulfochloride in pyridine and dimethylformamide. 6α-fluoro-21-hydroxy-16α-methyl-19(11)-pregnatriene-3,20-dione is obtained in a very simple way by saponification of the corresponding 21-ester.

For addering av halogen til A^"*"^ -dobbeltbindingen kan man velge mellom en rekke muligheter. Således kan man f.eks. direkte addere til dobbeltbindingen halogener såsom klor eller brom, eller innbyrdes forbindelser av halogener, såsom f.eks. klormonofluorid eller bromraonoklorid, eller halogen fra polyhalogenider, såsom f. eks. kaliumtrijodid eller jodbenzendiklorid. ;Særlig godt lykkes adderingen av halogen når man samtidig ;lar både et positivt og et negativt halogen innvirke på A^^"'"^-steroidet. Som reagenser inneholdende det positive halogen kan man f.eks. anvende halogensuceinimider, halogenacetamider eller halogenene selv. Som reagenser for levering av det negative halo- ;gen kan man f.eks. anvende hydrogenhalogenider og alkalimetall-halogenider. ;Adderingen av halogener til ^-dobbeltbindingen i steroidet skjer alltid således at det positivt ladede halogen leirer seg til 9-stillingen, mens det negativt ladede halogen leirer seg til- 11-stillingen. Molekylvekten av halogenet i 9-stillingen kan derfor ikke være mindre enn molekylvekten av halogenet i 11-stillingen. Halogentilleiringen til A^"^-dobbeltbindingen utfores fortrinns-vis ved temperaturer mellom -75°C og-+50°C. ;En fri hydroxylgruppe eller en estergruppe i 21-stillingen kan forestres, henholdsvis forsåpes etter konvensjonelle metoder. Det anbefales imidlertid å anvende mest mulig skånsomme betingelser dersom man onsker å oppnå gode utbytter. ;De nye forbindelser oppviser ved vasokonstriksjonstesten på mannlige forsøkspersoner ved lokal administrering en utpreget antiinflammatorisk virkning som i den etterfølgende tabell er vist for de nye forbindelser II-IX i sammenligning med den kjente forbindelse 6a-fluor-lip,21-dihydroxy-16a-methy1-1,^-pregnadien-3,20-dion (I). Vasokonstriksjonstesten som ble anvendt for den klinisk-eksperimentelle påvisning av de nye forbindelsers for-bedrede egenskaper, ble utfort på folgende måter På ryggen av mannlige forsøkspersoner (18 - 38 år) ble Stratum corneum odelagt og en utpreget hyperaemia frembrakt ved 20 på hverandre folgende avrivninger med en 2 cm bre tesafilm. Deretter ble det på avmerkede ;2 00 ;h cm store felter innenfor det irriterte området påfort under samme trykk ca. 50 mg av et vann/oljesalvegrunnlag inneholdende henholdsvis 0,01 %, 0,001 % og 0,0001 % av testforbindelsen. For-sokspersonenes rygg ble deretter med bestemte tidsintervaller fotografert med en "Kodak" farvefilm. For vurdering av hyperaemiaen og vasokonstriksjonen ble farven av de individuelle hudfelter på "Kodak" farvefilmen omgjort til lyshetsverdier. Ved projisering av farvefilmen på et interferensfilter gjennom et diafragma, skiller de projiserte partier seg ut ved sin lyshet. Som lyshetsindikator ble det anvendt en sekundærelektronforsterker av typen "FS 9 A" og for bestemmelse av farveverdien ble sekundærforsterkerens anodestrom målt. For bestemmelse av vasokonstriksjoner, som kan anses som et representativt syndrom på den antiinflammatoriske virkning, og som ble vurdert med hensyn på inntreden av virkningen, virkningsgrad og varighet av virkningen, ble farveverdien av den ubehandlede og den behandlede irriterte hud sammenlignet, idet farveverdien av den normale hud ble satt til 100 og farveverdien av den ubehandlede, ;irriterte hud ble satt til 0. Liten, midlere og stor vasokonstrik-sjon ble gitt verdier mellom 0 og 100. ;De i tabell I angitte forsøksresultater viser tydelig at de nye forbindelser foruten å begynne å virke tidligere enn den kjente forbindelse også når det onskede maksimum av virkningen raskere enn sammenligningsforbindelsen. Dessuten er virkningsintensiteten av de nye forbindelser under hele den tid virkningen pågår, hoyere enn for den kjente forbindelse. ;Videre er bivirkningene av de nye forbindelser små. Eksempel-vis over de nye forbindelser ingen eller bare meget liten innflytelse på carbohydratstoffskiftet. Den gluconeogenetiske virkning er også sterkt redusert, hvilket spesielt gir seg til kjenne ved at blod-sukkerkonsentrasjonen ikke oker og mengden av leverglucogen tiltar forst ved ekstremt hoy dosering. Nevnes kan også at der bare oves liten innflytelse på leverenzymene tryptophanpyrrolase og trans-aminasene GOT og GPT. Betydningsfullt lav er også innvirkningen på natrium-, kalium- og fosfatutskillelsen under innvirkningen av de nye forbindelser. ;De nye forbindelser er - i kombinasjon med de i den gale-niske farmasi vanlige bærere - velegnede for behandling ved lokal administrering av f.eks. kontaktdermatitis, eksemer av forskjellige arter, neurodermitis, erythrodermi a, forste grads forbrenninger, pruritus vulvae et ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruber planus et verrucosus; og ved oral administrering f.eks. av akutt og kronisk polyarthritis, neurodermitis, bronkial asthma, hoyfeber o. a. ;Eksempel 1 ;Ved -75°C ble 18 ml vannfri flussyre omsatt med 25 ml tetrahydrofuran og 35 ml methylenklorid. I denne blanding opploses 8,70 g 6cc-fluor-21-acetoxy-l6a-me thyl-1 ,^4-, 9(11) -pregnatrien-3,20-dion (smeltepunkt 160 - 162°C) og h, 6 g N-bromsuccinimid. Blandingen- omror es i 3,5 timer ved -50°C, helles over i en opplosning av 120 g natriumhydrogencarbonat i 3,5 liter vann og ekstraheres med methylenklorid, og den organiske fase vaskes med vann og torres, og opplosningsmidlet avdestilleres i vakuum. Fra aceton/hexan fåes ;■ 6,39 g 6a,llp-difluor-9-brom-21-acetoxy-l6a-methyl-l,<L>i--pregnadien-3,20-dion av smeltepunkt 210,5 - 211°C. ;UV: £ 23g= 15200.;Eksempel 2 ;Ved -75°C blandes h2 ml vannfri flussyre, 57 ml tetrahydrofuran og 80 ml methylenklorid. I denne blanding opploses 20 g 6a-f luor-21-acetoxy-l6a-methyl-l,'+, 9(11) -pregnatrien-3,20-dion og 10 g N-klorsuccinimid. Blandingen omrores i 5 timer ved -60°, hvoretter det ytterligere tilsettes 20 g N-klorsuccinimid, og blandingen tillates å stå i 16 timer ved 0°C. Blandingen helles over i en opplosning av 270 g natriumhydrogencarbonat i 3 liter vann, hvoretter det ekstraheres med methylenklorid, den organiske fase vaskes med natriumhydrogensulfitopplosning, natriumhydrogencarbonatopplosning og vann og torres, og opplosningsmidlet avdestilleres i vakuum. Fra aceton/hexan fåes 12-, h g 6a, HB-dif luor-9-klor-21-acetoxy-l6a-methyl-],If-pregnadien-3,20-dion av smeltepunkt 2^9,5 - 250°C ;UV: £ 236= 15900. ;Eksempel ;En opplosning av 1,0 g 6a,HB-difluor-9-brom-21-acetoxy-l6a-methyl-ljV-pregnadien-S^O-dion i 3,0 ml methylenklorid omsettes ved -10°C med 6,2 ml av en 0,2 n natriummethylatopplosning i methanol. Blandingen omrores i <>>+5 minutter under nitrogenatmosfære ved -10°C, nøytraliseres med eddiksyre og ekstraheres med methylenklorid. Den organiske fase vaskes med natriumhydrogencarbonatopplosning og vann, torres og inndatnpes i vakuum. Residuet omkrystalliseres fra aceton/ hexan. Det erholdes 77^ mg 6a,HB-difluor-9-brom-21-hydroxy-l6a-methyl-l,Li--pregnadien-3,20-dion med smeltepunkt 206-206,5°C. ;UV: £ g=llf900. ;Eksempel h ;1,0 g 6a,lip-difluor-9-klor-21-acetoxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion forsåpes med natriummethylat under de i eksempel 3 beskrevne betingelser. Det erholdes 770 mg 6a,llB-difluor-9-klor-21-hydroxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion av smeltepunkt 211,5_211+0C (aceton/hexan). ;UV: E 236= 16500.;Eksempel ;En opplosning av 2,75 g 6a,118-difluor-9-brom-21-hydroxy-l6a-methyl-l,<1>f-pregnadien-3,20-dion i 11 ml pyridin og 5,5 ml smbrsyreanhydrid tillates å stå i 16 timer ved romtemperatur. ;Etter tilsetning av vann isoleres det utfelte, krystallinske materiale, hvoretter det omkrystalliseres to ganger fra aceton. Det erholdes 2,'+5 g 6a,HB-difluor-9-brom-21-but<y>r<y>lox<y>-l6a-meth<y>l-l, h-pregnadien-3,20-dion av smeltepunkt 16U-, 5-165, 5°G. ;UV: É.238= 15000. ;Eksempel 6 ;3,95 g 6a,llB-difluor-9-klor-21-hydroxy-l6a-methyl-l,1+- ;sukkerkonsentrasjonen ikke oker og mengden av leverglucogen tiltar forst ved ekstremt hoy dosering. Nevnes kan også at der bare oves liten innflytelse på leverenzymene tryptopb.anpyrroJ.ase og trans-aminasene GOT og. GPT. Betydningsfullt lav er også innvirkningen på natrium-, kalium- og fosfatutskillelsen under innvirkningen av de nye forbindelser. ;De nye forbindelser er - i kombinasjon med de i den gale-niske farmasi vanlige bærere - velegnede for behandling ved lokal, administrering av f.eks. kontaktdermatitis, eksemer av, forskjellige-arter,.neurodermitis, erythrodermi a, forste grads forbrenninger, pruritus vulvae et ani, rosacea,. erythematodes cutaneus, psoriasis,, lichen ruber planus et verrucosus; og ved oral administrering, f.eks. av akutt og kronisk polyarthritis, neurodermitis, bronkial asthma, hdyfeber o. a. ;Eksempel 1 ;Ved -75° C ble 18 ml vannfri- flussyre omsatt me.d 25 ml tetra-. hyd r of-ur an og 35 ml methylenklorid. I denne blanding opploses 8,70 g 6a-fluor-21-acetoxy-l6a-methyl-l,<l>f,9(11)-pregnatrien-3,20-, dion (smeltepunkt 160 - 162 C) og.. ^,6 g N-bromsuccinimid. Blandingen, omror.es-i 3,-5 timer.ved -50°C, .helles over i en opplosning av 120 g natriumhydrogencarbonat i 35 5 liter, vann og ekstraheres med methylenklorid, og den organiske fase vaskes med vann og torres-, og opplosningsmidlet avdestilleres i vakuum. Fra aceton/hexan fåes 6,39 g 6a,lip-difluor-9-brom-21-acetoxy-l6a-methyl-l,<1>+-pregnadien-_. 3,20-dion. av smeltepunkt 210,5 - 211°C. ;UV: £ 23g= 15200., ;Eksempel 2 ;Ved -75°C blandes ^2 ml vannfri f lus s<y>r<e>57 ml tetrahydrp-furan og 80 ml methylenklorid. I denne blanding opploses 20 g 6a-fluor-21-acetoxy-l6a-methyl-l,^-, 9(11) -pregnatrien-3,20-dion og.10 g N-klorsuccinimid. Blandingen omrores i 5 timer ved --60°, hvoretter dejb. ytterligere tilsettes.. 20 g N-klorsuccinimid, og blandingen'tillates å stå i 16 timer ved 0°C. Blandingen'helles over i en opplosning av 270 g natriumhydrogencarbonat i 3 liter vann, hvoretter det ekstraheres med methylenklorid, den organiske fase vaskes, med natriumhydrogensulfitopplosning, natriumhydrogencarbonatopplosning og vann og torres,' og opplosningsmidlet av- ;Eksempel ' 10" ;Ved -75°C blandes 6 ml vannfri flussyre med 9 ml' tetrahydrofuran og 12 ml methylenklorid. I denne blanding opploses 3,0 g 6a-fluor-21-hydroxy-l6a-methyl-l,^,9(11)-pregnatrien-3,20-dion (smeltepunkt 172 - 173°C) og 1,5 g N-bromsuccinimid. Blandingen omrores i h timer ved -50°C og helles over i en opplosning av ^0 g natriumhydrogencarbonat i 1,2 1 vann, hvoretter det torres og inndampes i vakuum. Etter omkrystallisering fra aceton/hexan fåes 1,57 g 6a-llB^difluor-9-brom-21-hydroxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion med smeltepunkt 205 - 206°C. ;UV: f. 239= 1^800.;Eksempel 11 ;En opplosning av 1,68 g 6a-fluor-21-acetoxy-l6a-methyl-lj^^tlD-pregnatrien i 85 ml eddiksyre omsettes med 8,5 g lithiumklorid, 1,68 g N-bromacetamid og 3 A ml saltsyremettet dioxan. Blandingen omrores i 1 time ved romtemperatur og helles deretter ;i vann, hvoretter det utfelte produkt frafiltreres, vaskes med vann og torres i vakuum. Etter omkrystallisering fra aceton/hexan fåes 1,29 g 6a-fluor-llB-klor-9-brom-21-acetoxy-l6a-methyl-l,+-pregnadien-3,20-dion med smeltepunkt 186,5 - 187,5°C. ;UV: f-239= 1V300.;Eksempel 12 ;6,7 g 6a-fluor-llB-klor-9-brom-21-acetoxy-l6a-methyl-l,<l>+-pregnadien-3,20-dion forsåpes med natriummethylat under de i eksempel 3 beskrevne betingelser. Utbytte: >+,88 g 6a-fluor-llB-klor-9-brom-21-hydroxy-l6a-methyl-l,<1>+-pregnadien~3,20-dion med smeltepunkt 162 - 163°C. : uv: f.: 238= 1;^00. ;Eksempel 1^ ;En opplosning av 250 mg 6a-fluor-llp-klor-9-brom-21-hy.droxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion i 125 ml dimethylformamid omsettes med kloracetylklorid under kjoling med is. Blandingen omrores i <*>+5 minutter ved romtemperatur og helles deretter over i vann. Utfelningen frafiltreres, vaskes, torres og omkrystalliseres fra aceton/hexan. Utbytte: 180 mg 6a-fluor-llB-klor-9-brom-21-kloracetoxy-l6a-methyl-l,^-pregnadien-3,20-dion med smeltepunkt 197,5 - 198°C. UV: ^238= 1^600. For the addition of halogen to the A^"*"^ double bond, one can choose from a number of possibilities. Thus, one can e.g. directly add to the double bond halogens such as chlorine or bromine, or mutual compounds of halogens, such as e.g. chlorine monofluoride or bromine monochloride, or halogen from polyhalides, such as e.g. potassium triiodide or iodobenzene dichloride. The addition of halogen is particularly successful when both a positive and a negative halogen are simultaneously allowed to act on the A^^"'"^-steroid. As reagents containing the positive halogen, one can e.g. use halogensuceinimides, halogenacetamides or the halogens themselves. As reagents for delivery of the negative halogen, one can e.g. use hydrogen halides and alkali metal halides. The addition of halogens to the ^-double bond in the steroid always occurs in such a way that the positively charged halogen settles to the 9-position, while the negatively charged halogen settles to the 11-position. The molecular weight of the halogen in the 9-position cannot therefore be less than the molecular weight of the halogen in the 11-position. The halogen addition to the A^"^ double bond is preferably carried out at temperatures between -75°C and -+50°C. A free hydroxyl group or an ester group in the 21-position can be esterified or saponified by conventional methods. However, it is recommended to use the most gentle conditions possible if one wishes to achieve good yields. ;The new compounds show in the vasoconstriction test on male subjects by local administration a pronounced anti-inflammatory effect which is shown in the following table for the new compounds II-IX in comparison with the known compound 6a-fluoro-lip,21-dihydroxy-16a-methyl-1,^-pregnadiene-3,20-dione (I) The vasoconstriction test used for the clinical-experimental demonstration of the improved properties of the new compounds was carried out in the following ways On the backs of male subjects (18 - 38 years), the Stratum corneum was broken down and a marked hyperaemia was produced by 20 successive tears with a 2 cm bre thesis film. Then, on marked 200 h cm-sized fields within the irritated area, it was continued under the same pressure approx. 50 mg of a water/oil ointment base containing respectively 0.01%, 0.001% and 0.0001% of the test compound. The subjects' backs were then photographed at specific time intervals with a "Kodak" color film. For assessment of the hyperaemia and vasoconstriction, the color of the individual skin fields on the "Kodak" color film was converted to lightness values. When projecting the color film onto an interference filter through a diaphragm, the projected parts are distinguished by their brightness. A secondary electron amplifier of the "FS 9 A" type was used as a lightness indicator and the secondary amplifier's anode current was measured to determine the color value. For the determination of vasoconstrictions, which can be considered a representative syndrome of the anti-inflammatory effect, and which was assessed with regard to the onset of the effect, degree of effect and duration of the effect, the color value of the untreated and the treated irritated skin was compared, the color value of the normal skin was set to 100 and the color value of the untreated, irritated skin was set to 0. Small, medium and large vasoconstriction were given values between 0 and 100. The experimental results given in Table I clearly show that the new compounds, apart from to start acting earlier than the known compound also reaches the desired maximum of action faster than the comparison compound. Moreover, the intensity of action of the new compounds during the entire time the effect is ongoing is higher than for the known compound. Furthermore, the side effects of the new compounds are small. For example, the new compounds have no or only very little influence on carbohydrate metabolism. The gluconeogenetic effect is also greatly reduced, which is particularly evident in the fact that the blood sugar concentration does not increase and the amount of liver glycogen only increases with extremely high dosages. It can also be mentioned that there is only a small influence on the liver enzymes tryptophan pyrrolase and the trans-aminases GOT and GPT. The impact on sodium, potassium and phosphate excretion under the influence of the new compounds is also significantly low. ;The new compounds are - in combination with the usual carriers in Galenic pharmacy - suitable for treatment by local administration of e.g. contact dermatitis, eczema of various species, neurodermatitis, erythroderma a, first degree burns, pruritus vulvae et ani, rosacea, erythematodes cutaneus, psoriasis, lichen ruber planus et verrucosus; and by oral administration e.g. of acute and chronic polyarthritis, neurodermatitis, bronchial asthma, high fever, etc.; Example 1; At -75°C, 18 ml anhydrous hydrofluoric acid was reacted with 25 ml tetrahydrofuran and 35 ml methylene chloride. In this mixture, 8.70 g of 6cc-fluoro-21-acetoxy-16a-methyl-1,^4-, 9(11)-pregnatriene-3,20-dione (melting point 160 - 162°C) are dissolved and h, 6 g of N-bromosuccinimide. The mixture is stirred for 3.5 hours at -50°C, poured into a solution of 120 g of sodium bicarbonate in 3.5 liters of water and extracted with methylene chloride, and the organic phase is washed with water and dried, and the solvent is distilled off in vacuo . From acetone/hexane, 6.39 g of 6a,11p-difluoro-9-bromo-21-acetoxy-16a-methyl-1,<L>i--pregnadiene-3,20-dione of melting point 210.5 - 211°C. ;UV: £ 23g= 15200.;Example 2 ;At -75°C, h2 ml of anhydrous hydrofluoric acid, 57 ml of tetrahydrofuran and 80 ml of methylene chloride are mixed. 20 g of 6α-fluoro-21-acetoxy-16α-methyl-1,'+, 9(11)-pregnatriene-3,20-dione and 10 g of N-chlorosuccinimide are dissolved in this mixture. The mixture is stirred for 5 hours at -60°, after which 20 g of N-chlorosuccinimide are further added, and the mixture is allowed to stand for 16 hours at 0°C. The mixture is poured into a solution of 270 g of sodium hydrogen carbonate in 3 liters of water, after which it is extracted with methylene chloride, the organic phase is washed with sodium hydrogen sulphite solution, sodium hydrogen carbonate solution and water and dried, and the solvent is distilled off under vacuum. From acetone/hexane, 12-, h g 6a, HB-difluoro-9-chloro-21-acetoxy-16a-methyl-],If-pregnadiene-3,20-dione of melting point 2^9.5 - 250°C is obtained ;UV: £ 236= 15900. ;Example ;A solution of 1.0 g of 6a,HB-difluoro-9-bromo-21-acetoxy-16a-methyl-ljV-pregnadiene-S^O-dione in 3.0 ml methylene chloride is reacted at -10°C with 6.2 ml of a 0.2 N sodium methylate solution in methanol. The mixture is stirred for <>>+5 minutes under a nitrogen atmosphere at -10°C, neutralized with acetic acid and extracted with methylene chloride. The organic phase is washed with sodium hydrogencarbonate solution and water, dried and absorbed under vacuum. The residue is recrystallized from acetone/hexane. 77^ mg of 6α,HB-difluoro-9-bromo-21-hydroxy-16α-methyl-1,Li-pregnadiene-3,20-dione with a melting point of 206-206.5°C are obtained. ;UV: £ g=llf900. Example h 1.0 g of 6a,lip-difluoro-9-chloro-21-acetoxy-16a-methyl-1,<1>+-pregnadiene-3,20-dione is saponified with sodium methylate under the conditions described in example 3 . 770 mg of 6α,11B-difluoro-9-chloro-21-hydroxy-16α-methyl-1,<1>+-pregnadiene-3,20-dione of melting point 211.5-211+0C (acetone/hexane) is obtained. ;UV: E 236= 16500.;Example ;A solution of 2.75 g of 6a,118-difluoro-9-bromo-21-hydroxy-16a-methyl-1,<1>f-pregnadiene-3,20-dione in 11 ml of pyridine and 5.5 ml of succinic anhydride is allowed to stand for 16 hours at room temperature. After adding water, the precipitated, crystalline material is isolated, after which it is recrystallized twice from acetone. 2.'+5 g of 6a,HB-difluoro-9-bromo-21-but<y>r<y>lox<y>-16a-meth<y>l-l,h-pregnadiene-3,20-dione are obtained of melting point 16U-, 5-165, 5°G. ;UV: É.238= 15000. ;Example 6 ;3.95 g 6a,11B-difluoro-9-chloro-21-hydroxy-16a-methyl-1,1+- ;the sugar concentration does not increase and the amount of liver glycogen increases first at extremely high dosage. It can also be mentioned that there is only a small influence on the liver enzymes tryptopb.anpyrroJ.ase and the trans-aminases GOT and. GPT. The impact on sodium, potassium and phosphate excretion under the influence of the new compounds is also significantly low. ;The new compounds are - in combination with the usual carriers in Galenic pharmacy - suitable for treatment by local, administration of e.g. contact dermatitis, eczema of, different-species,.neurodermitis, erythroderma a, first degree burns, pruritus vulvae et ani, rosacea,. erythematodes cutaneus, psoriasis, lichen ruber planus et verrucosus; and by oral administration, e.g. of acute and chronic polyarthritis, neurodermatitis, bronchial asthma, high fever etc.; Example 1; At -75° C, 18 ml anhydrous hydrofluoric acid was reacted with 25 ml tetra-. hyd r of-ur an and 35 ml of methylene chloride. In this mixture, 8.70 g of 6a-fluoro-21-acetoxy-16a-methyl-1,<l>f,9(11)-pregnatriene-3,20-, dione (melting point 160 - 162 C) are dissolved and.. ^.6 g of N-bromosuccinimide. The mixture, stirred for 3.5 hours at -50°C, is poured into a solution of 120 g of sodium bicarbonate in 35 5 liters of water and extracted with methylene chloride, and the organic phase is washed with water and dried , and the solvent is distilled off in a vacuum. 6.39 g of 6α,lip-difluoro-9-bromo-21-acetoxy-16α-methyl-1,<1>+-pregnadiene-_ are obtained from acetone/hexane. 3,20-dione. of melting point 210.5 - 211°C. ;UV: £ 23g= 15200., ;Example 2 ;At -75°C, ^2 ml of anhydrous f lus are mixed with<y>r<e>57 ml of tetrahydrofuran and 80 ml of methylene chloride. 20 g of 6α-fluoro-21-acetoxy-16α-methyl-1,3-,9(11)-pregnatriene-3,20-dione and 10 g of N-chlorosuccinimide are dissolved in this mixture. The mixture is stirred for 5 hours at -60°, after which dejb. 20 g of N-chlorosuccinimide are further added, and the mixture is allowed to stand for 16 hours at 0°C. The mixture is poured into a solution of 270 g of sodium hydrogen carbonate in 3 liters of water, after which it is extracted with methylene chloride, the organic phase is washed with sodium hydrogen sulphite solution, sodium hydrogen carbonate solution and water and dried, and the solvent is removed. °C, 6 ml of anhydrous hydrofluoric acid are mixed with 9 ml of tetrahydrofuran and 12 ml of methylene chloride. In this mixture, 3.0 g of 6a-fluoro-21-hydroxy-16a-methyl-1,^,9(11)-pregnatriene-3, are dissolved. 20-dione (melting point 172 - 173°C) and 1.5 g of N-bromosuccinimide.The mixture is stirred for h hours at -50°C and poured into a solution of ^0 g of sodium bicarbonate in 1.2 1 of water, after which it is dried and evaporated in vacuo. After recrystallization from acetone/hexane, 1.57 g of 6a-11B^difluoro-9-bromo-21-hydroxy-16a-methyl-1,<1>+-pregnadiene-3,20-dione with melting point 205 - 206° C. ;UV: f. 239= 1^800.;Example 11 ;A solution of 1.68 g of 6a-fluoro-21-acetoxy-16a-methyl-lj^^tlD-pregnatriene in 85 ml of acetic acid is reacted with 8.5 g lithiumk chloride, 1.68 g of N-bromoacetamide and 3 A ml of hydrochloric acid-saturated dioxane. The mixture is stirred for 1 hour at room temperature and then poured into water, after which the precipitated product is filtered off, washed with water and dried in a vacuum. After recrystallization from acetone/hexane, 1.29 g of 6α-fluoro-11B-chloro-9-bromo-21-acetoxy-16α-methyl-1,+-pregnadiene-3,20-dione with melting point 186.5 - 187.5°C. ;UV: f-239= 1V300.;Example 12 ;6.7 g 6a-fluoro-11B-chloro-9-bromo-21-acetoxy-16a-methyl-1,<l>+-pregnadiene-3,20- dione is saponified with sodium methylate under the conditions described in example 3. Yield: >+.88 g of 6α-fluoro-11B-chloro-9-bromo-21-hydroxy-16α-methyl-1,<1>+-pregnadiene~3,20-dione with melting point 162 - 163°C. : uv: f.: 238= 1;^00. ;Example 1^ ;A solution of 250 mg of 6a-fluoro-11p-chloro-9-bromo-21-hydroxy-16a-methyl-1,<1>+-pregnadiene-3,20-dione in 125 ml of dimethylformamide reacted with chloroacetyl chloride while cooling with ice. The mixture is stirred for <*>+5 minutes at room temperature and then poured into water. The precipitate is filtered off, washed, dried and recrystallized from acetone/hexane. Yield: 180 mg of 6α-fluoro-11B-chloro-9-bromo-21-chloroacetoxy-16α-methyl-1,3-pregnadiene-3,20-dione with melting point 197.5 - 198°C. UV: ^238= 1^600.

Eksempel lh Example lh

1,0 g 6a-fluor-9,lip-diklor-21-acetoxy-l6a-methyl-l,^-pregnadlen-3,20-dion forsåpes under de i eksempel 3 beskrevne betingelser. Det erholdes 78O mg 6a-fluor-9,lip-diklor-21-hydroxy-I6a-m'ethyl-l,<1>+-pregnadien-3,20-dion med smeltepunkt 213 - 2l8°C (aceton/hexan). 1.0 g of 6α-fluoro-9,lip-dichloro-21-acetoxy-16α-methyl-1,3-pregnadlene-3,20-dione is saponified under the conditions described in example 3. 780 mg of 6α-fluoro-9,lip-dichloro-21-hydroxy-16α-m'ethyl-1,<1>+-pregnadiene-3,20-dione with melting point 213 - 218°C (acetone/hexane) is obtained .

UV r «^235= 17000.UV r «^235= 17000.

Eksempel 15 Example 15

Til en blanding av 7,0 ml eddiksyreanhydrid og ^,5 ml konsentrert salpetersyre av -10°C tilsettes der under omroring en opplosning av 700 mg 6a-fluor-9,ilB-diklor-21-hydroxy-l6a-methyl-l,1+-pregnadien-3,20-dion i 30.ml kloroform. Blandingen omrores i 30 minutter ved -10°C, helles over i isvann og ekstraheres med methylenklorid, hvoretter den organiske fase vaskes med natriumhydrogencarbonatopplosning og vann, torres og, inndampes i vakuum. Residuet omkrystalli seres fra aceton/hexan. Det erholdes ^-07 mg 6a-fluor-9,lip-diklor-21-nitryl-l6a-methyl-1A-pregnadien-3,20- A solution of 700 mg of 6α-fluoro-9,1β-dichloro-21-hydroxy-16α-methyl-1, 1+-pregnadiene-3,20-dione in 30 ml chloroform. The mixture is stirred for 30 minutes at -10°C, poured into ice water and extracted with methylene chloride, after which the organic phase is washed with sodium bicarbonate solution and water, dried and evaporated in vacuo. The residue is recrystallized from acetone/hexane. ^-07 mg of 6a-fluoro-9,lip-dichloro-21-nitrile-16a-methyl-1A-pregnadiene-3,20-

dion med smeltepunkt 198 - 200°C. dione with melting point 198 - 200°C.

UV: £236= 16700. UV: £236= 16700.

Eksempel 16 Example 16

En opplosning av 500 mg 6a-fluor-21-hexanoyloxy-l6a-methyl-l,<1>+,9(ll)-pregnatrien-3,20-dion (smeltepunkt 119,5 - 120°C) i 25 ml konsentrert eddiksyre omsettes med 2,5 g lithiumklorid, A solution of 500 mg of 6a-fluoro-21-hexanoyloxy-16a-methyl-1,<1>+,9(ll)-pregnatriene-3,20-dione (melting point 119.5 - 120°C) in 25 ml of concentrated acetic acid is reacted with 2.5 g of lithium chloride,

500 mg N-bromsuccinimid og 1,0 ml saltsyremettet dioxan. Blandingen omrores i ^5 minutter ved romtemperatur, hvoretter den helles over i vann og det utfelte produkt frafiltreres, vaskes med vann og torres i vakuum. Etter omkrystallisering fra methanol erholdes hhk mg 6a-fluor-lip-klor-9-brom-21-hexanoyloxy-l6a-methyl-lA- . pregnadien-3,20-dion med smeltepunkt 113 - 115°C. 500 mg N-bromosuccinimide and 1.0 ml hydrochloric acid-saturated dioxane. The mixture is stirred for 5 minutes at room temperature, after which it is poured into water and the precipitated product is filtered off, washed with water and dried in a vacuum. After recrystallization from methanol, hhk mg of 6α-fluoro-lip-chloro-9-bromo-21-hexanoyloxy-16α-methyl-1A- is obtained. pregnadiene-3,20-dione with melting point 113 - 115°C.

UV:^239= 15200.UV:^239= 15200.

Eksempel 17 Example 17

3.,0 g 6a-fluor-9,lip-diklor-21-hydroxy-l6a-methyl-l,f- 3.0 g 6α-fluoro-9,lip-dichloro-21-hydroxy-16α-methyl-1,f-

Eksempel 2k Example 2k

En opplosning av 600 ml 6a,llB-difluor-9-klor-21-hydroxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion i 18 ml konsentrert maursyre og 5 ml tetrahydrofuran omsettes med 120 mg p-toluensulfonsyre, og blandingen tillates å stå i 1 time ved romtemperatur. Reaksjonsblandingen helles over i vann under omrøring, og det utfelte produkt frafiltreres, vaskes og tas opp i methylenklorid. Opp-løsningen torres over natriumsulfat og inndampes i vakuum. Residuet kromåtograferes. Det fåes etter omkrystallisering fra aceton/hexan 200 mg 6a ,llB-dif luor-9-klor-21-f ormyloxy-^a-methyl-lA-pregnadien-S^O-dion av smeltepunkt 220 - 223°C. UV:£ 235= 16700. A solution of 600 ml of 6α,11B-difluoro-9-chloro-21-hydroxy-16α-methyl-1,<1>+-pregnadiene-3,20-dione in 18 ml of concentrated formic acid and 5 ml of tetrahydrofuran is reacted with 120 mg p-toluenesulfonic acid, and the mixture is allowed to stand for 1 hour at room temperature. The reaction mixture is poured into water while stirring, and the precipitated product is filtered off, washed and taken up in methylene chloride. The solution is dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed. After recrystallization from acetone/hexane, 200 mg of 6a,11B-difluoro-9-chloro-21-formyloxy-2a-methyl-1A-pregnadiene-S2O-dione of melting point 220 - 223°C is obtained. UV: £235= 16700.

Eksempel 25 Example 25

Til 7,5 ml vannfritt pyridin tildryppes der ved -15°C 0,^5 ml svoveltrioxyd, hvoretter denne blanding omsettes ved"0°C med 3,7 g 6a,11B-difluor-9-klor-21-hydroxy-l6a-méthyl-l,<!>+-pregnadien-3,20-dion, og reaksjonsblandingen deretter omrores i en time ved 20°C. Reaksjonsopplosningen fortynnes med 80 ml vann, innstilles på pH 8,6 med natronlutog ekstraheres deretter flere ganger med methylenklorid. 0.5 ml of sulfur trioxide is added dropwise to 7.5 ml of anhydrous pyridine at -15°C, after which this mixture is reacted at 0°C with 3.7 g of 6a,11B-difluoro-9-chloro-21-hydroxy-16a -methyl-1,<!>+-pregnadiene-3,20-dione, and the reaction mixture is then stirred for one hour at 20° C. The reaction solution is diluted with 80 ml of water, adjusted to pH 8.6 with sodium hydroxide and then extracted several times with methylene chloride.

,o ,o

Den vandige fase inndampes i vakuum ved 4-0 C, og residuet digereres med methanol. " Det uoppløselige materiale frafiltreres, methanolen avdestilleres fra filtratet i vakuum, og residuet torres over fosforpentoxyd. Det erholdes ^-,6 g natrium- (6a-llB-difluor-9-klor-3,20-dioxo-16a-methyl-l,'+-pregnadien-21-yl)-sulfat, som ved temperaturer over 160°C spaltes under sintring. The aqueous phase is evaporated in vacuo at 4-0 C, and the residue is digested with methanol. The insoluble material is filtered off, the methanol is distilled off from the filtrate under vacuum, and the residue is dried over phosphorus pentoxide. ,'+-pregnadien-21-yl)-sulphate, which at temperatures above 160°C decomposes during sintering.

UV: £237= ^700.UV: £237= ^700.

Eksempel 26 Example 26

1,0 g 6a-fiuor-9,llB-diklbr-21-hydroxy-l6a-methyl-l,<1>+-pregnadien-3^20-dion omsettes på' samme måte som beskrevet i eksempel 25 med- svoveltrioxyd/pyridin og deretter med natronlut. Det erholdes l,2g natrium-(6a-f luor^9,HB-diklor-3,20-dioxb-16a-methyl-l,<L>)--pregnadien^21-yl)-sulfat, som ved temperaturer over 150°C 1.0 g of 6a-fluoro-9,11B-dichloro-21-hydroxy-16a-methyl-1,<1>+-pregnadiene-3^20-dione is reacted in the same way as described in example 25 with sulfur trioxyd/ pyridine and then with caustic soda. 1.2 g of sodium (6a-fluoro^9,HB-dichloro-3,20-dioxb-16a-methyl-1,<L>)--pregnadien^21-yl)-sulfate is obtained, which at temperatures above 150°C

spaltes under sintring. UV:£23g= 15900. split during sintering. UV:£23g= 15900.

betingelser. Råproduktet kromatograferes på kiselsyregel. Ved eluering med 10 - 16 % aceton/pentan fåes 1,06 g 6a-fluor-9a, 11(3-diklor-21-butyryloxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion med smeltepunkt 203 - 203,5 C (aceton/hexan). conditions. The crude product is chromatographed on silica gel. Elution with 10 - 16% acetone/pentane yields 1.06 g of 6a-fluoro-9a, 11(3-dichloro-21-butyryloxy-16a-methyl-1,<1>+-pregnadiene-3,20-dione with melting point 203 - 203.5 C (acetone/hexane).

UV: £237= 1600°-UV: £237= 1600°-

Eksempel 21 Example 21

En opplosning av 3,3 g 6a-fluor-9,llB-diklor-21-hydroxy-l6a-methyl-1A-pregnadien-3,20-dion i 13,2 ml pyridin og 6,6 ml valeriansyreanhydrid omrores i 16 timer ved romtemperatur. A solution of 3.3 g of 6α-fluoro-9,11B-dichloro-21-hydroxy-16α-methyl-1A-pregnadiene-3,20-dione in 13.2 ml of pyridine and 6.6 ml of valeric anhydride is stirred for 16 hours at room temperature.

Deretter avdestilleres pyridinet og overskytende mengder valeriansyreanhydrid med vanndamp. Destillasjonsresten ekstraheres med methylenklorid og ekstrakten vaskes med natriumhydrogencarbonatopplosning og vann, torres over natriumsulfat og inndampes i vakuum. Residuet kromatograferes på kiselsyregel. Ved eluering med 10 - 13 % aceton/pentan fåes 2,2 g 6a-f luor-9cc, llB-diklor-21-valeryloxy-l6ct-methyl-1 ,^--pregnadien-3,20-dion med smeltepunkt 122 - 123°C (aceton/hexan). The pyridine and excess amounts of valerian anhydride are then distilled off with steam. The distillation residue is extracted with methylene chloride and the extract is washed with sodium bicarbonate solution and water, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on silica gel. Elution with 10 - 13% acetone/pentane yields 2.2 g of 6a-fluoro-9cc, 11B-dichloro-21-valeryloxy-16ct-methyl-1,^--pregnadiene-3,20-dione with melting point 122 - 123°C (acetone/hexane).

UV: <£>237= 1^800. UV: <£>237= 1^800.

Eksempel- 22 Example- 22

5,0 g 6a,HB-difluor-9-klor-21-h<y>drox<y>-l6a-meth<y>l-l, h-pregnadien-3,20-dion omsettes med valeriansyreanhydrid under de i eksempel 29 beskrevne betingelser. Det isolerte råprodukt omkrystalliseres 2 ganger fra aceton/hexan. Det erholdes <1>+,4-0 g 6a ,11 B-d i f luor-9a-klor-21-valeryloxy-l6a-methyl-l ,.^-pregnadien-3,20-dion med smeltepunkt l<>>+2 - lM-3°C. 5.0 g of 6a,HB-difluoro-9-chloro-21-h<y>drox<y>-16a-meth<y>l-l,h-pregnadiene-3,20-dione are reacted with valeric anhydride under those in example 29 described conditions. The isolated crude product is recrystallized twice from acetone/hexane. It is obtained <1>+,4-0 g 6a ,11 B-d i f fluoro-9a-chloro-21-valeryloxy-16a-methyl-1,.^-pregnadiene-3,20-dione with melting point l<> >+2 - 1M-3°C.

UV: £ 23^= 15800. UV: £ 23^= 15800.

Eksempel 23 Example 23

En opplosning' av 100 mg 6a-fluor-9a,lip-diklor-21-hydroxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion i 2,0 ml pyridin omsettes med A solution of 100 mg of 6α-fluoro-9α,lip-dichloro-21-hydroxy-16α-methyl-1,<1>+-pregnadiene-3,20-dione in 2.0 ml of pyridine is reacted with

<>>+00 mg ravsyreanhydrid, og blandingen omrores i 2h timer ved romtemperatur, helles deretter over i vann og ekstraheres med ether. Etherekstrakten vaskes med h n svovelsyre og vann, torres og inndampes i vakuum. Residuet tritureres med hexan, og det krystallinske materiale isoleres. Det erholdes 73 mg 6a-fluor-9a,llB-diklor-3,20-dioxo-l6a-methyl-l,<L>H-pregnadien-21-yl-hydrogen-succinat med smeltepunkt 176 - 179°C. <>>+00 mg succinic anhydride, and the mixture is stirred for 2 hours at room temperature, then poured into water and extracted with ether. The ether extract is washed with sulfuric acid and water, dried and evaporated in vacuo. The residue is triturated with hexane, and the crystalline material is isolated. 73 mg of 6a-fluoro-9a,11B-dichloro-3,20-dioxo-16a-methyl-1,<L>H-pregnadien-21-yl-hydrogen succinate with melting point 176 - 179°C are obtained.

UV: £ = 15900. UV: £ = 15900.

235 235

Eksempel 2h Example 2h

En opplosning av 600 ml 6a,llB-difluor-9-klor-21-hydroxy~ l6a-methyl-lA-pregnadien-3,20-dion i 18 ml konsentrert maur syre og 5 ml tetrahydrofuran omsettes med 120 mg p-toluensulfonsyre, og blandingen tillates å stå i 1 time ved romtemperatur. Reaksjonsblandingen helles over i vann under omroring, og det utfelte produkt frafiltreres, vaskes og tas opp i methylenklorid. Opp-løsningen torres over natriumsulfat og inndampes- i vakuum. Residuet kromatograferes. Det fåes etter omkrystallisering fra aceton/hexan 200 mg 6a ,llB-difluor-9-klor-21-formyloxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion av smeltepunkt 220 - 223°C. A solution of 600 ml of 6α,11B-difluoro-9-chloro-21-hydroxy~16α-methyl-1A-pregnadiene-3,20-dione in 18 ml of concentrated formic acid and 5 ml of tetrahydrofuran is reacted with 120 mg of p-toluenesulfonic acid, and the mixture is allowed to stand for 1 hour at room temperature. The reaction mixture is poured into water while stirring, and the precipitated product is filtered off, washed and taken up in methylene chloride. The solution is dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed. After recrystallization from acetone/hexane, 200 mg of 6a,11B-difluoro-9-chloro-21-formyloxy-16a-methyl-1,<1>+-pregnadiene-3,20-dione of melting point 220 - 223°C is obtained.

UV:£ 23?= 16700. UV: £23?= 16700.

Eksempel 25 Example 25

Til 7,5 ml vannfritt pyridin tildryppes der ved -15°C 0,^5 ml svoveltrioxyd, hvoretter denne blanding omsettes ved 0°C med 3,7 g 6a,lip-difluor-9-klor-21-hydroxy-l6a-methyl-1,^-pregnadien-3,20-dion, og reaksjonsblandingen deretter omrores i en time ved 20°c. Reaksjonsopplosningen fortynnes med 80 ml vann, innstilles på pH 8,6 med natronlut og ekstraheres deretter flere ganger med methylenklorid. Den vandige fase inndampes i vakuum ved ^0°C, og residuet digereres med methanol. Det uoppløselige materiale frafiltreres, methanolen avdestilleres fra filtratet i vakuum, og residuet torres over fosforpentoxyd. Det erholdes >+,6 g natrium- (6a-llB-difluor-9-klor-3,20-dioxo-l6a-methyl-l,<1>+-pregnadien-21-yl)-sulfat, som ved temperaturer over 160°C spaltes under sintring. 0.5 ml of sulfur trioxide is added dropwise to 7.5 ml of anhydrous pyridine at -15°C, after which this mixture is reacted at 0°C with 3.7 g of 6a,lip-difluoro-9-chloro-21-hydroxy-16a- methyl-1,^-pregnadiene-3,20-dione, and the reaction mixture is then stirred for one hour at 20°c. The reaction solution is diluted with 80 ml of water, adjusted to pH 8.6 with caustic soda and then extracted several times with methylene chloride. The aqueous phase is evaporated in vacuo at 0°C, and the residue is digested with methanol. The insoluble material is filtered off, the methanol is distilled off from the filtrate under vacuum, and the residue is dried over phosphorus pentoxide. >+.6 g of sodium (6α-11B-difluoro-9-chloro-3,20-dioxo-16α-methyl-1,<1>+-pregnadien-21-yl)-sulfate is obtained, which at temperatures above 160°C splits during sintering.

UV: f2i7= 15700.UV: f2i7= 15700.

Eksempel 26 Example 26

1,0 g 6a-fluor-9,lip-diklor-21-hydroxy-l6a-methyl-l,<1>+-pregnadien-3,20-dion omsettes på samme måte som beskrevet i eksempel 25 med svoveltrioxyd/pyridin og deretter med natronlut. Det erholdes 1,2g natrium-(6a-fluor-9,lip-diklor-3,20-dioxo-l6a-methyl-l ,!+-pregnadien-21-yl)-sulf at, som ved temperaturer over 150°C 1.0 g of 6α-fluoro-9,lip-dichloro-21-hydroxy-16α-methyl-1,<1>+-pregnadiene-3,20-dione is reacted in the same way as described in example 25 with sulfur trioxide/pyridine and then with caustic soda. 1.2 g of sodium (6α-fluoro-9,lip-dichloro-3,20-dioxo-16α-methyl-1,!+-pregnadien-21-yl)-sulphate is obtained, which at temperatures above 150°C

spaltes under sintring. split during sintering.

UV: f. 238= 15900. UV: f. 238= 15900.

Claims

Analogous method for the production of therapeutically effective 6a-fluoro-9a,11B-dihalo-16a-methyl-1A-pregnadiene-21-01-3 20-diones or esters thereof with the general formula:

where R denotes hydrogen, alkanoyl with 1-15 carbon atoms which may optionally be substituted with chlorine or a carboxyl group, a nitrosyl residue or sodium sulphate residue, and X and Y denote halogen, the molecular weight of Y being equal to or greater than the molecular weight of X, characterized by that one adds halogen to the ^-double bond in a corresponding steroid in a manner known per se and then optionally, depending on the desired meaning of R in the final product, saponifies and/or esterifies the 21-position of the molecule.