SE431656B - SET TO MAKE NEW 9-FLUORPREDNISOLOND DERIVATIVES - Google Patents

SET TO MAKE NEW 9-FLUORPREDNISOLOND DERIVATIVES

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Publication number
SE431656B
SE431656B SE7803168A SE7803168A SE431656B SE 431656 B SE431656 B SE 431656B SE 7803168 A SE7803168 A SE 7803168A SE 7803168 A SE7803168 A SE 7803168A SE 431656 B SE431656 B SE 431656B
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SE
Sweden
Prior art keywords
dione
fluoro
pregnadiene
hydroxy
yield
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Application number
SE7803168A
Other languages
Swedish (sv)
Other versions
SE7803168L (en
Inventor
K Annen
H Laurent
H Hofmeister
R Wiechert
H Wendt
J-F Kapp
Original Assignee
Schering Ag
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Publication date
Priority claimed from DE2712862A external-priority patent/DE2712862C2/en
Priority claimed from DE19782809732 external-priority patent/DE2809732C2/en
Application filed by Schering Ag filed Critical Schering Ag
Publication of SE7803168L publication Critical patent/SE7803168L/en
Publication of SE431656B publication Critical patent/SE431656B/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
    • C07J7/008—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21
    • C07J7/0085—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms substituted in position 21 by an halogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
    • C07J71/0005—Oxygen-containing hetero ring
    • C07J71/001—Oxiranes
    • C07J71/0015—Oxiranes at position 9(11)

Description

H0 O i vilken H1 betecknar en alkanoylgrupp med 'l - 8 kolatomer eller en bensoylgrupp och X 'betecknar en fluoratom, en kloratom eller en alkanoyloxigrupp med 3 - 8 kolatomer. H 0 O in which H 1 represents an alkanoyl group having '1 to 8 carbon atoms 'or a benzoyl group and X' represents a fluorine atom, a chlorine atom or an alkanoyloxy group having 3 to 8 carbon atoms.

Med 831 såsom alkanoylgrupp innehållande 'l - 8 kolatomer och me-í X såsom alkanoyloxigrupp innehållande 5 - 8 kolatomer avses en grupp, som härrör från en karbonsyra med öppen eller oyklisk, rak eller gre- nad kedja, exempelvis smör-, isosmör-, valerian-, isovalerian-, tri- metylättik-, kapron-, tert.-butylättik-, cyklopentylkarbonq cyklo- hexylkarbon- och kaprylsyra, eller eventuellt myrsyra, ättiksyra och propionsyra.By 831 as alkanoyl group containing 1 to 8 carbon atoms and with X as alkanoyloxy group containing 5 to 8 carbon atoms is meant a group derived from a carbonic acid having an open or cyclic, straight or branched chain, for example, butter, isose butter, valeric, isovaleric, trimethyl acetic, caproic, tert-butyl acetic, cyclopentyl carbonic, cyclohexyl carboxylic and caprylic acid, or optionally formic acid, acetic acid and propionic acid.

Särskilt föredragna alkanoylgrupper Rq och alkanoyloxigrupper X är sådana, som härrör från en alkan-karbonsyra med upp till 6 kol- atomer. 9-fluorprednisolonderivat med den allmänna formeln I, där X 'betecknar en kloratom, är exempelvis: 'l 'PoL-acetoxi-ïl -klor-Qa-fluor-'l ”l ß-hydroxi-'l , Ll-pregnadien- -aßo-diøn, _ ' 2'l -klor-(Boc-fluor-'l 'l ß-hydroxi-”l 'Zoc-propionyloxi-'l , ll-pregnadíen- -5,20-díon, 'l 7oc-butyry1oxí-21 -klor-9 oc-fluor-'l 1 ß-hydroxi-'l , 4-pregnadi en- -5,20-dion, 21 -klor-Qa-fluor-'l 'l ß-hydroxi-'l 'ha-isobutyryloxi-'l , Ål-pregnadien- -š,20-dion, 21 -kl or-*Boz-fluor-'lfl ß-hydroxi-'l 7a-val erylozd-'l Jl-pregnadien- -5,20-dion och 'I 7a-bensoyloxí-21 -klor-9oc-fluor-'l 'l ß-hydroxí-'l , LL-pregnadien- -3,20-dion. 9,2“l-difluorprednisolonderivat med den allmänna formeln I är exempelvis: 'l 'Zuc-acetoxi-Qoc , 21 -difluor-'Vl ß-hydroxí-'l Jl-pregnadien-š , âO-dicn , 90: , 21 -difluor-'l ”l ß-hydroxi-'l 7 oc-propionyloxi-'l , ll-pregnadien- -5,20-dion, 17a-butyryloxi-9a,21-difluor-11%-hydroxi-1,4-pregnadien- -5,2-dion och 9a,21-difluor-115-hydroxi-17a-isobutyryloxí-1,4-pregnadien- -5,20-dion. 9-fluorprednisolonderívat med den allmänna formeln I, där X betecknar en alkanoyloxigrupp, är företrädesvis sådana, í vilka rester~ na R4 och X tillsammans har 5 - 14 kolatomer. Sådana fluorprednisolon~ derivat är exempelvis: 17a-acetoxi~9a-fluor-11B-hydroxi-21-propionyloxí-1,4-pregna- dienf5,20-dion, 47a-acetoxi-24~butyryloxi-9a-fluor-11B-hydroxi-4,4-pregnadien~ -5,20-dion, 1?u-acetøxi-9a-íluor-11ß-hydroxi-21~ísobutyryloxi-1,4-pregna- dien-5,20-dion, 17a-acetoxi-9a-fluor-41ß-hydroxi~21-valeryloxi-1,4-pregnadien- -5,20-dion, 21-butyryloxi-9a-fluor~11B-hydroxi-17a-valeryloxi-1,4-pregna- dien-5,ëO-díon, 17a-bensoyloxi-21-butyryloxi-9a-fluor-11ß-hydroxi-1,4-pregna- dien-5,20-dion, 9a-fluor-11B-hydroxi-17,21-diisobutyryloxi-1,4-pregnadíen- -5,20-dion och 9a-fluor-11B-hydroxi-17a,21-divaleryloxi-1,4-pregnadien-5,20- -dion.Particularly preferred alkanoyl groups Rq and alkanoyloxy groups X are those derived from an alkane carboxylic acid having up to 6 carbon atoms. 9-Fluoro-prednisolone derivatives of the general formula I, wherein X 'represents a chlorine atom, are for example:' 1 'PoL-acetoxy-η-chloro-Qa-fluoro-'1' 1 ß-hydroxy-'1, L1-pregnadiene- - aßo-dione, 2'-chloro- (Boc-fluoro-1,1'β-hydroxy-) 1'Zoc-propionyloxy-1,1'-pregnadiene-5,20-dione, 1,7-oct butyryloxy-21-chloro-9-oc-fluoro-1,1-hydroxy-1,4-pregnadiene-5,20-dione, 21-chloro-Qa-fluoro-1,1'β-hydroxy- 1 'ha-isobutyryloxy-'1, Ål-pregnadien- -š, 20-dione, 21 -kl or- * Boz-fluoro-'l fl ß-hydroxy-'l 7a-val erylozd-'l Jl-pregnadien- - 5,20-dione and 7α-benzoyloxy-21-chloro-9oc-fluoro-1,1'β-hydroxy-1,1'L-pregnadiene-3,20-dione 9,2 "1-difluoroprednisolone derivatives with the general formula I is, for example: '1 'Zuc-acetoxy-Qoc, 21 -difluoro-'V1 ß-hydroxy-'1 J1-pregnadien-š, âO-dicn, 90:, 21 -difluoro-'l' l ß -hydroxy-1,7-propionyloxy-1,11-pregnadiene-5,20-dione, 17α-butyryloxy-9α, 21-difluoro-11% -hydroxy-1,4-pregnadiene--5,2- dione and 9α, 21-difluoro-115-hydroxy-17α-isobutyryloxy-1,4-pregnadiene--5,20-dione. Fluoroprednisolone derivatives of the general formula I, in which X represents an alkanoyloxy group, are preferably those in which the radicals R4 and X together have 5 to 14 carbon atoms. Such fluoropridnisolone derivatives are, for example: 17α-acetoxy-9α-fluoro-11β-hydroxy-21-propionyloxy-1,4-pregnadiene-5,20-dione, 47α-acetoxy-24-butyryloxy-9α-fluoro-11β-hydroxy -4,4-pregnadiene--5,20-dione, 1,10-acetoxy-9α-fluoro-11β-hydroxy-21-isobutyryloxy-1,4-pregnadiene-5,20-dione, 17α-acetoxy- 9α-fluoro-4β-hydroxy-21-valeryloxy-1,4-pregnadiene-5,20-dione, 21-butyryloxy-9α-fluoro-11β-hydroxy-17α-valeryloxy-1,4-pregnadiene-5 ε-dione, 17α-benzoyloxy-21-butyryloxy-9α-fluoro-11β-hydroxy-1,4-pregnadiene-5,20-dione, 9α-fluoro-11β-hydroxy-17,21-diisobutyryloxy-1 , 4-pregnadiene--5,20-dione and 9α-fluoro-11β-hydroxy-17α, 21-divaleryloxy-1,4-pregnadiene-5,20-dione.

De nya 9-fluorprednísolonderivaten kan framställas medelst ett ?3rfaríngssätt, kännetecknat av att man på i ødh för sig känt sätt a) öppnar epoxidringen i en förening med den allmänna formeln II II ?803168-9 med fluorväte, eller b) halogenerar eller förestrar i 21-ställning ett 9-fluor- derivat med den allmänna formeln III FHEOH I C=O H0 ._ _ _ ORq . III O i vilken H4 betecknar detsamma som ovan, eller c) för framställning av 9-flunrprednisolonderivat med den allmänna formeln I, där X betecknar en fluor- eller kloratom, spaltar en ortoester med den allmänna formeln IV H0 - - - -O R.. 0/ i vilken RB betecknar en väteatom, en alkylgrupp ellr en cykloalkyl- grupp med upp till 7 kolatomer eller en fenylgrupp och R2 betecknar en alkylgrupp med 1 - 4 kolatomer, medelst en trimetylsilylhalogenid eller trifenylmetylhalogenid.The new 9-fluoroprednisolone derivatives can be prepared by a process, characterized in that in a manner known per se a) the epoxide ring is opened in a compound of the general formula II II? 803168-9 with hydrogen fluoride, or b) halogenates or esterifies in 21-position a 9-fluoro derivative of the general formula III FHEOH IC = O H0 ._ _ _ ORq. III o in which H4 represents the same as above, or c) for the preparation of 9-fluoronprednisolone derivatives of the general formula I, where X represents a fluorine or chlorine atom, an orthoester of the general formula IV H0 - - - -O R. In which RB represents a hydrogen atom, an alkyl group or a cycloalkyl group having up to 7 carbon atoms or a phenyl group and R2 represents an alkyl group having 1 to 4 carbon atoms, by means of a trimethylsilyl halide or triphenylmethyl halide.

Sättet i överensstämmelse med uppfinningen enligt förfarings- varianterna a, b och c kan utföras under de förhållanden, som beskri- ves i de amerikanska patentskrifterna 5 678 054, 5 718 671 odh 5 828 085. Utgàngsföreningarna för dessa förfaranden kan framställas under de förhållanden, som beskrives i den amerikanska patentskriften 5 152 154 och i de tyska Offenlegungsschriften 25 40 591 och 20 55 22”.The process according to the invention according to process variants a, b and c can be carried out under the conditions described in U.S. Pat. Nos. 5,678,054, 5,718,671 and 5,828,085. The starting compounds for these processes can be prepared under the conditions as described in U.S. Patent Nos. 5,152,154 and in German Offenlegungsschrifts 25,409,91 and 20,5522 ”.

Sättet i överensstämmelse med uppfinningen enligt förfarings- varianten a kan likaledes utföras på i och för sig känt sätt, företrä- desvis genom att man omsätter föreningen med formeln Il i ett inert IV ?fiO?%ës~9 lösningsmedel innehållande fluorväte. Lämpliga inerta lösningsmedel är exempelvis etrar (dietyleter, diisopropyleter, tetrahydrofuran, pyridin etc) eller klorerade kolväten (metylenklorid, kloroform, koltetraklo- rid, tetrakloretan etc).The process according to the invention according to process variant a can likewise be carried out in a manner known per se, preferably by reacting the compound of formula II in an inert solvent containing hydrofluoride. Suitable inert solvents are, for example, ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, pyridine, etc.) or chlorinated hydrocarbons (methylene chloride, chloroform, carbon tetrachloride, tetrachloroethane, etc.).

Sättet i överensstämmelse med uppfinningen enligt förfarings- varianten b kan likaledes utföras på i och för sig känt sätt.The method in accordance with the invention according to process variant b can likewise be carried out in a manner known per se.

Sålunda kan man exempelvis förestra hydroxisteroiderna med acylklorider eller acylanhydrider i närvaro av syror, t ex klorvätesypq p-toluensulfonsyra, trifluorättiksyra, eller i närvaro av baser, t ex kaliumkarbonat, pyridin, kollidin och p-dimetylaminopyridin.Thus, for example, the hydroxisteroids may be esterified with acyl chlorides or acyl anhydrides in the presence of acids, for example hydrochloric acid p-toluenesulfonic acid, trifluoroacetic acid, or in the presence of bases, for example potassium carbonate, pyridine, collidine and p-dimethylaminopyridine.

Ett föredraget förfaringssätt för klorering av föreningarna med den allmänna formeln III består däri, att man förestrar 21-hydroxigrup~ pen med en sulfonsyra, företrädesvis med metansulfonsyra eller p-toluen- sulfonsyra, och därefter byter ut sulfonsyragruppen mot klor. Förest- ringen av 21-hydroxigruppen åstadkommas exempelvis genom att man bringur en sulfonsyraklorid att i närvaro av en organisk bas, t ex pyridin, eller i närvaro av en alkalivattenlösning inverka på föreningarna med formeln III. Utbytet av sulfonsyragruppen mot en kloratom åstadkommes företrädesvis genom att man omsätter 21-sulfonsyraestern med en alkali- metallklorid, t ex litiumklorid, i närvaro av ett polärt lösningsmedel, t ex dimetylformamid.A preferred procedure for chlorinating the compounds of general formula III consists in esterifying the 21-hydroxy group with a sulfonic acid, preferably with methanesulfonic acid or p-toluenesulfonic acid, and then replacing the sulfonic acid group with chlorine. The esterification of the 21-hydroxy group is effected, for example, by causing a sulfonic acid chloride to act on the compounds of formula III in the presence of an organic base, for example pyridine, or in the presence of an alkali aqueous solution. The exchange of the sulfonic acid group with a chlorine atom is preferably effected by reacting the 21-sulfonic acid ester with an alkali metal chloride, eg lithium chloride, in the presence of a polar solvent, eg dimethylformamide.

Sättet i överensstämmelse med uppfinningen enligt förfarings- varianten o utföres likaledes på i och för sig känt sätt.The method according to the invention according to the process variant o is likewise carried out in a manner known per se.

Spaltningen av ortoestern med den allmänna formeln IV medelst trimetylsilylfluorid, trimetylsilylklorid eller trifenylmetylklorid âstadkommes företrädesvis i ett inert lösningsmedel, t ex ett dipolärt, aprotiskt lösningsmedel (dimetylformamid, N-metylpyrrolidon, dimetyl- sulfoxid, hexametylfosforsyratriamid etc), en eter (díetyleter, diiso- propyleter, tetrahydrofuran, dioxan, glykoldimetyleter etc), ett klore- rat kolväte (metylenklorid, kloroform, tetrakloretan etc), ett kolväte (bensen, toluen, cyklohexan etc) eller en blandning av dessa lösnings- medel.The cleavage of the orthoester of the general formula IV by means of trimethylsilyl fluoride, trimethylsilyl chloride or triphenylmethyl chloride is preferably effected in an inert solvent, for example a dipolar, aprotic solvent (dimethylformamide, N-methylpyrrolidone, dimethylethersulfite etc propyl ether, tetrahydrofuran, dioxane, glycol dimethyl ether, etc.), a chlorinated hydrocarbon (methylene chloride, chloroform, tetrachloroethane, etc.), a hydrocarbon (benzene, toluene, cyclohexane, etc.) or a mixture of these solvents.

Utgångsföreningarna för sättet enligt uppfinningen kan således framställas pà ett enkelt sätt ooh med höga utbyten av prednisolon, som i sin tur relativt lätt kan syntetiseras av diosgenin. Detta medför att föreningarna enligt uppfinningen kan framställas med en relativt ringa kostnad och med ett totalutbyte av ca 15 % av diosgenin. I mot- sats härtill är synteserna av kända kortikoider med hög verkan av oi- osgenin betydligt kostsammare och de erhållna totalutbytena sígnifikan; lägre (ca 0,5 - 5 %). Detta är icke utan betydelse med hänsyn till de vaozlas-9 6 växande svårigheterna att skaffa lämpliga utgângsföreningar i tillräck~ lig mängd för kortikoidsynteser och med hänsyn till de höga kostnader- na för verksamma substanser, med vilka kortikoidhaltiga läkemedelspe- cialiteter belastas.The starting compounds of the method according to the invention can thus be prepared in a simple manner and with high yields of prednisolone, which in turn can be relatively easily synthesized by diosgenin. This means that the compounds according to the invention can be prepared at a relatively low cost and with a total yield of about 15% of diosgenin. In contrast, the syntheses of known corticoids with a high effect of oiosgenin are considerably more expensive and the total yields obtained are significant; lower (about 0.5 - 5%). This is not without significance in view of the growing difficulties in obtaining suitable starting compounds in sufficient quantities for corticoid synthesis and in view of the high costs of active substances with which corticoid-containing drug specialties are loaded.

Föreningarna enligt uppfinningen har, såsom redan angivits, vi: topisk applicering en stark antiinflammatorisk verkan men är vid syste- misk applicering endast svagt verksamma.The compounds according to the invention have, as already stated, topical application a strong anti-inflammatory effect but are only weakly active in systemic application.

Den antiinflammatoriska verkan har bestämts på följande sätt.The anti-inflammatory effect has been determined as follows.

På människohud framkallades på följande sätt en hyperemi.In human skin, a hyperemia was induced in the following manner.

På ryggen av frivilliga manliga och kvinnliga försökspersoner sönderdelades medelst tjugo på varandra anbringade rivningar med en 2 cm bred Tesafilm Stratum corneum och därmed framkallades en utpräglai hyperemi.On the backs of voluntary male and female subjects, by means of twenty superimposed tears with a 2 cm wide Tesafilm Stratum corneum and thus a pronounced hyperemia was induced.

På särskilda 4 cmg stora fält inom det nakna området anbringades ca 50 mg av salvberedningarna.On special 4 cmg fields within the bare area, about 50 mg of the ointment preparations were applied.

För att erhålla jämförbara utgångsvärden använde man relativtal, då färgen av obehandlad hud och även rödfärgningen av det hyperemiska området har individuella skillnader.To obtain comparable starting values, relative numbers were used, as the color of untreated skin and also the red coloration of the hyperemic area have individual differences.

Eärgvärdet för obehandlad hud angavs som 100 och värdet för naken hud som O. ' Hudfärgvärdet av den i vasokonstriktion befintliga huden (100) bestämdes medelst en proportionalitetsbildning.The intrinsic value for untreated skin was given as 100 and the value for bare skin as O. The skin color value of the skin present in vasoconstriction (100) was determined by a proportionality formation.

Ringa, mellanliggande och höggradig vasokonstriktion värdesat- tes på motsvarande sätt mellan O och 100.Small, intermediate and high-grade vasoconstriction were valued correspondingly between 0 and 100.

I nedanstående tabell angives medelvärden, som härrör från undersökningar av olika provsubstanser och olika ryggområden.The table below gives average values, which are derived from examinations of different test substances and different back areas.

Den systemiska verkan av föreningarna har bestämts på följande sätt medelst adjuvans-ödem-testet.The systemic activity of the compounds has been determined in the following manner by the adjuvant-edema test.

SPF-råttor vägande 150 - ¶5O g injiceras för framkallande av en inflammationshärd med 0,1 ml av en 0,5-procentig Mycobacterium butyricus-suspension (tillhandahålles av den amerikanska firman Difko) i högra bakfoten. Före injektionen bestämmer man râttornas fotvolym. 24 timmar efter injektionen bestämmes på nytt fotvolymen för faststäl- lande av graden av ödem. Därefter tillför man oralt till râttorna olika mängder av testsubstansen. Fotvolymen bestämmes på nytt efter ytterli- gare 24 timmar.SPF rats weighing 150-50 g are injected to induce a 0.1 ml myocbacterium butyricus suspension (supplied by the American company Difko) in the right hindfoot. Before the injection, the foot volume of the rats is determined. 24 hours after the injection, the foot volume is determined again to determine the degree of edema. Then different amounts of the test substance are added orally to the rats. The foot volume is determined again after another 24 hours.

På brukligt sätt bestämmas av de erhållna fotvolymerna den mänrd testsubstans, som erfordras för att åstadkomma en 50-procentig läkning av fotödemet.In the usual way, from the obtained foot volumes, the male test substance required to achieve a 50% cure of the foot edema is determined.

De i denna test erhållna resultaten är angivna i nedanstående tabell. -:$3”9 ?sc?* wM\wH ß.m wx\wa o.m mM\ma o.ß wm\ws ß.ß mM\wS w.m wm\wa :o.o ommm Pmwp|Bwøw|mGm>dwu< ßw mm mm må mm mw Nå ww ïß wm än wa Nä mw om mm mm wo .flflv w md mm Nm om mm mm mm um ßm mw Om ßw vm mm mm Nm fim mm .afip w nwpwø pwpfløwmm \ ? voooo,o a «oo.o x «.o x øooo.o & x voo.o a «.o voooo.o & voø.o a v.o voøoø.o a voo.o a v.o «øooo.o a «oo.o x «.o voooo.o a voo.ø x «.ø .nvflmo LQQM »mwpmQoflpMfln»mGoMomm> flofl@|Om.m|Qøfi©mQwmHmx |#.v|HMoflhflofimoHm|ßßv|fiNoHfihn| lavvlhoflfiwxsmlflfioflhhhuäßnvw qofi@|oN.m| lfiwfiømdwwnmlä.vlflwoflhflofimonmflfil 1v~.§ßv|flwon@hn|@«f|H°øHH|ä@ noflU|ON.m|Qøflumcmmnm| nå.v|Hx0»wowflhp@aHH»|«N1flx°nuhn| nuvv|no5HM|am|Hxoumom|aßv doflv|ON.m|dmflflmdmwHm| Ià.v|flNoHhoflmNwn|vN|fiNoHwhQ| nßrv|HoäHH|öm|fläoumom|aßv Avmw mm om momv floHU|Om.m|flwflflmdwwnm| lä.vlflwoahnmamblaßvnfläonøhfll |@vv|HoøHH1ß@|flxop@0«|«m ^vmflmflnmHm> |:oHo»nousHwflunv q0H@|ow.m| |QmfifiwflwwHm|d.v|HMoHhHmHm>|vm| |Hxonøh@|@«v|H°:HMflø|ß@.öw mflmvmßdm H> >H HHH . Z wx\wE ofl fiw>m wx\wE æ.m wx\wE ofl nm>m wx\wE ofi nw>w wx\mE ofi nw>m wx\ws Qfiw ømom vww»|Emwn|w:m>:wu< .Ewa w mm mm § floooono ON Nw w floono æß ON R fl.@ mm mm ä fl@oo@.@ M» mw w fioo.0 :F mß § fl.@ mr M: & fioooono :Q wm R fi@o.@ N» om § fi.@ mm fim m«Oooo_o ow Nw § fi@Q.@ Nw ww @ fi.@ M: O: &HooQo.O ON mm & fi@o.o æw _@w & fiflo m: Q: §\ooO@.o wß Nm ä fi@o.o mß om x fi.@ .Efiu z .åvümo hwß%w umßflñmwm ICOM Pm®DwQOfi@XfiäQwSOXOwd> :oflø|om.m|QofiumcwmaQ |:flfi«fixo»v»:|@@fi|fio=H@ lyå|noHx|fim|fixoflæ:oflmonQ|Xšfi Aßzß ßm :N won m =@»m>0efiwn=V soflflxom^m|:mflumsmwmm|:.fl| |H»pws-@@fl|flxo»u>n|@@fi|ho:Hm| nfiäxfiofixnfimnflxoflæcofiaonmnæšfl :0fi@1ON.n|cmfiw |mcwmnm|=~fl|flxonU>s|mfifi|mosfim1 |@°m-LoHx|H~|fix0H»0w=@n| uæfi Gofluxomflmxswfiøacmwmau -=.fi-fixo»w»Q|uflfi|»ø:H«|.fiml ufixofl>n>usn|flw|fixoHæomzon|«KNfi Qoflø|om.m|QwflømcwmfiQ| 1:Qflnflxoflmcofimonaxfimxwxonøæsx |Qflfl|no5fim|.fiälfixofihownwnn fläfi :oflø:om.m|:øHømcwwnm|:.fif |flxoflmhmHm>|fimuflxofimcøflmonnx |)Owfi|wxofiøæ§x&@fi|%0:Hm1.Km mømuwnsm HHN HN KH HHH> ?dU316a-9 Man erhåller liknande resultat, då man bestämmer den syste- miska verkan av 9-fluorprednisolonderivaten enligt uppfinningen med hjälp av det kända thymolystesuazeller det kända natrium-kaliumreten- tionstestet.The results obtained in this test are given in the table below. -: $ 3 ”9? Sc? * WM \ wH ß.m wx \ wa om mM \ ma o.ß wm \ ws ß.ß mM \ wS wm wm \ wa: oo ommm Pmwp | Bwøw | mGm> dwu <ßw mm mm må mm mw Nå ww ïß wm än wa Nä mw om mm mm wo .flfl v w md mm Nm om mm mm mm um ßm mw Om ßw vm mm mm Nm fi m mm .a fi p w nwpwø pwp fl øwmm \? voooo, oa «oo.ox« .ox øooo.o & x voo.oa «.o voooo.o & voø.oa vo voøoø.oa voo.oa vo« øooo.oa «oo.ox« .o voooo.oa voo.ø x «.ø .nv fl mo LQQM» mwpmQo fl pM fl n »mGoMomm> fl o fl @ | Om.m | Qø fi © mQwmHmx | # .v | HMo fl h fl o fi moHm | ßßv | fi NoH fi hn | lavvlho flfi wxsml flfi o fl hhhuäßnvw qo fi @ | oN.m | l fi w fi ømdwwnmlä.vl fl wo fl h fl o fi monm flfi l 1v ~ .§ßv | fl won @ hn | @ «f | H ° øHH | ä @ no fl U | ON.m | Qø fl umcmmnm | nå.v | Hx0 »wow fl hp @ aHH» | «N1 fl x ° nuhn | nuvv | no5HM | am | Hxoumom | aßv do fl v | ON.m | dm flfl mdmwHm | Ià.v | fl NoHho fl mNwn | vN | fi NoHwhQ | nßrv | HoäHH | öm | fl äoumom | aßv Avmw mm om momv fl oHU | Om.m | fl w flfl mdwwnm | lä.vl fl woahnmamblaßvn fl äonøh fl l | @vv | HoøHH1ß @ | fl xop @ 0 «|« m ^ vm fl m fl nmHm> |: oHo »nousHw fl unv q0H @ | ow.m | | Qm fifi w fl wwHm | d.v | HMoHhHmHm> | vm | | Hxonøh @ | @ «v | H °: HM fl ø | ß @ .öw m fl mvmßdm H>> H HHH. Z wx \ wE o fl fi w> m wx \ wE æ.m wx \ wE o fl nm> m wx \ wE o fi nw> w wx \ mE o fi nw> m wx \ ws Q fi w ømom vww »| Emwn | w: m>: wu <.Ewa w mm mm § fl oooono ON Nw w fl oono æß ON R fl. @ mm mm ä fl @ oo @. @ M »mw w fi oo.0: F mß § fl. @ mr M: & fi oooono: Q wm R fi @ o. @ N »om § fi. @ Mm fi m m« Oooo_o ow Nw § fi @ Q. @ Nw ww @ fi. @ M: O: & HooQo.O ON mm & fi @ oo æw _ @ w & fifl o m: Q: § \ ooO @ .o wß Nm ä fi @ oo mß om x fi. @ .E fi u z .åvümo hwß% w umß fl ñmwm ICOM Pm®DwQO fi @ X fi äQwSOXOwd>: o fl ø | om.m | Qo fi umcw «Fi xo» v »: | @@ fi | fi o = H @ lyå | noHx | fi m | fi xo fl æ: o fl monQ | Xš fi Aßzß ßm: N won m = @» m> 0e fi wn = V so flfl xom ^ m |: m fl umsmwmm | :. fl | | H »pws - @@ fl | fl xo» u> n | @@ fi | ho: Hm | n fi äx fi o fi xn fi mn fl xo fl æco fi aonmnæš fl: 0fi @ 1 ON.n | cm fi w | mcwmnm | = ~ fl | fl xonU> s | m fifi | mos fi m1 | @ ° m-LoHx | H ~ | fi x0H »0w» uæ fi Go fl uxom fl mxsw fi øacmwmau - =. fi-fi xo »w» Q | u flfi | »ø: H« |. fi ml u fi xo fl> n> usn | fl w | fi xoHæomzon | «KN fi Qo fl ø | om.m | Qw fl øm | Qw fl øm | 1: Q f n f xo al MCO fi monax fi mxwxonøæsx | Q flfl | no5 f m |. Fi lov f xo fi hownwnn fl o f o FLOW: om.m |: øHømcwwnm | :. f f | f xo al mhmHm> | fi mu al xo fi MCO al monnx |) Ow fi | wxo fi øæ§x & @ fi |% 0: Hm1.Km mømuwnsm HHN HN KH HHH Similar results are obtained when determining the systemic activity of the 9-fluoroprednisolone derivatives according to the invention by means of the known thymolystesuazole or the known sodium-potassium retention test.

De nya föreningarna lämpar sig i kombination med de inom den galeniska farmacin brukliga bärarna för lokal behandling av kontakt- dermatitis, eksem av de mest skilda slag, neurodermatoser, erythrodermi, brännskador, Pruritis vulvae et ani, Rosacea, Erythematodes cutaneus, Psoriasis, Lichen ruber planus et verrucosus och liknande hudsjukdomar.The new compounds are suitable in combination with the carriers commonly used in galenic pharmacy for local treatment of contact dermatitis, eczema of the most varied types, neurodermatoses, erythroderma, burns, Pruritis vulvae et ani, Rosacea, Erythematodes cutaneus, Psoriasis, Lichen ruber planus et verrucosus and similar skin diseases.

Framställningen av läkemedelsspeoialiteter âstadkommes pà bruk- ligt sätt genom att man överför de verksamma substanserna medelst lämp- liga tillsatser till de önskade appliceringsformerna, exempelvis lös- ningar, lotioner, salvor, krämer och plåster. I de sålunda formulerade läkemedlen beror koncentrationen av verksam substans av applicerings- formen. Vid lotioner och salvor använder man företrädesvis en kon- centration av verksam substans av 0,001 - 1 %.The preparation of pharmaceutical specialties is achieved in the usual manner by transferring the active substances by means of suitable additives to the desired forms of application, for example solutions, lotions, ointments, creams and plasters. In the drugs thus formulated, the concentration of active substance depends on the form of application. For lotions and ointments, a concentration of active substance of 0.001 - 1% is preferably used.

De nya föreningarna lämpar sig dessutom eventuellt i kombinatibn med brukliga bärare och hjälpmedel för framställning av inhalations- medel, som kan användas för behandling av allergiska sjukdomar i and- ningsvägarna, exempelvis bronkialastma och rhínitis.The new compounds are also possibly suitable in combination with customary carriers and aids for the preparation of inhalants, which can be used for the treatment of allergic diseases of the respiratory tract, for example bronchial asthma and rhinitis.

Följande exempel tjänar till att belysa uppfinningen.The following examples serve to illustrate the invention.

Framställningar Exempel 1 a) Till 500 mg pyridintosylat, som indunstats två gånger med bensen i vakuum till torrhet, i 500 ml bensen och 40 ml N,N-dimetyl- formamid sättes 5 g 9a-fluorprednisolon. Vid en badtemperatur av 15000 avdestillerar man därefter 50 ml lösningsmedel och tillsätter 6 ml orte- ättiksyratrietylester. Återstoden av bensenen avdestilleras inom 2 1/2 timme och efter tillsättning av 2,4 ml pyridin indunstar man blandningen i vakuum. Man isolerar 17d,91-(1-etoxietylidendioxi)-9a-fluor-11p- -hydroxi-1,4-pregnadien-5,10-dion som en gul, oljeartad epimerblandning. b) En löfsning av den sålunda erhållna oljan i 150 ml metanol upphettas med àterflöde med en blandning av 54 ml 0,1-normal ättiksyra och 6 ml 0,1-normal vattenlösning av natriumacetat 1 timme vid 9000. Nan indunstar därefter blandningen till torrhet, tillsätter vatten och extraherar med ättikester. De organiska extrakten tvättas med vatten, torkas och indunstas i vakuum. Utbyte: 9 g 17d~acetoxi-9a-fluor-11;,21- -dihydroxi-1,4-pregnadien-3,20-dion som skum. c) Man rör om 5,0 g 17a-acetoxi-9u-fluor-11ß,21-dihydroxi-1,4~ -pregnadien-5,20-dion i 1? ml pyridin och 8 ml propionsyraanhydrid 7803168-9 '10 '1 '1/2 timme vid rumstemperatur. Man fäller därefter blandningen i is- vatten, filtrerar, tager upp återstoden i metylenkloríd., tvättar, tor- kar över natriumsulíat och indunstar. Man isolerar 4,9 g, som man kro- matograíerar på 450 g kiselgel medelst en metylen-aceton-gradient (0 - '15 % aceton). Utbyte: 2,96 g '17oz-acetoxi-9on-íluor-'11ß-hydroxi- -Zhpropionyloxi-'l,¿1-pregnadien~5,20~dion. Smp.: 21900. f 371235 = +81° (pyridin). Uvzß 259 = '15 '100 (metanol).Preparations Example 1 a) To 500 mg of pyridine tosylate, evaporated twice with benzene in vacuo to dryness, in 500 ml of benzene and 40 ml of N, N-dimethylformamide are added 5 g of 9a-fluoroprednisolone. At a bath temperature of 15,000, 50 ml of solvent are then distilled off and 6 ml of orthoacetic acid triethyl ester are added. The residue of the benzene is distilled off within 2 1/2 hours and after adding 2.4 ml of pyridine the mixture is evaporated in vacuo. 17d, 91- (1-ethoxyethylidenedioxy) -9a-fluoro-11β-hydroxy-1,4-pregnadiene-5,10-dione is isolated as a yellow, oily epimer mixture. b) A solution of the oil thus obtained in 150 ml of methanol is heated at reflux with a mixture of 54 ml of 0.1-normal acetic acid and 6 ml of 0.1-normal aqueous solution of sodium acetate for 1 hour at 9000. Nan then evaporates the mixture to dryness , add water and extract with vinegar ester. The organic extracts are washed with water, dried and evaporated in vacuo. Yield: 9 g of 17d-acetoxy-9a-fluoro-11;, 21--dihydroxy-1,4-pregnadiene-3,20-dione as foam. c) 5.0 g of 17α-acetoxy-9u-fluoro-11β, 21-dihydroxy-1,4--pregnadiene-5,20-dione in 1? ml pyridine and 8 ml propionic anhydride 7803168-9 '10 '1' 1/2 hour at room temperature. The mixture is then precipitated in ice-water, filtered, the residue is taken up in methylene chloride, washed, dried over sodium sulfate and evaporated. 4.9 g are isolated, which are chromatographed on 450 g of silica gel using a methylene-acetone gradient (0-15% acetone). Yield: 2.96 g of 17β-acetoxy-9-one-fluoro-11β-hydroxy-2-zpropionyloxy-1,1-pregnadiene-5,20-dione. M.p .: 21900. f 371235 = + 81 ° (pyridine). Uvzß 259 = '15 '100 (methanol).

Exempel 2 4,5 *g '17oz-acetoxi-9a-fluor-11ß,2'1-dihydroxi-'1 A-pregnadien- -5,20-dion omröres i 50 ml pçyridin och 25 ml smörsyraanhydrid över nattez vid nimstemperatur. Reaktíonsprodukten fälles med isvatten, avfiltrerax: och löses i metylenklorid. Lösningen tväflas med vatten, torkas över natriumsulfat och indunstas i vakuum. Återstoden kromatograferas pà 700 g kiselgel medelst en metylenklorid-aceton-gra-iient (0 - '15 36 ace- ton). Utbyte: 5,6 g '17a-acetoxi-21-butyryloxi-Qa-fluor-'VIß-hydroxi-'lJL- -pregnadien-BQO-dion. Smp.: 21800.Example 2 4.5 * g of 17α-acetoxy-9α-fluoro-11β, 2,1'-dihydroxy-11α-pregnadiene-5,20-dione are stirred in 50 ml of pyridine and 25 ml of butyric anhydride overnight at room temperature. The reaction product is precipitated with ice water, filtered off and dissolved in methylene chloride. The solution is washed with water, dried over sodium sulphate and evaporated in vacuo. The residue is chromatographed on 700 g of silica gel using a methylene chloride-acetone gradient (0 - '36 36 acetone). Yield: 5.6 g of 17α-acetoxy-21-butyryloxy-Qa-fluoro-'Vis-hydroxy-'1JL- -pregnadiene-BQO-dione. M.p .: 21800.

Exempel å '1 ,0 g '17oc-acetoxi-9zx-fluor-'Vl13,21 -dihydroxi-'I A-pregnadien- -5,20-dion omsättes analogt med exempel 2 medelst 6 ml valeriansyraan- hydrid i stället för smörsyraanhydrid i '10 ml pyridin. Utbyte: 680 mg '1 Toc-acetoxi-Qoz-fluor-'l 'I ß-hydroxi-Ql -valeryloxi-'l , ll-pregnadien-š , 20- -diorn smp.= 215%.Example of '0.0 g 'of 17oc-acetoxy-9zx-fluoro-1,113,21-dihydroxy-1,1-A-pregnadiene-5,20-dione is reacted analogously to Example 2 by means of 6 ml of valeric anhydride instead of butyric anhydride in '10 ml pyridine. Yield: 680 mg of 1-Toc-acetoxy-Q 2 -fluoro-1,1-β-hydroxy-Q1 -valeryloxy-1,1'-pregnadiene-β, 20-diorn, m.p. = 215%.

Exemgel 11- Man rör om 5,0 g '1'7a-acetoxi-9oa-fluor-11ß,2'1-dihydro:ci-'1 ,4- -pregnadien-5,20~dion i 50 ml pyridin medelst '15 ml kapronsyraanhydrid '1 '1/2 timme vid mlmstemperatur. Man upparbetar analogt med exempel 2.Example Gel 11- 5.0 g of 1,7α-acetoxy-9α-fluoro-11β, 2,1'-dihydro: c1-1,1-4-pregnadiene-5,20-dione in 50 ml of pyridine by means of 15 ml caproic anhydride '1' 1/2 hour at mlm temperature. Work up analogously to Example 2.

Råprodukten renas på 450 g kiselgel med en metylenklorid-aceton-gra- - dient (0 - ':2 % aceton). Utbyte: 2,56 g '17oc-acetoxi-9oc-fluor-21-hexanogfl- oxí-'Iflß-hydgroxi-'l,L1--pregnadien-5,20-dion. Smp.: 22200. [gås = -f- S20 (pyridin). 'Gvze 259 = '15 500 (metanol).The crude product is purified on 450 g of silica gel with a methylene chloride-acetone gradient (0 - ': 2% acetone). Yield: 2.56 g of 17α-acetoxy-9α-fluoro-21-hexanogloxy-1,6-hydroxy-1,1,1-pregnadiene-5,20-dione. M.p .: 22200. [goose = -f- S20 (pyridine). 'Gvze 259 = '15 500 (methanol).

Exempel 5 3,0 g '17a-acetoxi-9a-fluor-'VlBßfl-dihydroxi-'l A-pregnadien- -5,20-dion omröres med '15 ml trimetylättiksyraanhydrid i 50 ml pyridin 48 timmar vid r-umstemperatur. Ràprodukten isoleras såsom beskrives i exempel 2 och kromatograferas på 700 g kiselgel med en metylenklorid- -aceton-gradient (0 - '12 % aceton). Utbyte: 2,06 g 'Woc-acetoxi-Qcc-fluozv- -'1 '1 13-hydroxi~2'1 -trimetylacetoxi-'1 A-pregnadien-š , 20-dion . Smp . : 22700 . fy? = + ç9'” (pyriain). img 239 = 15 5oo (metanol). 11 Exempel 6 5,0 g 9a-fluor-110,21-dihydroxi-17a-propionyloxi-1,4-pregna- dien-5,20-dion, som framställts analogt med exempel 1a och 1b medelst ortopropionsyratrietylester i stället för ortoättiksyratrietylester och 9a-fluor-prednisolon, omröres i 50 ml pyridin med 25 ml propion~ syraanhydrid 2 timmar vid rumstemperatur. Man upparbetar såsom beskri- ves i exempel 2. 4,8 g råprodukt renas på 450 g kiselgel med en mety- ienkloria-eoeton-greaient (o - 15 %). Utbyte: 4,62 g 9e-r1uor-11p- -hydroxi-17a,21-dípropionyloxi-1,4-pregnadien-5,20-dion. Smp.: 191°C. ¿f§7š5 = + 51° (kloroform). UV:E 259 = 15 700 (metanol).Example 5 3.0 g of 17α-acetoxy-9α-fluoro-1,1Bβ-dihydroxy-1,1-pregnadiene-5,20-dione are stirred with 15 ml of trimethylacetic anhydride in 50 ml of pyridine for 48 hours at room temperature. The crude product is isolated as described in Example 2 and chromatographed on 700 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 2.06 g of Woc-acetoxy-Qcc-fluosyl-1,1'-13-hydroxy-2,1-trimethylacetoxy-1,1-pregnadiene-β, 20-dione. M.p. : 22700. fy? = + ç9 '”(pyriain). img 239 = 1500 (methanol). Example 6 5.0 g of 9α-fluoro-110,21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-5,20-dione, prepared analogously to Examples 1a and 1b by orthopropionic acid triethyl ester instead of orthoacetic acid triethyl ester and 9α-fluoro-prednisolone, is stirred in 50 ml of pyridine with 25 ml of propionic anhydride for 2 hours at room temperature. The mixture is worked up as described in Example 2. 4.8 g of crude product are purified on 450 g of silica gel with a methylene chloride-eoethone grain (o - 15%). Yield: 4.62 g of 9e-fluoro-11β-hydroxy-17α, 21-dipropionyloxy-1,4-pregnadiene-5,20-dione. Mp: 191 ° C. ¿F§7š5 = + 51 ° (chloroform). UV: E 259 = 15 700 (methanol).

Exempel 2 5,0 g 9a-fluor-11ß,21-dihydroxi-17a-propionyloxi-1,4-pregna- dien-5,20-dion omsättes analogt med exempel 2 medelst smörsyraanhydrid.Example 2 5.0 g of 9α-fluoro-11β, 21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 2 with butyric anhydride.

Ràprodukten kromatograferas på 450 g kiselgel med en metylenklorid- -aceton-gradient (O - 12 % aceton). Utbyte: 4,95 g 21-butyryloxi~9u- -fluor-11B-hydroxi-17d-propionyloxí~1,4-pregnadien-5,20~dion. Smp.: 179%. [gš5 = + 51° (kloroform). Uv=$ 259 = 15 700 (metanol).The crude product is chromatographed on 450 g of silica gel with a methylene chloride-acetone gradient (0 - 12% acetone). Yield: 4.95 g of 21-butyryloxy-9u-fluoro-11B-hydroxy-17d-propionyloxy-1,4-pregnadiene-5,20-dione. Mp: 179%. [α] 5 = + 51 ° (chloroform). Uv = $ 259 = 15,700 (methanol).

Exemgel 8 Man bringar 5 g 9a-fluor-116,21-dihydroxi-17a-propionyloxi- ~1,4-pregnadien-5,20-dion reagera analogt med exempel 2 medelst valeri» ansyraanhydrid i stället för smörsyraanhydrid. Nan upparbetar på samma sätt som beskrives i exempel 2. Ràprodukten renas genom kromatografe- ring på 750 g kiselgel med en metylenklorid-aceton-gradient (0 ~ 15 % aceton). Utbyte: 5,05 g 9a-fluor-115-hydroxi-17u-propionyloxi~21- -valeryloxi-1,4-pregnadien~5,20-dion. Smp.: 19000. Åfgyâs = +54° (Kloroform). Uv=E 259 = 15 soo (metanol).Example Gel 5 5 g of 9α-fluoro-116,21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 2 by valeric anhydride instead of butyric anhydride. Nan is worked up in the same manner as described in Example 2. The crude product is purified by chromatography on 750 g of silica gel with a methylene chloride-acetone gradient (0 ~ 15% acetone). Yield: 5.05 g of 9α-fluoro-115-hydroxy-17β-propionyloxy-21- -valeryloxy-1,4-pregnadiene-5,20-dione. M.p .: 19000. Åfgyâs = + 54 ° (Chloroform). Uv = E 259 = 15 soo (methanol).

Exemnel 9 Man omsätter 5,0 g 9a-fluor-11ß,21-dihydroxi-17a-propionyloxi- -1,4-pregnadienf5,20-dion analogt med exempel 2 medelst kapronsyraan- hydrid i stället för smörsyraanhydrid. 5,8 g ràprodukt renas genom kro~ matografering på 700 g kiselgel med en metylenklorid-aceton-gradient (0 - 12 % aceton). Utbyte: 4,52 g 9a-fluor-21-hexanoyloxi-11ß-§ydroxi- -17a-propionyloxi-1,4-pregnadien-5,20-dion. Smp.: 208°C. ¿fg7% = + 52° (kloroform). UV:E 259 = 15 900 (metanol).Example 9 5.0 g of 9α-fluoro-11β, 21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 2 by means of caproic anhydride instead of butyric anhydride. 5.8 g of crude product are purified by chromatography on 700 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 4.52 g of 9α-fluoro-21-hexanoyloxy-11β-hydroxy-17α-propionyloxy-1,4-pregnadiene-5,20-dione. Mp: 208 ° C. ¿Fg7% = + 52 ° (chloroform). UV: E 259 = 15 900 (methanol).

Exemgel 10 5,0 g 9a-fluor-11ß,21-dihydroxi-17a-propiony1oxi~1,4-pregna- dien-5,20-dion omsättes analogt med exempel 2 medelst trimetylättiksyra« anhydrid i stället för smörsyraanhydrid och upparbetas. 5,9 g råprodukt kromatograferas på 450 g kiselgel med en metylenklorid-aceton-gradient '280316 00 -9 12 (O - 12 % aceton). Utbyte: 2,25 g 9a-fluor-11ß-hydroxi-17u-propionyl- oxi-21-trimetylacetoxi-1,4-pregnadien-5,20-dionr Smp.: 21400. ¿f§7%5 = +55° (kloroform). UV:2'259 = 15 700 (metanol).Example 10 5.0 g of 9α-fluoro-11β, 21-dihydroxy-17α-propionyloxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 2 with trimethyl acetic anhydride instead of butyric anhydride and worked up. 5.9 g of crude product are chromatographed on 450 g of silica gel with a methylene chloride-acetone gradient (0 - 12% acetone). Yield: 2.25 g of 9α-fluoro-11β-hydroxy-17β-propionyloxy-21-trimethylacetoxy-1,4-pregnadiene-5,20-dione M.p .: 21400. ¿f§7% 5 = + 55 ° (chloroform). UV: 2.259 = 15 700 (methanol).

Exemgel 11 a) 25 g 9a-fluor-prednisolon omröres i 250 ml pyridin och 125 ml smörsyraanhydrid över natten vid rumstemperatur. Man fäller blandningen i isvatten, filtrerar och löser återstoden i metylenklorid.Example gel 11 a) 25 g of 9α-fluoro-prednisolone are stirred in 250 ml of pyridine and 125 ml of butyric anhydride overnight at room temperature. The mixture is poured into ice water, filtered and the residue is dissolved in methylene chloride.

Lösningen tvättas med vatten, torkas över natriumsulfat och indunstas i vakuum. Ãterstoden kromatograferas på 2,5 kg kiselgel med en metylen~ klorid-aceton-gradient (O ~ 15 % aceton). Utbyte: 25,1 g 21-butyryloxi- -9a-fluor-116,17u-dihydroxi-1,4-pregnadienf5,20-dion. b) Till en suspeaïion av 24 g koppar(I)jodid i 480 ml torr tetrahydrofuran sâttes droppvis vid 0°C under argon 100 ml av en 5-pro~ centig lösning av metyllitium i eter. Den gula blandningen kyles till -5000 och därtill sättes en lösning av 22,5 g 21-butyryloXi-9a-fluor- -11ß,1?a-dihydroxi-1,4-pregnadien~5,20-dion i 400 ml torr tetrahydro- furan. Man rör om blandningen 5 - 4 timmar vid denna temperatur. Över- skottet av reaktionskomponent förstöras med en vattenlösning av ammo~ niumklorid. Man extraherar med metylenklorid, tvättar den organiska fasen, torkar den över natriumsulfat och indunstar i vakunm. Utbyte: 20,5 g 1?a-butyryloxi-9a-fluor-11ß,21-dihydroxi-1,4-pregnadien-5,20- dion. c) 2,0 g 1?a-butyryloxí-9u-fluor-11E,21-dihydroxi-1,4-pregna- dien-5,20-dion omsättes analogt med exempel 10 medelst propionsyraan- hydrid, upparbetas ooh renas. Utbyte: 1,4 g 1?a-butyryloxi-9a-fluor- -11ß-hydroxi-21-propionyloxi-1,4-pregnadien-5,20-dion. Smp.: 14600.The solution is washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 2.5 kg of silica gel with a methylene chloride-acetone gradient (0 ~ 15% acetone). Yield: 25.1 g of 21-butyryloxy-9a-fluoro-116,17u-dihydroxy-1,4-pregnadiene or 5,20-dione. b) To a suspension of 24 g of copper (I) iodide in 480 ml of dry tetrahydrofuran was added dropwise at 0 ° C under argon 100 ml of a 5% solution of methyl lithium in ether. The yellow mixture is cooled to -5000 and to this is added a solution of 22.5 g of 21-butyryloxy-9a-fluoro-11β, 1α-dihydroxy-1,4-pregnadiene-5,20-dione in 400 ml of dry tetrahydro - furan. The mixture is stirred for 5 - 4 hours at this temperature. The excess reactant is destroyed with an aqueous solution of ammonium chloride. It is extracted with methylene chloride, the organic phase is washed, dried over sodium sulphate and evaporated in vacuo. Yield: 20.5 g of 1α-butyryloxy-9α-fluoro-11β, 21-dihydroxy-1,4-pregnadiene-5,20-dione. c) 2.0 g of 1α-butyryloxy-9u-fluoro-11E, 21-dihydroxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 10 with propionic anhydride, worked up and purified. Yield: 1.4 g of 1α-butyryloxy-9α-fluoro-11β-hydroxy-21-propionyloxy-1,4-pregnadiene-5,20-dione. M.p .: 14600.

Exemgel 12 1,5 g 17m-butyryloxi-9a-fluor-11ß,21-dihydroxi-1,4-pregnadien~ -5,20-dion omsättes analogt med exempel 2 medelst valeriansyraanhydrid i stället för smörsyraanhydrid till 17a-butyryloxi-9a-fluor-11ß-hydroxi- -21 -vaieryloxi-fn ß-pregnaaien-a, zo-aion. smp. = 220%.Example 12 1.5 g of 17m-butyryloxy-9α-fluoro-11β, 21-dihydroxy-1,4-pregnadiene--5,20-dione is reacted analogously to Example 2 by means of valeric anhydride instead of butyric anhydride to 17α-butyryloxy-9α-dione. fluoro-11β-hydroxy-21-vaieryloxy-fn β-pregnaaien-a, zo-aion. m.p. = 220%.

Exemgel 15 1,4 g 17a-butyryloxi-9a-fluor-11ß,21~dihydroxi-1,4-pregnadien- -5,20-dion omröres i 15 ml pyridin och 10 ml önantsyraanhydrid över natten vid rumstemperatur. Därefter rör man in blandningen i isvatten och extraherar med metylenklorid. Extraktet tvättas med vatten, torkas över natriumsulfat och indunstas i vakunn. Överskottet av önantsyra av- lägsnas från återstoden genom vattenángdestillation. Råprodukten kro- matograferas på 250 g kiselgel med en metylenklorid-acetonfgradient 15 (0 - 12 % aceton). Utbyte: 790 mg 17a-butyryloxi-9a-fluor-21-heptanoyl- oxi-11ß-hydroxi-1,4~pregnadien-5,20-dion.Example 15 1.4 g of 17α-butyryloxy-9α-fluoro-11β, 21-dihydroxy-1,4-pregnadiene--5,20-dione are stirred in 15 ml of pyridine and 10 ml of onionic anhydride overnight at room temperature. The mixture is then stirred into ice water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated in vacuo. The excess oleic acid is removed from the residue by steam distillation. The crude product is chromatographed on 250 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 790 mg of 17α-butyryloxy-9α-fluoro-21-heptanoyloxy-11β-hydroxy-1,4-pregnadiene-5,20-dione.

Exempel 14 4,5 g 17a-butyryloxi-9u-fluor-115,21-dihydroxi-1,4-pregnadien- -5,20-dion omsättes analogt med exempel 2 medelst isosmörsyraanhydrld i stället för smörsyraanhydrid. Råprodukten renas genom kromatografering på 700 g kiselgel med en metylenklorid-aceton~gradient (O - 12 % aceton) Utbyte: 2,1 g 17a-butyryloxi-9a-fluor-11B-hydroxi-21-isobutyryloxi- -1,4~pregnadien~5,20-dion.Example 14 4.5 g of 17α-butyryloxy-9u-fluoro-115,21-dihydroxy-1,4-pregnadiene--5,20-dione are reacted analogously to Example 2 by isobutyric anhydride instead of butyric anhydride. The crude product is purified by chromatography on 700 g of silica gel with a methylene chloride-acetone gradient (0 - 12% acetone) Yield: 2.1 g of 17α-butyryloxy-9α-fluoro-11β-hydroxy-21-isobutyryloxy-1,4-pregnadiene ~ 5,20-dione.

Exem el 1 a) 5 g 9d-fluorprednisolon omröres i 30 ml pyridin och 15 ml valeriansyraanhydrid över natten vid rumstemperatur. Därefter röres blandningen in i isvatten och extraheras med metylenLlorid. Extraktet tvättas med vatten, torkas över natriumsulfat och indunstas i vakuum. Överskottet av valeriansyra avlägsnas från återstoden genom vattenång- destillation. Råprodukten kromatograferas på 300 g kiselgel med en matg- 1enklorid-aceton-gradient (0 - 15 % aceton). Utbyte: 2,87 3 9m-fluor- -11ß,17a-dihydroxi-21-valeryloxi-1,4-pregnadien~3,20-dion. b) 2 g 9a-fluor-11ß,17a-dihydroxi-21~valeryloxi-1,4-pregnadien~ -5,20-dion omlagras analogt med exempel 11b medelst litiumdimetylkuprat till 1,86 g 9a~fluor-11B,21-dihydroxi-17u-valeryloxi-1,4-pregnadien- -5,20-dion. c) Man omsätter 1,8 g 9a-fluor-11ß,21~dihydroxi-1?u-valery1- oxi-1,4-pregnadien-š,20~dion analogt med exempel 2 men medelst propion~ syraanhydrid i stället för smörsyraanhydrid. Utbyte: 920 mg 9a-fluor- -11B-hydroxi-21-propionyloxi-17a-valeryloxi-1,4-pregnadien-3,20~dion.Example 1 a) 5 g of 9d-fluoroprednisolone are stirred in 30 ml of pyridine and 15 ml of valeric anhydride overnight at room temperature. The mixture is then stirred into ice water and extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated in vacuo. The excess valeric acid is removed from the residue by steam distillation. The crude product is chromatographed on 300 g of silica gel with a food chloride-acetone gradient (0-15% acetone). Yield: 2.87 39 m-fluoro--11β, 17α-dihydroxy-21-valeryloxy-1,4-pregnadiene-3,20-dione. b) 2 g of 9α-fluoro-11β, 17α-dihydroxy-21-valeryloxy-1,4-pregnadiene--5,20-dione are rearranged analogously to Example 11b by lithium dimethyl cupoprate to 1.86 g of 9α-fluoro-11β, 21- dihydroxy-17H-valeryloxy-1,4-pregnadiene--5,20-dione. c) 1.8 g of 9α-fluoro-11β, 21-dihydroxy-1,10-valeryl-oxy-1,4-pregnadiene-1,4-dione are reacted analogously to Example 2 but by propionic anhydride instead of butyric anhydride. . Yield: 920 mg of 9α-fluoro-11β-hydroxy-21-propionyloxy-17α-valeryloxy-1,4-pregnadiene-3,20-dione.

Smp.: 20600.M.p .: 20600.

Exempel 16 Man omsätter 5,4 g 9u-fluor-11ß,21~dihydroxi-17d-valeryloXi~ -1,4-pregnadienf5,20-dion analogt med exempel 2 med smörsyraanhydrid och upparbetar pà samma sätt. Utbyte: 1,96 g 21-butyryloxi-9u-fluor-11:- -hydroxi-17m-valeryloxi-1,4-pregnadien~5,20-dion. Smp.: 25400.Example 16 5.4 g of 9u-fluoro-11β, 21-dihydroxy-17d-valeryloxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 2 with butyric anhydride and worked up in the same manner. Yield: 1.96 g of 21-butyryloxy-9u-fluoro-11: -hydroxy-17m-valeryloxy-1,4-pregnadiene-5,20-dione. M.p .: 25400.

Exem el 1 En lösning av 2,0 g 9a-fluor-11E,21-dihydroxi-17a-valeryloxi- -1,4-pregnadien~5,20-dion i 20 ml pyridin omröres med 10 ml kapronsyra» amqßhfid 1 1/2 timme vid rumstemperatur. Reaktionsprodukten fälles med isvatten, avfiltreras och löses i metylenklorid. Lösningen tvättas med vatten, torkas och indunstas i vakuum. Ätersumkm, 1,96 g ràprodukt, kromatograferas på 200 g kiselgel med en metylenklorid-aceton-gradient ?803168-9 14 (0 - 12 % aceton). Utbyte: 1,58 g 9a-fluor-21-hexanoyloxi-11ß-hydroxi- -17u-valeryloxi-1,4-pregnadien-5,20~dion.Example 1 A solution of 2.0 g of 9α-fluoro-11E, 21-dihydroxy-17α-valeryloxy-1,4-pregnadiene-5,20-dione in 20 ml of pyridine is stirred with 10 ml of caproic acid. 2 hours at room temperature. The reaction product is precipitated with ice water, filtered off and dissolved in methylene chloride. The solution is washed with water, dried and evaporated in vacuo. The residue, 1.96 g of crude product, is chromatographed on 200 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 1.58 g of 9α-fluoro-21-hexanoyloxy-11β-hydroxy-17H-valeryloxy-1,4-pregnadiene-5,20-dione.

Exempel 18 a) 12 g 9a-fluorprednisolon omsättes analogt med exempel 11a men med isosmörsyraanhydrid i stället för smörsyraanhydrid. Utbyte: 10,4 g 9a-fluor-11ß,17a-dihydroxi-21-isobutyryloxi-1,4-pregnadien-E,20- -dion. b) 10 g 9u-fluor-11ß,17u-dihydroxi-21~ísobutyryloxi-1,4-pregnn- dien-5,20-dion omlagras analogt med exempel 11b medelst litiumdimetyl- kuprat. Utbyte: 6,9 g 9m~fluor-11B,21-dihydroxi-17a-isobutyryloxi-1,4- -pregnadien-5,20-didn. c) 2,1 g 9a-fluor-115,21-dihydroxi-17a-isobutyryloxi-1,4- -pregnadien-5,20-dion omsättes analogt med exempel 1c medelst propion- syraanhydrid. Utbyte: 1,5 g 9a-fluor-11ß-hydroxi-1?u-ísobutyryloxi- -f1~propionyloxi-1,4~pregnadien-5,20-dion.Example 18 a) 12 g of 9a-fluoroprednisolone are reacted analogously to Example 11a but with isobutyric anhydride instead of butyric anhydride. Yield: 10.4 g of 9α-fluoro-11β, 17α-dihydroxy-21-isobutyryloxy-1,4-pregnadiene-E, 20-dione. b) 10 g of 9u-fluoro-11β, 17u-dihydroxy-21-isobutyryloxy-1,4-pregnenediene-5,20-dione are rearranged analogously to Example 11b by means of lithium dimethylcuprate. Yield: 6.9 g of 9m-fluoro-11β, 21-dihydroxy-17α-isobutyryloxy-1,4- -pregnadiene-5,20-didn. c) 2.1 g of 9α-fluoro-115,21-dihydroxy-17α-isobutyryloxy-1,4- -pregnadiene-5,20-dione are reacted analogously to Example 1c with propionic anhydride. Yield: 1.5 g of 9α-fluoro-11β-hydroxy-1,10-isobutyryloxy-β-propionyloxy-1,4-pregnadiene-5,20-dione.

Exempel 12 1,2 g 9u-fluor-11B,21-dihydroxi-17a-isobutyryloxi-1,4-pregna- dien-5,20-dion omsättes analogt med exempel 2 medelst smörsyraanhydrid, upparbetas och kromatograferas. Utbyte: 670 mg 21-butyryloxi-9u-fluor- -11B-hydroxi-17a~isobutyryloxi-1,4-pregnadien-3,20-díon.Example 12 1.2 g of 9u-fluoro-11B, 21-dihydroxy-17α-isobutyryloxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 2 with butyric anhydride, worked up and chromatographed. Yield: 670 mg of 21-butyryloxy-9u-fluoro-11B-hydroxy-17α-isobutyryloxy-1,4-pregnadiene-3,20-dione.

Exempel 20 a) 5,0 g 9a-fluor-11B,17a-dihydroxi-21-trimetylacetoxi-1,4- iregnadíen-5,20dion omlagras analogt med exempel 11b medelst litiumdí- metylknprat. Utbyte: 5,4 g 9a-fluor-116,21-dihydroxi-17u-trimetylacet~ oxi-1,4-pregnadien-5,20-dion. b) 2,4 g 9a-fluor~11ß,21-dihydroxi-1?a-trimetylacetoxi-1,4- -pregnadienfš,20-dion omsättes analogt med exempel 1c medelst propion- syraanhydrid. Utbyte: 1,2 g 9u-fluor-11ß-hydroxi-21-propionyloxí-17a- -trímetylacetoxí-1,4-pregnadien-5,20-dion.Example 20 a) 5.0 g of 9α-fluoro-11β, 17α-dihydroxy-21-trimethylacetoxy-1,4-iregnadiene-5,20dione are rearranged analogously to Example 11b by lithium dimethyl niprate. Yield: 5.4 g of 9α-fluoro-116,21-dihydroxy-17H-trimethylacetoxy-1,4-pregnadiene-5,20-dione. b) 2.4 g of 9α-fluoro-11β, 21-dihydroxy-1,1α-trimethylacetoxy-1,4- -pregnadienphis, 20-dione are reacted analogously to Example 1c with propionic anhydride. Yield: 1.2 g of 9u-fluoro-11β-hydroxy-21-propionyloxy-17α-trimethylacetoxy-1,4-pregnadiene-5,20-dione.

Exempel 21 p 5,1 g 17a-bensoyloxi-9a-fluor-11§,21-dihydroxi-1,4~pregnadien- -5,20-dion, som framställts analogt med exempel 1a och 1b medelst orto- bensoesyratríetylester i stället för ortoättiksyratrietylester och 9u- -fluorprednisolon, omröres i 50 ml pyridin och 15 ml propionsyraanhyd- rid 1 timme vid rumstemperatur. Man upparbetar blandningen såsom i exempel 1c. Råprodnkten renas genom kromatografering på 450 g kiselgel med en metylenklorid-acetonfgradient (0 - 12 % aceton). Utbyte: 1,54 g 17a-bensoyloxi-9a~fluor-11B-hydroxi-21-propionyloxi-1,4-pregnadien- -5,20-dion. Smp.: 255°C (sönderdelning). Åfgyšs = +22° (pyridin).Example 21 p 5.1 g 17α-benzooyloxy-9α-fluoro-11§, 21-dihydroxy-1,4-pregnadiene--5,20-dione, prepared analogously to examples 1a and 1b by orthobenzoic acid triethyl ester instead of orthoacetic acid triethyl ester and 9u-fluoroprednisolone, is stirred in 50 ml of pyridine and 15 ml of propionic anhydride for 1 hour at room temperature. The mixture is worked up as in Example 1c. The crude product is purified by chromatography on 450 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 1.54 g of 17α-benzoyloxy-9α-fluoro-11β-hydroxy-21-propionyloxy-1,4-pregnadiene--5,20-dione. Mp: 255 ° C (dec.). Åfgyšs = + 22 ° (pyridine).

UV:¿'254 = 28 800 (metanol). ?afl:~@e-9 4 15 Exempel 22 5,0 g 17a-bensoyloxi-9d-fluor-11ß,ï1-dihydroxi-1,4-pregnadien- -5,20-dion omsättes analogt med exempel I i 50 ml pyridin och 15 ml smörsyraanhydrid och upparbetas. Råprodukten renas genom kromatografe- ring på 450 g kiselgel med en metylenklorid-aceton-gradient (0 - 12 % aceton). Utbyte: 1,9 g 17a-bensoyloxi-21-butyryloxi-9d~fluor-11B- -hydroxi~1,4-pregnadíen-5,20-dion. Smp.: 21800 (sönderdelning). zfgfâb +21° (pyriain). Uvf 254 = 28900 (metanol).UV: 254 = 28,800 (methanol). Example 22 5.0 g of 17α-benzooyloxy-9d-fluoro-11β, β-dihydroxy-1,4-pregnadiene--5,20-dione are reacted analogously to Example I in 50 ml pyridine and 15 ml of butyric anhydride and worked up. The crude product is purified by chromatography on 450 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 1.9 g of 17α-benzoyloxy-21-butyryloxy-9d-fluoro-11β-hydroxy-1,4-pregnadiene-5,20-dione. M.p .: 21800 (decomposition). zfgfâb + 21 ° (pyriain). Uvf 254 = 28900 (methanol).

Exem el 2 2,8 g 17a-bensoyloxi-9a-fluor-11ß,21~dihydroxi-1,4-pregnadien- -5,20-dion omsättes analogt med exempel 2 men med valeriansyraanhydrid i stället för smörsyraanhydrid och upparbetas. Råprodukten renas genom kromatografering på 450 g kiselgel med en metylenklorid~acetonfgradient (0 - 12 % aceton). Utbyte: 1,81 g 17a-bensoyloxi-9a-fluor-11ß-hydroxi- -21-valeryloxi-1,4-pregnadien-5,20-dion. Smp.: 20800. ¿fÉ7%5 = +22° (pyridin). UVuÉ-zöq = 29 000 (metanol).Example 2 2.8 g of 17α-benzoyloxy-9α-fluoro-11β, 21-dihydroxy-1,4-pregnadiene--5,20-dione are reacted analogously to Example 2 but with valeric anhydride instead of butyric anhydride and worked up. The crude product is purified by chromatography on 450 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone). Yield: 1.81 g of 17α-benzooyloxy-9α-fluoro-11β-hydroxy-21-valeryloxy-1,4-pregnadiene-5,20-dione. M.p .: 20800. ¿fÉ7% 5 = + 22 ° (pyridine). UVuÉ-zöq = 29,000 (methanol).

Exemgel 24 2,1 g 17d-bensoyloxi-Qu-fluor-11ß,21-dihydroxi-1,4-pregnadien- -5,20-dion omsättes analogt med exempel 2 medelst isosmörsyraanhydrid 1 stället för smörsyraanhydrid och upparbetas. Ràprodukten kromatografe- ras på 200 g kiselgel med en metylenklorid-aceton-gradient (0 - 12 Q aceton). Utbyte: 1,09 g 17a-bensoyloxi-9a-fluor-11B-hydroxi-21-íso- butyryloxi-1,4-pregnadien-5,20-díon.Example 24 2.1 g of 17d-benzoyloxy-Qu-fluoro-11β, 21-dihydroxy-1,4-pregnadiene--5,20-dione are reacted analogously to Example 2 with isobutyric anhydride instead of butyric anhydride and worked up. The crude product is chromatographed on 200 g of silica gel with a methylene chloride-acetone gradient (0 - 12 acet acetone). Yield: 1.09 g of 17α-benzoyloxy-9α-fluoro-11β-hydroxy-21-isobutyryloxy-1,4-pregnadiene-5,20-dione.

Exemgel 25 1,8 g 17u-bensoyloxi-9a-fluor-11b,21-díhydroxi-1,4-pregnadien- -5,20-dion omsättes analogt med exempel 2 medelst trimetylättiksyraanf hydrid i stället för smörsyraanhydrid, upparbetas och kromatograferas enligt exempel 2. Utbyte: 720 mg 17a-bensoyloxi-9a-fluor-113-hydroxi- -21-trimetylacetoxi-1,4-pregnadien-5,20-dion.Example gel 1.8 g of 17u-benzoyloxy-9a-fluoro-11b, 21-dihydroxy-1,4-pregnadiene--5,20-dione are reacted analogously to Example 2 by means of trimethylacetic anhydride instead of butyric anhydride, worked up and chromatographed according to Example Yield: 720 mg of 17α-benzoyloxy-9α-fluoro-113-hydroxy-21-trimethylacetoxy-1,4-pregnadiene-5,20-dione.

Exemgel 26 Man rör om 10 ml hexametylfosforsyratriamid och 1,5 ml tionyl~ klorid 50 minuter vid 000. Till blandningen sätter man därefter 800 mg 1?u-acetoxi-9a-fluor-11ß,21-dihydroxi-1,4-pregnadien~5,20-dion och rör om 5 1/2 timme vid 000. Man häller blandningen i isvatten, extraherar med ättíkester och tvättar extrakten neutrala med natriumvätekarbonat och vatten. Man torkar över natriumsulfat och indunstar i vakuum, var~ vid man erhåller 1 g ràprodukt, som man renar genom kromatografering på 65 g kiselgel med en metylenkloríd-aceton-gradient (0 - 15 % aceton).Example 26 Stir in 10 ml of hexamethylphosphoric triamide and 1.5 ml of thionyl chloride for 50 minutes at 000. To the mixture is then added 800 mg of 1β-acetoxy-9α-fluoro-11β, 21-dihydroxy-1,4-pregnadiene. 5,20-dione and stir for 5 1/2 hours at 000. The mixture is poured into ice water, extracted with acetic ester and the extracts are washed neutral with sodium bicarbonate and water. Dry over sodium sulfate and evaporate in vacuo to give 1 g of crude product, which is purified by chromatography on 65 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone).

Utbyte: 555 mg 17a-acetoxi-21-klor-9a-fluor-11B-hydroxi-1,4~pregnadien~ -5,20-dion. Smp.: 26500 (sönderdelníng). ¿f§7š5 = +101° (pyridín).Yield: 555 mg of 17α-acetoxy-21-chloro-9α-fluoro-11β-hydroxy-1,4-pregnadiene--5,20-dione. M.p .: 26500 (decomposition). ¿F§7š5 = + 101 ° (pyridine).

II 7803168-9 16 Uv=6 259 = 15 soo (metanol).II 7803168-9 16 Uv = 6 259 = 15 soo (methanol).

Exemgel 22 Han omsätter 1,2 g 9a-fluor-11ß,21~dihydroxi~1'hc-propionyloxi- -1 ,4-pregnadien-5,20-dion medelst tionylklorid i hexametylfosforsyratri- amid analogt med exempel 26. Râprodukten kromatograferas på 150 g kisel- gel med en metylenklorid-aceton-gradient (0 ~ 15 % aceton). Utbyte: 860 mg 21-klor-9d-fluor-116-hydroxi-17a-propionyloxi-1,4~pregnadien~ -5,20-dion. Smp.: 22900 (sönderdelning). ¿f§7š5 = +98° (pyridin).Example Gel 22 He converts 1.2 g of 9α-fluoro-11β, 21-dihydroxy-1,1'hc-propionyloxy-1,4-pregnadiene-5,20-dione by thionyl chloride into hexamethylphosphoric acid triamide analogously to Example 26. The crude product is chromatographed on 150 g of silica gel with a methylene chloride-acetone gradient (0 ~ 15% acetone). Yield: 860 mg of 21-chloro-9d-fluoro-116-hydroxy-17α-propionyloxy-1,4-pregnadiene--5,20-dione. M.p .: 22900 (decomposition). ¿F§7š5 = + 98 ° (pyridine).

Ulïzfizšg = 15 900 (metanol).Uliz fi zšg = 15,900 (methanol).

Exempel 28 950 mg 9a-fluor-11B,21-dihydroxi~17a-isobutyryloxi-1,4-pregna- dienf5,20~dion omsättes analogt med exempel 26 medelst tíonylklorid i hexametylfosforsyratriamid. Man renar råprodukten genom kromatografe~ ring på 120 g kiselgel med en metylenklorid-aceton-gradient (0 - 15 % aceton). Utbyte: 520 mg 21-klor-9a-fluor-116-hydroxi-1?a-isobutyryloxi- -1,4-pregnadien~5,20-dion. Smp.: 216°0.Example 28 950 mg of 9α-fluoro-11β, 21-dihydroxy-17α-isobutyryloxy-1,4-pregnadiene-5,20-dione are reacted analogously to Example 26 by thionyl chloride in hexamethylphosphoric triamide. The crude product is purified by chromatography on 120 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 520 mg of 21-chloro-9α-fluoro-116-hydroxy-1α-isobutyryloxy-1,4-pregnadiene-5,20-dione. Mp: 216 ° 0.

Exemgel 29 2,5 g 17a-bensoyloxi-9a-fluor-116,21-dihydroxi-1,4-pregnadien- -5,20-dion omsättes analogt med exempel 26 och råprodukten renas genom kromatograferíng på 250 g kiselgel med en metylenklorid-acetonfgradíen.Example Gel 29 2.5 g of 17α-benzoyloxy-9α-fluoro-116,21-dihydroxy-1,4-pregnadiene--5,20-dione are reacted analogously to Example 26 and the crude product is purified by chromatography on 250 g of silica gel with a methylene chloride. acetonefgradine.

(O - 12 % aceton). Utbyte: 1,1 g 1?a-bensoyloxi-21-klor~9a-fluor-11b- -hydroxi-1,4-pregnadien-5,20-dion. Smp.: 25600 (sönderdelning). 1171235 = +15° (pymidizm). Uwe 254 = 28 eoo (metanol).(O - 12% acetone). Yield: 1.1 g of 1α-benzoyloxy-21-chloro-9α-fluoro-11β-hydroxy-1,4-pregnadiene-5,20-dione. M.p .: 25600 (decomposition). 1171235 = + 15 ° (pymidism). Uwe 254 = 28 eoo (methanol).

Exem el O a) En suspension av 8,7 g 21-fluor-17a-hydroxí-1,4,9(11)- -pregnatrien~5,20-dion i 100 ml dietylenglykoldimetyleter omröres med 12 g N,NFdimetylaminopyridin och 8,8 ml acetanhydrid 6 1/2 timme vid 3000. Reaktionsblandningen spädes med metylenklorid och tvättas med 2-normal klorvätesyra. Man extraherar efter vattenångdestillation med metylenklorid, torkar över natriumsulfat och indunstar. Utbyte: 7,9 g 1Tm-acetoxí-21-fluor-1,4,9(11)-pregnatrien~5,20-dion. b) 7,6 g 17d-acetoxi-21-flucr-1,4,9(11)1pregnatrien-5,20-dion löses i 76 ml dioxan och därtill sättes 7,2 g Nebromsuccinimid. Därefter tillsättes droppvis 58 ml 10-procentig vattenlösning av perklorsyra och mxn rör om blandningen 50 minuter vid rumstemperatur och tillsätter en lösning av 5,5 g natriumvätesulfit i 550 ml vatten. Man suger av den bildade fällningen och torkar den. Utbyte: 10 g 17a-acetoxi-9a-brom- -.1-fluor-11ß~hydroxi-1,4-pregnadienf5,20-dion. c) 10 g av ovanstående råprodukt upphettas med återílöde i :so-o m1 etanol med 14,0 g keliumeeetet 2 timmer via 11o°c. men indmm-mem- 17 lösningen i vakuum och häller den i isvatten. Fällningen avfiltreras och råprodukten renas genom kromatografering på 700 g kiselgel med en metylenklorid-aceton-gradient (0 - 6 % aceton). Utbyte: 5,4 g 17e~acetui -9,115-epoxi-21-fluor-1,4-pregnadien~5,20~dion. d) 51 ml av en 70-procentig (HF)n/pyridin-lösning kyles till -6000 och därtill sattes en lösning av 5 g 17a-acetoxi~9,11B-epoxi~21- ~fluor-1,4~pregnadien-5,20-dion i 5 ml pyridin. Reaktionslösningen om- röres 10 timmar vid -5°C ooh får därefter stå 5 dagar i kylskåp. Man sätter därefter lösningen till ammoniakaliskt isvatten och avfiltrerar den bildade fällningen. Råprodukten renas genom kromatografering på 550 g kiselgel med en metylenklorid-aceton-gradient (0 - 15 % aceton).Example 0 a) A suspension of 8.7 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-5,20-dione in 100 ml of diethylene glycol dimethyl ether is stirred with 12 g of N, NF-dimethylaminopyridine and 8 g .8 ml of acetane hydride 6 1/2 hours at 3000. The reaction mixture is diluted with methylene chloride and washed with 2-hydrochloric acid. The mixture is extracted after steam distillation with methylene chloride, dried over sodium sulphate and evaporated. Yield: 7.9 g of 1H-acetoxy-21-fluoro-1,4,9 (11) -pregnatriene-5,20-dione. b) 7.6 g of 17d-acetoxy-21-flucr-1,4,9 (11) 1pregnatrien-5,20-dione are dissolved in 76 ml of dioxane and to this is added 7.2 g of nebromosuccinimide. Then 58 ml of 10% aqueous solution of perchloric acid are added dropwise and the mixture is stirred for 50 minutes at room temperature and a solution of 5.5 g of sodium hydrogen sulphite in 550 ml of water is added. The formed precipitate is sucked off and dried. Yield: 10 g of 17α-acetoxy-9α-bromo-1,1-fluoro-11β-hydroxy-1,4-pregnadiene-5,20-dione. c) 10 g of the above crude product are heated with reflux in: 50 ml of ethanol with 14.0 g of the potassium ether for 2 hours via 110 ° C. but immerse the solution in vacuum and pour it into ice water. The precipitate is filtered off and the crude product is purified by chromatography on 700 g of silica gel with a methylene chloride-acetone gradient (0-6% acetone). Yield: 5.4 g of 17α-acetyl-9,115-epoxy-21-fluoro-1,4-pregnadiene-5,20-dione. d) 51 ml of a 70% (HF) n / pyridine solution is cooled to -6000 and to this was added a solution of 5 g of 17α-acetoxy-9,11B-epoxy-21--fluoro-1,4-pregnadiene. 5,20-dione in 5 ml of pyridine. The reaction solution is stirred for 10 hours at -5 ° C and then allowed to stand for 5 days in the refrigerator. The solution is then added to ammoniacal ice water and the precipitate formed is filtered off. The crude product is purified by chromatography on 550 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone).

Utbyte: 2,15 g 17a-acetoxi-9u,21-difluor-11;-hydroxi-1,4-pregnadien- -5,20-dion. Smp.: 276°C (sönderdelning). zfgyšš = +16° (kloroform).Yield: 2.15 g of 17α-acetoxy-9u, 21-difluoro-11β-hydroxy-1,4-pregnadiene--5,20-dione. Mp: 276 ° C (dec.). zfgyšš = + 16 ° (chloroform).

UV:ê'259 = 15 800 (metanol).UV: ê'259 = 15 800 (methanol).

Exem el 1 a) Man framställer analogt med exempel 50a av 7,9 g 21-fluor- -17a-hydroxi-1,4,9(11)-pregnatrien-5,20-dion och propionsyraanhydrii 5 5 21-fluor-17a-propionyloxi-1,4,9(11)~pregnatrien-5,20-dion, som man omsätter med N-bromsuccinimid under de i exempel 50b beskrivna förhål- landena. Utbyte: 8,5 g 9a-brom-21-fluor-115-hydroxi-17a~propionyloxi- -1,4-pregnadien-5,20-dion. b) 8,5 g av ovanstående råprodukt omsättes under de i exempel 500 beskrivna förhållandena med kaliumacetat. Ràprodnkten renas genom kromatografering på 700 g kíselgel med en metylenklorid-aceton~gradienL (0 - 6 % aoeton). Utbyte: 5,5 g 9,11b-epoxi-21-fluor-17a-propionyloxi- -1,4-pregnadien-5,20-dion. c) Man omsätteranalogt med exempel 50d 5,0 g 9,11B-epoxi- ~21-fluor-17d-propionyloxi-1,4-pregnadien-5,20-dion med an70-proceutig (HF)n/pyridin-lösning. Reaktionsblandningen renas genom kromatografering på 700 g kiselgel med en metylenklorid-aceton-gradient (0 - 15 % ace- ton). Utbyte: 5,98 g 9n,21-difluor-11B-hydroxi-17a-propionyloxi-1,4- -pregnadien- ,20~dion. onp.: 214°C. [f@7É5 = +15° (kloroform)- UV=5'2f I 15 800 (metanol). " Exemgel 52 a) Man omsätter 20,0 g 17d-butyryloxi~21-fluor-1,4,9(11)-pregna- trienf5,20-dion, framställd analogt med exempel 50a av 21-fluor~17o- -hydroxi-1,4,9(11)~pregnatrien-5,20-dion och smörsyraanhydrid, med Ä- -bromsuccinimid analogt med exempel 50b. Utbyte: 24,9 g 9d-brom-17d- -butyryloxi-21-fluor-11ß-hydroxi-1,4~pregnadien-5,20-díon. b) Han omsätter ovanstående ràprodukt medelst kaliumacetat '?8Û3168-9 '18 under de i exempel 50:: beskrivna förhållandena. Utbyte: 16,1 g “[704- -butyryloxi-Q , 'l '1 ß-epoxi-Efi -fluor-'l , Ll--pregnadien-š , EO-dion. o) Analogt med exempel 50d omsättes 15,1 g 'Woc-butyryloxi- -9,“l'lB-epoxi~21 -fluor-'l ,4-pregnadien-5,20-díon med en '70-procentig (HEÛn/pyridin-lösníng. Råprodukten renas genom kromatografering på 1,5 kg kiselgel med en metylenklorid-aceton-gradient (O - '15 % aceton).Example 1 a) An analogous to Example 50a is prepared from 7.9 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-5,20-dione and propionic anhydride 21-fluoro-17α -propionyloxy-1,4,9 (11) -pregnatrien-5,20-dione, which is reacted with N-bromosuccinimide under the conditions described in Example 50b. Yield: 8.5 g of 9α-bromo-21-fluoro-115-hydroxy-17α-propionyloxy-1,4-pregnadiene-5,20-dione. b) 8.5 g of the above crude product are reacted under the conditions described in Example 500 with potassium acetate. The crude product is purified by chromatography on 700 g of silica gel with a methylene chloride-acetone gradient (0-6% acetone). Yield: 5.5 g of 9,11b-epoxy-21-fluoro-17α-propionyloxy-1,4-pregnadiene-5,20-dione. c) In an analogous manner to Example 50d, 5.0 g of 9,11B-epoxy-21-fluoro-17d-propionyloxy-1,4-pregnadiene-5,20-dione are reacted with an70-proceutical (HF) n / pyridine solution. The reaction mixture is purified by chromatography on 700 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 5.98 g of 9n, 21-difluoro-11B-hydroxy-17α-propionyloxy-1,4- -pregnadiene-, 20-dione. mp: 214 ° C. [f @ 7É5 = + 15 ° (chloroform) - UV = 5'2f I 15 800 (methanol). Example 52 a) 20.0 g of 17d-butyryloxy-21-fluoro-1,4,9 (11) -pregnantriene-5,20-dione are prepared, prepared analogously to Example 50a of 21-fluoro-17o-hydroxy -1,4,9 (11) -pregnatriene-5,20-dione and butyric anhydride, with β-bromosuccinimide analogous to Example 50b Yield: 24.9 g of 9d-bromo-17d-butyryloxy-21-fluoro-11β -hydroxy-1,4-pregnadiene-5,20-dione b) He reactes the above crude product with potassium acetate under the conditions described in Example 50. Yield: 16.1 g -butyryloxy-Q, '1 '1β-epoxy-Efi -fluoro--1, L1-pregnadiene-š, EO-dione. o) Analogously to Example 50d, 15.1 g of Woc-butyryloxy- -9, 11'-Epoxy-21-fluoro-1,4-pregnadiene-5,20-dione with a 70% (HEUn / pyridine solution. The crude product is purified by chromatography on 1.5 kg of silica gel with a methylene chloride. acetone gradient (0-15% acetone).

Utbyte: 15,4 g 'l'Zoa-butyryloxí-Cjcz,21-dífluor-'l1ß-hydroxi-'l ,4-pregnadien~ _;,2Q_di0n_ Smpfi 126%. [271235 = +11° (lnoroform). uv=5 259 = -w :zoo (metanol).Yield: 15.4 g of 1'Zoa-butyryloxy-Cl 2, 21-difluoro-1,1'-hydroxy-1,4-pregnadiene - _, 2Q_di0n_ mp fi 126%. [271235 = + 11 ° (lnoroform). uv = 5 259 = -w: zoo (methanol).

Exempel 55 a) Man framställer analogt med exempel šOa av 9,0 g 21-ïluor- -4 'Wx-hydroxi-'I ,4,9('l'l)-pregnatrien-5,20-dion och valeriansyraarmydrid 7,1 g 21 -fluor-'Woz-valeryloxi-'l,¿P,9('|'|l-pregnatrien-EQO-díon, som man omsätter med N-bromsuccinimid analogt med exempel šOb. Utbyte: 8,7 g 9oc-brom-21 -fluor-'lfl ß-hydroxi-'l 'You-val eryloxí-'l , lk-pregnadi en-š , 20-dion. b) 6,0 g av ovanstående ráprodukt omsättes med kaliumacetat ana- logt med exempel šOc. Man renar råprodukten genom kromatografering på 700 g kiselgel med en metylenklorid-aceton-gradient (O - 5 % aceton).Example 55 a) An analogous to Example šOa is prepared from 9.0 g of 21-fluoro--4 'Wx-hydroxy-1', 4,9 ('1'1) -pregnatriene-5,20-dione and valeric acid anhydride 7, 1 g of 21-fluoro-'-Woz-valeryloxy-'1, ¿P, 9 (' | '| 1-pregnatrien-EQO-dione, which is reacted with N-bromosuccinimide analogously to Example šOb. Yield: 8.7 g of 9oc -bromo-21 -fluoro-1,1-β-hydroxy-β-You-val eryloxy-1,1-β-impregnated en-β, 20-dione b) 6.0 g of the above crude product are reacted with potassium acetate analogously with example šOc. The crude product is purified by chromatography on 700 g of silica gel with a methylene chloride-acetone gradient (0 - 5% acetone).

Utbyte: 4,2 g 9,44ß-epoxi-Zfl-fluor-'Woc-valeryloxi-'lA-pregnadien-LQO- -dion. c) Han omsätter analogt med exempel 5011 5,8 g Qfflß-epoxi- -ïl-fluor-'lWx-valeryloxí-'l A-pregnadíen-LEO-dion med en 70-procentig (HF)n/pyríd:ï_n-lösning. Man renar råprodukten genom kromatografering på 450 g kiselgel med en metylenklorid-aceton-gradient (O - '15 96 aceton).Yield: 4.2 g of 9.44β-epoxy-Z 2 -fluoro-Woc-valeryloxy-1A-pregnadiene-LQO-dione. c) He reacts analogously to Example 5011 5.8 g of Qf fl ß-epoxy-ï-fluoro-1Hx-valeryloxy-1A-pregnadiene-LEO-dione with a 70% (HF) n / pyrid: ï_n solution . The crude product is purified by chromatography on 450 g of silica gel with a methylene chloride-acetone gradient (0 - '96 96 acetone).

Utbyte: 5,1 g 9oc,2'l-difluor-'l'lß-hydroxi-'Woc-valerwloxi-”IA-pregnadiem -Lao-dion. smp.= 159%. [g7š5 = +1o° (kloroform). Uv=6 239 = 15 eøo (metanol).Yield: 5.1 g of 9oc, 2,1'-difluoro-1,1'-1-hydroxy-'Woc-valerwloxy- '1A-pregnadiem -Lao-dione. mp = 159%. [g7š5 = + 10 ° (chloroform). Uv = 6 239 = 15 eøo (methanol).

Exem el lt- a) Man framställer under de i exempel šOa beskrivna förhål- landena av 8,9 g 21-fluor-'l7on-hydrofl-1 ,¿l-,9(1'1)-pregnatrien-5,20-díon och kapronsyraanhydrid 7,5 g 21-fluor-'Woc-hexanoyloxi-fi ,-'-l-,9('l'l)-pregna-- trien-šßO-dion, som man omsätter med N-bromsuccinimid analogt med exempel šOb. Utbyte: 8,2 g 9oc-brom-21-fluor-'Woc-hexanoyloxi-'VlB-hydrozi- -'1 , il-pregnadíen-š , 20-dion. b) Man omsätter 8,0 g av ovanstående råprodukt med kalíumace- tat analogt med exempel šOc och renar ràprodukten genom kromatograferirlg på kís-elgel med en metylenkloríd-aceton-gradient (O - 5 % aceton). Ut- bynte: 5,8 g 9,'l1ß-epoxí-2'l-íluor-'Woc-hexanoyloxi-'lA-pregnadien-LEO- -dion. c) 5,2 g 9,11ß-epoxi-Qfl-fluor-'Wa-hexanoyloxi-'l A-pregnadien- H ,. , zR”p1@H-Q 19 -5,20-dion omsättes med en 70-procentig (HF)n/pyridin-lösning analogt med exempel 50d. Han renar reaktionsprodukten genom kromatograferíng på 550 g kiselgel med en metylenklorid-aceton-gradient (O - 15 % ace- ton). Utbyte: 2,6 g 9a,24-difluor-17u-hexanoyloxi-11ß-hydroxi-1,4- -pregnadien-5,20-dion.Examples e lt- a) Under the conditions described in Example šOa, 8.9 g of 21-fluoro-'17on-hydro fl-1, ¿l-, 9 (1'1) -pregnatriene-5,20- dione and caproic anhydride 7.5 g of 21-fluoro-'-Woc-hexanoyloxy-fi, -'- 1-, 9 (' 1'1) -pregna-trien-ßßO-dione, which is reacted with N-bromosuccinimide analogously to example šOb. Yield: 8.2 g of 9oc-bromo-21-fluoro-1'-Woc-hexanoyloxy-1,1B-hydroxy-1,1'-pregnanine-β, 20-dione. b) React 8.0 g of the above crude product with potassium acetate analogously to Example šOc and purify the crude product by chromatography on silica gel with a methylene chloride-acetone gradient (0 - 5% acetone). Yield: 5.8 g of 9,11'-epoxy-2,1'-fluoro-1'-Woc-hexanoyloxy-1'-pregnadiene-LEO-dione. c) 5.2 g of 9,11ß-epoxy-fl-fluoro-'Wa-hexanoyloxy-1'-A-pregnadiene-H,. , zR ”p1 @ H-Q 19 -5,20-dione is reacted with a 70% (HF) n / pyridine solution analogous to Example 50d. He purifies the reaction product by chromatography on 550 g of silica gel with a methylene chloride-acetone gradient (0 - 15% acetone). Yield: 2.6 g of 9α, 24-difluoro-17H-hexanoyloxy-11β-hydroxy-1,4- -pregnadiene-5,20-dione.

Exempel §§ a) Mankramställer analogt med exempel 50a av 8,1 g 2¶-fluor- -1?u-hydroxi-1,ë,9(11)-pregnatrien~5,20-dion och isosmörsyraanhydrid 6,2 g 21-fluor-17x-isobutyryloxi-1,4,9(11)-pregnatrien-5,20-dion, som man omsätter med N-bromsuccinimid analogt med exempel 50b. Utbyte: 6,9 g 9u-brom-21-fluor-11ß-hydroxi-1?a-isobutyryloxi-1,4-pregnadien- -5,20-dion. b) 6,0 g av ovanstående råprodukt omsätter man med kaliumace- tat analogt med exempel 500 och renar reaktionsprodukten genom kremato- grafering på 600 g kiselgel med en metylenklorid-aceton-gnæfient ( 0 - 5 % aceton}. Utbyte: 4,1 g 9,11ß-epoxi-21-fluor-17a-isobutyryloxi-1,4- -pregnadien~5,20-dion. c) Man bringar 5,5 g 9,¶1B-epoxi-21-fluor-47a-isobutyrylox1- -1,4-pregnadien-5,20-dion reagera med en 70-procentig (HF)n/pyridin- -lösning analogt med exempel 30d. Man renar råprodukten genom kremato- grafering på 400 g kiselgel med en metylenklorid-aceton-gradient (0 - 15 % aoeton). Utbyte: 2,9 g 9d,2¶-difluor-11B-hydroxi-17a-isobutyryl- oxi-1,4-pregnadien-5,20-dion.Examples §§ a) Deficiencies analogous to Example 50a of 8.1 g of 2α-fluoro-1β-hydroxy-1,6,11 (11) -pregnatriene-5,20-dione and isosobutyric anhydride 6.2 g of 21 -fluoro-17x-isobutyryloxy-1,4,9 (11) -pregnatriene-5,20-dione, which is reacted with N-bromosuccinimide analogously to Example 50b. Yield: 6.9 g of 9u-bromo-21-fluoro-11β-hydroxy-1α-isobutyryloxy-1,4-pregnadiene--5,20-dione. b) 6.0 g of the above crude product are reacted with potassium acetate analogously to Example 500 and the reaction product is purified by cremating 600 g of silica gel with a methylene chloride-acetone gel (0-5% acetone}. Yield: 4.1 9,11β-epoxy-21-fluoro-17α-isobutyryloxy-1,4--pregnadiene-5,20-dione c) 5.5 g of 9,11B-epoxy-21-fluoro-47α-isobutyryloxy - 1,4-pregnadiene-5,20-dione react with a 70% (HF) n / pyridine solution analogous to Example 30d. The crude product is purified by cremating on 400 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 2.9 g of 9d, 2α-difluoro-11β-hydroxy-17α-isobutyryloxy-1,4-pregnadiene-5,20-dione.

Exempel §6 a) 8,0 g 21-fluor-17d-hydroxi-1,4,9(11)-pregnatrien-5,20- -dion sättes till en blandning av 80 ml isovaleriansyra och 52 ml tri- fluorättiksyraanhydrid och därefter omröres blandningen 2 1/2 timme vin 80°C. Man häller den därefter i varmt vatten för att förstöra överskot- tet av anhydrid och extraherar därpå med metylenklorid. Man neutralise- rar extraktet med 1-procentig pyridin-vatten, torkar över natriumsulfat och indunstar i vakuum. Nan löser återstoden i en ringa mängd pyridin, häller lösningen i isvatten och neutraliserar pyridinet med utspädd klorvätesyra och upparbetar på brukligt sätt. Utbyte: 5,8 g 21-fluor- -1?a-isovaleryloxi-1,4,9(14)-pregnatrien-5,20-dion. b) 5,5 g 24-fluor-47u-isovaleryloxi-4,4,9(11)-pregnatrien- -5,20-dion omsättes med N-bromsuccínimid analogt med exempel 50b. Ut- byte: 6,2 g 9d-brom-21-fluor-11ß-hydroxi-17a-isovaleryloxi-1,4-pregna- dien-5,20-dion. c) 6,0 g av ovanstående râprodukt omsättes med kaliumacetat '?8Û5'168'9 20 analogt med exempel 500. Reaktionsprodukten renas genom kromatografe- ring på 600 g kiselgel med en metylenklorid-aceton-gradient (0 - 5 N aceton). Utbyte: 5,7 g 9,11ß-epoxi-21-fluor-17a-ísovaleryloxi-1,ü~ -pregnadien-5 , 20-dion. d) Man bringar 5 g 9,11ß~qmnd:21-fluor-1?a~isovaleryloxi-1,4- -pregnadien-5,20-dion att reagera med en 70-procentig (HF)n/pyridin- -lösning analogt med exempel 50d. Man renar råprodukten genom kromato- graíering på 500 g kiselgel med en metylenklorid-aceton-gradient (0 - 155% aceton). Utbyte: 2,1 g 9u,21-diíluor-115-hydroxi-1Ta-isovaleryloxi-i -1,4-pregnadien-5,20-dion.Example §6 a) 8.0 g of 21-fluoro-17d-hydroxy-1,4,9 (11) -pregnatriene-5,20-dione are added to a mixture of 80 ml of isovaleric acid and 52 ml of trifluoroacetic anhydride and then the mixture is stirred for 2 1/2 hours in wine at 80 ° C. It is then poured into hot water to destroy the excess anhydride and then extracted with methylene chloride. The extract is neutralized with 1% pyridine water, dried over sodium sulphate and evaporated in vacuo. Nan dissolves the residue in a small amount of pyridine, pours the solution into ice water and neutralizes the pyridine with dilute hydrochloric acid and reprocesses in the usual manner. Yield: 5.8 g of 21-fluoro-1α-isovaleryloxy-1,4,9 (14) -pregnatrin-5,20-dione. b) 5.5 g of 24-fluoro-47u-isovaleryloxy-4,4,9 (11) -pregnatriene-5,20-dione are reacted with N-bromosuccinimide analogously to Example 50b. Yield: 6.2 g of 9d-bromo-21-fluoro-11β-hydroxy-17α-isovaleryloxy-1,4-pregnadiene-5,20-dione. c) 6.0 g of the above crude product are reacted with potassium acetate, analogous to Example 500. The reaction product is purified by chromatography on 600 g of silica gel with a methylene chloride-acetone gradient (0-5 N acetone). Yield: 5.7 g of 9,11β-epoxy-21-fluoro-17α-isovaleryloxy-1,6-pregnadiene-5,20-dione. d) 5 g of 9,11 [mu] m / ml: 21-fluoro-1-isovaleryloxy-1,4- -pregnadiene-5,20-dione are reacted with a 70% (HF) n / pyridine solution. analogous to Example 50d. The crude product is purified by chromatography on 500 g of silica gel with a methylene chloride-acetone gradient (0 - 155% acetone). Yield: 2.1 g of 9u, 21-diluoro-115-hydroxy-1Ta-isovaleryloxy-1,4-pregnadiene-5,20-dione.

Exempel 52 a)W 8,7 g 21-fluor-1?a-hydroxi-1,4,9(11)-pregnatrien-5,20- -dion och trimetylacetanhydrid omsättes såsom beskrivas i exempel 50a till 6,5 g 21-fluor-17a-trimetylacetoxi-1,4,9(11}-pregnatrien-5,20- -dion, som man omsätter med N-bromsuccinimid analogt med exempel 50b och upparbetar på brukligt sätt. Utbyte: 6,5 g 9a4brom-21-fluor~11b- -hydroxi-17a-trímetylacetoxi-1,4-pregnadien-5,20-dion. b) 6,0 g av ovanstående råprodukt omsätter man med kaliumace- tat analogt med exempel 50c och renar råprodukten genom kromatografering på 600 g kiselgel med en metylenklorid-acetonfgradiont (O - 5 % aceton,.Example 52 a) W 8.7 g of 21-fluoro-1α-hydroxy-1,4,9 (11) -pregnatriene-5,20-dione and trimethylacetanhydride are reacted as described in Example 50a to 6.5 g of 21 -fluoro-17α-trimethylacetoxy-1,4,9 (11} -pregnatriene-5,20- -dione, which is reacted with N-bromosuccinimide analogously to Example 50b and worked up in the usual manner Yield: 6.5 g of 9a4bromo- 21-fluoro-11b-hydroxy-17α-trimethyllacetoxy-1,4-pregnadiene-5,20-dione b) 6.0 g of the above crude product are reacted with potassium acetate analogously to Example 50c and the crude product is purified by chromatography on 600 g of silica gel with a methylene chloride-acetonefgradion (0 - 5% acetone ,.

Utbyte: 5,1 g 9,11ß-epoxi-21~fluor-17m-trimetylaceto:/i-1,4-pregnadien~ -5,20-dion. o) Man bringar 5,0 g 9,11ß-epoxi-21-fluor-1?a%trimetylacetoxi- -1,4-pregnadien-5,20-dion att reagera med en 70-procentig (HF)n/pyridin-¿ -lösning analogt med exempel 50d och renar råprodukten genom kromatogra~* fering på 500 g kiselgel med en metylenklorid-aceton-gradient (O - 15 3 , aceton). Utbyte: 1,9 g 9a,21-difluor-113-hydroxi-1?m-trimetylacetoxi- -1,4-pregnadien-5,20-dion.Yield: 5.1 g of 9,11β-epoxy-21-fluoro-17m-trimethylaceto: -1-1,4-pregnadiene--5,20-dione. o) 5.0 g of 9,11β-epoxy-21-fluoro-1% trimethyllacetoxy-1,4-pregnadiene-5,20-dione are reacted with a 70% (HF) n / pyridine ¿Solution analogous to Example 50d and purify the crude product by chromatography on 500 g of silica gel with a methylene chloride-acetone gradient (0 - 3, acetone). Yield: 1.9 g of 9α, 21-difluoro-113-hydroxy-1β-trimethylacetoxy-1,4-pregnadiene-5,20-dione.

Exempel 58 a) Man framställer analogt med exempel 50a av 15,4 g 21-fluor~ -1?a-hydroxi-1,4,9(11)-pregnatrienf5,20-dion och 2-fenylpropionsyra- klorid 7,0 g 21-fluor-1?a-(2-fenylpropionyloxi)-1,4,9(11)-pregnatrien- -5,20-dion, som man omsätter med Nëbromsuccinimid analogt med exempel 50b. Utbyte: 6,9 g 9a-brom-21-fluor-116-hydroxi-17a-(2-fenylpropion"l~ oxi)-1,4-pregnadien-5,20-dion. b) 6,5 g av ovanstående ràprodukt omsättes med kaliumacetat under de i exempel 50c beskrivna förhållandena. Râprodukten renas genom kromatografering på 650 g kiselgel med en metylenklorid-aceton-gradient (O ~ 5 % aceton). Utbyte: 5,8 g 9,11ß-epoxi-21-fluor-174-(2-fenylpro~ pionyloxi)-1,4-pregnadien-5,20-dion.Example 58 a) Analogously to Example 50a, 15.4 g of 21-fluoro-1α-hydroxy-1,4,9 (11) -pregnatrienf5,20-dione and 2-phenylpropionic acid chloride 7.0 g are prepared. 21-fluoro-1α- (2-phenylpropionyloxy) -1,4,9 (11) -pregnatriene-5,20-dione, which is reacted with Nebromosuccinimide analogously to Example 50b. Yield: 6.9 g of 9α-bromo-21-fluoro-116-hydroxy-17α- (2-phenylpropion "-loxy) -1,4-pregnadiene-5,20-dione. B) 6.5 g of the above The crude product is reacted with potassium acetate under the conditions described in Example 50c The crude product is purified by chromatography on 650 g of silica gel with a methylene chloride-acetone gradient (0 ~ 5% acetone) Yield: 5.8 g of 9,11ß-epoxy-21-fluorine -174- (2-phenylpropionyloxy) -1,4-pregnadiene-5,20-dione.

F* Fe feßfiifin-Q 21 c) Han omsätter 5,5 g 9,11B-epoxi-21-fluor-1?u-(2~feny1propi0- nyloxi)-1,4-pregnadien-5,20-dion med en 70-procentig (HF)n/pyridin- -lösning analogt med exempel 50d och renar räprodukten genom kromatogra~ fering på 400 g kiselgel med en metylenklorid-aceton-gradient (0 - 15 % aceton). Utbyte: 2,1 g 9a,21-dífluor-11t-hydroxi-17a-(2-íenylpropionyl- oxi)-1,4-pregnadien-5,20-dion.F * Fe feß fi i fi n-Q 21 c) He reacts 5.5 g of 9,11B-epoxy-21-fluoro-1? U- (2-phenylpropyl-nyloxy) -1,4-pregnadiene-5,20-dione with a 70% (HF) n / pyridine solution analogous to Example 50d and purify the crude product by chromatography on 400 g of silica gel with a methylene chloride-acetone gradient (0-15% acetone). Yield: 2.1 g of 9α, 21-difluoro-11β-hydroxy-17α- (2-phenylpropionyloxy) -1,4-pregnadiene-5,20-dione.

Exem el 7 a) Man framställer av 9,1 g 21-fluor-17a-hydroxí-1,4,9(11)- -pregnatríen-5,20-dion, 91 ml cyklopentansyra och 44 ml trifluorättik- syraanhydrid 5,8 g 17d-cyklopentankarbonyloxi-21-fluor-1,4,9(11)-pregn;- trien-5,20-dion analogt med exempel 56, som man omsätter med N-brom- suocinimid analogt med exempel 50b och upparbetar på brukligt sätt.Example 7 a) 9.1 g of 21-fluoro-17α-hydroxy-1,4,9 (11) -pregnatriene-5,20-dione, 91 ml of cyclopentanoic acid and 44 ml of trifluoroacetic anhydride are prepared. g 17d-cyclopentanecarbonyloxy-21-fluoro-1,4,9 (11) -pregn; triene-5,20-dione analogous to Example 56, which is reacted with N-bromosuocinimide analogously to Example 50b and worked up in the usual manner. way.

Utbyte: 6,1 g 9a-brom-17a-cyklopentankarbonyloxi-21-fluor-11ß-hydroxi- -1,4-pregnadien-5,20-dion. b) Man omsätter 6,0 g av ovanstående råprodukt med kaliumace- tat analogt med exempel 500 och renar råprodukten genom kromatografe- ring på 600 g kiselgel med en metylenklorid-aceton~gradient (0 - 5 w aoeton). Utbyte: 4,5 g 17u-cyklopentan-karbonyloxi-9,11L-epoxi-21~fluor~ -1,4-pregnadien-5,20~dion. c) Nan bringar 4,0 g 17d-cyklopentankarbonyloxi-9,115-epoxi- -21-fluor-1,4-pregnadien-5,20-dion att reagera med en 70-procentig (HF)n/pyridin-lösning analogt med exempel 50d. Man renar ràprodukten genom kromatografering på 400 g kiselgel med en metylenklorid-aceton- -gradient (O ~ 15 % aceton). Utbyte: 2,8 g 1?d-cyklopentankarbonyloxi- -9a,21-difluor-11¿-hydroxi-1,4-pregnadien-5,20-dion.Yield: 6.1 g of 9α-bromo-17α-cyclopentanecarbonyloxy-21-fluoro-11β-hydroxy-1,4-pregnadiene-5,20-dione. b) 6.0 g of the above crude product are reacted with potassium acetate analogously to Example 500 and the crude product is purified by chromatography on 600 g of silica gel with a methylene chloride-acetone gradient (0-5 w acetone). Yield: 4.5 g of 17H-cyclopentane-carbonyloxy-9,11L-epoxy-21-fluoro-1,4-pregnadiene-5,20-dione. c) Nan causes 4.0 g of 17d-cyclopentanecarbonyloxy-9,115-epoxy-21-fluoro-1,4-pregnadiene-5,20-dione to react with a 70% (HF) n / pyridine solution analogous to Example 50d. The crude product is purified by chromatography on 400 g of silica gel with a methylene chloride-acetone gradient (0 ~ 15% acetone). Yield: 2.8 g of 1,4-cyclopentanecarbonyloxy-9α, 21-difluoro-11β-hydroxy-1,4-pregnadiene-5,20-dione.

Exempel 40 a) Nan âramställer under de i exempel 56 beskrivna förhållan- dena av 9,2 g 2^~fluor-1?d-hydroxi-1,4,9(11)-pregnatrien-5,20~dion, 92 ml cyklohexanäarbonsyra och 40 ml trifluorättiksyraanhydrid 5,8 Q 17d-cyklohexankuroonyloxi~21-ïluor-1,4,9(11)-pregnatrien-5,20-dion, som man omsätter med N-bromsuccinimid analogt med exempel 50b. Utbyte: 6,1 g 9d-brom~17a~cyklohexankarbonyloxi-21~fluor-11ß-hydroxi-1,4-pregna~ dien-5,20-dion. b) Man omsätter 6,0 g av ovanstående ráprodukt med kaliumace- tat analogt med exempel 500 och renar råprodukten genom kromatografe- ring på 600 g kiselgel med en metylenklorid-aceton-gradient (O - 5 % aceton). Utbyte: 5,4 g 1?a-cyklohexankarbonyloxi-9,11ß-epoxi-21-fluor- -1,4-pregnadien-5,20-dion. c) Man bringar 5,1 g 17a-cyklohexankarbonyloxi-9,11ß-epoxi- '?80316_,-9 22 -°'I -d-fluor-'l A-pregnadien-LEO-dion att reagera med en 'ZO-procentig (HEÛn/pyridin-lösning analogt med exempel šOd och renar ráprodxikten genom lcromatografering; på 500 g; kiselgel med en metylenlcloricí-acoto1z- -gradient (0 - '15 95 aceton). Utbyte: 2,4 g 'Woz-cyklohexarikarbonyloxi- -9a,21-difluor-115-hydroxi-4,4-pregnadien-5,20-dion.Example 40 a) Nan prepares under the conditions described in Example 56 9.2 g of 2-fluoro-1,1-d-hydroxy-1,4,9 (11) -pregnatriene-5,20-dione, 92 ml cyclohexanerobonic acid and 40 ml of trifluoroacetic anhydride 5.8 17 17d-cyclohexanecuroonyloxy-21-fluoro-1,4,9 (11) -pregnatriene-5,20-dione, which are reacted with N-bromosuccinimide analogously to Example 50b. Yield: 6.1 g of 9d-bromo-17α-cyclohexanecarbonyloxy-21-fluoro-11β-hydroxy-1,4-pregna-diene-5,20-dione. b) 6.0 g of the above crude product are reacted with potassium acetate analogously to Example 500 and the crude product is purified by chromatography on 600 g of silica gel with a methylene chloride-acetone gradient (0 - 5% acetone). Yield: 5.4 g of 1α-cyclohexanecarbonyloxy-9,11β-epoxy-21-fluoro-1,4-pregnadiene-5,20-dione. c) 5.1 g of 17α-cyclohexanecarbonyloxy-9,11β-epoxy-α-β-pregnadiene-LEO-dione are reacted with a percent (HEÛn / pyridine solution analogous to Example šOd and purify the crude product by chromatography; on 500 g; silica gel with a methylene chloride-acotyl) gradient (0 - '95 95 acetone). Yield: 2.4 g 'Woz-cyclohexaricarbonyloxy- -9a, 21-difluoro-115-hydroxy-4,4-pregnadiene-5,20-dione.

Exemgel 44 'l g 'l7cc,2'l-('|-etoxibensylidendioxi)-9oc-fluor-'l'1 ß-hydroxi-'l ,L'!-- -pregnadien-5,20-dion omröres i 40 ml dimetylformamid med 4 ml trime- tylsilylfluorid 2 timmar vid rumstemperatur. Nan fäller blandningen i isvafien och upparbetar den.på brukligt sätt och indunstar i vakuum.Example 44 '1g' 17cc, 2'1- (1'-ethoxybenzylidenedioxy) -9oc-fluoro-1,1'-hydroxy-1,1'1 -pregnadiene-5,20-dione is stirred in 40 ml dimethylformamide with 4 ml of trimethylsilyl fluoride for 2 hours at room temperature. Nan precipitates the mixture in the ice and works it up in the usual way and evaporates in vacuo.

Man renar råprodukten genom kromatografering på '120 g kiselgel med en metylenklorid-aceton-gradient (O - '10 % aceton). Utbyte: 240 mg 17m- -bensoyloxi~9oc , 21 -difluor-”l 'I ß-hydroxi-“l , ÅP-pregnadien-š , EO-dion.The crude product is purified by chromatography on 120 g of silica gel with a methylene chloride-acetone gradient (0-10% acetone). Yield: 240 mg of 17m- -benzoyloxy-9oc, 21 -difluoro- "l 'I ß-hydroxy-" l, ÅP-pregnadien-š, EO-dione.

Far-maceutiska beredningar Exemgel 'I ' Sammansättning av en salva. 0,05 % 9a~fluor-11B-hydroxi-47a,21-dipropionyloxi~1,4-pregna- di en-š , 20-dion 2,50 % A lercurhexaklorfenat, mikroniserat, partikelstorlek ca 8/u Cållercuråè inregistrerat varumärke för 1-p-klorbensyl~2- -pyrrolidylmetylbensimidazol) 6,00 % Hostaphat KW 540C) (tertiär ester av o-fosforsyra och vaxalkoholtetraglylcoleter) 0,10 % sorbinsyra 40,00 ïá neutralolja (Migloyol 812®) 5,50 *šá stearylalkohol 'I ,5O % ullfett, vattenfritt DAB 6 76,36 ef, avsaltat vatten.Pharmaceutical preparations Exemgel 'I' Composition of an ointment. 0.05% 9a-fluoro-11B-hydroxy-47a, 21-dipropionyloxy-1,4-pregnadiene en-š, 20-dione 2.50% A lercur hexachlorophenate, micronized, particle size approx. 8 / u Cållercuråè registered trademark for 1-p-chlorobenzyl-2-pyrrolidylmethylbenzimidazole) 6.00% Hostaphate KW 540C) (tertiary ester of o-phosphoric acid and wax alcohol tetraglyl ether) 0.10% sorbic acid 40.00 in neutral oil (Migloyol 812®) 5.50 * in stearyl alcohol 1.5% wool fat, anhydrous DAB 6 76.36 ef, desalinated water.

Exemgel 2 Framställning av ett inhalationsmedel.Example gel 2 Preparation of an inhalant.

'I ,O00 g mikroniserad 9oc-fluor-'lflß-hydroxi-”í 701,21 -dipropionyl- oxi~1,4-pregnadien-5,20-dion (medelkornstorlek mindre än 7/u) och 59,000 g mald laktos blandas.10000 g of micronized 9OC-fluoro-1,1'-hydroxy- ", 701,21-dipropionyloxy-1,4-pregnadiene-5,20-dione (average grain size less than 7 .mu.m) and 59,000 g of ground lactose are mixed. .

För inlnalation användes en dosering av 20 mg inhalations- medel .For inhalation, a dose of 20 mg of inhalant was used.

Claims (1)

1. 23 Patentkrav Sätt att framställa 9-fluorprednisolonderivat med den allmänna form- meln I HO -~- oR 1 /f /” O i vilken R1 betecknar en alkanoylgrupp med 1-8 kolatomer eller en bensoylgrupp och X betecknar en fluoratom, en kloratom eller en alkanoylgrupp med 3-8 kolatomer, k ä n n e t e c k n a t av att man på i och för sig känt sätt a) öppnar epoxidringen i en förening med den allmänna formeln II, i vilken R1 och X betecknar detsamma som ovan O medelst fluorväte, eller b) halogenerar eller förestrar i 21-ställning ett 9~fluorderivat med den allmänna formeln III CH2OH C=0 HO _ _.OR1 III \ 7863168-9 24 i vilken R1 betecknar detsamma som ovan, eller c) för framställning av 9-fluorprednisolonderivat med den allmänna formeln I, där X betecknar en fluor- eller kloratom, SPa1tar en Or' toester med den allmänna formeln IV CH O OR IV HO _ ___0 113 i vilken R3 betecknar en väteatom, en alkylgrupp eller en cykloalkyl- grupp med upp till 7 kolatomer eller en fenylgrupp och R2 betecknar en alkylgrupp med 1-4 kolatomer, med en trimetylsilylhalogenid eller trifenylmetylhalogenid.A process for the preparation of 9-fluoroprednisolone derivatives of the general formula I HO - ~ - oR 1 / f / ”O in which R 1 represents an alkanoyl group having 1-8 carbon atoms or a benzoyl group and X represents a fluorine atom, a chlorine atom or an alkanoyl group having 3 to 8 carbon atoms, characterized in that in a manner known per se a) the epoxide ring is opened in a compound of the general formula II, in which R 1 and X represent the same as above by means of hydrogen fluoride, or b ) halogenates or esterifies in the 21-position a 9-fluorine derivative of the general formula III CH 2 OH C = O HO _ _.OR1 III \ 7863168-9 24 in which R 1 represents the same as above, or c) to prepare 9-fluoroprednisolone derivatives with the general formula I, wherein X represents a fluorine or chlorine atom, SPa1tar an Or 'toester of the general formula IV CH 3 OR IV HO - ___0 113 in which R 3 represents a hydrogen atom, an alkyl group or a cycloalkyl group having up to 7 carbon atoms or a phenyl group and R 2 represents an alkyl group of 1-4 carbon atoms, with a trimethylsilyl halide or triphenylmethyl halide.
SE7803168A 1977-03-21 1978-03-20 SET TO MAKE NEW 9-FLUORPREDNISOLOND DERIVATIVES SE431656B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2712862A DE2712862C2 (en) 1977-03-21 1977-03-21 Derivatives of 9-fluorprednisolone, process for their preparation and pharmaceuticals containing them
DE19782809732 DE2809732C2 (en) 1978-03-03 1978-03-03 Derivatives of 9-fluorprednisolone, process for their production, and pharmaceutical preparations containing these active ingredients

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SE7803168L SE7803168L (en) 1978-09-22
SE431656B true SE431656B (en) 1984-02-20

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CA (1) CA1104124A (en)
CH (1) CH638226A5 (en)
CS (1) CS202591B2 (en)
DD (1) DD134955A5 (en)
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ES (1) ES468107A1 (en)
FR (1) FR2384792A1 (en)
GB (1) GB1603281A (en)
GR (1) GR70385B (en)
IE (1) IE46584B1 (en)
IL (1) IL54308A (en)
IT (1) IT1095477B (en)
LU (1) LU79271A1 (en)
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DE2853785A1 (en) * 1978-12-11 1980-06-19 Schering Ag NEW PREDNISON DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS AND THE USE THEREOF
JPH07116215B2 (en) * 1989-04-19 1995-12-13 エスエス製薬株式会社 Novel steroid compound
JPH07213320A (en) * 1994-02-04 1995-08-15 Daiwa:Kk Bag for long sized article

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DE2055221A1 (en) * 1970-11-10 1972-05-18 Laboratorio Chimico Farmaceutico Dr. P. Blasina S.R.L., Mailand (Italien) 17-acyloxy-3-keto-pregn-4-enes prepn - by acylating 17-hydroxy steroids in presence ofstannic chloride
CH529739A (en) * 1972-02-28 1972-10-31 Sdc Steroidi Dev Co 11,16,17,21-tetrahydroxy-3,20-diketo-1,4-pregnadienes prepn - - from cpds without 16-hydroxy grp
US3832366A (en) * 1973-07-30 1974-08-27 Squibb & Sons Inc Process for preparing 21-chloro-17-acyloxy-20-ketosteroids

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ATA195978A (en) 1981-05-15
GR70385B (en) 1982-10-05
CS202591B2 (en) 1981-01-30
CH638226A5 (en) 1983-09-15
NZ186735A (en) 1980-10-24
CA1104124A (en) 1981-06-30
IT1095477B (en) 1985-08-10
IT7821364A0 (en) 1978-03-20
AU525614B2 (en) 1982-11-18
IE46584B1 (en) 1983-07-27
JPS53130651A (en) 1978-11-14
FR2384792A1 (en) 1978-10-20
IL54308A0 (en) 1978-06-15
DD134955A5 (en) 1979-04-04
IE780545L (en) 1978-09-21
LU79271A1 (en) 1978-06-29
IL54308A (en) 1984-03-30
AU3434678A (en) 1979-09-27
FR2384792B1 (en) 1980-04-04
DK126378A (en) 1978-09-22
JPS6131116B2 (en) 1986-07-17
GB1603281A (en) 1981-11-25
NO780984L (en) 1978-09-22
SE7803168L (en) 1978-09-22
RO81525A (en) 1983-04-29
NO151043C (en) 1985-01-30
ES468107A1 (en) 1979-07-01
AT365203B (en) 1981-12-28
NO151043B (en) 1984-10-22
RO81525B (en) 1983-04-30

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