NO153601B

NO153601B - DEVICE FOR CONTAINERS.

Info

Publication number: NO153601B
Application number: NO812910A
Authority: NO
Inventors: Sigvard Larsson
Original assignee: Sigvard Larsson
Priority date: 1981-08-27
Filing date: 1981-08-27
Publication date: 1986-01-13
Also published as: NO812910L; NO153601C

Description

Fremgangsmåte for fremstilling av terapeutisk virksomme 9a-klor-eller 9a-fluor-118,21-dihydroksy-168-metyl-17a-alkanoyloksy-pregna-l,4-dien-3,20-dioner. Process for the production of therapeutically effective 9a-chloro-or 9a-fluoro-118,21-dihydroxy-168-methyl-17a-alkanoyloxy-pregna-1,4-diene-3,20-diones.

Denne oppfinnelse angår fremstilling av nye steroid-forblndelser som har høy anti-inflammatorisk virkning ved topisk administrering. This invention relates to the production of new steroid mixtures which have a high anti-inflammatory effect when administered topically.

En viktig bruk av anti-inflammatoriske forbindelser er An important use of anti-inflammatory compounds is

deres anvendelse i topiske preparater for lokal behandling av betennelse, og betraktelig forskning har vært utført for å finne forbindelser som har god lokal virkning ved topisk administrering. their use in topical preparations for the local treatment of inflammation, and considerable research has been carried out to find compounds that have good local action by topical administration.

Det er et formål ved foreliggende oppfinnelse å tilveie-bringe nye steroidforbindelser som har særlig høy anti-inflammatorisk virkning ved topisk administrering. It is an aim of the present invention to provide new steroid compounds which have a particularly high anti-inflammatory effect when administered topically.

Det er funnet at visse nye 17a-monoestere som beskrives It has been found that certain new 17a-monoesters which are described

i det følgende, i alminnelighet tilveiebringer betraktelig øket in the following, in general provides considerably increased

anti-inflammatorisk virkning ved topisk anvendelse sammenlignet med nær beslektede forbindelser og/eller de tilsvarende 17a,21-dihydroksy utgangsforbindelser. Disse nye monoestere er funnet å ha anti-inflammatorisk virkning ved topisk anvendelse som over-stiger virkningen for de forbindelser som hittil har vært ansett å være de beste for topiske formål (som f.eks. bedømt ved flekk-prøven ifølge McKenzie et al. Arch. Derm., 1962, 86, 608). anti-inflammatory effect when applied topically compared to closely related compounds and/or the corresponding 17α,21-dihydroxy starting compounds. These new monoesters have been found to have anti-inflammatory action when applied topically that exceeds the action of the compounds that have hitherto been considered to be the best for topical purposes (as e.g. judged by the spot test according to McKenzie et al. Arch. Derm., 1962, 86, 608).

I henhold til foreliggende oppfinnelse tilveiebringes således forbindelser av den generelle formel: According to the present invention, compounds of the general formula are thus provided:

hvor X er fluor eller klor, og R er en alkanoylgruppe inneholdende 2 til 6 karbonatomer. where X is fluorine or chlorine, and R is an alkanoyl group containing 2 to 6 carbon atoms.

Forbindelsene som fremstilles ved fremgangsmåten ifølge oppfinnelsen, har i alminnelighet en meget høy anti-inflammatorisk virkning ved topisk administrering, og er således egnet til lokal behandling av inflammasjon. The compounds produced by the method according to the invention generally have a very high anti-inflammatory effect when administered topically, and are thus suitable for local treatment of inflammation.

Betegnelsen "alkanoylgruppe" som her anvendt i den viste betydning skal forståes å omfatte lineære og forgrenete alkanoyl-grupper og cykloalkanoylgrupper. The term "alkanoyl group" as used here in the sense shown shall be understood to include linear and branched alkanoyl groups and cycloalkanoyl groups.

Gruppen R kan f.eks. være en acetyl-, propionyl-, butyryl-, isobutyryl-, valeryl- eller cyklopentankarbonylgruppe, og X er fortrinnsvis fluor. Det foretrekkes forbindelser i hvilke gruppen R ikke inneholder mer enn 5 karbonatomer, og en forbindelse som er av særlig interesse, er hetametason-17-valerat, hvis anti-inf lammatoriske virkning er meget god (bedømt både ved flekkprøven og ved klinisk prøvning). The group R can e.g. be an acetyl, propionyl, butyryl, isobutyryl, valeryl or cyclopentanecarbonyl group, and X is preferably fluorine. Compounds in which the group R does not contain more than 5 carbon atoms are preferred, and a compound of particular interest is hetamethasone-17-valerate, whose anti-inflammatory action is very good (assessed both by the spot test and by clinical testing).

Det aktive steroid kan formuleres til et preparat som The active steroid can be formulated into a preparation which

er egnet for topisk administrering, på vanlig måte ved hjelp av ett eller flere bærestoffer. is suitable for topical administration, in the usual way by means of one or more carriers.

Mengden av det aktive steroid i preparatene vil være avhengig av den type preparat som skal anvendes, men vil i alminnelighet være innen omrade fra 0,0001 til 5 vekt-%. For de fleste typer preparater er imidlertid den anvendte mengde i alminnelighet fra 0,001 til 0,5% og fortrinnsvis 0,01 til 0,25%. The amount of the active steroid in the preparations will depend on the type of preparation to be used, but will generally be in the range from 0.0001 to 5% by weight. For most types of preparations, however, the amount used is generally from 0.001 to 0.5% and preferably 0.01 to 0.25%.

De nye 17a-monoestere fremstilles i henhold til oppfinnelsen ved hydrolyse av en tilsvarende 17a,21-orto-ester eller 17a,21-diester. Hydrolyse av den tilsvarende 17a,21-ortoester The new 17a-monoesters are produced according to the invention by hydrolysis of a corresponding 17a,21-ortho-ester or 17a,21-diester. Hydrolysis of the corresponding 17a,21-orthoester

(hvis fremstilling er beskrevet i britisk patent nr 1 043 347) (whose production is described in British patent no. 1 043 347)

gjennomføres fortrinnsvis under lempelige betingelser for å unngå at den resulterende 17a-monoester omleires til den isomere 21-monoester. De ovennevnte ortoestere er forbindelser av formelen is preferably carried out under mild conditions to avoid the resulting 17a-monoester being rearranged to the isomeric 21-monoester. The above orthoesters are compounds of the formula

hvor R er en alkylgruppe inneholdende 1-5 karbonatomer, og R*~ er f.eks. en metyl- eller etylgruppe. ;Hydrolyse av ortoesterene utføres fortrinnsvis i nærvær ;av en syrekatalysator, f.eks. en lavere alkansyre såsom eddiksyre eller propionsyre, eller en sterk mineralsyre såsom saltsyre eller svovelsyre. Konsentrasjonen av den anvendte syre varierer i henhold til dens styrke og de estere som skal fremstilles. Når det gjelder svake syrer, kan reaksjonsmediene bestå i alt vesentlig av syren, ;mens for sterke syrer og lett hydrolyserte forbindelser kan spor av syre være tilstrekkelig. Reaksjonen kan utføres i nærvær av vann og et polart oppløsningsmiddelmedium, med eller uten oppvarmning i henhold til betingelser som er nødvendig for en gitt forbindelse. Oppløsningsmidlet som kan anvendes, omfatter estere såsom etylacetat, og etere såsom dioksan og tetrahydrofuran. , Når svake syrer såsom eddiksyre eller propionsyre anvendes til hydrolysen, kan disse også tjene som oppløsningsmiddel. Tilstedeværelsen av noe vann er nødvendig, men det kan være i meget små mengder. ;Reaksjonen etterfølges av tynnskikts- eller papirkromato-grafering av prøver av reaksjonsblandingen ettersom reaksjonen skrider frem. ;17a-monoesterene kan også fremstilles ved hydrolyse av 17a,21-diesterene, og denne fremstillingsmåte er i alminnelighet mer egnet for fremstilling av estere med større acylradikaler enn ;for fremstilling av de som har mindre acylradikaler. ;Denne reaksjon utføres fortrinnsvis under sure betingelser, f.eks. ved å anvende en sterk syre såsom saltsyre eller perklorsyre i et polart oppløsningsmiddel, f.eks. en lavere alkanol såsom metanol eller etanol. ;17,21-diesterene som anvendes som utgangsmateriale ved fremgangsmåten ifølge oppfinnelsen, kan ha alkanoyl-, aroyl- eller aralkanoylgrupper i 21-stillingen, men fortrinnsvis en lavere alkanoylgruppe inneholdende 2-5 karbonatomer. Disse diestere kan fremstilles ved enhver hensiktsmessig metode, f.eks. ved de metoder som er beskrevet i britisk patent 1 047 519. ;Den anti-inflammatoriske aktivitet ved topisk administrering av steroidforbindelsene ble undersøkt i den Farmakologiske avdeling av Glaxo Research Limited. Undersøkelsen ble utført på frivillige mennesker ved den såkalte vasokonstriktormåling av McKenzie et al., beskrevet i Arch. Derm. 1962, 86 608 og mer fullstendig beskrevet i Arch. Derm., 1964 89 741. De to undersøkelsesmetoder som ble ;anvendt, var (a) en enkel prøvning og (b) en flertallig prøvning, ;idet forbindelsen "Synalar" (Fluocinolon-16,17-acetonid) ble anvendt som standard i hvert tilfelle og ble gitt en vilkårlig aktivitet på 100. ;Forbindelsene merket med en enkel x i tabellen ble kun underkastet enkel prøvning, mens alle andre ble prøvet i henhold til den flertallige prøvning. De metoder som ble fulgt ved prøvene, ;er gitt i det følgende: ;( a) Enkel prøvning ;Fem steder for steroidpåføring ble avmerket på innsiden ;av underarmen for en gruppe på ti friske frivillige mennesker av begge kjønn. Fem doser av standard og fem doser av prøvesteroid i 0,2 ml alkohol ble anbragt på disse steder på en slik måte at hver dose ble gitt til hvert individ, men på forskjellig sted. Forholdet mellom suksessive doser av samme steroid var 3:1. ;( b) Flertallig prøvning ;Seks steder ble avmerket på hver underarm hos tolv individer av begge kjønn. Fire doser av standard og enten fire doser av to prøvesteroider eller to doser av fire prøvesteroider, alle i 0,02 ml alkohol ble anbragt på disse steder. Så med den enkle prøve ble hver dose gitt til hvert individ, men på forskjellig sted. Forholdet mellom suksessive doser av samme steroid var 4:1. ;Ved alle målinger ble hver steroid-dose påført så jevnt ;som mulig på et 2,8 m 2 sirkelformet område av huden. Da oppløsnings-midlet var inndampet, ble underarmene fullstendig innesluttet i polyten-rør som ble festet i begge ender med heftplaster som dannet et tett omslag. De tette omslag ble fjernet efter 16 timer, og en time senere ble armene undersøkt for å se om det var noen vasokon-strikte flekker. ;Noen av vasokonstriktor-aktivitetene ble opprinnelig oppnådd fra de kombinerte resultater av to målinger. I disse tilfeller er den beste måling valgt, idet man som indikasjon anvender helningen og lineæriteten av dose-aktivitetskurvene for både standard og prøve. Vasokonstriktoraktiviteten ble derefter beregnet på nytt under anvendelse av resultatene fra bare den ene prøven. Hvor slik ny beregning er utført, er aktivitetene merket med to kryss. Alle aktiviteter som er angitt i tabellen, er derfor satt fra én prøve, som enten er oppnådd ved enkel eller flertallig prøvning. ;McKenzie-prøven som anvendes ved undersøkelsene, antaes ;å være en pålitelig indikasjon på den anti-inflammatoriske aktivitet for et gitt steroid ved topisk anvendelse. Resultatene i tabellen representerer resultater som ble oppnådd ved helt parallelle målinger og kan derfor sammenlignes direkte. ;;Fremgangsmåten ifølge oppfinnelsen beskrives nærmere i de følgende eksempler. ;EKSEMPEL 1 ;17a-acetoksy-9a-f luor-HB, 21-dihydroksy-16B-metyl-pregna-l, 4-dien-3,20-dion (Betametason-17-acetat) ;9a-fluor-116-hydroksy-16B-metyl-17a,21-(1'-etoksy-1'-metylmetylendioksy)pregna-1,4-dien-3,20-dion (2 g) ble oppløst i eddiksyre (22 ml), og vann (2 ml) ble tilsatt. Efterat oppløsningen var holdt i 30 minutter ved romtemperatur, ble vann tilsatt, og det krystallinske, faste stoff ble oppsamlet. To krystalliseringer fra aceton-petroleter ga betametason 17-acetat (1,49 g), sm.p. 240 - 241°C (spaltning), [o]D + 85,6° (c 1,26, dioksan) , A^j^ 239 mu ( £ 15.910) (Funnet: C, 66,7; H, 7,3. C24H31F06 krever C, 66,3; ;H, 7,2%) . ;EKSEMPEL 2 ;9a-f luor-HB, 21-dihydroksy-166-metyl-17a-propionyloksypregna-l,4-dien-3,20-dion (Betametason 17-propionat) ;En oppløsning av 9a-fluor-llB-hydroksy-166-metyl-17a,21-(1<1>etyl-1'-etoksymetylendioksy)pregna-1,4-dien-3,20-dion (538 mg) ;i eddiksyre (20 ml), inneholdende 2 dråper vann, fikk stå ved romtemperatur i 5 timer. Fortynning av blandingen med vann ga et nytt, fast stoff (457 mg), som, efter å være filtrert fra og tørket, ;ble omkrystallisert fra aceton for å gi 9a-fluor-HB, 21-dihydroksy-16B-metyl-17ct-propionyloksypregna-l,4-dien-3,20-dion (361 mg) ;sm.p. 230 - 235°C [a]D + 82,0° (c, 1,0, dioksan), Å^aks <2>38 T ;(£ 15.400). ;(Funnet: C, 66,8; G, 7,2; F, 4,1 C25H33F06 krever C, 66,9; ;H, 7,4; F, 4,2%). ;EKSEMPEL 3 ;17a-butyryloksy-9a-f luor-HB, 21-dihydroksy-16B-metylpregna-l, 4-dien-3,20-dion (Betametason 17-butyrat) ;En oppløsning av 9a-fluor-llB-hydroksy-16B-metyl-17a,21-(1'-propyl-1<1->metoksymetylendioksy)pregna-1,4-dien-3,20-dion (587 mg) ;i eddiksyre (5 ml) inneholdende vann (0,2 ml) fikk stå ved romtemperatur i 2 timer og ble derefter fortynnet med isvann. Det hvite, faste materiale (523 mg) som ble utfelt, ble fjernet ved filtrering, tørket og omkrystallisert fra aceton-petroleter for å gi 17a-butyryloksy-9a-f luor-HB, 21-dihydroksy-16B-metylpregna-l, 4-dien- ;3,20-dion (455 mg) sm.p. 195°. [a]D + 79° (c 1,0, dioksan), ;^EtOH 238 _ 239 q 16.050). ;'maks. / 0;(Funnet: C, 67,4; H, 7,5; F, 4,0 C26H35F06 krever C, 67,5; H, 7,6; ;F, 4,1%). ;EKSEMPEL 4 ;9a-f luor-116, 21-dihydroksy-16B-metyl-17a-valeryloksy-pregna-l, 4-dien-3,20-dion (Betametason 17-valerat) 1) 9a-fluor-116-hydroksy-166-metyl-17a,21-(1'-butyl-1'-metoksymetylendioksy)pregna-1,4-dien-3,20-dion (1 g) ble oppløst i eddiksyre (20 ml) inneholdende noen få dråper vann, og blandingen fikk stå natten over ved romtemperatur. Fortynning av oppløsningen med vann (100 ml) ga et fast stoff som ble fjernet ved filtrering. ;Det vandige filtrat ble ekstrahert med eter, eterekstraktet ble vasket med fortynnet natriumkarbonatoppløsning og vann, tørket over magnesiumsulfat og inndampet for å gi et krystallinsk, fast stoff som ble kombinert med det faste stoff som var fjernet tidligere. Omkrystallisering fra acetonpetroleter ga 9a-fluor-HB, 21-dihydroksy-16B-metyl«*17a-valeryloksy-pregna-l, 4-dien-3 , 20-dion (529 mg) som nåler med sm.p. 183 - 184°, [a]D + 77° (c 1,0 dioksan)A^£g 239 mu (£ 15.920). where R is an alkyl group containing 1-5 carbon atoms, and R*~ is e.g. a methyl or ethyl group. Hydrolysis of the orthoesters is preferably carried out in the presence of an acid catalyst, e.g. a lower alkanoic acid such as acetic or propionic acid, or a strong mineral acid such as hydrochloric or sulfuric acid. The concentration of the acid used varies according to its strength and the esters to be produced. In the case of weak acids, the reaction media can essentially consist of the acid, while for strong acids and easily hydrolysed compounds traces of acid may be sufficient. The reaction can be carried out in the presence of water and a polar solvent medium, with or without heating according to conditions required for a given compound. The solvent that can be used includes esters such as ethyl acetate, and ethers such as dioxane and tetrahydrofuran. , When weak acids such as acetic acid or propionic acid are used for the hydrolysis, these can also serve as solvents. The presence of some water is necessary, but it may be in very small amounts. ;The reaction is followed by thin layer or paper chromatography of samples of the reaction mixture as the reaction progresses. The 17a-monoesters can also be prepared by hydrolysis of the 17a,21-diesters, and this method of preparation is generally more suitable for the preparation of esters with larger acyl radicals than for the preparation of those with smaller acyl radicals. ;This reaction is preferably carried out under acidic conditions, e.g. by using a strong acid such as hydrochloric acid or perchloric acid in a polar solvent, e.g. a lower alkanol such as methanol or ethanol. The 17,21-diesters used as starting material in the process according to the invention can have alkanoyl, aroyl or aralkanoyl groups in the 21-position, but preferably a lower alkanoyl group containing 2-5 carbon atoms. These diesters can be prepared by any suitable method, e.g. by the methods described in British patent 1 047 519. ;The anti-inflammatory activity of topical administration of the steroid compounds was investigated in the Pharmacological Department of Glaxo Research Limited. The investigation was carried out on human volunteers by the so-called vasoconstrictor measurement by McKenzie et al., described in Arch. Derm. 1962, 86,608 and more fully described in Arch. Derm., 1964 89 741. The two test methods used were (a) a single test and (b) a multiple test, the compound "Synalar" (Fluocinolone-16,17-acetonide) being used as a standard in each case and was given an arbitrary activity of 100. ;The compounds marked with a single x in the table were subjected to single test only, while all others were tested according to the majority test. The methods followed for the tests are given below: (a) Simple test Five steroid application sites were marked on the inside of the forearm of a group of ten healthy volunteers of both sexes. Five doses of the standard and five doses of the test steroid in 0.2 ml of alcohol were placed at these sites in such a way that each dose was given to each individual, but at a different site. The ratio between successive doses of the same steroid was 3:1. ;( b) Multiple testing ;Six sites were marked on each forearm in twelve individuals of both sexes. Four doses of standard and either four doses of two test steroids or two doses of four test steroids, all in 0.02 ml of alcohol were placed at these sites. So with the simple test, each dose was given to each individual, but at a different location. The ratio between successive doses of the same steroid was 4:1. In all measurements, each steroid dose was applied as evenly as possible on a 2.8 m 2 circular area of the skin. When the solvent had evaporated, the forearms were completely enclosed in polythene tubes which were fixed at both ends with adhesive plasters which formed a tight wrap. The tight wraps were removed after 16 hours, and one hour later the arms were examined to see if there were any vasoconstrictive spots. ;Some of the vasoconstrictor activities were originally obtained from the combined results of two measurements. In these cases, the best measurement is selected, using as an indication the slope and linearity of the dose-activity curves for both standard and sample. The vasoconstrictor activity was then recalculated using the results from only one sample. Where such a new calculation has been carried out, the activities are marked with two crosses. All activities listed in the table are therefore set from one sample, which has either been obtained by simple or multiple testing. The McKenzie test used in the investigations is believed to be a reliable indication of the anti-inflammatory activity of a given steroid when applied topically. The results in the table represent results that were obtained by completely parallel measurements and can therefore be compared directly. The method according to the invention is described in more detail in the following examples. ;EXAMPLE 1 ;17a-acetoxy-9a-fluoro-HB, 21-dihydroxy-16B-methyl-pregna-1,4-diene-3,20-dione (Betamethasone-17-acetate) ;9a-fluoro-116- hydroxy-16B-methyl-17a,21-(1'-ethoxy-1'-methylmethylenedioxy)pregna-1,4-diene-3,20-dione (2 g) was dissolved in acetic acid (22 ml), and water ( 2 ml) was added. After the solution was held for 30 minutes at room temperature, water was added and the crystalline solid was collected. Two crystallizations from acetone-petroleum ether gave betamethasone 17-acetate (1.49 g), m.p. 240 - 241°C (decomposition), [o]D + 85.6° (c 1.26, dioxane) , A^j^ 239 mu ( £ 15,910) (Found: C, 66.7; H, 7, 3. C24H31F06 requires C, 66.3;;H, 7.2%) . ;EXAMPLE 2 ;9a-fluoro-HB, 21-dihydroxy-166-methyl-17a-propionyloxypregna-1,4-diene-3,20-dione (Betamethasone 17-propionate) ;A solution of 9a-fluoro-llB- hydroxy-166-methyl-17a,21-(1<1>ethyl-1'-ethoxymethylenedioxy)pregna-1,4-diene-3,20-dione (538 mg); in acetic acid (20 ml), containing 2 drops water, allowed to stand at room temperature for 5 hours. Dilution of the mixture with water gave a new solid (457 mg), which, after being filtered off and dried, was recrystallized from acetone to give 9α-fluoro-HB, 21-dihydroxy-16B-methyl-17ct- propionyloxypregna-1,4-diene-3,20-dione (361 mg); m.p. 230 - 235°C [a]D + 82.0° (c, 1.0, dioxane), Å^aks <2>38 T ;(£15,400). ;(Found: C, 66.8; G, 7.2; F, 4.1 C25H33F06 requires C, 66.9; ;H, 7.4; F, 4.2%). ;EXAMPLE 3 ;17a-butyryloxy-9a-fluoro-HB, 21-dihydroxy-16B-methylpregna-1,4-dien-3,20-dione (Betamethasone 17-butyrate) ;A solution of 9a-fluoro-llB- hydroxy-16B-methyl-17a,21-(1'-propyl-1<1->methoxymethylenedioxy)pregna-1,4-diene-3,20-dione (587 mg); in acetic acid (5 ml) containing water ( 0.2 ml) was allowed to stand at room temperature for 2 hours and was then diluted with ice water. The white solid (523 mg) which precipitated was removed by filtration, dried and recrystallized from acetone-petroleum ether to give 17α-butyryloxy-9α-fluoro-HB, 21-dihydroxy-16B-methylpregna-1, 4 -diene-;3,20-dione (455 mg) m.p. 195°. [α]D + 79° (c 1.0, dioxane), ;^EtOH 238 _ 239 q 16.050). ;'max. / 0;(Found: C, 67.4; H, 7.5; F, 4.0 C26H35F06 requires C, 67.5; H, 7.6; ;F, 4.1%). ;EXAMPLE 4 ;9a-fluoro-116, 21-dihydroxy-16B-methyl-17a-valeryloxy-pregna-1,4-diene-3,20-dione (Betamethasone 17-valerate) 1) 9a-fluoro-116- Hydroxy-166-methyl-17α,21-(1'-butyl-1'-methoxymethylenedioxy)pregna-1,4-diene-3,20-dione (1 g) was dissolved in acetic acid (20 mL) containing a few drops water, and the mixture was allowed to stand overnight at room temperature. Dilution of the solution with water (100 mL) gave a solid which was removed by filtration. The aqueous filtrate was extracted with ether, the ether extract was washed with dilute sodium carbonate solution and water, dried over magnesium sulfate and evaporated to give a crystalline solid which was combined with the solid previously removed. Recrystallization from acetone petroleum ether gave 9a-fluoro-HB, 21-dihydroxy-16B-methyl«*17a-valeryloxy-pregna-1,4-diene-3,20-dione (529 mg) as needles m.p. 183 - 184°, [α]D + 77° (c 1.0 dioxane)A^£g 239 mu (£ 15,920).

(Funnet: C,67,7; H, 7,8; F, 3,<5.> C27H37F06 krever C, 68,05; (Found: C, 67.7; H, 7.8; F, 3.<5.> C27H37F06 requires C, 68.05;

H, 7,8; F, 4,0%). H, 7.8; F, 4.0%).

2) En suspensjon av 9a-f luor-HB, 17a, 21-trihydroksy-16B-metylpregna-1,4-dien-3,20-dion (2 g) i natrium-tørket benzen (500 2) A suspension of 9a-fluoro-HB, 17a, 21-trihydroxy-16B-methylpregna-1,4-diene-3,20-dione (2 g) in sodium-dried benzene (500

ml) ble destillert kraftig i noen få minutter, toluen-p-sulfonsyre-monohydrat (30 mg) og metylortovalerat (5 ml) ble tilsatt, og destillering ble fortsatt i 10 minutter. Blandingen ble derefter ~' kokt under tilbakeløpskjøling i 1,5 time, hvorefter uomsatt betametasonalkohol (400 mg) ble fjernet ved filtrering. Benzenoppløs-ningen ble behandlet med fast natriumbikarbonat og noen få dråper pyridin, filtrert og inndampet til tørrhet ved ca. 50°C. • Residuet i eter ble filtrert gjennom grad III basisk aluminiumoksyd (20 g) ml) was vigorously distilled for a few minutes, toluene-p-sulfonic acid monohydrate (30 mg) and methyl orthovalerate (5 ml) were added, and distillation was continued for 10 minutes. The mixture was then refluxed for 1.5 hours, after which unreacted betamethasone alcohol (400 mg) was removed by filtration. The benzene solution was treated with solid sodium bicarbonate and a few drops of pyridine, filtered and evaporated to dryness at approx. 50°C. • The residue in ether was filtered through grade III basic alumina (20 g)

for å fjerne spor av uomsatt betametasonalkohol, eteren ble fjernet i vakuum, og residuet av rå betametason 17,21-metylortovalerat ble behandlet med eddiksyre (20 ml) og noen få dråper vann, og fikk stå natten over ved romtemperatur. Eddiksyreoppløsningen ble tømt i vann (100 ml) og ekstrahert med kloroform. Kloroformekstraktene to remove traces of unreacted betamethasone alcohol, the ether was removed in vacuo, and the residue of crude betamethasone 17,21-methyl orthovalerate was treated with acetic acid (20 mL) and a few drops of water, and allowed to stand overnight at room temperature. The acetic acid solution was poured into water (100 mL) and extracted with chloroform. The chloroform extracts

ble vasket efter tur med vann, mettet natriumbikarbonatoppløsning og was washed in turn with water, saturated sodium bicarbonate solution and

vann, tørket og inndampet i vakuum. Den gjenværende gummi ble malt eller gnidd med eter, og et hvitt, krystallinsk, fast stoff (1,16 g) ble isolert ved filtrering. Omkrystallisering fra eter (inneholdende en liten mengde aceton) - petroleter ga 9a-fluor-116,21-dihydroksy-16B-metyl-17a-valeryloksypregna-l,4-dien-3,20-dion (871. mg) som fine nåler. water, dried and evaporated in vacuo. The remaining gum was ground or triturated with ether, and a white crystalline solid (1.16 g) was isolated by filtration. Recrystallization from ether (containing a small amount of acetone) - petroleum ether gave 9α-fluoro-116,21-dihydroxy-16B-methyl-17α-valeryloxypregna-1,4-diene-3,20-dione (871. mg) as fine needles .

EKSEMPEL 5 EXAMPLE 5

9a-fluor-118,21-dihydroksy-17a-isobutyryloksy-16B-metylpregna-1,4-dien-3,20-dion (Betametason 17-isobutyrat) 9a-fluoro-118,21-dihydroxy-17a-isobutyryloxy-16B-methylpregna-1,4-diene-3,20-dione (Betamethasone 17-isobutyrate)

En oppløsning av betametason (1 g) i dioksan (40 ml) A solution of betamethasone (1 g) in dioxane (40 ml)

ble behandlet med toluen-p-sulfonsyre-monohydrat (50 mg) og metyl-ortoisobutyrat (2,0 ml) ved romtemperatur i 10 minutter. Reaksjonsblandingen ble hellet i fortynnet natriumbikarbonat (400 ml) og det utfelte betametason-ortoisobutyrat ble isolert ved filtrering. Dette materiale ble behandlet med eddiksyre (20 ml) inneholdende was treated with toluene p-sulfonic acid monohydrate (50 mg) and methyl orthoisobutyrate (2.0 ml) at room temperature for 10 minutes. The reaction mixture was poured into dilute sodium bicarbonate (400 mL) and the precipitated betamethasone orthoisobutyrate was isolated by filtration. This material was treated with acetic acid (20 ml) containing

noen få dråper vann, ved romtemperatur i 10 minutter, og ble derefter tømt i vann (400 ml). Det utfelte materiale ble filtrert fra, opp-løst i eter, og tørket over magnesiumsulfat. Residuet som var igjen efter at eteren var fjernet, ble krystallisert to ganger fra en blanding av eter, inneholdende en liten mengde aceton, og petroleum for å gi betametason-17-isobutyrat (186 mg) som staver, sm.p. 248° a few drops of water, at room temperature for 10 minutes, and then poured into water (400 ml). The precipitated material was filtered off, dissolved in ether and dried over magnesium sulfate. The residue remaining after the ether was removed was crystallized twice from a mixture of ether, containing a small amount of acetone, and petroleum to give betamethasone-17-isobutyrate (186 mg) as spelled, m.p. 248°

(spaltning), [a<]>D + 79,7° (c 1,0 dioksan), Amaks 237 " 239 T (decomposition), [a<]>D + 79.7° (c 1.0 dioxane), Amax 237 " 239 T

(£ 15.950), (£15,950),

(Funnet: C, 67,75; H, 7,4. C26H35F06 krever C, 67,55; H, 7,65%). (Found: C, 67.75; H, 7.4. C26H35F06 requires C, 67.55; H, 7.65%).

EKSEMPEL 6 EXAMPLE 6

9a-f luor-HB, 21-dihydroksy-17a-isovaleryloksy-166-metylpregna-l,4-dien-3,20-dion (Betametason 17-isovalerat) 9a-fluoro-HB, 21-dihydroxy-17a-isovaleryloxy-166-methylpregna-1,4-diene-3,20-dione (Betamethasone 17-isovalerate)

Betametason (2 g) ble behandlet med metyl-ortoisovalerat (4,0 ml) og mellomproduktet betametason-ortoisovalerat ble omleiret med vandig eddiksyre som beskrevet i eksempel 5 for å gi betametason-17-isovalerat (361 mg) som nåler, sm.p. 220°, [a]D + 76,0° Betamethasone (2 g) was treated with methyl orthoisovalerate (4.0 mL) and the betamethasone orthoisovalerate intermediate was rearranged with aqueous acetic acid as described in Example 5 to give betamethasone 17-isovalerate (361 mg) as needles, m.p. . 220°, [a]D + 76.0°

(c 0,93 dioksan) , Ama"ks 238 " 239 T (^ 15-68°) • (c 0.93 dioxane) , Ama"ks 238 " 239 T (^ 15-68°) •

(Funnet C, 68,3; H, 8,2, C27H3?F06 krever C, 68,05; H, 7,8%). (Found C, 68.3; H, 8.2, C27H3?F06 requires C, 68.05; H, 7.8%).

EKSEMPEL 7 EXAMPLE 7

9a-fluor-17a-heksanoyloksy-116,21-dihydroksy-16B-metylpregna-l,4-dien-3,20-dion (Betametason 17-heksanoat) 9a-fluoro-17a-hexanoyloxy-116,21-dihydroxy-16B-methylpregna-1,4-diene-3,20-dione (Betamethasone 17-hexanoate)

Metylortoheksanoat (0,6 ml) ble satt til en oppløsning av betametason (500 mg) i dioksan (20 ml) inneholdende toluen-p-sulfonsyre (5 mg). Efter 20 minutter ved romtemperatur ble blandingen tømt i fortynnet natriumbikarbonatoppløsning, og det utfelte, faste stoff ble filtrert fra og vasket omhyggelig med vann. Omkrystallisering fra acetonpetroleter ga betametason-17,21-metyl-orto-heksanoat (424 mg), sm.p. 147 - 149°, [ a]^ + 68,1° (c 0,93 dioksan), ^maks 237 " 238 T ^ 16.340). Methyl orthohexanoate (0.6 mL) was added to a solution of betamethasone (500 mg) in dioxane (20 mL) containing toluene-p-sulfonic acid (5 mg). After 20 minutes at room temperature, the mixture was poured into dilute sodium bicarbonate solution and the precipitated solid was filtered off and washed thoroughly with water. Recrystallization from acetone petroleum ether gave betamethasone 17,21-methyl-ortho-hexanoate (424 mg), m.p. 147 - 149°, [ a]^ + 68.1° (c 0.93 dioxane), ^max 237 " 238 T ^ 16.340).

(Funnet: C, 68,75; H, 8,4<5.> C2gH41F06 krever C, 69,05; H, 8,2%). (Found: C, 68.75; H, 8.4<5.> C2gH41F06 requires C, 69.05; H, 8.2%).

Den ovennevnte ortoester (295 mg) ble oppløst i eddiksyre The above orthoester (295 mg) was dissolved in acetic acid

(5 ml) inneholdende vann (0,11 ml), og oppløsningen ble holdt ved romtemperatur i 30 minutter. Fortynning med vann og omkrystallisering av det utfelte, faste stoff fra aceton-petroleter ga betametason-17-heksanoat (193 mg), sm.p. 166 - 169°, [a]D + 69,2 (c 0,9 dioksan), Amaks T (i 16•00°)• (5 mL) containing water (0.11 mL), and the solution was kept at room temperature for 30 minutes. Dilution with water and recrystallization of the precipitated solid from acetone-petroleum ether gave betamethasone 17-hexanoate (193 mg), m.p. 166 - 169°, [a]D + 69.2 (c 0.9 dioxane), Amax T (i 16•00°)•

(Funnet: C, 68,25; H, 7,95; C28H39F06 krever C' 68,55; H, 8,0%). (Found: C, 68.25; H, 7.95; C28H39F06 requires C' 68.55; H, 8.0%).

EKSEMPEL 8 EXAMPLE 8

17a-cyklopentankarbonyloksy-9a-fluor-116,21-dihydroksy-16B-metyl-pregna-1,4-dien-3,20-dion (Betametason 17-cyklopentankarboksylat) 17a-cyclopentanecarbonyloxy-9a-fluoro-116,21-dihydroxy-16B-methyl-pregna-1,4-diene-3,20-dione (Betamethasone 17-cyclopentanecarboxylate)

Betametason-17,21-metyl-ortocyklopentankarboksylat Betamethasone-17,21-methyl-orthocyclopentanecarboxylate

(400 mg) ble oppløst i eddiksyre (5 ml)inneholdende vann (0,1 ml), (400 mg) was dissolved in acetic acid (5 ml) containing water (0.1 ml),

og oppløsningen fikk stå ved romtemperatur i 25 minutter. Fortynning med vann og omkrystallisering av det utfelte, faste stoff fra aceton-petroleter ga betametason-17-cyklopentankarboksylat and the solution was allowed to stand at room temperature for 25 minutes. Dilution with water and recrystallization of the precipitated solid from acetone-petroleum ether gave betamethasone-17-cyclopentanecarboxylate

(233 mg), sm.p. 227,5 - 229,5° [a],D + 72,3° (c 0,95 i dioksan), ^maks. 237" 238 T (£ 16-l0°)-(233 mg), m.p. 227.5 - 229.5° [a],D + 72.3° (c 0.95 in dioxane), ^max. 237" 238 T (£ 16-l0°)-

(Funnet: C, 68,75; H, 7,7, C28H3?F06 krever C, 68,85; H, 7,65%). (Found: C, 68.75; H, 7.7, C28H3?F06 requires C, 68.85; H, 7.65%).

EKSEMPEL 9 EXAMPLE 9

9a-fluor-116,21-dihydroksy-166-metyl-17a-valeryloksy-pregna-l,4-dien-3,20-dion (Betametason 17-valerat) 9a-fluoro-116,21-dihydroxy-166-methyl-17a-valeryloxy-pregna-1,4-diene-3,20-dione (Betamethasone 17-valerate)

Betametasonalkohol (12,1 g) ble suspendert ved omrøring Betamethasone alcohol (12.1 g) was suspended by stirring

i etylacetat (242 ml). Toluen-p-sulfonsyre-monohydrat (0,66 g) in ethyl acetate (242 mL). Toluene p-sulfonic acid monohydrate (0.66 g)

og metyl-ortovalerat (11 ml) ble tilsatt. Fullstendig oppløsning and methyl orthovalerate (11 mL) was added. Complete resolution

fant sted ved svak oppvarmning. Oppløsningen ble derefter behandlet med 2N vandig svovelsyre (2,5 ml) ved romtemperatur i 15 minutter før vasking med mettet natriumbikarbonatoppløsning (150 ml) og vann (150 ml). Den organiske fase ble tørket over vannfritt magnesiumsulfat, filtrert og inndampet til tørrhet under redusert trykk. took place on weak heating. The solution was then treated with 2N aqueous sulfuric acid (2.5 mL) at room temperature for 15 minutes before washing with saturated sodium bicarbonate solution (150 mL) and water (150 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure.

Det rå betametason-17-valerat ble oppløst ved omrøring ved tilbakeløpstemperatur i aceton (30 ml); 80 - 100 petroleter (100 ml) ble tilsatt langsomt før blandingen fikk avkjøles ved romtemperatur, produktet ble oppsamlet ved filtrering, vasket ved fortrengning med 10% aceton-bensin (25 ml) og tørket i vakuum ved 40°C for å gi et hvitt, krystallinsk, fast stoff, 12,1 g (81,5%), sm.p. 180 - 182°, [a]D + 75,8° (c 1,0 aceton). The crude betamethasone-17-valerate was dissolved by stirring at reflux temperature in acetone (30 mL); 80-100 petroleum ether (100 ml) was added slowly before the mixture was allowed to cool to room temperature, the product was collected by filtration, washed by displacement with 10% acetone-petrol (25 ml) and dried in vacuo at 40°C to give a white , crystalline solid, 12.1 g (81.5%), m.p. 180 - 182°, [α]D + 75.8° (c 1.0 acetone).

EKSEMPEL 10 EXAMPLE 10

9a-fluor-116, 21-dihydroksy-166-metyl-17ct-valeryloksy-pregna-l, 4-dien-3,20-dion (Betametason 17-valerat) 9α-fluoro-116, 21-dihydroxy-166-methyl-17ct-valeryloxy-pregna-1, 4-diene-3,20-dione (Betamethasone 17-valerate)

Betametason-17,21-ortovalerat som var fremstilt fra betametasonalkohol (200 g), ble oppløst i aceton (1,0 1), og vann (300 ml) ble tilsatt, fulgt 2N vandig svovelsyre (30 ml) og omrørt ved romtemperatur i 15 minutter, vann (1,0 1) ble tilsatt og blandingen ble omrørt inntil krystallisering fant sted, og mer vann (5,0 1) ble tilsatt. Blandingen ble omrørt ved romtemperatur i 20 minutter før produktet ble oppsamlet ved filtrering og vasket med vann. Betamethasone 17,21-orthovalerate prepared from betamethasone alcohol (200 g) was dissolved in acetone (1.0 L), and water (300 mL) was added, followed by 2N aqueous sulfuric acid (30 mL) and stirred at room temperature for 15 minutes, water (1.0 L) was added and the mixture was stirred until crystallization occurred, and more water (5.0 L) was added. The mixture was stirred at room temperature for 20 minutes before the product was collected by filtration and washed with water.

Den fuktige kake ble oppløst i aceton (1,5 1) og omrørt med trekull (10 g) ved romtemperatur i 1 time. Trekullet ble fjernet ved filtrering gjennom et kiselgurlag og vasket med aceton (50 ml). Til det omrørte filtrat ble det langsomt tilsatt destillert vann (5,0 1). Blandingen ble omrørt i 30 minutter før produktet ble oppsamlet ved filtrering, vasket med destillert vann (1,5 1) og tørket i vakuum ved 40°C for å gi betametason-17-valerat som et hvitaktig, krystallinsk, fast stoff 222 g (91,4%), sm.p. The moist cake was dissolved in acetone (1.5 L) and stirred with charcoal (10 g) at room temperature for 1 hour. The charcoal was removed by filtration through a pad of diatomaceous earth and washed with acetone (50 mL). Distilled water (5.0 1) was slowly added to the stirred filtrate. The mixture was stirred for 30 minutes before the product was collected by filtration, washed with distilled water (1.5 L) and dried in vacuo at 40°C to give betamethasone-17-valerate as a whitish crystalline solid 222 g ( 91.4%), m.p.

188 - 190°, [a]D + 78,6° (c 1,0 aceton). 188 - 190°, [α]D + 78.6° (c 1.0 acetone).

EKSEMPEL 11 EXAMPLE 11

9a-fluor-116,21-dihydroksy-16B-metyl-17a-valeryloksy-pregna-1,4-dien-3,20-dion (Betametason-17-valerat) 9a-fluoro-116,21-dihydroxy-16B-methyl-17a-valeryloxy-pregna-1,4-diene-3,20-dione (Betamethasone-17-valerate)

9a-fluor-116-hydroksy-166-metyl-17a,21-divaleryloksy- 9a-fluoro-116-hydroxy-166-methyl-17a,21-divaleryloxy-

pregna-1,4-dien-3,20-dion (514 mg) ble oppløst i metanol (30 ml), pregna-1,4-diene-3,20-dione (514 mg) was dissolved in methanol (30 mL),

og vandig perklorsyre (72%, 2ml) ble tilsatt. Oppløsningen fikk stå ved romtemperatur i 5 timer, og ble derefter tømt i koldt vann. Den utfelte blanding (415 mg) av 17-mono- og 17,21-diester ble oppsamlet og kromatografert på aluminiumoksyd (12 g). Eluering med etylacetat-benzen (1:9 og 1:3) ga, efter krystallisering fra eter, 9a-fluor-HB,21-dihydroksy-16B-metyl-17a-valeryloksypregna-l,4-dien-3,20-dion (111 mg), sm.p. 177 - 178°C (spaltning), [a]D + 76,4° and aqueous perchloric acid (72%, 2ml) was added. The solution was allowed to stand at room temperature for 5 hours, and was then emptied into cold water. The precipitated mixture (415 mg) of 17-mono- and 17,21-diester was collected and chromatographed on alumina (12 g). Elution with ethyl acetate-benzene (1:9 and 1:3) gave, after crystallization from ether, 9α-fluoro-HB,21-dihydroxy-16B-methyl-17α-valeryloxypregna-1,4-diene-3,20-dione (111 mg), m.p. 177 - 178°C (decomposition), [α]D + 76.4°

(c 1,1 dioksan). (c 1,1 dioxane).

EKSEMPEL 12 EXAMPLE 12

9a-klor-llB,21-dihydroksy-16B-metyl-17a-propionyloksy-pregna-l,4-dien-3,20-dion 9a-chloro-11B,21-dihydroxy-16B-methyl-17a-propionyloxy-pregna-1,4-diene-3,20-dione

9a-klor-llB-hydroksy-16S-metyl-17a,21-(l'-etoksy-1'-etylmetylendioksy)-pregna-1,4-dien-3,20-dion (300 mg) i aceton (35 ml) ble omrørt og behandlet med vann (1 ml) og 2N svovelsyre (0,1 ml). Efter 50 minutter ble oppløsningen fortynnet med vann, 9α-chloro-11B-hydroxy-16S-methyl-17α,21-(1'-ethoxy-1'-ethylmethylenedioxy)-pregna-1,4-diene-3,20-dione (300 mg) in acetone (35 ml ) was stirred and treated with water (1 mL) and 2N sulfuric acid (0.1 mL). After 50 minutes, the solution was diluted with water,

og det utfelte, faste stoff ble oppsamlet og omkrystallisert fra aceton-petroleter for å gi 9a-klor-llB,21-dihydroksy-16B-metyl-17a-propionyloksypregna-l,4-dien-3,20-dion, sm.p. 196 -198°C (spaltning), [aL + 107,5° (c 0,78, kloroform) , \Et°H 237 - 239 mu JJ ITlcLKS • / and the precipitated solid was collected and recrystallized from acetone-petroleum ether to give 9α-chloro-11B,21-dihydroxy-16B-methyl-17α-propionyloxypregna-1,4-diene-3,20-dione, m.p. . 196 -198°C (decomposition), [aL + 107.5° (c 0.78, chloroform) , \Et°H 237 - 239 mu JJ ITlcLKS • /

(£ 15.500). (£15,500).

(Funnet: C, 64,2; H, 6,9; Cl, 7,7. C. CH_ ..CIO- krever C, 64,55; (Found: C, 64.2; H, 6.9; Cl, 7.7. C. CH_ ..CIO- requires C, 64.55;

H, 7,15; Cl, 7,6%). H, 7.15; Cl, 7.6%).

EKSEMPEL 13 EXAMPLE 13

9a-klor-116,21-dihydroksy-17-isobutyryloksy-16B-metylpregna-l,4-dien-3,20-dion 9a-chloro-116,21-dihydroxy-17-isobutyryloxy-16B-methylpregna-1,4-diene-3,20-dione

Krystallisert 9a-klor-llB-hydroksy-17,21-(1'-isopropyl-l<1->metoksymetylendioksy)-16B-metylpregna-l,4-dien-3,20-dion (1,42 Crystallized 9α-chloro-11B-hydroxy-17,21-(1'-isopropyl-1<1->methoxymethylenedioxy)-16B-methylpregna-1,4-diene-3,20-dione (1.42

g) i aceton (5 ml) ble behandlet med vann (3 ml) og 2N-svovelsyre (0,3 ml). Efter å ha stått ved romtemperatur i 30 minutter ble g) in acetone (5 ml) was treated with water (3 ml) and 2N-sulfuric acid (0.3 ml). After standing at room temperature for 30 minutes was

oppløsningen helt i fortynnet natriumbikarbonat, og det utfelte faste materiale ble fjernet ved filtrering. Dette våte produkt ble oppløst i kloroform, tørket (MgSO^) og oppløsningsmidlet bør fjernes i vakuum. Krystallisering av residuet fra aceton-petroleter ga 9a-klor-llB,21-dihydroksy-17-isobutyryloksy-16B-metylpregna-I, 4-dien-3,20-dion (680 mg), sm.p. 200 - 210° spaltn., [a]D + lo6,5° the solution completely in dilute sodium bicarbonate, and the precipitated solid material was removed by filtration. This wet product was dissolved in chloroform, dried (MgSO 4 ) and the solvent removed in vacuo. Crystallization of the residue from acetone-petroleum ether gave 9α-chloro-11B,21-dihydroxy-17-isobutyryloxy-16B-methylpregna-1,4-diene-3,20-dione (680 mg), m.p. 200 - 210° split, [a]D + lo6.5°

(c 0,7, dioksan) .A^^s 238 239 (£ 15.300). (c 0.7, dioxane) .A^^s 238 239 (£ 15,300).

(Funnet: C, 65,0; H, 7,2; Cl, 7,65. C26H35Cl06 krever C, 65,2; (Found: C, 65.0; H, 7.2; Cl, 7.65. C26H35Cl06 requires C, 65.2;

H, 7,4; Cl, 7,4%). H, 7.4; Cl, 7.4%).

EKSEMPEL 14 EXAMPLE 14

9a-klor-llB,2l-dihydroksy-16B-mety1-17-valeryloksypregna-1,4-dien-3,20-dion 9a-chloro-11B,2l-dihydroxy-16B-methyl-17-valeryloxypregna-1,4-diene-3,20-dione

17,21-(1'-butyl-1"-metoksymetylendioksy)-9a-klor-116-hydroksy-168-metylpregna-l,4-dien-3,20-dion (1,8 g) i aceton (35 ml) ble behandlet med vann (4 ml) og 2N-svovelsyre (0,4 ml). Efter 30 minutter ved romtemperatur ble reaksjonsblandingen fortynnet med vann og ekstrahert med kloroform. Den organiske ekstrakt hlB vasket med vann, tørket (MgSO^) og inndampet i vakuum. Omkrystallisering av residuet fra aceton-petroleter ga 9a-klor-116-21-dihydroksy-166-metyl-17-valeryloksypregna-l,4-dion-3,20-dion (635 mg) sm.p. 191° [a]_ + 103° (c 0,8, dioksan) , AEtvH 17,21-(1'-butyl-1"-methoxymethylenedioxy)-9a-chloro-116-hydroxy-168-methylpregna-1,4-diene-3,20-dione (1.8 g) in acetone (35 ml ) was treated with water (4 ml) and 2N sulfuric acid (0.4 ml). After 30 minutes at room temperature, the reaction mixture was diluted with water and extracted with chloroform. The organic extract hlB washed with water, dried (MgSO 4 ) and evaporated in vacuo Recrystallization of the residue from acetone-petroleum ether gave 9α-chloro-116-21-dihydroxy-166-methyl-17-valeryloxypregna-1,4-dione-3,20-dione (635 mg) mp 191° [a]_ + 103° (c 0.8, dioxane) , AEtvH

239 mu 15.000). 239 mu 15,000).

(Funnet: C, 65,7; H, 7,5; Cl, 7,45: C_-7H_.7C10, krever C, 65,8; (Found: C, 65.7; H, 7.5; Cl, 7.45: C_-7H_.7C10, requires C, 65.8;

2. I 5 I O2. I 5 I O

H, 7,6; Cl, 7,2%). H, 7.6; Cl, 7.2%).

Claims

1. Process for the production of therapeutically effective 9a-chloro- or 9a-fluoro-116,21-dihydroxy-166-methyl-17a-alkanoyl-oxy-pregna-1,4-diene-3,20-diones with the general formula : where X is fluorine or chlorine and R is an alkanoyl group containing 2-6 carbon atoms, characterized in that a corresponding 17a,21-ortho-ester or 17a,21-diester is subjected to hydrolysis.

2. Method as stated in claim 1, characterized in that a 9a-fluoro-17,21-orthovalerate or a 9a-fluoro-17-valeryloxy-21-ester is subjected to hydrolysis.