SE184873C1

SE184873C1 -

Info

Publication number: SE184873C1
Authority: SE
Publication date: 1963-01-01

Description

Uppfinnare: F H Lincoln Jr, W P Schneider och G B Spero Prioritet begard treat den 10 september och 23 november 1956 saint den 17 maj 1957 (USA) Foreliggande uppfinning avser ett fOrfarande for framstallning av 6-mety1-9a-fluor-11/3,17adihydroxi-1,4-pregnadien-3,20-dion, narmare bestdmd saval 6a- som 6fl-epimeren, vilka foreningar bada visat sig ha en vardefull kortikosteroidal hormonaktivitet. Inventors: FH Lincoln Jr., WP Schneider and GB Spero Priority Begard Treat on September 10 and November 23, 1956 Since May 17, 1957 (USA) The present invention relates to a process for the preparation of 6-methyl-9a-fluoro-11 / 3,17adihydroxy. -1,4-pregnadiene-3,20-dione, more specifically both the 6a- and 6fl-epimer, both of which compounds have been shown to have valuable corticosteroid hormone activity.

De nya foreningarna och forfarandet enligt fiireliggande uppfinning askadliggores av foljande formel: CH, C=0 HOCELL OH \\ CH,,' 0 CFI, Fi5rfarandet enligt fOreliggande uppfinning be-star i att foreningen I ovan, dvs. 6-mety1-9afluor- 11p,17 a- dihydroxi -21 -j o d- 1,4- pregnadien3,20-dion (6a- eller 6,8-epimeren), underkastas reduktiv dehalogenering for bildning av 6-metyl9 a-fluor - 1113,17 a- dihydroxi- 1,4-pregna dien- 3, 20- dion (II). The novel compounds and the process of the present invention are incorporated by the following formula: CH, C = O HOCELL OH \\ CH 2+ CFI, The process of the present invention consists in that the compound I above, i.e. 6-methyl-9afluoro-11β, 17α-dihydroxy -21-iodo-1,4-pregnadiene3,20-dione (6α- or 6,8-epimer), is subjected to reductive dehalogenation to form 6-methyl9α-fluorine - 1113,17 α-dihydroxy-1,4-pregna dien-3,20-dione (II).

Den nya foreningen 6a-mety1-9a-fluor-11,6,17adihydroxi-1,4-pregnadien-3,20-dion uppvisar en hog fysiologisk aktivitet och ger aktivitetsspektra, corn isynnerhet med avseende pa verkan pa mineral- och yattenmetabolismen skiljer sig frail de i naturen forekommande adrenokortikoida hormonerna, t. ex. hydrokortison och kortison. Dessa foreningar ger upphov till en forlust av salt och vatten fran kroppen och denna verkan Or dem sarskilt vardefulla for behandling av kronisk kongestiv hjartsvaghet och vid behandling av Dupl. kl. 12 o: 25/0 C=0 HOC1-131OH CH, / skrumplever, njursyndrom oak vid behandling av eklampsi och preklampsi. Da nya syntaiska kortikosteroida hormonet enligt foreliggande uppfinning uppvisar Oven antiinflammatorisk, glykokortikoidal verkan samt effekt pa livmodern, aggstockarna avensom adrenal tillvaxthammande och adreno-kortikoidal aktivitet. Den antiinflammatoriska verkan Or synnerligen anmarkningsyard hos steroiderna enligt fbreliggande uppfinning. 68-epimeren, 6/3-mety1-9a-fluor-1113,17a-dihydroxi-1,4-pregnadien-3,20-dion, uppvisar samma slag av aktivitet som 6a-epimeren. The new compound 6a-methyl-9a-fluoro-11,6,17adihydroxy-1,4-pregnadiene-3,20-dione exhibits a high physiological activity and gives activity spectra, but in particular with regard to the effect on mineral and surface metabolism differ frail the naturally occurring adrenocorticoid hormones, e.g. hydrocortisone and cortisone. These compounds give rise to a loss of salt and water from the body and this effect Or they are especially valuable for the treatment of chronic congestive heart weakness and in the treatment of Dupl. at 12 o: 25/0 C = 0 HOC1-131OH CH, / cirrhosis, renal syndrome oak in the treatment of eclampsia and preeclampsia. As the new synthetic corticosteroid hormone of the present invention also exhibits anti-inflammatory, glycorticoidal action and effect on the uterus, the ovaries as well as adrenal growth inhibitory and adrenocorticoidal activity. The anti-inflammatory effect is particularly remarkable in the steroids of the present invention. The 68-epimer, 6β-methyl-9α-fluoro-1113,17α-dihydroxy-1,4-pregnadiene-3,20-dione, exhibits the same kind of activity as the 6α-epimer.

Genom ett ref erat i Chemical Abstracts, vol. 50, spalt 4179 f (1956) Or det fOrut kant att framstalla pregnadiener, corn Or snarlika de som framstallts enligt det patentsokta forfarandet (6-H i stallet for 6-mety1). Till skillnad mot de i refe-; ratet beskrivna foreningarna liar emellertid slut. 2— -- produkterna enligt foreliggande uppfinning, som innehaller 6-metylgruppen, en antiinflammatorisk effekt, som betraffande 6a-epimeren, dvs. foreningen 6 a-mety1-9 a-fluor-1113,17 a, 21-trihydroxi1,4-pregnadien-3,11,20-trion, är 121 ganger sa stor som hos hydrokortison. Fareningarna enligt referatet synes dessutom vara saltkvarhallande, medan foreningarna enligt ansokningen astadkomliner saltforlust. Vidare visar foreningarna enligt foreliggande uppfinning en distinkt delad aktivitet, dvs. den glykokortikoidala aktiviteten är endast 25 ggr hydrokortisonets, medan den antiinflammatoriska är 120-140 ggr hydrokortisonets. Detta terapeutiska forhallande gar foreningarna enligt uppfinningen synnerligen anvandbara for .kompositioner avsedda fOr lokal applikation. Through a reference in Chemical Abstracts, vol. 50, column 4179 f (1956) Or it fOrut edge to produce pregnadienes, corn Or similar to those produced according to the patent-pending process (6-H instead of 6-methyl1). Unlike those in refe-; However, the associations described above are coming to an end. 2 - - the products of the present invention, which contain the 6-methyl group, an anti-inflammatory effect, as regards the 6a-epimer, i.e. The compound 6α-methyl-9α-fluoro-1113,17α, 21-trihydroxy-1,4-pregnadiene-3,11,20-trione, is 121 times as large as in hydrocortisone. The compounds according to the minutes also appear to be salt-retaining, while the compounds according to the application achieve salt loss. Furthermore, the compounds of the present invention show a distinctly divided activity, i.e. the glycocorticoid activity is only 25 times that of hydrocortisone, while the anti-inflammatory is 120-140 times that of hydrocortisone. This therapeutic ratio makes the compounds of the invention particularly useful for compositions for topical application.

Vid framstallningen av 6 -metyl -9a - fluor - 1116,17a-dihydroxi-1,4-pregnadien-3,20-dion omsates 6-mety1-9a-fluor-11p7a-dihydroxi-21-jod1,4-pregnadien-3,20-dion med ett reduktionsmedel, t. ex, natrium- eller kaliumtiosulfat, natriumbisulfit, natriumsulfit eller zink och dttiksyra eller liknande. Vid den foredragna utforingsformen av uppfinningen uppslammas 6-mety1-9a-fluor1116,17a - dihydroxi- 21-j od - 1,4- pregnadien- 3,20 - dion i attiksyra, och till denna uppslamning sattes en vattenlosning av natrium- eller kaliumtiosulfat, -bisulfit, -sulfit, zinkstoft och attiksyra eller liknande och blandningen °mitres vid rumsternperatur under en tid av 10 min till 2 tim. Produkten isoleras fran den vattenhaltiga reaktionsblandningen pa vanligt satt, t. ex. filtrering eller extraktion med ett i vatten joke blandbart organiskt losningsmedel, sasom eter, bensen, metylenkkrid, etylenklorid, koltetraklorid, kloroform, hexan, heptan eller liknande, varefter extrakten indunstas. Den erhallna foreningen 6-mety1-9afluor-11/3,17a-dihydroxi-1,4-pregnadien-3,20-dion renas enligt vanliga metoder, t. ex. genom omkristallisation ur eter, aceton, metanol, etanol, Skelleysolve B-hexan, blandningar darav eller liknande; eller genom kromatografering. In the preparation of 6-methyl-9a-fluoro-1116,17a-dihydroxy-1,4-pregnadiene-3,20-dione, 6-methyl-9a-fluoro-11p7a-dihydroxy-21-iodo-1,4-pregnadiene-3 is reacted , 20-dione with a reducing agent, for example, sodium or potassium thiosulfate, sodium bisulfite, sodium sulfite or zinc and acetic acid or the like. In the preferred embodiment of the invention, 6-methyl-9a-fluoro1116,17a-dihydroxy-21-iodo-1,4-pregnadiene-3,20-dione is slurried in acetic acid, and to this slurry was added an aqueous solution of sodium or potassium thiosulfate. , -bisulfite, -sulfite, zinc dust and acetic acid or the like and the mixture is metered at room temperature for a period of 10 minutes to 2 hours. The product is isolated from the aqueous reaction mixture in the usual way, e.g. filtration or extraction with a water joke miscible organic solvent such as ether, benzene, methylene chalk, ethylene chloride, carbon tetrachloride, chloroform, hexane, heptane or the like, after which the extracts are evaporated. The obtained compound 6-methyl-9afluoro-11 / 3,17a-dihydroxy-1,4-pregnadiene-3,20-dione is purified according to usual methods, e.g. by recrystallization from ether, acetone, methanol, ethanol, Skelleysolve B-hexane, mixtures thereof or the like; or by chromatography.

Exempel. Example.

I delta exempel beskrivs framstallningen av -6 a-mety1-9 a-fluor-1113,17 a-dihydroxi-1,4-pregnadien-3,20-dion. Eftersom emellertid den. far reduktiv dehalogenering avsedda foreningen 6-me-ty1-9a-fluor-11fl,17a-dihydroxi-21-jod-1,4-pregna-dien-3,20-dion ej insattes som den uppvagda, rena foreningen, utan erholls slutprodukt frail tva tidigare reaktioner, beskrivs under a) och b) nedan forst den av patentanspraket ej omfattade framstallningen av utgangsforeningen, medan det av patentanspraket omfattade forfarandet exemplifieras under c). a) En losning av 250 mg 6a-mety1-9a-fluor11,6,17a,21 -trihydroxi -1,4 -pregnadien- 3,20 -dion {1-dehydro-6 a-mety1-9a-fluorhydrokortison, Georg B. Spero m. fl., J. Am. Chem. Soc. 79, 1515 (1957)] i 6 ml pyridin kyldes till 0° C och behandlades med 0,25 nil metansulfonylklorid. Darefter omrifirdes losningen 18 tim vid 0-5° C. Darefter tillsattes is och 2 ml vatten, foljt av 30 ml 5-proc. saltsyra for att neutralisera pyridinet. Blandningen filtrerades darefter, fallningen tvattades med vatten och torkades for bildning av 197 mg orent 6 a-metyl- 9 a-fluor- 11/3,17 a,21 -trihydroxi1,4-pregnadien-3,20-dion-21-metansulfonat med smaltpunkten 165-185° C. 197 mg av den orena produkten av 6a-metyl9 a - fluor - 11,17a,21-trihydroxi-1,4-pregnadien3,20-dion-21-metansulfonat lostes i 5 ml aceton och behandlades med en laming av 197 mg natriumj odid i 5 ml aceton. Blandningen varmdes 15 min under aterflode och omraring. Varmningen fortsattes darefter och blandningen indunstades till torrhet under reducerat tryck. Som aterstod erholls foreningen 6a-mety1-9a-fluor1119,17 a- dihydroxi- 21 -j od -1,4- pregnadien- 3,20 - dion i oren form. The following examples describe the preparation of -6α-methyl-9α-fluoro-1113,17α-dihydroxy-1,4-pregnadiene-3,20-dione. Because, however, it. The reductive dehalogenation compound 6-methyl-9a-fluoro-11fl, 17a-dihydroxy-21-iodine-1,4-pregna-diene-3,20-dione was not used as the weighted, pure compound, but the final product obtained frail two previous reactions, are described under a) and b) below first the preparation of the starting compound not covered by the patent claim, while the process covered by the patent claim is exemplified under c). a) A solution of 250 mg of 6α-methyl- 9a-fluorine 11,6,17a, 21-trihydroxy-1,4 -pregnadiene-3,20-dione {1-dehydro-6α-methyl- 9a-fluorocarboncortisone, Georg B Spero et al., J. Am. Chem. Soc. 79, 1515 (1957)] in 6 ml of pyridine was cooled to 0 ° C and treated with 0.25 ml of methanesulfonyl chloride. The solution was then stirred for 18 hours at 0-5 ° C. Then ice and 2 ml of water were added, followed by 30 ml of 5%. hydrochloric acid to neutralize the pyridine. The mixture was then filtered, the precipitate washed with water and dried to give 197 mg of crude 6α-methyl-9α-fluoro-11 / 3,17α, 21-trihydroxy-1,4-pregnadiene-3,20-dione-21-methanesulfonate m.p. 165-185 ° C. 197 mg of the crude product of 6α-methyl9α-fluoro-11,17α, 21-trihydroxy-1,4-pregnadiene3,20-dione-21-methanesulfonate were dissolved in 5 ml of acetone and treated with a paralysis of 197 mg of sodium iodide in 5 ml of acetone. The mixture was heated for 15 minutes under reflux and stirring. The heating was then continued and the mixture was evaporated to dryness under reduced pressure. As a residue, the compound 6α-methyl-9α-fluoro1119,17α-dihydroxy-21-iodo-1,4-pregnadiene-3,20-dione is obtained in crude form.

Den orena foreningen 6a-mety1-9 a-fluor1113,17a- dihydroxi- 21 -j od -1,4 -pregnadien- 3,20 - dion uppslammades med 5 ml attiksyra °eh omrordes 45 min. Darefter tillsattes en losning av 250 mg natriumtiosulfatpentahydrat i 5 ml vat-ten, varvid jodfargen forsvann. Ytterligare vatten tillsattes (30 ml) och reaktionsblandningen filtrerades. Den erhallna fallningen tvattades med .vatten och torkades, varvid erholls 146 mg orent 6 a-mety1-9 a-fluor-11 p,17 a- dihydroxi-1,4-pregnadien-3,20-dion. The crude compound 6α-methyl-9α-fluoro1113,17α-dihydroxy-21-iodo-1,4 -pregnadiene-3,20-dione was slurried with 5 ml of acetic acid and stirred for 45 minutes. Then a solution of 250 mg of sodium thiosulphate pentahydrate in 5 ml of water was added, the iodine color disappearing. Additional water was added (30 ml) and the reaction mixture was filtered. The resulting precipitate was washed with water and dried to give 146 mg of crude 6α-methyl-9α-fluoro-11β, 17α-dihydroxy-1,4-pregnadiene-3,20-dione.

Den orena substansen kromatograferades darefter pa folj ande satt: 120 mg 6a-mety1-9a-fluor-11/3,17a-dihydroxi1,4-pregnadien-3,20-dion lostes i 300 ml metylenklorid. Den erhallna losningen bringades i adsorptionskontakt med en kromatografisk pelare, innehallande 10 g vattenfritt magnesiumsilikat Pelaren framkallades under uttagande av fraktioner pa 20 ml vardera enligt foljande: Tabell. The crude substance was then chromatographed as follows: 120 mg of 6α-methyl-9α-fluoro-11β, 3,17α-dihydroxy-1,4-pregnadiene-3,20-dione were dissolved in 300 ml of methylene chloride. The resulting solution was brought into adsorption contact with a chromatographic column containing 10 g of anhydrous magnesium silicate. The column was developed while taking fractions of 20 ml each as follows: Table.

FraktionLoan ingsmedel 1— Skellysolve B-hexan- 5 °A aceton 6-Skellysolve B-hexan-10 °A aceton 11-Skellysolve B-hexan-15 % aceton 16-Skellysolve B-hexan-20 % aceton 21-Skellysolve B-hexan-30 % aceton 26-28 Aceton Fraktionerna 11 t. o. m. 24 forenades, indunstades och omkristalliserades tva ganger ur aceton for bildning av rent 6a-mety1-9a-fluor-11/3,17adihydroxi-1,4-pregnadien-3,20-dion .med smallpunkten 292-303° C. Fractional Solvent 1— Skellysolve B-hexane-5 ° A acetone 6-Skellysolve B-hexane-10 ° A acetone 11-Skellysolve B-hexane-15% acetone 16-Skellysolve B-hexane-20% acetone 21-Skellysolve B-hexane -30% acetone 26-28 Acetone Fractions 11 to 24 were combined, evaporated and recrystallized twice from acetone to give pure 6α-methyl-9α-fluoro-11 / 3,17adihydroxy-1,4-pregnadiene-3,20-dione . with the small point 292-303 ° C.

Den. nya foreningen 6-mety1-9a-fluor-11fl,17adihydroxi-1,4-pregnadien-3,20-dion ar anvandbar i orala, parenterala och for topisk applikation avsedda kompositioner. I orala kompositioner kan produkten ges som tabletter, t. ex. med anvandning av antingen polyetylenglykol 4000 eller 6000 som barare eller laktos och/eller sackaros som utspadningsmedel. Den nya foreningen 6a-metyl9 a-fluor-11A 17 a-dihydroxi-1,4-pregnadien-3,20- dion är anvandbar far topisk applikation i form av salvor, tinkturer, vaseliner, kramer, suppositorier, katetrar, vattenhaltiga suspensioner etc. — —3 The. The new compound 6-methyl-9a-fluoro-11fl, 17adihydroxy-1,4-pregnadiene-3,20-dione is useful in oral, parenteral and topical application compositions. In oral compositions the product may be given as tablets, e.g. using either polyethylene glycol 4000 or 6000 as barer or lactose and / or sucrose as diluent. The new compound 6α-methyl9α-fluoro-11α 17α-dihydroxy-1,4-pregnadiene-3,20-dione is useful for topical application in the form of ointments, tinctures, vaselines, hugs, suppositories, catheters, aqueous suspensions etc. - —3

Claims

Patent claim:

Process for the preparation of compounds with corticosteroidal hormone activity, characterized in that 6α-methyl- or 6β-methyl-9afluoro-11 / 3,17α-dihydroxy-21-iodine-1,4-pregnadiene3,20-dione is subjected to reductive dehalogenation to form 6α-methyl- resp. 6β-methyl-9afluoro-11β, 17α-dihydroxy-1,4-pregnadiene-3,20-dione.

Process according to claim 1, characterized in that 6α-methyl-9α-fluoro-11β, 17α dihydro3d-21-iodine-1,4-pregnadiene-3,20-dione is subjected to reductive dehalogenation with sodium thiosulfate. Request publications: Chemical abstracts. 50 (1956) 3 sp. 4179 f Journal of the American chemical society. 77 (1955), pp. 4181-4182.