SE191715C1

SE191715C1 -

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Publication number: SE191715C1
Authority: SE
Publication date: 1964-01-01

Description

Uppfinnare: .G B Spero Prioritet begtird frdn den 29 november 1956 (USA) FOreliggande uppfinning avser ett forfarande fOr framstallning av steroidforeningar med forstarkt glykokortikoid aktivitet och minskad saltJetentiv verkan och kannetecknas ddrav, att 6-mety1-9p, 11p-epoxi-17a, 21-dihydroxi-1,4-:pregnadien-3,20-dion-acetat omsattes med fluorvdte Jor bildning av motsvarande 1-dehydro-6-metyl- CH2OCOCH3 ° C=0 'CH3 _OH CH3 De enligt uppfinningen framstallda foreningarna, dvs. 1-dehydro-6-mety1-9a-iluorhydrokortison och dess 21-dttiksyraester, isynnerhet 6aepimererna, har Visat sig vara myeket aktiva adrenokortikoida hormoner, vilkas glykokorikoida verkan vdsentligt overtraffar den hos de naturliga adrenokortikoida hormonerna hydrokortison och kortison, och som dessutom visar en utomordentligt hog anti-inflammatorisk verkan. De är M.- lunda viirdefullai parenterala och for topisk applikation avsedda preparat. I stallet for 6a-epime- rerna av nAmnda foreningar kan man fOr Astadkommande av samma resultat anvanda 6/3-epimererna i terapeutiskt ekvivalenta mdngder. En pmfOrande undersokning Indian den forening enligt uppfinningen, 1-dehydro-6a-metyl. 9a-fluorhydrokortison-acetat, och en analog hand 9a-fluorhydrokortison-21-acetat, och att den sa erhallna attiksyra-estern eventuellt hydrolyseras med en has till motsvarande 1-dehydro-6-mety1- 9a-fluorhydrokortison. Inventor: GB Spero Priority Started November 29, 1956 (USA) The present invention relates to a process for the preparation of steroid compounds with enhanced glycocorticoid activity and reduced salt. -dihydroxy-1,4-: pregnadiene-3,20-dione-acetate was reacted with fluorine to give the corresponding 1-dehydro-6-methyl-CH 2 OCOCH 3 ° C = O 'CH 3 -OH CH 3 The compounds of the invention, i.e. 1-dehydro-6-methyl-9a-fluorohydrocortisone and its 21-acetic acid ester, especially the 6aepimers, have been shown to be very active adrenocorticoid hormones, the glycocuricoid effect of which substantially exceeds that of the natural adrenocorticoid hormones, and in addition hydrocortisone. high anti-inflammatory effect. They are M.- lunda viirdefullai parenteral and for topical application intended preparations. Instead of the 6a epimers of said compounds, the 6/3 epimers can be used in therapeutically equivalent amounts to achieve the same result. A preliminary study of the compound of the invention, 1-dehydro-6α-methyl. 9a-fluorohydrocortisone acetate, and an analogous hand 9a-fluorohydrocortisone-21-acetate, and that the resulting attic acid ester is optionally hydrolyzed with a has to the corresponding 1-dehydro-6-methyl-9a-fluorohydrocortisone.

Forfarandet kan askadliggoras med foljande reaktionsformel: CH2OCOCH3 I • C-0• HOCH31...011 CH 0 CH3 steroid, ndmligen 1-dehydro-9a-fluorhydro-kortison-acetat, betraffande glykokortikoid aktivitet och saltretentiv verkan, utfoll till fOrman f Or den enligt uppfinningen framstallda foreningen, vilket framgar av foljande tabell: Tabell I. The process can be ash-ligated by the following reaction formula: CH2OCOCH3 I • C-0 • HOCH31 ... 011 CH the compound prepared according to the invention, as shown in the following table: Table I.

Glyko- kortikoid Na-retention aktivitet (desoxikorti- (hydrokosteron . kortison= 1) = 1) 1-dehydro-9a-fluorhydro-4,6 kortisonacetat .1-clehydro-6a-mety1-9a-1900,08 fluorhydrokortisona ce tat \/ 2-f91 715 - Av tab ellen framgar salunda, att den glykortikoida aktiviteten has 1 - dehydro - 6a - metyl9a - fluorhydrokortisonacetat är vasentligt for-, starkt jamfort med den kanda fOreningen. Likaledes är saltretentionen has foreningen enligt uppfinningen mycket lagre an has den kanda eningen. En lag saltretention är onskvard, emedan en saltretention orsakar ett kvarhallande av vatten i kroppen och ar ansvarig for ett flertal icke Onskvarda biverkningar vid den adrenokortikoida steroidterapin. Glyco-corticoid Na-retention activity (deoxycorti- (hydrocosterone. Cortisone = 1) = 1) 1-dehydro-9a-fluorohydro-4,6 cortisone acetate .1-clehydro-6a-methyl-9a-1900,08 fluorohydrocortisone ce / 2-f91 715 - From the table it thus appears that the glycorticoid activity has 1 - dehydro - 6a - methyl9a - fluorocorticortisone acetate is essentially pre-, strongly compared with the known compound. Likewise, the salt retention of the compound of the invention is much lower than that of the compound. A low salt retention is unhealthy, because a salt retention causes a retention of water in the body and is responsible for a number of undesirable side effects in adrenocorticoid steroid therapy.

Vid genomforandet av forfarandet enligt uppfinningen gar man exempelvis till vaga pa sa Ott, att foreningen 6-mety1-9/3, 11/3-epoxi-17a,. 21-dihydroxi-1,4-pregnadien-3,20-dion-21-acetat omsattes med 48-procentig fluorvatesyra i ett organiskt losningsmedel. Sam losningsmedel for denna reaktion kan man anvanda metylenklorid, etylendiklorid, kloroform, koltetraklorid eller liknande, varvid metylenklorid foredrages. Reaktionen genomfores vid rumstemperatur (20-30° C), foretradesvis under omroring. Reaktionstiden Egger mellan 1 och 24 tim, varvid det vanligtvis ar tillrackligt med 1-12 tim. Efter avslutad reaktion Mlles blandningen i vatten och neutraliseras med utspatt alkali, t. ex. natriumbikarbonat, -kaliumbikarbonat eller liknande. Overskott av starka baser kan aven anvandas. Reaktionsblandningen extraheras darefter med ett med vatten icke blandbart losningsmedel sasom metylenklorid, det organiska skiktet separeras frau vattenblandningen, tvattas med vatten, torkas och indunstas. Den erhallna arena foreningen, 6-metyl9a-fluor-11p, 17a, 21-trihydroxi-1,2-pregnadien3,20-dion-21-acetat kan renas genom omkristallisering eller kromatografering. In carrying out the process according to the invention, it is for example vague that the compound 6-methyl-9/3, 11/3-epoxy-17a ,. 21-Dihydroxy-1,4-pregnadiene-3,20-dione-21-acetate is reacted with 48% fluorvate acid in an organic solvent. Solvent for this reaction may be to use methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride or the like, with methylene chloride being preferred. The reaction is carried out at room temperature (20-30 ° C), preferably with stirring. The reaction time Egger between 1 and 24 hours, with 1-12 hours usually being sufficient. After completion of the reaction, the mixture is diluted in water and neutralized with dilute alkali, e.g. sodium bicarbonate, potassium bicarbonate or the like. Excess strong bases can also be used. The reaction mixture is then extracted with a water-immiscible solvent such as methylene chloride, the organic layer is separated from the aqueous mixture, washed with water, dried and evaporated. The resulting arena compound, 6-methyl9a-fluoro-11β, 17α, 21-trihydroxy-1,2-pregnadiene3,20-dione-21-acetate can be purified by recrystallization or chromatography.

Det vid forfarandet erhallna 6-mety1-9a-fluor11/1, 17a, 21-trihydroxi-1,4-pregnadien-3,20-dion21-acetatet kan hydrolyseras till 6-mety1-9a-fluor11fl, 17a, 21-trihydroxi-1,4-pregnadien-3,20-dion, som eventuellt kan omestras med acylhalogenider eller syraanhydrider, i pyridinlosning vid rumstemperatur for bildning av andra 21-estrar. The 6-methyl-9a-fluoro11 / 1,17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione21-acetate obtained in the process can be hydrolyzed to 6-methyl-9a-fluoro11fl, 17a, 21-trihydroxy- 1,4-pregnadiene-3,20-dione, which may optionally be transesterified with acyl halides or acid anhydrides, in pyridine solution at room temperature to give other 21-esters.

Exempel 1, 6a-mety1-9a-fluor-1119, 17a, 21-trihydroxi-1,4-pregnadien-3,20-dion-21-acetat (1- dehydro-6 a-mety1-9 a-fluorhydro-kortison-21-acetat). Example 1, 6a-methyl-9a-fluoro-1119, 17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione-21-acetate (1-dehydro-6a-methyl-9a-fluorohydrocortisone -21-acetate).

Till en losning av 230 mg 6a-mety1-9fi, llflepoxi-17cz, 21-dihydroxi-1,4-pregnadien-3,20-dion21-acetat i 5 ml metylenklorid sattes 1,2 ml 48- procentig fluorvatesyralosning. Tvafasblandningen omrordes 20 tim, spaddes darefter med 15 ml metylenklorid och halides forsiktigt i 40 ml vatten, innehallande 4 g natriumbikarbonat. Efter skakning for neutralisering av fluorvatetiverskottet franseparerades metylenkloriden. Vattenfasen extraherades med en ytterligare mangd metylenklorid. De forenade metylenkloridextrakten (c:a 75 ml) torkades Over vattenfritt natriumsulfat, spaddes med 25 ml eter och kromatograferades Over 20 g syntetiskt magnesiumsilikat (Florisil). Pelaren eluerades pa foljande salt: Tabell II. To a solution of 230 mg of 6α-methyl-9β, ilephleoxy-17cz, 21-dihydroxy-1,4-pregnadiene-3,20-dione21-acetate in 5 ml of methylene chloride was added 1.2 ml of 48% fluorvate acid solution. The biphasic mixture was stirred for 20 hours, then diluted with 15 ml of methylene chloride and carefully halided in 40 ml of water containing 4 g of sodium bicarbonate. After shaking to neutralize the fluorate excess, the methylene chloride was separated. The aqueous phase was extracted with an additional amount of methylene chloride. The combined methylene chloride extracts (about 75 ml) were dried over anhydrous sodium sulfate, diluted with 25 ml of ether and chromatographed on 20 g of synthetic magnesium silicate (Florisil). The column was eluted with the following salt: Table II.

Fraktion nrLosningsmedel 1 (100 I111)Metylenklorid-eter (3 : 1) 2-6Skellysolve B (40 ml vardera) hexan aceton (12 %) 7-16Skellysolve B (40 ml vardera) hexan aceton (15 1/0) 16-21Skellysolve B (40 ml vardera) hexan aceton (20 %) 21-26Skellysolve B (40 ml vardera) hexan aceton (35 %) 27-Skellysolve B (40 ml vardera) hexan aceton (50 %) Fraktionerna 2-13, innehallande totalt 140 mg, fiirenades, indunstades och den salunda erhallna atersto den omkristalliserades ur aceton-Skellysolve B hexan och ur metylenklorid for bildning av 89 mg 6a-mety1-9a-fluor-11/9, 17a, 2146- hydroxi-1,4-pregnadien-3,20-dion-21-acetat (1- dehydro-6 a-mety1-9 a-fluorhydrokortis on-21-acetat) med smaltpunkten 233-237° C. FOreningen visade foljande ultraviolettabsorption: 238,5 my; ai = 15.325. Infraroda absorptionen matt i paraffinolja var foljande: hydroxyl, 3430 cm-1; 21-acetoxi-20-keto, 1735, 1717 cm-1; konjugerad 3-ketogrupp, 1658 cm-1; 41,4-dubbelbindningar, 1615, 1610 cm-1; acetat-C-0-bindning, 1270, 1239 cm-1. Fraction No. Solvent 1 (100 μl) Methylene chloride-ether (3: 1) 2-6Skellysolve B (40 ml each) hexane acetone (12%) 7-16Skellysolve B (40 ml each) hexane acetone (15 1/0) 16-21Skellysolve B (40 ml each) hexane acetone (20%) 21-26Skellysolve B (40 ml each) hexane acetone (35%) 27-Skellysolve B (40 ml each) hexane acetone (50%) Fractions 2-13, containing a total of 140 mg, was evaporated, evaporated and the resulting residue was recrystallized from acetone-Skellysolve B hexane and from methylene chloride to give 89 mg of 6α-methyl-9a-fluoro-11/9, 17a, 2146-hydroxy-1,4-pregnadiene. 3,20-dione-21-acetate (1-dehydro-6α-methyl-9α-fluorohydrocortisone-21-acetate) with a melting point of 233-237 ° C. The compound showed the following ultraviolet absorption: 238.5 ml; ai = 15,325. The infrared absorption matt in paraffin oil was as follows: hydroxyl, 3430 cm-1; 21-acetoxy-20-keto, 1735, 1717 cm-1; conjugated 3-keto group, 1658 cm-1; 41.4 double bonds, 1615, 1610 cm-1; acetate C-O bond, 1270, 1239 cm-1.

Exempel 2, 6a-inetyl-9a-f1uor-11/3, 17a, 21-trihydroxi-1,4-pregnadien-3,20-dion (1-dehydro-6amety1-9a-fluorhydrokortison). 100 mg 6a-mety1-9a-fluor-10, 17a, 21-trib.ydroxi-1,4-pregnadien-3,20-dion-21-acetat lostes i en blandning av 2 ml metanol och 0,1 ml vatten, vilken dessforinnan befriats Iran luftsyre medelst genomledande av kvave. Losningen ftirsattes darefter med 50 mg kaliumkarbonat och fick sta 6 tim vid rumstemperatur i kva.veatmosfar. Darefter neutraliserades den med 5-procentig vattenhaltig saltsyraltisning, utspaddes med 5 ml vatten och Wills under kyla. Blandningen filtrerades darafter och den fasta substansen omkristalliserades ur aceton-Skellysolve B hexaner for bildning av den rena foreningen 6a-mety1-9a-fluor-11/3, 17a, 21-trihydrcod-1,4-pregnadien-3,20 dion (1-dehydro-6 a-mety1-9 a-fluorhydrokortison). Example 2, 6a-methyl-9a-fluoro-11 / 3,17a, 21-trihydroxy-1,4-pregnadiene-3,20-dione (1-dehydro-6amethyl-9a-fluorohydrocortisone). 100 mg of 6α-methyl-9α-fluoro-10,17α, 21-tribhydroxy-1,4-pregnadiene-3,20-dione-21-acetate were dissolved in a mixture of 2 ml of methanol and 0.1 ml of water, which was previously liberated from Iran by atmospheric nitrogen. The solution was then reconstituted with 50 mg of potassium carbonate and allowed to stand for 6 hours at room temperature in a quaternary atmosphere. It was then neutralized with 5% aqueous hydrochloric acid thawing, diluted with 5 ml of water and Wills under cooling. The mixture was then filtered and the solid recrystallized from acetone-Skellysolve B hexanes to give the pure compound 6a-methyl-9a-fluoro-11/3, 17a, 21-trihydrode-1,4-pregnadiene-3,20 dione (1 -dehydro-6α-methyl-9α-fluorohydrocortisone).

Claims

Patent claim:

A process for the preparation of steroid compounds having enhanced glycocorticoid activity and reduced salt retention activity, characterized in that 6-methyl-913, 11β-epoxy-17α, 21-dihydroxy-1,4-pregnadiene-3,20-dione 21-acetate is reacted with fluorate to give the corresponding 1- - 191 7 I --- 3 d ehydro-6-methyl-9α-fluorocorticortone-21-acetate, and that the attic acid ester thus obtained is optionally hydrolyzed with a base to the corresponding 1 dehydro-6-methyl-9α-fluorocarboncortisone.

Process according to claim 1, characterized in that the fra 6a-methyl epimer of the said starting compound is started. Anfkirda publications: Chemical abstracts 49 (1955), sp. 15059 f, 50 (1956), sp. 4179 bcd, 6497 b.