NO122591B

NO122591B -

Info

Publication number: NO122591B
Application number: NO14416162A
Authority: NO
Inventors: M Tishler; N Steinberg; R Hirschmann
Original assignee: Merck & Co Inc
Priority date: 1961-05-01
Filing date: 1962-04-27
Publication date: 1971-07-19
Also published as: DK108168C; CH423768A; ES277085A1; DE1468211B1; BE617105A; DK114342B; SE309590B

Description

Fremgangsmåte til fremstilling av nye 17a, 21-dihydroxy-20-oxo-4,6-pregnadien- [3,2-c]-pyrazol-forbindelser eller deres 21-estere med antiflammatorisk virkning. Process for the production of new 17a, 21-dihydroxy-20-oxo-4,6-pregnadiene-[3,2-c]-pyrazole compounds or their 21-esters with anti-inflammatory action.

Foreliggende oppfinnelse angår en fremgangsmåte til fremstilling av nye 17a,21-dihydroxy-20-oxo-4,6-pregnadien-[ 3,2-c]-pyra-zol-forbindelser eller deres 21-estere. The present invention relates to a method for the production of new 17a,21-dihydroxy-20-oxo-4,6-pregnadiene-[3,2-c]-pyrazole compounds or their 21-esters.

Disse forbindelser tilsvarer én av de nedenstående generel- ■ le formler: These compounds correspond to one of the general formulas below:

i hvilke R^betegner p-halogen, en p-hydroxy eller keto-gruppe, og X betegner hydrogen eller halogen, idet R^kari være p-halogen bare i de tilfelle hvor1 også X er halogen, R_ betegner hydrogen, fluor eller en raethylgruppe, R^ betegner en a-methyl-, p-methyl- eller en methylen-gruppe, R4 betegner hydrogen eller et acylradikal eller et fosforsyre-radikal og R5betegner et alkyl-, cycloalkyl-, aralkyl- eller arylradikal. in which R^ denotes p-halogen, a p-hydroxy or keto group, and X denotes hydrogen or halogen, R^ can be p-halogen only in those cases where X is also halogen, R_ denotes hydrogen, fluorine or a raethyl group, R 1 denotes an α-methyl, p-methyl or a methylene group, R 4 denotes hydrogen or an acyl radical or a phosphoric acid radical and R 5 denotes an alkyl, cycloalkyl, aralkyl or aryl radical.

Det karakteristiske hovedtrekk ved oppfinnelsen er at man omsetter en 17a,21-dihydroxy-3,20-dioxo-2-hydroxymethylen- eller 2-alkoxymethylen-4,6-pregnadien-forbindelse tilsvarende en av de ovenfor angitte forbindelser, og i hvilken beskyttende grupper kan være tilstede i 17-, 20- og 21-stillingene, med et hydrazin med formelen R5-NHNH2, hvor R,, har den ovenfor angitte betydning, hvorpå man fjer-ner eventuelt tilstedeværende beskyttende grupper i 17-, 20- og 21- stillingene, og, om onskes, overforer det erholdte produkt til et 21-organisk acylat eller til et 21-fosfat. The characteristic main feature of the invention is that one reacts a 17a,21-dihydroxy-3,20-dioxo-2-hydroxymethylene- or 2-alkoxymethylene-4,6-pregnadiene compound corresponding to one of the above-mentioned compounds, and in which protective groups can be present in the 17-, 20- and 21-positions, with a hydrazine of the formula R5-NHNH2, where R,, has the above meaning, after which any protective groups present in the 17-, 20- and the 21-positions, and, if desired, transfers the product obtained to a 21-organic acylate or to a 21-phosphate.

De forbindelser som fåes ved fremgangsmåten ifolge oppfinnelsen, har en sterk anti-inflammatorisk virkning og er særlig effektive til behandling av arthrit og beslektede sykdommer, da de har cortison-lignende virkning i så sterk grad at de kan anvendes i relativt små doser, hvorved uonskede bivirkninger blir ubetydelige. The compounds obtained by the method according to the invention have a strong anti-inflammatory effect and are particularly effective for the treatment of arthritis and related diseases, as they have a cortisone-like effect to such a strong extent that they can be used in relatively small doses, whereby unwanted side effects become negligible.

Utgangsmaterialene for fremgangsmåten ifolge oppfinnels en kan fremstilles fra et 17a,21-dihydroxy-4,6-pregnadien-3,20-dion med den generelle formel: The starting materials for the method according to the invention can be prepared from a 17a,21-dihydroxy-4,6-pregnadiene-3,20-dione with the general formula:

i hvilken R^, R,,, R^og X har den ovenfor angitte betydning og be-grensning av betydningen av R^. Således kan f.eks. kold, konsentrert saltsyre og formalin tilsettes til en omrort suspensjon i kloroform, med temperatur ca. 0°C, av den ovenfor angitte forbindelse. Man lar derpå blandingens temperatur stige til romtemperatur og omrorer den i flere timer, hvorved der dannes det tilsvarende 17a,20,20,21-bis-(methylendioxy)-derivat. in which R^, R^,, R^ and X have the above stated meaning and limitation of the meaning of R^. Thus, e.g. cold, concentrated hydrochloric acid and formalin are added to a stirred suspension in chloroform, at a temperature of approx. 0°C, of the above compound. The temperature of the mixture is then allowed to rise to room temperature and it is stirred for several hours, whereby the corresponding 17a,20,20,21-bis-(methylenedioxy)-derivative is formed.

Ved behandling av en lip-hydroxy-, lip-halogen- ellar 11-keto-17a,20,20,21-bis(methylendioxy)-4,6-pregnadien-3-on-fprbindelse med et alkylformiat og natriumhydrid i inert atmosfære dannes det tilsvarende 17a,20,20,21-bis(methylendioxy)-2-hydrpxymethylen-4,6-pregnadien-3-on med den generelle formel: On treatment of a lip-hydroxy-, lip-halo- or 11-keto-17a,20,20,21-bis(methylenedioxy)-4,6-pregnadien-3-one compound with an alkyl formate and sodium hydride in an inert atmosphere the corresponding 17a,20,20,21-bis(methylenedioxy)-2-hydrpxymethylene-4,6-pregnadien-3-one is formed with the general formula:

i hvilken R^, R^> Rg°9x nar de foran angitte betydninger, inklusi-ve begrensningen at R^kan være p-halogen bare i de tilfelle at også in which R^, R^> Rg°9x have the previously stated meanings, including the restriction that R^ can be p-halogen only in the case that also

X er halogen. X is halogen.

Således kan steroid opploses i et opplosningsmiddel som benzen, og den erholdte opplosning avkjoles til romtemperatur med på-i Thus, steroid can be dissolved in a solvent such as benzene, and the resulting solution is cooled to room temperature with on-i

folgende behandling med ethylformiat. Luften i reaksjonssonen erstat-tes hensiktsmessig med nitrogen, natriumhydrid tilsettes, hvorpå blandingen omrores ved romtemperatur i flere timer. following treatment with ethyl formate. The air in the reaction zone is suitably replaced with nitrogen, sodium hydride is added, after which the mixture is stirred at room temperature for several hours.

Ved behandling av en 17a,20,20,21-bis(methylendioxy)-2-hydroxymethylen-4,6-pregnadien-3-on-forbind else med en lavere alkanol i nærvær av et surt stoff som p-toluensulfonsyre, dannes det tilsvarende 17a,20,20,21-bis(methylendioxy)-2-alkoxymethylen-4,6-pregnadien-3-on. On treatment of a 17a,20,20,21-bis(methylenedioxy)-2-hydroxymethylene-4,6-pregnadien-3-one compound with a lower alkanol in the presence of an acidic substance such as p-toluenesulfonic acid, it is formed corresponding to 17a,20,20,21-bis(methylenedioxy)-2-alkoxymethylene-4,6-pregnadien-3-one.

Sorn det fremgår av det foran angitte omsetter man, ifolge oppfinnelsen, dette utgångsmateriale med et hydrazin som inneholder substituenten R^_. As can be seen from the foregoing, according to the invention, this starting material is reacted with a hydrazine containing the substituent R^_.

De N-substituerte-4,6-pregnadien-[3,2-c]-pyrazoler som tilsvarer nedenstående generelle formel A kan betegnes som 1'-substituerte 4,6-pregnadien-[3,2-c]-pyrazoler, mens de N-substituerte pyra-zol-forbindelser tilsvarende nedenstående generelle formel B kan betegnes som 2'-substituerte 4,6-pregnadien-[3,2-c]-pyrazoler. The N-substituted-4,6-pregnadiene-[3,2-c]-pyrazoles corresponding to the general formula A below can be designated as 1'-substituted 4,6-pregnadiene-[3,2-c]-pyrazoles, while the N-substituted pyrazole compounds corresponding to the general formula B below can be designated as 2'-substituted 4,6-pregnadiene-[3,2-c]-pyrazoles.

I disse generelle formler har R^, R^, R^, R^og X de ovenfor angitte betydninger. In these general formulas R^, R^, R^, R^ and X have the meanings given above.

Ved behandling av en 17a,20,20,21-bis-(methylendioxy)-2-hydroxymethylen-4,6-pregnadien-3-on-forbindelse direkte med et monosubstituert arylhydrazin, uten dannelse av 2-alkoxymethylenderivatet som mellomprodukt, dannes i alminnelighet den ene isomer i overveien-de mengde. Når man derimot omsetter en 17a,20,20,21-bis(methylendi-oxy)-2-alkoxymethylen-4,6-pregnadien-3-on-forbindelse med et monosubstituert arylhydrazin, får man betydelige mengder av begge isomere. Når man utforer disse reaksjoner med monosubstituerte alkylhydraziner får man blandinger uansett om man går ut fra 2-hydroxymethylensteroi-det eller fra 2-alkoxymethylensteroidet. En blanding av de isomere kan også dannes ved omsetning av et monosubstituert hydrazin med en 2-hydroxymethylen-forbindelse som eventuelt inneholder varierende mengder av 2-alkoxymethylenderivatet, i avhengighet av de anvendte arbeidsbetingelser, f.eks. på grunn av omkrystallisasjon i nærvær av et spor av alkohol av en opplosning av 2-hydroxymethylen-forbindel-sen, fra hvilken syre ikke er fjernet fullstendig. On treatment of a 17a,20,20,21-bis-(methylenedioxy)-2-hydroxymethylene-4,6-pregnadien-3-one compound directly with a monosubstituted arylhydrazine, without formation of the 2-alkoxymethylene derivative as an intermediate, is formed in usually the one isomer in the predominating amount. On the other hand, when one reacts a 17a,20,20,21-bis(methylenedi-oxy)-2-alkoxymethylene-4,6-pregnadien-3-one compound with a monosubstituted arylhydrazine, significant amounts of both isomers are obtained. When these reactions are carried out with monosubstituted alkylhydrazines, mixtures are obtained, regardless of whether one starts from the 2-hydroxymethylene steroid or from the 2-hydroxymethylene steroid. A mixture of the isomers can also be formed by reacting a monosubstituted hydrazine with a 2-hydroxymethylene compound which optionally contains varying amounts of the 2-alkoxymethylene derivative, depending on the working conditions used, e.g. due to recrystallization in the presence of a trace of alcohol of a solution of the 2-hydroxymethylene compound from which acid has not been completely removed.

Blant de monosubstituerte hydraziner som kan anvendes i fremgangsmåten ifolgeOppfinnelsen er alkylhydraziner, som methylhyd-razin, ethylhydrazin, propyohydraziner og butylhydraziner, cycloalkyl-hydraziner, arylhydraziner deriblant fenylhydraziner som kan være substituert med et halojenatom samt aralkylhydraziner, som benzylhyd-razin og fenylethylenhydrazin. Among the monosubstituted hydrazines that can be used in the method according to the invention are alkylhydrazines, such as methylhydrazine, ethylhydrazine, propiohydrazines and butylhydrazines, cycloalkylhydrazines, arylhydrazines including phenylhydrazines which may be substituted with a halogen atom and aralkylhydrazines, such as benzylhydrazine and phenylethylenehydrazine.

Ved behandling av hvilken som helst av de ovenfor beskrev-ne 17a,20,20,21-bis(methylendioxy)-4,6-pregnadien-[3,2-c]-pyrazol-forbindelser med en fortynnet organisk syre, f.eks. en 60 %'s vandig maursyre, fjernes den gruppe som beskytter 17a,20,20,21-bis(methylen-dioxy), og man får den tilsvarende 17a,21-dihydroxy-20-oxo-4,6-pregna-dien- [3,2-c]-pyrazol. When treating any of the above-described 17a,20,20,21-bis(methylenedioxy)-4,6-pregnadiene-[3,2-c]-pyrazole compounds with a dilute organic acid, e.g. e.g. a 60% aqueous formic acid, the group protecting 17a,20,20,21-bis(methylenedioxy) is removed, and the corresponding 17a,21-dihydroxy-20-oxo-4,6-pregna-diene is obtained - [3,2-c]-pyrazole.

21-acylat-derivatene av de ovenfor angitte 17a,21-dihydroxy-20-oxo-4,6-pregnadien-[3,2-c]-pyrazoler kan fremstilles ved omsetning av disse med et acyleringsmiddel. Egnede acyleringsmidler for dette formål er hydrocarboncarboxylsyrer eller derivater av sådanne som benzoesyreanhydrid, tertiært butyl-acetylklorid, alkansyreanhydrider eller -halogenider, som eddiksyreanhydrid, propionsyreanhydrid, eller anhydrider av flerbasiske syrer som B,B-dimethyl-glutarsyreanhydrid, ravsyreanhydrid og lignende. Man arbeider herved i nærvær av en organisk base som pyridin. The 21-acylate derivatives of the above-mentioned 17a,21-dihydroxy-20-oxo-4,6-pregnadiene-[3,2-c]-pyrazoles can be prepared by reacting these with an acylating agent. Suitable acylating agents for this purpose are hydrocarbon carboxylic acids or derivatives thereof such as benzoic anhydride, tertiary butyl acetyl chloride, alkanoic anhydrides or halides, such as acetic anhydride, propionic anhydride, or anhydrides of polybasic acids such as B,B-dimethyl-glutaric anhydride, succinic anhydride and the like. This is done in the presence of an organic base such as pyridine.

I det fblgende beskrives som eksempler noen utforelsesfor-mer for oppfinnelsen. In the following, some embodiments of the invention are described as examples.

Eksempel 1 Example 1

1,19 g 17a,20,20,21-bis-(methylendioxy)-llB-hydroxy-2-hydroxymethylen-6,16a-dimethyl-4,6-pregnadien-3-on opploses i 25 ml ethanol. Oppløsningen tilsettes 300 mg fenylhydrazin, og blandingen oppvarmes i nitrogenatmosfære under tilbakelopskjoling i 1 time, hvorpå den tilsettes 25 ml vann. Produktet ekstraheres med 150 ml ether. Ekstraktene vaskes med 2 N saltsyre, med mettet natriumbicarbonatopplosning, med vann og med mettet natriumkloridopplosning. De befries derpå for vann med natriumsulfat og inndampes til torrhet, hvorved man får ca. 1,2 g råprodukt. Dette omkrystalliseres fra ether, hvorved man får ét stoff hvis hovedbestanddel er 17a,20,20,21-bis-(methy-len )-llS-hydrqxy-6,16a-dimethyl-ll-oxo-2*-fenyl-4,6-pregnadien- 1.19 g of 17a,20,20,21-bis-(methylenedioxy)-11B-hydroxy-2-hydroxymethylene-6,16a-dimethyl-4,6-pregnadien-3-one is dissolved in 25 ml of ethanol. 300 mg of phenylhydrazine is added to the solution, and the mixture is heated in a nitrogen atmosphere under reflux for 1 hour, after which 25 ml of water is added. The product is extracted with 150 ml of ether. The extracts are washed with 2 N hydrochloric acid, with saturated sodium bicarbonate solution, with water and with saturated sodium chloride solution. They are then freed from water with sodium sulphate and evaporated to dryness, whereby approx. 1.2 g raw product. This is recrystallized from ether, whereby one substance is obtained whose main constituent is 17a,20,20,21-bis-(methylene)-11S-hydroxy-6,16a-dimethyl-11-oxo-2*-phenyl-4, 6-pregnadien-

[3,2-c]-pyrazol, med sm.p. 258 - 262°C. a^<4>= -123(CHC13) [3,2-c]-pyrazole, with m.p. 258 - 262°C. a^<4>= -123(CHC13)

UltrafiolettÅ^^g = 283.315 mp.. £=17200, 20800. UltravioletÅ^^g = 283.315 mp.. £=17200, 20800.

17a,20,20,21-bis-(methylendioxy)-llB-hydroxy-6,16-dimeth-yl-2'-fenyl-4,6-pregnadien-[3,2-c]-pyrazolet (430 mg) oppvarmes på dampbad i nitrogenatmosfære med 40 ml 60 %'s vandig maursyre i ca. 30 minutter. Derefter tilsettes ca. 40 ml vann, og blandingen ekstraheres med 2O0 ml kloroform. Kloroformekstraktet vaskes med vann, med mettet natriumbicarbonatopplosning og påny med,vann, hvorpå den befries for vann med na triumsulfat og inndampes i vakuum, hvorved man får ca. 430 mg urent produkt. Dette opploses i 60 ml absolutt methanol, og oppløsningen tilsettes O,1 ekvivalent natrium-methylat i methanol. Blandingen omrbres i nitrogenatmosfære ved romtemperatur i 15 minutter. Den surgjdres derpå med eddiksyre, og opplosningsmidlet fjernes i vakuum ved romtemperatur. Der tilsettes ca. 20 ml vann, og produktet ekstraheres med 150 ml ethylacetat. Ethylacetatekstraktet vaskes med mettet natriumbicarbonatopplosning og derpå med vann. Det befries for vann med natriumsulfat og inndampes til torrhet, hvorved man får et amorft stoff. 17a,20,20,21-bis-(methylenedioxy)-11B-hydroxy-6,16-dimeth-yl-2'-phenyl-4,6-pregnadiene-[3,2-c]-pyrazole (430 mg) heated on a steam bath in a nitrogen atmosphere with 40 ml of 60% aqueous formic acid for approx. 30 minutes. Then add approx. 40 ml of water, and the mixture is extracted with 200 ml of chloroform. The chloroform extract is washed with water, with saturated sodium bicarbonate solution and again with water, after which it is freed from water with sodium sulphate and evaporated in a vacuum, whereby approx. 430 mg impure product. This is dissolved in 60 ml of absolute methanol, and 0.1 equivalent of sodium methylate in methanol is added to the solution. The mixture is stirred in a nitrogen atmosphere at room temperature for 15 minutes. It is then acidified with acetic acid, and the solvent is removed in vacuo at room temperature. Add approx. 20 ml of water, and the product is extracted with 150 ml of ethyl acetate. The ethyl acetate extract is washed with saturated sodium bicarbonate solution and then with water. It is freed from water with sodium sulphate and evaporated to dryness, whereby an amorphous substance is obtained.

Dette urene produkt torres i hoyt vakuum og opploses i 4 ml pyridin. Oppløsningen tilsettes ca. 3 ml eddiksyreanhydrid. Blandingen oppvarmes derpå på dampbad i ca. 15 minutter og inndampes til torrhet i vakuum. Residuet tilsettes ca. 20 ml vann. Produktet ekstraheres med 150 ml ethylacetat, ekstraktet vaskes med mettet natriumbicarbonatopplosning og med vann, hvorpå det befries for vann med nat-riumsulf at.. Opplosningsmidlet fjernes i vakuum, hvorved man får et residuum som omkrystalliseres fra en blanding av ethylacetat og benzen. Man får ca. 250 mg 116,17a,21-trihydroxy-6,16a-dimethyl-20-oxo-2'-fen-yl-4, 6-pregnadien- [3, 2-c]pyrazol-21-acetat med sm.p. (dobbelt) 160 165°C og 229 230°C. a^<3>= + 14°C (CHC13). Ultrafiolett A ^aks This impure product is dried under high vacuum and dissolved in 4 ml of pyridine. The solution is added approx. 3 ml of acetic anhydride. The mixture is then heated in a steam bath for approx. 15 minutes and evaporated to dryness in a vacuum. The residue is added approx. 20 ml of water. The product is extracted with 150 ml of ethyl acetate, the extract is washed with saturated sodium bicarbonate solution and with water, after which it is freed from water with sodium sulphate. The solvent is removed in vacuo, whereby a residue is obtained which is recrystallized from a mixture of ethyl acetate and benzene. You get approx. 250 mg of 116,17a,21-trihydroxy-6,16a-dimethyl-20-oxo-2'-phenyl-4, 6-pregnadiene-[3, 2-c]pyrazole-21-acetate with m.p. (double) 160 165°C and 229 230°C. a^<3>= + 14°C (CHCl 3 ). Ultraviolet A ^aks

283,315 mp. S. = 15,700, 19000. 283.315 mp. S. = 15,700, 19000.

Eksempel 2 Example 2

111,5 mg 17a,20,20,21-bis-(methylendioxy)-llB-hydroxy-2-hydroxymethylen-16a-methyl-4,6-pregnadien-3-on suspenderes i 2,5 ml ethanol, og suspensjonen behandles med 24,5 mg natriumacetat, hvorpå 111.5 mg of 17a,20,20,21-bis-(methylenedioxy)-11B-hydroxy-2-hydroxymethylene-16a-methyl-4,6-pregnadien-3-one are suspended in 2.5 ml of ethanol, and the suspension is treated with 24.5 mg of sodium acetate, whereupon

den tilsettes 48,5 mg p-fluorfenylhydrazinhydroklorid. Luften i reaksjonssonen fortrenges med nitrogen, og blandingen bringes raskt på ko-ketemperatur. Efter kokning under tilbakelbpskjbling i 1 time inndampes blandingen til torrhet. Residuet opploses i ether, etherskiktet 48.5 mg of p-fluorophenylhydrazine hydrochloride is added to it. The air in the reaction zone is displaced with nitrogen, and the mixture is quickly brought to boiling temperature. After boiling under reflux for 1 hour, the mixture is evaporated to dryness. The residue is dissolved in ether, the ether layer

behandles tre ganger med 2,5 N saltsyre og derpå tre ganger med 2,5 treated three times with 2.5 N hydrochloric acid and then three times with 2.5

N natriumhydroxydopplosning samt sluttelig med vann. Etherskiktet befries for vann med magnesiumsulfat, filtreres og inndampes til torrhet i vakuum, hvorved man får et residuum hvis hovedbestanddel er 17a,20,20,21-bis-(methylendioxy)-2'-p-fluorfenyl-llB-hydroxy-16a-methyl-4,6-pregnadien-[3,2-c]pyrazol. Denne forbindelse kan isoler-es ved å opplose reaksjonsblandingen i methanol og omkrystallisere. N sodium hydroxide solution and finally with water. The ether layer is freed from water with magnesium sulfate, filtered and evaporated to dryness in vacuo, whereby a residue is obtained whose main constituent is 17a,20,20,21-bis-(methylenedioxy)-2'-p-fluorophenyl-11B-hydroxy-16a- methyl-4,6-pregnadiene-[3,2-c]pyrazole. This compound can be isolated by dissolving the reaction mixture in methanol and recrystallizing.

70 mg 17a,20,20,21-bis-(methylendioxy)-16a-methyl-2'-(p-fluorfenyl)-lip-hydroxy-4,6-pregnadien-[3,2-c]pyrazol oppvarmes på dampbad med 2 ml 60 %'s vandig maursyre i 35 minutter. Overskuddet av reagens fjernes i vakuum på vannbad med temperatur ca. 50°C. Residuet vaskes grundig med vann og torres ved 80°C. Residuet vaskes grundig med vann og torres ved 80°C, hvorved man får 61,1 eng residuum. Dette residuum opploses i 3 ml spektrografisk ren methanol hvorpå det omsettes med 0,5 ml av en 0,1 N opplosning av natrium-methylat i methanol ved romtemperatur i 10 minutter. Produktet nbytraliseres med eddiksyre. Blandingen inndampes derpå til torrhet og vaskes grundig med vann, filtreres og torres til konstant vekt, hvorved man får lip,17a,21-trihydroxy-2'-(p-fluorfenyl)-16a-methyl-20-oxo-4,6-pregna-dien- [3,2-c]pyrazol, med sm.p. 197 - 203°C. a^5 = -26° (aceton) 70 mg of 17a,20,20,21-bis-(methylenedioxy)-16a-methyl-2'-(p-fluorophenyl)-lip-hydroxy-4,6-pregnadiene-[3,2-c]pyrazole is heated on a steam bath with 2 ml of 60% aqueous formic acid for 35 minutes. The excess reagent is removed in a vacuum in a water bath with a temperature of approx. 50°C. The residue is washed thoroughly with water and dried at 80°C. The residue is washed thoroughly with water and dried at 80°C, whereby 61.1 eng of residue is obtained. This residue is dissolved in 3 ml of spectrographically pure methanol, after which it is reacted with 0.5 ml of a 0.1 N solution of sodium methylate in methanol at room temperature for 10 minutes. The product is neutralized with acetic acid. The mixture is then evaporated to dryness and washed thoroughly with water, filtered and dried to constant weight, whereby lip,17a,21-trihydroxy-2'-(p-fluorophenyl)-16a-methyl-20-oxo-4,6- pregna-diene-[3,2-c]pyrazole, with m.p. 197 - 203°C. a^5 = -26° (acetone)

Ultrafiolett A = 280,313 m\ i. 15800, 19300. Ultraviolet A = 280.313 m\ in. 15800, 19300.

Eksempel 3 Example 3

En blanding av 71,6 mg 17a,20,20,21-bis-(methylendioxy)-9a-fluor-2-hydroxymethylen-16a-methyl-4,6-pregnadien-3,11-dion og 0,02 ml fenylhydrazin oppvarmes under tilbakelbpskjbling i 0,97 ml absolutt ethanol i 1 time. Et krystallinsk stoff skiller sig ut i varmen. Reaks jonsblandingen avkjbles og filtreres. Produktet vaskes med kold methanol, hvorved man får et stoff hvis hovedbestanddel er 17a,20,20,21-bis-(methylendioxy)-9a-fluor-16a-methyl-ll-oxo-2<1->fenyl-4,6-pregnadieh-[3,2-c]pyrazol. A mixture of 71.6 mg of 17a,20,20,21-bis-(methylenedioxy)-9a-fluoro-2-hydroxymethylene-16a-methyl-4,6-pregnadiene-3,11-dione and 0.02 ml of phenylhydrazine heated under reflux in 0.97 ml of absolute ethanol for 1 hour. A crystalline substance stands out in the heat. The reactive ion mixture is cooled and filtered. The product is washed with cold methanol, whereby a substance is obtained whose main constituent is 17a,20,20,21-bis-(methylenedioxy)-9a-fluoro-16a-methyl-11-oxo-2<1->phenyl-4,6 -pregnadieh-[3,2-c]pyrazole.

29,5 mg av sistnevnte forbindelse oppvarmes i nitrogenatmosfære på dampbad i 1 time samt 5 minutter i nitrogenatmosfære med 12 ml 60 %'s vandig maursyre. Den erholdte opplosning inndampes til torrhet, tilsettes vann og produktet f raf Utreres, hvorved man får 9a-fluor-17a,21-dihydroxy-16a-methyl-ll,20-dioxo-2'-fenyl-4,6-pregna-dien- [3,2-c]pyrazol. 29.5 mg of the latter compound are heated in a nitrogen atmosphere on a steam bath for 1 hour and 5 minutes in a nitrogen atmosphere with 12 ml of 60% aqueous formic acid. The obtained solution is evaporated to dryness, water is added and the product from raf is extracted, whereby 9a-fluoro-17a,21-dihydroxy-16a-methyl-11,20-dioxo-2'-phenyl-4,6-pregna-diene is obtained - [3,2-c]pyrazole.

15 mg 17a,20,20,21-bis-(methylendioxy)-9a-fluor-16a-methyl-ll-oxo-2<1->fenyl-4,6-pregnadien-[3,2-c]pyrazol opploses i methylenklo- 15 mg of 17a,20,20,21-bis-(methylenedioxy)-9a-fluoro-16a-methyl-11-oxo-2<1->phenyl-4,6-pregnadiene-[3,2-c]pyrazole is dissolved in methylene chloride

Claims

rid og opplosningen tilsettes 0,03 ml av et reagens som fremstilles ved å opplose 0,55 ml triethylamin i 1,45 ml isopropyl, og derpå 2,5 ml av en opplosning fremstillet ved å tilsette 1 g natriumborhydrid til lOO ml isopropanol og frafiltrere uopploselig materiale. Der tilsettes 1 dråpe vann, hvorpå man lar blandingen stå natten over ved romtemperatur. Overskuddet av natriumborhydrid spaltes så med syre og residuet vaskes med vann, hvorved man får 17a,20,20,2l-bis-methyl-endioxy)-9a-fluor-llB-hydroxy-16a-methyl-2'-fenyl-4,6-pregnadien-[3,2-c]pyrazol. 9,4 mg av sistnevnte forbindelse oppvarmes i nitrogenatmosfære på dampbad i 35 minutter med 6 ml 60 %'s vandig maursyre. Den erholdte opplosning inndampes til torrhet, tilsettes vann og produktet frafiltreres, hvorved man får 9a-fluor-llS,17a,21-trihydroxy-16a-methyl-20-oxo-2'-fenyl-4,6-pregnadien-[3,2-c]pyrazol, med sm.p. 241 - 245°C (spaltning). a^<4>= -46°C (CHC13) Ultrafiolett A<=>283,314 mu.. i = 17700, 20900. Fremgangsmåte til fremstilling av nye 17a,21-dihydroxy-20-oxo-4,6-pregnadien-[3,2-c]-pyrazol-forbindelser eller deres 21^estere, som har åntiinflammatorisk.virkning, og -som tilsvarer én av de nedenstående generelle formler: rid and to the solution is added 0.03 ml of a reagent prepared by dissolving 0.55 ml of triethylamine in 1.45 ml of isopropyl, and then 2.5 ml of a solution prepared by adding 1 g of sodium borohydride to lOO ml of isopropanol and filtering insoluble material. 1 drop of water is added, after which the mixture is left overnight at room temperature. The excess of sodium borohydride is then split with acid and the residue is washed with water, whereby 17a,20,20,2l-bis-methyl-endioxy)-9a-fluoro-11B-hydroxy-16a-methyl-2'-phenyl-4, 6-pregnadiene-[3,2-c]pyrazole. 9.4 mg of the latter compound are heated in a nitrogen atmosphere on a steam bath for 35 minutes with 6 ml of 60% aqueous formic acid. The resulting solution is evaporated to dryness, water is added and the product is filtered off, whereby 9a-fluoro-11S,17a,21-trihydroxy-16a-methyl-20-oxo-2'-phenyl-4,6-pregnadiene-[3, 2-c]pyrazole, with m.p. 241 - 245°C (decomposition). a^<4>= -46°C (CHC13) Ultraviolet A<=>283.314 mu.. i = 17700, 20900. Process for the production of new 17α,21-dihydroxy-20-oxo-4,6-pregnadiene-[3,2-c]-pyrazole compounds or their 21α-esters, which have anti-inflammatory action, and which correspond to one of the following general formulas:

i hvilke 1^ betegner p-halogen, en p-hydroxy- eller ketogruppe, ag X betegner hydrogen eller halogen, idet R, kan være p-halogen bare i de tilfelle hvor også X er halogen, R2betegner hydrogen, fluor eller en methylgruppe,;R3 betegner en a-methyl-, p-methyl- eller methylengrup-pe, R4betegner hydrogen eller et acylradikal eller et fosforsyreradi-kal og R5 betegner et alkyl-, cycloalkyl-, aralkyl- eller arylradikal,karakterisert vedat man omsetter en ti. lsvarende 17a, 21-dihydroxy-3,20-dioxo-2-hydroxymethylen- eller 2-alkoxymethylen-4,6-pregnadien-forbindelse, i hvilken beskyttende grupper kan være tilstede i 17-, 20- og 21-stillingene, med et hydrazin med formelen R,_-NHNH2, hvor R,, har den ovenfor angitte betydning, hvorpå man fjer-ner eventuelt i tilstedeværende beskyttende grupper i 17-, 20- og 21-stillingene, og, om onskes, overforer det erholdte produkt til et 21-organisk acylat eller til et 21-fosfat.in which 1^ denotes p-halogen, a p-hydroxy or keto group, and X denotes hydrogen or halogen, as R can be p-halogen only in those cases where X is also halogen, R2 denotes hydrogen, fluorine or a methyl group, R3 denotes an α-methyl, p-methyl or methylene group, R4 denotes hydrogen or an acyl radical or a phosphoric acid radical and R5 denotes an alkyl, cycloalkyl, aralkyl or aryl radical, characterized by reacting a ti. lcorresponding to 17a, 21-dihydroxy-3,20-dioxo-2-hydroxymethylene- or 2-alkoxymethylene-4,6-pregnadiene compound, in which protecting groups may be present in the 17-, 20- and 21-positions, with a hydrazine with the formula R,_-NHNH2, where R,, has the meaning given above, after which any protective groups present in the 17-, 20- and 21-positions are removed, and, if desired, the product obtained is transferred to a 21-organic acylate or to a 21-phosphate.