NO142668B

NO142668B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 2H-PYRAN-2,6 (3H) -DION DERIVATIVES

Info

Publication number: NO142668B
Application number: NO752638A
Authority: NO
Inventors: Lawrence William Chakrin; Kenneth Means Snader; Chester Rhodes Willis
Original assignee: Smithkline Corp
Priority date: 1974-07-29
Filing date: 1975-07-25
Publication date: 1980-06-16
Also published as: ATA584475A; NO752638L; DE2533843A1; FI59406B; NL7509032A; DE2533843C2; JPS5136458A; FI752139A; DK134552B; CH615433A5; ES439664A1; FR2280367B1; IE41709L; GB1521712A; IE41709B1; HU174067B; FR2280367A1; DK134552C; NO142668C; DD118626A5

Description

Oppfinnelsen vedrorer en analogifrera<rangsmåte til fremstilling The invention relates to an analogous method of production

av terapeutisk virksomme, substituerte 2H-pyran-2,6(3H)-dionderi- of therapeutically active, substituted 2H-pyran-2,6(3H)-dionedi-

vater som er inhibitorer av antigen-antistoffreaksjonen. vats which are inhibitors of the antigen-antibody reaction.

De substituerte 2H-pyran-2,6(3H)-dionderivater, som fremstilles The substituted 2H-pyran-2,6(3H)-dione derivs., which are prepd

ved fremgangsmåten ifolge oppfinnelsen, har den folgende gene- in the method according to the invention, the following gene-

relle strukturformel real structural formula

hvori R er lavere alkyl med rettlinjet eller forgrenet kjede og fra 3-6 karbonatomer, hydroksyfenyl, alkanoyloksyfenyl, idet alkanoyldelen har fra 2-7 karbonatomer, karbamoyloksyfenyl, N-metylkarbamoyloksyfenyl, N-benzylkarbamoyloksyfenyl, N,N-dimetylkarbamoyloksyfenyl, p-merkaptofenyl, aminofenyl eller ureidofenyl. in which R is lower alkyl with a straight or branched chain and from 3-6 carbon atoms, hydroxyphenyl, alkanoyloxyphenyl, the alkanoyl part having from 2-7 carbon atoms, carbamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, N,N-dimethylcarbamoyloxyphenyl, p-mercaptophenyl, aminophenyl or ureidophenyl.

Fordelaktige forbindelser fremstilt ved fremgangsmåten er de forbindelser med formelen I, hvori R er n-propyl, p-merkapto- Advantageous compounds produced by the method are those compounds of the formula I, in which R is n-propyl, p-mercapto-

fenyl, hydroksyfenyl, p-acetoksyfenyl, p-pentanoyloksyfenyl, p-aminofenyl eller p-ureidofenyl. Fortrinnsvis er R p-hydroksy- phenyl, hydroxyphenyl, p-acetoxyphenyl, p-pentanoyloxyphenyl, p-aminophenyl or p-ureidophenyl. Preferably, R is p-hydroxy

fenyl. phenyl.

Fremgangsmåten ifolge oppfinnelsen omfatter omsetning av 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on med et. amin, RNH?, i hvilket R har samme betydning som i formelen I f Dg at man om ønsket omsetter en forbindelse, hvori R er hydroksyfenyl, ned et alkanoylhalogenid, hvilket gir de tilsvarende forbindel- The method according to the invention comprises reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with a amine, RNH?, in which R has the same meaning as in the formula I f Dg that, if desired, one converts a compound, in which R is hydroxyphenyl, down an alkanoyl halide, which gives the corresponding compounds

ser, hvori R er alkanoyloksyfenyl. Reaktantene o<p>pvarmes vanligvis til tilbakesvalingstemperatur i et indifferent, ser, wherein R is alkanoyloxyphenyl. The reactants are usually heated to reflux temperature in an indifferent,

organisk oppløsningsmiddel, såsom benzen, toluen eller en alka-nol, såsom metanol eller etanol, i 2 til 12 timer til oppnåelse av produktene. organic solvent such as benzene, toluene or an alkanol such as methanol or ethanol for 2 to 12 hours to obtain the products.

Forbindelsene, hvori R er alkanoyloksyfenyl, fremstilles hensiktsmessig ut fra det tilsvarende hydroksyfenylderivat ved omsetning med dét behorige alkanoylklorid, fortrinnsvis i en organisk base, såsom trietylamin, og et ikke-reaktivt opplos-ningsmiddel, såsom tetrahydrofuran. The compounds, in which R is alkanoyloxyphenyl, are suitably prepared from the corresponding hydroxyphenyl derivative by reaction with the appropriate alkanoyl chloride, preferably in an organic base, such as triethylamine, and a non-reactive solvent, such as tetrahydrofuran.

For letthets skyld betegnes det ved den omhandlede fremgangs-måte benyttede utgangsmaterialet her som 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on og oppnås ved omsetning av aceton-dikarboksylsyre og eddiksyre, idet omsetningen utfores i svovelsyre ved foroket temperatur. Imidlertid er det ved denne omsetningen oppnådde produkt den nedenfor viste tautomere struktur: For the sake of simplicity, the starting material used in the method in question is referred to here as 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and is obtained by reacting acetone-dicarboxylic acid and acetic acid, the reaction being carried out in sulfuric acid at increased temperature. However, the product obtained by this reaction is the tautomeric structure shown below:

13 13

Dette har vært konkludert ut fra c kjernemagnetisk resonans-spektrale og rontgenkrystallografiske undersokelser. Tauto-merisasjonsomfanget representert ved (X),som ovenfor anfort, påvirkes blant andre faktorer av det benyttede opplosningsmid-del ved C 13-spektralundersokelsen. Folgelig resulterer omsetning av dette produkt med et amin, RNi^, ved fremgangsmåten ifolge oppfinnelsen i et produkt med de nedenfor viste tautomere formler: This has been concluded from nuclear magnetic resonance spectral and X-ray crystallographic investigations. The extent of tautomerization represented by (X), as stated above, is influenced by, among other factors, the solvent used in the C 13 spectral examination. Consequently, reaction of this product with an amine, RNi^, by the method according to the invention results in a product with the tautomeric formulas shown below:

i hvilke R har samme betydning som i formelen I. in which R has the same meaning as in formula I.

Selv om det ikke har vært mulig ved hjelp av C 13-kjernemagnetisk resonans å identifisere den eksakte tautomer representert ved (iT) i opplosning, har rontgenkrystallografisk undersokelse av forbindelsen i fast form, hvori R betyr p-hydroksyfenyli vist at karbon-karbonbindingene som folge av vidtgående konjuga-sjon er hybridisert gjennom hele molekylet, hvorfor båndleng-dene ligger et sted mellom verdiene for dobbeltbindinger og enkeltbindinger. Ettersom et av de utskiftbare hydrogenato-mer i denne forbindelsen er plassert ved nitrogenatornet, har man for letthets skyld valgt å benytte en tautomerform, nemlig den intermediære enamin-pyran-2,6-dionstruktur, til å repre-sentere alle forbindelsene dannet ved omsetning av (a) med et amin, RNH2, som angitt ved den ovenfornevnte formel I. Det vil imidlertid fremgå for fagmannen at den mer fullstendige angivelsen av forbindelsene med formelen I fremgår av tauto-merisasjonen ( b) . Although it has not been possible by means of C 13 nuclear magnetic resonance to identify the exact tautomer represented by (iT) in solution, X-ray crystallographic examination of the compound in solid form, where R is p-hydroxyphenyl, has shown that the carbon-carbon bonds as follows of extensive conjugation are hybridized throughout the molecule, which is why the band lengths lie somewhere between the values for double bonds and single bonds. As one of the exchangeable hydrogen atoms in this compound is located at the nitrogen atom, for the sake of simplicity it has been chosen to use a tautomeric form, namely the intermediate enamine-pyran-2,6-dione structure, to represent all the compounds formed by reaction of (a) with an amine, RNH2, as indicated by the above-mentioned formula I. However, it will be apparent to the person skilled in the art that the more complete indication of the compounds with the formula I appears from the tautomerization (b).

Forbindelsene fremstilt ved fremgangsmåten ifolge oppfinnelsen inhiberer frigjorelse og/eller dannelse av farmakologisk aktive formidlere fra effektorceller utlost ved hjelp av vekselvirk-ningen mellom antigen og et spesifikt antistoff, som er fast-gjort til behandling av allergiske sykdommer, såsom astma, rhinitis og urticaria. The compounds produced by the method according to the invention inhibit the release and/or formation of pharmacologically active mediators from effector cells released by means of the interaction between antigen and a specific antibody, which is attached to the treatment of allergic diseases, such as asthma, rhinitis and urticaria.

Den inhiberende virkning av forbindelsene fremstilt ved fremgangsmåten ifolge oppfinnelsen på formidlerfrigjdreise i vev, som er gjort folsomt, måles ved hjelp av det aktive medi-kaments evne til å inhibere den passive hudoverfolsomhet (PCA)-reaksjon hos rotter. Ved dette avprovningssystem injiseres titerinstilt og på passende måte fortynnet serum (fra rotter, som på forhånd er blitt immunisert ved hjelp av intraperitoneal injeksjon av ovalbuminaluminiumhydroksyd eller ovalbumin-i.m.-bordatella pertussis U.S.P. i.p.- og N-brasiliensis i.p.) inneholdende reaginiske antistoffer overfor ovalbumin intradermalt på fire steder på de barberte rygger på normalejvoksne hanrotter. 48 timer senere injiseres dyrene intravenost med 0,5 ml isoto-nisk saltopplosning inneholdende 5 mg av ovalbuminantigenet og 5 mg av Evans blå fargestoff. Kjemiske formidlere, såsom histamin ogserotonin, som frigjores på de folsomtgjorte steder som resultat av en lokal cellular overfølsomhet, bevirker en for-okelse av den kapillare permeabilitet med resulterende utsiv-ning av plasma og dannelse av en vable. Vablen gjores synlig ved hjelp av det plasmaproteinbundne Evans blå fargestoff. Under forsøksbetingelsene er den gjennomsnittlige kontroll-vable ca. 12 x 12 mm. 30 minutter etter antigenpåvirkningen drepes dyrene, rygg skinnet betraktes og diameteren av vablene måles. En forsoksforbindelse administreres intravenost til å begynne med 1/2 minutt for antigenpåvirkningen (lengre forbe-handlingstider og andre legemiddeladministråsjonsveier, d.v.s. The inhibitory effect of the compounds produced by the method according to the invention on mediator release in sensitized tissue is measured by the ability of the active drug to inhibit the passive skin hypersensitivity (PCA) reaction in rats. In this testing system, titrated and appropriately diluted serum (from rats, which have been previously immunized by intraperitoneal injection of ovalbumin aluminum hydroxide or ovalbumin-i.m.-bordatella pertussis U.S.P. i.p.- and N-brasiliensis i.p.) containing reaginic antibodies to ovalbumin is injected intradermally in four places on the shaved backs of normal adult male rats. 48 hours later, the animals are injected intravenously with 0.5 ml isotonic saline solution containing 5 mg of the ovalbumin antigen and 5 mg of Evans blue dye. Chemical mediators, such as histamine and serotonin, which are released at the sensitized sites as a result of a local cellular hypersensitivity, cause an increase in the capillary permeability with resulting leakage of plasma and formation of a blister. The blister is made visible using the plasma protein-bound Evans blue dye. Under the experimental conditions, the average control-vable is approx. 12 x 12 mm. 30 minutes after the antigen exposure, the animals are killed, the back skin is examined and the diameter of the blisters is measured. A test compound is administered intravenously initially 1/2 minute before antigen exposure (longer pretreatment times and other drug administration routes, i.e.

oral eller intraperitoneal, kan benyttes). Prosent inhibering beregnes ut fra forskjellen i middelvabeldiameter mellom en behandlet gruppe og kontrolldyr inngitt saltvann eller et passende fortynningsmiddel. oral or intraperitoneal, can be used). Percent inhibition is calculated from the difference in mean blister diameter between a treated group and control animals administered saline or an appropriate diluent.

Forbindelsene med formelen I administrert intravenost til rotter i doser fra 0,5 til 10 mg/kg fremkaller en uttalt inhibering av PCA-reaksjonen. En foretrukket forbindelse, 5-acetyl-4-hydroksy-3-[1- (p-hydroksyfenylamino)-etyliden]-2H-pyran-2,6(3H)-dion, fremkalte 73^ inhibering av rotte-PCA-vablen ved 5,0 mg/kg- i.v. En annen foretrukket forbindelse, 5-acetyl-4-hydroksy-3-[1-(p-merkaptofenylamino)-etyliden]-2-H-pyran-2,6 (3H)-dion, fremkalte 100% inhibering av rotte-PCA-vablen ved 5,0 mg/kg, i.v. På lignende måte fremkalte 5-acetyl-3-[1-(p-aminofenylamino)etyliden j-4-hydroksy-2H-pyran-2,6(3H)-dion 58% inhibering av rotte-PCA-vablen ved 0,5 mg/kg, i.v. The compounds of formula I administered intravenously to rats in doses from 0.5 to 10 mg/kg produce a pronounced inhibition of the PCA reaction. A preferred compound, 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)-ethylidene]-2H-pyran-2,6(3H)-dione, produced 73^ inhibition of the rat PCA bladder by 5.0 mg/kg- i.v. Another preferred compound, 5-acetyl-4-hydroxy-3-[1-(p-mercaptophenylamino)-ethylidene]-2-H-pyran-2,6 (3H)-dione, produced 100% inhibition of rat PCA -vablen at 5.0 mg/kg, i.v. Similarly, 5-acetyl-3-[1-(p-aminophenylamino)ethylidene j-4-hydroxy-2H-pyran-2,6(3H)-dione produced 58% inhibition of the rat PCA bladder at 0.5 mg/kg, i.v.

Ved avprovning av virkningsmekanismen viste forbindelsene med formelen I seg ikke å frembringe en sammenlignbar eller tilsvarende inhibering av vabler av tilsvarende alvorlighet frem-kalt på rotter ved intracutan administrasjon av histamin og serotonin etter intravenøs administrasjon av forsøksforbindel-sen ved samme dosis- og forbehandlingstid, som fremkalte signi-fikant inhibering av 48 timers rotte-PCA-reaksjonen. When testing the mechanism of action, the compounds of formula I did not prove to produce a comparable or equivalent inhibition of blisters of similar severity induced in rats by intracutaneous administration of histamine and serotonin after intravenous administration of the test compound at the same dose and pretreatment time, which produced significant inhibition of the 48 h rat PCA reaction.

Etter oral administrasjon fremkalte 5-acetyl-4-hydroksy-3-[1-(p-hydroksyfenyl amino)ety1iden]—2H—pyran—2,6(3H)—dion 58%'s inhibering i 48 timers rotte-PCA-systemet ved 25 mg/kg og en forbehandlingstid på 15 minutter. Denne forbindelsen er også aktiv in vitro til inhibering av antigenindusert formidlerfrigjørelse fra apelunge- og hud-, samt rottelunge-systemer ved konsentra-sjoner på 3,3 x 10 -4 " til 3,3 x 10 -6M. På lignende måte fremkaller 5-acetyl-3-[1-(p-aminofenylamino)-etyliden]-4-hydroksy-2H-pyran-2,6(3H)-dion etter oral administrasjon 32%'s inhibering i 4 8 timers rotte-PCA-systemet ved 25 mg/kg og en forbehandlingstid på 5 minutter. After oral administration, 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6(3H)-dione produced 58% inhibition in 48 hours of rat PCA- system at 25 mg/kg and a pretreatment time of 15 minutes. This compound is also active in vitro to inhibit antigen-induced mediator release from monkey lung and skin, as well as rat lung systems at concentrations of 3.3 x 10 -4 " to 3.3 x 10 -6 M. Similarly, 5 induces -acetyl-3-[1-(p-aminophenylamino)-ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione after oral administration 32% inhibition in the 4 8 hour rat PCA system at 25 mg/kg and a pretreatment time of 5 minutes.

I den etterfølgende tabell vises forsøksdata erholdt ved rotte-PCA-forsøksmetoden for en rekke forbindelser med den generelle The following table shows experimental data obtained by the rat PCA experimental method for a number of compounds with the general

formel I. formula I.

Inhibering av passiv hudoverfølsomhet (PCA)-reaksjon hos rotter Inhibition of passive skin hypersensitivity (PCA) reaction in rats

Forbindelsene fremstilt ved fremgangsmåten ifølge oppfinnelsen benyttes hensiktsmessig i form av et farmasøytisk preparat om-fattende en passende mengde av et substituert 2H-pyran-2,6(3H)-dionderivat som angitt ved formelen I i forbindelse med et farmasøytisk bæremateriale eller fortynningsmiddél. Typen av preparatet og det farmasøytiske bæremateriale eller fortynningsmiddél vil selvsagt avhenge av den påtenkte administrasjonsvei, dvs. oralt, parenteralt eller ved innhalering. Det aktive medi-kamentet administreres fortrinnsvis til et dyr i et preparat inneholdende en tilstrekkelig mengde til å fremkalle en inhibering av antigen-antistoffreaksjonen. Ved sådan benyttelse er doseringen av preparatet slik at det administreres fra 0,5 mg til 500 mg aktiv bestanddel ved hver administrasjon. Det administreres hensiktsmessig samme doser 1 til 4 ganger daglig, idet den daglige dosering er fra ca. 0,5 mg til ca. 2000 mg. The compounds produced by the method according to the invention are suitably used in the form of a pharmaceutical preparation comprising a suitable amount of a substituted 2H-pyran-2,6(3H)-dione derivative as indicated by formula I in connection with a pharmaceutical carrier material or diluent. The type of the preparation and the pharmaceutical carrier material or diluent will of course depend on the intended route of administration, i.e. oral, parenteral or by inhalation. The active drug is preferably administered to an animal in a preparation containing a sufficient amount to induce an inhibition of the antigen-antibody reaction. In such use, the dosage of the preparation is such that from 0.5 mg to 500 mg of active ingredient is administered at each administration. The same doses are appropriately administered 1 to 4 times a day, the daily dosage being from approx. 0.5 mg to approx. 2000 mg.

De følgende eksempler illustrerer fremgangsmåten ifølge oppfinnelsen og fremstillingen av spesifikke forbindelser med formelen I. The following examples illustrate the method according to the invention and the preparation of specific compounds of the formula I.

Eksempel 1 Example 1

Til en kokende opplosning av 4,2 g (0,02 mol) 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on i 150 ml benzen/metanol settes 1,2 g (0^02 mol) n-propylamin, og den resulterende blanding varmes under tilbakesvaling natten over. Reaksjonsblandingen konsentreres og filtreres, og det faste materiale behandles med vann til oppnåelse av ren 5-acetyl-4-hydroksy-3-[l-(n-propylamino)etyliden]-2H-pyran-2,6(3H)-dion med smeltepunkt 145-148°C. To a boiling solution of 4.2 g (0.02 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml of benzene/methanol is added 1.2 g (0^02 mol ) n-propylamine, and the resulting mixture is heated under reflux overnight. The reaction mixture is concentrated and filtered, and the solid is treated with water to obtain pure 5-acetyl-4-hydroxy-3-[1-(n-propylamino)ethylidene]-2H-pyran-2,6(3H)-dione with melting point 145-148°C.

På lignende måte varmes 1,8 g (0,025 mol) n-butylamin og 5,3 g (0,025 mol) 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on under tilbakesvaling natten over i 50 ml benzen, og det resulterende faste materiale frafiltreres til oppnåelse av 5-acetyl-3-[l-(n-butylamino)etyliden]-4-hydroksy-2H-pyran-2,6(3H)-dion med smeltepunkt 112-114°C. In a similar manner, 1.8 g (0.025 mol) of n-butylamine and 5.3 g (0.025 mol) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are heated under reflux overnight in 50 ml benzene, and the resulting solid material is filtered off to obtain 5-acetyl-3-[1-(n-butylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione with melting point 112-114° C.

Eksempel 2 Example 2

Til en kokende opplosning av 4,2 g (0,02 mol) 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on i 150 ml benzen settes 2,0 g (0,02 mol) n-heksylamin, blandingen inndampes, og den oljeaktige rest findeles med petroleumseter til oppnåelse av 5-acetyl-2-[l-(n-heksylamino)-etyliden]-4-hydroksy-2H-pyran-2,6(3H)-dion 2.0 g (0.02 mol) of n -hexylamine, the mixture is evaporated, and the oily residue is triturated with petroleum ether to obtain 5-acetyl-2-[1-(n-hexylamino)-ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione

med smeltepunkt 80-82°C." with a melting point of 80-82°C."

Eksempel 3 Example 3

Til en kokende opplosning av 4,24 g (0,02 mol) 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on i 200 ml metanol settes 2,18 g (0,02 mol) p-hydroksyanilin. Den resulterende blanding varmes under tilbakesvaling natten over og filtreres til oppnåelse av 5-acetyl-4-hydroksy-3-[1-(p-hydroksyfenylamino)-etyl iden]-2H-pyran-2,6 (3H)-dion med smeltepunkt 223-225°C. 2.18 g (0.02 mol) p -hydroxyaniline. The resulting mixture is heated under reflux overnight and filtered to obtain 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)-ethylidene]-2H-pyran-2,6(3H)-dione of m.p. 223-225°C.

På lignende måte omsettes m-hydroksyanilin og o-hydroksyanilin med en ekvimolær mengde 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on i.metanol til oppnåelse av de respektive produkter hen-holdsvis 5-acetyl-4-hydroksy-3-[l-(m-hydroksyfenylamino)-etyli-den] -2H-pyran-2,6(3H)-dion med smeltepunkt 213-216°C og 5-ace-tyl_4-hydroksy-3-[l-(o-hydroksyfenylamino)-etyliden]-2H-pyran-2,6(3H)-dion med smeltepunkt 210-212°C. In a similar manner, m-hydroxyaniline and o-hydroxyaniline are reacted with an equimolar amount of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol to obtain the respective products 5-acetyl- 4-hydroxy-3-[1-(m-hydroxyphenylamino)-ethylidene]-2H-pyran-2,6(3H)-dione with melting point 213-216°C and 5-acetyl_4-hydroxy-3- [1-(o-Hydroxyphenylamino)-ethylidene]-2H-pyran-2,6(3H)-dione with melting point 210-212°C.

Til en opplosning av 3,03 g (0,01 mol) 5-acetyl-4-hydroksy-3-[l-(p-hydroksyfenylamino)etyliden]-2H-pyran-2,6 (3H)-dion og 1,0 g (0,01 mol) trietylamin i 150 ml tetrahydrofuran settes 0,78 g (0,01 mol) acetylklorid. Den resulterende blanding varmes under tilbakesvaling i 2 timer, kjoles og filtreres. Det faste materiale rekrystalliseres til oppnåelse av 3-[l-(p-acetoksyfenylamino)etyliden]-5-acetyl-4-hydroksy-2H-pyran-2,6 (3H)-dion med smeltepunkt 199-201°C. To a solution of 3.03 g (0.01 mol) of 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6 (3H)-dione and 1, 0 g (0.01 mol) of triethylamine in 150 ml of tetrahydrofuran is added to 0.78 g (0.01 mol) of acetyl chloride. The resulting mixture is heated under reflux for 2 hours, cooled and filtered. The solid material is recrystallized to obtain 3-[1-(p-acetoxyphenylamino)ethylidene]-5-acetyl-4-hydroxy-2H-pyran-2,6 (3H)-dione with melting point 199-201°C.

På lignende måte omsettes ekvimolære mengder av 5-acetyl-4-hydroksy-3-[l-(p-hydroksyfenylamino)etyliden]-2H-pyran-2,6-(3H)-dion og et passende alkanoylklorid som ovenfor beskrevet til oppnåelse av folgende alkanoyloksyderivater: 5-acetyl-4-hydroksy-3-[l- (p-propionyloksyfenylamino)etyliden]-2H-pyran-2,6 (3H) dion, smeltepunkt 168-170°C$In a similar manner, equimolar amounts of 5-acetyl-4-hydroxy-3-[1-(p-hydroxyphenylamino)ethylidene]-2H-pyran-2,6-(3H)-dione and an appropriate alkanoyl chloride are reacted as described above to obtain of the following alkanoyloxy derivatives: 5-acetyl-4-hydroxy-3-[1-(p-propionyloxyphenylamino)ethylidene]-2H-pyran-2,6 (3H)dione, melting point 168-170°C$

5-acetyl-3-[1- (p-butyryloksyfenylamino)etyliden]-4-hydroksy-2H-pyran-2,6(3H)-dion, smeltepunkt 158-160°C^5-acetyl-3-[1-(p-butyryloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione, melting point 158-160°C^

5-acetyl-4-hydroksy-3-[1-(p-pentanoyloksyfenylamino)etyliden]-2H-pyran-2 ,6 (3H)-dion, smeltepunkt 155-157°C-, 5-acetyl-4-hydroxy-3-[1-(p-pentanoyloxyphenylamino)ethylidene]-2H-pyran-2,6 (3H)-dione, melting point 155-157°C-,

5-acetyl-3-[1- (p-heksanoyloksyfenylamino)etyliden]-4-hydroksy-2H-pyran-2,6 (3H)-dion, smeltepunkt 148-149°C; 5-acetyl-3-[1-(p-hexanoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6 (3H)-dione, melting point 148-149°C;

5-acetyl-3-[1-(p-heptanoyloksyfenylamino)etyliden]-4-hydroksy-2H-pyran-2,6 (3H)-dion, smeltepunkt 147-148°C. 5-acetyl-3-[1-(p-heptanoyloxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6 (3H)-dione, melting point 147-148°C.

Eksempel 4 Example 4

En blanding av 2,12 g 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on , 1,25 g p-aminotiofenol og 75 ml metanol varmes under tilbakesvaling i 2 timer, kjoles og filtreres' til oppnåelse av 5-ace-tyl-4-hydroksy-3-[1-(p-merkaptofenylamino)etyliden]-2H-pyran-2,6 (3H)-dion med smeltepunkt 207-210°c. A mixture of 2.12 g of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 1.25 g of p-aminothiophenol and 75 ml of methanol is heated under reflux for 2 hours, cooled and filtered to obtaining 5-acetyl-4-hydroxy-3-[1-(p-mercaptophenylamino)ethylidene]-2H-pyran-2,6 (3H)-dione with melting point 207-210°c.

Eksempel 5 Example 5

o-fenylendiamin (2,1 g, 0,02 mol) settes til en varm opplosning av 4,2 g (0,02 mol) 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on i metanol, og den resulterende blanding varmes under tilbakesvaling i 2 timer. Reaksjonsblandingen kjoles og filtreres til oppnåelse av 5-acetyl-3-[1-(o-aminofenylamino)etyliden]-4-hydroksy-2H-pyran-2,6(3H)-dion med smeltepunkt 179-181°C. o-Phenylenediamine (2.1 g, 0.02 mol) is added to a hot solution of 4.2 g (0.02 mol) 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol, and the resulting mixture is heated under reflux for 2 hours. The reaction mixture is cooled and filtered to obtain 5-acetyl-3-[1-(o-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6(3H)-dione with melting point 179-181°C.

På lignende måte resulterer omsetning av en ekvimolær mengde p-fenylendiamin som ovenfor beskrevet i den tilsvarende 5-ace-tyl-3-[l-(p-aminofenylamino)etyliden]-4-hydroksy-2H-pyran-2,6 (3H)-dion med smeltepunkt 215-218°C. Similarly, reaction of an equimolar amount of p-phenylenediamine as described above results in the corresponding 5-acetyl-3-[l-(p-aminophenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6 (3H )-dione with melting point 215-218°C.

Eksempel & Example &

Til en kokende opplosning av 2,1 g (0,01 mol) 3,5-diacetyl-4,6-dihydroksy-2H-pyran-2-on i 150 ml metanol settes 2,4 g To a boiling solution of 2.1 g (0.01 mol) 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml of methanol, add 2.4 g

(O,01 mol) p-(N-benzylkarbamoyloksy)anilin, og den resulterende blanding varmes under tilbakesvaling i 1 time. Den avkjolte reaksjonsbla nding filtreres, og det faste materiale rekrystalliseres til oppnåelse av 5-acetyl-3-[l-(p-N-benzylkarbamoyl-oksyfenylamino)etyliden]-4-hydroksy-2H-pyran-2,6-(3H)-dion med smeltepunkt 195-197 C. (0.01 mol) of p-(N-benzylcarbamoyloxy)aniline, and the resulting mixture is heated under reflux for 1 hour. The cooled reaction mixture is filtered, and the solid material is recrystallized to obtain 5-acetyl-3-[1-(p-N-benzylcarbamoyl-oxyphenylamino)ethylidene]-4-hydroxy-2H-pyran-2,6-(3H)-dione with melting point 195-197 C.

Eksempel 7 Example 7

En opplosning av 1,88 g (0,01 mol) p-karbamoyloksyanilin-hydroklorid og 1,0 g (0,01 mol) trietylamin i 50 ml metanol settes til en varm opplosning av 2,21 g (0,01 mol) 3,5-diace-tyl-4,6-dihydroksy-2H-pyran-2-on i 150 ml metanol. Den resulterende blanding varmes under tilbakesvaling i 2 timer, kjoles, og det frafiltrerte faste materiale rekrystalliseres til oppnåelse av 5-acetyl-3-[l-(p-karbamoyloksyfenylamino)-etyliden]-4-hydroksy-2H-pyran-2,6(3H)-dion med smeltepunkt 213-215°C. A solution of 1.88 g (0.01 mol) of p-carbamoyloxyaniline hydrochloride and 1.0 g (0.01 mol) of triethylamine in 50 ml of methanol is added to a hot solution of 2.21 g (0.01 mol) 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml of methanol. The resulting mixture is heated at reflux for 2 hours, cooled, and the filtered solid recrystallized to give 5-acetyl-3-[1-(p-carbamoyloxyphenylamino)-ethylidene]-4-hydroxy-2H-pyran-2,6 (3H)-dione with melting point 213-215°C.

Claims

Example 3 A solution of 1.5 g (0.01 mol) p-ureidoaniline in 50 ml methanol is added to a solution of 2.1 g (0.01 mol) 3,5-diacetyl-4,6-dihydroxy-2H -pyran-2-one in 150 ml of methanol. A solid immediately forms and the mixture is heated under reflux for 12 hours. The filtered off solid is recrystallized to obtain 5-acetyl-4-hydroxy-3-[1-(p-ureidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione with melting point 250-253°C .

Analogous method for the preparation of therapeutically active compounds of the formula: in which R denotes a lower alkyl group with a straight or branched chain and from 3-6 carbon atoms, hydroxyphenyl, alkanoyloxyphenyl, in which the alkanoyl part has from 2-7 carbon atoms, carbamoyloxyphenyl, N-methylcarbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl , N,N-dimethylcarbamoyloxyphenyl, p-mercaptophenyl, aminophenyl or ureidophenyl, characterized by reacting 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one with an amine, RNf^, in which R has the meaning given above, and that, if desired, a compound in which R is hydroxyphenyl is reacted with an alkanoyl halide, which gives the corresponding compounds in which R is alkanoyloxyphenyl.