NO744184L

NO744184L -

Info

Publication number: NO744184L
Application number: NO744184A
Authority: NO
Inventors: T B Lee; D N Hardern; J R Bantick
Original assignee: Fisons Ltd
Priority date: 1973-11-21
Filing date: 1974-11-20
Publication date: 1975-06-16
Also published as: FR2257287A1; SE7414597L; AU7528074A; FR2257287B1; IL46028A0; ES432101A1; JPS50105667A; CH605890A5; NL7415175A; DK603774A; FI331474A; DE2454670A1; SE415760B

Description

Fremgangsmåte til fremstilling av terapeutisk virksomme forbindelser. Process for the production of therapeutically active compounds.

Foreliggende oppfinnelse vedrører fremstilling av nye, terapeutisk virksomme forbindelser med den generelle formel: The present invention relates to the production of new, therapeutically active compounds with the general formula:

hvor enten Ra er hydrogen og Rb er ■ en 4-karboksyfenylgruppe eller Ra og, Rb sammen danner, med karbonatomene til hvilke de er festet, en 6-leddet aromatisk karbocyklisk ring substituert i en enkelt tilgjengelig stilling med en karboksylgruppe, R 1 , R 2, 3 4 . • where either Ra is hydrogen and Rb is ■ a 4-carboxyphenyl group or Ra and, Rb together form, with the carbon atoms to which they are attached, a 6-membered aromatic carbocyclic ring substituted in a single accessible position by a carboxyl group, R 1 , R 2, 3 4 . •

R og R , som kan være Like eller forskjellige, hver er hydrogen, hydroksy, alkenyl, alkanoyl eller alkyl, og X er en hydrokarbonkjede inneholdende 2-10 karbonatomer, eventuelt substituert med en hydroksygruppe, samt farmasøytisk akseptable derivater derav. R and R , which may be the same or different, each is hydrogen, hydroxy, alkenyl, alkanoyl or alkyl, and X is a hydrocarbon chain containing 2-10 carbon atoms, optionally substituted with a hydroxy group, as well as pharmaceutically acceptable derivatives thereof.

De nye forbindelser med formel I eller deres farmasøytisk akseptable derivater fremstilles ifølge oppfinnelsen ved: The new compounds of formula I or their pharmaceutically acceptable derivatives are prepared according to the invention by:

a) hydrolyse av en forbindelse med formelen:a) hydrolysis of a compound of the formula:

12 3 4 hvor R , R , R , R og X har den ovenfor angitte betydning, og hvor enten Rc er hydrogen og Rd er en fenylgruppe substituert i 4-stillingen med en gruppe D, hvor D er en gruppe som kan hydrolyseres til en karboksygruppe, eller Rc og Rd danner sammen med karbonatomet til hvilke de er festet, en 6-leddet aromatisk karbocyklisk ring substituert i en enkel 'tilgjengelig stilling med en gruppe D som definert ovenfor, eller b) omsetning av en forbindelse med formel III eller en ester derav med en forbindelse med formel IV: 12 3 4 where R , R , R , R and X have the above meaning, and where either Rc is hydrogen and Rd is a phenyl group substituted in the 4-position with a group D, where D is a group that can be hydrolyzed to a carboxy group, or Rc and Rd, together with the carbon atom to which they are attached, form a 6-membered aromatic carbocyclic ring substituted in a single accessible position by a group D as defined above, or b) reacting a compound of formula III or a ester thereof with a compound of formula IV:

12 3 4 12 3 4

hvor Ra, Rb, R , R , R og R har den ovenfor angitte betydning,where Ra, Rb, R , R , R and R have the above meaning,

og Y og Z er paret av grupper i) hydrogen eller et reaktivt metall og ii) en hydrokarbonkjede med 2-10 karbonatomer og inneholdende en aniondannende gruppe eller en epoksydgruppe, og and Y and Z are the pair of groups i) hydrogen or a reactive metal and ii) a hydrocarbon chain of 2-10 carbon atoms and containing an anion-forming group or an epoxide group, and

c) om ønsket eller nødvendig, omdannelse av den resulterende forbindelse med formel I til et farmasøytisk akseptabelt c) if desired or necessary, converting the resulting compound of formula I into a pharmaceutically acceptable

derivat derav eller vice versa.derivative thereof or vice versa.

I metode a) kan gruppen D f.eks. være en karboksylisk ester - (spesielt en C 1 til C 6 alkansyreester), amid- eller nitrilgruppe, som kan hydrolyseres til en -COOH-gruppe. Hydrolysen kan utføres under anvendelse av konvensjonell teknikk, f.eks. In method a), the group D can e.g. be a carboxylic ester - (especially a C 1 to C 6 alkanoic acid ester), amide or nitrile group, which can be hydrolysed to a -COOH group. The hydrolysis can be carried out using conventional techniques, e.g.

under milde basiske betingelser, f.eks. ved benyttelse av natriumbikarbonat. under mild basic conditions, e.g. using sodium bicarbonate.

I metode b), når Y eller Z er et reaktivt metall,In method b), when Y or Z is a reactive metal,

kan metallet f.eks. være et alkalimetall f.eks. natrium, eller et annet reaktivt metall, f.eks. thallium. Når Y eller Z er en hydrokarbonkjede inneholdende en aniondannende gruppe, kan denne gruppe f.eks. være et halogenatom, f.eks. brom eller en sulfonatgruppe f.eks. en metylsulfonat- eller p-toluensulfonat-gruppe. Når Y eller Z er en hydrokarbonkjede inneholdene et halogenatom kan reaksjonen utføres i nærvær av et oppløsnings-middel som er inert under reaksjonsbetingelsene, f.eks. aceton og i nærvær av en syreakseptor, f.eks. kaliumkarbonat. Reaksjonen utføres også fortrinnsvis under vannfrie betingelser og i nærvær can the metal e.g. be an alkali metal, e.g. sodium, or another reactive metal, e.g. thallium. When Y or Z is a hydrocarbon chain containing an anion-forming group, this group can e.g. be a halogen atom, e.g. bromine or a sulphonate group e.g. a methylsulfonate or p-toluenesulfonate group. When Y or Z is a hydrocarbon chain containing a halogen atom, the reaction can be carried out in the presence of a solvent which is inert under the reaction conditions, e.g. acetone and in the presence of an acid acceptor, e.g. potassium carbonate. The reaction is also preferably carried out under anhydrous conditions and in the presence of

av en egnet katalysator, f.eks. Kl. Når Y eller Z er en hydro-karbongruppe inneholdende en epoksydgruppe, kan reaksjonen ut- of a suitable catalyst, e.g. At When Y or Z is a hydrocarbon group containing an epoxide group, the reaction can

føres ved forhøyet temperatur i et oppløsningsmiddel som er inert under reaksjonsbetingelsene, f.eks. dioksan eller dimetylformamid og i nærvær av en egnet katalysator, f.eks. trimetylbenzyl-ammoniumhydroksyd. Reaksjonen kan alternativt utføres i nærvær av en tertiær alkohol, f.eks. t-butanol eller 1,1-dimetylpropan-l-ol og i nærvær av kaliumsaltet av alkoholen som katalysator. is conducted at an elevated temperature in a solvent which is inert under the reaction conditions, e.g. dioxane or dimethylformamide and in the presence of a suitable catalyst, e.g. trimethylbenzyl ammonium hydroxide. The reaction can alternatively be carried out in the presence of a tertiary alcohol, e.g. t-butanol or 1,1-dimethylpropan-l-ol and in the presence of the potassium salt of the alcohol as a catalyst.

Forbindelsene med formlene III, IV og XIII er entenThe compounds of formulas III, IV and XIII are either

kjent eller de kan fremstilles fra kjente utgangsmaterialer på i og for seg kjent måte for fremstilling av lignende kjente forbindelser. Forbindelsene med formel XIII kan fremstilles f.eks. known or they can be prepared from known starting materials in a manner known per se for the preparation of similar known compounds. The compounds of formula XIII can be prepared, e.g.

ved hjelp av en metode analog med metode b) ovenfor.using a method analogous to method b) above.

Forbindelser med formel I og, om ønsket eller nødvendig, mellomproduktene for oppnåelse derav, kan innvinnes fra reaksjons blandingene hvori de dannes, ved hjelp av konvensjonelle teknikker. Compounds of formula I and, if desired or necessary, the intermediates for obtaining them, can be recovered from the reaction mixtures in which they are formed, by means of conventional techniques.

Forbindelsene med formel I og deres farmasøytisk akseptable derivater, f.eks. deres farmasøytisk akseptable salter, estere, spesielt C 1-6 alkansyreestere, og amider, f.eks. deres natrium-, lavere alkylamin-, f.eks. etylamin- og hydroksysubstituerte lavere alkylaminsalter, er også nyttige fordi de er i besittelse av farmakologiske egenskaper. Forbindelsene er spesielt antagonister for det langsomt reagerende stoff av anafylakse (SRS-A), eller dets patologiske effekter, som vist ved deres aktivitet i forsøket angitt i eksempel A. Forbindelsene antagoniserer også effektene for SRS-A oppnådd ved antigen-innvirkning•av sensitivert opphakket lunge fra mennesker på isolert marsvinileum som beskrevet i eksempel A. Forbindelsene har også samme nyttevirkning ved de samme doseringer som forbindelsene i tysk patent nr. 68.11740. The compounds of formula I and their pharmaceutically acceptable derivatives, e.g. their pharmaceutically acceptable salts, esters, especially C 1-6 alkanoate esters, and amides, e.g. their sodium, lower alkylamine, e.g. ethylamine and hydroxy substituted lower alkylamine salts are also useful because they possess pharmacological properties. The compounds are particularly antagonists of the slow-reacting substance of anaphylaxis (SRS-A), or its pathological effects, as shown by their activity in the experiment set forth in Example A. The compounds also antagonize the effects of SRS-A obtained by antigen exposure of sensitized minced human lung on isolated porcine leucorrhoea as described in example A. The compounds also have the same beneficial effect at the same dosages as the compounds in German patent no. 68.11740.

Forbindelsene anvendes således ved behandling av for-styrrelser hvori SRS-A er en faktor, f.eks. hudlidelser, høyfeber og lidelser i luftveiene, f.eks. astma. The compounds are thus used in the treatment of disorders in which SRS-A is a factor, e.g. skin disorders, hay fever and respiratory disorders, e.g. asthma.

Forbindelsene med formel I og farmasøytisk akseptable derivater derav er også nyttige fordi de antagoniserer bronko-spasmer indusert av metakolin og histamin i marsvin (se metoden til Konzett J. og Rossler R. Arch. exp. Path. Pharmak. 1940, The compounds of formula I and pharmaceutically acceptable derivatives thereof are also useful because they antagonize bronchospasm induced by methacholine and histamine in guinea pigs (see the method of Konzett J. and Rossler R. Arch. exp. Path. Pharmak. 1940,

195 71 som modifisert av Burden D.T.og Parkes M.W. J. Pharmac.195 71 as modified by Burden D.T. and Parkes M.W. J. Pharmac.

1971 4l 122). Forbindelsene er nyttige som bronkodilatorer hos mennesker. 1971 4l 122). The compounds are useful as bronchodilators in humans.

For den ovenfor nevnte bronkospasmolytiske og bronko-dilatoriske anvendelse vil den administrerte dose naturligvis variere med den forbindelse som benyttes, administrasjonsmåten og den ønskede behandling. I Alminnelighet oppnås imidlertid tilfredsstillende resultater når forbindelsene administreres i en dose på fra 0,5 til 5,0 mg pr. kg legemsvekt i ovennevnte forsøk. For mennesker er den totale daglige dose i området fra ca. 20 mg til 200 mg og den kan administreres i oppdelte doser fra 2 til 3 ganger daglig eller i en form med forlenget frigjøring av medikamentet. Enhetdoseringsformer egnet for administrasjon (ved inhalering eller ved inntagelse gjennom munnen) omfatter således fra ca. 10 mg til 100 mg av forbindelsen blandet med et fast eller flytende farmasøytisk akseptabelt fortynningsmiddel, For the above-mentioned bronchospasmolytic and bronchodilator use, the dose administered will naturally vary with the compound used, the method of administration and the desired treatment. In general, however, satisfactory results are obtained when the compounds are administered in a dose of from 0.5 to 5.0 mg per kg body weight in the above experiments. For humans, the total daily dose is in the range from approx. 20 mg to 200 mg and it can be administered in divided doses from 2 to 3 times daily or in an extended release form of the drug. Unit dosage forms suitable for administration (by inhalation or oral intake) thus include from approx. 10 mg to 100 mg of the compound mixed with a solid or liquid pharmaceutically acceptable diluent,

bærer eller hjelpemiddel.carrier or aid.

For ovennevnte anti SRS-A bruk, vil den administrerteFor the above anti SRS-A use, the administered will

dose naturligvis variere avhengig av den forbindelse som benyttes, administrasjonsmåte og ønsket behandling. I alminnelighet oppnås imidlertid tilfredsstillende resultater når man foretar administrering i en daglig dose på fra ca. 1 mg til ca. 10 mg pr. kg legemsvekt, fortrinnsvis gitt i oppdelte doser 2-4 ganger daglig eller i en form med forlenget frigjøring av medikamentet. For større patte- dose naturally vary depending on the compound used, method of administration and desired treatment. In general, however, satisfactory results are achieved when administration is carried out in a daily dose of from approx. 1 mg to approx. 10 mg per kg body weight, preferably given in divided doses 2-4 times a day or in a form with extended release of the drug. For larger teats

dyr er den totale daglige dose i området fra ca. 50 til ca. 70 mg,animal is the total daily dose in the range from approx. 50 to approx. 70mg,

og doseringsformer egnet for administrasjon omfatter fra ca. 12and dosage forms suitable for administration include from approx. 12

til ca. 350 mg av forbindelsen blandet med en fast eller flytende to approx. 350 mg of the compound mixed with a solid or liquid

farmasøytisk bærer eller fortynningsmiddel. Forbindelsene kan administreres under eller før den sykdom som skal behandles. pharmaceutical carrier or diluent. The compounds can be administered during or before the disease to be treated.

Forbindelsene kan administreres i blanding med et farmasøytisk akseptabelt hjelpemiddel, fortynningsmiddel eller bærer, idet sammensetningen avhenger av mange faktorer inkludert den sykdom som skal behandles. Forbindelsene kan administreres parenteralt, oralt, ved inhalering eller topisk. The compounds may be administered in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, the composition depending on many factors including the disease to be treated. The compounds can be administered parenterally, orally, by inhalation or topically.

Ifølge oppfinnelsen er det også tilveiebragt en fremgangsmåte til fremstilling av et farmasøytisk akseptabelt salt av en forbindelse med formel I, omfattende behandling av en forbindelse med formel I, en ester eller et amid derav eller et annet salt derav med en passende base, f^eks. en natriumbase, eller med et egnet salt ved hjelp av et metateseprosess. According to the invention, there is also provided a method for producing a pharmaceutically acceptable salt of a compound of formula I, comprising treating a compound of formula I, an ester or an amide thereof or another salt thereof with a suitable base, e.g. . a sodium base, or with a suitable salt by means of a metathesis process.

Flavonylforbindelser hvori -OXO-gruppen er festet til kromonkjernen i 7-stillingen er foretrukket, hvilket også gjelder for de xantonylforbindelser hvori -OXO-gruppen er festet til xantonkjernen i 6- eller 7-^stillingen. De foretrukne xantonfor-bindelser med formel I er de hvori Ra og Rb sammen danner en gruppe -CH=C(COOH)-CH=CH-, dvs. -COOH-gruppen er festet til 2-eller 3_stillingen i xantonkjernen. Flavonyl compounds in which the -OXO group is attached to the chromone nucleus in the 7-position are preferred, which also applies to the xanthonyl compounds in which the -OXO group is attached to the xanthone nucleus in the 6- or 7-position. The preferred xanthone compounds of formula I are those in which Ra and Rb together form a group -CH=C(COOH)-CH=CH-, i.e. the -COOH group is attached to the 2- or 3-position in the xanthone nucleus.

Det er foretrukket at R<4>er hydrogen eller lavereIt is preferred that R<4> is hydrogen or lower

alkyl. Det er også foretrukket at R^ er i 6- eller 8-stillingen i flavonylforbindelsene eller i 5- eller 8-stillingen og til-støtende til -OXO-kjeden i xantonylforbindelsene. alkyl. It is also preferred that R 1 is in the 6- or 8-position in the flavonyl compounds or in the 5- or 8-position and adjacent to the -OXO chain in the xanthonyl compounds.

12 3 4 12 3 4

Foretrukne betydninger for R , R , R^ og R er hydrogen, hydroksy, lavere alkanoyl eller lavere alkyl. Preferred meanings for R 1 , R 1 , R 1 and R 2 are hydrogen, hydroxy, lower alkanoyl or lower alkyl.

4 Foretrukne forbindelser med formel I er de hvor R er hydrogen eller propyl, R<1>er hydrogen eller propyl, R<2>er hydroksy 4 Preferred compounds of formula I are those where R is hydrogen or propyl, R<1> is hydrogen or propyl, R<2> is hydroxy

3 3

og R er acetyl.and R is acetyl.

Gruppen X er fortrinnsvis en rettkjedet alkylengruppe inneholdende f.eks. fra 2 til 7 karbonatomer og eventuelt substituert med en hydroksygruppe. X er fortrinnsvis et 2-hydroksytri-metylenradikal. The group X is preferably a straight-chain alkylene group containing e.g. from 2 to 7 carbon atoms and optionally substituted with a hydroxy group. X is preferably a 2-hydroxytrimethylene radical.

Spesielle foretrukne forbindelser som fremstilles ifølge oppfinnelsen er: 7-/3-(4-acetyl-3-hydroksy-2-propylfenoksy)- 2-hydroksypropoksy/-9-okso-xanten-2-karboksylsyre, og dets natriumsalt, Special preferred compounds which are produced according to the invention are: 7-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy/-9-oxo-xanthene-2-carboxylic acid, and its sodium salt,

7-/3-(4-acetyl-3~hydroksy-2-propylfenoksy)-2-hydroksypropoksy7-9- 7-/3-(4-acetyl-3~hydroxy-2-propylphenoxy)-2-hydroxypropoxy7-9-

okso-8-propylxanten-2-karboksylsyre, og dets natriumsalt, 4-/7-(3"(4-acety1-3-hydroksy-2-propylfenoksy)-2-hydroksypropoksy)-4-okso-8-propyl-4H-l-benzopyran-2-yl7benzosyre, og dets natriumsalt, 4-Z7-(3-(4-acetyl-3-hydroksy-2-propylfenoksy)propoksy)-4-okso-8-propyl-4H-l-benzopyran-2-yl7-benzosyre og dets natriumsalt, og 4-/7_(2-(4-acetyl-3~hydroksy-2-propylfenoksy)etoksy)-4-okso-8-propyl-4H-l-benzopyran-2-yl7benzosyre, og dets natriumsalt. oxo-8-propylxanthene-2-carboxylic acid, and its sodium salt, 4-/7-(3"(4-acety1-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy)-4-oxo-8-propyl-4H -1-benzopyran-2-yl7benzoic acid, and its sodium salt, 4-Z7-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy)-4-oxo-8-propyl-4H-1-benzopyran- 2-yl7-benzoic acid and its sodium salt, and 4-[7_(2-(4-acetyl-3~hydroxy-2-propylphenoxy)ethoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-yl7benzoic acid , and its sodium salt.

Med den benyttede betegnelse "lavere" menes en gruppe inneholdende opptil og inkludert 6 karbonatomer. The term "lower" used means a group containing up to and including 6 carbon atoms.

Oppfinnelsen illustreres ved hjelp av nedenstående eksempler. The invention is illustrated using the examples below.

Eksempel AExample A

Den nedenfor angitte metode anvendes for å bestemme effektiviteten av en forbindelse ved antagonisering av SRS-A. Forsøket gjør bruk av antagonist-(kontraktil)effekt til SRS-A The method set forth below is used to determine the effectiveness of a compound in antagonizing SRS-A. The trial makes use of the antagonist (contractile) effect of SRS-A

på isolert marsvinileum.on insulated marvinileum.

Et tilfredsstillende preparat av SRS-A kan oppnås fra eggalbumen-sensitiverte marsvin. Tre uker etter sensitivering fjernes lungene fra slike marsvin, perfuseres frie for blod og hakkes opp. Prøver på vasket, opphakket lunge blir deretter behandlet med eggalbumen (antigen) oppløsning. De ovenstående væsker oppsamlet 15 minutter etter tilsetning av antigen inneholder histamin og SRS-A og kan benyttes, i nærvær av et anti-histamin, for å indusere effekter som skyldes SRS-A. A satisfactory preparation of SRS-A can be obtained from egg albumen-sensitized guinea pigs. Three weeks after sensitization, the lungs are removed from such guinea pigs, perfused free of blood and chopped up. Samples of washed, chopped lung are then treated with egg albumen (antigen) solution. The supernatants collected 15 minutes after addition of antigen contain histamine and SRS-A and can be used, in the presence of an anti-histamine, to induce effects due to SRS-A.

En isolert seksjon av ^endedelen av marsvinileum, suspenderes i en Tyrod-oppløsning som inneholder atropinsulfat 10- fi M (700 g/liter) og mepyraminmaleat 10- f,M (400 g/liter). Atropinsulfat benyttes for å redusere den spontane aktivitet An isolated section of the end of a guinea pig is suspended in a Tyrod solution containing atropine sulfate 10-µM (700 g/liter) and mepyramine maleate 10-µM (400 g/liter). Atropine sulfate is used to reduce the spontaneous activity

til ileumpreparatet og for å utelukke effektene av mulige kolinergiske midler. Mepyraminmaleat benyttes for å utelukke effektene av histamin. Sammensetningen til Tyrod-oppløsningen i g/l destillert vanner NaCl 8,0, KC1 0,2, CaCl20,2, MgCl20,1, NaHCO^1,0, NaH2P01|2H20 0,05 og dekstrose 1,0. Et 2 ml organ- to the ileum preparation and to rule out the effects of possible cholinergic agents. Mepyramine maleate is used to exclude the effects of histamine. The composition of the Tyrod solution in g/l distilled water NaCl 8.0, KC1 0.2, CaCl20.2, MgCl20.1, NaHCO^1.0, NaH2PO1|2H20 0.05 and dextrose 1.0. A 2 ml organ-

bad foretrekkes på grunn av prisen på SRS-A, idet spenningen i vevet bør være ca. 600 mg og badtemperaturen 37°C. bath is preferred due to the price of SRS-A, as the tension in the tissue should be approx. 600 mg and the bath temperature 37°C.

Det velges en dose av urenset SRS-A som produsererA dose of impure SRS-A is chosen which produces

like repeterende submaksimale kontraksjoner i ileum. Hver kon- equally repetitive submaximal contractions in the ileum. Each con-

traksjon registreres i 90 sekunder idet vevet da vaskes for å tillate relaksasjon. Det anvendes et opphold på 5 minutter mellom dosene av SRS-A. traction is recorded for 90 seconds as the tissue is then washed to allow relaxation. A 5-minute interval is used between doses of SRS-A.

Forbindelsen som undersøkes tilsettes til organ-badetThe compound under investigation is added to the organ bath

30 sekunder før en dose av SRS-A. Det benyttes forskjellige konsentrasjoner av forbindelsen for dermed å oppnå en log konsentrasjon/inhiberende response-kurve. Fra denne kurve bestemmes den konsentrasjon av forbindelse som vil inhibere ileum-kontraksjonen til SRS-A med 50$ (IC,_n). 30 seconds before a dose of SRS-A. Different concentrations of the compound are used in order to obtain a log concentration/inhibitory response curve. From this curve, the concentration of compound which will inhibit the ileum contraction of SRS-A by 50$ (IC,_n) is determined.

Eksempel 1 Example 1

Natrium 7~/ 3~ ( 4- acetyl- 3~ hydroksy-_ 2- propylf enoksy )- 2- hydroksy-propoksy7- 9~ okso- xanten- 2- karboksylat Sodium 7~/ 3~ ( 4- acetyl- 3~ hydroxy-_ 2- propylphenoxy )- 2- hydroxy- propoxy 7- 9~ oxoxanthene- 2- carboxylate

a) Etyl 7-/ 3-( 4- acetyl- 5~ hydroksy- 2- propylfenoksy)- 2-hydroksypropoksy7- 9~ okso- xanten- 2- karboksylat a) Ethyl 7-/ 3-( 4- acetyl- 5~ hydroxy- 2- propylphenoxy)- 2-hydroxypropoxy7- 9~ oxoxanthene- 2- carboxylate

En oppløsning■av etyl-7-hydroksy-9-okso-xanten-2-karboksylat (13,6 g), 4^-(2,3-epoksypropoksy)-2-hydroksy-3-propylacetofenon (13,8 g) og benzyltrimetylammoniumhydroksyd (3 dråper) A solution of ethyl 7-hydroxy-9-oxo-xanthene-2-carboxylate (13.6 g), 4^-(2,3-epoxypropoxy)-2-hydroxy-3-propylacetophenone (13.8 g) and benzyltrimethylammonium hydroxide (3 drops)

i tørr dimetylformamid (200 ml) ble oppvarmet ved 100°C i 60 timer. Inndampning av oppløsningsmidlet ga en rest som ble oppløst i etylacetat og vasket med 5$ natriumhydroksydoppløsning, og vann, tørket og inndampet til et fast stoff. Det faste stoff ble vasket med varm etanol og deretter kromatografert på silisium-dioksydgel under anvendelse av kloroform som elueringsmiddel og dette ga etyl-7-/3_(4-acetyl-3-hydroksy-2-propylfenoksy)-2-hydroksypropoksy7-9-okso-xanten-2-karboksylat (2,5 g), smp. 170-•172°C. in dry dimethylformamide (200 mL) was heated at 100°C for 60 h. Evaporation of the solvent gave a residue which was dissolved in ethyl acetate and washed with 5% sodium hydroxide solution, and water, dried and evaporated to a solid. The solid was washed with hot ethanol and then chromatographed on silica gel using chloroform as eluent to give ethyl 7-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy7-9- oxo-xanthene-2-carboxylate (2.5 g), m.p. 170-•172°C.

Funnet: C 67,0$; . H 5, 9%], C^qH^qO^Found: C 67.0$; . H 5.9%], C^qH^qO^

Krever: C 67,4$; H 5,7$.Claims: C 67.4$; H 5.7$.

b) 7-/ 3-( 4- acety1- 5- hydroksy- 2- propylfenoksy)- 2- hydroksy-propoksy7- 9- okso- xanten- 2- karboksylsyre b) 7-/ 3-( 4- acety1- 5- hydroxy- 2- propylphenoxy)- 2- hydroxy-propoxy7- 9- oxo- xanthene- 2- carboxylic acid

Esterproduktet fra a) (2,1 g) ble oppvarmet under til-bakeløp med 10$ natriumhydroksydoppløsning (5 ml) i etanol (30 ml) The ester product from a) (2.1 g) was heated under reflux with 10% sodium hydroxide solution (5 ml) in ethanol (30 ml)

i 1 time. Oppløsningen ble deretter behandlet med vann og surgjort og dette ga et fast stoff, som krystalliserte fra vandig dioksan til 7-/3-(4-acetyl-3-hydroksy-2-propylfenoksy)-2-hydroksy-propoksy/-9-okso-xanten-2-karboksylsyre (1,4 g), smp. 245-246°C. for 1 hour. The solution was then treated with water and acidified to give a solid which crystallized from aqueous dioxane to 7-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propoxy)-9-oxo -xanthene-2-carboxylic acid (1.4 g), m.p. 245-246°C.

Funnet: C 65,0$; H 5,<3$;><C>28H26°9'^<H>2°Found: C 65.0$; H 5,<3$;><C>28H26°9'^<H>2°

Krever: C 65,2$; H 5,2$.Claims: C 65.2$; H 5.2$.

c) Natrium 7~/ 3~( 4- acetyl- 3- hydroksy- 2- propylfenoksy)- 2-hydroksypropoksy7- 9~ okso- xanten- 2- karboksylat c) Sodium 7~/ 3~( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- 2-hydroxypropoxy7- 9~ oxoxanthene- 2- carboxylate

Den ovenfor fremstilte syre (1,17 g) i etanol (150 ml) ble behandlet med en oppløsning av natriumbikarbonat (0,194 g) i vann (5 ml). Oppløsningen ble filtrert og inndampet til et glassaktig fast stoff, som ble oppløst i vann og fryset.ørket og dette ga natrium 7_/3_(4-acetyl-3~hydroksy-2-propylfenoksy)-2-hydroksypropoksy/-9~okso-xanten-2-karboksylat (1,1 g). The acid prepared above (1.17 g) in ethanol (150 ml) was treated with a solution of sodium bicarbonate (0.194 g) in water (5 ml). The solution was filtered and evaporated to a glassy solid, which was dissolved in water and freeze-dried to give sodium 7_/3_(4-acetyl-3~hydroxy-2-propylphenoxy)-2-hydroxypropoxy/-9~oxo- xanthene-2-carboxylate (1.1 g).

Funnet: C 59,0$; H 5,1$; C^gH^NaOg + 7,2$ H20 Krever: C 57,0$; H 5,3$. Found: C 59.0$; H 5.1$; C^gH^NaOg + 7.2$ H20 Requires: C 57.0$; H 5.3$.

Eksempel 2Example 2

Natrium 7~/ 3~( 4- acetyl~ 3~ hydroksy- 2- propylfenoksy)- 2- hydroksy-propoksy7- 9~ okso- 8- propylxanten- 2- karboksylat Sodium 7~/ 3~( 4- acetyl~ 3~ hydroxy- 2- propylphenoxy)- 2- hydroxy-propoxy7- 9~ oxo- 8- propylxanthene- 2- carboxylate

a) Etyl 7~ allyloksy- 9~ oksaxanten- 2- karboksylata) Ethyl 7~ allyloxy- 9~ oxaxanthene- 2- carboxylate

En blanding av 16,0 g etyl 7-hydroksy-o-oksaxanten-2-karboksylat, 8,0 g kaliumkarbonat og 7,0 g allylbromid i aceton (100 ml) ble kok£ under tilbakeløp ég"6mrørt i 16 timer og deretter filtrert. Filtratet ble inndampet og resten oppløst i kloroform, vasket med 5$ natriumhydroksydoppløsning, deretter med vann, tørket og inndampet til et fast stoff som krystalliserte til nåler fra etanol. Dette ga 17 g etyl 7-allyloksy-9_okso-xanten-2-karboksylat, smp. l40-l40,5°C. A mixture of 16.0 g of ethyl 7-hydroxy-o-oxaxanthene-2-carboxylate, 8.0 g of potassium carbonate and 7.0 g of allyl bromide in acetone (100 ml) was refluxed with stirring for 16 hours and then filtered. The filtrate was evaporated and the residue dissolved in chloroform, washed with 5% sodium hydroxide solution, then with water, dried and evaporated to a solid which crystallized as needles from ethanol. This gave 17 g of ethyl 7-allyloxy-9_oxo-xanthene-2- carboxylate, mp 140-140.5°C.

Analyse, funnet: C 70,6$; H 5,2$Analysis, found: C 70.6$; H 5.2$

C19Hl6°5 krever: c 70,4$; H 5,0$C19H16°5 requires: c 70.4$; H 5.0$

b) Etyl 7~ acetoksy- 8- allyl- 9~ oksaxanten- 2- karboksylatb) Ethyl 7~ acetoxy- 8- allyl- 9~ oxaxanthene- 2- carboxylate

Etyl 7-allyloksy-9-oksaxanten-2-karboksylat (1,0 g)Ethyl 7-allyloxy-9-oxaxanthene-2-carboxylate (1.0 g)

og eddiksyreanhydrid (15 ml) ble kokt under tilbakeløp i en nitrogenatmosfære i 15 dager og deretter helt i et overskudd fortynnet saltsyre. Det oppnådde faste stoff ble omkrystallisert fra etanol og dette ga etyl 7-acetoksy-8-allyl-9-oksasanten-2-karboksylat (0,2 g), smp. l6l-l6l,5°C. and acetic anhydride (15 mL) was refluxed under a nitrogen atmosphere for 15 days and then poured into an excess of dilute hydrochloric acid. The resulting solid was recrystallized from ethanol to give ethyl 7-acetoxy-8-allyl-9-oxasanthene-2-carboxylate (0.2 g), m.p. 16l-16l.5°C.

Analyse, funnet: C 68,5$; H 4,9$Analysis, found: C 68.5$; H 4.9$

C21Hl8°6 krever: C 68,8$; H 4,9 5$C21H18°6 requires: C 68.8$; H 4.9 5$

c) Etyl 7~ hydroksy- 9~ ok' so- 8- propylxanten - 2- karboksylatc) Ethyl 7~ hydroxy- 9~ ok' so- 8- propylxanthene - 2- carboxylate

Etyl 7-alkoksy-9_oksoxanten-2-karboksylat (28,5 g) iEthyl 7-Alkoxy-9_oxoxanthene-2-carboxylate (28.5 g) in

en blanding (1:1) av dioksan-etano1 ble hydrogenert ved et trykk på 3,15 kg/cm2 over 5$ palladium/trekull ved- ca. 40°C. Blandingen ble fortynnet med varm dioksan og filtrert. Filtratet ble deretter inndampet og resten kokt under tilbakeløp i 10 minutter med etanol mettet med hydrogenklorid. Fortynning med vann ga et fast stoff som ble krystallisert fra etanol og dette ga etyl 7-hydroksy-9-okso-8-propylxanten-2-karboksylat (22,2 g) i form av nåler, smp. 179-l80°C. a mixture (1:1) of dioxane-ethane1 was hydrogenated at a pressure of 3.15 kg/cm2 over 5$ palladium/charcoal at approx. 40°C. The mixture was diluted with hot dioxane and filtered. The filtrate was then evaporated and the residue refluxed for 10 minutes with ethanol saturated with hydrogen chloride. Dilution with water gave a solid which was crystallized from ethanol to give ethyl 7-hydroxy-9-oxo-8-propylxanthene-2-carboxylate (22.2 g) as needles, m.p. 179-180°C.

Analyse, funnet: C 70,2$; H 5,7; ci9Hi8°5Analysis, found: C 70.2$; H 5.7; ci9Hi8°5

Krever : C 69,9$; H 5,6$.Claims : C 69.9$; H 5.6$.

d) Etyl 7-/ 3~( 4- acetyl- 3- hydroksy- 2- propylfenoksy)- 2-hydroksypropoksy7- 9- okso- 8- propylxanten- 2- karboksylat d) Ethyl 7-/ 3~( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- 2- hydroxypropoxy7- 9- oxo- 8- propylxanthene- 2- carboxylate

Etyl 7-hydroksy-9-okso-8-propylxanten-2-karboksylatEthyl 7-hydroxy-9-oxo-8-propylxanthene-2-carboxylate

(6,5 g) og 4-(2,3-epoksypropoksy)-2-hydroksy-3-propylacetofenon ble kokt under tilbakeløp i dimetylformamid (100 ml) inneholdende 4 dråper benzyltrimetylammoniumhydroksyd i 3,5 timer. Oppløsnings-midlet ble inndampet og resten oppløst i etylacetat, og dette ble vasket gjentatte ganger med iskald 10$ natriumhydroksydoppløsning. Inndampning av etylacetatet og kromatografi av resten over silisium-dioksydgel under anvendelse av metylenklorid inneholdende etylacetat (1$) ga etyl 7-/3-(4-acetyl-3-hydroksy-2-propylfenoksy)-2-hydroksypropoksy7-9-okso-8-propylxanten-2-karboksylat (2,6 g), (6.5 g) and 4-(2,3-epoxypropoxy)-2-hydroxy-3-propylacetophenone were refluxed in dimethylformamide (100 ml) containing 4 drops of benzyltrimethylammonium hydroxide for 3.5 hours. The solvent was evaporated and the residue dissolved in ethyl acetate, which was washed repeatedly with ice-cold 10% sodium hydroxide solution. Evaporation of the ethyl acetate and chromatography of the residue over silica gel using methylene chloride containing ethyl acetate (1$) gave ethyl 7-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy7-9-oxo- 8-propylxanthene-2-carboxylate (2.6 g),

smp. 169,5-170,5°C. m.p. 169.5-170.5°C.

Analyse, funnet: G 68,4$; H 6,4$Analysis, found: G 68.4$; H 6.4$

C33H36°9 krever: C 68,7$; H 6,3$C33H36°9 requires: C 68.7$; H 6.3$

e) 7/ 3-( 4- acetyl- 3- hydroksy- 2- propylfenoksy)- 2- hydroksy-propoksy7- 9~ okso- 8- propylxanten- 2- karboksylsyre e) 7/ 3-( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- 2- hydroxy- propoxy7- 9~ oxo- 8- propylxanthene- 2- carboxylic acid

Den ovenfor fremstilte xantenester (2,2 g) ble omrørtThe above-prepared xanthene ester (2.2 g) was stirred

og kokt under tilbakeløp med 10$ vandig natriumhydroksyd (4 ml)and refluxed with 10% aqueous sodium hydroxide (4 mL)

og etanol (80 ml) i 20 minutter. Blandingen ble surgjort og ekstrahert med etylace.tat, som ble ekstrahert med natriumbikarbonat-oppløsning. Surgjøring ga en gul gummi som krystalliserte fra etanol til 7-/3"(4-acetyl-3-hydroksy-2-propylfenoksy)-2-hydroksy-propoksy7-9_okso-8-propylxanten-2-karboksylsyre (1,2 g), smp. 173-175°C. and ethanol (80 mL) for 20 minutes. The mixture was acidified and extracted with ethyl acetate, which was extracted with sodium bicarbonate solution. Acidification gave a yellow gum which crystallized from ethanol to 7-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxy-propoxy7-9_oxo-8-propylxanthene-2-carboxylic acid (1.2 g) , mp 173-175°C.

Analyse, funnet: C 67,9$; H -6,236Analysis, found: C 67.9$; H -6.236

C33H3g09 krever: C 67,9$; H 5,9$C33H3g09 requires: C 67.9$; H 5.9$

f) Natrium 7~/ 5~( 4- acetyl- 5~ hydroksy- 2- propylfenoksy- 2-hydroksypropoksy7- 9~ okso- 8- propylxanten- 2- karboksylat f) Sodium 7~/ 5~( 4- acetyl- 5~ hydroxy- 2- propylphenoxy- 2- hydroxypropoxy7- 9~ oxo- 8- propylxanthene- 2- carboxylate

Den ovenfor fremstilte xantensyre (0,83 g) ble oppløst i varm etanol (20 ml). En ekvivalent av natriumbikarbonat oppløst i et minimum vann ble tilsatt for dermed å gi en klar oppløsning, som deretter ble inndampet til en gel. Gelen ble krystallisert The xanthenic acid (0.83 g) prepared above was dissolved in hot ethanol (20 ml). One equivalent of sodium bicarbonate dissolved in a minimum of water was added to give a clear solution, which was then evaporated to a gel. The gel was crystallized

fra etanol inneholdende spor av vann og dette ga natrium 7-/3-(4-acety1-3-hydroksy-2-propylfenoksy)-2-hydroksypropoksy7-9-okso-8-propylxanten-2-karboksylat (0,6 g). from ethanol containing traces of water and this gave sodium 7-(4-acety1-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy7-9-oxo-8-propylxanthene-2-carboxylate (0.6 g) .

Analyse, funnet: C 60,5$; H 5,8$; Na 3,7$ C-.nH^,NaOn inneholdende 7,3$ H„0 Analysis, found: C 60.5$; H 5.8$; Na 3.7$ C-.nH^,NaOn containing 7.3$ H„0

3± 31 9<L3± 31 9<L

Krever: C 60,5$; H 5,9$; Na 3,7$Claims: C 60.5$; H 5.9$; Well 3.7$

Eksempel 3Example 3

Natrium 4-/ 7-( 3-( 4- acetyl- 3- hydroksy- 2- propylfenoksy)- 2- hydroksy-propoksy ) - 4- okso- 8- propy 1- 4H- l- benzopyran- 2- yl7benzoat Sodium 4-/ 7-( 3-( 4- acetyl- 3- hydroxy- 2- propylphenoxy)- 2- hydroxy- propoxy ) - 4- oxo- 8- propy 1- 4H- 1- benzopyran- 2- yl7benzoate

a) 4-( 7- hydroksy- 4- okso- 8- propy1- 4H- 1- benzopyran- 2- yl) benzosyre a) 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)benzoic acid

Til en oppløsning av 4-metoksykarbonylbenzoylklorid (19,85 g) i tørr pyridin (50 ml) ble det tilsatt en oppløsning av 3-propylresacetofenon (9,7 g) i tørr pyridin (50 ml), og opp-løsningen ble omrørt ved romtemperatur i 24 timer. Blandingen ble helt i fortynnet saltsyre og ekstrahert med etylacetat. To a solution of 4-methoxycarbonylbenzoyl chloride (19.85 g) in dry pyridine (50 ml) was added a solution of 3-propylreacetophenone (9.7 g) in dry pyridine (50 ml), and the solution was stirred at room temperature for 24 hours. The mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate.

Den organiske fasen ble vasket med fortynnet saltsyre, natrium-hydrogenkarbonatoppløsning og vann, tørket over magnesiumsulfat og filtrert. Inndampning av oppløsningsmidlet ga en gul olje som ble oppløst i tørr pyridin,.. pulverformet kaliumhydroksyd (2,3 g) ble tilsatt og blandingen oppvarmet ved 100°C i 1 time. Den resulterende blanding ble helt i fortynnet eddiksyre og det faste stoff oppsamlet ved filtrering, tørket og deretter behandlet med eddiksyre (100 ml) og konsentrert svovelsyre (10 ml). Blandingen ble oppvarmet under tilbakeløp i 1 time og deretter helt i vann. Det oppnådde faste stoff ble oppsamlet ved filtrering og oppløst i fortynnet natriumhydroksyd. Surgjøring med fortynnet saltsyre ga et brunt fast stoff som ble oppsamlet ved filtrering og omkrystallisert to ganger fra etanol og dette ga 5,0 g 4-(7- hydroksy-4-okso-8-propyl-4H-l-benzopyran-2-yl)benzosyre som et fargeløst fast stoff. The organic phase was washed with dilute hydrochloric acid, sodium bicarbonate solution and water, dried over magnesium sulfate and filtered. Evaporation of the solvent gave a yellow oil which was dissolved in dry pyridine, powdered potassium hydroxide (2.3 g) was added and the mixture heated at 100°C for 1 hour. The resulting mixture was poured into dilute acetic acid and the solid collected by filtration, dried and then treated with acetic acid (100 mL) and concentrated sulfuric acid (10 mL). The mixture was heated under reflux for 1 hour and then poured into water. The resulting solid was collected by filtration and dissolved in dilute sodium hydroxide. Acidification with dilute hydrochloric acid gave a brown solid which was collected by filtration and recrystallized twice from ethanol to give 5.0 g of 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2- yl)benzoic acid as a colorless solid.

b) Etyl 4-( 7- hydroksy- 4- okso- 8- propyl- 4H- l- benzopyran- 2- yl) benzoat b) Ethyl 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)benzoate

Det faste syreprodukt fra trinn aa) (5,0 g) ble suspendert i tørr etanol og blandingen mettet med hydrogenklorid, The solid acid product from step aa) (5.0 g) was suspended in dry ethanol and the mixture saturated with hydrogen chloride,

og dette ga en oppløsning av det faste stoffet. Oppløsningen ble tilbakeløpskokt i 1 time og inndampet til tørrhet. Det oppnådde faste stoff ble oppsamlet i etylacetat, vasket med natriumhydrogen-karbonatoppløsning og vann, tørket over magnesiumsulfat, filtrert og inndampet til et rosa fast stoff. Det faste stoff ble omkrystallisert fra vandig etanol til 3,5 g etyl 4-(7-hydroksy-4-okso-8-propyl-4H-l-benzopyran-2>-yl)benzoat, smp. 225-226°C. and this gave a solution of the solid. The solution was refluxed for 1 hour and evaporated to dryness. The resulting solid was taken up in ethyl acetate, washed with sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and evaporated to a pink solid. The solid was recrystallized from aqueous ethanol to 3.5 g of ethyl 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2>-yl)benzoate, m.p. 225-226°C.

Analyse, funnet: C 71,6; H 5,8Analysis, found: C 71.6; H 5.8

C21<H>20°5krever: c 71,6; H 5,7C21<H>20°5 requires: c 71.6; H 5.7

c) 4-( 7-/ 3-( 4- acetyl- 3~ hydroksy- 2- propylfenoksy)- 2- hydroksy-propoksy?^- 4- okso- 8 - propyl- 4H- 1- ben zopyr an- 2- yl) benzosyre c) 4-( 7-/ 3-( 4- acetyl- 3~ hydroxy- 2- propylphenoxy)- 2- hydroxy-propoxy?^- 4- oxo- 8 - propyl- 4H- 1- benzopyr an- 2- yl) benzoic acid

En blanding av 4-(2,3-epoksypropoksy)-2-hydroksy-3-propylacetofenon (2,5 g) og esterproduktet fra trinn b) (3,15 g) A mixture of 4-(2,3-epoxypropoxy)-2-hydroxy-3-propylacetophenone (2.5 g) and the ester product from step b) (3.15 g)

i dimetylformamid (25 ml) ,med 3 dråper av "Triton B" som katalysator, ble oppvarmet under tilbakeløp i 4 timer og deretter inndampet hvilket ga en mørk olje. Oljen ble oppløst i etylacetat og vasket med 1% natriumhydroksydoppløsning, tørket over magnesiumsulfat, filtrert og inndampet til et fast stoff. Dette faste stoff ble krystallisert to ganger fra etanol hvilket ga 3,5 g etyl 4-(7-/3-(4-acetyl-3-hydroksy-2-propylfenoksy)-2-hydroksypropoksy/-4-okso-8-propyl-4H-1-benzopyran-2-y1)benzoat. in dimethylformamide (25 ml), with 3 drops of "Triton B" as catalyst, was heated under reflux for 4 hours and then evaporated to give a dark oil. The oil was dissolved in ethyl acetate and washed with 1% sodium hydroxide solution, dried over magnesium sulfate, filtered and evaporated to a solid. This solid was crystallized twice from ethanol to give 3.5 g of ethyl 4-(7-(3-(4-acetyl-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy)-4-oxo-8-propyl -4H-1-benzopyran-2-yl)benzoate.

Denne ester ble hydrolysert ved oppvarming under til-bakeløp med 30 ml 10% natriumkarbonatoppløsning og 30 ml etanol i 1 time. Oppløsningen ble surgjort og dette ga et fast stoff som ble krystallisert fra etanol tre ganger til 1,4 g 4-(7-/3-(4-acety1-3-hydroksy-2-propylfenoksy)-2-hydroksypropoksy?-4-okso-8-propy1-4H-l-benzopyran-2-yl)benzosyre, smp. 204-206°C. This ester was hydrolyzed by heating under reflux with 30 ml of 10% sodium carbonate solution and 30 ml of ethanol for 1 hour. The solution was acidified and this gave a solid which was crystallized from ethanol three times to give 1.4 g of 4-(7-/3-(4-acety1-3-hydroxy-2-propylphenoxy)-2-hydroxypropoxy?-4- oxo-8-propyl-4H-1-benzopyran-2-yl)benzoic acid, m.p. 204-206°C.

Analyse, funnet: C 66,0; H 6,1Analysis, found: C 66.0; H 6.1

C^ E^^ Og 11 H20 krever: C 65,8; H 6,0.C^ E^^ And 11 H 2 O requires: C 65.8; H 6.0.

d) Natrium 4-( 7~/ 3~( 4- acetyl- 3- hydroksy- 2- propylfenoksy)-2- hydroksypropoksy7- 4- okso- 4H- 1- benzopyran- 2- yl) benzoat d) Sodium 4-( 7~/ 3~( 4- acetyl- 3- hydroxy- 2- propylphenoxy)-2- hydroxypropoxy7- 4- oxo- 4H- 1- benzopyran- 2- yl) benzoate

En blanding av syreproduktet fra trinn c) (2,5 g) og natriumbikarbonat (0,37 g) i etanol (200 ml) og vann (50 ml) ble oppvarmet på et dampbad for å bevirke oppløsning. Oppløsningen ble inndampet til nesten tørrhet og det resterende vann fjernet som sin benzen-azeotrop. Det oppnådde lyse brune faste stoff ble tørket til 2,6 g natrium 4-(7-( J>-(4-acetyl-3_hydroksy-2-propylfenoksy)-2-hydroksypropoksy7-4-okso-4H-l-benzopyran-2-yl)benzoat. A mixture of the acid product from step c) (2.5 g) and sodium bicarbonate (0.37 g) in ethanol (200 ml) and water (50 ml) was heated on a steam bath to effect dissolution. The solution was evaporated to near dryness and the remaining water removed as its benzene azeotrope. The light brown solid obtained was dried to 2.6 g of sodium 4-(7-( J>-(4-acetyl-3_hydroxy-2-propylphenoxy)-2-hydroxypropoxy7-4-oxo-4H-1-benzopyran-2 -yl)benzoate.

Analyse, funnet: C 64,6; H 5,8Analysis, found: C 64.6; H 5.8

C^H-^OgNa 1H20 krever: C 64,4; H 5,7-C^H-^OgNa 1H 2 O requires: C 64.4; H 5,7-

Eksempel 4Example 4

Natrium 4-/ 7-( 2-( 4- acetyl- 3~ hydroksy- 2- propylfenoksy) etoksy)- 4- okso-8- propyl- 4H- 1- benzopyran- 2- yl7benzoat Sodium 4-/ 7-( 2-( 4- acetyl- 3~ hydroxy- 2- propylphenoxy) ethoxy)- 4- oxo-8- propyl- 4H- 1- benzopyran- 2- yl7benzoate

a) 4-( 2- brometoksy)- 2- hydroksy- 3- propylacetofenona) 4-(2-bromoethoxy)-2-hydroxy-3-propylacetophenone

Til en omrørt, tilbakeløpskokende blanding av 2,4-dihydroksy-3-propylacetofenon (19,4 g), 1,2-dibrometan (75,0 g) To a stirred, refluxing mixture of 2,4-dihydroxy-3-propylacetophenone (19.4 g), 1,2-dibromoethane (75.0 g)

og vann (300 ml) ble det langsomt tilsatt en oppløsning av natriumhydroksyd (4,0 g) i vann (60 ml) i løpet av 15 minutter. Etter 5 timer ble blandingen avkjølt og skilt mellom kloroform og vann. and water (300 ml) a solution of sodium hydroxide (4.0 g) in water (60 ml) was slowly added over 15 minutes. After 5 hours, the mixture was cooled and partitioned between chloroform and water.

Den organiske fasen ble vasket med fortynnet ( 5%) natriumhydroksyd-oppløsning og vann, tørket og inndampet til en olje som ble destillert ved 205-210°C/ll mm Hg hvilket ga 4-(2-brometoksy)-2-hydroksy-3-propylacetofenon i form av en olje (8,8 g) som deretter stivnes (smp. 54-58°C). Dette stoff hadde en renhet på over 96% The organic phase was washed with dilute (5%) sodium hydroxide solution and water, dried and evaporated to an oil which was distilled at 205-210°C/11 mm Hg to give 4-(2-bromomethoxy)-2-hydroxy- 3-propylacetophenone in the form of an oil (8.8 g) which then solidifies (m.p. 54-58°C). This substance had a purity of over 96%

ved gle og viste et ensartet NMR-spektrum og m/e = 300/302.at gle and showed a uniform NMR spectrum and m/e = 300/302.

b) Etyl 4-/ 7-( 2-( 4- acetyl- 3- hydroksy- 2- propylfenoksy) etoksy)-4- okso- 8- propyl- 4H- 1- benzopyran- 2- yl7benzoat b) Ethyl 4-/ 7-( 2-( 4- acetyl- 3- hydroxy- 2- propylphenoxy) ethoxy)-4- oxo- 8- propyl- 4H- 1- benzopyran- 2- yl7benzoate

En blanding av-det ovenfor fremstilte bromid (6,85 g), etyl 4-(7-hydroksy-4-okso-8-propyl-4H-l-benzopyran-2-yl)benzoat (7,3g ), vannfri kaliumkarbonat (3,1 g), kaliumiodid (0,5 g) A mixture of the bromide prepared above (6.85 g), ethyl 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)benzoate (7.3 g), anhydrous potassium carbonate (3.1 g), potassium iodide (0.5 g)

og tørr aceton (200 ml) ble tilbakeløpskokt og omrørt i 24 timer og deretter filtrert i varm tilstand. Filtratet ble inndampet til en olje som ble oppløst i etylacetat og vasket med 2% natrium-hydroksydoppløsning. Inndampning ga et fast stoff som ble krystallisert fra en etanol/dioksan-blanding til 5,0 g etyl 4//7_ and dry acetone (200 mL) was refluxed and stirred for 24 h and then filtered while hot. The filtrate was evaporated to an oil which was dissolved in ethyl acetate and washed with 2% sodium hydroxide solution. Evaporation gave a solid which was crystallized from an ethanol/dioxane mixture to give 5.0 g of ethyl 4//7_

(2-(4-acety1-3-hydroksy-2-propylfenoksy)etoksy)-4-okso-8-propyl- (2-(4-acety1-3-hydroxy-2-propylphenoxy)ethoxy)-4-oxo-8-propyl-

4H-1-benzopyran-2-yl/benzoat, smp. 167-168°C..4H-1-benzopyran-2-yl/benzoate, m.p. 167-168°C..

Analyse, funnet: C 70,5; H 6,4$Analysis, found: C 70.5; H 6.4$

C^H^gOg krever: C 71,3; H 6,3$C^H^gOg requires: C 71.3; H 6.3$

c) 4-/ 7-( 2-( 4- acetyl- 3- hydroksy- 2- propylfenoksy) etoksy)- 4-okso- 8- propyl- 4H- 1- benzopyran- 2- yl/ benzo syre c) 4-/ 7-( 2-( 4- acetyl- 3- hydroxy- 2- propylphenoxy) ethoxy)- 4-oxo- 8- propyl- 4H- 1- benzopyran- 2- yl/ benzoic acid

Den ovenfor fremstilte ester (4,5 g) ble oppløst i etanol (600 ml) og 0,1N natriumhydroksyd (120 ml) ble tilsatt. Blandingen ble kokt under tilbakeløp i 1 time, avkjølt, fortynnet med vann og surgjort og dette ga 4,0 g 4-/7-(2-(4-acetyl-3_hydroksy-2-propylfenoksy)etoksy)-4-okso-8-propy1-4H-1-benzopyran-2-yli benzosyre i form av et fast stoff, smp. 271-272°C (dekomponering). The above-prepared ester (4.5 g) was dissolved in ethanol (600 ml) and 0.1 N sodium hydroxide (120 ml) was added. The mixture was refluxed for 1 hour, cooled, diluted with water and acidified to give 4.0 g of 4-(7-(2-(4-acetyl-3_hydroxy-2-propylphenoxy)ethoxy)-4-oxo-8 -propyl1-4H-1-benzopyran-2-yl benzoic acid in the form of a solid, m.p. 271-272°C (decomposition).

Analyse, funnet: C 70,55; H 6,2Analysis, found: C 70.55; H 6.2

C^H 20Q krever: C 70,6; H 5,9$C^H 20Q requires: C 70.6; H 5.9$

d) Natrium 4-/ 7-( 2-( 4- acetyl- 3~ hydroksy- 2- propylfenoksy) etoksy)- 4- okso- 8- propyl- 4H- 1- benzopyran- 2- yl/ benzoat d) Sodium 4-/ 7-( 2-( 4- acetyl- 3~ hydroxy- 2- propylphenoxy) ethoxy)- 4- oxo- 8- propyl- 4H- 1- benzopyran- 2-yl/ benzoate

Den ovenfor fremstilte syre (4,0 g) og natriumbikarbonat (0,6o8 g) ble oppvarmet ved 60°C i 90$ etanol inntil man fikk oppløsning. Oppløsningen ble filtrert og inndampet til 3,8 g natrium 4-/7-(2-(4-acety1-3-hydroksy-2-propylfenoksy)etoksy)-4-okso-8-propyl-4H-1-benzopyran-2-yl7benzoat. The above prepared acid (4.0 g) and sodium bicarbonate (0.608 g) were heated at 60°C in 90% ethanol until solution was obtained. The solution was filtered and evaporated to 3.8 g of sodium 4-(7-(2-(4-acety1-3-hydroxy-2-propylphenoxy)ethoxy)-4-oxo-8-propyl-4H-1-benzopyran-2 -yl7benzoate.

Eksempel 5Example 5

Natrium 4-/ 7-( 5-( 4- acety1- 3- hydroksy- 2- propylfenoksy) propoksy)- 4-okso- 8- propyl- 4H- l- benzopyran- 2- yl/ benzoat Sodium 4-/ 7-( 5-( 4- acety1- 3- hydroxy- 2- propylphenoxy) propoxy)- 4-oxo- 8- propyl- 4H- 1- benzopyran- 2- yl/ benzoate

a) 4- ( 3- brompropoksy )- 2- hydroksy- 5~ pr, opylacetof enona) 4- ( 3- bromopropoxy )- 2- hydroxy- 5~ pr, opylacetof enone

Til en blanding av 1,3-dibrompropan (80,8 g), kaliumkarbonat (27,6 g) og kaliumiodid (0,5 g) i tørr aceton (500 ml), oppvarmet under tilbakeløp, ble det tilsatt 3-propylresacetofenon (38,8 g) og blandingen ble holdt under tilbakeløpskoking i 24 timer. To a mixture of 1,3-dibromopropane (80.8 g), potassium carbonate (27.6 g) and potassium iodide (0.5 g) in dry acetone (500 ml) heated under reflux was added 3-propylreacetophenone ( 38.8 g) and the mixture was kept under reflux for 24 hours.

Blandingen ble filtrert og oppløsningen inndampet tilThe mixture was filtered and the solution was evaporated

en mørk olje, som ble destillert i to fraksjoner. Kokepunktfrak-sjonen (0,2 mm Hg) 190-195°C ble oppsamlet og utgjorde 13,0 g 4-(3-brompropoksy)-2-hydroksy-3-propylacetofenon som viste et ensaretet NMR-spektrum. a dark oil, which was distilled into two fractions. The boiling point fraction (0.2 mm Hg) 190-195°C was collected and constituted 13.0 g of 4-(3-bromopropoxy)-2-hydroxy-3-propylacetophenone which showed a single-phase NMR spectrum.

b) Etyl 4- 77-( 5-( 4- acetyl- 3- hydroksy- 2- propylfenoksy) propoksy)-4- okso- 8- propyl- 4H- 1- benzopyran- 2- y l7- benzoat b) Ethyl 4- 77-( 5-( 4- acetyl- 3- hydroxy- 2- propylphenoxy) propoxy)-4- oxo- 8- propyl- 4H- 1- benzopyran- 2- y l7- benzoate

En blanding av etyl 4-(7-hydroksy-4-okso-8-propyl-4H-l-benzopyran-2-yl)benzoat (10,6 g) og det ovenfor fremstilte bromid A mixture of ethyl 4-(7-hydroxy-4-oxo-8-propyl-4H-1-benzopyran-2-yl)benzoate (10.6 g) and the bromide prepared above

(9,9 g) ble kondensert ved hjelp av metoden i eksempel 4 b) til 7,0 g etyl 4-/7-(3-(4-acety1-3-hydroksy-2-propylfenoksy)propoksy)-4-okso-8-propyl-4H-1-benzopyran-2-yl7benzoathemihydrat, i form av et fast stoff etter krystallisering fra etanol, smp. 170-171°C. (9.9 g) was condensed using the method in example 4 b) to 7.0 g of ethyl 4-(7-(3-(4-acety1-3-hydroxy-2-propylphenoxy)propoxy)-4-oxo -8-propyl-4H-1-benzopyran-2-yl7benzoate hemihydrate, as a solid after crystallization from ethanol, m.p. 170-171°C.

Analyse, funnet: C 70,7; H 6,6; Analysis, found: C 70.7; H 6.6;

C^H^gOg lE20 krever: C 70,6; H 6,55; C^H^gOg lE20 requires: C 70.6; H 6.55;

c ) 4-/ 7~( 3-( 4- acetyl- 3- hydroksy- 2- propylfenoksy) propoksy)-4- okso- 8- propyl- 4H- 1- benzopyran- 2- yl7benzosyre c ) 4-/ 7~( 3-( 4- acetyl- 3- hydroxy- 2- propylphenoxy) propoxy)-4- oxo- 8- propyl- 4H- 1- benzopyran- 2- yl7benzoic acid

Den ovenfor fremstilte ester (5,85 g) ble hydrolysertThe ester prepared above (5.85 g) was hydrolyzed

ved hjelp av metoden i eksempel 4 c) til 3,4 g 4-/7-(3"(4-acety1-3-hydroksy-2-propylfenoksy)propoksy)-4-oks0-8-propyl-4H-1-benzopyran-2-yl7benzosyre, smp. 226-228°C, etter krystallisering fra etylacetat. using the method in example 4 c) to 3.4 g of 4-(7-(3"(4-acety1-3-hydroxy-2-propylphenoxy)propoxy)-4-oxo-8-propyl-4H-1- benzopyran-2-yl7benzoic acid, mp 226-228°C, after crystallization from ethyl acetate.

Analyse, funnet: C 70,55; H 6,35; Analysis, found: C 70.55; H 6.35;

C^H^Og krever: C 70,95; H 6,14; C^H^Og requires: C 70.95; H 6.14;

d) Natrium 4-/ 7-( 3-( 4- acetyl- 3- hydroksy- 2- propylfenoksy) propoksy)- 4- okso- 8- propy1- 4H- 1- benzopyran- 2- yl| benzoat d) Sodium 4-/ 7-( 3-( 4- acetyl- 3- hydroxy- 2- propylphenoxy) propoxy)- 4- oxo- 8- propyl- 4H- 1- benzopyran- 2- yl| benzoate

Den ovenfor fremstilte syre (3,54 g) og natriumbikarbonat (0,533 g) ble omsatt ved hjelp av metoden i eksempel 4 d) til 3,5 g natrium 4-/7-(3-(4-acetyl-3-hydroksy-2-propylfenoksy)propoksy)-4-okso-8-propy1-4H-1-benzopyran-2-yl7benzoat. The above-prepared acid (3.54 g) and sodium bicarbonate (0.533 g) were reacted using the method in example 4 d) to 3.5 g of sodium 4-/7-(3-(4-acetyl-3-hydroxy- 2-Propylphenoxy)propoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-yl7benzoate.

Analyse, funnet: C 67,2; H 6,2Analysis, found: C 67.2; H 6.2

C^H-^NaOg krever:C 67,6; H 5,9 C^H-^NaOg requires: C 67.6; H 5.9

Claims

1. Procedure for the preparation of compounds of the general formula:

where either Ra is hydrogen and Rb is a 4-carboxyphenyl group or Ra and Rb together with the carbon atoms to which they are attached form a 6-membered aromatic carbocyclic ring substituted in a single 12*3 4 accessible position with a carboxy group, R , R , R and R , which may be the same or different, each representing hydrogen, hydroxy, alkenyl, alkanoyl or alkyl, and X is a hydrocarbon chain containing 2-10 carbon atoms, optionally substituted with a hydroxy group, as well as pharmaceutically acceptable salts thereof, characterized by that mana) hydrolyzes a compound with the formula:

12 3 4 where R , R , R , R and X have the above meaning, and where either Rc is hydrogen and Rd is a phenyl group substituted in the 4-position with a group D, where D is a group that can be hydrolyzed to a carboxy group, or Rc and Rd together with the carbon atoms to which they are attached form a 6-membered aromatic carbocyclic ring substituted in a single accessible position with a group D as defined above, orb) reacts a compound of formula III or an ester thereof with a compound of formula IV:

12 3 4 where Ra, Rb, R , R , R and R have the above meaning, and Y and Z are the pair of groups (i) hydrogen or a reactive metal and (ii) a hydrocarbon chain of 2-10 carbon atoms and containing an anion-forming group or an epoxide group, and c) if desired or necessary, converts the resulting compound of formula I to a pharmaceutically acceptable derivative thereof or vice versa.

2. Method according to claim la), characterized in that D is a carboxylic ester, amide or nitrile group.

3. Method according to claim lb), characterized in that one of Y and Z is an alkali metal or thallium.

4. Method according to claim 1 b) or claim 3, characterized in that one of Y and Z is a hydrocarbon chain containing a halogen atom, a sulphonate group or an epoxide group.

5- Method according to claim 4, characterized in that one of Y and Z is a hydrocarbon chain containing a halogen atom, and that the reaction is carried out in the presence of a solvent which is inert under the reaction conditions, and in the presence of an acid acceptor.

6. Process according to claim 4, characterized in that one of Y and Z is a hydrocarbon chain containing an epoxide group, and that the reaction is carried out at elevated temperature in a solvent which is inert under the reaction conditions, and in the presence of a catalyst.

7. Process according to claim 4, characterized in that one of Y and Z is a hydrocarbon chain containing an epoxide group and that the reaction is carried out in the presence of a tertiary alcohol and in the presence of the potassium salt of the alcohol.

8. Method according to claim lc), characterized in that a compound of formula I or an ester, salt or derivative thereof is reacted with a suitable base, or with a suitable salt by means of a metathesis process, to obtain a pharmaceutically acceptable salt of a compound of formula I.

9. Method according to any one of claims 1-8, characterized in that a compound of formula I as defined in claim 1 and which is a flavonyl compound is prepared.

10. Method according to any one of claims 1-8, characterized in that a compound of formula I as defined in claim 1 is prepared, and which is a xanthonyl compound.