NO744506L

NO744506L -

Info

Publication number: NO744506L
Application number: NO744506A
Authority: NO
Inventors: J R Pfister; I T Harrison; J H Fried
Original assignee: Syntex Inc
Priority date: 1974-01-08
Filing date: 1974-12-13
Publication date: 1975-08-04
Also published as: AT339297B; JPS50126667A; ATA9475A; GB1464561A; FR2256755A2; FR2256755B2; FI334874A; ZA747671B; AU7571774A; BE823030R; ES433626A2; NL7500218A; DK645674A; DE2461059A1; SE7415844L; GB1464562A

Description

Foreliggende oppfinnelse vedrører modifikasjoner i forhold til norsk søknad 2495/72. Denne søknad omfatter fremstilling av 5j7-disubstituerte xanton-2-karboksylsyrederivater. I The present invention relates to modifications in relation to Norwegian application 2495/72. This application covers the preparation of 5j7-disubstituted xanthone-2-carboxylic acid derivatives. IN

de forbindelser som skrives i nevnte søknad inngår de hvori en av substituentene er lavere alkyl eller lavere alkoksy med hver 1-5 karbonatomer. Det er nå oppdaget en ny klasse forbindelser som er nær beslektet med de som omtales i nevnte søknad, idet de nye forbindelser i det minste har de samme eller bedre egenskaper i forhold til de i nevnte søknad. Den nye klasse forbindelser er 5,7-disubstituerte xanton-2-karboksylsyrederivater hvori en av substituentene er alkyl eller alkoksy, hver med 6-12 karbonatomer . the compounds written in said application include those in which one of the substituents is lower alkyl or lower alkoxy with 1-5 carbon atoms each. A new class of compounds has now been discovered which is closely related to those mentioned in the said application, the new compounds having at least the same or better properties compared to those in the said application. The new class of compounds are 5,7-disubstituted xanthone-2-carboxylic acid derivatives in which one of the substituents is alkyl or alkoxy, each with 6-12 carbon atoms.

Foreliggende oppfinnelse angår således forbindelser med formelen: The present invention thus relates to compounds with the formula:

og farmasøytisk akseptable, ikke-toksiske estere, amider og salter derav, hvor en R<1->gruppe er valgt fra alkyl og alkoksy hver med 6-12 karbonatomer og den andre R<1->gruppe er gruppen -S(0) hvor n er 1 eller 2 og R er lavere alkyl. R and pharmaceutically acceptable, non-toxic esters, amides and salts thereof, where one R<1-> group is selected from alkyl and alkoxy each having 6-12 carbon atoms and the other R<1-> group is the group -S(0) where n is 1 or 2 and R is lower alkyl. R

De nye forbindelser som fremstilles ifølge oppfinnelsen er nyttige for å lette symptomer forbundet med allergiske lidelser av den type som frembringes ved antigen-antistoff (allergiske) reaksjoner. Ved bruk av forbindelsene hemmer man effektene av den allergiske reaksjon når nevnte forbindelser administreres i en effektiv mengde. Uten å være bundet av en spesiell teoretisk virkningsmekanisme, antas det at de aktive forbindelser virker slik at de hemmer frigjøringen og/eller virkningen av toksiske produkter, f.eks. histamin, 5-hydroksytriptamin, langsomt fri-gjørende stoff (SRS-A) eller andre toksiske forbindelser, som produseres som et resultat av en kombinasjon av spesifikt antistoff og antigen (allergisk reaksjon). Disse egenskaper gjør de fremstilte forbindelser nyttige ved behandling av forskjellige allergiske tilstander. The new compounds produced according to the invention are useful for alleviating symptoms associated with allergic disorders of the type produced by antigen-antibody (allergic) reactions. When using the compounds, the effects of the allergic reaction are inhibited when said compounds are administered in an effective amount. Without being bound by a particular theoretical mechanism of action, it is assumed that the active compounds act so that they inhibit the release and/or action of toxic products, e.g. histamine, 5-hydroxytryptamine, slow-releasing substance (SRS-A) or other toxic compounds, which are produced as a result of a combination of specific antibody and antigen (allergic reaction). These properties make the manufactured compounds useful in the treatment of various allergic conditions.

De nye forbindelser virker også avslappende på glatte muskler, de virker f.eks. som bronkiedilatorer og kan føl-gelig brukes ved behandling av tilstander hvor slike midler er ønskelige, f.eks. ved behandling av bronkiekonstriksjon. Forbindelsene er også vasodilatorer og er derfor nyttige ved behandling av tilstander hvor slike midler forordnes, som f.eks. ved behandling av lidelser i nyrer eller hjerte. The new compounds also have a relaxing effect on smooth muscles, they work e.g. as bronchial dilators and can therefore be used in the treatment of conditions where such agents are desirable, e.g. in the treatment of bronchial constriction. The compounds are also vasodilators and are therefore useful in the treatment of conditions where such agents are prescribed, such as e.g. when treating disorders of the kidneys or heart.

Man bruker således de ifølge foreliggende oppfinnelse fremstilte forbindelser til å inhibere effektene ved allergisk reaksjon ved at man administrerer en effektiv mengde av en forbindelse som definert ovenfor. The compounds produced according to the present invention are thus used to inhibit the effects of an allergic reaction by administering an effective amount of a compound as defined above.

Ved bruk av de ifølge oppfinnelsen fremstilte forbindelser blir en effektiv mengde av en slik forbindelse eller et farmasøytisk preparat derav, administrert ved hjelp av vanlige og akseptable metoder, enten alene eller i kombinasjon med en annen forbindelse eller forbindelser fremstilt ifølge oppfinnelsen eller andre farmasøytiske midler, slik som antibiotiske stoffer, hormo-nelle midler osv. Disse forbindelser eller preparater kan således administreres oralt, topisk, parenteralt eller ved inhalering og enten som fast stoff, væske eller i gassformige doseringer inkludert tabletter, suspensjoner og aerosoler, som også omtalt i det nedenstående. Administrasjonen kan utføres i form av enkle doser under kontinuerlig behandling eller ved enkeltdoseterapi ad libi-tum. I foretrukne utførelser vil man bruke forbindelsene når det er ønskelig med lettelse av visse symptomer, men forbindelsene kan også brukes ved kontinuerlig eller profylaktisk behandling. When using the compounds produced according to the invention, an effective amount of such a compound or a pharmaceutical preparation thereof is administered by means of common and acceptable methods, either alone or in combination with another compound or compounds produced according to the invention or other pharmaceutical agents, such as antibiotic substances, hormonal agents etc. These compounds or preparations can thus be administered orally, topically, parenterally or by inhalation and either as a solid, liquid or in gaseous dosages including tablets, suspensions and aerosols, as also discussed below . The administration can be carried out in the form of single doses during continuous treatment or by single-dose therapy ad libitum. In preferred embodiments, the compounds will be used when relief of certain symptoms is desired, but the compounds can also be used for continuous or prophylactic treatment.

Sett på bakgrunn av det ovenstående og også i betrakt-ning av graden av den tilstand som skal behandles, pasientens alder osv. og dette er faktorer som lett kan bestemmes ved rutine-eksperimenter, vil den effektive dose variere innenfor et vidt område. Vanligvis vil en effektiv mengde variere fra 0,005 - 100 mg/kg legemsvekt pr. dag og fortrinnsvis fra 0,01 - 100 mg/kg legemsvekt pr. dag. Sagt på en annen måte, vil en effektiv mengde vanligvis variere fra ca. 0,5 - 7000 mg/dag pr. pasient. Seen against the background of the above and also in consideration of the degree of the condition to be treated, the patient's age etc. and these are factors which can be easily determined by routine experiments, the effective dose will vary within a wide range. Generally, an effective amount will vary from 0.005 - 100 mg/kg body weight per day and preferably from 0.01 - 100 mg/kg body weight per day. Put another way, an effective amount will usually range from approx. 0.5 - 7000 mg/day per patient.

Egnede farmasøytiske bærere for formulering av nevnte preparater kan være faste stoffer, væsker eller gasser. Prepara-tene kan således være i form av tabletter, piller, kapsler, pul-vere, preparater med forlenget frigjøring av aktive forbindelser, oppløsninger, suspensjoner, eliksirer, aerosoler og lignende. Bærerne kan velges fra forskjellige oljer inkludert petroleum-oljer, animalske, vegetabilske eller syntetiske oljer, f.eks. peanøttolje, soyaolje, mineralolje, sesamolje og lignende. Vann, saltvann, vandig dekstrose og glykoler foretrekkes som flytende bærere, spesielt for injeksjonsoppløsninger. Egnede farmasøytiske hjelpemidler er stivelse, cellulose, talk, glukose, laktose, suk-rose, gelatin, malt, ris, mel, kritt, silisiumdioksydgel, magne-siumstearat, natriumstearatglycerylmonostearat, natriumklorid, tørket skummetmmelk, glycerol, propylenglykol, vann, etanol og lignende. Egnede farmasøytiske bærere og deres preparater er-beskrevet i "Remingtons Pharmaceutical Sciences" av E.W. Martin. Slike preparater vil i alle tilfeller inneholde en effektiv mengde av den aktive forbindelse sammen med en egnet mengde bærer for å danne den riktige doseringsform for korrekt administrasjon til pasienten. Suitable pharmaceutical carriers for formulating said preparations can be solids, liquids or gases. The preparations can thus be in the form of tablets, pills, capsules, powders, preparations with prolonged release of active compounds, solutions, suspensions, elixirs, aerosols and the like. The carriers can be selected from various oils including petroleum oils, animal, vegetable or synthetic oils, e.g. peanut oil, soya oil, mineral oil, sesame oil and the like. Water, saline, aqueous dextrose and glycols are preferred liquid carriers, especially for injection solutions. Suitable pharmaceutical aids are starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicon dioxide gel, magnesium stearate, sodium stearate glyceryl monostearate, sodium chloride, dried skimmed milk, glycerol, propylene glycol, water, ethanol and the like . Suitable pharmaceutical carriers and their preparations are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such preparations will in all cases contain an effective amount of the active compound together with a suitable amount of carrier to form the correct dosage form for correct administration to the patient.

De nye forbindelser viser aktivitet som inhibitorer av effektene av allergiske reaksjoner slik disse kan måles ved prøver som indikerer slik aktivitet og innebærer passiv kutan anafylakse beskrevet >av J. Goose et al, Immunology, 16, 7^9 (1969). The new compounds show activity as inhibitors of the effects of allergic reactions as these can be measured by tests which indicate such activity and involve passive cutaneous anaphylaxis described >by J. Goose et al, Immunology, 16, 7^9 (1969).

De nye forbindelser kan fremstilles i overensstemmelse med følgende reaksjonsskjerna: The new compounds can be prepared according to the following reaction core:

hvor halogen er brom-, klor, fluor eller jod, fortrinnsvis brom, where halogen is bromine, chlorine, fluorine or iodine, preferably bromine,

R 7 . er lavere alkyl, fortrinnsvis metyl, R 8 er alkyl eller alkoksy. R7. is lower alkyl, preferably methyl, R 8 is alkyl or alkoxy.

inneholdende 6.-12 karbonatomer, og R^, R<10>og R<11>er laverecontaining 6-12 carbon atoms, and R^, R<10>and R<11> are lower

alkyl. alkyl.

Noen av forbindelsene kan fremstilles i overensstemmelse Some of the compounds can be prepared in accordance

■med følgende reaksjonsskjerna': ■with the following reaction core':

hvor hver halogengruppe,R^,R"^ og R har den ovenfor angitte betydning R 12er alkyl eller alkoksy med 6-12 karbonatomer, og. where each halogen group, R^, R"^ and R has the meaning given above. R 12 is alkyl or alkoxy with 6-12 carbon atoms, and.

13 ' 13'

R er lavere.alkyl.R is lower.alkyl.

Under henvisning til de ovenfor angitte reaksjonsskjemaer A og B så kan 5-alkyl- eller alkoksy-7_lavere alkyltioforbindelsene With reference to the above-mentioned reaction schemes A and B, the 5-alkyl or 7-alkyl-lower alkylthio compounds can

£>9) og tilsvarende 5_lavere alkyltio-7-alkyl- eller alkoksyforbindelser (15) fremstilles som beskrevet i norsk søknad 2^95/72 og i nedenstående- eksempler . De respektive produkter blir deretter oksydert £>9) and corresponding 5_lower alkylthio-7-alkyl or alkoxy compounds (15) are prepared as described in Norwegian application 2^95/72 and in the examples below. The respective products are then oxidized

til. sulfinyl- og sulfonylforbindelsene (1,2) og (3,^) enten direkte eller gjennom syreestrene (10) og. (15) som også beskrevet i nevnte • søknad og i de riedens¥aende~eksempler. to. the sulfinyl and sulfonyl compounds (1,2) and (3,^) either directly or through the acid esters (10) and. (15) as also described in the aforementioned • application and in the accompanying examples.

o-alkyl- eller -alkoksy-p-alkyltiofenol-utgangs-forbindelsene, dvs. (6) fremstilles hensiktsmessig ved behandling av tilsvarende o-alkyl- eller -alkoksyfenol med klorsulfonsyre i , kloroform fulgt av reduksjon med sink - HC1 i eddiksyre, fulgt av The o-alkyl- or -alkyl-p-alkylthiophenol starting compounds, i.e. (6) are conveniently prepared by treating the corresponding o-alkyl- or -alkoxyphenol with chlorosulfonic acid in , chloroform followed by reduction with zinc - HC1 in acetic acid, followed of

*alkylering som beskrevet i norsk søknad 2U95/72 eller ved behandling av en o-alkyl- eller -alkoksyfenol med dialkylsulfoksyd og gass-'formig hydrogenklorid for oppnåelse av det tilsvarende 3-alkyl-eller -alkoksy-4-hydroksybenzendialkylsulfoniumklorid. Sistnevnte forbindelse oppvarmes til tilsvarende o-alkyl- eller -alkoksy-p-alkyltiofenolprodukt. *alkylation as described in Norwegian application 2U95/72 or by treatment of an o-alkyl- or -alkoxyphenol with dialkylsulfoxide and gaseous hydrogen chloride to obtain the corresponding 3-alkyl-or -alkoxy-4-hydroxybenzenedialkylsulfonium chloride. The latter compound is heated to the corresponding o-alkyl- or -alkoxy-p-alkylthiophenol product.

o-alkylfenolforbindelsen som benyttes som utgangsmateriale ved fremstilling,av o-alkylforbindelsene med f.eks. formel (6), fremstilles ved behandling av .fenol med et alkanoylklorid The o-alkylphenol compound which is used as starting material in the production of the o-alkyl compounds with e.g. formula (6), is prepared by treating .phenol with an alkanoyl chloride

(f.eks. n-oktanoylklorid) for oppnåelse av det tilsvarende fenylalkanoat (f.eks. fenyl n-oktanoat) som deretter behandles med aluminiumklorid ved 150°C for oppnåelse hovedsakelig av o-alkanoyl-f enolf orbindelsen (f .eks. o-n-oktanoylf enol) som fjernes fra eventuell' p-isomer som kan være tilstede, ved dampdestillasjon. o-alkanoylfenolforbindelsen (f.eks. o-n-oktanoylfenol) reduseres deretter med . sinkamalgam-saltsyre for oppnåelse av o-alkylfenolforbindelsen (f.eks. o-n-oktylfenol). (e.g. n-octanoyl chloride) to obtain the corresponding phenylalkanoate (e.g. phenyl n-octanoate) which is then treated with aluminum chloride at 150°C to obtain mainly the o-alkanoyl-phenol compound (e.g. o-n-octanoyl enol) which is removed from any p-isomer that may be present, by steam distillation. The o-alkanoylphenol compound (eg o-n-octanoylphenol) is then reduced by . zinc amalgam-hydrochloric acid to obtain the o-alkylphenol compound (e.g. o-n-octylphenol).

De tilsvarende o-alkyltio-p-alkyl- eller -alkoksyfenol-utgangsforbindelsene, dvs. (11), fremstilles ved behandling av The corresponding o-alkylthio-p-alkyl- or -alkoxyphenol starting compounds, i.e. (11), are prepared by treatment of

den tilsvarende p-alkyl- eller -alkoksyfenol med klorsulfonsyre, fulgt av reduksjon, alkylering, som beskrevet ovenfor. the corresponding p-alkyl or -alkoxyphenol with chlorosulfonic acid, followed by reduction, alkylation, as described above.

p-alkylfenolforbindelsen som benyttes som utgangsmateriale ved fremstilling av p-alkylforbindelsene med f.eks. formel (11), fremstilles ved behandling av fenol med et alkanoylklorid (f.eks. n-oktanoylklorid) for oppnåelse av det tilsvarende fenylalkanoat (f.eks. fenyl'n-oktanoat), som deretter behandles med aluminiumklorid ved 25°C i nærvær av nitrobenzen for oppnåelse hovedsakelig av p-alkanoylfenol (f.eks. p-n-6ktanoylfenol), som deretter renses ved dampdestillasjon for å fjerne eventuell o-isomer som kan være tilstede, p-alkanoylfenolforbindelsen (f.eks. p-n-oktanoylfenol) reduseres deretter med sinkamalgam-saltsyre for oppnåelse av p-alkylfenolforbindelsen (f.eks. p-n-oktylfenol). The p-alkylphenol compound which is used as starting material in the production of the p-alkyl compounds with e.g. formula (11), is prepared by treating phenol with an alkanoyl chloride (e.g. n-octanoyl chloride) to obtain the corresponding phenylalkanoate (e.g. phenyl'n-octanoate), which is then treated with aluminum chloride at 25°C in presence of nitrobenzene to obtain mainly p-alkanoylphenol (e.g. p-n-6ctanoylphenol), which is then purified by steam distillation to remove any o-isomer that may be present, the p-alkanoylphenol compound (e.g. p-n-octanoylphenol) is reduced then with zinc amalgam hydrochloric acid to obtain the p-alkylphenol compound (e.g. p-n-octylphenol).

Syreestrene av xanton-2-karboksy lsyrene. fremstilles som beskrevet i nevnte norske søknad nr. 2^95/72, dvs. ved behandling av The acid esters of the xanthone-2-carboxylic acids. produced as described in the aforementioned Norwegian application no. 2^95/72, i.e. by processing of

syren med et eterisk diazoalkan slik som diazometan og diazoetan eller med det ønskede lavere alkyljodid i nærvær av litiumkarbonat ved romtemperatur eller med den ønskede lavere alkanol i nærvær av . spor av svovelsyre under tilbakeløpskoking. Glycerolestrene fremstilles ved behandling av syren med tionylklorid fulgt av behandling med hensiktsmessig beskyttet etylenglykol eller propylenglykol (f.eks. "Solketal")•i pyridin, og hydrolysering av den beskyttende gruppe i den således dannede.ester med fortynnet syre. the acid with an ethereal diazoalkane such as diazomethane and diazoethane or with the desired lower alkyl iodide in the presence of lithium carbonate at room temperature or with the desired lower alkanol in the presence of . traces of sulfuric acid during reflux. The glycerol esters are produced by treating the acid with thionyl chloride followed by treatment with suitably protected ethylene glycol or propylene glycol (eg "Solketal") in pyridine, and hydrolyzing the protecting group in the thus formed ester with dilute acid.

Amidene av xanton-2-karboksylsyrene fremstilles ved " behandling av syrene med tionylklorid fulgt av■behandling med vannfri ammoniakk, alkylamin, dialkylamin, dialkylaminoalkylamin, alkoksyalkylamin, eller fenetylamin. I lavere alkylsulfinylrekken, blir karboksylsyrearnidene fortrinnsvis fremstilt ved det tilsvarende lavere alkyltiotrinn fulgt av oksydasjon, som beskrevet ovenfor. The amides of the xanthone-2-carboxylic acids are prepared by treatment of the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkylamine, dialkylamine, dialkylaminoalkylamine, alkoxyalkylamine, or phenethylamine. In the lower alkylsulfinyl series, the carboxylic acid amides are preferably prepared by the corresponding lower alkylthio step followed by oxidation , as described above.

Saltene av xanton-2-karboksylsyrene fremstilles ved behandling av tilsvarende syrer med farmasøytisk akseptable baser. Representative.salter avledet fra slike farmasøytisk akseptable baser er natrium-, kalium-, litium-, ammonium-, kalsium-, magnesium-, f erro-, ferri-, sink-, manga.no-, aluminium-, mangani- , • trimetylamin-, tr ietylamin- , tripropylamin- , 8'- (dimétylamino ) étanol - , trietanolamin- , 6-(dietylamino)etanol-, arginin-,lysin-,hist idin-,N-etylpiperidinT, hydrabamin-, kolin-, betain-, etylendiamin-, glukosamin-, metyl-glukamin-, teobromin-, purin-, piperazin-, piperidin-, polyamin-harpiks-, kaffeitiTog prokainsalter. Reaksjonen utføres i vandig oppløsning, alene eller i kombinasjon med et inert, vannblandbart organisk oppløsningsmiddel, ved en temperatur på fra ca. 0 til ca. 100°C, fortrinnsvis ved romtemperatur. Typiske inerte, vannblandbare. organiske oppløsningsmidler er metanol, etanol, isopropanol, butanol, aceton, dioksan og tetrahydrofuran. Ved fremstilling av toverdige metallsalter, slik som kalsiumsalter eller magnesiumsalter av syrene, blir fri syre-utgangsmateriale behandlet med omkring molar ekvivalent farmasøytisk akseptabel, base. Når aluminiumsalter av syrene fremstilles, blir omkring 1/3 molar ekvivalent av den farmasøytisk akseptable base benyttet. The salts of the xanthone-2-carboxylic acids are prepared by treating the corresponding acids with pharmaceutically acceptable bases. Representative salts derived from such pharmaceutically acceptable bases are sodium, potassium, lithium, ammonium, calcium, magnesium, iron, ferric, zinc, manganese, aluminum, manganese, • trimethylamine-, triethylamine-, tripropylamine-, 8'- (dimethylamino) ethanol-, triethanolamine-, 6-(diethylamino)ethanol-, arginine-, lysine-, histidine-, N-ethylpiperidineT, hydrabamine-, choline-, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, polyamine resin, caffeine and procaine salts. The reaction is carried out in aqueous solution, alone or in combination with an inert, water-miscible organic solvent, at a temperature of from approx. 0 to approx. 100°C, preferably at room temperature. Typical inert, water miscible. organic solvents are methanol, ethanol, isopropanol, butanol, acetone, dioxane and tetrahydrofuran. In the preparation of divalent metal salts, such as calcium salts or magnesium salts of the acids, free acid starting material is treated with about a molar equivalent of a pharmaceutically acceptable base. When aluminum salts of the acids are prepared, about 1/3 molar equivalent of the pharmaceutically acceptable base is used.

I en foretrukken utførelse av oppfinnelsen blir kalsium-.■ saltene og magnesiumsaltene av syrene fremstilt ved behandling av de tilsvarende natrium- eller kaliumsalter av syrene med minst en molar ekvivalent kalsiumklorid eller magnesiumklorid, respektivt, i en vandig oppløsning', alene eller i kombinasjon med et inert, vannblandbart organisk oppløsningsmiddel. ved en temperatur fra 20 til 100°C. In a preferred embodiment of the invention, the calcium and magnesium salts of the acids are prepared by treating the corresponding sodium or potassium salts of the acids with at least one molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution, alone or in combination with an inert, water-miscible organic solvent. at a temperature from 20 to 100°C.

I en annen foretrukken utførelse av oppfinnelsen blir aluminiumsaltene av syrene fremstilt ved behandling av syrene med minst 1/3 molar ekvivalent av et aluminiumalkoksyd, slik som aluminiumtrietoksyd, aluminiumtripropoksyd og lignende, i et hydrokarbonoppløsningsmiddel slik som benzen, xylen,.cykloheksan og lignende ved en temperatur fra 20 til 115°C. In another preferred embodiment of the invention, the aluminum salts of the acids are prepared by treating the acids with at least 1/3 molar equivalent of an aluminum alkoxide, such as aluminum trioxide, aluminum triproxide and the like, in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like at a temperature from 20 to 115°C.

Med den benyttede betegnelse "lavere alkyl" menes en lavere alkylgruppe inneholdende 1-5 karbonatomer inkludert rette With the term "lower alkyl" used is meant a lower alkyl group containing 1-5 carbon atoms including straight

og forgrenede grupper og cykliske alkylgrupper, f.eks. metyl, etyl, n-propyl, isopropyl, n-butyl,. isobutyl, sek-butyl, t-butyl, n-pentyl, isopentyl, sek-pentyl, t->pentyl, cyklop.ropyl, cyklobutyl og cyklo-pentyl. Med .den benyttede betegnelse "alkyl" menes rette og forgrenede alkylgrupper med 1-12 karbonatomer inkludert de ovennevnte lavere alkylgrupper, og f ..eks. • n-heksyl, isoheksyl, n-heptyl, iso-heptyl, n-oktyl, isooktyl, n-nonanyl, n-dekanyl, n-undekanyl, n-dodekanyl og lignende. Med den benyttede betegnelse "alkoksy" and branched groups and cyclic alkyl groups, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl,. isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, sec-pentyl, t->pentyl, cyclopropyl, cyclobutyl and cyclopentyl. The term "alkyl" used means straight and branched alkyl groups with 1-12 carbon atoms including the above-mentioned lower alkyl groups, and e.g. • n-hexyl, isohexyl, n-heptyl, iso-heptyl, n-octyl, isooctyl, n-nonanyl, n-decanyl, n-undecanyl, n-dodecanyl and the like. With the term "Alkoxy" used

menes gruppen "O-alkyl" hvor "alkyl" har den ovenfor angitte betydning.. means the group "O-alkyl" where "alkyl" has the meaning given above.

Med den benyttede betegnelse "farmasøytisk akseptable, ikke-toksiske estere, amider og salter" menes henholdsvis en alkyl-eller glyeerolester; et usubstituert monoalkyl, dialkyl, dialkyl-aminoalkyl, alkoksyalkyl eller fenetylsubstituert amid og et salt som definert ovenfor. With the term used "pharmaceutically acceptable, non-toxic esters, amides and salts" is meant respectively an alkyl or glyceryl ester; an unsubstituted monoalkyl, dialkyl, dialkylaminoalkyl, alkoxyalkyl or phenethyl substituted amide and a salt as defined above.

I de lavere alkylsulfinylserier har forbindelsene et asymmetrisk karbonatom. Foreliggende fremgangsmåter vil da gi både d- og 1-, samt dl-former hvilke således omfattes av oppfinnelsen. Isomerene kan om ønsket separeres på'vanlig måte slik som dannelse av alkaloidsaltene av produktene og anvendelse av fraksjonert krystallisering. In the lower alkylsulfinyl series, the compounds have an asymmetric carbon atom. Present methods will then give both d- and 1-, as well as dl-forms which are thus covered by the invention. If desired, the isomers can be separated in the usual way, such as forming the alkaloid salts of the products and using fractional crystallization.

Den nomenklatur som er benyttet er i overensstemmelse med Chemical Abstracts, 56, Subject Index (1962, januar-juni). The nomenclature used is in accordance with Chemical Abstracts, 56, Subject Index (1962, January-June).

Av hensiktsmessige grunner refererer bruken av nomenklaturen 5(7)-substituent A-7(5)-substituent B-xanton til 5-substituent A-7-substituent B-xanton og 5-substituent B-7~substituent A-xanton. Følgende eksempler illustrerer oppfinnelsen. Når det har vært nødvendig er eksemplene blitt gjentatt for å få tilveiebragt utgangsmaterialene for de etterfølgende eksempler. For convenience, the use of the nomenclature 5(7)-substituent A-7(5)-substituent B-xanthone refers to 5-substituent A-7-substituent B-xanthone and 5-substituent B-7~substituent A-xanthone. The following examples illustrate the invention. When it has been necessary, the examples have been repeated in order to obtain the starting materials for the subsequent examples.

Eksempel 1 A) •" En blanding av 4,188 g' 1,3-dikarbbmetoksy-4-brombenzen, 3,2. g o-n-okty l-p- (metyltio) f enol, 1,32 g kuprooksyd i 20 ml dimetyl-.-acetamid, oppvarmes til l60°C og holdes ved denne temperatur under omrøring og i nitrogehatmosfære. Etter styring via tynnsjikts-kromatogra.fi som.angir at reaksjonen er vesentlig fullstendig, for-' tynnes reaksjonsblandingen med vann og ekstraheres med dietyleter: metylenklorid (3:1)- Ekstraktene kromatograferes på 150 g aluminiumoksyd og de ensartede fraksjoner kombineres og er 1,3-dikarbometoksy-4-/o-n-oktyl-p-(metyltio)-fenyloksy7-benzen. B) 1, 3-dika.rbometoksy-4-/o-n-oktyl-p-(metyltio )-fen<y>loksy7-benzen (4 g) kombineres med 150 ml - 5% kaliumhydroksyd i metanol. Example 1 A) A mixture of 4.188 g of 1,3-dicarbmethoxy-4-bromobenzene, 3,2 g o-n-octyl-p-(methylthio)phenol, 1.32 g of cuprous oxide in 20 ml of dimethyl-.- acetamide, is heated to 160° C. and maintained at this temperature with stirring and in a nitrogen atmosphere. After control via thin layer chromatography indicating that the reaction is substantially complete, the reaction mixture is diluted with water and extracted with diethyl ether: methylene chloride (3 :1)- The extracts are chromatographed on 150 g of aluminum oxide and the uniform fractions are combined and are 1,3-dicarbomethoxy-4-/o-n-octyl-p-(methylthio)-phenyloxy-7-benzene. B) 1,3-dicarbomethoxy- 4-/o-n-octyl-p-(methylthio)-phen<y>loxy7-benzene (4 g) is combined with 150 ml - 5% potassium hydroxide in methanol.

Den resulterend.e blanding tilbakeløpskokes i 1 time hvoretter den surgjøres, avkjøles og filtreres, og dette gir 1, 3-d.ikarboksy-4-/o-n-oktyl-p-(metyltio)-fenyloksy7-benzen. C) 2 ,5 g 1, 3-dikarboksy-4-/o-n-oktyl-p-(metyltio )-f:enyloksy7-benzen i 20 ml konsentrert svovelsyre, omrøres ved 80C i 1 time. Deretter helles reaksjonsblandingen i 200.ml isvann og den resulterende blanding oppvarmes på et dampbad i 15 minutter. Blandingen avkjøles og filtreres idet bunnfallet vaskes med vann og omkrystalliseres deretter fra. eddiksyre og dette gir 5-n-oktyl-7_ (metyltio )-xanton-2-karboksylsyre. The resulting mixture is refluxed for 1 hour after which it is acidified, cooled and filtered, and this gives 1,3-dicarboxy-4-[o-n-octyl-p-(methylthio)-phenyloxy-7-benzene. C) 2.5 g of 1,3-dicarboxy-4-(o-n-octyl-p-(methylthio)-phenyloxy7-benzene in 20 ml of concentrated sulfuric acid, stirred at 80C for 1 hour. The reaction mixture is then poured into 200 ml of ice water and the resulting mixture is heated on a steam bath for 15 minutes. The mixture is cooled and filtered, the precipitate being washed with water and then recrystallized from it. acetic acid and this gives 5-n-octyl-7-(methylthio)-xanthone-2-carboxylic acid.

Eksempel 2Example 2

En blanding av 4 g 5-n-okty-7-(metyltio)-xanton-2-karboksylsyre, 10 g'metyljodid og 10 g litiumkarbonat i 50 ml dimetylformamid, omrøres ved romtemperatur i 16 timer. Deretter helles reaksjonsblandingen i fortynnet saltsyre-is og den resulterende blanding ekstraheres med etylacetat. Ekstraktene filtreres gjennom aluminiumoksyd og dette gir metyl-5-n-oktyl-7-(metyltio)-xanton-2-karboksylat som kan omkrystalliseres fra metanol. A mixture of 4 g of 5-n-octy-7-(methylthio)-xanthone-2-carboxylic acid, 10 g of methyl iodide and 10 g of lithium carbonate in 50 ml of dimethylformamide is stirred at room temperature for 16 hours. The reaction mixture is then poured into dilute hydrochloric acid ice and the resulting mixture is extracted with ethyl acetate. The extracts are filtered through aluminum oxide and this gives methyl 5-n-octyl-7-(methylthio)-xanthone-2-carboxylate which can be recrystallized from methanol.

Eksempel 3 Example 3

Metyl-5-n-okty1-7-(metyltio)-xanton-2-karboksylatMethyl 5-n-octyl-7-(methylthio)-xanthone-2-carboxylate

(927 mg) i 60 ml metylenklorid avkjøles til 0°C (is). m-klorper-benzosyre (555 mg) tilsettes deretter og blandingen omrøres ved 0°C (927 mg) in 60 ml of methylene chloride is cooled to 0°C (ice). m-chloroper-benzoic acid (555 mg) is then added and the mixture is stirred at 0°C

i 75 minutter. Reaksjonsblandingen filtreres så gjennom aluminiumoksyd og vaskes med metylenklorid og dette gir metyl-5-n-oktyl-7-met<y>lsulfin<y>lxanton-2-karboks<y>lat' som kan omkrystalliseres fra ' benzen/heptan for 75 minutes. The reaction mixture is then filtered through alumina and washed with methylene chloride and this gives methyl-5-n-octyl-7-meth<y>lsulfin<y>lxanthone-2-carbox<y>late' which can be recrystallized from 'benzene/heptane

Metyl-5-n-okt<y>1-7-met<y>.1sulfinylxanton-2-karboksylat.Methyl 5-n-oct<y>1-7-met<y>.1sulfinylxanthone-2-carboxylate.

( 720 mg), 75 ml etanol ,og 10 ml 5% natriumhydroksyd kokes- under tilbakeløp i 30 minutter. Blandingen avkjøles, inndampes delvis og surgjøres. Bunnfallet frafiltreres, vaskes og.tørkes og dette gir 5-n-oktyl-7-metyl-sulfinylxanton-2-karboksylsyre som kan omkrystalliseres fra eddiksyre.. (720 mg), 75 ml of ethanol and 10 ml of 5% sodium hydroxide are boiled under reflux for 30 minutes. The mixture is cooled, partially evaporated and acidified. The precipitate is filtered off, washed and dried and this gives 5-n-octyl-7-methyl-sulfinylxanthone-2-carboxylic acid which can be recrystallized from acetic acid.

Ekse mpel 4 Example 4

Metyl-5_n-okty1-7-(metyltio)-xanton-2-karboksylatMethyl 5-n-octyl-7-(methylthio)-xanthone-2-carboxylate

(764 mg), 2 ml bydrogenperoksyd (3.0$), og 40 ml eddiksyre oppvarmes på et dampbad (80°C.) i 90 minutter. Tynnsj iktskromatograf i indikerer' fravær av utgangsmaterialet. Blandingen fortynnes med 60 ml varmt vann og blandingen avkjøles, det faste material frafiltreres og tørkes og dette gir metyl-5-n-oktyl-7-metylsulfonylxanton-2-karboksylat. som kan omkrystalliseres fra eddiksyre/vann. (764 mg), 2 ml of hydrogen peroxide (3.0$), and 40 ml of acetic acid are heated on a steam bath (80° C.) for 90 minutes. Thin-layer chromatography indicates the absence of the starting material. The mixture is diluted with 60 ml of hot water and the mixture is cooled, the solid material is filtered off and dried and this gives methyl 5-n-octyl-7-methylsulfonylxanthone-2-carboxylate. which can be recrystallized from acetic acid/water.

Metyl-5-n-okty l-7-m'etyl su lf onylxanton-2-karboksylatMethyl 5-n-octyl-7-methyl sulfonylxanthone-2-carboxylate

(660 mg), 1 g kaliumhydroksyd og 60 ml 80$ vandig etanol kokes under tilbakeløp i 30 minutter. Blandingen filtreres, surgjøres og det faste stoffet frafiltreres og dette gir 5-n-oktyl-7~mety1sulfonylxanton-2-karboksylsyre. (660 mg), 1 g of potassium hydroxide and 60 ml of 80% aqueous ethanol are refluxed for 30 minutes. The mixture is filtered, acidified and the solid is filtered off and this gives 5-n-octyl-7-methylsulfonylxanthone-2-carboxylic acid.

.Eksempel 5.Example 5

Andre 5_alkyl- eller -alkoksy-7-(lavere-alkyltio)-xanton-2-karboksylsyrer som kan fremstilles er: 5-n-beksy1-7_(metyltio)-xanton-2-karboksyl syre, Other 5-alkyl- or -alkoxy-7-(lower-alkylthio)-xanthone-2-carboxylic acids that can be prepared are: 5-n-bexy1-7_(methylthio)-xanthone-2-carboxylic acid,

5-n-dodecy1-7-(metyltio)-xanton-2-karboksylsyre, 5-n-dodecyl-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-heks<y>loks<y->7~(met<y>ltio)-xanton-2-karboks<y>lsyre, 5-n-hex<y>lox<y->7~(met<y>lthio)-xanthone-2-carboxylic<y>lic acid,

5-n-oktyloksy-7-(metylt io)-xanton-2-karboksy1syre, 5-n-octyloxy-7-(methylthio)-xanthone-2-carboxylic acid,

5-n-dodecyloksy-7-(metyltio)-xanton-2-karboksy1syre,5-n-dodecyloxy-7-(methylthio)-xanthone-2-carboxylic acid,

og de tilsvarende 5-substituerte forbindelser i. hver av 7-etyltio-, 7-n-propyltio-, 7~isopropyltio-, 7-n-butyltio-,• 7~isobutyltio-, 7-sek-butyltio-, 7~t-butyltio-, 7-n-pentyltio-, 7-isopentyltio- og 7-(cyklopentyltio)-xanton-2-karboksylsyreseriene, fremstilles ifølge and the corresponding 5-substituted compounds i. each of 7-ethylthio-, 7-n-propylthio-, 7~isopropylthio-, 7-n-butylthio-,• 7~isobutylthio-, 7-sec-butylthio-, 7~ The t-butylthio-, 7-n-pentylthio-, 7-isopentylthio- and 7-(cyclopentylthio)-xanthone-2-carboxylic acid series are prepared according to

■metodene A), B) og C) i eksempel 1.■methods A), B) and C) in example 1.

De således fremstilte forbindelser behandles slik som angitt i eksemplene 3 og 4 for dannelse av.andre 5-substituerte-7-laverealkylsulfinyl- og 7-laverealkylsulfonyl-xanton-2-karboksy1-syrer, f.eks. 5-n-heksyl-7-metylsulfinylxanton-2-karboksylsyre, 5-n-heksyl-7-metylsulfonylxanton-2-karboksylsyre, The thus prepared compounds are treated as indicated in examples 3 and 4 to form other 5-substituted-7-lower alkylsulfinyl and 7-lower alkylsulfonyl-xanthone-2-carboxylic acids, e.g. 5-n-hexyl-7-methylsulfinylxanthone-2-carboxylic acid, 5-n-hexyl-7-methylsulfonylxanthone-2-carboxylic acid,

5-n-dodecy1-7-metylsulfinylxanton-2-karboksyIsyre, 5-n-dodecyl-7-metylsulfonylxanton-2-karboksylsyre, osv., 5-n-heksyloksy-7-metylsulfinylxanton-2-karboksyl syre, 5-n-heksyloksy-7_metylsulfon'ylxanton-2-karboksylsyre, 5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre, sm.p. 258-260°C I 5-n-oktyloksy-7-rnetylsulf onylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-metylsulfinylxanton-2-karboksylsyre, sm.p. 254-255°C 5-n-dodecyloksy-7-metylsulfonylxanton-2-karboksylsyre,"osv., 5-n-dodecyl-7-methylsulfinylxanthone-2-carboxylic acid, 5-n-dodecyl-7-methylsulfonylxanthone-2-carboxylic acid, etc., 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylic acid, 5-n- hexyloxy-7-methylsulfonylxanthone-2-carboxylic acid, 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 258-260°C I 5-n-octyloxy-7-rnetylsulfonylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylic acid, m.p. 254-255°C 5-n-dodecyloxy-7-methylsulfonylxanthone-2-carboxylic acid,"etc.,

5-n-heksyl-7-etylsulfinylxanton-2-karboksylsyre, 5-n-hexyl-7-ethylsulfinylxanthone-2-carboxylic acid,

5-n-heksy1-7-etylsulfonylxanton-2-karboksylsyre, 5-n-hexy1-7-ethylsulfonylxanthone-2-carboxylic acid,

5'-n-okt yl-7-ety lsulf inylxanton-2-karboksyl syre , 5'-n-octyl-7-ethylsulfinylxanthone-2-carboxylic acid,

5-n-oktyl-7-etylsulfonylxanton-2-karboksyl syre, 5-n-octyl-7-ethylsulfonylxanthone-2-carboxylic acid,

5-n-dodecyl-7-etylsulfinylxanton-2-karboksylsyre, 5-n-dodecy 1-7-ety lsulf onylxanton-2-karboksyl syre , osv . 5-n-heksyloksy-7-etylsulfinylxanton-2-karboksyl syre, 5-n-heksyl-oksy-7- ety lsulf onylxanton-2-karboksyl syre , 5-n-okty loksy - 7- etylsulf inylxanton-2-kar.boksy lsyre , 5-n-oktyloksy-7-etylsulfonylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-etylsulfinylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-etylsulfonylxanton-2-karboksylsyre, osv., 5-n-heksy1-7-n-propylsulfinylxanton-2-karboksylsyre, 5-n-heksy1-7-n-propylsulfonylxanton-2-karboksylsyre, 5-n-oktyl-7-n-propylsulfinylxanton-2-karboksylsyre, 5-n-oktyl-7-n-propylsulfonylxanton-2-karboksylsyre, 5-n-dodecyl-7_n-propylsulfinylxanton-2-karboksylsyre, 5-n-dodecyl-7~n-propylsulfonylxanton-2-karboksylsyre / .osv., 5-n-heksyloksy-7-n-propylsulfinylxanton-2-karboksylsyre, 5-n-heksyloksy-7-n-propylsulfonylxanton-2-karboksylsyre, 5-n-oktyloksy-7-n-propylsulfinylxanton-2-karboksyl syre, 5-n-oktyloksy-7"n-propylsulfonylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-n-propylsulfinylxanton-2-karboksylsyre, 5-n-dodecyloksy-7_n-propylsulfonylxanton-2-karboksylsyre, osv., 5-n-heksy1-7-isopropylsulfinylxanton-2-karboksylsyre, 5-n-dodecyl-7-ethylsulfinylxanthone-2-carboxylic acid, 5-n-dodecy 1-7-ethylsulf onylxanthone-2-carboxylic acid, etc. 5-n-hexyloxy-7-ethylsulfinylxanthone-2-carboxylic acid, 5-n-hexyl-oxy-7-ethylsulfonylxanthone-2-carboxylic acid, 5-n-octyloxy-7-ethylsulfinylxanthone-2-car. carboxylic acid, 5-n-octyloxy-7-ethylsulfonylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7-ethylsulfinylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7-ethylsulfonylxanthone-2-carboxylic acid, etc., 5- n-hexy1-7-n-propylsulfinylxanthone-2-carboxylic acid, 5-n-hexy1-7-n-propylsulfonylxanthone-2-carboxylic acid, 5-n-octyl-7-n-propylsulfinylxanthone-2-carboxylic acid, 5-n- octyl-7-n-propylsulfonylxanthone-2-carboxylic acid, 5-n-dodecyl-7_n-propylsulfinylxanthone-2-carboxylic acid, 5-n-dodecyl-7~n-propylsulfonylxanthone-2-carboxylic acid / .etc., 5-n- Hexyloxy-7-n-propylsulfinylxanthone-2-carboxylic acid, 5-n-hexyloxy-7-n-propylsulfonylxanthone-2-carboxylic acid, 5-n-octyloxy-7-n-propylsulfinylxanthone-2-carboxylic acid, 5-n-octyloxy -7"n-propylsulfonylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7-n-propylsulfinylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7_n-propylsulfonylxanthone-2-carboxylic acid ylic acid, etc., 5-n-hexy1-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-n-heksy1-?-isopropylsulfonylxanton-2-karboksylsyre, 5-n-oktyl-7-isopropylsulfinylxanton-2-karboksylsyre, 5-n-hexy1-?-isopropylsulfonylxanthone-2-carboxylic acid, 5-n-octyl-7-isopropylsulfinylxanthone-2-carboxylic acid,

5-n-oktyl-7-isopropylsulfonylxanton-2-karboksylsyre, 5-n-dodecyl-7-isopropylsulfinylxanton-2-karboksylsyre, 5-n-dodecyl^7-isopropylsulfonylxanton-2-karboksylsyre, osv.,. '5-n-heksy loksy-7"isopropy lsulf inylxanton-2-karboksy lsyre, 5-n-heksyloksy-7-isopropylsulfonylxanton-2-karboksylsyre, 5-n-oktyloksy-7-isopropylsulfinylxanton-2-karboksylsyre, 5-n-oktyloksy-7-isopropylsulfonylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-isopropylsulfinylxanton-2-karboksylsyre, 5-n-dodecyloksy-7-isopropylsulfonylxanton-2-karboksylsyre, osv. 5-n-octyl-7-isopropylsulfonylxanthone-2-carboxylic acid, 5-n-dodecyl-7-isopropylsulfinylxanthone-2-carboxylic acid, 5-n-dodecyl^7-isopropylsulfonylxanthone-2-carboxylic acid, etc.,. 5-n-hexyloxy-7"isopropylsulfinylxanthone-2-carboxylic acid, 5-n-hexyloxy-7-isopropylsulfonylxanthone-2-carboxylic acid, 5-n-octyloxy-7-isopropylsulfinylxanthone-2-carboxylic acid, 5-n- -octyloxy-7-isopropylsulfonylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7-isopropylsulfinylxanthone-2-carboxylic acid, 5-n-dodecyloxy-7-isopropylsulfonylxanthone-2-carboxylic acid, etc.

Eksempel 6Example 6

Eksempel 5 gjentas for fremstilling av 5~(lavere alkyltio)-7-alkyl- eller -alkoksy-xanton-2-karboksylsyreforbindelsene og de tilsvarende sulfinyl- og sulfonylforbindelser, dvs.:. 5-metyltio-7_n-heksylxanton-2-karboksylsyre, Example 5 is repeated for the preparation of the 5~(lower alkylthio)-7-alkyl- or -alkoxy-xanthone-2-carboxylic acid compounds and the corresponding sulfinyl and sulfonyl compounds, i.e.:. 5-methylthio-7_n-hexylxanthone-2-carboxylic acid,

5-metyltio-7_n-oktyIxanton-2-karboksylsyre, 5-methylthio-7_n-octylxanthone-2-carboxylic acid,

5-metyltio-7-n-dodecylxanton-2-karboksylsyre, osv., 5-methylthio-7-n-dodecylxanthone-2-carboxylic acid, etc.,

5-metyltio-7-n-heksyloksyxanton-2-karboksylsyre, 5-methylthio-7-n-hexyloxyxanthone-2-carboxylic acid,

5-metyltio-7"n-oktyloksyxanton-2-karboksylsyre, 5-methylthio-7"n-octyloxyxanthone-2-carboxylic acid,

5-metyltio-7-n-dodecyloksyxanton-2-karboksylsyre, osv.5-methylthio-7-n-dodecyloxyxanthone-2-carboxylic acid, etc.

og de tilsvarende forbindelser i hver av 5~etyltio-, t-n-propyl-, 5-n-propyltio- , 5-iso'propyltio , osv., seriene: 5-metylsulfinyl-7-n-heksyIxanton-2-karboksylsyre, and the corresponding compounds in each of the 5~ethylthio-, t-n-propyl-, 5-n-propylthio-, 5-iso'propylthio, etc., series: 5-methylsulfinyl-7-n-hexyIxanthone-2-carboxylic acid,

5-metylsuIfony1-7-n-heksyIxanton-2-karboksylsyre, 5-methylsuIfony1-7-n-hexyIxanthone-2-carboxylic acid,

5-metylsulfinyl-7-n-oktyIxanton-2-karboksylsyre, 5-methylsulfinyl-7-n-octylxanthone-2-carboxylic acid,

5-metylsulfony1-7-n-oktyIxanton-2-karboksylsyre, 5-methylsulfony1-7-n-octylxanthone-2-carboxylic acid,

5-metylsulfinyl-7-n-dodecyIxanton-2-karboksylsyre, 5-methylsulfinyl-7-n-dodecylxanthone-2-carboxylic acid,

5-me tylsulfony1-7-n-dodecyIxanton-2-karboksylsyre, 5-methylsulfonyl 1-7-n-dodecylxanthone-2-carboxylic acid,

5-metylsulfinyl-7-n-heksyloksyxanton-2-karboksylsyre, 5-methylsulfinyl-7-n-hexyloxyxanthone-2-carboxylic acid,

5-metylsulfonyl-7-n-heksyloksyxanton-2-karboksylsyre, 5-metylsulfinyl-7-n-oktyloksyxanton-2-karboksylsyre, sm.p. 218-219°C 5-metylsulfonyl-7-n-oktyloksyxanton-2-karboksylsyre, 5-metylsulfinyl-7-n-dodecylpksyxanton-2-karboksylsyre sm.p. 196-197°C 5-metylsulfonyl-7-n-dodecyloksyxanton-2-karboksylsyre, osv., 5-etylsulfinyl-7"n-heksyIxanton-2-karboksylsyre, 5-methylsulfonyl-7-n-hexyloxyxanthone-2-carboxylic acid, 5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid, m.p. 218-219°C 5-methylsulfonyl-7-n-octyloxyxanthone-2-carboxylic acid, 5-methylsulfinyl-7-n-dodecyl poxyxanthone-2-carboxylic acid m.p. 196-197°C 5-methylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylic acid, etc., 5-ethylsulfinyl-7"n-hexyIxanthone-2-carboxylic acid,

5-etylsulfonyl-7-n-heksylxanton-2-karboksylsyre, 5-ethylsulfonyl-7-n-hexylxanthone-2-carboxylic acid,

5-etylsulfinyl-7-n-oktylxanton-2-karboksylsyre, - j 5-etylsulfony1-7-n-oktyIxanton-2-karboksylsyre, r 5~etylsulfinyl-7-n-dodecyIxanton-2-karboksylsyre, 5-ethylsulfinyl-7-n-octylxanthone-2-carboxylic acid, - j 5-ethylsulfonyl-7-n-octylxanthone-2-carboxylic acid, r 5-ethylsulfinyl-7-n-dodecylxanthone-2-carboxylic acid,

5-etylsulfonyl-7-n-dodecylxanton-2-karboksylsyre, osv., 5-Ethylsulfonyl-7-n-dodecylxanthone-2-carboxylic acid, etc.,

5-etylsulfinyl-7-n-beksyloksyxanton-2-karboksylsyre, 5-etylsulfony1-7-n-beksyloksyxanton-2-karboksyl syrej 5-etylsulfinyl-7-n-oktyloksyxanton-2-karboksylsyre, 5-ethylsulfinyl-7-n-bexyloxyxanthone-2-carboxylic acid, 5-ethylsulfonyl-7-n-bexyloxyxanthone-2-carboxylic acid 5-ethylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid,

5-etylsulfony1-7-n-oktyloksyxanton-2-karboksylsyre, 5-ethylsulfony1-7-n-octyloxyxanthone-2-carboxylic acid,

5-etylsulfinyl-7-n-dodecyloksyxanton-2-karboksylsyre, 5-etylsulfonyl-7-n-dodecyloksyxanton-2-karboksylsyrejosv., 5-n-propy lsulf inyl-7-n-heksy Ixanton-2-karboksyl syre', 5-n-propylsulfony1-7-n-heksyIxanton-2-karboksylsyre, 5-ethylsulfinyl-7-n-dodecyloxyxanthone-2-carboxylic acid, 5-ethylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylic acid etc., 5-n-propylsulfinyl-7-n-hexy Ixanthone-2-carboxylic acid', 5-n-propylsulfony1-7-n-hexyIxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-n-oktylxanton-2-karboksylsyre, 5-n-propylsulfinyl-7-n-octylxanthone-2-carboxylic acid,

5-n-propylsulfony1-7~n-oktylxanton-2-karboksylsyre, 5-n-propylsulphonyl-7~n-octylxanthone-2-carboxylic acid,

5-n-propylsulfinyl-7-n-dodecyIxanton-2-karboksylsyre, 5-n-propylsulfonyl-7-n-dodecylxanton-2-karboksylsyre, osv., 5-n-propylsulfinyl-7-n-heksyloksyxanton-2-karboksylsyre, 5-n-propylsulfon.yl-7-n-heksyloksyxanton-2-karboksyl syre, 5-n-propylsulfinyl-7-n-oktyloksyxanton-2-karboksylsyre, 5-n-propylsulfony1-7-n-oktyloksyxanton-2-karboksylsyre, 5-n-pr opy l.sulf inyl-7 -n-dodecy loksy xanton--2- karboksyl syre 5-n-propylsulfonyl-7-n-dodecyloksyxanton-2-karboksylsyre, osv., 5-isopropylsulfiny1-7-n-heksyIxanton-2-karboksylsyre, 5-isopropylsulfonyl-7-n-heksyIxanton-2-karboksylsyre, 5-isopropylsulfinyl-7-n-oktyIxanton-2-karboksylsyre, 5-isopropy1sulfony1-7-n-oktylxanton-2-karboksylsyre, 5-isopropylsulfinyl-7-n-dodecyIxanton-2-karboksylsyre, 5-isopropylsulf ony 1-7-n-dodecylxanton-J2-karboksylsyre , osv., 5- i so pr opy lsulf inyl-7-n-heksy l.oksyxan ton-2-karboksyl syre , 5-isopropylsulfony1-7-n-heksyloksyxanton-2-karboksylsyre, 5-isopropylsulfinyl-7_n-oktyloksyxanton-2-karboksylsyre,. 5-i sopropylsulfony1-7-n-oktyloksyxanton-2-karboksyl syre, 5-isopropylsulfinyl-7_n-dodecyloksyxanton-2-karboksylsyre, 5-isopropylsulfonyl-7-n-dodecyloksyxanton-2-karboksylsyre, osv. 5-n-propylsulfinyl-7-n-dodecylxanthone-2-carboxylic acid, 5-n-propylsulfonyl-7-n-dodecylxanthone-2-carboxylic acid, etc., 5-n-propylsulfinyl-7-n-hexyloxyxanthone-2-carboxylic acid , 5-n-propylsulfonyl-7-n-hexyloxyxanthone-2-carboxylic acid, 5-n-propylsulfinyl-7-n-octyloxyxanthone-2-carboxylic acid, 5-n-propylsulfony1-7-n-octyloxyxanthone-2- carboxylic acid, 5-n-propy l.sulf inyl-7-n-dodecyloxy xanthone-2- carboxylic acid 5-n-propylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylic acid, etc., 5-isopropylsulfinyl-7 -n-hexyIxanthone-2-carboxylic acid, 5-isopropylsulfonyl-7-n-hexyIxanthone-2-carboxylic acid, 5-isopropylsulfinyl-7-n-octylxanthone-2-carboxylic acid, 5-isopropylsulfonyl-7-n-octylxanthone-2-carboxylic acid . oxyxanthone-2-carboxylic acid , 5-isopropylsulfony1-7-n-hexyloxyxanthone-2-carboxylic acid, 5-isopropylsulfinyl-7_n-octyloxyxanthone-2-carboxylic acid,. 5-isopropylsulfonyl-7-n-octyloxyxanthone-2-carboxylic acid, 5-isopropylsulfinyl-7_n-dodecyloxyxanthone-2-carboxylic acid, 5-isopropylsulfonyl-7-n-dodecyloxyxanthone-2-carboxylic acid, etc.

Eksempel 7Example 7

En blanding av 4,5 g 5-n-oktyl-7-metylsulfinyl-xanton-2-karboksylsyre, 10 g metyljodid og 10 g litiumkarbonat i 75 ml dimetylformamid omrøres ved romtemperatur i 18 timer. Deretter helles reaksjonsblandingen i fortynnet saltsyre-is, og det resulterende bunnfall frafiltreres og vaskes, hvilket gir mety1-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat. A mixture of 4.5 g of 5-n-octyl-7-methylsulfinyl-xanthone-2-carboxylic acid, 10 g of methyl iodide and 10 g of lithium carbonate in 75 ml of dimethylformamide is stirred at room temperature for 18 hours. The reaction mixture is then poured into dilute hydrochloric acid ice, and the resulting precipitate is filtered off and washed, yielding methyl 1-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate.

Ovenstående metode gjentas under anvendelse av forskjellige lavere alkyljodider for dermed å oppnå de tilsvarende lavere alkylsyreestere, f.eks.: etyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, n-propy1-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, isopropy1-5-n-okty1-7-metylsulfinylxanton-2-karboksylat, n-propy1-5-n-okty1-7-metylsulfinylxanton-2-karboksylat, isobutyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, sek-buty1-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, n-pentyl-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, osv. The above method is repeated using different lower alkyl iodides to thereby obtain the corresponding lower alkyl acid esters, e.g.: ethyl 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, n-propyl 1-5-n-octyl-7 -methylsulfinylxanthone-2-carboxylate, isopropyl 1-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, n-propyl 1-5-n-octy1-7-methylsulfinylxanthone-2-carboxylate, isobutyl-5-n-octyl-7 -methylsulfinylxanthone-2-carboxylate, sec-butyl 1-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, n-pentyl-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, etc.

Likeledes kan de andre xanton-2-karboksylsyrene inneholde substituenter ved C-5,7-stillingene, fremstilt som angitt ovenfor, omdannes til de tilsvarende syreestere, f.eks.: mety1-5-n-oktyl-7-metylsulfonyIxanton-2-karboksylat, ety1-5-metylsulfony1-7-n-oktyloksyxanton-2-karboksylat, n-propy1-5-n-oktyl-7-sulfamoyIxanton-2-karboksylat, metyl-5-acetyl-7-n-oktyIxanton-2-karboksylat, osv. Likewise, the other xanthone-2-carboxylic acids containing substituents at the C-5,7 positions, prepared as indicated above, can be converted into the corresponding acid esters, e.g.: methyl 1-5-n-octyl-7-methylsulphonylxanthone-2- carboxylate, ethyl 1-5-methylsulfonyl 1-7-n-octyloxyxanthone-2-carboxylate, n-propyl 1-5-n-octyl-7-sulfamoylxanthone-2-carboxylate, methyl 5-acetyl-7-n-octylxanthone-2-carboxylate carboxylate, etc.

I sulfoseriene fremstilles estrene ved behandling av syren med den passende lavere alkanol under tilbakeløp og i fravær av syre til f.eks.: metyl-5-n-oktyl-7-sulfoxanton-2-karboksylat og In the sulpho series, the esters are prepared by treating the acid with the appropriate lower alkanol under reflux and in the absence of acid to e.g.: methyl 5-n-octyl-7-sulfoxanthone-2-carboxylate and

ety1-5-n-okty1-7-sulfoxanton-2-karboksylat.ethyl 1-5-n-octyl-7-sulfoxanthone-2-carboxylate.

Eksempel 8Example 8

Til en oppløsning av 10 g 5-n-oktyl-7-metylsulfi-nylxanton-2-karboksylsyre i 200 ml etanol tilsettes den teore-tiske mengde natriumhydroksyd oppløst i 200 ml 90% etanol. Reaksjonsblandingen konsentreres deretter i vakuum og dette gir natrium-5-n-oktyl-7-metylsulfonyIxanton-2-karboksylat. To a solution of 10 g of 5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid in 200 ml of ethanol is added the theoretical amount of sodium hydroxide dissolved in 200 ml of 90% ethanol. The reaction mixture is then concentrated in vacuo and this gives sodium 5-n-octyl-7-methylsulphonylxanthone-2-carboxylate.

På samme måte fremstilles kalium- og litiumsaltene. The potassium and lithium salts are prepared in the same way.

Likeledes, ved å erstatte natriumsaltet ved hjelp av en passende metallsalt-reagent, f.eks. kalsiumklorid, manganklorid osv., fremstilles de andre xanton-2-karboksylsyresaltene, f.eks.: magnesium-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, kalsium-5-n-oktyl-7-metylsulfinyIxanton-2-karboksylat, aluminium-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, ferro-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, sink-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat , mangan-5-n-okty1-7-metylsulfinylxanton-2-karboksylat, ferri-5-n-oktyl-7-metylsulfinylxanton-2-karboksylat, osv. Likewise, by replacing the sodium salt with a suitable metal salt reagent, e.g. calcium chloride, manganese chloride, etc., the other xanthone-2-carboxylic acid salts are prepared, e.g.: magnesium 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, calcium 5-n-octyl-7-methylsulfinylxanthone-2- carboxylate, aluminum 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, ferro-5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, zinc 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, manganese 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, ferric 5-n-octyl-7-methylsulfinylxanthone-2-carboxylate, etc.

På lignende måte fremstilles xanton-2-karboksylsyre-saltene av de andre C-5,7-disubstituerte xanton-2-karboksylsyre-ne, f.eks.: kalium-5-n-oktyl-7-metylsulfonyIxanton-2-karboksylat, natrium-5-n-heksyl-7-metylsulfinylxanton-2-karboksylat, natrium-5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylat, natrium-5-metylsulfony1-7-n-oktyloksyxanton-2-karboksylat, natrium-5-metylsulfinyl-7-n-oktyloksyxanton-2-karboksylat, natrium-5-n-dodecyloksy-7-metylsulfonyIxanton-2-karboksylat, natrium-5-n-dodecyloksy-7-metylsulfinylxanton-2-karboksylat, natrium-5-n-heksyloksy-7-metylsulfonyIxanton-2-karboksylat, natrium-5-n-heksyloksy-7-metylsulfinylxanton-2-karboksylat, natrium-5-n-oktyloksy-7-metylsulfonylxanton-2-karboksylat, osv. In a similar way, the xanthone-2-carboxylic acid salts are prepared from the other C-5,7-disubstituted xanthone-2-carboxylic acids, for example: potassium 5-n-octyl-7-methylsulphonylxanthone-2-carboxylate, sodium 5-n-hexyl-7-methylsulfinylxanthone-2-carboxylate, sodium 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylate, sodium 5-methylsulfony1-7-n-octyloxyxanthone-2-carboxylate, sodium- 5-methylsulfinyl-7-n-octyloxyxanthone-2-carboxylate, sodium 5-n-dodecyloxy-7-methylsulfonyIxanthone-2-carboxylate, sodium 5-n-dodecyloxy-7-methylsulfinylxanthone-2-carboxylate, sodium 5- n-hexyloxy-7-methylsulfonylxanthone-2-carboxylate, sodium 5-n-hexyloxy-7-methylsulfinylxanthone-2-carboxylate, sodium 5-n-octyloxy-7-methylsulfonylxanthone-2-carboxylate, etc.

Eksempel 9Example 9

En oppløsning av 10 g 5-n-oktyl-7_metylsulfiny1-xanton-2-karboksylsyre i 50 ml tionylklorid oppvarmes under til-bakeløp i 1 time. Deretter inndampes oppløsningen til tørrhet til det tilsvarende syreklorid hvortil man tilsetter en konsentrert eterisk ammoniakkalsk oppløsning. Den resulterende oppløs-ning inndampes, hvilket gir 5-n-oktyl-7_metylsulfinylxanton-2-karboksylsyreamid. A solution of 10 g of 5-n-octyl-7-methylsulfinyl-1-xanthone-2-carboxylic acid in 50 ml of thionyl chloride is heated under reflux for 1 hour. The solution is then evaporated to dryness to the corresponding acid chloride to which a concentrated ethereal ammoniacal solution is added. The resulting solution is evaporated to give 5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid amide.

På lignende måte kan de lavere alkylamider fremstilles under anvendelse av monoalkylamin eller dialkylamin i stedet for ammoniakk i de ovenfor angitte metoder. Således fremstilles f.eks.: 5-n-oktyl-7-metylsulfamoylxanton-2-karboksylsyreamid, N-mety1-5-n-oktyl-7-n-propylsulfinyIxanton-2-karboksylsyreamid, N,N-diety1-5-n-oktyl-7-etylsulfonyIxanton-2-karboksylsyreamid, N-n-propy1-5-n-okty1-7-(propylsulfinyIxanton-2-karboksylsyre-amid, osv. In a similar manner, the lower alkyl amides can be prepared using monoalkylamine or dialkylamine instead of ammonia in the above methods. Thus, for example: 5-n-octyl-7-methylsulfamoylxanthone-2-carboxylic acid amide, N-methyl-5-n-octyl-7-n-propylsulfinylxanthone-2-carboxylic acid amide, N,N-diethyl-5-n -octyl-7-ethylsulfonyIxanthone-2-carboxylic acid amide, N-n-propyl-5-n-octyl-7-(propylsulfinyIxanthone-2-carboxylic acid amide, etc.

Eksempel 10Example 10

Til en blanding av 20 g prokain og 500 ml vandig metanol tilsettes 20 g 5-n-oktyl-7-metylsulfinylxanton-2-karbok-sylsyre. Den resulterende blanding omrøres ved romtemperatur i l6 timer. Den inndampes deretter under redusert trykk og dette gir prokainsaltet av 5-n-oktyl-7-metylsulfinylxanton-2-karboksyl-syre. To a mixture of 20 g of procaine and 500 ml of aqueous methanol, 20 g of 5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid is added. The resulting mixture is stirred at room temperature for 16 hours. It is then evaporated under reduced pressure and this gives the procaine salt of 5-n-octyl-7-methylsulfinylxanthone-2-carboxylic acid.

På samme måte oppnås lysin-, kaffein- og argininsaltene. Videre oppnås på lignende måte f.eks. prokain-, lysin-, kaffein- og argininsaltene av de andre C-5,7-disubstituerte xanton-2-karboksylsyrene, f.eks.: prokainsaltet av 5-n-oktyl-7-etylsulfonyIxanton-2-karboksylsyre, kaffeinsaltet av 5-(propylsulfinyl)-7-n-oktyloksyxanton-2-karbok-sylsyre, In the same way, the lysine, caffeine and arginine salts are obtained. Furthermore, in a similar way, e.g. The procaine, lysine, caffeine and arginine salts of the other C-5,7-disubstituted xanthone-2-carboxylic acids, eg: the procaine salt of 5-n-octyl-7-ethylsulfonyIxanthone-2-carboxylic acid, the caffeine salt of 5 -(propylsulfinyl)-7-n-octyloxyxanthone-2-carboxylic acid,

prokainsaltet av 5-(sek-butylsulfinyl)-7-n-oktyloksyxanton-2-karboksylsyre. the procaine salt of 5-(sec-butylsulfinyl)-7-n-octyloxyxanthone-2-carboxylic acid.

Eksempel 11Example 11

Følgende metode illustrerer den måte hvorved de farmasøytiske preparater med de nye forbindelser fremstilles. The following method illustrates the way in which the pharmaceutical preparations with the new compounds are prepared.

Natriumklorid (0,44 g) oppløses i 80 ml av en 9,47 g/l vann) natriumhydrogenfosfatoppløsning. Én natriumdihydrogen-fosfat (8,00 g/l vann) oppløsning (20 ml) tilsettes deretter. Den resulterende oppløsning med en pH-verdi på 7,38 steriliseres i en autoklav. Denne bærer tilsettes deretter til fast, tørr 5-n-oktyloksy-7-metylsulfinylxanton-2-karboksylsyre og man oppnår dermed et preparat egnet for intravenøs injeksjon inneholdende 2,5 mg 5-n-oktyloksy-7_metylsulfinylxanton-2-karboksylsyre pr. ml totalt preparat. Sodium chloride (0.44 g) is dissolved in 80 ml of a 9.47 g/l (water) sodium hydrogen phosphate solution. One sodium dihydrogen phosphate (8.00 g/l water) solution (20 ml) is then added. The resulting solution with a pH value of 7.38 is sterilized in an autoclave. This carrier is then added to solid, dry 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid and a preparation suitable for intravenous injection is thus obtained containing 2.5 mg of 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid per ml total preparation.

Eksempel 12Example 12

Den nedenfor angitte forbindelse ble undersøkt under anvendelse av den rotte-passive kutane anafylakseprøve (PCA) med homocytotropisk reaginisk antistoff ifølge I. Mota, Immunology 7, 68l (1964). Denne test måler virkningen av stoffer med hensyn til inhibering av frigjøringen av spasmogener (toksiske produkter) fra antigen-antistoff (allergisk) reaksjonen. The compound below was tested using the rat passive cutaneous anaphylaxis (PCA) test with homocytotropic reaginic antibody according to I. Mota, Immunology 7, 681 (1964). This test measures the effectiveness of substances in inhibiting the release of spasmogens (toxic products) from the antigen-antibody (allergic) reaction.

Normale hunrotter (Spraque-Dawley) med legemsvekt 140-160 g, ble passivt sensitivert i begge sider ved intradermal injeksjon av rotte-anti-eggalbumin reaginisk serum (antistoff). Etter 24 timer ble det i hver rotte injisert 1 ml normal salt-vannsoppløsning inneholdende 0,5 % Evans blå fargestoff, 1 mg eggalbumin (antigen) og forsøksforbindelsen. Den inflammatoriske respons som resulterer fra antigen-antistoffreaksjonen fremtrer som et blåfarget hudområde som måles 15-25 minutter etter injek-sjonen, idet områdets midlere diameter (mm— S.E.) måles og anvendes for å bestemme inhiberingen av inflammatorisk respons, som uttrykkes som prosent mot kontrollprøve. Normal female rats (Spraque-Dawley) with a body weight of 140-160 g were passively sensitized on both sides by intradermal injection of rat anti-egg albumin reaginic serum (antibody). After 24 hours, 1 ml of normal saline solution containing 0.5% Evans blue dye, 1 mg of egg albumin (antigen) and the test compound was injected into each rat. The inflammatory response resulting from the antigen-antibody reaction appears as a blue-colored skin area that is measured 15-25 minutes after the injection, the mean diameter (mm—S.E.) of the area being measured and used to determine the inhibition of the inflammatory response, which is expressed as a percentage against control sample.

Eksempel 13 Example 13

En dose på 100 mg/kg legemsvekt av 5-n-oktyloksy-7_ metylsulfinylxanton-2-karboksylsyre ble gitt intraperitonealt til marsvin. Andre marsvin ble holdt som en kontrollgruppe. Etter behandling ble de behandlede marsvin og kontrollgruppen uttatt for en vandig dusj av 0,05 % histamindifosfat (beregnet som base) levert ved hjelp av en fprstøvningsdyse, inntil dyrene viste tegn til å ha tapt retningsevnen. Under påvirkning av dusjen ble dyrene observert for graden av reaksjon. Denne reaksjon varierer fra noe dypere pusting til dyp pusting, videre til krampeaktig gisping og ataksi og over til kollaps. Marsvinene som mottok 5-n-oktyloksy-7_metylsulfinylxanton-2-karboksylsyre viste en betydelig motstand overfor histaminaerosolen, mens alle kontrollmarsvinene falt sammen under påvirkningen. A dose of 100 mg/kg body weight of 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid was given intraperitoneally to guinea pigs. Other guinea pigs were kept as a control group. After treatment, the treated guinea pigs and the control group were subjected to an aqueous shower of 0.05% histamine diphosphate (calculated as base) delivered by means of a fpr dusting nozzle, until the animals showed signs of having lost their ability to direct. Under the influence of the shower, the animals were observed for the degree of reaction. This reaction varies from somewhat deeper breathing to deep breathing, further to convulsive gasping and ataxia and over to collapse. The guinea pigs receiving 5-n-octyloxy-7-methylsulfinylxanthone-2-carboxylic acid showed a significant resistance to the histamine aerosol, while all the control guinea pigs collapsed under the influence.

En beskyttelse mot histaminaerosolindusert bromko-konstriksjon, slik det er beskrevet ovenfor, ansees å være representativ for og kan overføres på bronkie-lungeaktivitet hos mennesker, inkludert bronkodilator aktivitet. Således ble pasienter som led av lidelser i bronkieroog lunger studert med hensyn til graden av bronkospasmer og forandringer både observer-bare og målbare med hensyn til ekspirasjonsfunksjonen. Slike målinger omfatter en kvantisering av den utgående lungeluft-strømmen målt med slike instrumenter som en toppstrømningsmåler og sammenligning av lungevoluene før og etter behandling med de fremstilte forbindelser slik dette kunne måles med spirometriske og/eller plethysomografiske metoder. Subjektive forbedringer med hensyn til symptomene ved administrasjon av forbindelsene kunne påvises ved forbedringer med hensyn til åndenød, gisping, hoste og opphostet spytt. A protection against histamine aerosol-induced bronchoconstriction, as described above, is believed to be representative of and transferable to human bronchial lung activity, including bronchodilator activity. Thus, patients who suffered from disorders in the bronchioles and lungs were studied with regard to the degree of bronchospasm and changes both observable and measurable with regard to expiratory function. Such measurements include a quantization of the outgoing lung air flow measured with such instruments as a peak flow meter and comparison of the lung volumes before and after treatment with the manufactured compounds as this could be measured with spirometric and/or plethysomographic methods. Subjective improvements in symptoms upon administration of the compounds could be demonstrated by improvements in shortness of breath, gasping, coughing and expectoration.

Claims

Analogy method for the preparation of compounds with prophylactic and therapeutic activity, e.g. for allergic and bronchopulmonary conditions, with the general formula:

and pharmaceutically acceptable, non-toxic esters, amides and salts thereof; where an R^ group is selected from alkyl and alkoxy, where each group has 6-12 carbon atoms and the other R~ ^ group is the group -S(0), where n is 1 or 2 and R is lower alkyl, t n R characterized in that a 5(7)-alkyl- or -Alkoxy-7(5)-(alkylthio)-xanthone-2-carboxylic acid or lower alkyl esters thereof are oxidized with a peracid or with hydrogen peroxide, optionally followed by hydrolysis to form the corresponding 5(7)-alkyl- or alkoxy-7 (5)-(Alkylsulfinyl)-xanthone-2-carboxylic acids or their lower alkyl esters or 5(7)-alkylsulfonyl-7(5)-alkyl- or -alkyl-xanthone-2-carboxylic acids or their lower alkyl esters, respectively, after which, if desired, an acid of the above formula is converted into pharmaceutically acceptable, non-toxic esters, amides and salts thereof.