NO137203B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF XANTON CARBOXYLIC ACID COMPOUNDS WITH PROPHYLATIC AND THERAPEUTIC EFFECT - Google Patents

Abstract

Analogy process for the production of xanthone carboxylic acid compounds with prophylactic and therapeutic action.

Description

The present invention relates to an analogue method for the production of new xanthone-carboxylic acid compounds with prophylactic and therapeutic action, e.g. for use in allergic and bronchopulmonary conditions, and with the general formula:

as well as pharmaceutically acceptable, non-toxic esters, amides and salts thereof, where either the X groups are the same and are selected from a group of the formula: where R is hydroxy, amino, monolower alkylamino or dilower alkylamino, or an X group is selected from lower alkyl and lower alkoxy and the second X group from a group of the formula:

where R has the meaning given above.

According to the present invention, the above-mentioned compounds are prepared by treating a 5,7-di(chlorosulfonyl)-xanthone-2-carboxylic acid or a 5-lower alkyl- or -lower alkyl-7-chlorosulfonylxanthone-2-carboxylic acid or a 5-chlorosulfonyl-1-7- lower alkyl- or -lower oxyxanthone-2-carboxylic acid with a base or with ammonia, mono-lower alkylamine or di-lower alkylamine to obtain the corresponding 5,7-disulfoxanthone-2-carboxylic acid or the corresponding 5,7-sulfamoyl-, -monolower alkylsulfamoyl- or -diloweralkylsulfamoylxanthone-2-carboxylic acid, respectively, or the corresponding 5-loweralkyl-or -loweralkyloxy-7-sulfo- or -sulfamoyl-, -monoloweralkylsulfamoyl- or -di1averealkylsu1famoyl-xanthone-2-carboxylic acid, respectively, or the corresponding 5-sulfo- or -sulfamoyl-, -monolower alkylsulfamoyl-1- or di-lower alkylsulfamoyl-7-lower alkyl- or -lower oxyxanthone-2-carboxylic acid, respectively;

and, if desired, convert the obtained products into their pharmaceutically acceptable, non-toxic esters, amides or salts.

The following compounds are thus produced by the present invention: 5,7-di(sulfo)-xanthone-2-carboxylic acid compounds,

5,7-di(sulfamoyl)xanthone-2-carboxylic acid compounds, 5,7-di(N-monolower alkylsulfamoyl)xanthone-2-carboxylic acid compounds, and

5,7-di(N,N-dilaverealkylsulfamoyl)xanthone-2-carboxylic acid compounds,

represented respectively by the formulas:

as well as their pharmaceutically acceptable, non-toxic esters, amides and salts, where each R is hydrogen or lower alkyl and 5-lower alkyl-7-(R o )-xanthone-2-carboxylic acid compounds, 5-lower oxy-7-(R 8 ) -xanthone-2-carboxylic acid compounds, 7-lower alkyl-5-(R 8 )-xanthone-2-carboxylic acid compounds and 7-lower alkyl-5-(R g )-xanthone-2-carboxylic acid compounds, where R is sulfo, sulfamoyl, N- monolower alkylsulfamoyl or N,N-dilower alkylsulfamoyl, represented respectively by the following formulas:

and pharmaceutically acceptable, non-toxic esters, amides and salts,

8 9 12

where R is as defined above and R - R is lower alkyl.

The novel compounds produced can be used to alleviate symptoms associated with allergic conditions of the type produced by antigen-antibody reactions (allergic reactions). In order to alleviate these symptoms, a compound produced according to the present invention is added in an effective amount to thereby inhibit the effects of the allergic reaction or reactions. Without being bound by theoretical considerations with regard to the mechanism of action, it is assumed that the present method works by preventing or inhibiting the release and/or the action of toxic products, such as histamine, 5-hydroxytryptamine, slow-release compounds (SRS -A) and other compounds, which are produced as a result of a combination of a specific antibody and antigenic reaction (allergic reaction). These properties mean that the manufactured compounds are very well suited for the treatment of various allergic conditions.

Compounds produced according to the present invention also act as relaxants on smooth muscles, e.g. as bronchial dilators, and they can consequently be used in the treatment of conditions where such agents are desirable, e.g. in the treatment of bronchial constriction. Furthermore, the compounds are also vasodilators and can consequently be used in the treatment of conditions where such agents are desirable, e.g. in the treatment of kidney and heart disorders.

The compounds can be used in preparations which can be used to inhibit the effects of one or more allergic reactions and which comprise an effective amount of a compound selected from the groups represented by the above formulas and pharmaceutically acceptable, non-toxic esters, -ides and salts thereof compounds in admixture with a pharmaceutically acceptable, non-toxic carrier.

Norwegian generally available application no. 4538/70 describes certain xanthone-2-carboxylic acid compounds which, however, differ from the new compounds produced according to the present invention. Comparison tests (see later in the description) show that the compounds produced according to the invention have biological activities that are very superior on the basis of what could reasonably be expected from the above-mentioned reference. The Norwegian generally available applications Nos. 2493/72 and 2494/72 deal with certain substituted xanthone-2-carboxylic acid compounds which are related to the compounds produced according to the present invention, but which are nevertheless different from them. The compounds produced according to the invention have a common, albeit unexpected, superior, beneficial effect of the same type, but of a different magnitude.

order compared to the compounds from the two latter references.

In practice, an effective amount of a compound produced according to the present invention or a pharmaceutical preparation containing such a compound could be administered in any commonly known and acceptable way, either individually or together with other compounds produced according to the present invention or other pharmaceutical agents, such such as antibiotics, hormonal compounds, etc. These compounds or preparations can thus be administered orally, topically, parenterally or by inhalation, and either in the form of solid, liquid or gaseous doses such as tablets, suspensions and aerosols, which will be described in detail in what follows. The supply can take place as single doses during continuous therapy or as single-dose therapy ad libitum. The compounds or preparations are used appropriately to ease symptoms, but can also be used for continuous or prophylactic treatment.

The effective dose will vary within a very wide range and will have to be determined due to the degree of the condition to be treated, the patient's age, etc., which means that the dose in practice can easily be determined by any experienced doctor. Usually, the effective amount will be in the range from approx. 0.005 to approx.

100 mg/kg body weight per day, preferably from 0.01 to 100 mg/kg body weight per day and night. Put another way, the effective amount will vary from approx. 0.5 to approx. 7000 mg/day per patient.

Usable pharmaceutical carriers for the preparation of the preparations can be solids, liquids or gases. Thus, the preparations can be in the form of tablets, pills, capsules, powders, compositions for delayed releases, solutions, suspensions, elixirs, aerosols and the like. The carriers can further be selected from various oils such as petroleum, animal, vegetable or synthetic oils such as pear oil, soya oil, mineral oil, sesame oil and the like. Water, saline solutions, aqueous dextrose and glycols are preferred liquid diluents, especially for injectable solutions. Suitable pharmaceutical carriers include e.g. starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, lime, silicon dioxide gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skimmed milk, glycerol, propylene glycol, water, ethanol. Suitable pharmaceutical carriers and their composition are described in "Remington's Pharmaceutical Sciences" by E.W. Martin. Such compositions will in any case contain an effective amount of the active compound together with a suitable amount of the carrier, thereby producing a suitable dose for suitable delivery to the patient.

Compounds produced according to the present invention show activity that alleviates the effects of allergic reactions as this can be measured by samples that indicate such activity, e.g. passive cutaneous anaphylaxis as essentially described by e.g. J. Goose et al., Immunology, 16, 749 (19^9)-

Certain compounds can be produced using the following reaction nucleus:

where halogen is bromine, chlorine, fluorine and iodine, preferably bromine, while R"^ and R^ are lower alkyl, of which R is preferably methyl.

As shown above, an ortho, para-disubstituted (SR^) phenol (1) is condensed with a 1,3-dicarbo (lower) alkoxy-4-halo-benzene compound (2) in the presence of copper oxide optionally in an organic liquid reaction medium, preferably an organic amide such as dimethylacetamide, dimethylformamide, N-methylpyrrolidone, tetra-methylurea, etc., whereby the corresponding 1,3-dicarbo(lower)-alkyloxy-4~(o,p-disubstituted phenyloxy)-benzene- connection (3h

The reaction is preferably carried out in an inert organic reaction medium of the type indicated above, or in a suitable mixture of one or more such media. The reaction is further carried out at temperatures varying from approx. 80 to approx. 220°C, preferably from approx. 120 to 200°C, and for a period of time sufficient to complete the reaction, i.e. from approx. 2 to approx. 24 hours.

The reaction consumes the reactants on the basis of 1 mol of the substituted phenol per moles of said dicarbo(lower)-carboxyhalobenzene per half a mole of copper oxide. The quantities of the reactants used are not critical, however, and certain of the desired compounds can be prepared when other quantities are also used. In the preferred embodiment, the reaction is carried out by converting from approx. 1 to approx. 3 ml of a substituted phenolic compound with from approx. 1 to approx. 1.2 mol of said dicarbo(lower)-carboxyhalo-benzene compound in the presence of from approx. 0.5 to approx. 0.6 mol copper oxide. The inert organic reaction medium, if one is used, can be used in dissolving amounts.

The compound of formula (3) produced is then base-hydrolyzed to the corresponding 1,3-dicarboxy-4~(o,p-di-substituted phenyloxy)-benzene (4). The base hydrolysis can be carried out in any conventionally known manner. Usually the reaction will be carried out using an alkali metal hydroxide at temperatures from 50 to

and for a period of time sufficient to complete the reaction, i.e. from approx. 15 to approx. 60 min., preferably in the presence of an inert organic reaction medium of the type normally used in such reactions, e.g. an ordinary alkanol solution. Although 2 moles of base are required per mol of the compound of formula (3)1 then the amounts used are not critical to produce the desired hydrolysis. It is preferably used from approx. 3 to approx. 5 m°l base per moles of compound (3)> and the reaction medium used can be used in dissolving amounts.

The thus produced diacid compound (4) is then cyclized with phosphoryl chloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or preferably polyphosphoric acid (PPA), thereby producing the corresponding 5»7~disubstituted xanthone-2-carboxylic acid compound (5). The reaction is preferably, but not necessarily, carried out in an inert organic reaction medium of the type usually used in such reactions, such as dimethylsulfoxide, sulfolane, benzene, toluene, etc. The reaction is further carried out at temperatures varying from approx. 60 to approx. l80°C, and for a sufficiently long period of time to complete the reaction, i.e. from approx. 15 to approx. °D min.

Although the reaction consumes the reactants on a basis of

1 mol of compound (4) per moles of cyclizing agent, then the reaction can also be carried out by using other quantity ratios. In the preferred embodiment, however, the reaction is carried out by using from approx. 20 to approx. 50 m°l cyclization agent per moles of the starting compound with formula (4).

The thus prepared 5>7~di(lower alkylthio)xanthone-2-carboxylic acid compounds are then esterified (R"^) to compounds of formula (6) which are then oxidized followed by an ester hydrolysis, or compounds of formula (5) is oxidized to the specified 5,7-di(lower alkylsulfonyl)- and 5>7-di(lower alkylsulfonyl)xanthone-2-carboxylic acid compounds of formula (A-3) and (A-4).

The esterification (5 to 6-) can be carried out with diazoalkane in ether or with a lower alkanol in the presence of a trace of sulfuric acid by refluxing. Hydrolysis in of the esters if this,. is necessary . can be ^performed., which . described above.' f on-conversion»'of v the compounds .(3 -t.il- 4-) :■• ; '••.! v-' . : '.V! -r* .-.....Lu-;" . t .v, r . r r.-Certain connections.are achieved 'vea help-of:following-reac-. r, , ... • .., . Reaks jonsk jerna B.. ... 00 H 3 • •..■■:<■' Ch' C . >\ " COOR1^' <->(<7>)<-> + ■ coo■ ■ R1 ■ 4 <>:>^ i\' Xj ' ?" halogiwvSr ..- ..... <w ,-..,, r ., f;,. (2) .'. COOR14,:■- -v v- . ■■■:■■:- ••j^'"5 :''' ; -'-CaOH' 1" ;C HxO >',J^>< s C00H (10) " 0CJ, ,: '<: >' " ' p.CH^......COOi: - .(.9.). - HO ■ 'lir- ■- ■ -POOH"- ■■■ '11 '•;'"'.''■-'"' (ia) ^ ■:^■' ^<0>H:; ^{^r... -■■•"'■n.• ;where halogen, <pj> and R<14> are as defined above. ;As shown above, the 5>7~dihydroxyxanthone-2-carboxylic acid esters with formula (13) prepared as described above under reaction core A for compounds 1 to 6 here included the step (10 to 11) where the methyl ethers are hydrolysed with hydrobromic acid or hydroiodic acid and acetic acid, which preferably occurs at temperatures from about 100 cil about 160° C. Then the compounds of formula 12 are treated with dialkylthiocarbamoyl chloride, for example dimethylmethylthiocarbamoyl chloride in the presence of a base such as an alkali metal hydride, and in an organic liquid reaction medium, preferably an organic amide of the type indicated above with respect to reaction (1+2 to 3)> whereby the products of formula (13) are produced. The reaction is carried out at temperatures varying from about 20 to about 100°C, preferably from about 60 to about 80 °C and for a sufficiently long period of time to complete the reaction, i.e. from about 1 to c a. 6 hours. In the preferred embodiment, the reaction is carried out with approx. 2.2 to 3>0 m°l of dialkylthiocarbamoyl chloride per moles of the compound of formula '12). The product compounds with formula (13) are then rearranged via a reaction at temperatures from approx. 200 to approx. 250°C, preferably from approx. 220 to approx. 230°C, and for a period of time varying from 1 to approx. 8 hours and in the presence of an organic medium such as sulfolane, nitrobenzene, triethylene glycol, etc., which is preferably used in dissolving amounts, whereby compounds of formula (14) are produced. These compounds are then converted into the corresponding 5,7-dimercapto acid compounds (15) by base hydrolysis of a type described above for the production of compounds of formula (4) from compounds of formula (3). Compounds of formula (15) are then treated with an excess of chlorine under acidic conditions, whereby compounds of formula (16) are produced. This reaction is carried out by using a pH from approx. 1 using hydrochloric acid, possibly in an acetic acid solution. The reaction is further carried out at temperatures varying from approx. 20 to approx. 100°C, preferably from 50 to 60°C, and for a period of time sufficient to complete the reaction, i.e. from approx. 2 to approx. 12 hours. Compound (16) is then reacted with a base such as an alkali metal hydroxide, preferably under aqueous conditions and at temperatures from approx. 20 to approx. 100°C, preferably from 80 to approx. 90°C and for a period of time from approx. 1 to approx. 2 hours, and then acidified whereby the specified 5>7~disulfo-substituted acid compounds (A-5) are produced. Compounds (16) can be treated with ammonia, monolower alkylamine or dilower alkylamine to 5>7_disulfamoyl-, -di(monoloweralkyl)sulfamoyl and -di(iiloweralkyl)sulfamoyl acid compounds of formula (A-6). This reaction can be carried out at temperatures from 0 to 80°C, preferably from 20 to 30°C, and for a sufficiently long period of time to complete the reaction, i.e. from approx. 1 to approx. 8 hours. In the preferred embodiment, the reaction is carried out by using from approx. 10 to approx. 20 mol amine per moles of compound (l6). The reaction can further be carried out in an organic reaction medium of the type described above, preferably tetrahydrofuran, dioxane, dimethylsulfoxide etc. Certain compounds can further be obtained using the following reaction core: where halogen, R 14 H and R 7 ' are as defined above , and R 20 is lower alkyl or lower alkoxy. As shown above, the specified 5~ or 7-lower alkyl or lower alkoxy compounds of formula (34) can be prepared as described above in reaction core A for compounds 1 to 6. Then the specified 5~ or 7_chlorosulfonyl compounds (35' ) and (35") are prepared by treating compounds of formula 34 with chlorosulfonic acid. This reaction can conveniently be carried out in an excess of reagent from about 100 to about 150°C and for a given period of time from 2 to 4 hours. In the in the preferred embodiment, chlorosulfonic acid is used in amounts of from 10 to 25 mol per mol of starting compound. The compounds (35') and (35") can then be converted into the sulfo compounds (B-1,2) or the sulfamoyl compounds (B~3»4) as it is described above for the preparation of the compounds (A-5) and (A-6). ;This reaction core D shows a method for the production of 5-lower alkyl-7-hydroxy compounds (51) which are useful as discussed in connection with reaction core B. ;Starting compounds that can be used in the present invention are known and can be produced by methods which in themselves themselves are known. Thus, the specified 1,3-dicarbo(lower)-alkyloxy-4-halobenzene starting compounds (2) can conveniently be prepared by oxidizing 1,3-dimethyl-4-halobenzene (4-halo-m-xylene) with potassium permanganate "followed" by ordinary esterification..o,p-dilaverealkylthiophenol compounds "(1) can conveniently be prepared by"-"to" treat o-hydroxybenzoic acid with an" excess of chlorosulfonic acid-Tor preparation-of the corresponding o-hydroxy -m,m-di(chlorosulfonyl)-benzoic acid. This is said to be reduced to the corresponding dimercapto compound with zinc and hydrogen chloride in acetic acid. The resulting compound is dialkylated with a lower alkyl halide and potassium carbonate in dimethylformamide or with dialkyl sulfate in aqueous sodium hydroxide to produce o-alkyloxy m,m-di.(alkyl-t-10)-benzoic acid.' This latter compound is then decarboxylated by heating in the presence of ibber and quinoline, and the resulting compound selectively hydrolyzed with pyridine hydrochloride or with hydrogen bromide in acetic acid to the indicated 0.p-.dl (layere--alkyitio )-phenol. ;'The indicated 0,p-dialkoxyphenol starting compounds; dull. compounds of formula (7)> can be prepared by treating o,p-dihydroxyacetophenone with a suitable alkyl halide and potassium carbonate 'i^diethylformamide,'' whereby the corresponding dialkoxy compound can be prepared. 'This can be treated under Baeryer-Villiger conditions with "ven 'perric acid,' e.g.' peracetic acid or m-chloroperbenzoic acid in chloroform containing p-toiuehsulfonic acid, whereby one obtains 1-acetoxy-2,4-dialkoxybenzen. This latter compound can be hydrolysed to o,p-dilaveréal oxyphenol compounds. The acid esters of the xahtone-2-carboxylic acids prepared according to the present invention can be obtained as described above (e.g. 5 to 6) by treating the acid with diazoalkane in ether, e.g. 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 a trace of sulfuric acid by refluxing. The glycerol esters can be prepared by treating the acid with thionyl chloride followed by a treatment with a suitable protected ethylene glycol or propylene glycol (e.g. solketal) in pyridine, after which the protecting group on the ester thus prepared is hydrolysed with dilute acid. In the sulfo series, carboxylic acid esters can preferably be prepared with the desired lower alkanol in the absence of an acid catalyst. Amides of the xanthone-2-carboxylic acids prepared can be prepared by treating the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl, amine, dialkylamine, dialkylaminoalkylamine, alkoxyalkylamine or phenethylamine. In the lower alkylsulfinyl series, the carboxylic acid amides can preferably be prepared from the corresponding (lower alkylthio) step followed by an oxidation as described above. Salts of the xanthone-2-carboxylic acids produced can be prepared by treating the corresponding acids with a pharmaceutically acceptable base. Representative salts are derived from such pharmaceutically acceptable bases including sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, ferric, zinc, manganese, aluminum, trimethylamine, triethylamine, tripropylamine, B-(dimethylaminoethanol, triethanolamine, p-( diethylaminoJethanol, arginine, lysine, histiain, N-ethyl-piperidine, hydratamine, choline, betaine, ethylenediamine, glucosamine, methyl-glucamine, theobrimin, purines, piperazine, piperfein, polyamine resins, caffeine and procaine salts The reaction is carried out in an aqueous solution either alone or together with an inert, water-miscible organic solvent, at temperatures from 0 to 100°C, ;preferably at room temperature. Typical inert, water-miscible organic solvents include methanol, ethanol, isopropanol, ;butanol, acetone, dioxane or tetrahydrofuran. When preparing divalent metal salts such as calcium salts or magnesium salts of the acids, then the free acid can be treated with about 1/2 mol equivalent of the pharmaceutical eptable base. When you want to produce the aluminum salts from the acids, you use approx. 1/3 mole equivalent of the pharmaceutically acceptable base. The preferred calcium salts and magnesium salts of the acids are prepared by treating the corresponding sodium or potassium salts of the acids with at least 1 mol equivalent of calcium chloride or magnesium chloride respectively, in an aqueous solution, either alone or together with an inert, water-miscible organic solvent, at temperatures from approx. 20 to approx. 100°C. The preferred aluminum salts of the acids are prepared by treating the free acid with at least 1/3 mol equivalent of an aluminum alkoxide, such as aluminum trioxide, aluminum tripropoxide, in a hydrocarbon solvent such as benzene, xylene, cyclohexane and the like, at temperatures from approx. 20 to approx. 115°C. In the sulpho series, the use of 1 equivalent of base will give sulpho acid monosalts, while two equivalents give the disalts. With the term "lower alkyl" used is meant a lower alkyl group with from 1 to 5 carbon atoms, including straight and branched as well as cyclic alkyl groups such as 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 "lower alkoxy" means the group ("O-lower alkyl", where "Lower alkyl" is as defined above). By the term "pharmaceutically acceptable, non-toxic esters, amides and salts" respectively, is meant an alkyl or glycerol ester, an unsubstituted monoalkyl, dialkyl, dialkylamino-alkyl, alkoxyalkyl or phenethyl-substituted amide, or a salt as defined above. The term "carboxylic acyl" means physiologically acceptable acyl groups, suitably of the type used in the pharmaceutical industry, preferably hydrocarbon, carboxylic acyl. Thus included are acetate, propionate, butyrate, trimethylacetate, valerate, methylethylacetate, caproate, t-butylacetate, 3-methylpentanoa',:'>enanthate, caprylate, triethylacetate, pelargonate, decanoate, undecanoate, benzoate, phenylacetate, diphenylacetate, cyclopentylpropionate, methoxyacetate , aminoacetate, diethylaminoacetate, trichloroacetate, B-chloropropionate, bicyclo/~2,2,27octane-l-carboxylate, adamanoate, dihydrogen phosphate, dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate. ;The nomenclature used here is in accordance with Chemical abstracts, 56,-Subject Index (I962, January-June). The following examples illustrate the present invention. ;Production I ;A) Is; cl arid i ng of , i 8u g I, .!• - d i car b erne t o k sy - 'i - b rom - ;benzene, 3.2 g c-metcksyphenol , 1.32 g copper oxide in 2C ml diin^ty 1- ;acecamide bee heated to iuO°? and holut on this; while stirring and is. nitrcgenatrnosphere. After thin layer chromatography indicated that the reaction was essentially complete, the reaction mixture was diluted with water and extracted with diethyl ether:methylene chloride (3:1). The extracts were chromatographed on 150 g of alumina and uniform fractions were combined to give 1,3-dicarbomethoxy-4-(o-methoxyphenyloxy)benzene and 1,3-dicarbomethoxy--(o-methoxyphenyloxy)benzene. with 150 ml of 5% potassium hydroxide in methanol. The resulting mixture was refluxed for 1 hour, then acidified, cooled and filtered to give 1,3-dicarboxy-3-(m-methoxyphenyloxy)-benzene. ;C) 2.5 g of 1,3-dicarboxy-4-(o-methoxyphenyloxy)benzene in ;20 ml of concentrated sulfuric acid was stirred at 30°C for 1 hour. The reaction mixture was then poured into 200 ml of ice water and the resulting mixture was heated on a steam bath for 15 min. The mixture was cooled and filtered, after which the precipitate was washed with water and then recrystallized from acetic acid to 5-methoxy-xanthone-2-carboxylic acid. The preceding procedure is used to prepare 7-isobutylxanthone-2-carboxylic acid and 7-ethylxanthone-2 -carboxylic acid. ;Preparation 2 ;The compounds 5-loweralkyl- or -loweralkyl-xanthone-2-carboxylic acid are prepared according to method A), B) and C) ;in preparation 1. ;5-methoxy-xanthone-2-carboxylic acid (2, 5 g) is dissolved in ;15 ml of chlorosulfonic acid. After heating the mixture to 1<<Q°C; for 3 hours, it is cooled (ice) and very slowly in 50 ml of 30%; aqueous acetic acid. After cooling, the precipitate is filtered off, the is washed neutrally and dried, and this gives 5-methoxy-7-chlorosulfonyl-xanthone-2-carboxylic acid. ;Preparation 3 ;The method in preparation 2 is repeated to form the corresponding 5-chlorosulfonyl compounds in 7-lower alkyl- or -lower alkyl- series, eg 5-chlorosulfonyl-7-ethylxanthone-2-carboxylic acid and 5-chlorosulfonyl-7-isobutylxanthone-2-k carboxylic acid. ;Example 1 ;A mixture of 5-methoxy-7-chlorosulfonylxanthone-2-carboxylic acid, dimethylamine and dioxane is stirred at room temperature overnight. The mixture is then diluted with water, acidified and the solid filtered off and dried to give 5-methoxy-7-dimethylsulfamoylxanthone-2-carboxylic acid, m.p. 305-307°C. In the same way, the compounds are prepared: 5-dimethylsulfamoyl-7-ethylxanthone-2-carboxylic acid, m.p. 274-276°C, and ;5-ethylsulfamoyl-7-isobutylxanthone-2-carboxylic acid, m.p. 2 9 0-292°C. ;Example 2 ;The production of esters and salts of the xanthone-2-carboxylic acid derivatives is described in examples 5 and 6 in application 2495/72. ;Comparative Example ;The compounds listed below were tested using the passive cutaneous anaphylaxis (PCA) test for rats with homocytotropic reaginic ar.*: ileum, essentially as described by I. Mota, Immunology 7, 681 (1964). This test measures the effect of substances with regard to inhibition of the release of spasmogens (toxic products) from the antigen-antibody (allergic) reaction.

Normal female rats (Spraque-Dawley) (140-160 g) are sensitized passively on both sides by intradermal injection of anti-egg albumen reaginic sera (antibody) from rats. After 24 hours, the rats are subjected to an intravenous injection of 1 ml of normal saline solution containing 0.5% Evans blue dye, 1 mg of egg albumin (antigen) and the test substance. The inflammatory response resulting from the antigen-antibody reaction is seen as an area of blue colored skin that is measured 15-25 min. after the administration, the mean diameter (mm+S.E.) being measured and thus used to determine the inhibition of inflammatory response which is expressed as a percentage against results from control experiments.

Claims (1)

Analogous process for the production of xanthone-carboxylic acid compounds with prophylactic and therapeutic action, e.g. for use in allergic and bronchopulmonary conditions, and with the general formula: as well as pharmaceutically acceptable, non-toxic esters, amides and salts thereof, where either the X groups are the same and are selected from a group of the formula: where R is hydroxy, amino, monolower alkylamino or dilower alkylamino, or one X group is selected from lower alkyl and lower alkoxy, and the other X group from a group of the formula: where R has the above-mentioned meaning, characterized by treating a 5,7-di(chlorosulfonyl)-xanthone-2-carboxylic acid or a 5-lower alkyl- or -iavere-alkoxy-7-chlorosulfonylxanthone-2-carboxylic acid or a 5 -chlorosulfony1-7-lower alkyl- or -lower oxyxanthone-2-carboxylic acid with a base or with ammonia, monolower alkylamine or dilower alkylamine to obtain the corresponding 5,7-disulfoxanthone-2-carboxylic acid or the corresponding 5,7-sulfamoyl-, -monolower alkylsulfamoyl- or di-lower alkyl sulfamoylxanthone-2-carboxylic acid, respectively, or the corresponding 5-lower alkyl- or -lower alkyl-7-sulfo- or -sulfamoyl-, -mono-lower alkyl sulfamoyl-, or -di-lower alkyl sulfamoyl-xanthone-2-carboxylic acid, respectively, or the corresponding 5-sulfo- or -sulfamoyl-, -monoloweralkylsulfamoyl-, or -dilaverealkylsulfamoyl-7-loweralkyl- or -loweralethoxyxanthone-2-carboxylic acid, respectively; and, if desired, converting an acid of the above formula into its corresponding pharmaceutically acceptable non-toxic esters, amides and salts.