NO137204B - ANALOGICAL PROCEDURE FOR THE PREPARATION OF NEW XANTON CARBOXYLIC ACID COMPOUNDS WITH PROPHYLATIC AND THERAPEUTIC EFFECT - Google Patents

Description

The present invention relates to an analog 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 meu 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 lower alkanoyl or one X group is selected from lower alkyl and lower alkoxy, and the other X group from lower alkanoyl.

According to the present invention, the above-

said compounds by oxidizing a 5,7-diloweralkyl-xanthone-2-carboxylic acid with chromium oxide in acetic acid acetic anhydride to obtain the corresponding 5,7-diloweralkanoylxanthone-2-carboxylic acid, or acylating a 5- or 7-lower alkyl- or

-lower oxyxanthene-2-carboxylic acid alkyl ester with lower alkanoyl-

chloride, oxidizes the acylated products to their corresponding compounds in the xanthone series, optionally followed by hydrolysis, to obtain the corresponding 5-lower alkyl- or -lower alkyl-7-lower alkanoylxanthone-2-carboxylic acids and 5-lower alkanoyl-7-

lower alkyl or lower oxyxanthone-2-carboxylic acids or their alkyl esters;

and if desired, they convert the obtained products into their pharmaceutical

technically acceptable, non-toxic esters, amides or salts.

The following compounds can thus be obtained by

invention:

5,7-Di(lower alkanoyl)xanthone-2-carboxylic acid, represented by the formula:

as well as their pharmaceutically acceptable, non-toxic esters, amides

4

and salts, wherein each R is lower alkyl, and

5-lower alkyl-7-(R Q )-xanthone-2-carboxylic acid compounds, 5-lower alkyl-7-(R 8 )-xanthone-2-carboxylic acid compounds, 7-lower alkyl-5-(R g )-xanthone-2-carboxylic acid compounds ,

and

7-lower oxy-5-(R g )-xanthone-2-carboxylic acid compounds,

where R is lower alkanoyl with the formulas:

and pharmaceutically acceptable, non-toxic esters, amides, and salts, wherein is as defined above, and R^, R"*"O, R"<*>""<*>" and R"^ are 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, amides and salts of these compounds, in admixture with pharmaceutically acceptable non-toxic carriers.

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. Comparative 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 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 unexpectedly superior, beneficial effect of the same type, but of a different order of magnitude, 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 by any commonly known and acceptable method, either individually or together with other compounds produced according to the present invention or other pharmaceutical agents, 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. The supply can take place as single doses during continuous therapy or as single-dose therapy ad libitum.

The compounds 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. Generally, the effective amount will be in the range from 0.005 to 100 mg/kg body weight per day, preferably from 0.01 to 100 mg/kg body weight per day and night. In other words, the effective amount will vary from 0.5 to 7000 mg/day per patient.

Usable pharmaceutical carriers for the preparation of said 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.

The carriers can further be selected from various oils such as petroleum, animal, vegetable or synthetic oils such as peanut oil, soya oil, mineral oil, sesame oil and the like. Water, saline solutions, aqueous dextrose and glycols are preferred liquid carriers, 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 "Remintong's Pharmaceutical Sciences" by E.W. Martin. Such preparations will in any case contain an effective amount of the active compound together with a suitable amount of the carrier, whereby a suitable dose can be produced for suitable delivery to the patient.

Compounds prepared according to the present invention show activity that alleviates the effects of allergic reactions as this can be measured by tests that indicate such activity, e.g. passive, cutaneous anaphylaxis as essentially described by e.g. J. Goose et al., Immunology, 16, 749 (1969).

Certain compounds can be obtained using the following reaction nucleus:

where R4 is as defined above and R<14> and R<15> are lower alkyl.

As shown above, 5,7-dialkylxanthone-2-carboxylic acid compounds of formula (5) are prepared as described in parent application no. 2495/72 according to reaction scheme A for compounds 1 to 6. Then compounds (5) are oxidized with chromium oxide in acetic acid/' acetic anhydride for the preparation of 5,7-di(lower alkanoyl) compounds (A-2).

Certain compounds can be obtained using the following reaction sequence:

where R 14 and R 4 are as defined above, and R 20 is lower alkyl or lower alkoxy.

14 15

where R , R are as defined above.

Reaction nucleus C indicates the preparation of 5-methoxy-7-alkyl compounds of formula (15) and can also be used for the preparation of 5-alkyl-7-methoxy compounds which can be used as is

described in reaction core C.

An alternative method which can be used for the preparation of certain compounds is set out below.

where R 22 in ortho- or para- or in both positions is lower alkoxy.

As shown above, an appropriate phenol of formula (16) is treated with a 1,3-dimethyl-4-halo-(preferably iodo)benzene (17) as described above to produce the corresponding 1,3-dimethyl- 4-phenyloxybenzene (18). This compound is then oxidized e.g. with potassium permanganate in aqueous t-butanol to the corresponding xanthone-2-carboxylic acid (20)-, which can be treated in various ways as described above, to produce compounds according to the present invention.

Starting compounds that can be used in the present invention are known and can be prepared by methods that are themselves 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-xylsn) with potassium permanganate as is described above (18) to (19) followed by conventional esterification. o,p-dilaverealkylthiophenol compounds (1) can conveniently be prepared by treating o-hydroxybenzoic acid with an excess of chlorosulfonic acid to produce the corresponding o-hydroxy-m,m-di(chlorosulfonyl)-benzoic acid. This is then 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-Alkoxy-m,m-di(alkylthio)-benzoic acid. This latter compound is then decarboxylated by heating in the presence of copper and quinoline, and the resulting compound selectively hydrolyzed with pyridine hydrochloride or with hydrogen bromide in acetic acid to the indicated o,p-di(lower)-alkylthio-phenol.

The indicated o,p-dilower alkylphenol starting compounds, i.e. with formula (1), can be prepared by treating l,e-dialkylbenzene with acetyl chloride and aluminum chloride, whereby the corresponding acyl compound is produced which is followed by a Baeyer-Villiger reaction and hydrolysis, or by treating 1,3-dialkylbenzene with nitric and sulfuric acids to produce 1-nitro-2,4-dialkylbenzene, reducing the latter compound with stannous chloride to the amine, treating this with sodium nitrite in HCl followed by a treatment with dilute sulfuric acid and heat, whereby the specified o,p-dialkylphenols are obtained.

The acid esters of the xanthone-2-carboxylic acids prepared according to the present invention can be prepared as shown above 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. sol ketal) in pyridine, after which the protecting group on the thus produced ester is hydrolysed with dilute acid.. _

Amides of the xanthone-2-carboxylic acids can

is prepared by treating the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl, amine, dialkylamine, di-alkylaminoalkylamine, alkoxyalkylamine or phenethylamine.

Salts of the xanthone-2-carboxylic acids can

are 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, aluminium, trimethylamine, triethylamine, tripropylamine, (3-(dimethylamino )ethanol, triethanolamine, |3-(diethylamino )ethanol, arginine, lysine., histidine, N-ethyl -piperidine, hydrabamine, choline, betaine, ethylenediamine, glycosamine, methylglucamine, tebrimin, purines, piperazine, piperidine, 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 hardened, 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 pharmaceutically acceptable base. When you want to prepare the aluminum salts of the acids, you use about

1/3 mol equivalent of the pharmaceutically acceptable base.

The preferred calcium salts and magnesium salts of the acids 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 20 to 100°C.

The preferred aluminum salts of the acids prepared by treating the free acid with at least 1/3 mole equivalent of an aluminum alkoxide, such as aluminum trietoxide, aluminum tripropoxide

in a hydrocarbon solvent such as benzene, xylene, cyclohexane at temperatures from approx. 20 to approx. 115°C.

The term "lower alkyl" used means 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-methylpentanoate, enanthate, caprylate, triethylacetate, pelargonate, decanoate, undecanoate, benzoate, phenylacetate, diphenylacetate, cyclopentylpropionate, methoxyacetate, aminoacetate , diethylamino-

acetate, trichloroacetate, 3-chloropropionate, bicyclo(2,2,2)octane-1-carboxylate, adamanoate, dihydrogen phosphate, dibenzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate.

The nomenclature used here is consistent

with Chemical Abstracts, 56, Subject Index (1962, January-June).

The following examples illustrate the present invention

nelze.

Production 1

A) A mixture of 4.188 g of 1,3-dicarbomethoxy-4-bromo-

benzene, 3.2 g o,p-diethylphenol, 1.32 g copper oxide in 20 ml dimethylacetamide was heated to 160°C and kept at this temperature

rature under stirring and a nitrogen atmosphere. After thin layer chromatography indicated that the reaction was substantially complete, the reaction mixture was diluted with water and extracted with diethyl ether:methylene chloride (3:1). The extracts were chromatographed on 150 g alumina and uniform fractions were pooled to give 1,3-dicarbomethoxy-4-(o,p-diethylphenyloxy)-benzene.

B) 4 g of 1,3-dicarbomethoxy-4-(o,p-diethylphenyloxy)benzene

was combined with 150 ml of 5% potassium hydroxide in methanol. The resulting mixture was refluxed for 1 hour, where-

after acidified, cooled and filtered, whereby 1,3-dicarboxy-4-(o,o-diethylphenyloxy)benzene was obtained.

C) 2.5 g of 1,3-dicarboxy-4-(o,p-diethylphenyloxy)benzene in

20 ml of concentrated sulfuric acid was stirred at 80°C for 1 hour.

The reaction mixture was then poured into 200 ml of ice water and

the resulting mixture 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 5,7-diethylxanthone-2-carboxylic acid.

Example 1

The compound, 5,7-diethylxanthone-2-carboxylic acid was

prepared from o,p-diethylphenols using methods A), B) and C) in preparation 1.

A suspension of 2.5 g of 5,7-diethylxanthone-2-carboxylic acid and 5 g of chromium oxide in 190 ml of acetic acid and 10 ml of acetic anhydride was stirred at room temperature for 6 hours. After a thin layer chromatography sample showed an absence of the starting material, 10 ml of isopropanol was added and the resulting mixture heated on a steam bath. 200 ml of water was then added portionwise and the resulting mixture cooled to room temperature. The precipitate was filtered off, washed and dried, whereby 5,7-diacetyl-xanthone-2-carboxylic acid was obtained, m.p. 302-303°C.

Example 2

To a solution of 25 g of 7-ethylxanthone-2-carboxylic acid in 200 ml of triethylene glycol is added 18 g of potassium hydroxide in 12.1 g of 95% hydrazine. The resulting mixture was heated to reflux (155°C) and held at this temperature for 1 hour. The distillate was removed and the temperature maintained at a temperature of approx. 200°C for 2 hours. The mixture was then cooled to 68°C and 200 ml of water was added, the resulting solution was poured into 110 ml of water containing 60 ml of concentrated hydrochloric acid. The resulting mixture was heated to 90°C, cooled to room temperature and filtered to give 7-ethylxanthene-2-carboxylic acid. 26 g of 7-ethylhexene-2-carboxylic acid was added to 400 ml of absolute methanol. To the resulting solution was added 18 ml of concentrated sulfuric acid, after which the mixture was heated under reflux for approx. 2 hours. The mixture was further cooled to 40°C and sufficient water was added to make the total volume 1400 ml. The resulting mixture was then filtered to give methyl 7-ethylxanthene-2-carboxylate.

A mixture of 130 g of methyl 7-ethylxanthene-2-carboxylate in 200 ml of dichloroethane was cooled to -5°C and to the cooled solution added 4.95 ml of acetyl chloride and then 17.0 g of aluminum trichloride. The resulting solution was stirred at room temperature for 1 hour and three quarters. The solution was then poured into a mixture of 300 g of ice, 700 ml of water and 20 ml of concentrated hydrochloric acid. The mixture was then extracted with three 500 ml portions of methylene chloride. The combined extracts were washed with 10% aqueous potassium hydroxide solution, after which the washed solution was evaporated to give methyl 5-acetyl-7-ethylxanthene-2-carboxylate.

A solution of 1.42 g of methyl 5-acetyl-7-ethylxanthene-2-carboxylate in 120 ml of acetone and 15 ml of dimethylformamide was added to 3.0 g of magnesium sulfate and 2.5 ml of 8N chromic acid in 8N sulfuric acid. The resulting mixture was stirred at room temperature for 50 min. after which a solution of 4 g of sodium bisulphite in 20 ml of water was added. Then 250 ml of water and 25 ml of sulfuric acid:water (1:1) were added. The mixture was distilled off solvent and then filtered. The precipitate was washed with 50 ml of water, whereby methyl 5-acetyl-7-ethylxanthone-2-carboxylate was obtained which was recrystallized from methanol (transfer from methylene chloride solution).

A solution of 2 g of methyl 5-acetyl-7-ethylxanthone-2-carboxylate in 200 ml of 10% aqueous, 10% potassium hydroxide in methanol was refluxed under a nitrogen atmosphere for 45 min. Then 20 ml of water was added and the resulting mixture heated under reflux for 35 min. 300 ml of water was then added and the resulting mixture acidified and filtered to give 5-acetyl-7-ethylxanthone-2-carboxylic acid, m.p. 267-o 268 OC.

The following compounds are prepared in this way: 5-propionyl-7-ethylxanthone-2-carboxylic acid, m.p. 238-240°C, 5-acetyl-7-isopropoxyxanthone-2-carboxylic acid, m.p. 245-246°C, 5-ethoxy-7-propionylxanthone-2-carboxylic acid, m.p. 309-311°C, and 5-isopropoxy-7-acetylxanthone-2-carboxylic acid, m.p. 303-305°C.

Example 3

A mixture of 4.5 g of 5-isopropoxy-7-acetylxanthone-2-carboxylic acid, 10 g of ethyl iodide and 10 g of lithium carbonate in 75 ml of dimethylformamide was stirred at room temperature for 18 hours. The reaction mixture was then poured into dilute hydrochloric acid ice and the resulting precipitate was filtered off and washed to give ethyl 5-isopropoxy-7-acetylxanthone-2-carboxylate, m.p. 185-186°C.

Example 4

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) in rats with homocytotropic reaginic antibody, 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 albumin 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 the inflammatory response, which is expressed as a percentage against results from control experiments.

(The test material marked with x and disodium cromoglycate standard was given by means of a tube through the mouth 30 min. before antigen introduction. In this experiment, disodium cromoglycate was inactive at 5 times the dose at which statistically significant activity was exhibited by the test material).

Claims (1)

Analogous process 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 lower alkanoyl or one X group is selected from lower alkyl and lower alkoxy and the other X group from lower alkanoyl, characterized by oxidizing a 5,7-dilower-realkylxanthone-2-carboxylic acid with chromic acid in acetic acid-acetic anhydride to obtain the corresponding 5,7-dilower-alkanoylxanthone-2-carboxylic acid, or acylating a 5- or 7-lower alkyl- or -lower alkylxanthone-2-carboxylic acid alkyl esters with lower alkanoyl chloride, oxidise the acylated products to their corresponding compounds in the xanthone series, optionally followed by hydrolysis to obtain the corresponding 5-lower alkyl- or -lower alkyl-7-lower alkanoylxanthone-2-carboxylic acids and 5-lower alkanoyl-7-lower alkyl or -lower oxy-xanthone-2-carboxylic acids or their alkyl esters; and, if desired, converting an acid of the above formula into its corresponding pharmaceutically acceptable non-toxic esters, amides and salts.