CH630885A5 - Process for preparing tricyclic compounds, and the use of these compounds. - Google Patents

Description

The invention relates to processes for the preparation of tricyclic compounds which are intended for the preparation of medicaments suitable for the treatment of allergic reactions in humans or in mammals, and to applications of these processes.

It has been found that tricyclic compounds of the formula 1 according to claim 1 in mammals and in mammalian preparations in vitro in allergic reactions associated with the formation of antibodies, which e.g. for which asthma is responsible in humans, are linked, act as inhibitors. This effect is attributable to the suppression of the occurrence of substances responsible for triggering the anaphylactic shock.

The inhibitory effect of the compounds of formula 1 could be demonstrated as follows:

a) In tests which evaluate the responsiveness of a passive skin anaphylaxis (PCA test), wherein the skin reaction is measured, which is due to an interaction between an intravenously injected specific antigen and a cell-fixed active antibody which had previously been injected into the skin of a mammal , occurs (see e.g. Z. Ovary, Fedn. Proc. Am. Soc. Exp. Biol.

24 (1965), 94;

b) by measuring the amount of histamine released after antigen formation in peritoneal mast cells from actively sinsibilized rats [see, for example: 1. Acta Pharmacol, et Toxi-col. 30, Supp. 1 (1971); 2. Thorax 27/1 (1972), 38]; and c) by measuring the amount of histamine released from comminuted human lung tissue which had been passively sensitized in vitro with active antibodies as soon as these had come into action with the homologous antigen [see Br. Med. J. 3 (1968), 272].

The effect of the acids of the formula I was demonstrated in the above test series using solutions of the carboxylate anion.

For the sake of simplicity, compounds of the formula 1 in which either Z1 or Z2 or both groups represent an alkyl carboxylate group are referred to below as “esters” of the compounds of the formula 1. The term “amides” of the compounds of the formula 1 is used for compounds of the formula 1 in which either Z1 or Z2 or both groups mean an optionally substituted carboxamide group. The term “salts” of the compounds of the formula 1 is used for compounds of the formula 1 in which either Z1 or Z2 or both groups mean a carboxylate salt group.

The pharmaceutically usable salts of the compounds of formula 1 include the ammonium salts, the alkali metal salts, such as, for example, the sodium and potassium salts, furthermore the alkaline earth metal salts, such as, for example, the magnesium and calcium salts, and also the salts of organic bases, for example the amine salts, e.g. the triethanolamine and diethylamine salts, as well as the piperazine and morpholine salts.

Of particular value are the water-soluble salts of the compounds of formula 1, preferably the salts which have a solubility of at least 1 mg per ml.

The anion is responsible for the anti-allergic activity of the salts of formula 1, while the nature of the cation does nothing to contribute to the activity. For medical purposes, however, it is necessary that the cation be pharmaceutically acceptable.

Suitable substituted carboxamide groups include i.a. the N-alkyl and N, N-dialkyl substituted carboxamide groups, wherein the alkyl portion is an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

The compounds excluded from protection in the claims are known from the following publications:

Helv. China. Acta 50, 1406 (1967)

J. Chem. Soc. 1955, 2686; 1957, 3228; 1954, 4676; 1929,

2203

J. Chem. Soc., Section C1966, 1729

J. Am. Chem. Soc. 71, 3223 (1949); 72: 4250 (1950); 65, 836

(1943); 32, 379 (1910); 58, 1443 (1936)

Bull. Internat. Acad. Polonaise 1934, 5-7a, 348 Yuki Gosei Kagaku Koykai Shi 17, 53 (1959); 20, 668 (1962) Fuel 42 (5), 347 (1963)

Ukr. Khim. Zh. 30 (9), 938 (1964)

J. Org. Chem. 35 (8), 2762 (1970)

Annals 229, 151 (1885); 496, 170 (1932)

Monthly Bulletins for Chemistry 35, 443 (1908); 29, 763 (1908); 32,

143 (1911)

Chem. Zvesti 8, 178 (1954)

Ann. Chim. Phys. 21 (8), 131 (1910)

Rad. Jugoslav Akad. Znanoski Umjetnosti 232, 165 Chem. Zentr. 1, 1353 (1938)

Zh. Fiz. Khim. 37, 371 (1963)

Holzforschung 15, III (1961); 17, 21 (1963)

Beilstein, Handbuch der organic chemistry 835; 10 / 1.405,

Syst. 1323; 10/2, 583, Syst. 1323 Bull. Soc. Chim. Beige 75, 9 khim. Prora. Ukr. 1966, 23

U.S. Patent 2,377,040, 3,096,343, 2,794,813, 3,089,879, 2,967,187,

3 189 527 CH-PS 247 603

GB-PS 908 193, 321 916.314 020.1 063 995 DE-PS 1 080 529, 1 046 317, 2 143 437 SU-PS 147 192, 62 203 FR-PS 1 453 062.

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According to the present processes, new products can be, in particular, solid disodium fluorenone-2,7-dicarb-oxylate, the monohydrate of disodium fluorenone-2,7-dicarb-oxylate and particles of disodium fluorenone-2,7-dicarb-oxylate with a diameter of 0.1 5 to 7 [im can be made.

Particularly preferred compounds of formula 1 are:

Fluorenone-2,7-dicarboxylic acid;

Monosodium salt of fluorenone-2,7-dicarboxylic acid;

Disodium salt of fluorenone-2,7-dicarboxylic acid;

Dipotassium salt of fluorenone-2,7-dicarboxylic acid;

Calcium salt of fluorenone-2,7-dicarboxylic acid;

Magnesium salt of fluorenone-2,7-dicarboxylic acid;

Diammonium salt of fluorenone-2,7-dicarboxylic acid;

Fluorenone-2,7-dicarboxamide;

Dimethylfluorenone-2,7-dicarboxylate;

Acridon-2,7-dicarboxylic acid;

Xanthone-2,6-dicarboxylic acid;

Disodium xanthone 2,7-dicarboxylate salt;

Disodium anthraquinone 2,6-dicarboxylate salt;

7-chlorofluorenone-2-carboxylic acid;

7-ethylfluorenone-2-carboxylic acid;

7-cyanofluorenone-2-carboxylic acid;

7-acetylfluorenone-2-carboxylic acid;

7-nitrofluorenone-2-carboxylic acid;

7-methoxyfluorenone-2-carboxylic acid;

Anthraquinone-2,6-dicarboxylic acid;

Disodium xanthone 2,6-dicarboxylate salt;

Diethylxanthone 2,6-dicarboxylate;

Dihexylfluorenone-2,7-dicarboxylate;

Sodium salt of 7-hexyloxyfluorenone-2-carboxylic acid;

Bis-ethanolamine salt of fluorenone-2,7-dicarboxylic acid;

Bisethanolamine salt of anthraquinone-2,6-dicarboxylic acid;

Dipotassium salt of acridon-2,6-dicarboxylic acid;

Dipotassium salt of 10-methylacridone-2,7-dicarboxylic acid;

Dimethylacridone 2,6-dicarboxylate;

Acridon-2,6-dicarboxamide;

Xanthone-2,6-dicarboxamide;

Dimethylxanthone-2,6-dicarboxamide.

Particularly effective compounds of formula 1 include: FIuorenone-2,7-dicarboxylic acid;

Xanthone-2,6-dicarboxylic acid;

Anthraquinone-2,6-dicarboxylic acid and the pharmaceutically acceptable salts of these acids.

In general, the compounds of formula 1, wherein either Z1 or 7? or both groups a carboxy lat derivative, e.g. an amide, an ester or a salt mean, prepared by appropriate treatment of the corresponding acid. However, in some cases it is possible to prepare such compounds without prior isolation of the carboxylic acid. This is done either by choosing suitable reagents or by forming the desired derivatives of the acid in a reaction mixture without first isolating the acid.

The oxidation of compounds of formula 2, wherein Y1 and / or Y2 are lower alkyl groups, on these groups can be carried out with the conventional oxidizing agents, e.g. acidic or alkaline aqueous potassium permanganate solution. Further examples of oxidizing agents in this case include: chromium trioxide, for example in the presence of acetic acid or sulfuric acid; Oxygen in the presence of a conventional catalyst, e.g. Lead, cobalt or manganese salts, especially lead acetate; or aqueous solutions of sodium dichromate.

The oxidation of compounds of formula 2, in which Y1 and / or Y2 represent a group -C (= 0) R, on these

Groups can also be carried out with conventional oxidizing agents. Examples are: Chromium trioxide in the presence of acetic acid or sulfuric acid; aqueous solutions of salts of hypochlorous or bromine acid in the presence of a base; Sodium or potassium dichromate in the presence of acetic acid; or nitric acid. These oxidation processes are advantageously carried out with heating in the liquid phase.

The oxidation of compounds of formula 2 to groups Y3 and / or Y4 can also be carried out using conventional oxidizing agents, such as nitric acid, aqueous solutions of hypochlorous or hypobromous acid in the presence of a base, with chromium trioxide, for example in the presence of acetic acid or sulfuric acid, or with aqueous Carry out solutions of sodium dichromate.

The oxidation of compounds of the formula 2, in which Y4 is a methylene group and Y3 is a bond, oxygen or -NR, where R is an alkyl group having 1 to 4 carbon atoms, or in which Y3 and Y4 are each = CH-, can also be carried out using conventional oxidizing agents , such as oxygen in the presence of "Triton B" in pyridine solution, or with oxygen in the presence of potassium t-butoxide, t-butanol and dimethyl sulfoxide.

Compounds of formula 2 can optionally be oxidized to dicarboxylate acids or salts of formula 1. In this case, the oxidation is carried out using oxidizing agents such as chlorine trioxide, for example in the presence of acetic acid or sulfuric acid, or using an aqueous sodium dichromate solution. In the case of compounds of formula 2 in which neither Y1 nor Y2 represent an alkyl group, the oxidation can also be carried out using conventional oxidizing agents, such as, for example, aqueous solutions of salts of hypobromous or hypochlorous acid in the presence of a base or with nitric acid.

The oxidation processes described above, in which aqueous sodium dichromate solutions are used, are preferably carried out at elevated temperature in sealed containers. In such a case, the oxidation of groups Y1 and Y2 is preferably carried out at a temperature of 200 to 210 ° C. The oxidation of the xanthone nucleus in such a case is preferably carried out at a temperature of 240 to 260 ° C. The oxidation of the tricyclic anthracene, the dialkylanthracene or the anthrone nucleus is preferably carried out at a temperature of 250 to 260 ° C.

Pharmaceutically acceptable salts of acids of formula 1 can be prepared by conventional methods. This can be done, for example, by neutralizing the corresponding carboxylic acid with a suitable Bronsted base or by double reaction of a salt of an acid of the formula 1 with a salt which contains the desired pharmaceutically acceptable cation. The carboxylic acid can either be isolated or dissolved in the reaction mixture which is used in the preparation of the acid, e.g. according to one of the methods described above, is used.

Suitable Bronsted bases are organic bases, e.g. Ethanolamine, and bases containing ammonium and alkali metal and alkaline earth metal cations. A double rearrangement can advantageously be carried out in an ion exchange resin, wherein a solution of a salt of an acid of formula 1 is passed through a cation exchange resin, the resin being loaded with a pharmaceutically acceptable cation of the appropriate base. Furthermore, the double reaction can also be carried out in an ordinary solution between a salt of an acid of the formula 1 and a salt with the desired pharmaceutically usable cation. For the manufacture of pharmaceutical

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Pharmaceutically usable salts of the formula 1 can use one or more of the following methods: 1) reaction of a compound of the formula 15

d wherein one of the groups Y 'and Y8 represents a hydrogen ion and the other group represents a hydrogen ion or a cation of the desired salt, in a polar medium with a base of the desired salt or when Y' and Y8 together or separately represent a single or two cations which are different from the cation of the desired salt and when Z3 has the same meaning as in formula 1.

2) reaction of a compound of formula 16

Y

wherein Y7 and Y8, which may be the same or different, represent a carboxyl group or a group Y1, as defined in formula 2, with a suitable Bronsted base in a polar medium or in the case when the Bronsted base contains no hydroxyl ion in the presence of water. Examples of a suitable Bronsted base are the alkali and alkaline earth oxides and hydroxides for the preparation of the corresponding alkali and alkaline earth metal salts of the formula 1. The reaction is preferably carried out with heating.

The salts of the compound of formula I can be isolated from a reaction medium by any known isolation method of salts from a solution in a polar medium. For example, the salts can be isolated by precipitating the salt or by removing the polar medium.

The salt can be precipitated out by crystallization from a solvent mixture or by adding an excess of base or a salt, so that the cations in the salt to be isolated reach a concentration which is greater than the molar ratio required for the cation to be isolated.

The crystallization from a solvent mixture can be carried out in such a way that another polar solvent miscible with the first polar solvent is added to a salt solution of the compound of formula 1 in which the salt of the compound of formula 1 is less soluble than in the solvent that is already present first.

The polar medium can be removed by evaporation, for example by freeze-drying or by azeotropic distillation.

The salts of the compound of formula 1 are preferably purified before being processed into a pharmaceutical preparation. This cleaning can be done in any known manner. A particularly favorable purification process provides for the isolation of a crude solid salt of the compound of formula 1 from the reactoin mixture in which this salt was produced. This isolation can be done in the ways already described above; Dissolving the salt in hydrochloric acid; Isolation of the corresponding acid as a solid; Neutralization of the acid of formula 1 with a Brönsted base, the cation of which is the cation of the desired salt of the compound of formula 1. Removing the solid contaminants by filtering Isolation of the salt of the compound of formula 1 in the manner already described above.

Typically, an acid of Formula 1 can be purified prior to neutralization by recrystallization or by isolation from an N, N-dimethylformamide adduct followed by heating the adduct to remove the N, N-dimethylformamide.

The esters and amides of the acids of formula 1 can be prepared in any known manner. This comprises the esterification of the acid or the acid chloride with an alkyl alcohol, resulting in the corresponding alkyl ester, or the reaction of the acid or acid chloride with ammonia or with an alkylamine, resulting in the corresponding amide or the N-alkyl-substituted amide. Likewise, the compounds of formula 1, wherein Z1 and Z2 are different and the compounds are either acids, esters, amides and salts, can be prepared in the ways described above and optionally by partial hydrolysis.

The compounds of formula 1 are used in the treatment or prophylaxis of various allergic affections in which the reaction of an externally acting antigen with the antibody acting against it is primarily responsible, for example in allergic asthma, hay fever (allergic rhinitis), allergic conjunctivitis, ulcerative aphthae of the oral mucosa, eczema and allergic urticaria, of particular benefit.

The size of a prophylactic or therapeutic dose of a compound of formula 1 naturally varies depending on the type and severity of the allergy to be treated and of course also depends on the type of compound of formula 1 and its dosage form. In general, the dose is in the range of 2 to 100 mg per kilogram of body weight in a mammal.

In the case of an allergic affection already mentioned above, for example in the case of allergic asthma, a dose of 5 (ig to 0.5 mg, preferably 20 (ig to 0.2 mg, for example approximately 0.1 mg) of a compound of formula 1 is per If the preparation is administered intravenously, a suitable dose is 0.2 to 100 mg of a compound of the formula 1 per kg body weight of the patient, in the case of an oral preparation the dose is 2 to 50 mg of a compound of the formula 1 per kg of body weight. If there is a preparation for the nose, for example for the treatment of allergic rhinitis, the suitable dose is 2 mg to 4 mg of a compound of the formula 1 per kg Body weight of the patient.

In the case of fluorenone-2,7-dicarboxylate salts, the doses listed below have proven to be particularly favorable for the treatment of allergic asthma. All of these doses are based on the weight of the free dicarboxylic acid and are the doses per kilogram of body weight of the patient: Pulmonary administration in allergic asthma: 20 ng to 0.2 mg, preferably 0.1 mg;

Intravenous administration: 1 to 10 mg;

Oral administration: 10 to 40 mg;

Nasal administration for allergic rhinitis: 10 (ig to 0.4 mg.

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The pharmaceutical preparations of the compounds of formula 1 prepared according to the present invention contain the latter as an active ingredient and can also have one or more pharmaceutically usable excipients or other therapeutic ingredients. The forms of preparation include preparations for oral, rectal, ophthalmological, pulmonary, nasal, dermatological, local or parenteral administration, including subcutaneous, intramuscular and intravenous administration. In any case, of course, the dosage form depends on the type and severity of the allergy to be treated and on the type of active ingredient. The preparations can also be present in single doses. The types of preparation can be done according to the well-known Gallic aspects.

The pharmaceutical preparations of the present compounds for oral administration can be in the form of capsules, cachets or tablets, each unit containing a certain amount of active ingredient. Furthermore, they can be present as powders or granules, as solutions or as a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion. All of these preparation forms can be produced in a known manner. In all of these preparations, the active ingredient is brought together with the carrier or with one or more other ingredients. In general, the preparations are prepared by thoroughly mixing the active ingredient with the liquid carriers or the finely divided solid carriers, or both, and then, if necessary, bringing the mixture into the desired shape. For example, a tablet is manufactured by pressing or molding, preferably together with one or more auxiliary substances. This tablet pressing is preferably carried out from the free-flowing active ingredient in powder or granular form, which is optionally mixed with a binder, lubricant, inert diluent, a surface-active substance or a dispersant in a suitable machine. The tablets can be produced in a suitable machine by molding a mixture of the powdered compound with the possible auxiliary substances, which are moistened with an inert liquid diluent. Preferably, each tablet contains 200 to 500 mg of the active ingredient and each cachet or capsule contains 500 to 2000 mg of the active ingredient.

A particularly preferred form of a pharmaceutical preparation of the present compounds for the treatment of allergic asthma is a preparation which is active in the lungs via the buccal route. Of course, other allergic disorders can also be treated with this pulmonary administration.

The preparation is preferably such that particles with a diameter of 0.5 to 7 μm, preferably 1 to 6 μm, which contain the active ingredient, are introduced into the lungs of a patient. This ensures a maximum amount of active ingredient administered to the alveolar alveoli, whereby the active ingredient is retained therein and can thus have a maximum effect. Such preparations are preferably in the form of a dry powder for administration in a powder inhalation device or in powder sprays.

The powders for this pulmonary administration preferably contain particles which contain the active ingredient and whose diameter is at least 98% greater than 0.5 [im and at least 95% less than 7 (im. Most preferred are powder particles whose diameter is at least 95% larger than 1 [im and at least 90% less than 6 jim.

The preparations in the form of dry powders preferably have the active ingredient in particles whose diameter is between 0.5 and 7 (im, preferably 1 to 6 (im. These preparations preferably contain a solid diluent in the form of a fine powder. These preparations lie generally in a perforated capsule made of a pharmaceutically usable material, for example gelatin.These preparations are generally prepared by comminuting the active ingredient, optionally together with a solid diluent.If required, the resulting powder can then be introduced into a perforatable capsule made of a pharmaceutical Other useful forms of a preparation of the present substances for pulmonary administration are the self-atomizing preparations.These self-atomizing preparations can either be powder-distributing preparations or preparations which contain the active ingredient in the form of Tr Distribute a small amount of a solution or a suspension.

Self-propelling powder-releasing preparations preferably contain dispersed particles of the solid active substance with a diameter of 0.5 to 7 (im, preferably 1 to 6 (im, and a liquid blowing agent with a boiling point below 18 ° C. at atmospheric pressure. The liquid blowing agent can be any known blowing agent which is suitable for medical administration and can contain one or more lower alkyl hydrocarbons or halogenated lower alkyl hydrocarbons or mixtures thereof. Chlorinated and fluorinated lower alkyl hydrocarbons are particularly preferred as blowing agents. In general, the blowing agents take up 50-99.9% by weight of the preparation while the active ingredient makes up 0.1 to 20% by weight, for example 2% by weight, of the preparation. The pharmaceutically usable excipients in such self-atomizing preparations can be other constituents in addition to the fuel. In particular, this can be a surface-active agent or a firmly it may be thinner or both together. The surface-active agents mainly serve to prevent aggregation of the active ingredient particles and help to keep the active ingredient in suspension. Liquid, nonionic surfactants and solid anionic surfactants or mixtures thereof are particularly suitable. Suitable liquid non-ionic surface-active agents are substances whose hydrophilic-ipophilic balance (HLB, see: Journal of the Society of Cosmetic Chemists 1, 311-326 (1949) is below 10. In particular, these are esters and partial esters of Fatty acids with aliphatic polyhydric alcohols, for example the sorbitan monooleate and the sorbitan trioleate, known under the trade names "Span 80" and "Span 85". The liquid nonionic surfactant can make up up to 20% by weight of the preparation, although the concentration thereof is preferably better below Suitable solid anionic surfactants include the alkali metal, ammonium and amine salts of dialkyl sulphosuccinate, in which the alkyl groups have 4 to 12 carbon atoms, and the alkylbenzenesulfonic acid, in which the alkyl group is 8 to The solid anionic surfactants can also contain up to 20% by weight of the preparations make up line, although their concentration is also preferably less than 1% by weight.

Solid diluents are advantageously incorporated into such self-atomizing preparations when the density of the active ingredient differs very greatly from the density of the propellant, and the diluents thus help to keep the active ingredient in suspension. The solid diluent is in the form of a fine powder

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which preferably has a particle size like that of the active ingredient. Suitable solid diluents include sodium chloride and sodium sulfate.

Preparations of the present substances can also be in a self-atomizing form in which the active ingredient is contained in solution. Such self-atomizing preparations can contain an active ingredient, a blowing agent and cosolvent, preferably they also contain a stabilizer which acts as an antioxidant. The blowing agent is generally at least one of the substances mentioned above. Co-solvents are selected according to their solubility in the blowing agent, their ability to dissolve the active ingredient and their nature and the lowest boiling point. Suitable co-solvents are lower alkyl alcohol and ether and their mixtures. The co-solvents can make up 5 to 40% by weight of the preparation, although preferably no more than 20% by weight is represented in the preparation.

The stabilizers acting as antioxidants can be incorporated into these solution preparations in order to prevent the destruction of the active ingredient. They are usually alkali metal ascorbates or bisulfides. They are preferably present in an amount of up to 0.25% by weight of the preparation.

The self-atomizing preparations can be made in any known manner. For example, the active ingredient can be mixed either as particles in suspension in a suitable liquid or in an up to 20% (weight by volume) solution in a suitable co-solvent with any other pharmaceutically acceptable carrier. The resulting mixture is cooled and poured into a suitable cooled container. The blowing agent is then added in liquid form and the container is closed.

On the other hand, such self-atomizing preparations can be prepared by mixing the active ingredient either in particles or in a 2-20% (weight per volume) alcoholic or aqueous solution and optionally together with other pharmaceutically usable excipients. The mixture obtained is then poured into a corresponding vessel, optionally with a little propellant, the vessel is closed and the propellant is injected under pressure into the vessel at ambient temperature through a valve in the vessel. This valve is an integral part of the container and will later be used to release the preparation in doses. The container is preferably made empty of air, as is customary in the production of self-atomizing preparations.

Containers with a manually operated valve made of aluminum, stainless steel or unbreakable glass are suitable for such a self-atomizing preparation. The valve should of course have the desired spraying action, i.e. the spray emerging from the valve should of course have the characteristic particle size mentioned above. Preferably there is a measuring valve which releases a precisely defined amount of the preparation, for example approximately 50 or 1001 of the preparation, for example approximately 50 or 100 1 of the preparation with each spray, each time the valve is actuated.

The present compounds can also be processed in the form of their aqueous or dilute alcoholic solution, optionally also sterile, for use in a nebulizer or atomizer, an accelerated air flow causing a fine mist of small droplets of the solution. These preparations usually contain a flavoring such as sodium saccharin and a volatile oil. In addition, a buffer such as sodium phosphate, an antioxidant such as sodium metabisulfite and a surfactant can be incorporated. Such a preparation preferably also contains a preservative such as, for example, methyl hydroxybenzoate.

Formulations of the present substances for parenteral administration usually contain sterile, aqueous solutions of the active ingredient, which are preferably isotonic with the blood of the patient to be treated. These preparations are preferably administered intravenously, although the administration can also be subcutaneous or intramuscular. These preparations are usually prepared by dissolving the active ingredient in water and then making this solution isotonic with human blood and sterilized.

The preparations for topical use include preparations for application to the skin, eyes, nose and mouth.

Preparations for use on the skin include lotions and creams, which comprise liquid or semi-solid emulsions, either oil-in-water or water-in-oil emulsions, preferably 0.2-5% by weight by volume of the active ingredient included. For topical application to the skin, ointments can also be used which contain 0.2 to 5% (weight per volume) of the active ingredient dissolved or dispersed in a semi-solid base. Such semi-solid bases usually contain liquid or semi-solid hydrocarbons, animal fats, wool alcohol or a "macrogol", if necessary with an emulsifier. Preferably, the creams or ointments also contain a preservative such as methyl hydroxybenzoate.

Preparations for use on the eye are mostly eye drops which contain the active ingredient in aqueous or oily solution, preferably in a concentration of 0.2 to 5% by weight per volume. Such solutions are preferably fungostatic and bacteriostatic and are advantageously made sterile. Eye ointments which preferably have the same active ingredient content can also be used. In general, the active ingredient is in the form of a salt and is either dissolved in a semi-solid ointment base or suspended therein in finely divided form.

Preparations for administration in the nose include powders, self-atomizing or spray preparations which are very similar to the preparations for pulmonary administration already described, but have a somewhat larger particle size, namely 10 to 200 (im. In the case of self-atomizing solutions and spray preparations, this effect can be achieved by a valve can be obtained which has the desired spraying properties, that is to say which produces a spray of the desired particle size, or by introducing the medicament as a suspended powder with the particle size set in. In this way, the preparation is largely retained in the nose without reaching the lungs Another form of preparation for administration in the nose comprises a coarse powder with a particle size of 20 to 500 μm, which is used in a similar way to snuff, that is to say by rapid inhalation through the nose from a powder container which is close to d he nose is held. Another nasal preparation is nasal drops, which contain 0.2 to 5% (weight per volume) of the active ingredient in aqueous or oily solution.

Lozenges containing 10 to 100 mg of the active ingredient in a flavor base, usually cane sugar and gum arabic or tragacanth, are suitable for local administration in the mouth. Pastilles with an active ingredient content of 10 to 100 mg in an inert basis, for example, are also suitable for this

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Gelatin and glycerin or cane sugar and gum arabic.

Bronchiodilators are other therapeutically effective additives for incorporation into the preparations described above, in particular for the preparations for the treatment of allergic asthma. Bronchiodilators of any kind can be used, but bronchiodilators such as isoprenaline, adrenaline, orciprenaline, isoethane and the physiologically usable acid addition salts thereof, in particular isoprenaline sulfate, are particularly suitable. In general, the bronchiodilator is present in the preparation in an amount of 0.1 to 50% by weight of the other active ingredient present.

Exemplary embodiments of the method according to the invention are described below. If no melting points are given for the compounds of the formula 1, the compounds decompose at temperatures below their melting point and / or their melting points are at temperatures which are no longer easy to determine using conventional techniques.

Example 1 Fluorenone-2,7-dicarboxylic acid a) 440 g of aluminum chloride suspended in 500 ml of dry 1,2-dichloroethane were stirred and 162 ml (175 g) of acetic anhydride were added dropwise at 0 ° C. The resulting solution was then added to a solution of 125 g of fluorene in 700 ml of 1,2-dichloroethane while stirring at 0 ° C. After the addition was completed, half of the di-chloroethane was removed under reduced pressure and the residue was poured into a mixture of ice and 2N hydrochloric acid. The resulting substance was separated by filtration, washed with water, dried and recrystallized from acetone. The substance was 2,7-diacetylfluorene.

Melting point: 177 to 180 ° C.

b) 75.6 g of finely ground 2,7-diacetyl fluorene were added to a stirred solution of 14 g of sodium hydroxide in 3.5 liters of 4.5% sodium hypochlorite solution. The mixture was heated to 80 ° C for five hours, then cooled and filtered. One liter of hot water was added to the solid so obtained, filtered to remove unreacted 2,7-diacetylfluorene. The filtrate was then washed twice with dichloromethane and acidified with concentrated hydrochloric acid. The resulting pale yellow precipitate was filtered, washed well with water and dried to give the pure fluorenone-2,7-dicarboxylic acid.

Melting point: 410 ° C (decomposition).

Example 2 Anthraquinone-2,6-dicarboxylic acid

3.09 g of 2,6-dimethylanthracene, 21.0 g of sodium dichromate and 75 ml of water were heated together at 215 ° C in an autoclave for 20 hours. The resulting mixture was filtered to remove the chromium oxide and the liquid acidified with excess hydrochloric acid. The precipitated acid was filtered off and dried, giving 1.14 g of a dark brown substance. The crude product was recrystallized from dimethylformamide and dried at 156 ° C. under a pressure of 15 mm Hg, whereupon the anthraquinone-2,6-dicarboxylic acid resulted.

Example 3 Anthraquinone-2,6-dicarboxylic acid

15.4 g of 2,6-dimethylanthraquinone, 78.0 g of chromium trioxide and 675 ml of glacial acetic acid were combined under reflux 64

Cooked for hours. After cooling, the crude product crystallized out and was filtered off and washed out with water. The crude product was recrystallized from dimethylformamide and dried at 110 ° C for three days, which resulted in 5 fiie anthraquinone-2,6-dicarboxylic acid. Analysis of the substance showed 64.69% by weight of carbon and 3.15% by weight of hydrogen.

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Example 4 F luorenone-2-carboxylic acid

A solution of 86 g of 2-acetylfluorene in 1075 ml of acetic acid was slowly mixed with 1020 g of sodium dichromate 15 at 60 ° C. and then with 185 ml of acetic anhydride. The mixture was heated under reflux and stirring for three hours, cooled and poured into 6 liters of water. The precipitate was filtered off and washed well with water. The solid obtained was heated with 520 ml of n-Na-20 trium hydroxide solution and the mixture was filtered. The aqueous filtrate was washed three times with 60 ml of dichloromethane each, then heated on a steam bath and carefully acidified with hydrochloric acid. The yellow reaction product was filtered off, washed well with water and dried in a vacuum. The result was fluorenone-2-carboxylic acid.

Melting point:> 300 ° C.

30th

Example S Anthraquinone-2-carboxylic acid

3 g of 2-methylanthraquinone were dissolved in 15 ml of sulfuric acid, the solution was cooled and diluted with 15 ml of water. The mixture was then cooled again and stirred vigorously during the portionwise addition of 9 g of powdered sodium dichromate and finally heated on the steam bath for 3 hours. It was then cooled and the whole was mixed with 100 ml of water. The solid precipitate 40 was filtered off, washed well with water and mixed with hot, dilute aqueous ammonia solution (60 ml of water and 2 ml of ammonia with a density of 0.88 at 15 ° C.). The solution was filtered hot and acidified with hydrochloric acid. The pale yellow precipitate was filtered off, 45 washed with water and dried. The anthraquinone-2-carboxylic acid resulted.

Melting point: 291 ° to 292 ° C.

The melting point remained unchanged after recrystallization from dimethylformamide.

50

Example 6 Anthraquinone-2,7-dicarboxylic acid

55 5.15 g (21.8 mmol) of 2,7-dimethylanthraquinone were refluxed with 26.00 g of chromium trioxide (200% excess) in 250 ml of glacial acetic acid for 65 hours. The dark green solution was cooled in an ice bath and the precipitate was filtered off. This was washed out with glacial acetic acid and then with water for 60 seconds, resulting in a pale green substance which was dried at 100 ° C. The raw material was then recrystallized from boiling dimethylformamide, decolorized with activated carbon and filtered to the boil. The solid, which separated on cooling, was filtered off, washed out with a little ice-cold dimethylformamide and dried under vacuum at 155.degree. The anthraquinone-2,7-dicarboxylic acid resulted.

Melting point: 399 ° to 401 ° C.

11

630885

Example 7 Methylfluorenone-2-carboxylate

Sulfuric acid was added to 3 g of fluorenone-2-carboxylic acid in 150 ml of dry methanol and the mixture was heated under reflux with stirring for 72 hours and then cooled. The yellow precipitate was filtered off, washed well with methanol and then with water and dried. The result was methylfluorenone-2-carboxylate.

Melting point: 182 ° to 185 ° C.

Example 8 7-Nitrofluorenone-2-carboxylic acid

A solution of 1.4 g of 2-acetyl-7-nitrofluorene in 100 ml of acetic acid was added in portions with 6.85 g of sodium dichromate, 5 ml of acetic anhydride were then added and the whole was heated under reflux for 8 hours. The reaction mixture was cooled slightly, then poured into 600 ml of hot water, cooled and filtered. The resulting solid was heated with 0.5% aqueous potassium hydroxide solution and is called filtered. The filtrate was acidified with hydrochloric acid. The precipitated acid was separated off by filtration, washed well with hot water and dried in vacuo. The result was 7-nitrofluorenone-2-carboxylic acid.

Melting point: 325 ° to 327 ° C.

Example 9 Disodium anthraquinone 2,6-dicarboxylate

0.50 g of anthraquinone-2,6-dicarboxylic acid was dissolved in sodium carbonate solution (1 equivalent of 0.18 g of sodium carbonate in 100 ml of water) with heating. Since the disodium salt did not separate after cooling, the solution was concentrated to about a third of its volume and diluted strongly with ethanol. The now separated solid was filtered off, dried at 100 ° C. and analyzed as dihydrate.

Elemental analysis:

Calculated: C 51.09 H 2.68 Found: C 50.67 H 2.78

Example 10 7-methoxyfluorenone-2-carboxylic acid

A suspension of 1.2 g of 2-acetyl-7-methoxyfluorene in 50 ml of a 5% aqueous sodium hypochlorite solution containing 200 mg of sodium hydroxide was stirred and heated at 80 ° C for 5 hours, then cooled to 0 ° C and filtered . The filtrate was discarded. The precipitate consisted of the starting material and the sodium salt of the reaction product. It was successively mixed with 50 ml and twice 25 ml of hot water and filtered hot. The combined filtrates were acidified with hydrochloric acid and the precipitate was filtered off, washed out with water and dried in vacuo. After recrystallization from a mixture of dimethylformamide and ethanol, 7-methoxyfluorenone-2-carboxylic acid resulted.

Melting point:> 300 ° C.

Example 11 Xanthone-2,7-dicarboxylic acid a) Xanthone-2,7-dicarbonitrile, which had been prepared from 2,7-diamino-xanthone by a Sandmeyer reaction, was hydrolyzed. This was done by refluxing for 24 hours with 25 parts of a 60 wt. % aqueous sulfuric acid with the addition of 10 parts of glacial acetic acid to improve the solubility. The solid which precipitated after cooling was filtered off, washed with water and dried. After recrystallization from dimethylformamide, the xanthone-2,7-dicarboxylic acid resulted as a white solid.

Melting point: approximately 420 ° C. (decomposition), io b) 1.75 g of 2,7-dimethylxanthone, which had been prepared by the method according to Köbrich [Annalen 664, (1963), 96], were dissolved in 70 ml of a mixture of a part of glacial acetic acid and a part of acetic anhydride heated with stirring at 60 ° to 65 ° C. At the same time, a warm solution of 3.5 g of chromium trioxide in 70 ml of a mixture of one part acetic acid and one part acetic anhydride was slowly added. After the addition was complete (after about 20 minutes), the mixture was heated to 70-75 ° C with stirring for 7 hours and then left to stand for 20 nights. The separated solid was washed out, dried and recrystallized from dimethylformamide. The result was the xanthone-2,7-dicarboxylic acid, which was identical to the carboxylic acid which had been prepared in section a).

25 c) 1 ml of the sodium salt of p-hydroxybenzonitrile was treated with 1 mol of 2,4-dicyanonitrobenzene in dry dimethylsulfoxide at 105 ° C for 18 hours to form the 4- (2,4-dicyanophenoxy) benzonitrile (melting point 222 ° to 223 ° C) heated. This solid was obtained by diluting the reaction mixture with water and by subsequent purification by crystallization from acetic acid. The compound was hydrolyzed with a mixture of 25 parts of a 60% aqueous sulfuric acid and 10 parts of glacial acetic acid, the mixture being heated under reflux for 24 hours. After cooling, the diphenyl ether-2,4,4'-tricarboxylic acid separated off. The tricarbonic acid was ring-closed, either a. by heating to 300 ° C for 5 minutes, or 40 b. by dissolving in concentrated sulfuric acid, heating to 100 ° C for three hours and then diluting with water.

The solid obtained in the two ways was recrystallized from dimethylformamide, whereupon the xanthone-45 -2,7-dicarboxylic acid resulted, which was identical to the carboxylic acids prepared in sections a) and b) above.

50

Example 12 Disodium fluorenone-2,7-dicarboxylate

10 g of fluorenone-2,7-dicarboxylic acid were stirred with 6.28 g of "Analar" sodium bicarbonate and 300 ml of water. After heating, a clear yellow solution was formed, which was concentrated to approx. 50 ml under reduced pressure and 500 ml of warm ethanol were added. The resulting pale yellow solid was collected, dried and found to be disodium fluorenone-2,7-dicarboxylate monohydrate.

The compound obtained having the formula

60

65

Nao2c

630885

12th

(Synonym: disodium 9-oxofluorene-2,7-dicarboxylate) provided the infrared spectrum shown in FIG. 1 when dispersed in "Nujol MuH".

Example 13 Dipotassium fluorenone-2,7-dicarboxylate

0.534 g of fluorenone-2,7-dicarboxylic acid was dissolved in warm water containing 0.544 g of "Analar" potassium carbonate. The yellow solution was concentrated to 3 ml under reduced pressure and ethanol was added. The resulting pale yellow solid was collected and dried at room temperature and atmospheric pressure. The hydrated dipotassium fluorenone-2,7-dicarboxylate resulted.

Example 14 Disodium fluorenone-2,7-dicarboxylate a) Preparation of the 2,7-diacetylfluorene

875 g of anhydrous aluminum chloride were suspended in 750 ml of 1,2-dichloroethane, the mixture was stirred with cooling in an ice-salt bath and 282 ml of acetic anhydride were added. This addition was done at such a rate that the internal temperature could be kept between 0 and 10 ° C. After the addition was complete, a solution of 200 g of fluorene in 800 ml of 1,2-dichloroethane was added dropwise, the temperature being kept below 20 ° C. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for two hours after which the cooling bath was replaced. At the same time, so much 3N hydrochloric acid was added slowly that two clear phases formed without any suspended solid.

The mixture was distilled under reduced pressure to remove all organic solvent residues. The solid was collected by filtration, the crude product was carefully washed with water on a filter and dried in an oven at approximately 100 ° C. The mixture was then recrystallized from boiling toluene, which resulted in 2,7-diacetylfluorene.

Melting point: 180 ° C.

b) Preparation of the disodium salt of fluorenone-2,7-dicarboxylic acid

30 g of finely ground 2,7-diacetyl fluorene were suspended in 1.0 l of sodium hypochlorite solution (approximately 8% available chlorine) and the suspension was heated to 90 ° C. with stirring. The heating was continued for five hours while the chloroform formed in the reaction was distilled off. At the end of the 5 hours, 100 g of sodium chloride were added and the suspension was cooled to about 30 ° C. with stirring and the solid was separated off by filtration. This solid was placed in a container, 500 ml of water was added and the whole was heated to approximately 80 ° C. The solution was filtered to remove unreacted 2,7-diacetyl fluorene. The filtrate was heated to 40 ° C and excess sodium chloride was added to precipitate the disodium salt of fluorenone-2,7-dicarboxylic acid.

Example 15

Disodium salt of fluorenone-2,7-dicarboxylic acid

30 g of fluorenone-2,7-dicarboxylic acid were suspended in 300 ml of water with stirring and neutralized with an approximately 10% sodium hydroxide solution.

3 g of coal were added to the solution and that

Whole at room temperature for 30 minutes. The mixture was then filtered through a "Hyflo" bed.

The filtrate was placed in a clean beaker and 1200 ml of filtered methanol was added to precipitate the solid disodium salt, which was filtered off, suspended in filtered methanol while stirring, filtered again, washed with methanol and dried in a vacuum oven at 100 ° C. The solid disodium fluoro-non-2,7-dicarboxylate resulted.

Example 16

Monosodium salt of fluorenone-2,7-dicarboxylic acid

9.906 g of the monohydrate of the disodium salt of fluorenone-2,7-dicarboxylic acid was dissolved in 50 ml of water. The solution was stirred and 6 ml of 5N-hydrochloric acid were added dropwise over 15 minutes. The mixture was then stirred at room temperature for a further 15 minutes and at 50 ° C for one hour. The mixture was cooled and filtered. The pale yellow substance was washed out and dried in vacuo to the monohydrate of the monosodium salt of fluore-non-2,7-dicarboxylic acid. The reaction product was then dispersed in “Nujol Mull” and showed the infrared spectrum shown in FIG. 2.

Example 17 Calcium salt of fluorenone-2,7-dicarboxylic acid

2 g of the monohydrate of the disodium salt of fluorenone-2,7-dicarboxylic acid were dissolved in 10 ml of water with gentle heating, stirred and a solution of 3 g of calcium nitrate in a little water was added. The mixture was warmed for a few minutes and the pale yellow precipitate was filtered off, washed with water and dried at room temperature and atmospheric pressure. The result was the dihydrate of the calcium salt of fluorenone-2,7-dicarboxylic acid, which was dispersed in "Nujol Mull" and gave the infrared spectrum shown in FIG. 3.

Example 18

Magnesium salt of fluorenone-2,7-dicarboxylic acid

2 g of the monohydrate of the disodium salt of fluorenone-2,7-dicarboxylic acid in 10 ml of warm water were stirred, and 1.7 g of magnesium nitrate dissolved in water were added. The resulting pale yellow precipitate was filtered off, washed with water and dried at room temperature and atmospheric pressure. The result was the dihydrate of the magnesium salt of fluorenone-2,7-dicarboxylic acid, which was dispersed in "Nujol Mull" and gave the infrared spectrum shown in FIG. 4.

Example 19

Dipotassium salt of fluorenone-2,7-dicarboxylic acid

4.0 g of fluorenone-2,7-dicarboxylic acid were added in portions to a stirred solution of 2.06 g of potassium carbonate in 30 ml of water and the whole was stirred overnight at room temperature. Excess ethanol was added to the resulting solution to precipitate a yellow solid, which was filtered off, washed with ethanol and dried in vacuo at 100 ° C. The result was the anhydrous dipotassium salt of fluorenone-2,7-dicarboxylic acid, which was dispersed in "Nujol Mull" and gave the infrared spectrum shown in FIG. 5.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

13

630885

Example 20

Diammonium salt of fluorenone-2,7-dicarboxylic acid

2 g of fluorenone-2,7-dicarboxylic acid were suspended in 40 ml of water, an excess of ammonia solution with a density of 0.88 was added at 15 ° C. and the mixture was heated to 50 ° C. with stirring. After 45 minutes the solid had dissolved and the solution was mixed with 150 ml of ethanol and cooled to 0 ° C. The yellow solid was filtered off and dried in vacuo. The result was the anhydrous diammonium salt of fluorenone-2,7-dicarboxylic acid, which was dispersed in "Nujol Mull" and gave the infrared spectrum shown in FIG. 6.

Example 21 Xanthone-2,6-dicarboxylic acid

0.9 g of 2,6-dimethylxanthone (prepared according to the method of Köbrich [Annalen 664, (1963), page 96] was under pressure with 3.6 g of sodium dichromate and 55 ml of water at 240 ° to 250 ° C. for 23 hours The resulting mixture was filtered off and the solid material was carefully extracted with hot water, and the combined filtrates, which were heated to boiling and acidified with dilute hydrochloric acid, gave a fine precipitate of xanthone-2,6-dicarboxylic acid on cooling slowly. 9-oxoxanthene-2,6-dicarboxylic acid).

Melting point:> 400 ° C.

Example 22 Disodium 9-oxoxanthene-2,6-dicarboxylate

9-Oxoxanthene-2,6-dicarboxylic acid was dissolved in dimethylformamide and neutralized with two equivalents of a methanolic n-sodium methoxide solution. After adding more methanol, a precipitate of disodium 9-oxoxanthene-2,6-dicarboxylate was formed. This crystallized out with 3 moles of water of crystallization per mole of disodium 9-oxoxanthene-2,6-dicarb-oxylate and was soluble in water.

previous examples further processed. The 7-bromo-f luorenone-2-carboxylic acid resulted.

Melting point:> 300 ° C.

5 Example 25

7-ethyl-fluorenone-2-carboxylic acid a) 2.67 g of acetic anhydride in 10 ml of dichloroethane were added dropwise to a stirred and cooled (0 ° C.)

io suspension of 6.95 g aluminum chloride in 20 ml dichloroethane added. Cooling and stirring was continued while dropwise adding a solution of 4.61 g of 2-ethyl fluorene in 50 ml of dichloroethane. The mixture was stirred at room temperature for one hour and

15 then decomposed by adding 40 ml of 2N hydrochloric acid dropwise to the cooled solution. The organic phase was separated, washed with water and aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure.

The residue was recrystallized from petroleum ether (approx. 250 ml, boiling point: 60 ° to 80 ° C). The result was 2-acety 1-7-ethyl fluorine.

Melting point: 120 ° to 122 ° C.

b) A solution of sodium hypobromite was prepared by dropwise adding 27.5 g (9.4 ml) of bromine to a cooled (0 ° C) stirred solution of 17.2 g of sodium hydroxide in 600 ml of water. 6.74 g of 2-acetyl-7-ethyl fluorene were added with stirring and the stirred mixture was heated to 70 ° C., this temperature was maintained for 5 hours and the whole was left to stand at room temperature overnight. The mixture was filtered and the filtrate was heated to 60 ° C. and 300 g of sodium acetate were added. The sodium salt thus precipitated was filtered off, dissolved in very little hot water and converted into the free acid with hydrochloric acid. The reaction product was filtered off, washed well with water and dried in vacuo. The result was pure 7-ethylfluorenone-2-carboxylic acid with a melting point of more than 300 ° C. Thin layer chromatography showed that the substance was present as a single product.

30th

35

Example 23 7-chloro-fluorenone-2-carboxylic acid

4 g of 2-acetyl-7-chlorofluorene dissolved in 60 ml of acetic acid at 60 ° were mixed with 25 g of sodium dichromate in portions of approximately 5 g each. The mixture was heated under reflux for 5 hours, cooled and poured into one liter of cold water. The solid precipitate was filtered off, washed well with water and stirred at room temperature with 50 ml of a 10% strength solution of ammonia with a density of 0.88 at 15 ° C. in water. The mixture was filtered off and the solid was extracted again with 50 ml of a 2% solution of ammonia with a density of 0.88 at 15 ° C. in water. After the combined ammionacal extracts were acidified with sulfuric acid, the 7-chloro-fluorenone-2-carboxylic acid resulted.

Melting point:> 300 ° C.

Example 24 7-bromo-fluorenone-2-carboxylic acid

4 g of 2-acetyl-7-bromofluorene dissolved in 40 ml of hot acetic acid were mixed in portions with 25 g of sodium dichromate over 45 minutes. Then 7.5 ml of acetic anhydride were added. The mixture was refluxed for 5 hours and then as in US Pat

Example 26 7-butyl-fluorenone-2-carboxylic acid

45 a) A mixture of 11.3 g of 2-butyryl fluorene, 4.16 g of powdered potassium hydroxide and 9 ml of 100% hydrazine hydrate in 104 ml of ethylene glycol was heated to the reflux temperature for one hour with stirring. The mixture was then slowly distilled until the boiling point reached 185 ° C

Had reached 50 and then continued to reflux for three hours. About 300 ml of water were added to the cooled mixture and the reaction product was isolated with ether in the usual way. After recrystallization from methanol, 2-butyl fluorene resulted.

55 Melting point: 65 ° to 66.5 ° C.

b) 6.1 g of 2-butyl fluorene were acetylated in the manner described in Example 25 like the 2-ethyl fluorene. This required 3.08 g of acetic anhydride and 8.66 g of aluminum chloride in dichloroethane. The reaction product was out

60 petroleum ether recrystallized and the result was 2-acetyl-7-butylfluorene.

Melting point: 102 ° to 104.5 ° C.

c) 1.98 g of this reaction product were mixed with sodium hypobromite (from 7.23 g bromine and 4.52 g sodium hydroxide

65 in 160 ml of water) in the manner described in the previous example as the 2-acetyl-7-ethyl fluorene oxidized. The 7-butylfluorenone-2-carboxylic acid isolated in this way had a melting point of more than 300 ° C. and proved to be due to

630885

14

a thin-layer chromatographic examination as a single product.

Example 27 Acridon-2,6-dicarboxylic acid

2,6-dimethylacridone, which had been prepared by a ring closure reaction of 4 ', 5-dimethyldiphenylamine-2-carboxylic acid, was heated with an aqueous solution of 3 mol of sodium dichromate dihydrate in an autoclave at 200 ° to 250 ° C. for 17 hours. After cooling overnight, the contents of the autoclave were washed with hot water in a beaker, hot filtered and the remaining chromium oxide was carefully washed out with hot water. The alkaline filtrate and washings were combined, evaporated to a small volume and acidified with concentrated hydrochloric acid. The mixture was centrifuged to collect the fine precipitate. The remaining substance cake was dried and dissolved in dimethyl sulfoxide. After adding ethanol to the filtered solution, acridone-2,6-dicarboxylic acid was obtained as an orange substance which decomposed above 460 ° C.

Example 28 Dipotassium anthraquinone 2,6-dicarboxylate

1.00 g of anthraquinone-2,6-dicarboxylic acid was dissolved with a very small amount of water (20 ml), which contained one equivalent (0.68 g) of potassium bicarbonate, at the boil. The solution was filtered hot and left to crystallize. The separated reaction product was filtered off, dried at 100 ° C. and analyzed as a dihydrate.

Elemental analysis:

calculated: C 47.06 H 2.47 found: C 47.09 H 2.48

5 Example 29

Fluorenone-2,7-dicarboxylic acid bisethanolamine salt

2.68 g of fluorenone-2,7-dicarboxylic acid are suspended in 10 ml of water and treated with 1.22 g of ethanolamine. The io mixture is heated and stirred until all of the solid has dissolved. The solution is treated with 100 ml of ethanol, cooled and filtered to remove a small amount of solid. The filtrate is evaporated under reduced pressure. The residue is dissolved in 2 to 3 ml of water and treated with 100 ml of ethanol. The solution is cooled at 0 ° C for one hour. The yellow crystalline solid obtained is filtered, washed with alcohol and dried in vacuo. Fluorenone-2,7-dicarboxylic acid bisethanolamine salt is obtained, which slowly decomposes at over 145 ° C 20.

Example 30

Anthraquinone-2,6-dicarboxylic acid bisethanolamine salt

25 2.96 g of anthraquinone-2,6-dicarboxylic acid are suspended in 50 ml of methanol. 1.36 g of ethanolamine are added and the mixture is boiled for 30 minutes. After cooling, the light yellow solid is filtered off, washed with methanol, dried in vacuo at room temperature and analyzed as the 30-bis-ethanolamine salt.

Analysis for: C20H22N2O8

calculated: C 57.41 H 5.30 N 6.70 found: C 57.48 H 5.33 N 6.70

v

3 sheets of drawings

Claims (25)

630885 2nd PATENT CLAIMS 1. Process for the preparation of tricyclic compounds which are intended for the preparation of medicaments suitable for the treatment of allergic reactions in humans or in mammals and which have the formula 1 Z2 ai, Z2 di in which mean: Z1 is a carboxyl group, a pharmaceutically acceptable carboxylate salt group, an alkyl carboxylate group with an alkyl portion having 1 to 6 carbon atoms or an unsubstituted or with an alkyl radical with 1 to 6 carbon atoms N-substituted carboxamide group; Z3 is a bond, a carbonyl group, an oxygen atom or an NR ^ group, where R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and Z2 is a substituent with one of the meanings of Z1 or a hydrogen atom or, if Z3 is a bond or an NR ^ group, a halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, where the alkyl portion of the acyl , Alkyl or alkoxy group has 1 to 6 carbon atoms; characterized in that in a compound of formula 2 (2), which has one 8a, 10a double bond or two 8a, 9 or 10.10a double bonds and in which: Y1 is an alkyl group or a Z'-group; Y2 is an alkyl group, a carboxyl group or a Z2 group; wherein at least one of the groups Y1 and Y2 is an alkyl group; and either a) Y3 is a Z3 group or a methylene group and Y4 is a methylene group or a carbonyl group; or b) Y3 and Y4, which are the same or different, each = CH- or = CR-, where R is a lower alkyl group, or, if Y4 = CH-, Y3 is also a nitrogen atom; with the proviso that Y4 is not a carbonyl group when Yl is Z1 and Y2 is Z2; with an oxidizing agent at least one of the groups Y1 and Y2, insofar as they are alkyl groups, is oxidized to carboxyl groups and the groups Y3 and Y4, insofar as they are methylene groups, are oxidized to carbonyl groups and the compounds obtained are optionally converted into their pharmaceutically acceptable salts. 2. Process for the preparation of tricyclic compounds which are intended for the preparation of medicaments which are suitable for the treatment of allergic reactions in humans or in mammals and which have the formula 1 Z1 is a carboxyl group, a pharmaceutically acceptable carboxylate salt group, an alkyl carboxylate group with an alkyl portion having 1 to 6 carbon atoms or an unsubstituted or with an alkyl residue with 1 to 15 6 carbon atoms N-substituted carboxamide group; Z3 is a bond, a carbonyl group, an oxygen atom or an NR ^ group, where R1 is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; and Z2 is a substituent with one of the meanings of 20 Z1 or a hydrogen atom or, if Z3 is a bond or an NR ^ group, a halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl -, alkyl or alkoxy group has 1 to 6 carbon atoms; 25 characterized in that in a compound of formula 2 (2), which has one 8a, 10a double bond or two 8a, 9 or 10.10a double bonds and in which: Y1 is an alkyl group or a Z ^ group; Y2 is an alkyl group, a carboxyl group or a Z2-40 group; wherein at least one of the groups Y1 and Y2 is an acyl group; and either a) Y3 is a Z3 group or a methylene group and Y4 is a 45 methylene group or a carbonyl group; or b) Y3 and Y4, which are the same or different, each = CH- or = CR-, where R is a lower alkyl group, or, if Y4 = CH-, Y3 is also a nitrogen atom; with the proviso that Y4 is not a carbonyl group if Y1 is Z1 and Y2 is Z2; with an oxidizing agent at least one of the groups Y1 and Y2, insofar as they are acyl groups, is oxidized to carboxyl groups and the groups Y3 and Y4, insofar as they are methylene groups, are oxidized to carbonyl groups and the compounds obtained are optionally converted into their pharmaceutically acceptable salts. 3. The method according to claim 1 or 2, characterized in that compounds of the formula 3rd (3) 3rd 630885 produces, in which mean: Z5 is an oxygen atom or an NR 'group; and Z4 is a substituent with one of the meanings of Z1; or, when Z5 is an NR ^ group, a halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group having 1 to 6 carbon atoms; or, if Z5 is a bond, a cyano group; with the proviso that when Z5 is an oxygen atom, Z4 is not a 7-carboxyl, 7-carboxylate salt, 7-alkyl carboxylate or unsubstituted or N-alkyl-substituted 7-carboxamide group. 4. The method according to claim 1 or 2, characterized in that compounds of the formula 4th produces, in which means: Z9 is a substituent with one of the meanings of Z1 or a halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group having 1 to 6 carbon atoms. 7. The method according to claim 1 or 2, characterized in that compounds of formula 7 Z2 0 (7) (4) produces, in which mean: Z8 is a carboxyl group or a carboxylate salt group; and Z7 represents a halogen atom, a cyano group, an alkyl group with 2 to 4 carbon atoms or an unsubstituted or N-substituted carboxamide group with an alkyl group with 1 to 6 carbon atoms. 5. The method according to claim 1 or 2, characterized in that compounds of the formula 5th 20th produces, wherein only one of the groups Z2 is a substituent with one of the meanings of Z1. 8. The method according to claim 1 or 2, characterized in that the oxidation in the liquid phase 25 elevated temperature. 9. The method according to claim 1 or 2, characterized in that the oxidizing agent is nitric acid, a dichromate salt of acetic acid, chromium trioxide or a mixture of chromium trioxide with acetic acid or with sulfur 30 acid used. 10. The method according to claim 1 or 2, characterized in that in the preparation of compounds of formula 1 in which neither Z1 nor Z2 has an alkyl portion, an aqueous solution as the oxidizing agent 35 of hypochlorous or bromonic acid used in the presence of a base. 11. Application of the method according to claim 1 or 2 for the preparation of compounds of formula 8 (8th), produces, in which means: Z8 represents a hydrogen atom or a substituent with one of the meanings of Z1 or a halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group having 1 to 6 carbon atoms; with the proviso that R1 and Z8 are not simultaneously hydrogen atoms. 6. The method according to claim 5, characterized in that compounds of the formula 6 in which mean: so Z10 is a carboxylate salt group with potassium, sodium, calcium, magnesium, ammonium or an organic base as a cation; and Z11 is a substituent with one of the meanings of Z10 or a carboxyl group; or, if Z3 is a bond 55 or an NR ^ group, a hydrogen or halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group having 1 to 6 carbon atoms having; except for connections where: eo 7 9 i H (6) 65 a) Z10 and Z11 are simultaneously sodium carboxylate salt groups or together form a calcium carboxylate salt group if Z3 is a carbonyl group and Z11 is arranged in 6-position; or b) Z10 is a sodium carboxylate group if Z3 represents a bond and Z11 is a methyl group in the 7-position. 12. Application according to claim 11 for the preparation of compounds of formula 9 630885 4th M n + m by an alkyl radical having 1 to 6 carbon atoms N-substituted carboxamide group. 15. Use according to claim 11 or 12 for the preparation of compounds of formula 12 in which mean: Z12 is a carboxylate group; Z13 is a carboxyl or carboxylate group or, if Z3 is a bond or an NR ^ group, a hydrogen or halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group has 1 to 6 carbon atoms; M is a sodium, potassium, calcium, magnesium or ammonium cation or the cation of an organic base; n and m each of the numbers 1 and 2, the product m. n is 2 when Z13 represents a carboxylate group and is 1 when Z13 does not represent a carboxylate group; with the proviso: a) that M is not sodium or calcium if Z13 is a carboxylate group in the 6-position and Z3 is a carbonyl group; and b) that M is not sodium when Z13 is 7-methyl and Z3 is bond; characterized in that the compounds of formula 9 are isolated as a solid from a solution containing the corresponding mono- or dicarboxylate anion in a polar solvent. 13. Application according to claim 11 or 12 for the preparation of compounds of formula 10 (10), (12), in which means: Z16 is a substituent having one of the meanings of Z10, a hydrogen or halogen atom or a nitro, 20 cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group having 1 to 6 carbon atoms; except for compounds in which R1 and Z18 are simultaneously hydrogen atoms. 25 16. Application according to claim 11 or 12 for the preparation of compounds of formula 13 (13), in which mean: Z15 is an oxygen atom or an NRX group; or, when Z14 is a cyano group, a bond; Z14 is a substituent with one of the meanings of Z10 or a carboxyl group; or, when Z15 is an NR ^ group, a halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group having 1 to 6 carbon atoms; or, if Z15 is a bond, a cyano group; except for compounds in which Z14 denotes a carboxyl or carboxylate salt group in the 7-position and Z15 denotes an oxygen atom. 14. Application according to claim 11 or 12 for the preparation of compounds of formula 11 (11), in which means: Z7 represents a halogen atom, a cyano group, an alkyl group having 2 to 4 carbon atoms or an unsubstituted or in which: Z17 is a substituent with one of the meanings of Z10 or a halogen atom or a nitro, cyano, acyl, alkyl or alkoxy group, the alkyl portion of the acyl, alkyl or alkoxy group having 1 to 6 carbon atoms. 17. Application according to claim 11 or 12 for the preparation of compounds of formula 14 (14), in which means: Z18 represents a hydrogen atom or a substituent with 60 one of the meanings of Z10; with the proviso that only one of the groups Z18 is a substituent of the meaning Z10. 18. Application according to claim 12, characterized in that the connections from the solution 65 fails. 19. Application according to claim 18, characterized in that the compounds precipitate out of the solution by adding a second solvent, which 5 630885 is miscible with the polar solvent and in which the compounds are less soluble than in the polar solvent. 20. Application according to claim 19, characterized in that a polar solvent is also used as the second solvent. 21. Application according to claim 19, characterized in that water is used as the polar solvent and an alkanol, in particular methanol or ethanol, is used as the second solvent. 22. Application according to claim 18, characterized in that the precipitation is effected by adding cations to the solution until their concentration exceeds the molar equivalent of the cation in the compounds. 23. Application according to claim 12, characterized in that the compounds are isolated by removing the polar solvent. 24. Application according to claim 23, characterized in that the solvent is removed by evaporation. 25. Use according to claim 24, characterized in that the solvent is removed by freeze-drying. 26. Use according to claim 24, characterized in that the solvent is removed by azeotropic distillation. 27. Application according to claim 11 for the production of disodium fluorenone-2,7-dicarboxylate. 28. Use according to claim 27, characterized in that 2,7-diacetylfluorene is oxidized to fluorenone - 2,7-dicarboxylic acid or a salt thereof and the acid or the salt in the disodium fluorenone-2,7-di-carboxylate transferred.