CH626613A5 - Process for the preparation of polycyclic compounds containing at least one tetrazole ring - Google Patents

Description

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PATENT CLAIMS 1. Process for the preparation of polycyclic compounds of formula 1 containing at least one tetrazole ring

in which mean:

one of the groups Z1 and Z2 a 5- (IR) tetrazolyl or 5- (2-R) tetrazolyl group, the other a carboxyl, 5- (IR) tetrazolyl or 5- (2-R) tetrazolyl group wherein R is hydrogen or an alkyl group having 1 to 6 carbon atoms;

Z3 is a bond, oxygen, a carbonyl group or the group NR1, wherein R1 is hydrogen or an alkyl group having 1 to 6 carbon atoms;

where Z2 can also denote hydrogen, halogen, a nitro or cyano group, an alkyl group with 1 to 6 carbon atoms or an alkoxy or acyl group with 1 to 6 carbon atoms in the alkyl portion if Z3 denotes a bond or the group NR1;

and their salts,

characterized in that a compound of formula 2

0

wherein Y1 is a group Z1 or a group of formula 3

and Y2 is a group Z2 or a group of the formula 3, where at least one of the groups Y1 and Y2 is a group of the formula 3, and in which R3 and R4 together are a bond or in which R3 is hydrogen or an alkyl group having 1 to 6 carbon atoms and R4 is an alkoxy or alkylthio group with 1 to 6 carbon atoms, the group -NH-NH2 or the amino group or where R3 is a hydroxyl group and R4 is the amino group or where R3 is an alkyl group with 1 to 6 carbon atoms and R4 is halogen, with hydrochloric acid or a salt of it.

2. The method according to claim 1, characterized in that the compounds obtained are converted into their salts.

3. The method according to claim 1, characterized in that compounds of formula 1 are prepared in which Z3 is a bond or a group NR2, wherein R2 is a

Is alkyl group with 1 to 4 carbon atoms, means and Z2 is in the 7-position.

4. The method according to claim 1, characterized in that compounds of formula 1 are prepared in which Z3 is oxygen, a carbonyl group or the group NH, and Z2 is in the 6-position.

5. The method according to claim 1, characterized in that compounds of formula 1 are prepared in which R is hydrogen.

6. The method according to claim 1, characterized in that compounds of formula 1 are prepared in which one of the groups Z1 and Z2 is a 5-tetrazolyl group, the other is a 5-tetrazolyl or carboxyl group.

7. The method according to claim 1, characterized in that 2,6-di- (5-tetrazolyl) anthraquinone, 2,7-di- (5-tetrazolyl) fluorenone or 2,6-di- (6-tetrazolyl) acridone manufactures.

8. Use of compounds of the formula 1 prepared by the process according to claim 1, in which one of the groups Z1 and Z2 is a free carboxyl group, for the preparation of the corresponding compounds having an esterified carboxyl group by esterification.

9. Use of compounds of the formula 1 prepared by the process according to claim 1, in which one of the groups Z1 and Z2 is a free carboxyl group, for the preparation of the corresponding compounds having an acid amide group by amidation.

10. A process for the preparation of at least one tetra-zolring containing polycyclic compounds of formula 1

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u in which mean:

one of the groups Z1 and Z2 is a 5- (IR) tetrazolyl or 5- (2-R) tetrazolyl group, the other is a carboxyl, 5- (IR) tetrazolyl or 5- (2-R) tetrazolyl group Group wherein R is hydrogen or an alkyl group having 1 to 6 carbon atoms;

Z3 is a bond, oxygen, a carbonyl group or the group NR1, wherein R1 is hydrogen or an alkyl group having 1 to 6 carbon atoms;

where Z2 can also denote hydrogen, halogen, a nitro or cyano group, an alkyl group with 1 to 6 carbon atoms or an alkoxy or acyl group with 1 to 6 carbon atoms in the alkyl portion if Z3 denotes a bond or the group NR1;

and their salts,

characterized in that a compound of formula 2

0

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wherein Y1 is a group Z1 or a group of formula 3

and Y2 is a group Z2 or a group of the formula 3, where at least one of the groups Y1 and Y2 is a group of the formula 3, and in which R3 is hydrogen or an alkyl group having 1 to 6 carbon atoms and R4 is the group -NH-NH2, reacted with nitrous acid.

11. The method according to claim 10, characterized in that the compounds obtained are converted into their salts.

12. The method according to claim 10, characterized in that compounds of formula 1 are prepared in which Z3 is a bond or a group NR2, wherein R2 is an alkyl group having 1 to 4 carbon atoms, and Z2 is in the 7-position.

13. The method according to claim 10, characterized in that compounds of formula 1 are prepared in which Z3 is oxygen, a carbonyl group or the group NH, and Z2 is in the 6-position.

14. The method according to claim 10, characterized in that compounds of formula 1 are prepared in which R is hydrogen.

15. The method according to claim 10, characterized in that compounds of formula 1 are prepared in which one of the groups Z1 and Z2 is a 5-tetrazolyl group, the other is a 5-tetrazolyl or carboxyl group.

16. The method according to claim 10, characterized in that 2,6-di- (5-tetrazolyl) anthraquinone, 2,7-di- (5-tetrazolyl) fluorenone or 2,6-di- (5-tetrazolyl) acridone manufactures.

17. Use of compounds of the formula 1 which have been prepared by the process according to claim 10 and in which one of the groups Z1 and Z2 is a free carboxyl group, for the preparation of the corresponding compounds having an esterified carboxyl group by esterification.

18. Use of compounds of the formula 1 prepared by the process according to claim 10, in which one of the groups Z1 and Z2 is a free carboxyl group, for the preparation of the corresponding compounds having an acid-amide group by amidation.

19. A process for the preparation of at least one tetra-zolring containing polycyclic compounds of formula 1

in which mean:

one of the groups Z1 and Z2 is a 5- (1H) tetrazolyl or 5- (2-H) tetrazolyl group, the other a carboxyl, 5- (IR) tetrazolyl or 5- (2-R) tetrazolyl group Group wherein R is hydrogen or an alkyl group having 1 to 6 carbon atoms;

Z3 is a bond, oxygen, a carbonyl group or the group NR1, wherein R1 is hydrogen or an alkyl group having 1 to 6 carbon atoms;

where Z2 can also denote hydrogen, halogen, a nitro or cyano group, an alkyl group with 1 to 6 carbon atoms or an alkoxy or acyl group with 1 to 6 carbon atoms in the alkyl portion if Z3 denotes a bond or the group NR1;

and their salts,

characterized in that a compound of formula 2

0

wherein Y1 is a group Z1 or a group of formula 3

-C = N

'Li 1 7 ^) 3

fr fr and Y2 are a group Z2 or a group of the formula 3, where at least one of the groups Y1 and Y2 is a group of the formula 3, and in which R3 is hydrogen and R4 is the amino group, reacted with nitrous acid and the nitrosation product formed in the process corresponding tetrazolyl compound reduced.

20. The method according to claim 19, characterized in that the compounds obtained are converted into their salts.

21. The method according to claim 19, characterized in that compounds of formula 1 are prepared in which Z3 is a bond or a group NR2, wherein R2 is an alkyl group having 1 to 4 carbon atoms, and Z2 is in the 7-position.

22. The method according to claim 19, characterized in that compounds of formula 1 are prepared in which Z3 is oxygen, a carbonyl group or the group NH, and Z2 is in the 6-position.

23. The method according to claim 19, characterized in that compounds of formula 1 are prepared in which R is hydrogen.

24. The method according to claim 19, characterized in that compounds of formula 1 are prepared in which one of the groups Z1 and Z2 is a 5-tetrazolyl group, the other is a 5-tetrazolyl or carboxyl group.

25. The method according to claim 19, characterized in that 2,6-di- (5-tetrazolyl) anthraquinone, 2,7-di- (5-tetrazolyl) fluorenone or 2,6-di- (5-tetrazolyl) acridone manufactures.

26. Use of compounds of the formula 1 prepared by the process according to claim 19, in which one of the groups Z1 and Z2 is a free carboxyl group, for the preparation of the corresponding compounds having an esterified carboxyl group by esterification.

27. Use of compounds of the formula 1 which have been prepared by the process according to claim 19 and in which one of the groups Z1 and Z2 is a free carboxyl group for the preparation of the corresponding compounds having an acid reamide group by amidation.

It has been found that compounds containing at least one tetrazole ring, as defined in the preambles of claims 1, 10 and 19, and their salts, esters and amides in mammals and in animal preparations

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act as inhibitors of allergic reactions associated with reactant antibodies of the type responsible for human asthma, and that this effect is attributable to the suppression of the release of anaphylactic mediators.

Suitable compounds of the type mentioned at the outset include the 2-Z1, 7-Z2-fluorenones, the 2-Z1-6-Z2-anthraquinones, the 2-Z1.6-Z2-xanthones and the 2-Z1.6 -Z2-acridones and the 2-Z1,7-Z2N-alkylacridones, in which one of the groups Z1 and Z2 represents a 5-tetrazolyl group and the other group a 5-tetrazolyl or carboxyl group.

Suitable esters of the compounds of formula 1 include the alkyl esters having 1 to 6 carbon atoms, suitable amides including the N-alkyl and the N, N-dialkyl amides, in which the alkyl groups have 1 to 6 carbon atoms.

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

a) In experiments using the sensitivity of passive cutaneous anaphylaxis (PCA test), measuring the skin reaction, which is the result of an interaction between an intravenously injected specific antigen and a cell-fixed reactine antibody, which was previously injected into the skin of a mammal was present (see for example: Z. Ovary: Fedn. Proc. Am. Soc. exp. Biol. 24, 94 [1965]),

b) by measuring the amount of histamine released after an antigen attack in peritoneal mast cells of actively sensitized rats (see, for example: 1. Acta Pharmacol. et Toxicol. 30 supp. 1 (1971), 2. Thorax, 27/1, 38 [1972] ), "

c) by measuring the amount of histamine released from comminuted human lung tissue, which was passively sensitized in vitro with reagents as soon as it was attacked with the homologous antigen (see, for example: (Br. Med. J. 3, 272 [1968). The effect of Acids of Formula 1 were proven as described above using the solutions of the anions.

For the sake of simplicity, the compounds of the formula 1 in which at least one of the groups Z1 or Z2 denotes an alkyl carboxylate group are referred to below as esters of the compound of the formula 1. Likewise referred to as amides of the compound of formula 1 are compounds in which either Z1 or Z2 or both mean an optionally substituted carboxyamide radical. Salts of the compound of formula 1 mean salts in which either Z1 or Z2 or both represent a carboxylate or tetrazolyl salt group.

Pharmaceutically usable salts of the compounds of formula 1 include the ammonium salts, the alkali metal salts, such as sodium and potassium salts, the alkaline earth salts, such as the magnesium and calcium salts, and the salts of organic bases, for example the amine salts, such as the triethanolamine or diethylaminoethyl -min, piperazine and morpholine. The water-soluble salts of the compound of formula 1 are particularly suitable, these should preferably have a solubility in water of at least 1 mg / ml of water.

The antiallergic action of the salts of the compounds of formula 1 is based on the anion and the type of cation does not influence the effectiveness. For medical purposes. However, the cation must be pharmaceutically usable.

Pharmaceutically usable cations in compounds of formula 1 include hydrogen, the ammonium ion, the alkali metal cations, such as sodium or potassium, the alkaline earth metal cations, such as calcium and magnesium, and the cations of organic bases, such as the alkylammonium cations of Al-

alkylamines such as triethanolamine and diethylamine, piperazine and morpholine.

Preferred substituted carboxamide groups include the N-alkyl and N, N-dialkyl-substituted carboxamide groups, in which the alkyl portion is an alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

The compounds mentioned at the outset are prepared according to the invention by the processes defined in the characterizing part of claims 1 and 10.

Compounds of the formula 1 in which one of the groups Z1 and Z2 is a carboxyl group can be converted into their salts, esters or amides in the customary manner. This is usually done by treating the isolated acid. In certain cases, however, it is possible to prepare such derivatives without prior isolation of the carboxylic acid either by suitable choice of the components or by formation of the desired derivative in a reaction mixture of the acid without prior isolation.

In the processes according to the invention, a group of the formula which is a precursor for a tetrazolyl group is converted at least once into a tetrazolyl group.

If hydrochloric acid or a salt thereof is used as the reagent, the precursor for the tetrazolyl group is a group in which R3 and R4 together form a bond (nitrii), or R3 is hydrogen or an alkyl group having 1 to 6 C atoms and R4 is an alkoxy group 1 to 6 carbon atoms (imido ester), a thioalkyl group with 1 to 6 carbon atoms (imidothioester), the group -NH-NH2 (amidrazone) or an amino group (amidine) or in which R3 is a hydroxyl group and R4 is an amino group (amidoxime) or R3 is an alkyl group with 1 to 6 carbon atoms and R4 is a halogen (imidohalide). In the case of the amidoximes and Ni-triles, only tetrazolyl compounds and in the case of the imidohalides only alkyltetrazolyl compounds can be prepared. The reaction is preferably carried out in a polar aprotic liquid medium using a salt of hydrochloric acid.

If nitrous acid is used, the precursor for the tetrazolyl group is group f! *

wherein R3 is hydrogen or an alkyl group having 1 to 6 carbon atoms and R4 is the group -NH-NH2 (amidrazone) or R3 is hydrogen and R4 is an amino group (amidine). In the latter case, reduction of the intermediate nitrosation product with or without prior isolation using, for example, sodium amalgam is required to give the corresponding tetrazolyl bond.

The tetrazolyl compounds of formula 1 thus produced can be isolated as free acid or as a tetrazolyl salt.

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These two forms can be converted into one another in a known manner and as described below for the carboxylic acids of the formula 1 and their salts.

The 5- (1- and 2-alkyl) tetrazolyl compounds of formula 1 can be prepared from the corresponding tetrazolyl compounds of formula 1 or their salts by alkylation.

The salts of the compound of formula 1 can be isolated from a reaction mixture in the manner known for the isolation of salts from their solution from a polar medium. The salts of the compound of formula 1 are preferably purified in a conventional manner before they are processed further into pharmaceutical preparations.

The esters and amides of the acids of formula 1 can also be prepared in a known manner, including the esterification of the acid or acid chloride with an alkyl or aryl alcohol, the corresponding alkyl or aryl ester being formed. For example, the reaction of the acid and the acid chloride with ammonia or an amine can give the corresponding amide or the substituted amide. The compounds of formula 1, in which the groups Z1 and Z2 are different and have an acid, ester, amide and salt function, can be prepared in the above-mentioned manner and also, if appropriate, by partial hydrolysis.

The compounds of formula 1 prepared by the present process are suitable for the treatment or prophylaxis of allergic conditions in mammals, for example asthma and other allergic bronchial infections, hay fever (allergic rhinitis), conjunctivitis, urticaria and eczema. In particular, they are extremely effective in the case of hypersensitive type I asthma, which is caused by Reagine (so-called "extrinsic asthma") and the so-called "intrinsic asthma", in which no sensitivity to an extrinsic antigen can be demonstrated.

The strength of a prophylactic or therapeutic dose of a compound of formula 1 depends, of course, on the nature and severity of the allergy to be treated, as well as on the particular compound of formula 1 and its dosage form. In general, the doses are between 2 ng to 100 mg per kg body weight of a mammal.

In the case of one of the allergic disorders described above, for example in the case of allergic asthma, a suitable dose ranges from 20 to 0.5 mg, preferably from 0.1 to 0.5 mg, for example approximately 0.1 mg of a compound of the formula 1 per kg body weight of the patient to be treated if the pulmonary application described below is to be carried out. In the case of intravenous administration, an appropriate dosage of 0.2 to 10 mg, preferably 1 to 6 mg, of a compound of formula 1 per kg of body weight of the patient is sufficient; in the case of an oral preparation, the dose is 1 to 50 mg, preferably 10 up to 40 mg, a compound of formula 1 per kg of body weight of the patient.

If a preparation for administration in the nose or on the eye, for example for the treatment of allergic rhinitis, is intended, a suitable dose of 0.5 to 25 mg of a compound of the formula 1 is sufficient.

The pharmaceutical preparations of the present compound contain a compound of formula 1 as an active ingredient and can also contain pharmaceutically usable excipients and, if appropriate, other therapeutically active additives. The types of preparation include preparations for oral, rectal, ophthalmic, pulmonary, nasal, dermatological, local or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable administration form in each case depends on the type and severity of the disease to be treated and on the type depends on the active ingredient used. The substances are generally offered in the form of dosage units and can be prepared by methods which are generally known in pharmacy.

The pharmaceutical preparations of the compounds of formula 1 for oral administration can be in the form of single dosage units, such as capsules, cachets or tablets, each individual unit containing a predetermined amount of active ingredient. The preparations can furthermore be present as powders or granules or as a solution or suspension in an aqueous liquid, a non-aqueous liquid, an oil in water emulsion or a water in oil emulsion. These forms of preparation can all be produced in the usual way. In all cases, however, the active ingredient is brought together with the carrier, which can consist of one or more ingredients.

In the most favorable case, each single-dose preparation contains 50 to 500 mg of active substance.

A particularly advantageous type of pharmaceutical preparation for the present compounds, in particular for the treatment of allergic asthma, is a preparation which is suitable for pulmonary use via the oral cavity.

The form of preparation is preferably such that the particles containing the active ingredient have a diameter of only 0.5 to 7 f-i, preferably 1 to 6 fi, and thus reach the lungs of the patients. These preparations are preferably in the form of a dry powder for administration by means of a powder inhaler or as self-atomizing powder preparations. It is most advantageous if the powders in the preparations described above have active ingredient-containing particles which have a diameter of at least 98% by weight which is greater than 0.5 μm and a diameter of less than 95% by weight than 7 fi. It is most advantageous if at least 95% by weight of the particles have a diameter of more than 1 fi and at least 90%, based on the number of particles, have a diameter of less than 6 fi. • The preparations in the form of dry powders preferably contain a solid, finely powdered diluent and are generally in the form of a separable capsule, for example made of gelatin.

The self-atomizing preparations can either be powder-dispensing preparations or preparations in which the active ingredient is dispensed in the form of droplets of a solution or a suspension. The self-atomizing, powder-dispensing preparations contain a liquid blowing agent with a boiling point of less than 18 ° C at atmospheric pressure. In general, the blowing agent can make up 50 to 99.9% by weight of the preparation, while the active ingredient makes up 0.1 to 20% by weight, for example about 2% by weight, of the preparation.

The pharmaceutically usable carrier in such a self-atomizing preparation can also contain other constituents in addition to the propellant, in particular a liquid nonionic or solid anionic, surface-active agent or a solid diluent with preferably the same particle size as the active ingredient or both. The surfactants can constitute up to 20% by weight of the formulation, although they are preferably less than 1% by weight of the formulation.

The compounds produced by the present process can also be in the form of a self-atomizing preparation in which the active ingredient is in solution. Such self-atomizing preparations contain an active ingredient, a blowing agent and a co-solvent as well as 5

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preferably a stabilizer which acts as an antioxidant. The cosolvents can make up 5 to 40% by weight of the preparation, although their proportion should preferably be less than 20% by weight of the preparation.

The present compounds can also be in the form of an aqueous or dilute alcoholic solution, optionally also as a sterile solution, for use in a nebulizer or atomizer.

The preparations of the compounds for parenteral administration produced by the present method usually contain sterile aqueous solutions of the active ingredient, these solutions preferably being isotonic with the blood of the patients to be treated.

The pharmaceutical preparations of the present compounds, which are intended for local applications, include preparations which are suitable for use on the skin, on the eye, in the nose and in the mouth.

The preparations for use on the skin comprise lotions and creams which in turn contain liquid or semi-liquid emulsions, either oil in water or water in oil, which preferably contain 0.2 to 5% by weight / volume of the active ingredient. Preferably the creams or ointments should contain a preservative such as methyl hydroxybenzoate.

Preparations for use on the eye include eye drops which contain the active ingredient in aqueous or oily solution or as an ointment, preferably in a concentration of 0.2 to 5% by weight / volume. These solutions are preferably fungistatic and bacteriostatic and are advantageously made sterile.

Preparations for use in the nose include powder, self-atomizing and spray preparations, similar to the preparations already described for pulmonary use. When dispersed, however, the preparations for the nose have somewhat larger particles in the order of 10 to 200 ji. Another form of preparation for use in the nose is a coarse powder with a particle size of 20 to 500 microns, which is used like snuff, i.e. by rapid inhalation through the nose from a container which is held close under the nose. Another form of preparation which is suitable for use in the nose is the nose drops, which contain 0.2 to 5% by weight / volume of active substance in aqueous or oily solution.

Formulations which are suitable for local use in the mouth include lozenges which contain 10 to 100 mg of active ingredient in a flavor base, for example usually sugar and gum arabic or tragacanth. Furthermore, lozenges with an active ingredient content of 10 to 100 mg can be present in an inert base, such as, for example, gelatin and glycerin or sugar and gum arabic.

Other therapeutic ingredients which are suitable for incorporation into the preparation forms described above, in particular for the preparations which are intended for the treatment of allergic asthma, include bronchodilators, such as, for example, isoprenaline, adrenaline, orciprenaline, isoethane and their physiologically usable acid addition salts, especially isoprenaline sulfate. In general, such a bronchodilator is used in these preparations in an amount of 0.1 to 50 wt .-% of the present active ingredient.

Example 1 2,6-di- (5-tetrazolyl) anthraquinone a) Anthraquinone-2,6-dicarboxamide

5.0 g of anthraquinone-2,6-dicarboxylic acid was boiled for 45 minutes with 50 ml of thionyl chloride and 0.25 ml of dimethylformamide. The clear solution obtained was evaporated to dryness and the remaining acid chloride was treated with ammonia (density 0.880 at 15 ° C.). After standing for 30 minutes, the crude amide was filtered off, washed with water and dried, melting point 420 ° C. (dec.).

b) 2,6-dicyanoanthraquinone

10.0 ml of thionyl chloride were added in 1 ml portions to 100 ml of dimethylformamide at -30 ° C. with stirring. To the solution obtained, 4.74 g of anthraquinone-2,6-dicarboxamide were added all at once and the temperature of the mixture was allowed to rise slowly to 5 ° C. by being placed in an ice bath. After 30 minutes at this temperature, the mixture was heated to 65 ° C over 30 minutes. The heterogeneous mixture was then poured into ice water, the solid filtered off, dried and recrystallized from dimethyl sulfoxide. Yield 2.60 g, melting point 392 ° C. (dec.) In an evacuated tube.

c) 2,6-di- (5-tetrazolyl) anthraquinone

2.06 g of 2,6-dicyanoanthraquinone, 1.30 g of sodium azide, 1.07 g of ammonium chloride and 100 ml of dimethylformamide were stirred together at 105 to 110 ° C. for 24 hours. The mixture was poured into excess dilute hydrochloric acid, the solid product filtered off and washed with water. The solid was treated with 100 ml of 2% potassium bicarbonate solution and some insoluble material was filtered off. The filtrate was acidified with dilute hydrochloric acid, heated to the boiling point to coagulate the gelatinous precipitate, the crude product was filtered off, dried and recrystallized from dimethylformamide, decomposed at about 300 ° C.

Example 2

5- (7-Propoxycarbonyl-2-fluorenone) tetrazole a) Dipropylfluorenone-2,7-dicarboxylate (melting point 146.5 to 148 ° C.) was prepared from fluorenone-2,7-dicarboxylic acid by esterification with propanol in the presence of sulfuric acid. This diester was hydrolyzed to 7-propoxycarbonylfluorenone-2-carboxylic acid (melting point 250 to 252 ° C) using sodium hydroxide in the presence of propane. This half ester was treated with thionyl chloride and gave the corresponding acid chloride. The latter was converted to the corresponding amide (melting point 278 to 279 ° C.) by treatment with aqueous ammonia.

b) 3.8 g of 7-propoxycarbonylfluorenone-2-carboxamide were dissolved in 50 ml of dimethylformamide while heating, the solution was stirred and cooled to -25 ° C. 7.55 ml of thionyl chloride was added dropwise over 10 minutes and the mixture was allowed to warm to 0 ° C at that temperature

Held for 60 hours and then treated with a mixture of ice and water. The light yellow solid was filtered, washed with water, dried in vacuo and gave 7-prop-oxycarbonylfluorenone-2-carbonitrile with a melting point of 198 to 199 ° C.

c) 2 g of this nitrile, 450 mg of sodium azide and 400 mg of ammonium chloride in 20 ml of dimethylformamide were heated to 100 ° C. with stirring for 18 hours. The mixture was cooled, poured into 200 ml of water and acidified with 2N hydrochloric acid until an acid reaction. The gelatinous precipitate was filtered, washed with water and redissolved in aqueous sodium bicarbonate. The solution was filtered and then acidified with 2N hydrochloric acid. The solid obtained was filtered, dissolved in aqueous 2N ammonia, reprecipitated with hydrochloric acid and then filtered. After washing with water and drying in vacuo, 5- (7-prop-oxycarbonyl-2-fluorenone) tetrazole, melting point 227 to 228 ° C. (dec) was obtained.

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Example 3

Preparation of 2,7-di- (5-tetrazolyl) fluorenone a) Preparation of 2,7-dicyanofluorenone A mixture of 14.92 g of 2,7-dibromofluorenone and 9.35 g of copper (I) cyanide in 40 ml of dimethylformamide was prepared heated under reflux for 5 hours. The hot mixture was added to a solution of 38 g of ferric chloride in 57 ml of water and 9.5 ml of concentrated hydrochloric acid. The mixture was filtered, heated on a steam bath for 2 hours, treated again with a similar aqueous acidic solution of iron (III) chloride, then filtered, washed well with water and dried in vacuo. 2,7-dicyanofluorenone was obtained as a yellow solid, melting point above 300 ° C.

b) Preparation of 2,7-di- (5-tetrazolyl) fluorenone A mixture of 4.6 g of 2,7-dicyanofluorenone, 2.62 g of sodium azide and 2.6 g of ammonium chloride in 25 ml of dimethylformamide was stirred and left on for 10 hours Heated to 100 ° C. The mixture was cooled, treated with excess 2N hydrochloric acid, the solid filtered, washed with water, dried in vacuo and recrystallized from a mixture of methylformamide and water. This product was dissolved in excess aqueous O, ln sodium hydroxide, the solution was filtered and acidified with hydrochloric acid. The precipitate obtained was filtered, washed with water, dried in vacuo and gave 2,7-di- (5-tetrazolyl) fluorenone, melting point above 300 ° C.

Example 4

Preparation of 2,6-di- (5-tetrazolyl) xanthone 2,6-dicyanoxanthone (alternative nomenclature 9-oxaxan-then-2,6-dicarbonitrile), prepared (a) by applying the Sandmeyer reaction to 2,6- Diaminoxanthone or (b) by dehydrating xanthone-2,6-dicarboxamide with thionyl chloride in dimethylformamide at -65 ° C was heated in dimethylformamide with 1 part sodium azide and 1 part ammonium chloride at 115 ° C for 24 hours. After adding water and dilute hydrochloric acid, 2,6-di- (5-tetrazolyl) xanthone, melting point> 400 ° C., was obtained, which was insoluble in most organic solvents, but was easily soluble in dilute sodium bicarbonate solution.

Example 5

Preparation of 2,6-di- (5-tetrazolyl) acridone 2,6-diaminoacridone was converted to acridone-2,6-dicarbonitrile using the Sand Meyer reaction, melting point> 350 ° C. 0.98 g of the dicarbonitrile was added after heating for 8 hours at 100 ° C. to a suspension of 0.52 g of sodium azide and 0.43 g of ammonium chloride in 10 ml of dry dimethylformamide. The reaction mixture was poured into dilute hydrochloric acid containing ice and the precipitate was obtained. Crystallization from dimethylformamide gave 2,6-di- (5-tetrazolyl) acridone, melting point> 400 ° C.

Example 6 10-Methyl-2,7-di- (5-tetrazolyl) acridone Following a procedure similar to that described in Example 2, 10-methyl-2,7-di- (5-tetrazolyl) acridone became melting point> 400 ° C obtained.

The dicarbonitrile intermediate was prepared from 2,7-diamino-no-N-methylacridone by the Sandmeyer reaction.

Example 7 5- (7-Butylfluorenone-2) tetrazole A mixture of 800 mg of 7-butylfluorenone-2-carboxylic acid, 5 ml of thionyl chloride and 2 drops of dimethylformamide was heated under reflux for two hours and then evaporated under reduced pressure. The residue was cooled to 0 ° C and treated with aqueous ammonia (density 0.880 at 15 ° C). The resulting mixture was stirred at room temperature for one hour and then at 100 ° C for 15 minutes. It was then cooled, filtered and gave 7-butyl-fluorenone-2-carboxamide, melting point 185 to 190 ° C.

650 mg of the above amide was dissolved in 11 ml of dimethylformamide, the solution was cooled to -20 ° C, stirred and treated dropwise with 1.5 ml of thionyl chloride. After stirring an additional 30 minutes at -20 ° C, the solution was allowed to cool to room temperature for 1 hour and then poured into 50 ml of ice water. The amorphous product obtained was extracted into chloroform, the chloroform solution washed well with water, dried over anhydrous sodium sulfate and evaporated. The remaining amorphous nitrii was dissolved in 10 ml of dimethylformamide, treated with 200 mg of sodium azide and 180 mg of ammonium chloride and heated at 110 ° C. for 20 hours with stirring. The mixture was poured into 50 ml of water, acidified with hydrochloric acid, the solid filtered, washed with water and dried. After recrystallization from ethanol, pure 5- (7-butylfluorenone-2) tetrazole was obtained, melting point 233 to 234 ° C. (dec.).

Example 8 5 - (7-Bromofluorenone-2) tetrazole A mixture of 850 mg of 7-bromofluorenone-2-carboxylic acid, 5 ml of thionyl chloride and 2 drops of dimethylformamide was heated under reflux for 4 hours and then evaporated under reduced pressure. The residue was cooled to 0 ° C and treated with aqueous ammonia. The mixture was first stirred at room temperature for 16 hours and then at 100 ° C for 30 minutes, then cooled and filtered. It gave 7-bromofluorenone-2-carboxamide, melting point 270 to 274 ° C.

700 mg of this amide was dissolved in 11 ml of hot dimethylformamide and the solution was cooled to -20 ° C. It was then stirred and treated dropwise with 1.5 ml of thionyl chloride. A yellow solid began to settle during the addition. The mixture was stirred for a further hour at -20 ° C. and then for 3 hours at room temperature and then poured onto 50 ml of ice water. The yellow solid was filtered, washed well with water and dried. It gave 7-bromofluorenone-2-carbonitrile, melting point 205 to 210 ° C. 500 mg of this nitrile in 10 ml of dimethylformamide were treated with 200 mg of sodium azide and 180 mg of ammonium chloride, the mixture was stirred and heated at 110 ° C. for 20 hours. The mixture was then poured into 50 ml of water, acidified with hydrochloric acid, the yellow solid filtered, washed with water and dried. This gave 5- (7-bromofluorenone-2) tetrazole, melting point 290 to 295 ° C. (dec.).

Example 9 Preparation of 2,6-di- (5-tetrazolyl) acridone disodium salt 0.2 g of 2,6-di- (5-tetrazolyl) acridone was suspended in 10 ml of water and with 1.2 ml of aqueous n-sodium hydroxide solution treated. The mixture was evaporated to 5 ml and ethanol was added to crystallize the disodium salt, which was dried over phosphorus pentoxide. The salt did not melt at 470 ° C and was hygroscopic.

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