IL28710A - Process for the production of 1,2,8,9-tetraazaphenalenes and new 1,2,8,9-tetraazaphenalenes - Google Patents

Description

28710/3 ο'στπ J½K3SKTKK-I¾O~9,8, 2,1 Process for the production of 1,2,8,9· tetraazaphenalenes and new 1,2,8,9-tetraazaphenalenes CIBA-GEIGY A.G.

C:27260 - la - 28710/2 This invention relates to a process for the preparation of substituted 1,2,8,9-tetraazaphenalenes, and to new 1,2,8,9-tetraazaphenalenes their addition salts with inorganic and organic acids, and their quaternary ammonium salts.

By the process according to the invention compounds of the general formula wherein a) R1 represents hydrogen, a lo¾calkyl group having at most 4 carbon atoms or the phenyl radical, R2 represents hydrogen or the phenyl radical, and R^ represents hydrogen, a bromine atom, a low alkoxy group having at most 4 carbon atoms, or the carboxyl gro p, provided that an( ^3 are no-t ko^*1 hydrogen at the same time, or b) R^ has the same meaning as above and Rg and ^ are both hydrogen, are prepared by replacing in a compound of the formula II (ID - 2 - 28710/2 wherein X represents a chlorine or bromine atom or the mercapto or hydrazino radical, the radical X by hydrogen, and, if required, converting the 1,2,8,9-tetraazaphenalene so obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid, or transforming it with a low allcylating agent into a quaternary ammonium compound.

In compounds of general formula I, the methyl, ethyl, propyl, lsopropyl, n-butyl, isobutyl, sec. utyl and tert. butyl groups as well as the methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, isobutoxy, sec.butoxy and tert.butoxy groups, for example, are understood by low alk l and alkoxy groups respectively.

The compounds of the general formula I are produced from a compound of the general formula II by eliminating therefrom the radical X and replacing said radical X by a hydrogen atom, the elimination being performed in a conventional manner, and converting, if desired, a compound so obtained into an addition salt with an inorganic or organic acid or into a quaternary ammonium salt with an alkylating agent .

Reactive esters of low alkanols and aralkanols can be used as alkylating ¾gents, e.g. methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec.butyl- chloride, -bromide or -iodide, also sulphuric and sulphonic acid esters such as dimethyl sulphate or diethyl sulphate, benzene- or p-toluene- sulphonic acid methyl or ethyl ester, also benzyl chloride or benzyl bromide.

The compounds of the general formula II, wherein X represents a chlorine or bromine atom, are dehalogenated by the combined action of hydroiodic acid and red phosphorus, the reaction being performed at elevated temperatures for at least two hours. Dehalogenation of compounds of the general formula II, wherein X represents a chlorine or bromine atom also occurs when such compounds are treated. with hydrogen in the presence of a heavy metal catalyst, such as palladium, which conveniently is in finely dispersed form on a carrier substance, such as charcoal, and in the presence of an acid binding agent, such as ammonia, the reaction being performed in an inert solvent, e.g. in a low alkanol such as ethanol, until hydrogen-uptake is complete.

During dehalogenation, the radical X is replaced by hydrogen.

The compounds of general formula II wherein X is a chlorine or bromine atom, are produced by heating an oxo compound corresponding to general , formula III wherein R-^, R2 and R^ have the meanings given above and which oxo compound can be in the : tautomeric forms shown, with phosphorus oxychloride or phosphorus pentachloride and phosphorus .oxychloride or phosphorus oxybromide or phosphorus pentabromide and phosphorus oxybromide, until the oxygen funcT r tio is performed by heating to the boiling temperature in excess phosphorus oxychloride or phosphorus oxybromide for 20 or more hours .

The compounds of the general formula II, wherein X represents a chlorine or bromine atom, can also be produced by treating a 1 , 2 , 8, -tetraazaphenalene which is unsubstituted in the 3-position, but otherwise substituted according to the definitions of R- R2 and 3, by treatment thereof with chlorine or bromine in the presence of an alkali salt of acetic acid, e.g. sodium acetate, the reaction being performed in acetic acid-acetic anhydride.

The compounds of the general formula III wherein R-^ and Rg represent hydrogen, can be produced, e.g. from a 3-(α,α-dibromomethyl) -phthalic acid anhydride substituted according to the definition of ^, by reaction with at least double the molar amount of hydrazine or hydrazine hydrate. On treating these compounds with alkylating agents such as alkyl θ*-¾«ίΐ«^·1 halides in the presence of a base, compounds of the general formula III are obtained therefrom wherein R is a low alkyl group and R is hydrogen. 3-(a,a~dibromomethyl) -phthalic acid anhydride can be obtained by brominating 3 -methyl phthalic acid anhydride compounds substituted corresponding to the definition of R^ can be obtained analogously.

Compounds of the general formula III wherein ^ is phenyl and Rj is hydrogen can be obtained, e.g. from the 3-(a, a-dibromo methyl) -phthalic acid anhydrides mentioned above by first hydrolysing these, then reacting the 7 -carboxy-3 -hydroxy-phthal--ides formed with phenyl hydrazine to form the 8-carboxy-2 -phenyl 1 ( 2H) phthalazinones , esterifying these and reacting the 8- - - - the compounds of general formula III wherein is phenyl and R2 is hydrogen., Compounds of general formula III wherein 2 is phenyl and R^ is hydrogen can be obtained by reacting an ester of 8-carboxy-4-phenyl-l(2H)phthalazinone with hydrazine. Thus, for example, 8~carboxy-4-phenyl-l(2H)phthalazinone, M.P. 257-259°, is obtained from the known 3-benzoyl phthalic acid and hydrazine. On using an alkyl or phenyl hydrazine, 8-carboxy-4-phenyl-l ( 2H) phthalazinones correspondingly substituted in the 2-position can be obtained in an analogous way. Esters of 8-carbalkoxy-4«phenyl-1 ( 2H) phthalazinones , e.g. the methyl or ethyl ester, are obtained by esterifying the 8-earboxy-4-phenyl-l ( 2H) phthalazinones . 1 , 2 , 859-Tetraazaphenalenes , wherein R^ and R2 represent hydrogen and has the meanings defined above, can also be obtained, e.g. from 236-dimethyl benzoic acids substituted in e.g. the 4-position corresponding to the definition of R » These are brominated to form the corresponding 2 , 6-(bis-dibromomethyl) -benzoic acids which can be hydrolysed to form the 2 , 6-diformyl benzoic acids or the 7»formyl~3»hydroxy-phthalides which are tautomers thereof, and these can then be converted with hydrazine into the tetraazaphenalenes substituted according to the definition Of Rg.

The compounds, of general formula II, wherein X represents the mercapto group are transformed into compounds of the general formula I by suspending them in an inert solvent and treating them with Raney nickel until desulfuration is substantially complete. An inert solvent such as methylcellosolve is suitable. Small amounts of water in the reaction mixture are The compounds of general formula II, wherein X represents the mercapto group can he prepared, by treating a compound of the general formula III with at least the equimolar amount of phosphorus pentasulphide in a solvent such as pyridine, at a raised temperature until the oxygen function has been replaced by the sulphur function, which also can be in tautomeric forms. These substances containing sulphur are termed mercapto or thiono compounds.

The compounds of the general formula I can further be produced by treating a compcoid of the general formula II, wherein X is the hydrazino radical and R-^, and Rg have the meanings given above under weakly alkaline conditions in an aqueous medium with a copper (II) salt, whereby the radical X is eliminated and replaced by hydrogen. For the elimination pH values of between 7.0 and 8.5 are advantageous. They can be attained by the use of suitable buffer solutions, e.g. phosphate-buffers. A pH range of 7,1 to 7,5 is preferred. As solutions of the copper (II) salts aqueous solutions of copper (II) sulfate, copper (II) nitrate etc. are suitable. The amount of copper (II) salt used is not critical. It has been found that elimination of the hydrazino radical also occurs without the addition of the copper (II) salt if the reaction is carried out at a pH of 7.2.

The compounds of the general formula II wherein X represents the hydrazino radical can be produced starting from a compound of the general formula II, wherein X represents a chlorine or bromine atom or the mercapto group, by reacting such compound with hydrazine in the presence of an acid binding agent. - 7 - 28710/2 The reaction is performed advantageously by heating in the presence of an at least equimolar amount of hydrazine hydrate until the reaction is complete. Higher boiling alcohols such as methyl cellosolve (2-methoxyethanol) or ether-type solvents .such as diethylene glycol dimethyl ether, can be used as solvent.

The reaction is advantageously performed at the boiling temperature for 12 to 48 hours or more.

The products obtained by eliminating the radical X from compounds of the general formula II are bases according to the general formula I, or acid addition salts thereof. These products can be isolated from the reaction mixtures by processes known p,er se and can be converted, by methods also known per se, into their acid addition salts, should they not already be in that form, or into their quaternary ammonium salts.

Some of the compounds of formula I, namely those of the formula (lb) wherein represents a hydrogen atom, an alkyl group containing at most 4 carbon atoms or a phenyl group and R2 represents a phenyl group or, when R^ represents a phenyl group, also a hydrogen atom and the pharmaceutically acceptable acid addition and quaternary ammonium salts thereof, have not been known hitherto. It has been found that these compounds as well as their physiologically acceptable acid addition salts and quaternary ammonium compounds have - 7a 28710/2 The compounds of formula lb above and their physiologi¬ cally acceptable addition salts with inorganic and organic acids can be administered parenterally or orally in any of the usual pharmaceutical forms such as tablets, capsules, powders, suspensions, syrups, etc. Particularly valuable forms for administration are sustained release preparations which can be produced by any of the known processes.

Salts suitable for therapeutic administration are those with pharmacologically acceptable inorganic and organic acids, which salts have no physiological action of their own in the usual dosages. Suitable salts are, e.g. those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, acetic acid, lactic acid, succinic acid, malic acid, maleic acid, aconitic acid, phthalic acid, tartaric acid and embonic ac'id. i According to the rules for nomenclature at present prevailing, the new ring system can be termed (lH)-2,3,4,5 (3H)-2,3,4,5- (1H) -1,2,8, 9- Tetraazaphenalene Tetraazaphenalene Tetraazaphenalene In the following examples the nomenclature shown below. 1,2,8, 9-Tetraazaphenalene which is closely related to the last mentioned system, will be used.

The following examples further illustrate the performance of the process according to the invention but in no way limit the scope thereof. The temperatures are given in degrees Centigrade.

Example 1 1 , 2 ,8, 9-Tetraazaphenalene from 3-chloro-l , 2 ,8 , 9-tetraazaphenalene a) 3-Chloro-l , 2 ,8 , 9-tetraazaphenalene (4.82 g.) is s spended in a mixture of powdered red phosphorus; (4 g) and .47% hydriodic acid (60 ml.) and heated at reflux for 18 hours. The mixture is poured into ice-water, filtered and the filtrate evaporated to dryness in vacuo . The yellow residue, is suspended in hot dilute sodium carbonate solution, cooled and the solid collected and dried. The infrared spectrum of the product is identical to that of an authentic sample of 1 , 2 , 8 , 9-tetraazaphenalene , M.P. 294-298°, prepared as described in Example 13.

The 3-chloro-l , 2 , 8 , -tetraazaphenalene used as starting material was obtained as follows: b) , -Dibromo-3-methylphthalic anhydride A mixture of 3-methylphthalic anhydride (81 g) , N-bromosuccinimide (182 g) , benzoyl peroxide (40 mg) and carbon tetrachloride (1500 ml) is irradiated and heated to reflux by a 100 watt insertion-type ultraviolet lamp under stirring and exclusion of moisture. After the mixture becomes brick red, an additional 40 mg of benzoyl peroxide is added. Illumination at reflux is carried out during 24 hours. The mixture is cooled and filtered free of succinimide and the filtrate is evaporated in vacuo. The residual yellowish brown solid is dissolved in hot ether, treated with decolorizing charcoal and filtered. Addition of hexane to the filtrate affords the crystalline product, M.P. 90.5-93°. Two recrystallizations from ether-hexane yield colorless needles melting at 93-95°. - - c) 3-Hydroxy-l ,2,8 , 9-tetraazaphenalene A suspension of ,a-dibromo-3-methylphthalic anhydride (80 g) in ethanol (500 ml) is treated with a solution of 100 hydrazine hydrate (100 ml) and water (100 ml) dropwise under stirring and cooling. A white suspension forms. After the addition, the temperature is raised gradually to reflux, whereupon the white suspension disappears and a yellow presi-pitate forms. After 88 hours at reflux, the mixture is cooled, filtered and the first crop of product is washed with water and ethanol and dried in vacuo. The mother liquors are evaporated in vacuo, dissolved in 500 ml of glacial acetic acid and heated under reflux for 18 hours. The mixture is cooled and filtered and a second crop of the product obtained.

The crops are combined and the product is recrystallized from 3 litres of boiling dimethylformamide to yield 3-hydroxy-l ,2 ,8,9-tetraazaphenalene as a yellow powder which, on heating, forms a microcrystalline solid at 220-270°, and melts above 350°. d) 3-Chloro-l , 2 ,8 , 9-tetraazaphenalene To a mixture of 9.3 g of 3-oxo-2 , 3-dihydro-l , 2 ,8 , -tetraazaphenalene ( 3-hydroxy-l , 2 , 8 , 9-tetraazaphenalene) and water (10 drops) is added phosphoryl chloride (60 ml) and the mixture heated 20 hours at reflux. The dark solution is evaporated in vacuo to a brown foam. The foam is triturated with ethanol and the resulting yellow solid collected and dried in vacuo. On standing in the cold for 24 hours the ethanol filtrate yields more of the same material, 3-chloro-l , 2 , 8 , 9-tetraazaphenalene hydrochloride as a yellow solid which begins to darken at 200° and finishes decomposing at 270°.

This compound is used for the reaction described under (a).

Example 2 1 , 2 , 8 , 9-Tetraazaphenalene from 3-mercapto-l , 2.8 , 9-tetraazaphenalene a) 3-Mercapto-l ,2 ,8, 9-tetraazaphenalene (4.04 g) is suspended in methyl cellosolve (200 ml) and ethanol (200 ml) and treated with Raney nickel (about 20 g). The mixture is heated for four hours on a steam bath, filtered hot and the filtrate allowed to cool. A small amount of starting material precipitates and is filtered off. The filtrate is evaporated to dryness, taken up in boiling ethanol (500 ml), filtered free of undissolved material and again evaporated. The residue is taken up in hot water (800 ml) , cooled, filtered and evaporated to dryness in vacuo . The substance was identified by thin layer chromatographic analysis as 1 ,2 ,8, 9-tetraazaphenalene , an authentic sample of which was prepared according to example 13. The starting material was obtained as follows: b) 3-Mercapto-l ,2,8.9-tetraazaphenalene ( 3-thiono-2 , 3-dihydro-l ,2,8 , -tetraazaphenalene) A mixture of 3-hydroxy-l , 2 , 8 , 9-tetraazaphenalene (44,14 g) phosphorus pentasulfide (58,2 g) and dry pyridine (356 ml) is heated under reflux for 2.5 hours under stirring and exclusion of moisture. The dark red solution is cooled and poured under stirring into one liter of ice-cold saturated salt solution.

The mixture is stirred for 1 1/2 hours, then filtered and the precipitate washed thoroughly with water and dried at 100° in vacuo. The orange solid of eM.P. 298-320° (dec.) is recrystallized once from methyl cellosolve/water and once from dimethylformarnide water. The powdery solid, 3-mercapto-l , 2 ,8 , 9-tetraazaphenalene melts at 318-322° on a block preheated to 250.

Example 3 1.2 ,8.9-Tetraazaphenalene from 3 -hydrazino-l , 2 , 8 , 9-tetraazaphenalene dlhydrochloride a) 3-Hydrazino-l , 2 , 8 , -tetraazaphenalene dlhydrochloride (28.7 g) is dissolved in water (800 ml) and treated with 10% aqueous cupric sulphate (400 ml). The suspension is heated on the steam bath for 1 hour, during which time gas bubbles are evolved from the mixture. The mixture is cooled and rendered strongly alkaline with 20 sodium hydroxide solution and filtered The dark precipitate is dissolved in 6N hydrochloric acid (2 litres) , filtered and the filtrate evaporated to dryness in vacuo The black residue is suspended in methanol and filtered.

The filtrate yields a precipitate which is collected. Addition of ether to the filtrate gives a second crop of solid. The combined material is suspended in water containing a little hydrochloric acid and treated with gaseous hydrogen sulfide until saturation. The mixture is filtered free of copper sulfide and the yellow filtrate evaporated to dryness in vacuo. The resulting residue is triturated with acetone, and collected by filtration. The precipitate is 1 , 2 ,8 , -tetraazaphenalene hydrochloride, as shown by infrared spectroscopy. The hydrochloride is suspended in 5% sodium carbonate (500 ml) and the yellow solid collected and dried. The infrared spectrum of the yellow crystalline product is identical to that of an authentic sample of 1 , 2 ,8 , 9-tetraazaphenalene .

The 3-hydrazino-l , 2 , 8 , 9-tetraazaphenalene dlhydrochloride used as starting material was obtained as follows: b) A mixture of 3 -hydroxy-1 , 2 , 8 , 9-tetraazaphenalene , M.P./' 3500 (9.3 g) , phosphorous oxychloride (60 ml) and water solution is evaporated to dryness in vacuo to ;a brown foam. The foam is triturated in cold ethanol to produce a yellow, solid which is collected and dried in vacuo . The product decomposes at about 270°. On standing, the ethanolic mother liquor deposits an additional crop of the same material. c) The yellow solid (1=0 g) is suspended in water (15 ml) and 100% hydrazine hydrate (85 ml) and stirred at reflux for 44 hours. The mixture is cooled, the solid collected, washed well with water and dried. The residue is suspended in 2N hydrochloric acid (100 ml) , filtered and the filtrate evaporated in vacuo . The residue consists of crude 3-hydrazino-l ,2 ,8,9-tetraazaphenalene dlhydrochloride which is recrystallised first from water-methanol-conc . HC1 and again from water-cone . HC1 to yield the pure dlhydrochloride, M.P. 245-248° (dec .) .

Example 4 9-Methyl-l , 2 ,8 , 9-tetraazaphenalene from 3-chloro-9-methyl~ 1 ,2 ,8 , 9-tetraazaphenalene a) A mixture of 3-chloro-9~methyl-l , 2 ,8 , -tetraazaphenalene (220 mg) , concentrated ammonium hydroxide (0.4 ml), 10% palladium on charcoal (0.8 g) and ethanol (200 ml) was stirred under a hydrogen atmosphere until no further hydrogen was absorbed. The catalyst was removed by gravity filtration, and the yellow filtrate evaporated to dryness. Thin layer chromatographic analysis of the residue showed identity to 9-methyl-l , 2 , 8 , 9-tetraazaphenalene as prepared according to the procedure of Examples 5 and 6.

In an analogous way, starting from 3-bromo-9-methyl-l ,2,8,9-tetraazaphenalene , 9-methyl-l , 2 , 8 , 9-tetraazaphenalene is obtained by the above procedure.

The 3-chloro-9-methyl-l ,2,8,9-tetraazaphenalene used above was obtained as follows: b) 3-Ghloro- 9 -methyl -1,2,8 , 9-tetraazaphenalene To a stirring mixture of phosphorus, pentachloride (11.25 in phosphorous oxychloride (90 ml) is added 9-methyl-3-oxo-2 , 3-dihydro-l , 2 , 8 , -tetraazaphenalene , and the mixture stirred at reflux under moisture exclusion for 2 hours. A thick yellow precipitate forms. The mixture is poured into ice and basified under stirring and cooling with 20 sodium hydroxide solution. The yellow solid is collected, washed thoroughly with water and dried in a dessicator over phosphorus;, pentoxide The crude material is twice recrystallized from ethanol, charcoal being used in the first recrystallization, to yield pure 3-chloro-9-methyl-l, 2, 8, -tetraazaphenalene, . M.P. 253-255° (dec). c) 9-Methyl -3 -oxo-2.3-dihydro-l ,2,8.9-tetraazaphenalene ( 3 -hydroxy-9 -methyl -1,2,8 , 9-te raazaphenalene) is obtained as follows: To a stirring suspension, of sodium methoxide (0.07 g) in dry dimethyl sulfoxide (100 ml) is added 3-oxo~2 , 3-dihydro-l ,2 , 8 , 9-tetraazaphenalene (1.86 g) , This is stirred at 60° under moisture exclusion until a red solution has formed. This is cooled to 50° : . and methyliodide (1 ml) added The solution darkens, and after 20 minutes, more methyliodide (1 ml) is added and the solution stirred for 125 minutes at 50-60°, The dark solution is poured into ice water (500 ml) containing 0.5 g of sodium bisulfite and 4 ml. of glacial acetic acid. The mixture is cooled overnight and then filtered, washed with water and dried. The yellow solid product is twice recrystallized from methyl cellosolve with the aid of decolorizing charcoal, thereby affording the yellow 9-methyl-3-oxo-2 , 3-dihydro-1 ,2 ,8, 9-tetraazaphenalene , M«P0 289-293°, which is identical to an authentic sample obtained by reaction of 8~carbethoxy~2~ methyl-1 ( 2H) phthalazinone with hydrazine hydrate.

Example 5 9-Methyl-l , 2 , 8 , 9-tetraazaphenalene from 3-chloro-9-methyl -1 ,2 ,8, -tetraazaphenalene A mixture of powdered red phosphorus (10 g) , l% hydriodic acid (150 ml) and 9~methyl-3-chloro-l ,2 ,8,9-tetraazaphenalene (10.8 g) is heated for 20 hours at reflux. The mixture is poured into ice water, filtered and the filtrate evaporated to a small volume. The solution is basified with b% sodium carbonate solution and extracted with chloroform. The chloroform solution is dried over sodium sulfate and evaporated in vacuo. The yellow residue ( 7 „ 5 g) is chromatographed over 300 g of oelm neutral alumina, grade II, with chloroform as eluent. After a 250 ml forerun, a 1500 ml portion of eluent yields 9-methyl-l , 2 , 8 , 9-tetraazaphenalene as yellow solid, M.P. 149-151°. The melting point is unchanged after recrystallization from benzene-hexane and the infrared spectrum is identical to that of the product obtained from 9-methyl-3-thiono-2 ,3-dihydro-l ,2 ,8 , 9-tetraazaphenalene in example 6.

Example 6 9- ethyl-l , 2 , 8 , 9-tetraazaphenalene from 9-methyl-3-thiono-2 , 3-dihydro-l ,2,8, 9-tetraazaphenalene a) 9-Methyl-3-thiono~2 , 3-dihydro-l , 2 , 8 , 9~tetraazaphenalene (1.08 g) is suspended in ethanol (200 ml) and Raney nickel (about 5 g) in .ethanol is added little by little. After addition is complete, the mixture is stirred for one hour on the steam bath and then filtered hot. The filtrate is evaporated in vacuo, taken up in ethanol and again filtered to remove nickel.

Evaporation of the ethanol solution yields a yellow solid. The product is purified by one recrystailization from benzene-hexane . Yellow crystals of 9~methyl~l , 2 , 8 , 9-tetraazaphenalene ,. M.P. 145-147° are obtained.

The 9-methyl-3~thiono-2 , 3-dihydro-l ,2,8, -tetraazaphenalene i s obtained as follows: b) 9-Methyl-3-oxo-2 , 3-dihydro-l , 2 ,8 , -tetraazaphenalene , (9.0 g) is dissolved in dry pyridine (120 ml) and phosphorus pentasulfide (12 g) added under stirring., The whole is refluxed under moisture exclusion for 2-1/2 hours, poured into an ice-salt mixture and stirred for 30 minutes » The yellow solid which forms is collected, washed with water and dried as well as possible in vacuo . The sticky orange solid is recrystallized from methyl cellosolve and yellow crystals are obtained « Two recrystalliz a-tions from methyl cellosolve yield 9-methyl-3-thiono~2 , 3-dihydro-1 ,2 ,8, -tetraazaphenalene which decomposes in the range 299°-316° .

Example 7 9-Methyl-l «2,8, 9-tetraazaphenalene hydriodide 9-Methyl-l ,2 ,8, -tetraazaphenalene (50 mg) is dissolved in Al% hydriodic acid at room temperature and the solution is evaporated in vacuo to a yellow solid. The solid is triturated with ethanol, washed with ether and dried. The product melts with decomposition in the range 247-248°=, Example 8 9-Methyl-l , 2 ,8 , 9-tetraazaphenalene from 3-hydrazino-9-methyl-1 , 2 ,8 , 9-tetraazaphenalene dlhydrochloride a) 3-Hydrazino 9-methyl-l 52 ?8 , 9-tetraazaphenalene dlhydrochloride (60 mg) was suspended in phosphate buffer, pH 1,2 (30 ml) and allowed to stand in the dark for 3 days. The mixture was evaporated to dryness at reduced pressure and the residue triturated with chloroform. The chloroform extract was dried over sodium sulphate and examined by thin layer chromatography. The product was shown to be 9-methyl-l , 2 ,8 , -tetraazaphenalene by comparison with the samples obtained in Examples 5 and 6.

The 3-hydrazino-9-methyl-l , 2 ,8 , 9-tetraazaphenalene dlhydrochloride, used as starting material was obtained as follows: b) 3-Hydrazino-9-methyl-l ? 2 ,8 , -tetraazaphenalene dihydrochloride In a 1-litre flask equipped with reflux condenser and mechanical stirrer is placed 100 hydrazine hydrate (162 ml) and water (60 ml) and the solution heated to 90°. 9-Methyl-3-thiono-2 , 3-dihydro-l , 2 ,8 , -tetraazaphenalene is added and the mixture stirred 20 hours at reflux. The mixture is filtered hot to remove some red solid and the filtrate evaporated in vacuo „ The residual yellow solid is taken up in 3N hydrochloric acid (400 ml) , filtered to remove insoluble yellow solid and evaporated to dryness in vacuo. The residue is dissolved as well as possible in water and refiltered. Evaporation of the filtrate in vacuo yields crude 9-methyl-3-hydrazino-l ,2 ,8,9-tetraaza-phenalene dlhydrochloride as a pale yellow solid residue,, This is further purified by dissolution in water (50 ml) and ethanol (50 ml) and treatment at 70° under mechanical stirring with benzaldehyde (15 ml) in ethanol (50 ml) « After several minutes water (25 ml) is added, followed by IN sodium bicarbonate (100 ml) and the mixture is stirred for .5 minutes at 70° „ More IN sodium bicarbonate is added and the mixture stirred for 10 minutes at reflux., The mixture is cooled and the orange precipitate collected, washed with water and treated with boiling excess 2N hydrochloric acid under stirring until no odor of benzaldehyde remains and a clear yellow solution is obtained (ca. 5 hours). The solution is cooled, filtered through sintered glass and the filtrate evaporated to dryness in vacuo . The residual solid is thoroughly dried in a desiccator under vacuum over phosphorus pentoxide and then recrystallized from methanol-ether . A second recrystallization from methanol-ether yields 3-hydrazino-9-methyl~l , 2 ,8 , 9-tetraazaphenalene dihydro-chloride as pale yellow crystals which decompose with gas evolution at about 260° „ Example 9 9-Methyl-l .2 ,8 , 9 -tetraazaphenalene methiodide A mixture of 9-methyl-l ,2 ,8 ,9-tetraazaphenalene (1,9 g) ? methyl iodide (8 ml) and absolute methanol (140 ml) is heated at. re lux for 25 hours* The solution is cooled, treated with dry ether and the precipitate collected. Three recrystallizations from methanol-ether yield the yellow 9-methyl-l , 2 ,8 , -tetraazaphenalene methiodide, MSP„ 207-208.59 Example 10 9-Phenyl-l<,2,8.9-tetraazaphenalene from 3-chloro-9~ phenyl-l , 2 ,8 ,9-tetraazaphenalene a) A mixture of 3-chloro-9~phenyl-l , 2 ,8 ,9-tetraazaphenalene (280 mg) concentrated ammonium hydroxide (0 = 4 ml), 10 palladium on charcoal (0,8 g) and ethanol (200 ml) was shaken in an atmosphere of hydrogen until no further hydrogen uptake was observed. The mixture was filtered and the filtrate concentrated to dryness. Analysis of the residue by thin layer chromatography showed identity to an authentic sample of 9-phenyi-l,2,8,9-tetraazaphenalene of M.P, 168.5--1700 , prepared according to Example 11.

The 3-chloro-9-phenyl-l , 2 ,8 ,9-tetraazaphenalene used as starting material was obtained as follows: b) To a stirring mixture of phosphorus pentachlor ide (6-3 g) in phosphorus oxychloride (40 ml) is added 7.8 g of finely powdered 3~oxo- -phenyl-2 , 3-dihydro-l ,2 ,8 , -tetraaza-phenalene, M.P. 255-257°. The mixture is stirred at reflux for 165 minutes under moisture exclusion and then poured cautiously into ice. The mixture is made alkaline under cooling with 20% sodium hydroxide solution and the fine yellow precipitate which forms is collected and washed with water. As this material still contains inorganic solid, it is stirred for 1/2 hour in 600 ml of warm (50°) water and again filtered. The precipitate is re-crystallized from ethanol and yields yellow crystals, M.P. 225-228°, of 3-chloro-9-phenyl-l,2,8,9-tetraazapherialene.

The 3-oxo-9-phenyl- 2, 3' . --dihydro-1 , 2 ,8 , S-tetraazaphenalene ;· is prepared as follows: c) . . . , a-Dibromo-3-methylphthalic anhydride (Μ„Ρ. 90„5-93°i 40 g), is added little by little to a hot solution of 2N sodium hydroxide (50.0.ml) under stirring „ After ten minutes, the clear solution is acidified strongly with concentrated hydrochloric acid and heated for one-half hour at 80° = The solution is evaporated to dryness in vacuo and the residue is dissolved in hot water (600 ml) , treated with decolorizing charcoal and filteredo After three days at 5C , the filtrate yields colorless blocks of 7-carboxy»3-hydroxyphthalide , M„P, 163 -166°.:. After two further crystallizations from water the M„P. d) A mixture of phenylhydrazine (3,6 ml), 7-carboxy-3-hydroxyphthalide (5„82 g) and glacial acetic acid (100 ml) is heated under reflux for 18 hours. The clear solution is evaporated to dryness in vacuo and the residual solid triturated with methanol and collected. The product, M„P= 197 - 199°, is recrystallized from benzene yielding colorless 8™-carboxy~2™ phenyl-l(2H) phthalazinone 5 M.P, 197-198° . e) To a solution of thionyl chloride (40 ml) in chloroben-zene (150 ml) is added under stirring 8-carboxy-2-phenyl-l ( 2H) phthalazinone (24,3 g) and the mixture heated at reflux under moisture exclusion for 2 hours. When the evolution of gas has ceased, the solution is evaporated to dryness in vacuo, The residual white solid (24„7 g) is treated with absolute ethanol (350 ml) and heated under reflux for 18 hours, The solution is filtered hot and allowed to cool slowly, whereupon 8-carbethoTcv 2-phenyl-l( 2H) phthalazinone precipitates in colorless needier-,, M„P. 150-151°, unchanged upon recrystallization from ethanol, f) A mixture of 8-carbethoxy-2-phenyl-l ( 2H) phthalazinone (11.76 g) , 1.00$ hydrazine hydrate (40 ml) and methyl cello-solve (160 ml) is heated at reflux for 25 hours. The yellow solution is filtered and treated with methanol (100 ml) followed by water dropwise under stirring . A flocculent yellow precipitate forms. The mixture is cooled and the product collected, washed thoroughly with water and ethanol and dried . in vacuo . The solid, M.P, 254-256°, is recrystallized from methyl cellosolve yielding 3-oxo-9-phenyl-2 , 3 -dihydro-1 , 2 ,8 ,9-tetraazaphenalene as yellow needles, M.P. 255-257°.

Example 11 9-Phenyl~l , 2 ,8 ,9-tetraazaphenalene Powdered amorphous red phosphorus (6,5 g) is suspended in 47% hydr iodic acid (65 ml) and to this is added 3-chloro-9-phenyl-l,2,8,9-tetraazaphenalene (9»Q g)„ The mixture is stirred at reflux for 18 hours and then poured into ice-water and filtered. The filtrate is basified with 5% sodium carbonate and extracted with chloroform » The chloroform extract is dried over sodium sulfate and evaporated in vacuo. The residual solid is recrystallized from benzene with the aid of decolorizing charcoal. A first crop cf yellow crystals is obtained Addition of hexane to the mother liquor causes precipitation of a second crop of solid. The crops are combined and recrystallized from benzene which yields pure 9-phenyl-1 , 2 ,8 ,9-tetraazaphenalene as yellow needles, MoP, 168,5 - 170°, Example 12 7 -Phenyl-! .2 „8.¾ 9 -tetraazaphenalene from 3-chloro-7-phenyl-1 , 2 ,8 , 9-tetraazaphenalene a). A mixture of 3 ~chloro»7-phenyl--l , 2 ,8 , 9-tetraazaphenalene (200 mg) , conecn,^--e4 ammonium hydroxyde (0,4 ml), 10% palladium on. charcoal (0.8 g) and ethanol (200 ml) was stirred in an atmosphere of hydrogen until no further hydrogen was absorbed. The catalyst was. removed by gravity filtration and the filtrate evaporated to dryness » Thin layer chromatographic analysis of the residue showed identity to authentic 7-phenyl-l , 2 ,8 ,9-tetraazaphenalene as prepared according to Example 14» The starting material, 3-chloro-7-phenyl-l,2,8,9-tetraazaphena~ lene, was prepared as follows; b) A mixture of 3-oxo-7-phenyl-2 ,3-dihydro-l,2 ,8,9-tetra-azaphenal.ene (5 g) , phosphoryl chloride (27 ml) and phosphorus pentachloride (4 g) was heated at reflux under moisture exclusion- The mixture was evaporated at reduced pressure to a small volume, taken up in acetone and poured into ice-water. The precipitate which formed was collected, washed with cold water . and dried. The product, 3-chloro-7-phenyl-l , 2 ,8 ,9-tetraazaphenalene 5 melted in the range 278-288°. The 3-oxo compound used in this process was prepared as follows: c) A mixture of 8-carbomethoxy-4-phenyl-l( 2H) hthalazlnone (18.6', g) , hydrazine hydrate (400 ml) and water (100 isI) was heated at reflux for 20 hours. The mixture was cooled and the precipitate collected, washed with water and recrystallized from methyl cellosolve to give pure 3-oxo--7-phenyl-2,3~dihydro~ 1 , 2 ,8 , -tetraazaphenalene melting above 350°« The 8~carbomethoxy-4«phenyl-l ( 2H) -phthalazlnone used as star ing d) 3-Benzoylphthalic acid (32.5 g) , hydrazine hydrate (85 ml.) and. wate (145 ml) .were heated at reflux , for 18 hours.

The mixture was cooled and acidified with hydrochloric acid.

The product which precipitated was recrystallized from glacial.. . acetic acid to afford pure 8-carboxy-4-phenyl-l (2H) phthalazin-one, M.P. 257-259°, e) A mixture of 8-carboxy-4-phenyl-l(2H)phthalazinone (19.0 g) thionyl chloride (32 ml) and chlorobenzene (115 ml) was stirred at reflux under moisture exclusion for three hours. The solution was concentrated at reduced pressure to give a white solid which was taken up in methanol (300 ml) and heated at reflux for 18 hours. The mixture was cooled and gave 8-carbomethoxy-4-phenyl-l(2H)phthalazinone, M.P. 198-202° ,which was collected and used directly in step (c) .

Example ¾r4 7-Phenyl-l , 2 ,8 , 9 -tetraazaphenalene a) 3-Hy.droxy-3-phenYl-7-dibromomethylphthalide 3-Hydroxy-3-phenyl-7~methylphthalide ( 2-benzoyl-6~ methyl-benzoic acid, (M.P. 124-126°) (2«4 g) is suspended in carbon tetrachloride (200 ml) in a 500 ml 3 -necked flask equipped with mechanical stirrer and two reflux condensers with drying tubes. A mixture of N-bromo-succinimide (3.5 g) and benzoyl peroxide (0,1 g) is added and the mixture stirred at reflux under illumination from a 250 watt tungsten lamp. After 3 hours, more benzoyl peroxide (0.05 g) is added and the mixture stirred at reflux overnight, The mixture is filtered hot to remove most of the succinimide and the filtrate evaporated in vacuo . The brownish-white residue is recrystallized from benzene-hexane and buff-coloured blocks are obtained.

Recrystallization of this product from benzene-hexane gives a melting point of 166-170° „ The once recrystallized material is suitable for further reactions. b) 3-Hydroxy-7-benzoylphthalide 3-Hydroxy-3-phenyl-7-dibromomethylphthalide (2.0 g) is added to a stirring solution of 5% sodium carbonate (300 ml) at about 80°. After one hour, the mixture is filtered hot and the clear filtrate cooled to 0-5° and acidified with concentrated hydrochloric acid. The mixture is refrigerated three hours and the white precipitate collected, washed with water and dried. The product is twice recrystallized from benzene-hexane and a constant melting point of 109-111° is obtained. c) 7-Phenyl-l , 2 ,8 ,9-tetraazaphenalene To a solution of 100% hydrazine hydrate (10 mi) in and. the mixture stirred at reflux for 112 hours. At first a white precipitate forms but this gradually changes to a yellow precipitate „ The mixture is filtered hot and yellow precipitate collected and dried. The crude product is recrystallized from ethanol to yield bright yellow needles of 7-phenyl-l, 2 ,8, 9-tetraazaphenalene, M„P, 292-293 The salt, 7-phenyl-l, 2,8, 9-tetraazaphenalene methane sulfonate , has a M„ P. of 256-257, 5° . !4 Example jr¾ 3-Bromo -9 -methy1-1 ,2 ,8 , 9 -tetraazaphenalene To a solution of 368 mg of 9-methyl-l,2,8,9-tetraaza-phenalene, M.P, 145-147°, anhydrous sodium acetate (165 mg) and glacial acetic acid (25 mi) was added dropwise under stirring bromine (320 mg) in glacial acetic acid (25 ml) and the solution stirred for 18 hours. The mixture was poured into water, filtered and the filtrate concentrated to dryness. The residual solid was triturated with warm water and filtered,, The precipitate was recrystallized from ethanol to afford 3-bromo-9-methyl-1,2,8, 9-tetraazaphenalene, M„P. 237-238°. 9-Methyl-l ? 2 ,8 , -tetraazaphenalene may be prepared, for example, by de sulphurisa-tion of 9-methyl-3-thiono-2 , 3-dihydro-l ,2,8 , 9 --tetraazaphenalene with Raney nickel in ethanol.

Example ί 1k- Using the procedure described in Example l-§, there is obtained in an analogous manner: a) 3-bromo-5-methoxy-l , 2 ,8 ,9-tetraazaphenalene from 5- methoxy-1, 2,8, -tetraazaphenalene , M.P. 291-294° b) 3 , -dibromo-l , 2 ,8 , 9-tetraazaphenalene from 5-bromo- 1 , 2 ,8 , 9 -tetraazaphenalene , M. P., >350° ; c) 3-bromo--5-n-butoxy-l , 2 ,8 ,9-tetraazaphenalene from 5-n- butoxy-1 , 2 ,8 , -tetraazaphenalene , M.P. 229-237°; d) 3-bromo-5-carboxy--l , 2 ,8, 9-tetraazaphenalene from 5- carboxy-1, 258, -tetraazaphenalene, M.P. 340°, or its sodium salt.

Example irf- Using the procedure described in Example 1(a) , there is obtained in an analogous manner: a) 5-bromo-l, 2,8, 9-tetraazaphenalene , M„ P„'_ 350° , from 3 , 5-dibromo-l ,2,8 , 9-tetraazaphenalene ; b) 5-carboxy-l , 2 ,8 , 9-tetraazaphenalene , M,P. approx. 340°, from 3-bromo-5-carboxy.-l , 2 ,8 , -tetraazaphenalene « The product is isolated from the filter residue obtained after adjusting the reaction mixture to pH approx „ , n Example Wr Using the procedure described in Example 10(a), there is obtained in an analogous manner: a) 5-methoxy-l, 2,8, 9-tetraazaphenalene, M. Po 290-292°, from 3-bromo-5-methoxy-l , 2,8, 9-tetraazaphenalene 5 b) 5-n-butoxy-l, 2,8, 9-tetraazaphenalene, M0P. 231-235°, from 3-bromo-5-n-butoxy-l ,2,8 , 9-tetraazaphenalene <, 31 - 32 - 28710/3

Claims (1)

1. CLAIMS 1. Process for the production of 1,2,8,9-tetraazaphenal-enes of the formula I wherein a) R^ represents hydrogen, a low alkyl group having at most 4 carbon atoms or the phenyl radical, R£ represents hydrogen or the phenyl radical, and represents hydrogen, a bromine atom, a low alkoxy group having at most 4 carbon atoms, or the carboxyl group, provided that ≥ and ^ are not both hydrogen at the same time, or b) ^ has the same meaning as above and 2 and are both hydrogen, are prepared by replacing in a compound of the formula II wherein X represents a chlorine or bromine atom or the mercapto or hydrazine radical, the radical X by hydrogen, and, if required, converting the 1,2,8,9-tetraazaphenalene so obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid, or transforming - 33 - 28710/2 it with a low alkylating agent into a quaternary aiamonium compound. 2o A process as claimed in Claim 1 a) in which a l,2, - i 8,9-tetraazaphenalene of formula II, wherein X represents chlorine or bromine, is reduced. 3. A process as claimed in Claim 2 wherein the reducing agent is hydriodic acid. 4» A process as claimed in Claim 2 wherein the reducing agent is catalytically activated hydrogen* 5. process as claimed in Claim 1 a) in which a 1(¾- , 8,9-tetraa2aphenalene of formula II, wherein X represents the mercapto radical, is treated with activated nickel. 6· A process as claimed in Claim 1 a) in which a 1,2,8,9-tetraazaphenalene of formula II, fherein X represents the hydrazino radical, is treated with an aqueous solution having a pH of from 7 to 8e5 in the presence of a copper (II) salt. 7· A process as claimed in Claim 6 wherein the pH range is from 7.1 to 7.5. 8. A process as claimed in Claim 7 wherein the pH is substantially 1,2. 9. Process for the production of l,2,8,9->tetraaza-phenalenes of the formula la - 34 - 28710/" wherein represents hydrogen, a low alkyl group having at most 4 carbon atoms or the phenyl radical, comprising eliminating from a compound of the formula Ila wherein X represents a chlorine or bromine atom or the mercapto or hydrazo radical, the radical X, and replacing it by hydrogen by methods known in the literature, and, when required, converting the I , 2 , 8 , 9-tetraazaphenalene so obtained into a pharmaceutically acceptable addition salt with an inorganic or organic acid, or transforming it in the known way with a low alkylating agent into a quaternary ammonium compound. 10. A process as claimed in claim 9 in which a 1 , 2 , 8 , 9-tetraazaphenalene of formula Ila wherein X represents chlorine or bromine, is reduced. II. Λ process as claimed in claim 10 wherein the reducing a .ont is hydriodic acid.and red phosphorus . 28710/2 - 35 - 12. A process as claimed in claim 10 wherein the reducing agent is catalytically activated hydrogen. 13. A process as claimed in claim 9 in which a 1 , 2 , 8 , 9-tetraaza phenalene of formula I¾ wherein X represents the mercapto radica is treated with activated nickel. 14. A process as claimed in claim 9 in which a 1 , 2 , 8 , 9-tetraaza phenalene of formula 13a, wherein X represents the hydrazino radical, is treated with an aqueous solution having a pH of from 7 to 8.5 in the presence of a copper (II) salt. 15. A process as claimed in claim 14 wherein the pH range is from 7.1 to 7.5. 16. A process as defined in claim 15 wherein the pH is substantially 7.2. 17. A process as defined in claim 9 substantially as herein before described with reference to any one of Examples 4, 8, 10, 12 and 14. ss as defined in claim la)substantially as herein bed with reference to any one of Examples 1 to 3 , 5 to T9. A 1,2,8,9-tetraazaphenalene having the formula I as defined in claim la) whenever prepared by a process as claimed in any one of claims 1 to 8 or 18. ?0. A 1,2,8,9-tetraazaphenalene having the formula la as defined in claim 9, whenever prepared by a process as claimed in any one of claims 9 to 17. 20.8.1971/HFO/FK - 36 - 28710/2 PC/rb