IL28709A - Process for the preparation of 1,2,8,9-tetraazaphenalenes and new 1,2,8,9-tetraazaphenalenes - Google Patents

Description

28709/2 D' J^SJSKTS-KTBB-"? ,8 ,2 ,1 "US' Τ"7ΠΓ1 D'WTn D ' 3 K3BKTK-M"1BB- ,8 , 2 , 1 — 1 Process for the preparation of 1,2,8, tetraazaphenalones and new 1,2,8,9~ tetraazaphenalenes J.E. GEIGY A.G. - la - 28709/2 The present invention relates to a process for the preparation of substituted 1,2,8,9-tetraazaphenalenes, xheir addition salts "with inorganic or organic acids, and their quaternary aiamonru salts.

According to the invention compounds of the general formula wherein represents the hydrazino or phenylhydrazino radical or an amino group of the formula wherein F represents hydrogen, a low alkyi group, a mononuclear aryl or aralkyl radical the aromatic nuclei of which may be chloro-, fluoro-, bromo- or alkyl-substituted; or Rg has the sa:ne meaning as R^- except that it may not "be hydrogen or and Kg, logether with the adjacent nitrogen atom, represent a heterocyclic radical having 5 to 7 ring members and containing 4 to 6 carbon atons, which radical may contain an oxygen atom or another nitrogen atom in its ring, and may also be fused with a mono-nuclear aromatic carbocyclic ring optionally chloro-, fluoro-, bromo- or - 2 - 28709/2 low alkyl substituted, R2 represents hydrogen or a lower alkyl phenyl or benzyl group, represents hydrogen or the phenyl group, and represents hydrogen, chlorine, fluorine or bromine as well as their acid addition salts and quaternary aiononiua salts are produced by reacting compound of the general formula wherein Y represents a chlorine or bromine atoi or the mercapto group, and R , R and R. have the meanings given above, with hydrazine, phenyl hydrazine or . amine of formula IV wherein and Kg have the meanings given above, the reaction being performed in the presence of an acid binding agent, and if desired, converting a compound so obtained into an addition salt with an inorganic or organic acid or into a quaternary ainmonium salt with an altylating agent.

Reactive esters of low alkanola and araikunolj can be used as alkylating agonto, e.g. iacthyl-» ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, soc. butyl- chloriae, - 3 - 28709/3 provided that when hydrazine is employed Y may not represent a mercapto group if R^, and simultaneously represent hydrogen atoms, and Y may not represent a chlorine atom if R2 represents a phenyl group and and ^ simultaneously represent hydrogen atoms.

Reactive esters of low alkanols and aralkanols can be used as alkylating agenxs, 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 bcm/.yl bromide.

In the compounds of general formula I, the methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. butyl and tert.butyl groups, for example, are understood by low alkyl .

The optionally substituted aryl and aralkyl radicals of formula II are carbocyclic and mononuclear and can contain up to two nuclear substituents. In addition, the aralkyl radicals can contain 1 to 4 carbon atoms in their alkylene member. ' These or aryl radicals occurring in aralkyl radicals can be: phenyl, (o,m,p)-fluorophenyl, (o,m,p)-chlorophenyl, (o,m,p)-bromo henyl, difluorophenyl , dichlorophenyl , dibromo henyl, (o,m,p)-tolyl and dimethyl-phenyl. The alkylene member in the aralkyl radicals can be linear or branched; methylene, ethylene, 1- and 2- 'methy1-ethylene, or propylene, trimethylene , 1,2-butylene, 1,3-butylene, 1,4-butylene can he mentioned. - 4 - 28709/2 Examples of heterocyclic radicals having 5 to 7 rin^ members and containing 4 to 6 carbon toms are pyrrolidine, piperidino, hexame h leneimino, morpholino and piper-azinyl-1 radicals which c an contain at most 2 methyl s bstitu ents. The phthalimido radical and the 1, , 3>4-tetrahydro-isotiuinolin-2-yl radical are examples of heterocyclic radicals as defined above which have a fused, -aoncnuclear aromatic ring,.

The reaction of compounds of general formula III wherein Y is a chlorine or bromine atom, or of their acid addition salts with hydrazine or phenyl hydrazine is performed advantageously by heating them in the presence of an at least equi-molar amount of hydrazine hydrate or phenyl hydrazine until the reaction is complete. There is no necessity for the use of an inert solvent when the amount of hydrazine compound used in the reaction is sufficient to attain the desired consistency of the reacting mixture. However, also high or higher boiling alcohols such as methyl cellosolve ( 2-methoxyethano) or ether-type solvents such as diethylene glycol dimethyl ether, can be used as solvent. In order to attain good yields, the reaction is advantageously performed at the boiling temperature for 12 to 8 hours or more.

When higher boiling amines of general formula IV are used such as morpholine, the compounds of general formula III are advantageously reacted : in excess amine, which also serves as solvent; the reaction is performed at reflux temperature for 20 to 72 hours „ Such amines, however, can also be used together ith Inert solvents c When lower boiling amines are used, the reaction can be performed in solvents, optionally under increased pressure. The reaction conditions are not particularly critical.

Compounds of the general formula III wherein Y is the mercapto group are heated with at least the equlmolar amount of hydrazine compound or amine of the general formula IV until the reaction is complete. The reaction can be performed in aqueous or alcoholic medium, eog0 in ethanol, 2-methoxy-ethanol or diethylene glycol, or also in diethylene glycol dimethyl ether; it is performed at the boiling temperature for l6 to 8 hours or more. The hydrazine compound can also be reacted be performed under increased pressure „ Basic products of the general formula I or their acid addition salts are obtained in the reaction described of compounds of the general formula III. These products can be isolated from the reaction mixtures formed by processes known per 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.

The compounds of general formula III wherein Y is a chlorine or bromine atom, are produced by heating an oxo compound corresponding to general formula V H wherein R2, R^ and R^ have the meanings given above and which oxo compound can be in the tautomeric forms shown, with phosphorus oxychloride or phosphorus pentachlor ide and phosphorus oxychlorlde or phosphorus oxybromide or phosphorus pentabromide and phosphorus oxybromide, until the oxygen function has been replaced by chlorine or bromine. The reaction is performed by heating to the boiling temperature in excess phosphorus oxychloride or phosphorus oxybromide for 20 or more hours.

The compounds of general formula III wherein Y is the general formula V 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.

Also, compounds of the general formula III can be obtained from those of general formula VI wherein R2, R^ and R^ have the meanings given above, by treating them with chlorine or bromine in the presence of an alkali metal salt of acetic acid, e.g. sodium acetate, in glacial acetic acid-aceticanhydride.

Compounds of the general formula VI wherein R2 and R^ are hydrogen, can be obtained, e.g. from 2,6-dimethyl benzoic acids substituted in the -position corresponding to the definition of R^„ These are brominated to form the corresponding 2,6- (bis-dibromomethyl)-benzoic acids which can be hydro-lysed to form the 2,6-diformyl benzoic acids or the 7-?ormyl-3-hydroxy-phthalides which are tautomers thereof, and these can then be converted with hydrazine into the tetraa^aphenalenes substituted according to the definition of R^ which are embraced halogenate tetraazaphenalenes . Thus, for example, U-bromo- or -chloro- tetraazaphenalene , both of which are embraced by general formula VI, are obtained, e.g. from tetraazaphenalene with N-bromosuccinimide or N-chlorosuccinimide in a strongly acid medium.

Compounds of the general formula V wherein and represent hydrogen, can be produced, e.g. from a 3- ( a, -dibromo- methyl) -phthalic acid anhydride substituted according to the definition of R^, by reaction with at least double the molar amount of hydrazine or hydrazine hydrate. On treating these compounds with alkylating agents such as alkyl or benzyl halides in the presence of a base, compounds of the general formula V are obtained therefrom wherein Rg is a low alkyl group or the benzyl 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 ^ can be obtained analogously.

Compounds of the general formula V wherein Rg Is phenyl and R^ is hydrogen can be obtained, e.g. from the 3- (a, -dibromo- methyD-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- l(2H)phthalazinones , esterifying these and reacting the 8- carbalkoxy-2-phenyl-l( 2H)phthalazinones with hydrazine to form 1 the compounds of general formula- V wherein Rg Is phenyl and R^ is hydrogen.

Compounds of general formula V wherein R^ is phenyl and R^ is hydrogen can be obtained by reacting an ester of 8-carboxy- -phenyl-l(2H)phthalazinone with hydrazine. Thus, for example, - 9 - 28709/3 from the known 3-benzoyl phthalic acid and hydrazine. Un using an alk l or phenyl hydrazine, 8-carboxy-4-phenyl-l(2H) phthalazinones correspondingly substituted in t«.e 2-pooition can be obtained in an analogous way. Esters of 8-carbaikoxy-4-phenyl-l( 2H)phthalazinones, e.g. the m thy1 or ethyl ester, are obtained by esterifying the 8-carboxy-4-phenyl-l(2K) phthalazinones.

The compounds of formula I are new. The.se new compounds and their acid addition and quaternary ammonium salts have valuable pharmacological properties. In animal trials, they reduce the blood pressure. They also manifest coronary and peripheral vascular dilation properties; in addition, effects on the central nervous system have been observed. These properties distinguish the nev compounds and their salts as cardiovascular agents, in articular as anti-hypertensives which can be used for the treatment of h ertension. They 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.

Halts suitable for therapeutic administration are those with pharmacologically acceptable inorganic and organic acids, whicn 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 acid.

Acc n t e e (1H) -2,3S4?5- (3H)2?3?4,5- (1H)132,859-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 ¾am le 1 3-MorDho1ino-1 , 2 T 8 T 9- etraazaphenalene a) To a mixture of 9.3 g of 3-<2}m-2?3-dihydro-l , 2 , 8, 9-tetraaza-phenalene ( 3-hydroxy-l , 2 , 8, 9-tetraazephenalene) 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 hydrochloride more of the same material , 3-chloro-l , 2 , 8, -tetraazaphenalene/; as a yellow solid which begins to darken at 200° and finishes decomposing at 270°. b) This yellow solid (12.05 g.) is suspended in morpholine (100 ml.) and heated for 48 hours at reflux. The resulting dark solution is poured into ice-water. The yellow precipitate which forms is collected, dried and triturated with chloroform (r-500 ml.). The chloroform mixture is filtered free of -impurity and evaporated to dryness in, vacuo . The residual solid is recrystallized from ethanol yielding 3-morpholino-l, 2 , 8, 9-tetraazaphenalene, M.P. 277-280° „ The starting material used in this procedure, 3-oxo-2?3 dihydro-ls 2 , 8, -tetraazaphenalene ( 3-hydroxy-l, 2, 8, 9-tetra-azaphenalene) is prepared as follows: c) A mixture of 3-methylphthalic anhydride (81 g.)? N-bromo-succinimide (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 red3 an additional 40 ml. 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 va uo . The residual yellowish brown solid is dissolved in hot ether, treated with decolorizing charcoal and filtered. Addition of hexane to the filtrate affords crystalline a, a-dibromo-3-methylphthalic anhydride. Two recrystallizations from ether-hexane yield colorless needles melting at 93-95°C„ d) A suspension of a, -dibromo-3-methylphthalic anhydride (80 g.) in ethanol (500 cc . ) is treated with a solution of 100% hydrazine hydrate (100 cc.) and water (100 cc.) 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 precipitate 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 same product obtained. The two crops are combined and recrystallized from 3 liters of boiling dimethyl-formamide yielding 3-oxo-293-dihydro-l, 2 ? 8, 9-tetraazaphenalene ( 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°C.

Exam le 2. 3-PiPflridino-l. ? ? 8? 9-t'etraazaphenalene 3-Hydroxy-l , 2 , 8, 9-tetraazaphenalene is converted to 3- chloro-1, 2 , 8, 9-tetraazaphenalene hydrochloride as described ' in fixample la; >:' , The chloro compound (12.05 g„) is added to a solution of piperidine (20 cc.) in methyl cellosolve (100 cc . ) and the mixture heated for 24 hours under reflux. The whole is evaporated to incipient dryness, treated with water (150 cc.) and the mixture filtered. The precipitate is taken up in hot chloroform and filtered. The resulting precipitate is set aside The filtrate is evaporated to-'dryness in vacuo and the residue recrystallized from ethanol. The product (M.P. 252-254°) is purified by two additional crystallizations from ethanol follow ed by a recrystallization from chloroform, yielding 3-piperi- dino-1, 2, 8, 9-tetraazaphenalene, M.P. 255-256.5°. ¾am le 3 3-Pvrrolidino-l , ? .8, 9-tetraazaphenalene A mixture of 3-chloro-l, 2, 8, 9-tetraazaphenalene (24.1 g.), methyl cellosolve (200 ml.) and pyrrolidine (40 ml.) was heated at reflux for 24 hours. The mixture was filtered hot and the filtrate evaporated to dryness at reduced pressure. The residue was triturated with water and the precipitate collected and dried. This material was recrystallized from ethanol to give 3-pyrrolidino-l52,8,9-tetraazaphenalene, M.P. 253-255°.

.Example 4 3-(ΐ,2?3; 4-te†,rahvdroisoquinolin-2-vl) -1, 2 T 8f 9-tetraazaphenalene A mixture of 1, 2 , 3 , 4-tetrahydroisoquinoline (18 ml.), methyl cellosolve (100 ml.) and 3-chloro-l, 2, 8, 9-tetraazaphenalene (12.05 g.) was stirred at reflux for 44 hours. The mixture was filtered and the filtrate concentrated to dryness at reduced pressure. The residue was purified by recrystallization from ethanol and gave 3-(l, 2 , 3 , 4-tetrahydroisoquinolin-2-yl) -■ 1,2, 8, 9-tetraazaphenalene, M.P. 224-228°.

Example 5 3-Hvdrazino-l., 2T8:9-tetraazaphenalene dihydrochloride a) A mixture of 3-hydroxy-l , 2 , 8, 9-tetraazaphenalene , M.P. >350° (9.3 g.), phosphorous oxychloride (60 ml.) and water (10 drops is heated under reflux for 20 hours. The dark 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 deposit an additional crop of the same material. b) 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 dihydrochloride tetraazaphenalene/which is recrystallised first from water-methanol-concentrated HCl and again from water-concentrated HCl to yield the pure dihydrochloride, M.P. 245-248° (dec) .

E am le 6 3-chloro-9-methvl-lr 2T 8, 9-tetraazaphenalene (7 -Chloro-1-methyl-1, 2, 8, -tetraazaphenalene) To a stirring mixture of phosphorous pentachloride (11.25 g. in phosphorous oxychloride (90 ml.) is added 9-methyl-3-oxo- 2, 3-dihydro-l, 2, 8, 9-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 phosphorous 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, 9-tetraazaphenalene, M.P. 253-255° (dec).

The starting material, 9-methyl-3-oxo-2 , 3-dihydro-l , 2 , 8, 9-tetraazaphenalene (3-hydroxy-9-methyl-l, 2 , 8, 9-tetraazaphenalene, 7 -hydroxy-l-methyl-1, 2, 8, 9-tetraazaphenalene) is obtained as follows: b) To a stirring suspension of sodium methoxide (0.07 g.) in dry dimethylsulfoxide (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°C. 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°C. 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.P. 289-293°, which is identical to an authentic sample obtained by reaction of 8-carbethoxy-2-methyl-l(2H)phthalazinone, with hydrazine hydrate.

Ex mple 7 9-Methvl-3-Morpholino-l, 2.8, 9-tetraazaphenalene A mixture of morpholine (100 ml.) and 3-chloro-9-methyl-1 , 2 , 8, 9-tetraazaphenalene (10.95 g., 0.05 mole) is heated under reflux for 22 hours. The morpholine is removed by evaporation in vacuo and the yellow residue triturated with water and filtered. The precipitate is combined with material obtained from a smaller run (0.01 mole scale) and recrystallized twice from ethanol. The product melts in the range 219-222°. The methane sulphonate salt was obtained as follows: 9-Methyl-3-morpholino-l, 2, 8, 9-tetraazaphenalene (10.9 g.) was added to a solution of methanesulphonic acid (4 ml.) in methanol (30 ml.). After 15 minutes, the solution was treated with dry ether, whereupon the salt precipitated. It was collected, washed with ether and dried, M.P. 233-235°.

Example 8 9-Methvl-3-morpholino-1.2T8.9-tetraazaphenalene a) A mixture of 3-bromo-9-methyl-l,2,8,9-tetraazaphenalene (50 mg'.), morpholine (1 ml.) and methyl cellosolve (5 ml.) was heated at reflux for 20 hours. The solution was concentrated to a solid residue at reduced pressure and the residue triturated with water and filtered. The product was dissolved in dilute hydrochloric acid, filtered and the filtrate basified with sodium carbonate. The product precipitated from solution and on recrystallization from water, and was shown by its infrared spectrum to be identical to 9-methyl-3-morpholino-l, 2,8, 9-tetraazaphenalene, M.P. 219-222° as prepared according to Example 7.

The starting material, 3-bromo-9-methyl-l,2,8,9-tetraazaphen-alene was prepared as follows: To a solution of 368 mg. of 9-methyl-l , 2 , 8, 9-tetraazaphen-alene, M.P. 145-147°, anhydrous sodium acetate (165 mg.) and glacial acetic acid (25 cc.) was added dropwise under stirring bromine (320 mg.) in glacial acetic acid (25 cc.) 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-l,2,8,9-tetraazaphenalene, M.P. 237-238°. 9-Methyl-l, 2,8, 9-tetraazaphenalene may be prepared, for example, by desulphurisationof 9-methyl-3-thiono-2 , 3-dihydro-l, 2 , 8, 9-tetraazaphenalene with Raney nickel in ethanol.

E ample 9 -f 2,6-DimethvlmorrYholino) -9 -methvl-1. .8, 9 -tetraazanhenalene A mixture of 2 , 6-dimethylmorpholine (35 ml.), 3-chloro-9-methyl-1, 2,8, 9-tetraazaphenalene (10.95 g.), and methyl-cellosolve (100 ml.) was stirred at reflux for 22 hours. The solution was concentrated to dryness and the residue triturated with water and filtered. The precipitate was taken up in hot benzene and the residual water in the material removed by azeotropic distillation. Evaporation of the benzene yielded the yellow product melting in the range 169-172°.

The methan esulphonate salt was prepared as follows: 3- ( 2 , 6-Dimethylmorpholino) -9rmethyl-1,2,8,9-tetraazaphenalene (6 g.) was dissolved in methanol (510 ml.) and methanesulphonic acid (3.5 ml.) added. The product formed on addition of ether to the solution. The product was collected and recrystallized from methanol-ether to give the pure product melting at 272- Exam le 10 9_-Methvl-3- l,2., 3, 4-tetrahvdroisoqi3i.nolin-?-vl') -1,2,8,9-tetraazauhenalene A mixture of 3-chloro-9.methyl-1, 2 , 8, 9-tetraazaphenalene (10 g.), 1, 2 , 3, 4-tetrahydroisoquinoline (10 ml.) and methyl cellosolve (100 ml.) was heated at reflux for 48 hours. The mixture was poured into ether and the yellow solid collected.

This solid was suspended in water and the desired product collected by filtration, washed with water and dried. It melted at 231-233°.

Exam le. II 9-Methvl-3-(4-methvlOlperazin-l-vl) —1 , 2 , 8, 9— et aazaDhenalene A mixture of 9-methyl-3-chloro-l, 2, 8, -tetraazaphenalene (10 g.) and 4-methyl-piperazine (50 ml.) was stirred at reflux for 24 hours. The solution was poured into cold ether and the product was collected, taken up in hot benzene, treated with charcoal and filtered. The benzene solution was evaporated at reduced pressure to a yellow solid which was dissolved in methanol saturated with hydrogen chloride. Addition of dry ether precipitated the hydrochloride, M.P. 293-304° with decomposition.

Example 12 3-Chloro-9-phenvl-lT 2 T 8, 9 -tetraa zaphenalene a) To a stirring mixture of phosphorus pentachloride (6.3 g.) in phosphorus oxychloride (40 ml.) is added 7.8 g of finely powdered 3-oxo-9 -phenyl-2 , 3-dihydro-l, 2 , 8, -tetraazaphenalene , 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, -tetraazaphenalene.

The starting material, 3-oxo-9-phenyl-2 , 3-dihydro-l, 2 , 8, -tetraazaphenalene , is prepared as follows: b) a,a-Dibromo-3-methylphthalic anhydride (M.P. 90.5-93°C., 40 g.) is added little by little to a hot solution of 2N sodium hydroxide (500 ml.) under stirring. After ten mintues, 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 filtered. After three days at 5°C., the filtrate yields colorless blocks of 7 -carboxy-3-hydroxyphthalide , M.P, 163.5-166°C. After two further crystallizations from water the M.P. is 165. -168.5°C. c) 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, M.P. 197-198°. d) To a solution of thionyl chloride (40 ml.) in chlorobenzene (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 if evaporated to dryness i& 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-carbethoxy-2-phenyl-l( 2H) phthalazinone precipitates in colorless needles, M.P. 150-151°, unchanged upon recrystallization from ethanol. e) A mixture of 8-carbethoxy-2-phenyl-l(2H) phthalazinone (11.76 g.), 100% 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-l, 2,8,9-tetraazaphenalene as yellow needles, M.P. 255-257°.

ESxaammpplee 1133 9 9--PPhhfifinnyyll--33--ppiippfifirriiddiinnoo..--lltt P?.-S8j?-g9--teetrraaaazzaapphheennaallfiennfie A A mmiixxttuurree ooff 33--cchhlloorroo--99--pphheennyyll--ll ,, 22 ?, 88,, 99--tteettrraaaazzaapphheennaalleennee ((88..00 gg..)) aanndd ffrreesshhllyy ddiissttiilllleedd ppiippeerriiddiinnee ((110000 mmll..)) iiss hheeaatteedd aatt rreefflluuxx uunnddeerr mmooiissttuurree eexxcclluussiioonn ffoorr 4488 hhoouurrss.. TThhee mmiixxttuurree iiss ccoooolleedd ttoo rroooomm tteemmppeerraattuurree aanndd tthhee pprreecciippiittaattee ccoolllleecctteedd..

TThhee mmootthheerr lliiqquuoorr iiss eevvaappoorraatteedd iinn, vvaaccuuoo aanndd,, oonn ttrriittuurraattiioonn wwiitthh bbeennzzeennee 5, iitt yyiieellddss aa ffiirrsstt ccrroopp ooff yyeellllooww ccrryyssttaallss.. TThhee ■ ■ bbeennzzeennee mmootthheerr lliiqquuoorr iiss eevvaappoorraatteedd inn vvaaccuuoo aanndd,, oonn ttrriittuurraattiioonn wwiitthh hheexxaannee,, yyiieellddss aa ffuurrtthheerr ccrroopp ooff tthhee ssaammee mmaatteerriiaall.. TThhee oorriiggiinnaall pprreecciippiittaattee ((ccoonnttaaiinniinngg mmoossttllyy ppiippeerriiddiinnee hhyyddrroocchhlloorriiddee)) ii iiss ttrriittuurraatteedd wwiitthh wwaatteerr aanndd ffiilltteerreedd.. TThhee rreeccoovveerreedd ssoolliidd iiss ccoommbbiinneedd wwiitthh tthhee ttwwoo ootthheerr ccrrooppss aanndd rreeccrryyssttaalllliizzeedd ffrroomm bbeennzzeennee--hheexxaannee ,, yyiieellddiinngg ppuurree 99--pphheennyyll--33--ppiippeerriiddiinnoo--ll,, 22 ,, 88,, 99-- 1 1 tteettrraaaazzaapphheennaalleennee,, MM..PP.. 117788--117799°°..

E Exxaamm llee,, 1144 A mixture of 3-chloro- -phenyl-1 , 2 , 8, 9-tetraazaphenalene (6 g.) and redistilled aniline (70 ml.) is stirred under nitrogen at 150° (bath temperature) for 16 hours. The aniline is distilled off at reduced pressure (14 mm. Hg) and the residue taken up in chloroform and washed several times with water. The chloroform layer is dried over sodium sulphate and concentrated to dryness in vacuo . The brownish residue is triturated with ether and filtered. The yellow precipitate is recrystallized three times from chloroform-ether and yellow crystals of 3- anilino-9 -phenyl-152,8, 9-tetraazaphenalene, M.P. 266-267° are obtained.

E ample 15 3-/o-Chlofoanilino) -9-phenvl-l72.8?9-tetraazaOhenalene A mixture of 3-chloro=9-phenyl~l,2,8,9-tetraazaphenalene (4.2 g.)and o-chloroaniline (23 ml.) was stirred at 150° for 20 hours 5 cooled and poured into cold ether. The precipitate was colleeted5 washed with ether and taken up in chloroform. The chloroform layer was washed with water, dried over sodium sulphate and evaporated to dryness at reduced pressure. The residue was recrystallized from ethanol to afford pure 3-(o-chloroanilino) -9~phenyl~l,2,8,9-tetraazaphenalene, M.P. 213-215°.

E am le 16, 9-Phfinyl-3-fl.?.3;4- fitrahvdroisoquinolin-2-yl)-lt2t8i9-tetraazaphenalene A mixture of 3-chloro~9-phenyl-l,2,8,9~tetraazaphenalene (10 g.), 1, 2 J 3 , 4-tetrahydroisoquinoline (5 ml.) and methyl cellosolve (200 ml.) was stirred at reflux for 40 hours, then evaporated to dryness at reduced pressure. The residue was triturated with water and the solid collected. This material was chromatographed on alumina with chloroform as solvent. Eluted fractions were checked by thin layer chromatography against starting material. Those fractions containing the new compound were combined, evaporated to dryness and the residue purified by recrystallization from chloroform-ether, yielding 9-phenyl-3- ( 1, 2 , 3 , 4-tetrahydroisoquinolin-2-yl) -1 , 2 , 8, 9-tetraazaphenalene M.P. 220-222°. : Example 11 3-Morpholino-9-phenvl-lT2?8.9-tetraazaphfina1 ene A mixture of morpholine (75 ml.) and 3-chloro-9 -phenyl-1,2,8,9-tetraazaphenalene (6 g.) is stirred at reflux for 24 hours under moisture exclusion. The solution is at first very dark but becomes light during the reaction. The solution is poured into ice-water and the yellow precipitate which forms is collected, washed with water and dried i , vacuo . The crude product is reerystallised once from aqueous ethanol and once from chloroform-ether j whereupon 3-morpholino-9-phenyl-1,2,8,9-tetraazaphenaiene was obtained in yellow crystals, M.P. 268-269°.

Example j8 .9-Phenvl-3-pvrrolidino-l,2.8,9-tetraazaphenalenfi A mixture of 3-chloro-9-phenyl-l32,8,9-tetraazaphenalene (1.0 g.), pyrrolidine (1 ml.) and methyl cellosolve (20 ml.) is stirred at reflux under nitrogen for 24 hours. The mixture is concentrated to dryness and the residue taken up in chloroform, washed with water and extracted with 3N hydrochloric acid. The acidic solution is basified with sodium carbonate whereupon an orange precipitate forms. The precipitate is collected by filtration, washed with water and dried. The product is twice recrystallized from carbon tetrachloride-ether and 9-phenyl~3-pyrrolidino-l, 2 , 8, 9-tetraazaphenalene is obtained in reddish-orange crystals, M.P. 177=179°. :¾¾fflple 19 3-Benzvlamino-9-Ohenvl-l?2T8?9--tetraaz3phenalene A mixture of 3-chloro~9-phenyl=l,2,8,9-tetraazaphenalene (6.0 g.) and benzylamine (120 ml,) is stirred at reflux for 66 hours. The resulting solution is concentrated under reduced pressure to incipient dryness and the residue triturated with ether and filtered, The precipitate is recrystallized from benzene-hexane and 3-benzylamino-9=phenyl-l,2,8,9-tetraaza-phenalene is obtained as orange crystals, M.P. 169-173°C, Example 20 3-Hvdrazino-9-phenvl-l, ,8, 9-tetraazaphenalene dihvdrochloride a) A mixture of 100% hydrazine hydrate (10 ml.), methyl cellosolve (30 ml.) and 3-chloro-9-phenyl-l , 2 , 8, 9-tetraazaphen-alene (2 g.) is stirred for 4 hours at reflux, during which time a yellow solution is obtained. This is filtered hot and the filtrate treated with water (30 ml.) and cooled overnight. The yellow precipitate which has formed is collected, washed with water and dried. This material represents crude 3-hydrazino-9-phenyl.-l, 2 , 8, 9-tetraazaphenalene and is purified as follows: b) The crude hydrazino compound (5.4 g) is taken up in excess 3N hydrochloric acid, the solution filtered and the filtrate evaporated in. vacuo . The residue is taken up in 60 ml. of cold water, filtered free of some insoluble solid and placed in a 3 necked 300 cc flask equipped with mechanical stirrers, condenser and dropping funnel. An equal volume of ethanol is added and the yellow solution heated to 70°C. Benzyldehyde (9 ml.) in ethanol (25 ml.) is added, whereupon a bright yellow precipitate forms. Normal sodium bicarbonate solution (20 ml.) is added dropwise over a five minute period and the yellow mixture stirred 15 minutes at 70°.. An additional 40 ml. of bicarbonate are added rather quickly, whereupon the precipitate turns orange. The mixture is stirred at 70-80° for 15 minutes and then filtered hot. The precipitate is washed with ethanol and dried in. vacuo , M„P. 210-215°C. When recrystallized from methyl cellosolve, 3-benzylidenehydrazino-9-phenyl-l , 2 , 8, -tetraazaphenalene is obtained in dark red plates melting in the range 216-222°C„ c) 3-Benzylidenehydrazino-9-phenyl-l, 2,8, 9-tetraazaphenalene (17.9 g.) was suspended in a large excess of 6N hydrochloric solution was evaporated to dryness at reduced pressure and the residue recrystallized twice from methanol-ether to afford 3-hydrazino-9-phenyl-l, 2,8, 9-tetraazaphenalene dihydrochloride as yellow crystals, M.P. 176-178°.

I Example 21 9-Phenvl-3-B-phfinvlhvdrazlno-l.?T8T9-tetT-aazaphenalRne A mixture of 3-chloro-9=phenyl-l, 2,8, 9-tetraazaphenalene (1.0 g.) and phenylhydrazine (25 ml.) is stirred at 150 °C, for 20 hours. Most of the phenylhydrazine is then removed by distillation at reduced pressure. The residue is triturated with aqueous sodium bicarbonate and then taken up in chloroform. The chloroform solution is dried over sodium sulfate, concentrated in vacuo to about 6 ml. and passed through a column of Woelm basic alumina. Grade III. Fractions are checked by thin layer chromatography of small samples. The desired material is obtained from the second and third fractions, which are concentrated in vacuo. The residue is recrystallized once from dimethylformamide-water and once from acetone, thus affording the orange crystalline 9-phenyl-3-P~phenylhydrazino-l , 2 , 8, 9-tetraazaphenalene, M.P. 265-267°.

\ \ Example 22 9-Methvl-3-thiono-2T3-dlhvdro-l, 2f 8f 9-tetraazaphenalene 9-Methyl-3-oxo-2 , 3-dihydro-l , 2 , 8, 9-tetraazaphenalene , (9.0 g.) is dissolved in dry pyridine (120 ml.) and phosphorous 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 recrystalliza-tions -from methyl cellosolve yield 9-methyl-3-thiono-2 , 3-dihydro-1, 2,8, 9-tetraazaphenalene which decomposes in the range 299° - 316°.

Exam le 23 3-Hvdrazin.o-9-methyl-l} 2 : 8? 9-tetraazaphenalene dlhvdrochloride 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-l52 , 839-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 i. 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? 258, 9-tetraazaphenalene dihydrochloride 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 cooled5 filtered through sintered glass and the filtrate evaporated to dryness in vacuo. The residual solid is thoroughly dried in a dessicator under vacuum over phosphorous pentoxide and then recrystallized from methanol-ether . A second recrystallization from methanol- ether yields 3-hydrazino-9-methyl-l,2,859-tetraazaphenalene dlhydrochloride as pale yellow crystals which decompose with gas evolution at about 260° .

Example 24 3-Hydrazino-9-phenyl-l, ?T8t 9-tetraazaphenalene dihvdrochloride a) To a solution of hydrazine hydrate (100$) (54 ml.) ahi water ,(10 ml.) at 80-9o° is added little by little under" stir ™ ring/5.6 g 9-phenyl-3-thiono-2 , 3-dihydro-l , 2 , 8, 9-tetraazaphena-lene, M.P. 232-234°. The reaction mixture is then heated at reflux for 18 hours and the orange mixture filtered hot. The precipitate is washed repeatedly with distilled water and then taken up in 3N hydrochloric acid. The mixture is washed twice with chloroform and the aqueous acidic layer is treated with charcoal, filtered and the filtrate evaporated at 60° to a small volume. Pale yellow crystals appear. The mixture is cooled and the crystals collected. Evaporation of the mother liquor to dryness yields an additional crop of crystals, The combined crops of crude 3-hydrazino-9-phenyl-l,2,859-tetraazaphenalene dihydrochloride are recrystallized from methanol-ether to give the pure dihydrochloride, identical with the material described in Example 20, The thiono derivative used in the above procedure is prepared as follows: b) A mixture of 3-oxo-9-phenyl-2, 3-dihydro-l, 238, 9-tetraaza-phenalene (2.6 g.)? phosphorus pentasulfide (2.5 g.) and dry pyridine (15 ml.) is stirred for 2-1/2 hours under reflux, cooled slightly and poured into ice-cold sodium chloride solution (200 ml.). The mixture is stirred for 1-1/2 hours and the yellow precipitate which is formed is collected by filtration, washed with water and dried. The product, -phenyl -3=-thiono-2, 3-dihydro-l, 2 , 8, -tetraazaphenalene is reerystall.1 ed from ethanol to yield golden yellow plates, M.P. 232-234cC.

Example 25 To a suspension of sodium methoxide (7 g.) in dry dimethyl-sulfoxide (500 ml.) is added 3-hydroxy-l, 2 , 859-tetraazaphenalene (18.6 g.) and the mixture is heated to 60°C. Benzyl bromide (14 ml.) is added under stirring and the mixture stirred at 60° for 2 hours. The dark mixture is poured into ice-water, stirred for 20 minutes and filtered. The dark brown precipitate is collected, washed with water, dried and then suspended in ethanol (400 ml.). The insoluble tan-colored solid is collected and recrystallized from methyl cellosolve with decolorizing charcoal added.. A first crop of solid is obtained on cooling and a second crop slowly crystallizes from the mother liquor. The combined material is thrice recrystallized from ethanol to yield pure 9-benzyl-3-oxoT2, 3-dihydro-l, 2, 8, -tetraazaphenalene, M.P. 239-243°. ¾ample 26 •9-Benzvl-3-hvdrazino-lt 2I8,9-tfitraazap enalene hydrochloride a) A mixture of 9-benzyl-3-thiono-2 , 3-dihydro-l , 2 , 8, 9-tetraazaphenalene (5.4 g.), 100% hydrazine hydrate (230 ml.) and water (60 ml.) is stirred under reflux for 18 hours. The mixture is cooled and the yellow product collected and dried. The solid is suspended in 6N hydrochloric acid, filtered and the filtrate evaporated to dryness iii vacuo. The residue is recrystallized once from methanol-ether and twice from methanol to give pale yellow needles of 9-benzyl-3-hydrazino-l , 2 ? 8, 9-tetraazaphenalene hydrochloride, M.P. 266-267°.

The starting material used in this procedure is prepared as follows: b) 9-Benzyl-3-oxo-2, 3-dihydro-l , 2, 8, 9-tetraazaphenalene (2.67 g.) is suspended in dry pyridine (25 ml,), phosphorous penta-sulfide (2.5 g.) is added under stirring and the mixture is stirred at reflux under moisture exclusion for 3 hours. The dark solution is poured into ice-water, whereupon an orange solid precipitates. The mixture is stirred 30 minutes, filtered and the precipitate washed with water and dried. The crude product is recrystallized from methyl cellosolve to afford 9-benzyl-3-thiono-2 , 3-dihydro-l, 2, 8, -tetraazaphenalene, yellow needles , : M.P. ^ 278-279.5° L Example 27 3-Hvdrazino-7-Ohenvl-l., ? ; 8? 9-tetraazaphenalene dihydrochlorlde a) A mixture of 3-chloro~7 -phenyl-1 , 2 , 8, 9-tetraazaphenalene '(8.3 g.)5 hydrazine hydrate (71 ml.) and water (15 ml.) was heated at reflux for 24 hours. The mixture was cooled and filtered and the precipitate collected, washed thoroughly with water and suspended in dilute hydrochloric acid. The mixture was filtered free of insoluble material and evaporated to dryness at reduced pressure. The residue was taken up in water, filtered free of insoluble material and evaporated to dryness. The residual solid was triturated with a mixture of absolute ethanol and ether and the dihydrochlorlde collected. It melted at 210-215° with decomposition.

The starting material, 3-chloro-7 -phenyl-1, 2,8, -tetraazaphenalene, was prepared as follows: b) A mixture of 3-oxo-7 =phenyl-2 , 3-dihydro-l, 2 , 8, 9-tetraazaphenalene (5 g.), phosphoryl chloride (27 ml.) and phosphorous entachloride (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-ehloro-7 -phenyl-1, 2 , 8, -tetraazaphenalene melted in the range 278-288° . The 3-oxo compound used in this process was prepared as described in Example 28.

Example 28 3-0x0-7 -phenyl-2 τ 3 -dihvdro-1 , 2 T 8.9-tetraazaphenalene a) A mixture of 8-carbomethoxy-4-phenyl-l ( 2H) phthalazinone (18.6 g.), hydrazine hydrate (400 cc») and water (100 cc.) 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 s 3-dihydro-1, 2?859-tetraazaphenalene melting above 350°C The 8-carbomethoxy-4-phenyl-l(2H) -phthalazinone used as starting material was prepared as follows: b) 3-Benzoylphthalic acid (32,5 g,)3 hydrazine hydrate (85 ml„) and water (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) phthalazinone ? M.P, 257-259°. c) 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°, collected and used directly in step (a) .

E ample 29 4-Bromo-l, 2:8,9-tetraazaphenalene hydrochloride 1 , 2 , 8, 9-Tetraazaphenalene (10 g.) is dissolved in 50% sulfuric acid (200 ml.) and treated with N-bromo-succinimide (12 g.) at room temperature under vigorous stirring. The mixture is stirred on a steam bath for one hour, cooled and poured into cracked ice. The mixture is made alkaline at 0° with 5N sodium hydroxide. The precipitated solid is collected, washed with water and recrystallized from 6N hydrochloric acid. The hydrochloride of 4-bromo-l , 2 , 8, 9-tetraazaphenalene (6.8 g„) is thus obtained in pale yellow crystals which decompose in the range 260-270°. The hydrochloride is decomposed with excess 2N sodium hydroxide and the free base extracted with chloroform. The chloroform extract is dried over sodium sulfate, filtered and the solvent evaporated in. vacuo „ A portion of the residue (800mg.) is passed through a column of Florisil (50 g.) with isopropanol as solvent, 100 ml. fractions being taken. Fractions containing the desired material are '.combined, concentrated in vacuo and the yellow residue recrystallized from 6N hydrochloric acid. The pure yellow crystalline hydrochloride melts in the range 258-260° with decomposition. is suspended in absolute ethanol 0 ml. and methane-- sulfonic acid (1.3 ml.) in ethanol (20 ml.) is added drop- wise under stirring. At first, an almost clear solution is formed but after about one-half hour, an orange precipitate forms. The mixture- is heated to about 50 °C. for 15 minutes, cooled and filtered. The product is recrystal- lized twice from methanol-ether and a constant melting point of 235-237°C. is obtained.

, Calcd; C, 33 - 67 H, 4.11; N, 21.42 ; Pound: 33 - 94; 4.40 . 21.46.

EXAMPLE 12 : 3-Ben'zylidinehydrazino-l ,2 , 8 , 9- etraazaphenalene 3-Hydrazino-l,2 , 8, 9-tetraazaphenalene dihydrochlc ride (23 -35 g») is dissolved in water (l40 ml.) under stirring at 80e and treated with benzaldehyde (9.14 g.) 28709/1 Example 31 3 -Diethylamino-9-methyl-l ,2,8, 9-tetraazaphenalene A mixture of 2.15 g of 3-chloro-9-methyl-l , 2 , 8 , 9-tetraazaphenalene , 15 ml of diethylamine and 20 ml of methyl cellosolve in a pressure vessel is evacuated at -70°C, the vessel is sealed and the mixture is heated at 190°C for 18 2 hours at 40 lbs/in . The solution is then concentrated to dryness at reduced pressure and the residue triturated with 150 ml of 1 N hydrochloric acid. The mixture is filtered and the filtrate is rendered alkaline with 570 sodium carbonate solution and extracted with chloroform. The chloroform extract is dried, clarified with charcoal and concentrated to dryness. The residue is triturated with ether and filtered. The filtrate is concentrated to dryness, dissolved in ethyl acetate and chroiuatographcd on aluminium oxide, eluting with ethyl acetate to yield the product, M.P. 122-125°C.

Using dimethylamine , there is analogously obtained 3-dimethylamino-9-methyl-l ,2 , 8 , 9-tetraazaphenalene , M.P. 151-153°C. - 40a - - 41 - 28709/2

Claims (1)

1. CLAIMS A process for the preparation of substituted having the general wherein represents the hydrazino or radical or an amino group wherein represents a hydrogen atom or a low group or a mononuclear aryl or aralkyl radical the aromatic nuclei of which may be or low and has the meaning given above for except that it may not represent a hydrogen or and together with the adjacent nitrogen atom form a cyclic radical having from 5 7 ring members and from 4 to 6 carbon a which radical may contain an oxygen atom or another nitrogen atom in its and may also be fused with a aononuclear aromatic carbocyclic ring optionally or low alk represents a hydrogen or a low phenyl or benzyl represents a hydrogen atom or a phenyl group and 42 a fluorine comprises in the presence binding the corresponding compound having the formula wherein Y represents a chlorine or bromine atom or a group and have the meaning as or an having th general wherein or and nitrogen have the meanings as that when hydrasine is employed Y may not represent a if R and simultaneously represent hydro and Y may not a chlorine atom if represents a phenyl group and and simultaneousl represent process as claimed in Claim comprising Use of a starting material of formula wherein represents a atom or a low or phenyl g 42 represents a fluorine or bromine which comprises in the presence of an acid binding the corresponding compound having the general formula wherein Y represents a chlorine or bromine atom or a nwrcapto group and have the same meaning as with phenylhydrazine or an amine having the general wherein and Rfi or and together with the J o above nitrogen have the meanings as provided that when hydrazine is employed Y may not represent a roup if R and simultaneously represent hydrogen and Y may not represent a chlorine atom if represents a phenyl group and and simultaneously represent hydrogen process as claimed in Claim comprisin the use of a starting of formula wherein represents a hydrogen atom or a low alicyl or phenyl group and represents a fluorine or bromine A process according to Claim wherein a starting material of formula in which R2 represents a hydrogen atom or a methyl and represent hydrogen atoms and Y represents chlorine or is treated with hydrazine or with ah amine of formula A process according to Claim wherein a starting material of formula in which represents a methyl and represent hydrogen atoms and Y represents bromine or a mercapto group is with A process according to Claim comprising the use of a starting material of formula wherein and represent hydrogen atoms and Y represents chlorine or A process according to any of Claims 1 to wherein the substituted reaction product is converted into a pharmaceutically acceptable acid addition or quaternary ammonium salt A process for the preparation of substituted having the general formula I in Claim substantially as described herein reference to Examples 1 to 24 and 27 to A process for the preparation of substituted having the general formula I in Claim in which 2 is substantially as described herein with reference to Examples 25 and Substituted of the formula I in Claim in which is a phenylhydrazino rou o 44 Compounds according to Claim wherein represents a hydrogen atom or a low alkyl or phenyl Substituted according to Claim substantially as described Pharmaceutically acceptable acid and quaternary ammonium salts of as claimed in any of Claims 9 to Substituted of the formula I in Claim in which is a hydrazino group and and have the same meaning as in Claim provided that they may not all simultaneously be Compounds according to Claim wherein represents a hydrogen atom or a lower phenyl or benzyl 1 Substituted according to Claim substantially described 45 as claimed in Claims 16 to Pharmaceutical compositions comprising substituted or pharmaceutically acceptable acid addition or quaternary salt tnereof as claimed in any of Claims 9 to 15 together with a pharmaceutically acceptable diluent or carrier Pharmaceutical compositions comprising substituued or pharmaceutically acceptable j acid addition or quaternary ammonium salt as claimed 24 in any of 16 to together with a pharmaceutically acceptable diluent or carrier therefor For the Applicants insufficientOCRQuality