IL25525A - 1,2,8,9-tetraazaphenalenes and their preparation - Google Patents

Description

fllUJl ]tl3 TJini"! Π DR. REINHOLD COHN DR. MICHAEL COHN ISRAEL SHACHTER B.Sc.

PATENTS AND DESIGNS ORDINANCE SPECIFICATION NEW 1 , 2, 8, 9 - TE RAAZ APHENALENES AND THEIR PREPARATION, .nniaju o»enn o» JVKJBRTKIOBB - 9 ,8 ,2 ,1 I (we) J.R. GEIGY A.G. A SWISS COMPANY OF BASLE, SWITZERLAND. do hereby declare the nature of this invention and in what manner the same is to be performed, to be particularly described and ascertained in and by the following statement: - J . R . G E I G Y A . G . B A S E L 2 1 2160/GC 159 DIV I* -rmnn nnn τιηρ ΦΠΤ? ρπηηττητ τητιτ nff 1 t 9 } w , Q- TOTB a a ?, .ΡΗΙΒ.Τ.ΒΙΙΒ,Ϊ This invention relates to new nitrogen containing organic compounds, i. e. substituted 3-hydrazino-l , 2 , 8 , 9-tetraazaphena-lene derivatives, their addition salts with inorganic and organic acids as well as a process for the preparation thereof.

Compounds of general formula I wherein R represents either 2 hydrogen atoms or a benzylidene radical *-e-s½ the benzene ring of which can be substituted by a cyano group, nitro group, an amino or low dialkylamino or acylamino group or by at most 3 halogen atoms or low alkoxy groups, or it represents the cinnamylidene , the radical 3-indolylmethylidene or 2-pyridylmethylidene r-esfc , have not been known hitherto. acid Compounds of formula I and their /addition salts have cardiovascular and sedative activity. They can be used in particular, as hypotensive agents. For this purpose they can be administered parenterally or orally in the usual pharmaceutical preparations such as tablets, capsules, powders, suspensions, solutions, Those formulations, which can be produced by any of the known processes, are particularly valuable in which the active ingredient is slowly incorporated into the system over a longe period.

The compounds of the general formula I can be prepared by heating 3-mercapto-l , 2 ,8 , 9-tetraazaphenalene of the formula II H with at least the equimolar amount of hydrazine hydrate, iso-lating the 3-hydrazino-l , 2 ,8 , 9-tetraazaphenalene and, if de- symbolR sired, reacting it with an aldehyde corresponding to the -re-st-s defined above a compound so obtained -de-f¾¾-e ΙΜ%4©·Ρ-¾· and, if desired, converting/into an addition salt with an inorganic or organic acid.

The reaction is carried out with aqueous hydrazine or 100 % hydrazine in a suitable solvent such as ethanol, methyl-cellosolve, diethyleneglycol , dimethyl ether at reflux temperature over periods of time ranging from about 16 to about 48 hours. The free base can be converted by conventional techniques to the corresponding salts such as the dihydrochloride and dimethanesulfonate .

The hydrazone derivatives of this invention are easily prepared : the hydrochloride acid salt of 3-hydrazino-l , 2 ,8, 9-tetraazaphenalene can be converted with aromatic aldehydes, such as benzaldehyde , in aqueous alcohols to the monohydrochloride of the benzylidene derivative, which upon neutralization with weak bases such as sodium bicarbonate, yields the free base.

An alternative route to the free base involves the reaction of 3-hydrazino-l , 2 ,8 , 9-tetraazaphenalene dissolved in IN acetic acid with an alcoholic solution of the aldehyde.

The starting material 3-mercapto-l , 2 ,8 , 9-tetraazaphena- lene(or its tautomeric designation 3-thiono-2 , 3-dihydro-l , 2 , - 8 , 9-tetraazaphenalene) can be prepared by the process which comprises heating 3-hydroxy-l , 2 ,8, 9-tetraazaphenalene with at least an equimolar ,amount of phosphorous pentasulfide until 0 replacement of the oxygen-containing group by a sulfur-containing group is substantially complete and recovering the desired compound. High yields of the sulfur-substituted compound are obtained if the reaction is carried out in refluxing pyridine for from about 40 minutes to about 3 hours. 3-Hydroxy-l , 2 ,8 , 9-tetraazaphenalene (3-oxo-2 ,3-dihydro- 1,2, 8, -tetraazaphenalene) can be prepared by treating 3- ee-, - dibromomethyl) -phthalic anhydride with at least twice the equimolar amount of hydrazine hydrate « 3- ( ,a-dibromomethyl) - phthalic anhydride can be obtained by bromination of the 0 known 3-methyl-phthalic anhydride.

The production of 3-hydroxy- and 3-mercapto-l , 2 ,8 , 9- tetraazaphenalene is the subject-matter of a parallel appli- ^/i cation. o. 25524.

The compounds of the general formula I and their physio- 5 logically acceptable acid addition salts with inorganic and organic acids may be administered parenterally or orally in any of the usual pharmaceutical forms including tablets, capsules, powders, suspensions, solutions, syrups and the like.

Particularly valuable formulations include sustained release 0 preparations which may be compounded by any of the known pro- By physiologically acceptable acid addition salts of the basesusable according to the invention are meant those acids, the anions of which are pharmacologically acceptable in the usual dosages i.e. those which cause no toxic effects, c ~)r* as for example the acids with hydrochloril, hydrobromic, sul-j/j furic, phosphoric, metharilulfonic , acetic, lactic, succinic, malic, maleic, aconitic, phthalic, tartaric acid.

According to the rules for nomenclature at present prevailing, the new ring system should be termed : 1H-2 ,3,4, 5-tetraazaphenalene.

In the following examples, however, the following nomenclature will be used \ 1 , 2 ,8, 9-tetraazaphenalene.

The following examples further illustrate the production of the new compounds of general formula I, but they are by no means the sole method of performing same. The temperatures are given in degrees Centigrade.

Example 1 3-Hydrazino-l, 2,8, 9-tetraazaphenalene A mixture of 3-mercapto-l , 2,8, 9-tetraazaphenalene (30 g) and 85 % hydrazine hydrate (500 ml) is refluxed under vigo-rous stirring for 20 hours. The mixture is cooled, filtered and the yellow precipitate washed with water and dried in vacuo. The yield of free base is 21,0 g (70 %) .

The same material is obtained by treatment of the mer-capto compound with 100 % hydrazine hydrate in diglyme at re-flux for 7 hours or with 100 % hydrazine hydrate in methyl cellosolve at reflux for 20 hours. The product can also be isolated on treatment of the mercapto compound with 100 % hydrazine hydrate in refluxing ethanol after 7 hours, but further purification is required to free the product from star-ting material. 3-Hydrazino-l, 2,8, 9-tetraazaphenalene dihydrochloride 3-Hydrazino-l, 2,8, -tetraazaphenalene, prepared by any of the methods described above, can be treated in the following way : The crude base (21,0 g) is suspended in excess 3N hydro-chloric acid, filtered free of residual solid and evaporated in vacuo. The residue is triturated with methanol and filtered. The crude i_HL4¾ydrochloride (20.7 g) is recrystallised by dissolution in water followed by addition of methanol and concentrated hydrochloric acid. A further recrystallization from water-concentrated hydrochloric acid, yields the analytical sample, m.p. 245-248° (dec). The starting material, 3-mercapto-1 , 2 , 8, 9-tetraazaphenalene was prepared as follows : a) q, q-dibromo-3-methylphthaiic anhydrjde - - Admixture of 3-methylphthalic- anhydride ^Sl g), -ί-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 our 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° in 72 % yield. Two recrystallizations from ether-hexane yield colorless needles melting at 93-95°. b). 3-Hvdroxy-l .2.8.9-tetraazaphenalene A suspension of a, a-dibromo-3-methylphthalic anhydride (80 g) in ethanol (500 ml) is treated with a solution of in >rj 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 ro 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 a?'id 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 overall yield of product, m.p.^> 347°, is 25.7 g, or 55 % of theory. The product is recrystallized from 3 litres of boiling dimethylformamide and obtained as a yellow powder which, on heating, forms a microcrystalline solid at 220-270°, and melts above 350°. c ) 3-Mercapto-l, 2 , 8, 9-tetraazaphenalene ( 3-thiono-2, 3-dihydro-l ,2,8, 9-tetraazaphenalene) A mixture of 3-hydroxy-l, 2,8, 9-tetraazaphenalene (44,14 g) phosphorous 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 (35.0 g, m.p. 298-320° dec.) is recrystallized once from methyl cellosolve/water and once from dimethylformamide-water . The powdery solid melts at 318-322° on a block preheated to 250°.

Example 2 3-Hydrazino-l, 2,8, -tetraazaphenalene dimethane-sulfonate 3-Hydrazino-l, 2, 8, 9-tetraazaphenalene (2.0 g) is suspended in absolute ethanol (60 ml) and methanesulfonic acid (1.3 ml) in ethanol (20 ml) is added dropwise 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° for 15 minutes, cooled and filtered. The product is recrystallized twice from methanol-ether and a constant melting point of 235-237° is obtained.

Example 3 3-Ben ;; lidene-hydraz ino-l , 2 ,8 ,-9-tetraazapherialene 3-Hydrazino-l , 2,8, 9-tetraazaphenalene dihydrochloride (23,35 g) is dissolved in water (140 ml) under stirring at 80° and treated with benzaldehyde (9.14 g) in ethanol (115 ml) The mixture is heated 30 minutes under reflux, cooled and the pale yellow solid collected by filtration. This material, the benzyl idene 'hydraaino-l , 2 ,8 , 9-tetratfzapherial^.ne is dissolved in hot water and treated with slightly more than one equivalent of IN sodium bicarbonate. The precipitated orange hydrazone is collected, dried and recrystallized from propylene glycol-methanol. The material changes color at 265-267° (orange to pale yellow) and decomposes at 330-338°.

The same material is obtained by treatment of 3-hydra-zino-1 , 2 , 8, 9-tetraazaphenalene in IN acetic acid with one equivalent of benzaldehyde dissolved in ethanol. After one hour at reflux, filtration yields 91% of crude hydrazone.

Example 4 3-Hydrazino-l ,2,8, 9-tetraazaphenalene dihydrochloride -- --The , 3-Benzylidene -hydrazino-1 , 2 , 8, 9-tetraazaphenalene (5.76 g) is suspended in hot 2N hydrochloric acid under stirring and is heated at the boiling point of the solvent until no odor of benzaldehyde remains. A small amount of impurity is filtered off and the clear yellow filtrate is evaporated in vacuo to incipient crystallization. An equal volume of concentrated hydrochloric acid is added, the mixture cooled and the yellow crystalline product is collected.

A further crystallization from water-methanol-concentrated hydrochloric acid yields the analytically pure material.

Example 5 3-m-Nitrobenzyliderjerhydrazino)-l ,2,8, 9- tetraazaphenalene 3-Hydrazino-l, 2, 8, 9-tetraazaphenalene dihydrochloride (1,4 g) in water (10 ml) and ethanol (10 ml) was heated to 70°, and a solution of m-nitrobenzaldehyde (0,75 g) in ethanol (10 ml) and water (10 ml) added under stirring. An orange color developed at once. Molar sodium bicarbonate solution (5 ml) was added and the solution refluxed 5 minutes. An orange-red precipitate developed. Addition of another 5 ml of IN sodium bicarbonate solution followed by 15 minutes at reflux resulted in the formation of a thick red precipitate. The material was collected from the cooled mixture, washed with water and ethanol and dried in vacuo. The yield of material, m.p. 350°, was 1.54 g, or 94 % of theory. Two recrystalliza-tionsfrom dimethylformamide yielded analytically pure material, m.p. 350°.

Example 6 3-fo-Acetamidobenzylidene-hydrazino)-l , 2 , 8, 9-t etraazaphenalene To a solution of 3-hydrazino-l , 2 , 8, 9-tetraazaphenalene dihydrochloride (1,4 g) in water (10 ml) was added p-aceta-mido benzaldehyde (0,75 g) in water (10 ml) and ethanol (10 ml) at 70° under stirring. After several minutes 5 ml of IN sodium bicarbonate were added and the mixture refluxed 30 minutes. The orange mixture was filtered hot and the solid washed with water and ethanol. The yield of product was 1.59 g, m.p. 350°. Two recrystallizations from aqueous methyl cellosolve yielded pure material. NMR analysis agreed with the assigned structure and showed the presence of water.

Analogous to the procedure of examples 3, 5 and 6, the following substituted 3-benzyliden-hydrazones were obtained. 7. 3- (p-Dimethylaminobenzylidene-hydrazino) -1, 2 , 8, 9- tetraaza- phenalene m.p. 274-276° recrystallized from methyl cellosolve, yield 96 %. 8. 3- ( 3, 4-Dimethoxybenzylidene-hydrazino) -1,2,8, 9- tetraaza- phenalene m.p. 235-237° recrystallized from dimethylformamide-water , yield 72 %. . 3- ( 3, 4 , 5-Trimethoxybenzylidenerhydrazino) -1,2,8, 9-tetraaza- phenalene m.p. 265-267°, recrystallized from methylcellosolve-water , yield 75 %. .3-fci-Cyanobenzylidene-hydrazino)-l, 2,8, 9- tetraazaphenalene m.p. > 350°, recrystallized from dimethylformamide, yield 77 %. 11. 3- ( 3, 4-Dichlorobenzylidene-hydrazino) -1, 2,8, 9- tetraaza- phenalene m.p.^> 350°, recrystallized from dimethylformamide , yield 97 %.

Example 12 3-Cinnamylidgie-hydrazino-l ,2,8, 9- te traazaphenalene To a solution of 3-hydrazino-l , 2 , 8, -tetraazaphenalene dihydrochloride (1,4 g) in water (10 ml) and ethanol (10 ml) at 70° under stirring was added cinnamaldehyde (0,66 g) in water (10 ml) and ethanol (10 ml). After a few minutes IN sodium bicarbonate (5 ml) was added and the mixture refluxed 5 minutes. The orange mixture was treated with more IN sodium bicarbonate (5 ml) and refluxed 15 minutes. The mixture was filtered hot, and the reddish-orange precipiate washed with water, then ethanol and dried in vacuo. The yield of product, m.p. 350°, was 1,56 g or 99 % of theory. Two recrystalli-zations from dimethylformamide yielded analytically pure material in reddish-orange plates, m.p.

Example 13 3- (-2--Pyridylmethylid6rie-hycfr¾g¾Sa?^l , 2-, 8 , 9- raa¾-"p ena1ene To a solution of 3-hydrazino-l, 2,8, 9-tetraazaphenalene dihydrochloride (7,0 g) in water (50 ml) and ethanol (50 ml) at 70° was added under stirring pyridine-2-aldehyde (5,2 g) in water (50 ml) and ethanol (50 ml). One normal sodium bicarbonate solution (25 ml) was added and the mixture stirred for about 10 minutes at 70°. More IN sodium bicarbonate (25 ml) was added and the mixture refluxed 15 minutes. The hot mixture was filtered and the orange precipitate washed with water and ethanol and dried in vacuo. The solid (4,0 g, 56 %) was recrystallized once from dimethylformamide and has a m.p. of 257-258°.

Example 14 3- ( 3 -Indol Imethy11aan-hyor-azino ) -1 , 2 ,8 9.-1e raaza ntnaiene 3-Hydrazino-l ,2,8, 9-tetraazaphenalene dihydrochloride (1,4 g) in water (10 ml) and ethanol (10 ml) was treated under stirring at 70° with indole-3-carboxaldehyde (0,73 g) in water (10 ml) and ethanol (10 ml). Sodium bicarbonate solution (IN, 5 ml) was added and the mixture stirred 5 minutes at reflux. Another 5 ml of IN sodium bicarbonate was added and the mixture stirred 30 minutes under reflux. The orange-red precipitate was collected from the hot mixture, washed with water and ethanol and dried in vacuo. A yield 1,57 g (96 % of theory) of solid, m.p.^> 350° was obtained. Two recrystalli-zations from DMF-methanol and one recrystallization from DMF-water gave the analytical sample.

Claims (14)

HAVING NOW PARTICULARLY DESORIBEO AND ASCERTAINED THE NATURE OF OUR SAID INVENTION ANO IN WHAT MANNER THE SAME IS TO BE PERFORMED , WE DECLARE THAT WHAT WE CLAIM IS: ' What we claim is

1. Process for the production of new compounds of the general formula I H 5 wherein R represents either 2 hydrogen atoms or a benzylidene radical _ ca-si the benzene ring of which can be substituted by a cyano group, nitro group, an amino or low dialkylamino or acylamino group or by at most 3 halogen atoms or low alkoxy groups, or it represents 10 the cinnamylidene , the 3-indolylmethylidene or 2- radical pyridylmethylidene p-e-s-k , and their physiologically acceptable acid addition salt, characterised by heating 3-mercapto-l , 2 ,8 , 9-tetraazaphenalene with at least the equimolecular amount of hydrazine hydrate, 15 isolating the 3-hydrazino-l , 2 ,8 , 9-tetraazaphenalene , if desired corresponding to the symbol > reacting this with an aldehyde ©•^-^he-^ests-deiift d-wi-d-e-i' R defined ^ above and, if desired, converting a compound so obtained into an addition salt with an inorganic or organic acid.

2. A compound of the general formula I wherein R represents either hydrogen atoms or a benzylidene radical && the benzene ring of which can be substituted by a cyano group, nitro group, an amino or low dialkylamino or acylamino group or by at most 3 halogen atoms or low alkoxy groups, or it repre- sents the cinnamylidene , the 3-indolylmethylidene radical or 2-pyridylmethylidene and its physiologically acceptable acid addition salts.

3. 3-Hydrazino-l , 2 ,8 , -tetraazaphenalene as well as its physiologically acceptable acid addition salts.

4. - 3-Benzylidenehydrazino-l , 2 ,8 , 9-te traazaphenalene as well as its physiologically acceptable acid addition salts.

5. 3-

6. 3- (3 , 4-Dimethoxybenzylidenehydrazino)-l , 2 ,8 , 9-t etraazaphenalene as well as its physiologically acceptable acid addition salts.

7. 3—(p-Cyanobenzylidenehydrazino)-l ,2,8, 9-t etraazaphenalene as well as its physiologically acceptable acid addition salts.

8. 3- ( 3 , 4 -Dichlorobenzylidenehydrazino ) -1 , 2, 8, -tetraazaphenalene as well as its physiologically acceptable acid addition salts.

9. 3-Cinnamylidenehydrazino-l ,2,8, 9-tetraazaphenalene as well as its physiologically acceptable acid addition salts.

10. 3- (2^ridyLiiethlidenehydra---no>-l ,2,8, 9-tetraazaphenalene as well as its physiologically acceptable acid addition salts.

11. 3-Hydrazino-l , 2 ,8 , -tetraazaphenalene derivatives of the general formula I, defined in claim 1, substantially as herein described with reference to and as illustrated in any of the foregoing examples.

12. A process for the production of 3-hydrazino-l , 2 ,8 , 9- tetraazaphenalene derivatives, according to claim 1, substantially as herein described with reference to and as illustrated in any of the foregoing examples.

13. 3-Hydrazino-l , 2 ,8 , 9-tetraazaphenalene- derivatives of the general formula I when produced by a process claimed in claim 1.

14. Pharmaceutical compositions containing as active ingredient at least one compound of general formula I together with at least one pharmaceutically acceptable carrier. DATEO THIS 3RD OAY OF APRIL 1966.