DE1695065A1 - Process for the preparation of new 1,2,8,9-tetraazaphenalenes - Google Patents

Description

Process for the preparation of new 1,2,8,9-tetraazaphenalenes

This invention relates to new nitrogen-containing compounds, i.e. substituted 3-hydrazino-1,2,8,9-tetraazaphenalenes, their addition salts with inorganic and organic acids, and a process for their preparation.

Compounds of general formula I,

R = N-NH

= N-N

(D

in which

R either 2 hydrogen atoms or a benzylidene radical, whose

/ a benzene ring also through a cyano group, nitro group, a

/ a / a

Amino, lower dialkylamino or acylamino group, or.

can be substituted by a maximum of three halogen atoms or lower alkoxy groups, or the cinnamylidene, 3-indolylmethylidene or 2-pyridylmethylidene radical has not yet become known. Compounds of Formula I. and their acid addition salts have cardiovascular and sedative properties Effectiveness. In particular, they can be used as antihypertensive agents. For this purpose it is a parenteral one or oral use possible, although we use the usual pharmaceutical

• Ash preparations such as tablets, capsules, powders, suspensions,

"Solutions, syrups and the like. Particularly valuable formulations

those who have won the drug for a long time

BATH

hand over ; they can be made using any of the well known Process are produced. The compounds of general formula I are prepared by adding S-mercapto-l ^ e ^ -tetraazaphenalen of formula II

(ID

reacts with at least an equimolar amount of hydrazine hydrate, the product is isolated and, if desired, converted into an addition salt Converted with an inorganic or organic acid and that in order to obtain products of the formula I in which R is different from hydrogen, 3-hydrazino-1,2,8,9-tetraazaphenalene is used or a salt thereof with one of the meanings of R corresponding to the defined under formula I aromatic Aldehyde converts and the product, if desired, in an addition salt transferred with an inorganic or organic acid .

The reaction is carried out with aqueous hydrazine or lOO ^ igem Hydrazine hydrate in a suitable solvent such as ethanol, methyl cellosolve, diethylene glycol, dimethyl ether at the reflux temperature the solvent is carried out for a period of about 16-48 hours.

The free bases are converted into their acid addition salts in a known manner, such as the dihydrochloride or the dimethanesulfonate.

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The hydrazone derivatives according to the invention become easier Way prepared by the hydrochloride of 3-hydrazino-1,2,8,9-tetraazaphenalene with aromatic aldehydes such as benzaldehyde. Suitable solvents for this reaction aqueous alcohols. This gives the monohydrochloride of the benzylidene compounds, which by neutralizing with weak Bases, such as sodium bicarbonate, can be converted to free bases.

The hydrazones corresponding to the general formula I _{1 are also obtained} if the 3-hydrazino-1,2,8,9-tetraazaphenalene is dissolved in 1N acetic acid and an alcoholic solution of the aldehyde is added to this solution.

The starting substance of the formula II, 3-xercapto-l, 2,8,9-tetraazaphenalen or in its tautomeric name 3-thiono-2,9-dihydro-3H-1,2,8,9-tetraazaphenalen _/ can be obtained by reacting 3-Hydroxy-l, 2,8,9-tetraazaphenalen (3-oxo-2,9-cihydro-3H-l, 2,8,9-tetraazaphenalen) with: at least the equimolecular amount of phosphorus pentasulfide until the hydroxyl group is replaced by the Sulfhydryl group can be obtained. This reaction is previously carried out in pyrulin at the reflux temperature.

The manufacture of 3-hydroxy- and 3-mercapto-1,2,8,9-tetraazaphenals is z. B. in Belgian patent specification No. 679.045 and in German patent application P 16 95 066.6 has been described.

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BATH

The compounds of general formula I and their physiologically acceptable addition salts with inorganic and organic acids can be administered parenterally or orally in any of the customary pharmaceutical administration forms, such as tablets, capsules, powders, suspensions, syrups and the like. Particularly valuable administration forms are those which release the active substance over a long period and which can be produced with the aid of any known method.

Suitable salts for therapeutic use are those with pharmacologically harmless inorganic and organic acids which, in the dosages in question, do not show any harmful physiological intrinsic effects. Suitable salts are, for example, the salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, lactic acid, succinic acid, malic acid, maleic acid, aconitic acid, phthalic acid, tartaric acid.

The new ring system, referred to in the present description and in the claims as 1,2,8,9-tetraazaphenalen, can also be called pyridazino according to Chemical Abstracts [3,4,5-delphthalazine

or .

IH-1,2,8,9-tetraazaphenals or 1H-pyridazino [3,4,5-d elphthalazine.

009850/2097 ._. BADORfGlNAL

In the following examples, however, the 2e ' ^: drawing "Tetraazaphenalen" and the following numbering; perishes;

(9K -) - 1,2,8,9-tetraazaphenals.

I The following examples explain the implementation of the

the inventive method in more detail but are in no way limit the scope of the invention w .. Temperatures are given in degrees Celsius'.

JB Si i ''"*> ι * ν * '

BATH

example 1 S-Hvdrazino-l ^ .B.g-tetraazaphenalen

A mixture of 30 g of 3TMercapto-l, 2,8,9-tetraazaphenalene and 500 ml of B5 # hydrazine hydrate are added with vigorous stirring Boiled under reflux for 20 hours. This gives 21 g of free base ($ 70 in theory).

The same product is obtained when using 3-mercapto-1,2,8,9-tetraazaphenalen and 100 #iges hydrazine hydrate in diglyme (ethylene glycol dimethyl ether) for 7 hours at reflux, or heated in methyl cellosolve for 20 hours. The 3-hydrazino-1,2,8,9-tetraazaphenalene is obtained after just 7 hours Boiling at reflux in ethanol, however, is so obtained Material impure and must be freed from the starting material.

3-hydrazino-1,2,8,9-t etraazaphenalen-dihydrochloride

21g of raw prepared according to one of these methods 3-hydrazino-1,2, S, 9-tetraazaphenalen are in excess suspended in 3 -N hydrochloric acid. You filter what does not appear dissolves and the filtrate is evaporated to dryness in vacuo. The residue is rubbed with methanol and filtered. The dihydrochloride crystallizes, and is filtered off. The yield is 20.7 g. It is recrystallized by first in Water dissolves, and then methanol and concentrated hydrochloric acid are added. After a further crystallization from water, more concentrated Hydrochloric acid gives analytically pure 3-hydrazino-1,2,8,9-tetraazaphenalene Dihydrochloride, which melts at 245-248 ° with decomposition.

The old starting material, 3-mercapto-1,2, ü, 9 ~ tetraazaphenalen became vif. fol ^ t made:

fv ■ ^π - Λ \ '' '> ■' * O "* ^

^ ^dvV '* ^v ''BAD ORIGINAL

a) a ^ g-Dlbromo-3-Methvl-phthalic anhydride

A mixture of 81 g of 3-methylphthalic anhydride, 182 g of N-bromosuccinimide, 40 mg of dibenzoyl peroxide and 1500 ml of carbon tetrachloride is heated to reflux with stirring while it is illuminated with a 100-watt UV lamp, which can be immersed in the solution. After the solution has turned brick-red, another 40 ml of dibenzoyl peroxide are added and the reaction is then allowed to continue for 24 hours with stirring and lighting.

/ to run. It is then cooled and the succinimide is filtered off. The filtrate is evaporated to dryness in a vacuum. The solid yellow-brown residue is then taken up in hot ether, treated with animal charcoal and filtered. Hexane is added to the filtrate, whereupon a colorless product crystallizes out in 72% yield on cooling. After recrystallizing twice from ether / hexane, the α-dibromo-3-methyl-phthalic anhydride is obtained as colorless crystals with a melting point of 93 ° -95 °.

b) 3-Hydroxy-l "tetraaza 8.9 to 2 _T

A suspension of 80 g of α, α-dibromo-3-methy! »Phthalic anhydride in 500 ml of ethanol is added dropwise with stirring and cooling with a solution consisting of 100 ml of hydrazine hydrate and 100 ml of water . A white suspension forms, which ^{gradually turns into a yellow precipitate, 1} after everything has been added and the temperature has gradually been increased to the reflux temperature. The reaction mixture is stirred at reflux for 88 hours, then cooled and a first portion of the end product is filtered off. The mother liquors are evaporated to dryness under vacuum, taken up in 500 ml of glacial acetic acid and refluxed for 18 hours. The reaction mixture is cooled and a second portion of air is filtered off from material. You give all the material

"09850/2097. ^ _0BielN AL

together, washed with water and ethanol and dried in vacuo. This gives a total of 25.7 g (55 % of theory) of crude 3-hydroxy-1,2,8,9-tetraazaphenalene, which has a melting point of over 347 °. The material is recrystallized from over 3 liters of boiling dimethylformamide, and gives a yellow powder which takes on a microcrystalline shape at 220-270 ° and melts at over 350 °.

c) 3-mercapto-1,2,8,9-tetraazaphenalene

The mixture is heated with stirring and exclusion of moisture a mixture of 58.2 grams of phosphorus pentasulfide, 44.14 grams of 3-hydroxy-1,2,8,9-tetraazaphenalene in 356 ml of absolute pyridine for 2 1/2 hours at reflux. Then leave the dark red liquid cool and then pour them into 1 l of ice-cold, saturated sodium chloride solution while stirring. The Geraisch becomes 1 1/2 Stirring is continued for hours, then the precipitate is filtered off, washed thoroughly with water and dried at 100 ° in vacuo. 35 g of orange material with a melting point of 298-320 ° are obtained, which is obtained once from methyl cellosolve-water and once from dimethylformamide-water is recrystallized. Powdered material is obtained in this way, which at 318-322 ° on a preheated to 250 ° Melting block melts.

Example 2

3-hydrazino-l _T 2,8,9-tetraazaphenalen-dimethanesulphonate 3-hydrazino-1,2,8,9-tetraazaphenalen is suspended in

60 ml of absolute ethanol and gives a solution of 1.3 ml of methane.

sulfonic acid in 20 ml of absolute ethanol. At first an almost clear solution forms, but after about half a time An orange precipitate separates out for an hour. One warms during

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BATH ORIGINAL

15 minutes to about 50 °, let cool and filtered. The salt is recrystallized twice from methanol-ether and the dirnethan sulfonate is obtained, which has a constant Has a melting point of 235-237 °.

Example 3

3-benzylidene hydrazino-1,2 , 8 _T 9-tetraazaphenal

To a stirred, heated to 80 ° solution of 23.35 g of 3-hydrazino-1,2,8,9-tetraazaphenal dihydrochloride in A solution of 9.14 g of benzaldehyde in 115 ml of ethanol is added to 140 ml of water. The mixture is then refluxed for 30 minutes, lets a cold and filters off the yellow precipitate that forms.

This precipitate, 3-benzylidene-hydrazino-l, 2,8,9-tetraazaphenalene Monohydrochloride, is dissolved in hot water and mixed with a little more than one equivalent of 1N sodium carbonate treated. The orange hydrazone precipitates, is filtered off, dried and recrystallized from propylene glycol-methanol. The substance changes color from orange to pale yellow when heated to 265-267 ° and decomposes at 330-338 °.

The same material is obtained if 3-hydrazino-1,2,8,9-tetraazaphenalene is refluxed in 1N acetic acid with one molar equivalent of benzaldehyde dissolved in ethanol for one hour. The crude hydrazone precipitates in 91 % yield on cooling.

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BATH ORIGINAL.

Example 4

3-hydrazino-1,2,8,9-tetraazaphenal dihydrochloride

5.76 g of S-benzylidene-hydrazino-l ^ je, 9-tetraazaphenalen are added in a stirred, hot 2 ~ N hydrochloric acid solution and boil until there is no more odor of benzaldehyde. It is then filtered and the light yellow filtrate is concentrated in vacuo until crystallization begins. Then you enter the same volume of concentrated hydrochloric acid is added, the mixture is cooled and finally the yellow crystalline precipitate is filtered off. He is recrystallized from water-methanol-concentrated hydrochloric acid and gives analytically pure material, m.p. 245-248 ° below Decomposition.

Example 5 S-fo-Nitrobenzyliden-hydrazino ^ l ^ Sng-tetraazaphenalen

1.4 g of 3-hydrazino-1,2> 8,9 ~ tetraazaphenal dihydrochloride, which is dissolved in 10 ml of water and 10 ml of ethanol, are heated to 70 ° and a solution of 0.75 g m is added with stirring -Nitrobenzaldehyde in 10 ml of water and 10 ml of ethanol to it. A yellow color develops immediately. 5 ml of a sodium bicarbonate solution are then added and the mixture is refluxed for 5 minutes. An orange precipitate develops. A further 5 ml of 1N sodium bicarbonate solution are added and the mixture is refluxed for 15 minutes. This time a voluminous red precipitate is obtained. It is cooled, filtered, and the precipitate is washed and dried in vacuo. This gives 1.54 g or 92 % theoretical of substance which does not melt below 350 °. After two recrystallizations from dimethylformamide, analytically pure 3- / ffi-nitrobenzylidene-hydi ⁱ az: ino> lj2,8,9-tetraazaphenalene is obtained.

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BATH ORIGINAL

Example 6 S-fo-Aeetaffiidobenzvliden-hydrazinoVl ^ S.g-tetraazaphenalen

To a solution of 1.4 g of 3-hydrazino-1,2,8,9-tetraazaphenalene in 10 ml of water is added at 70 ° with stirring a solution of 0.75 g of p-acetamido-benzylidene in 10 ml of water and 10 ml of ethanol. After a few minutes are added to 5 ml of 1N sodium bicarbonate solution and boiled under reflux for 30 mewed. The orange reaction mixture is filtered hot and the precipitate is washed with water and ethanol. 1.59 g of 3 - ^ - acetamidobenzylidene hydrazino> -l, 2,8,9-tetraazaphenalene, which does not melt below 350 °, are obtained. After recrystallizing twice from methyl cellosolve water, the substance is obtained in pure form. The NMR spectrum confirms the expected structure and indicates the presence of crystal water.

According to the procedure described in Examples 3, 5 and 6, the following substituted 3-Hap.zylidenhydrazones are also produced

7. 3- (p-Dimethvlaminobenzvliden-hvdrazino) -1.2,8.9-tetraazaphenal melting point 274-276 ° from methylcellosolve, yield 96 % of theory.

8. 3- (3,4-Dimethylbenzylidene-hvdrazino) -1,2,8,9-tetraazaphenal melting point 235-236 ° from dimethylformamide-water. Yield 72 % of theory.

9. 3- (3 _? 4,5-tricethoxybenzylidene-hydrazino) -1,2,8,9-tetraazaphenalei melting point 265-267 ° from methylcellosolve water. yield

10. S-fo-Cyanobenzylidenhydrazindt-l ^ S ^ -tetraazaphenalen melting point> 350 ° from dimethylformamide. Yield ΊΊ% of theory.

11. 3- (3, ^ dichlorobenzylidene hydrazino) -1,2,8,9-tetraazaphenalenes melting point> 350 ° from dimethylformamide. Yield 97 % of theory.

Example 12

3-Cin namyliden-hydrazino-l, 2,8,9-tetraa zap henalen

1.4 g of 3-hydrazino-1,2,8,9-tetraazaphenalene dihydrochloride are dissolved in 10 ml of water, heated to 70 ° and a solution of 0.66 g of cinnamaldehyde in 10 ml of ethanol and 10 ml of water is added with stirring After a few minutes, 5 ml of 1N sodium bicarbonate solution are added and the mixture is then refluxed for 5 minutes. Another 5 ml of 1N sodium bicarbonate solution are added to the reaction mixture, and the mixture is boiled for a further 15 minutes. Then the red-orange precipitate is filtered off hot, washed with water, then with ethanol and dried in vacuo. This gives 1.56 g (99 % of theory) of 3-cinnamylidene-hydrazino-1,2,8,9 · tetrahydrophenalene, which after two recrystallization from dimethylformamide gives red-orange, analytically pure platelets, which

2.35 - 2.30 *

before melting at JIItLt ■ iiiU'i.

ο ■ · -

oo example 13 .

° 3- ( ? -P ^ ridyl methyli aen-hyarazino) -! , 2,8,9-tetraazaphenalen

7 g of 3-hydrazino-1,2,8,9-tetraazaph.enalen are dissolved. Dihydro

- ^ j chloride in a solution of 50 ml of water and 50 ml of ethanol, heated to 70 ° and added, with stirring, 5.2 g of pyridine-2-aldehyde,

which is dissolved in 50 ml of ethanol and 50 ml of water, too. 25 ml of 1N sodium bicarbonate solution are then added to this solution and the mixture is stirred at 70 ° for 10 minutes. After another 25 ml of 1N sodium bicarbonate solution has been added, the mixture is refluxed for 15 minutes. From the still hot reaction mixture, the orange precipitate is filtered off, which is washed with water and ethanol and finally dried in vacuo. This gives 4 g (56 % of theory) of 3- (2-pyridylmethylidene hydrazino) -1,2,8,9-tetraazaphenalene, which is recrystallized from dimethylformamide. M.p. 257-258 °.

Example 14

3 ~ (3-Indolvlmethylidenhydrazlno) -1,2,8,9-tetraa zaphen alen

1.4 g of 3-hydrazino-l, 2,8,9-tetraazaphenalene dihydrochloride are dissolved in 10 ml of water and 10 ml of ethanol, this solution is heated to 70 ° and a solution of 0.73 g of indole-3-3 is added with stirring. aldehyde in 10 ml of ethanol and 10 ml of water. Then 5 ml of 1N sodium bicarbonate solution are added and the mixture is refluxed for 5 minutes. Another 5 ml of sodium bicarbonate solution are added and the mixture is boiled and stirred for a further 30 minutes. Then the red-orange reaction mixture is filtered hot and the precipitate is washed with water and ethanol. Drying under vacuum uriG gives 1.5? g (96% of theory) of 3- (3-Indolylmethylidenhydra zino) -l, 2,8,9-tetraaza which are recrystallized from dimethylformamide-water ser. The melting point is above 330 °.

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Claims (5)

169üOÖ5 claims 1. 3-hydrazino-1,2,8, ⁽ J-tetraazaphenalenes of the general formula I, R = N - NH ^ N ^ p-v- T ¹ p (I) in which R either 2 hydrogen atoms or a benzylidene radical whose benzene ring is replaced by a cyano group Nitro group, an amino group, a dialkyl lower anino group or a lower alkanoylamido group or by at most 3 halogen atoms or lower Alkoxy groups can be substituted, or the cinnamylidene, 3-indolylmethylene or 2-pyridylmethylidene radical means, and their addition salts with inorganic or organic acids. 2. 3-hydrazino-1,2,8,9-tetraazaphenalen and its addition salt with hydrochloric acid, methanesulfonic acid and pharmaceutical acceptable inorganic and organic acids. 3. 3-Benzyliddenhydrazino-1,2,8,9-tetraazaphenalen. 4. 3-cinnamylidene hydrazino-1,2,8,9-tetraa2aphenalen. 009850/709?
Documents (Art / Γ 5. Process for the preparation of compounds of the formula I as defined in claim 1, characterized in that one 3-Mercapto-1,2,8,9-tetreazaphenslene with at least equimolar Reacts amount of hydrazine hydrate, the product is isolated and, if desired, in an addition salt with an inorganic one or organic acid transferred and that to obtain products of the formula I, in the R is different from hydrogen, 3-hydrazino-1,2,8,9-tetraazaphenalene or a salt thereof with one of the meanings of R corresponding to the defined under formula I aromatic Aldehyde converts and the product, if desired, in an addition salt with an inorganic or organic acid Convicted. 009850/2097