DE1165013B - Process for the preparation of guanylhydrazones - Google Patents

Description

Process for the preparation of guanylhydrazones It is known that the condensation products of aminoguanidine with various carbonyl compounds have good bacteriostatic effectiveness.

The invention relates to a process for the preparation of guanylhydrazones and salts of the same, which have increased antibacterial efficacy as opposed to have known compounds.

The compounds that can be prepared according to the invention are characterized by the following general formula: wherein R is a C6H5CH2, C6H5 - CH2 - CH2, C6H5 - CH = CH group or a NH2-C-NH-N --CH-C8H4-CH2-, II NH NH2-C-NH-N CH-C6H4-CH2-CH2-, NH NH2-C-NH-N CH-CßH4-CH = CH- II NH and NH0 - C - NH - N = CH - C6H4 - S group II NH represents.

The guanylhydrazones of the invention are prepared by an aldehyde of the formula R'- -CHO where R 'is C6H5-CH2-, C6H5CH2-CH2-, C6HsCH = CH-, OHC - C6H4CH2-, OHC C6H4CH2- - CH2-, OHC C6H4 CM CM- or OHC - C6H4 - S group represents, with aminoguanidine, which is free or in the form of a salt with organic or inorganic acids is present.

The condensation reaction, which takes place in a manner known per se, is carried out by adding the starting aldehyde as well as an addition compound, like the hydrate, the acetal or the alkali bisulfite addition compound with which calculated amount of aminoguanidine converts. Generally the aldehyde is in one inert, water-miscible solvent, and the solution is in a aqueous solution of an aminoguanidine salt allowed to drip. Particularly suitable solvents are the alcohols or other oxygen-containing, water-miscible solvents, such as dioxane, tetrahydrofuran.

An advantageous reaction temperature is that of the boiling point of the used Solvent, and it varies from 50 to 100 "C. In general, the mixture Heated under reflux for 30 minutes to 4 hours. The guanylhydrazone becomes through the addition of alkali precipitated as the free base, and it can be easily removed by centrifugation or filtration be separated. In order to produce the corresponding salts, one works, as usual, by dissolving the hydrazones obtained in a suitable solvent, the solution treated with the desired acid and then precipitated with ether.

The starting aldehydes are well known, with the exception of 4,4'-bis-formyl-diphenyl sulfide and stilbene. The production of these aldehydes is usually via the corresponding 4,4'-dimethyl derivatives or carried out according to the Sommelet reaction. The stilbene-4,4'-dialdehyde can also by reacting the diazo compound of p-aminobenzaldehyde with the p-formylcinnamic acid according to M e r w e i n.

The guanylhydrazones according to the invention have an important antibacterial property Effect with a broad spectrum of effectiveness. They inhibit even at low seF Concentrations the growth of gram-positive and gram-negative bacteria, such as z. B. Salmonella tiphi, Sarcina lutea, Streptococcus pyogens var. Aureus, Streptococcus haemolyticus, Corynebacterium diphtheriae, Eschesichia coli, and also some Fungal strains such as B. Candida albicans and Neurospora sitophila; their effect is particularly valuable against Streptococcus pyogens var. aureus.

The guanylhydrazones are opposite to those from the British patent 768 089 known compounds, diphenyl-4,4'-bis-formylguanylhydrazone and diphenylether-4,4'-bis-formylguanylhydrazone, consider, as explained in the table below, where the lowest concentrations (y / cm3), the compounds compared showing the growth of, for example, Streptococcus pyogens var. aureus.

Bacteriostatic effect against Streptococcus pyogens var. Aureus Compared compounds γ / cm² Stilbene-4formylguanylhydrazone ..... 1.25 Diphenylmethane-4-formylguanylhydrazone. . 3 Diphenylethane-4-formylguanylhydrazone ... 3 Diphenylmethane-4,4'-bis-formylguanyl- hydrazone .. .. 3 Diphenylethane-4,4'-bis-formylguanyl- hydrazone ... ...... ...... 3 Diphenyl sulfide-4,4'-bis-formylguanyl- hydrazone ................................. 1.5 Diphenyl-4,4'-bis-formylguanylhydrazone ... 12.5 Diphenyl ether-4,4'-bis-formylguanyl- hydrazone ................................ 6 The following examples illustrate the invention.

Example 1 In one equipped with a dropping funnel and mechanical stirrer 2.72 g of aminoguanidine bicarbonate in 30 cm3 of water are added to the three-necked flask; the The solution obtained in this way is added to 2 cm3 of concentrated hydrochloric acid, then a Add dropwise a solution of 3.88 g of 4-diphenylmethanaldehyde in 50 cm3 of ethanol. After 15 The addition of the aldehyde is complete in minutes. The mixture is stirred for 2 hours refluxed, then cooled and diluted with water. One poses with Caustic soda and phenolphthalein alkaline and centrifuges the resulting precipitate, by washing well with water. Diphenylmethane-4-formylguanylhydrazone is obtained in this way as a white crystalline body, which after recrystallization from dilute ethanol melts at 177 to 178 "C. Yield 83%.

The product thus obtained is dissolved in anhydrous ethanol and treated with hydrogen chloride gas.

The corresponding crystalline hydrochloride precipitates through the addition of ether the end; 198 to 200 ° C.

Diphenylethane-4-formylguanylhydrazone is obtained in the same way, which melts after recrystallization from benzene petroleum ether at 176 to 177 ° C.

Yield 82%. The chlorohydrate usually obtained melts 228 to 229 ° C.

Example 2 An aminoguanidine chlorohydrate solution consisting of 2.72 g of the corresponding carbonate is obtained, 4.1 g of 4-stilbene aldehyde are added dropwise in 60 cm3 of dioxane added. By working as described in Example 1, one obtains the stilbene-4-formylguanylhydrazone chlorohydrate, which after recrystallization from methanol-ether melts at 286 to 287 "C.

Yield 82%.

Example 3 a) A mixture of 93 g of diphenyl sulphide, 1000 cm3 of glacial acetic acid, 400 cm3 of 40% formaldehyde, 350 cm8 of concentrated hydrochloric acid and 20 g of aluminum chloride 400 cm3 of concentrated sulfuric acid are slowly added at 40 ° C. After 6 hours Standing at 50 ° C., the reaction mixture is poured into 3 l of water and extracted with ether and washed neutral with a sodium carbonate solution. The essential extracts will be dried with sodium sulfate and then evaporated; the residue distills at 170 ° C / 0.2 torr. After recrystallization from methanol, 4,4'-bis-chloromethyl-diphenyl sulfide is obtained; M.p. 95 to 96 ° C. 7.08 g of the 4,4'-bis-chloromethyl-diphenyl sulfide thus obtained are refluxed with 60 cm3 of chloroform and 11 g of hexamethylenetetramine for 4 hours, then the chloroform is evaporated and the residue with 70 cm3 of 50% acetic acid Heated for 3 hours at 80 ° C. The mixture is poured into water and extracted with ether and then first with a saturated sodium bicarbonate solution, then with Water washed. The dried and evaporated essential extracts provide 4,4'-diformyl-diphenyl sulfide, which after recrystallization from ethanol at 129 melts up to 130 ° C. Yield 4g. b) To an aqueous aminoguanidine chlorohydrate solution, obtained from 5.44 g of the corresponding carbonate, a solution is left slowly drop in 5.1 g of 4,4'-diformyl diphenyl sulfide in 60 cm3 of tetrahydrofuran. The mixture is refluxed with stirring for 3 hours, then cooled, diluted with water and made alkaline with sodium hydroxide solution and phenolphthalein. The resulting precipitate is filtered off with suction and washed out with water. So get one the diphenyl sulfide-4,4'-bis-formylguanylhydrazone, which after recrystallization from alcohol-water melts at 265 ° C. Yield 750 / o. The base crystallizes with it 2 molecules of water.

The diphenyl sulfide 4,4'-bis-formylguanylhydrazone prevents the growth of Micrococcus piogenes var. areus, of Bacterium coli comm. (Escherichia coli) and Salmonella tiphi at concentrations of 1.5, 3 and 3 y / cm8, respectively. The product is superior to similar, already known compounds; for example, it is more effective than the diphenyl disulfide-4,4'-bis-guanylhydrazone known from Austrian patent specification 190 941, the growing of the above Microorganisms at concentrations of 1.5 to 3.5, 15 to 31 or 15 y / cm3 prevented.

Example 4 In an aminoguanidine chlorohydrate solution consisting of 5.44 g of the corresponding carbonate was obtained, a solution of 5.7 g of 4,4'-diphenylethane dialdehyde tetramethylacetal is left Drip slowly into 100 cm3 of anhydrous ethanol. The mixture is stirring Boiled under reflux for 3 hours, then cooled and diluted with water. One poses alkaline with caustic soda and phenolphthalein and centrifuges the resulting Precipitate by washing well with water. This is how diphenylethane is obtained - 4,4 '- bis - formylguanylhydrazone, which after recrystallization from dilute methanol melts at 271 ° C.

Diphenylmethane-4,4'-bis-formylguanylhydrazone, F. 268 to 270 "C, that of the corresponding chlorohydrate, M. 2620 C, usually is converted.

Claims (1)

Claim: Process for the preparation of guanylhydrazones of the general formula wherein R is a C6H5CH2-, C6H5-CH2-CH2-, C6H5-CH = CH- group or a NH2-C-NH N -N = CH¼H4 CH2 - CHr, II NH NH2-C-NH-N = CH-CßH4-CH = CH- II NH and NH2-C-NH-N = CH-C6H4-S-Gnippe NH represents, and their salts, characterized in that an aldehyde of the formula is used in a manner known per se where R 'represents a C6H5-CH2-, C8H5CH2 - CHr, C6H5CH = CH-, OHC - C8H4CH2-, OHC - C8H4 - CH2 - CH2-, OHC - C8H4 - CH = CH- or OHC - C6H4 - S group, reacts with the calculated amount of aminoguanidine or its salts and then isolates the guanylhydrazone thus obtained as a free base or in the form of a salt. Publications considered: Austrian patent specification No. 190941.