DE1468022B - - Google Patents

Description

The invention relates to hydrazine compounds of the general formula I.

H ₃ C-NH-NH-CH ₂ ^ VcH ₂ -CO-NHX

in which X is a hydrogen atom, the isopropyl or the tertiary butyl group and salts thereof Links.

The invention also relates to processes for the preparation of such hydrazine compounds and also cytostatically effective medicaments containing such hydrazine compounds.

Preferred connections are those

l- {p - [(Isopropylcarbamoyl) methyl] benzyl} -

2-methyl-hydrazine
and the
l - {- [(tert-Butylcarbamoyl) methyl] benzyl} -

2-methyl-hydrazine.

The process for the preparation of the compounds of the general formula I is characterized in that that in a known manner in a compound of the general formula II

H ₃ CNN-CH ₂
RR

CH ₂ -CO-NHX

in which X has the meaning given above and R is an arylalkoxycarbonyl radical, the R residues are split off by hydrogenolysis or acidolysis or that a compound of the general Formula III

H, C-NH-N =

CH ₂ -CO-NHX

(III)

in which X has the meaning given above, hydrogenated and optionally the compound obtained of the general formula I converted into a salt.

Starting compounds of the formula II can be prepared, for example, as follows: 1 mol of 1,4-bis-chloromethylbenzene is with 1 mol of the sodium salt of 1,2 - bis - (aryloxycarbonyl) - 2 - methyl - hydrazine condensed (German patent 1,215,725). 1,2-bis-aryloxycarbonyl-1 - [p-Chloromethyl-benzyl] -2-methylhydrazine is converted into 1,2-bis (aryloxycarbonyl) -1 - [p - cyanomethyl - benzyl] - 2 - methylhydrazine with potassium cyanide transferred whose cyano group by treatment with alcoholic hydrochloric acid and then is converted into the carboxyl group with alcoholic alkali. By the action of thionyl chloride the l ^ -bis-tAryloxycarbonyrj-l-ftj-chlorocarbonylmethyl is produced - benzyl] - 2 - methyl - hydrazine, which is converted into the desired by condensation with suitable amines [Carbamoylmethyl-benzyl] -methyl-hydrazine substituted by protective groups, ζ. B. in the 1,2 - bis (benzyloxycarbonyl) -1 - {p - [(isopropylcarbamoyl) - methyl] - benzyl} - 2 - methyl - hydrazine can be converted.

Starting compounds of the formula III can be prepared, for example, as follows: p-chloromethylphenylacetic acid is obtained by introducing ethyl alcoholic hydrochloric acid into the ethyl p-chloromethylphenyl acetic acid ester and then converted to p-formyl-phenylacetic acid ethyl ester according to Sommelet converted. The ester is saponified, treated with thionyl chloride and with suitable Amines converted into the corresponding p-carbamoylmethylbenzaldehydes, which with methylhydrazine to the desired [carbamoylmethylbenzyl] hydrazones, for example to the l- {p - [(isopropylcarbamoyl) - methyl] - benzyl} - 2 - methyl - hydrazone are condensed.

The protective groups R present in compounds of the formula II can be used in a manner known per se, z. B. be split off by hydrogenolysis or acidolysis.

The hydrogenolysis is expediently carried out with catalytically excited hydrogen. As a catalyst Palladium black is preferably used. The acidolysis can be carried out in an acidic anhydrous medium be carried out, e.g. B. with the aid of a hydrohalic acid in the presence of a lower carboxylic acid, primarily with the aid of hydrogen bromide in glacial acetic acid at room or elevated temperature. The conditions depend on the substituents present in the molecule.

It is possible that under the conditions for the splitting off of the protective groups, at the same time also the Substituents X, Y and Z are converted into the desired final form.

The hydrazones of the formula III can be prepared in a manner known per se by hydrogenation, advantageously in Presence of noble metal catalysts such as platinum oxide or palladium carbon, preferably in one inert solvents, such as methyl or ethyl alcohol, converted into the desired end products will.

The substituted hydrazine compounds of the formula I obtainable according to the invention form salts, both with organic acids, e.g. B. with hydrohalic acids, such as hydrochloric acid, hydrobromic acid, Hydriodic acid, with other mineral acids, such as sulfuric acid or phosphoric acid, as well as with organic acids, e.g. B. with tartaric acid, citric acid, oxalic acid, camphor sulfo- * acid, ethanesulfonic acid, toluenesulfonic acid, mandelic acid and others. Preferred salts are the hydrohalides, in particular the hydrochlorides and hydrobromides and also the oxalates.

The Säureadditionsssalze are preferably prepared by treating an inert solvent, the hydrazine derivative with the appropriate acid in _Λ.

The hydrazine compounds of the general formula I are cytostatically active. The l- {p - [(isopropylcarbamoyl) - methyl] - benzyl} - 2 - methyl - hydrazine completely inhibits the growth of an implanted Walker carcinosarcoma in rats after intraperitoneal administration of 20 mg / kg / day. The daily administration of 20 mg of 1 - {p - [(tert. Butylcarbamoyl) - methyl] - benzyl} - 2 - methyl - hydrazine or 25 mg of 1 - [p - (carbamoylmethyl) - benzyl results in the same way ] -2-methyl-hydrazine per kilogram of body weight in rats resulted in a complete inhibition of Walker's carcinosarcoma.
The new hydrazine compounds are also extremely well tolerated. In contrast to Trisäthyleniminobenzochinon they have no damaging effect on the blood, and they are still in a concentration that the therapeutic dose by a lot

times exceeding, tolerable. Another advantage is that the process products with others Cytostatica show no cross-resistance.

The products of the process can therefore be used as agents for the treatment of cancer diseases, e.g. Am Find the form of pharmaceutical preparations use.

example 1

22 g of 1,2 - bis (benzyloxycarbonyl) - 1 - [p - (carbamoylmethyl) - benzyl] - 2 - methyl - hydrazine dissolved in 25 ml of glacial acetic acid and treated with 75 ml of a 33% strength solution of hydrogen bromide in glacial acetic acid. The mixture is left to stand for 4 hours at room temperature, then the precipitated crystals are filtered off and washes them with glacial acetic acid and with ether. By recrystallization l- [p- (carbamoylmethyl) - benzyl] - 2 - methyl - hydrazine - hydrobromide is obtained from ethanol; Melting point 192 to 194 ° C.

The starting material used above can be prepared as follows: A solution of 96 g of 1,2-bis- (benzyloxycarbonyl) -1 - (p-formyl-benzyl) -2-methylhydrazine in 200 ml of bis- (2-methoxyethyl) ether a solution of 4.25 g of sodium borohydride in 10 ml of water is added, while cooling in an ice bath, and the mixture is stirred for 1 hour. Then it is poured onto 21 water, acidified with hydrochloric acid and etherified. The ether extract is washed with water, soda solution and again with water, dried and evaporated. The oil thus obtained (91 g) is dissolved in 200 ml of absolute ether and refluxed with 17 ml of thionyl chloride for 3 hours. The 1,2 - bis - (benzyloxycarbonyl) - 1 - [(p - chloromethyl) benzyl] -2-methyl-hydrazine formed in this way can also be produced in the following way: 35 g 1,4-bis-chloromethylbenzene in 100 ml of absolute dimethylformamide is treated with a solution of 36.7 g of the sodium salt of 1,2 - bis - benzyloxycarbonyl - 2 - methyl hydrazine for 1 hour at 70 ⁰ C heated. The dimethylformamide is distilled off under reduced pressure. The oily residue is adsorbed on silica gel (Merck, particle size 0.2 to 0.5 mm). The 1,2-bis (benzyloxycarbonyl) -1 - (p - chloromethyl - benzyl) - 2 - methyl - hydrazine (22 g) obtained by elution with benzene is treated with a solution of 10 g of sodium cyanide in 300 ml of dimethylformamide for 20 hours Stirred at room temperature. It is then poured into 5 l of water, hardened and washed with water. The residue obtained after drying and evaporation of the ether is a yellow oil and consists of 1,2-bis- (benzyloxycarbonyl) -1 - [p - (cyanomethyl) -benzyl] -2-methylhydrazine. The product obtained is converted into 1,2 - bis (benzyloxycarbonyl) -1 - [ρ - (carbamoylmethyl) benzyl] -2-methylhydrazine by the action of alkaline hydrogen peroxide.

Example 2

12.8 g of 1,2 - bis (benzyloxycarbonyl) -1 - {p - [(tert-butylcarbamoyl) methyl] benzyl} -2-methyl-hydrazine are dissolved in 100 ml of methanol and after the addition of 2 g of 5% palladium-carbon catalyst in shaken in a hydrogen atmosphere. After the uptake of hydrogen has ended, the catalyst is removed filtered off, the filtrate was mixed with one equivalent of ethanolic hydrochloric acid and concentrated to about 30 ml. By adding 250 ml of absolute ether, a crystalline precipitate is obtained, which is filtered off and is recrystallized from methanol / ether. The 1 - {p - [(tert-Butylcarbamoyl) -methyl] -benzyl} obtained in this way - 2 - methyl - hydrazine - hydrochloride melts at 149 to 151 ° C.

The starting product used in Example 2 can be prepared as follows: 9.3 g of that in the example 1, 1,2-bis (benzyloxycarbonyl) -1 - [p - (cyano - methyl) - benzyl] - 2 - methyl - hydrazine are dissolved in a mixture of 11 g of glacial acetic acid and 2.5 g of tert-butyl alcohol. This is done while cooling with an ice bath 3.1 g of concentrated sulfuric acid and then left for 20 hours at room temperature stand. Then it is poured onto ice water, ether is extracted and the ether extract is washed with water, soda solution and again with water. That obtained after drying by evaporation of the ethereal solution yellow oil consists of 1,2-bis- (benzyloxy carbonyl) -1 - {p - [(tert. - butylcarbamoyl) - methyl] - benzyl} -2-methyl-hydrazine.

Example 3

24.2 g 1,2 - bis - (benzyloxycarbonyl) -1 - {p - [(isopropylcarbamoyl) - methyl] - benzyl} - 2 - methyl - hydrazine are mixed with 150 ml of 33% hydrogen bromide in Glacial acetic acid added. The mixture remains at room temperature for 14 hours with occasional shaking stand. Crystalline 1 - {p - [(isopropylcarbamoyl) - methyl] - benzyl} - 2 - methylhydrazine hydrobromide. The pure, through repeated Recrystallization of the colorless crystalline compound obtained from methyl alcohol / ether melts at 197 ° C (decomposition).

The 1,2-bis (benzyloxycarbonyl) -1 - {p - [(isopropylcarbonyl) - methyl] benzyl} -2-methylhydrazine used as the starting product can be prepared as follows: To a solution of 6.8 g of sodium hydride in 140 ml of absolute dimethylformamide, a solution of 89.5 g of dicarbobenzoxymethylhydrazine in 280 ml of dimethylformamide is added dropwise with stirring. Ester are added dropwise in 140 ml of absolute dimethylformamide over 30 minutes into the resulting solution of the sodium salt of the Dicarbobenzoxymethylhydrazins at 8O ⁰ C with vigorous stirring 60.3 g (p-chloromethylphenyl) acetate äthy!. The mixture is stirred for a further 30 minutes at 8O ⁰ C, then cooled and neutralized with a few drops of glacial acetic acid. The dimethylformamide is distilled off at 10 torr.

The oily residue is distributed between 1500 ml of water and 500 ml of methylene chloride. The methyl chloride eluate is disconnected. The aqueous layer is extracted twice with 300 ml of methylene chloride each time. The combined methylene chloride eluates are washed again in 500 ml of water, using dehydrated from sodium sulfate and evaporated under reduced pressure. The oily residue is in 900 ml of absolute methyl alcohol and dissolved with a solution of 16 g of potassium hydroxide in 50 ml of water offset. The reaction mixture remains at 4 ° C. for 16 hours. Then the methyl alcohol distilled off after dilution with 300 ml of water at 10 torr. The aqueous solution is after addition of a further 700 ml of water to remove unsaponified components twice with 250 ml of ethyl acetate each time extracted.

The aqueous layer is separated, made acidic by adding concentrated aqueous hydrochloric acid and exhaustively once with 1000 ml of ethyl acetate and twice with 500 ml of acetic acid

1 4 bö UZZ

acid ethyl ester extracted. The combined ethyl acetate eluates are repeatedly shaken with water until a neutral reaction occurs, with the aid dehydrated from sodium sulfate and evaporated at 10 torr. The oily residue is taken up in benzene and adsorbed on 1.5 kg of silica gel (Merck, core size 0.2 to 0.5 mm). The by eluting 1,2 - bis - (benzyloxycarbonyl) -1 - (p - carboxymethylbenzyl) -2-methylhydrazine obtained with a benzene-ethyl ether mixture 8: 2 After the solvent mixture has been distilled off, it separates out as an almost colorless oil.

A mixture of 21 g of 2-bis (benzyloxycarbonyl) -1 - (p-carboxymethyl-benzyl) _{-2-methyl-hydrazine and 210 ml of thionyl chloride is heated for 2} hours under reflux conditions. The clear, light yellow solution is evaporated at 10 torr and taken up three times with 100 ml of benzene each time to remove the excess thionyl chloride and evaporated again.

The remaining oily acid chloride can be processed further without purification.

22 gl ^ -bis- ^ Benzyloxycarbonyty-l-ip-chlorcarbonyl - methylbenzyl) - 2 - methyl - hydrazine are dissolved in 50 ml of absolute benzene and a solution of 13.6 g of isopropylamine in 100 ml of absolute benzene is added dropwise in the cold . The internal temperature in this case is kept by cooling to a temperature below 2O ⁰ C.

• After completion of the addition, the reaction mixture still is: 2 hours at 20 ° C and an additional hour at 6O ⁰ C stirred. Benzene and excess isopropylamine are distilled off at 10 torr. The oily residue is partitioned between 200 ml of water and 200 ml of methylene chloride. The methylene chloride eluate is separated off. The aqueous layer is extracted twice with 100 ml of methylene chloride each time. The combined methylene chloride eluates are washed one after the other with 50 ml of 2N hydrochloric acid, 50 ml of water, 50 ml of 2N sodium hydroxide solution and twice with 50 ml of water each time, dehydrated with sodium sulfate and evaporated at 10 torr. The remaining 1,2 - bis - (benzyloxycarbonyl) -1 - {ρ - [(isopropylcarbamoyl) - methyl] - benzyl} - 2 - methyl - hydrazine can be further processed without purification.

Claims (3)

Patent claims: 1. Hydrazine compounds of the general formula I HX-NH-NH-CH- CH ₂ -CO-NHX (I) in which X denotes a hydrogen atom, the isopropyl or the tertiary butyl group and salts of these connections. 2. Process for the preparation of hydrazine compounds according to claim 1, characterized in that that in a known manner in a compound of the general formula II H ₃ CNN-CH ₂ - ^ f S ^ CH ₂ -CO-NHX R R in which X has the meaning given above and R is an arylalkoxycarbonyl radical, the R residues are split off by hydrogenolysis or acidolysis or that a compound of the general Formula III H, C-NH-N = CH ₂ -CO-NHX (III) in which X has the meaning given above, hydrogenated and optionally the compound obtained of the general formula I converted into a salt. 3. Cytostatically active drug, characterized in that there is one or more Hydrazine compound (s) according to claim 1 contains.