NO116314B - - Google Patents

Description

Process for the production of substituted 3-amino-hydan-toins.

The present invention relates to the production of pharmacologically active

hydantoin derivatives, namely 5,5-disubstituted 3-amino-hydantoin with the general

formula

in which

R, and R2 mean the same or different,

possibly with O or S interrupted

and/or in occurring aromatic nuclei halogen-substituted carbon hydrogen residues, which can also be connected in between, and

Rs means a hydrogen residue or a

low molecular weight alkyl residue. It is

in particular found that these compounds have a strong diuretic effect.

5,5-disubstituted 3-amino-hydantoins

is so far not known. C-monosubstituted

glycine-N-carbon diester was transferred by K.

Schlbgl and G. Korger, Monatshefte fiir

Chemie 82, 799-814 (1951) by treatment

with hydrazine in alkali-soluble compds., which were first considered C-substituted

as-triazinediones. Later, K. Schlogl,

J. Derkosch and E. Wawersich (ibidem 85,

607—626 (1954), however, demonstrate that at

by all the -mentioned reaction products

with a high probability it was about 5-monosubstituted 3-amino-hydantoins. The aforementioned authors have neither indicated pharmacological properties nor proposed pharmacological application possibilities for the compounds they produced. All the more surprising was the realization that 5,5-disubstituted 3-aminohydantoins according to the above general formula have the already mentioned diuretic effect.

These 5,5-disubstituted 3-aminohydantoins can be prepared in a manner known per se, by exposing, in the presence or absence of solvents, a reactive functional derivative of a monohydrazide of a C,C-disubstituted glycine-N-carboxylic acid with the general formula

in which Rj, R2 and R3 have the meaning given above, with respect to the remaining carboxyl group, or the monohydrazide of such an acid with respect to the carboxyl group in the N-position, i.e. with a free carboxyl group in the C-position, whereby the hydrazide nitrogen atom in end position may also carry an easily cleavable substituent, for material-closing conditions, especially elevated temperature. An advantageous embodiment of this method consists, for example, of in that the dihydrazide is heated according to the reaction scheme where R1, R0 and R3 have the meaning indicated above, in an aqueous suspension or solution. In this way, for continuous removal of the liberated hydrazine, a large part of the water can be gradually distilled. The dihydrazides required for this can be obtained, e.g. by heating diesters of C,C-disubstituted glycine-N-carboxylic acids with an excess of hydrazine in alcoholic solution. According to another embodiment, esters of monohydrazides of C,C-disubstituted glycine-N-carboxylic acids are heated until complete cleavage of the oxy compound present in the ester bond

In this reaction scheme, X means the residue in the oxy compound present in the ester bond. The monohydrazide esters of C,C-disubstituted glycine-N-carboxylic acids serving as starting material for this embodiment are obtained, e.g. when on the corresponding diester at room temperature or only slightly elevated temperature, hydrazine is allowed to act in alcoholic solution.

Instead of the mentioned hydrazides and esters, functional derivatives of monohydrazides of C,C-disubstituted glycine-N-carboxylic acids with regard to their other carboxyl function, e.g. also the nitriles, i.e. the monohydrazide nitriles of C,C-disubstituted glycine-N-carboxylic acids:

Instead of boiling in water or heating to higher temperatures, possibly also heating in an acidic or alkaline medium comes into consideration as a further ring-closing condition. Thus, one can e.g. boil a C,C-disubstituted N-benzylidenehydrazinocarbonylglycine in acetic acid, hydrochloric acid solution.

In the series of starting materials mentioned above, the nitrogen atom of the hydrazine group carries a benzylindene residue in the terminal position. As a further example of an easily cleavable substituent of the hydrazide group, the isopropylidene residue can be mentioned. These substituents are split off during the ring closure, especially when this occurs by boiling in water or in aqueous acids. The diesters of C,C-disubstituted glycine-N-carboxylic acids already mentioned as starting materials for the production of the dihydrazides and monohydrazide esters used for ring closure can, in turn, e.g. by proceeding from ketones with the general formula Rj-CO-R0 prepared according to various per se known reaction processes, why readily available ketones form the starting materials for numerous disubstituted 3-amino-hydantoins according to the invention. Such ketones can be transferred, e.g. first in the nitriles of C,C-disubstituted glycines and these in the corresponding esters, which on reaction with chloroformic acid esters give the desired diesters of C,C-disubstituted glycine-N-carboxylic acids. One can also arrive at the esters of C,C-disubstituted glycines if one transfers the ketones in a known manner (compare e.g. Org. Synth. 20, 42) in the corresponding hydantoins, splits these up and esterifies the amino acids obtained. For the preparation of the immediate starting materials for such 5,5-disubstituted 3-amino-hydantoins, which do not correspond to any readily available ketones R,-CO-R2, there is a further series of reactions which offers numerous variation possibilities with regard to reaction the course of the residues R, and R2 available in the preceding Hoffmann decomposition of C,C-disubstituted cyanacetamines according to Errera during cyclization to disubstituted hydantoins. Other possibilities for the preparation of the starting materials arise from the syntheses described in the literature for α-amino acids.

The following examples will explain the production of the compounds in more detail. In the examples, parts means parts by weight, unless parts by volume are expressly mentioned. Parts by weight relate to parts by volume such as gr. to cm<?>».

Example 1:

A solution of 20.3 parts of N-carbethoxy-α-amino-isobutyric acid ethyl ester and 50 parts of hydrazine hydrate is heated in 200 parts by volume of absolute ethyl alcohol for 20 hours under reflux.

The alcohol is evaporated off, the residue is dissolved in 500 parts by volume of distilled water, and the solution is concentrated at normal pressure by evaporating the water to 50 parts by volume. On cooling, 5,5-dimethyl-3-amino-hydantoin crystallizes out in colorless crystals. The melting point after recrystallization from water is 184° C.

Example 2:

A solution of 24.5 parts of N-carbethoxy-a-amino-a-isobutyl-propionic acid ethyl ester (boiling point 20 mm 150—153° C) and 50 parts of hydrazine hydrate in 200 parts by volume of absolute alcohol is heated for 20 hours under reflux . The alcohol is then evaporated off, the residue is dissolved in 500 parts by volume of distilled water, and the solution is concentrated at normal pressure by evaporating the water to approx.

50 parts by volume. Crystallizes on cooling

5-methyl-5-isobutyl-3-amino-hydantoin in colorless crystals. The melting point for this compound after recrystallization from dilute methanol is 171° C.

Example 3:

A solution of 23.1 parts of N-carbethoxy-(x-amino-α-ethyl-butyric acid ethyl ester (boiling point 21 mm 138—140° C) and 50 parts of hydrazine hydrate is heated in 200 parts by volume of absolute ethanol for 30 hours under to -baking run. The alcohol is then evaporated, the residue is suspended in 500 parts by volume of distilled water, and the solution is concentrated at normal pressure by evaporating the water to about 50 parts by volume. On cooling, 5,5-diethyl-3-amino-hydantoin crystallizes out in colorless crystals. Melting point is after recrystallization from dilute ethanol 178-180° C.

Example 4:

A solution of 25.9 parts of N-carbethoxy-a-amino-a-butyl-butyric acid ethyl ester (boiling point 20 ,,„„ 160—162° C) and 50 parts of hydrazine hydrate is heated in 200 vol.

shares absolute ethanol for 20 hours during add-

back race. The alcohol is then evaporated off, the residue is suspended in 500 parts by volume of distilled water and concentrated by evaporating the water at normal pressure to approx. 70 volume

parts. On cooling, 5-ethyl-5-n-butyl-3-amino-hydantoin crystallizes out in colored

loose crystals, which after recrystallization from water have a melting point of 143—

144°C.

Example 5:

A solution of 27.3 parts of N-carbethoxy-n-hexyl-α-amino-propionic acid-ethyl-

ester (boiling point 22 „„„ 180—181° C) and 65

parts hydrazine hydrate is dissolved in 175 volume

shares absolute methanol for 30 hours under add-

back race. The solvent is then evaporated off, the residue is suspended in 750 parts by volume of distilled water and concentrated by de-

steaming the water at normal pressure to approx. 55 parts by volume. On cooling, the crystals

sers 5-methyl-5-n-hexyl-3-amino-hydan-

toin out in colorless crystals. After recrystallization from ethanol, this compound melts at 136°C.

Example 6:

A solution of 24.3 parts of N-carbethoxy-1-amino-cyclohexanecarboxylic acid-ethyl-

ester (which is obtained from 1-amino-cyclohexanecarboxylic acid ethyl ester with boiling point i4 = 100° by treatment with chloroformic acid ethyl ester in chloroform while shaking with dilute aqueous caustic soda) and 60 parts of hydrazine hydrate are dissolved in 200 parts by volume of absolute ethanol for 30 hours under reflux .

The ethanol is then evaporated off, the rest suspended

their in 500 parts by volume of distilled water and brought to a boil, whereupon dissolution of the dihydrazide gradually occurs. By off-

evaporation of the water is concentrated at nor-

template press the solution to approx. 60 volume de-

laughing. After cooling, 5,5-pentamethylene-3-amino-hydantoin is separated and recrystallized

seres from ethanol.

Example 7:

A solution of 23.9 parts of N-carbo-methoxy-α-amino-α-benzyl-propionic acid-

methyl ester, melting point 45°, or 26.7 parts N-carbethoxy-a-amino-a-benzyl-propion-

acid ethyl ester and 60 parts of hydrazine hydrate are heated in 200 parts by volume of absolute ethanol for 30 hours under reflux. After evaporation

of the solvent, the residue is suspended in 1000 parts by volume of water and con-

centers by evaporating the water under normal pressure the total volume to approx. 80 volume

parts. After cooling, it is filtered off

distinguished 5-methyl-5-benzyl-3-amino-

hydantoin and recrystallized from ethanol.

Analogously, the following conjunc-

share produce:

5-methyl-5-ethyl-3-amino-

hydantoin M.p. 157° C 5-methyl-5-n-propyl-3-amino-hydantoin » 137° C 5-ethyl-5-n-amyl-3-amino-hydantoin » 140° C 5-methyl-5-cyclopropyl-3 -

amino-hydantoin » 160° C 5-methyl-5-phenyl-3-amino-hydantoin » 166° C 5-ethyl-5-phenyl-3-amino-

hydantoin » 146° C 5,5-diphenyl-3-amino-hydantoin » 188° C 5 - methyl 1- 5 - ally 1- 3 - amino -hy dantoin 5-ethyl-5-cyclohexenyl-3-amino-

hydantoin 5-methyl-5-(p-chloro-phenyl)-3-amino-

hydantoin 5-methyl-5-(p-methoxy-phenyl-3-

amino-hydantoin 5-methyl-5-phenoxyethyl-3-amino-

hydantoin 5-ethyl-5-methylmercaptoethyl-3-

amino-hydantoin 5-methyl-5-sec.butyl-3-amino-• hydantoin l,5-diethyl-5-methyl-3-amino-hydantoin l,5-dimethyl-5-isobutyl-3-amino-hydantoin l ,5-dimethyl-5-phenyl-3-amino-hydantoin l-methyl-5,5-tetramethylene-3-amino-

hydantoin

Claims (3)

1. Process for the production of substituted 3-amino-hydantoins, character- characterized by subjecting, in the presence or absence of solvents, to ring-closing conditions, particularly elevated temperature, a reactive functional derivative of a monohydrazide of a C,C-disubstituted glycine-N-carboxylic acid with the general formula in which RL and R2 mean the same or different, possibly at O or S interrupted and/or in occurring aromatic nuclei halogen-substituted carbon hydrogen residues, which can also be connected in between, and R., means hydrogen or a low molecular alkyl residue. with respect to the remaining vessel boxyl function, or the monohydrazide of such an acid with regard to the carboxyl group in the N-position, whereby the hydrazide nitrogen atom in the terminal position may optionally also carry an easily cleavable substituent. 2. Method according to claim 1, characterized in that the dihydrazide of a C,C-substituted glycine-N-carboxylic acid with the general formula defined in claim 1 is heated in water. 3. Process according to claim 1, characterized in that one heats an ester of the monohydrazide of a C,C-disubstituted glycine-N-carboxylic acid with the general formula defined in claim 1 until complete cleavage of the oxy compound present in the ester compound.