NO121400B - - Google Patents

Description

Process for the production of hitherto unknown, therapeutically active derivatives of the sulfanilamide.

The present invention relates to a method for the production of previously unknown, therapeutically active derivatives of the sulfanilamide.

Compounds of the general formula I,

where R means a lower alkyl residue with at most 5 carbon atoms or a monocycloalkyl- or monocyclo-

alkenyl radical with at least 6 carbon atoms,

and their addition salts with inorganic and organic acids are hitherto unknown.

As has now been found, these compounds possess valuable pharmacological properties, in particular strong hypoglycemic action. This is particularly unexpected, as it is known that sulfaguanidine and N-alkyl derivatives of the same as also N-(1-imidazolin-2-yl)-p-chlorobenzenesulfonamide do not have a hypoglycaemic effect. The N-(1-imidazolin-2-yl)-p-chlorobenzenesulfonamide like also the compounds of the general formula I contains a cyclic guanidine group. Cyclic analogues of hypoglycemically active arylsulphonylureas, namely 1-aryl-sulphonyl-2-imidazolidinones, on the contrary, show a hyperglycemic effect. In contrast to sulfaguanidine and N-sulfanylyl-N<1->alkyl ureas, the new compounds of the general formula I are free of antibacterial action. The new compounds produced according to the invention are suitable for peroral or parenteral administration for the treatment of diabetes.

In the new compounds with the general formula I, R as a lower alkyl residue can mean, for example: methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, sec.butyl-, tert.butyl-, pentyl-, isopentyl-, 1,1-dimethylpropyl as well as the 2,2-dimethylpropyl group and as the monocycloaliphatic hydrocarbon residue cyclopropyl-, cyclopropylmethyl-, cyclobutyl-, cyclobutylmethyl-, cyclopentyl-, cyclopentyl-methyl-, cyclohexyl-, cyclohexylmethyl-, cyclohexylethyl-, cycloheptyl- , cycloheptylmethyl-, cyclooctyl-, cyclooctylmethyl-, cyclononyl-, cyclodecyl-, 2-cyclopenten-1-yl-, 2-cyclohexen-1-yl-, 3-cyclohexen-1-yl-, 2-methyl-2-cyclohexene -1-yl-, 3-methyl-2-cyclohexen-1-yl-, 3-methyl-5-isopropyl-2-cyclohexen-1-yl and 4-cycloocten-1-yl group.

For the preparation of compounds with the general formula I according to the invention, a reactive functional derivative of a sulfonic acid with the general formula II, where X means a residue, which by hydrolysis, reduction or reductive cleavage can be transferred to a

amino group,

optionally in the presence of an acid-binding agent with an amine of the general formula III,

where R has the meaning given under formula I, hydrolyze or reduce the reaction product to convert the group X into the free amino group and, if desired, transfer the resulting compound with an inorganic or organic acid to an addition salt.

As a reactive functional derivative of a sulphonic acid with the general formula II, e.g. halide, in particular a chloride, or also an anhydride of the general formula Ila. The reaction preferably takes place in the presence of a water-miscible or immiscible inert organic solvent in the presence or absence of water. Suitable inert organic solvents are e.g. hydrocarbons, such as benzene, toluene or xylene, ether-like liquids such as diethyl ether, dioxane or tetrahydrofuran, chlorinated hydrocarbons, such as methylene chloride, and lower ketones, such as acetone or methyl ethyl ketone. Inorganic bases or salts can be used as acid-binding agents, such as e.g. an alkali hydroxide, acetate, hydrogen carbonate, carbonate and phosphate, such as sodium hydroxide, acetate, hydrogen carbonate, carbonate and phosphate or as the corresponding potassium compounds. Furthermore, calcium oxide, -carbonate as well as -phosphate and magnesium carbonate can also be used. Instead of inorganic bases or salts, organic bases such as e.g. pyridine, trimethyl- or triethylamine, N,N-diisopropylmethylamine or collidine. These can be added in excess, also used as a solvent.

The subsequent conversion of the group X in the reaction product to the free amino group which transfers this to a compound of the general formula I is carried out depending on the type of the group X by hydrolysis, reduction or reductive cleavage.

Upon hydrolysis to the free amino group transferable residues X

is e.g. acylamino residues, such as the acetamido group. Furthermore, such residues are lower alkoxycarbonylamino residues, such as e.g. the ethoxycarbonyl group, aryloxycarbonylamino residues, such as the phenoxycarbonylamino residue or arylmethoxycarbonylamino residues, such as the benzyloxycarbonylamino residue or residues of corresponding thiocarboxylic acid derivatives. Further examples are substituted methylene amino residues, such as e.g. the benzylideneamino or p-dimethylamino-benzylideneamino group. The hydrolysis to release the amino group can e.g. take place in an acidic medium such as by heating in dilute methanolic hydrochloric acid, or if X represents an alkoxycarbonylamino residue, also under mild alkaline conditions, e.g. using l-n to 2-n caustic soda.

An example of a residue transferable for reduction to the amino group

X is the nitro group and examples of such residues as wood

reductive cleavage leading to the amino group is the phenylazo or p-dimethylamino-phenylazo groups. The reduction of these residues can generally take place catalytically, e.g. by means of hydrogen in the presence of Raney nickel, palladium or platinum charcoal, in an inert solvent such as e.g. ethanol. Alongside this, other common reduction methods are also taken into account, e.g. the reduction of nitro groups or the reductive cleavage of azo groups by means of iron in acetic or hydrochloric acid.

Examples of starting compounds with the general formula III are 1-methyl-, 1-ethyl-, 1-propyl-, 1-isopropyl-, 1-butyl-, 1-isobutyl-, 1-sec.butyl-, 1-tert. butyl-, 1-pentyl-, 1-isopentyl-, 1-(1,1-dimethyl-propyl)-, 1-cyclopropyl-, 1-cyclopropylmethyl-, 1-cyclobutyl-, 1-cyclobutylmethyl-, 1-cyclopentyl- , 1-cyclopentyl-methyl-, 1-cyclohexyl-, 1-cyclohexylmethyl-, 1-(2-cyclohexylethyl)-, 1-cycloheptyl-, 1-cycloheptylmethyl-, 1-cyclooctyl-, 1-cyclooctylmethyl-, 1-cyclononyl -, 1-cyclodecyl-, 2-cyclopenten-1-yl-, 2-cyclohexen-1-yl-, 3-cyclohexen-1-yl-, 2-methyl-2-cyclohexen-1-yl-, 3-methyl -2-cyclohexen-1-yl-, 3-methyl-5-isopropyl-2-cyclohexen-1-yl- and 4-cycloocten-1-yl-2-amino-2-imidazoline.

The 1-methyl-, 1-cyclohexyl- and 1-(2-cyclohexylethyl)-2-amino-imidazoline are e.g. described in the literature. Further connections are obtained e.g. according to the methods used for the production of the aforementioned known compounds, of which by proceeding from the corresponding definition for R substituted ethylene diamines. These N-substituted ethylenediamines are reacted, e.g. with carbon disulphide to 1-substituted 2-imidazolidin ions, and transferred with methyl iodide to correspondingly substituted 2-methylthio-2-imidazolinium iodides, which on reaction with ammonia give the desired compounds of the general formula III. According to another method, these compounds are obtained by condensation of N-substituted ethylenediamines with cyanogen chloride, while a third method consists in reacting an N-substituted ethylenediamine with a salt of S-methylisothiocarbamide to the corresponding salt of an N-(2-subst. aminoethyl)-guanidine and

heats this until the ring hydration of the corresponding salt of 1-substituted 2-amino-imidazoline has taken place. As a fourth method, analogous to the preparation of the known homologues 1-dodecyl-2-amino-imidazoline, the reaction of 2-imino-imidazolidine with a lower alkyl halide or a suitable monocycloaliphatic halide comes into consideration.

The compounds of the general formula I obtained according to the process according to the invention are then transferred, if desired, to their salts with inorganic as well as organic acids. The production of these salts can be found e.g. place by reacting compounds of the general formula I with the equivalent amount of an acid in a suitable aqueous-organic or organic solvent such as e.g. methanol, ethanol, diethyl ether, chloroform or methylene chloride.

For use as pharmaceuticals, instead of the free compounds of the general formula I, their pharmaceutically usable salts with acids can be used. Suitable addition salts are e.g. salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-hydroxy-ethanesulfonic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid and embonic acid.

The following examples explain in more detail the preparation of the new compounds of the general formula I and of previously undescribed intermediates. The temperatures are indicated in degrees Celsius.

EXAMPLE 1

a) 355 g of 1-butyl-2-amino-2-imidazoline hydrochloride is added in portions to a solution of 198 g of sodium hydroxy in 2 liters of water. A solution of 443 g of p-nitrobenzene sulphochloride in 2 liters of acetone is then added dropwise over the course of 15 minutes and the resulting red reaction mixture is heated for 3 hours at 70°, whereby the acetone is distilled off. The remainder is poured onto ice and the raw product is suctioned off. For purification, this is taken up in 2 liters of 2-n hydrochloric acid. Filter from insoluble parts, wash with water and precipitate the free base from the hydrochloric acid solution by pouring this onto ice and concentrated ammonia. The precipitate is sucked off, washed with water and recrystallized

from benzene. The pure 1-(p-nitro-phenylsulfonyl)-2-imino-3-butyl-imidazolidine obtained melts at 98 - 99°.

b) Dissolve 390 g of the nitro compound prepared according to a) in 15 liters of ethanol and reduce the nitro group in the presence

of platinum-coal (5% platinum) with hydrogen at 20° and normal pressure. It is then filtered from the catalyst and the filter residue is washed with ethanol. The filtrate is evaporated in a vacuum, the residue, the crude base, is added with one liter of 2-N hydrochloric acid, the undissolved parts are filtered off and washed in water. The crystalline, pure base is then precipitated from the hydrochloric acid filtrate with 2-n caustic soda. It is sucked off, washed with water and dried in a vacuum at 90°. The obtained 1-sulfanyl-2-imino-3-butyl-imidazolidine melts

at 179 - 181°.

EXAMPLE 2

a) 60 ml of 5-n caustic soda and 30 g of ice are added to 20.5 g of 1-cyclohexyl-2-amino-2-imidazoline hydrochloride and a solution of 26 g of p-nitro-benzene sulphochloride in 100 ml of acetone is added to the mixture. The crude 1-(p-nitro-phenylsulfonyl)-2-imino-3-cyclohexyl-imidazolidine crystallizes out immediately. It is suctioned off, washed with water and recrystallized from a little ethanol m.p.

160 - 161° during cleavage.

b) 35.2 g of the nitro compound prepared according to a) are dissolved in 1 liter of ethanol and hydrated in the presence of palladium charcoal (50%

palladium) with hydrogen at 20° and normal pressure until standstill. It is then filtered from the catalyst, washed with ethanol and the filtrate evaporated in a vacuum. Recrystallization of the residue from dioxane water gives the pure 1-sulfanylyl-2-imino-3-cyclohexylimidazolidine with m.p. 181 - 183°.

EXAMPLE 3

a) 10.0 g of 1-butyl-2-amino-2-imidazoline hydrochloride is added to 5.5 g of sodium hydroxide in 55 ml of water. It obtained

clear solution, 15 g in 100 ml of hot acetone dissolved in p-acetylamino-benzene sulphochloride are added, whereby the reaction mixture heats up and precipitates a thick, white precipitate. The mixture is heated for 1/2 hour at 90 - 95° and concentrated in vacuo. The remaining crystal mass is sucked off, washed with water and recrystallized from 1 liter of ethanol. The colorless p-(2-imino-3-butyl-1-imidazolidinyl-sulfonyD-acetanilide is obtained, which melts at 243 - 244°. b) 15 g of the acetanilide derivative prepared according to a) is heated in 50 ml of 2-n hydrochloric acid one hour at 80°. The solution cooled to 20° is then made alkaline with 2-n caustic soda, the precipitate formed is sucked off, and it is washed with water. The filter residue is recrystallized from ethanol and the 1-sulfanilyl-2-imino-3-butyl-imidazolidine is obtained with m.p. 179 - 181°.

EXAMPLE 4

a) 10.0 g of 1-butyl-2-amino-2-imidazoline hydrochloride is added to 5.5 g of sodium hydroxide in 55 ml of water. It obtained

When the solution is clear, 12.5 g of N-methoxycarbonyl-sulfanyl chloride in 100 ml of acetone are added. The solution briefly changes color to yellow, after which a black, colorless precipitate immediately falls out. The mixture is added to 100 ml of water, the precipitate is filtered off and washed with water. Recrystallized from methanol, the pure p-(2-imino-3-butyl-1-imidazolidinylsulfonyl)-carbanilic acid ethyl ester obtained melts at 198 - 200°. b) 17.7 g of the methoxycarbonyl compound produced according to a) is refluxed for 1 hour in 100 ml of 90% methanol,

which contains 6 g of sodium hydroxide. The reaction mixture obtained is concentrated in vacuo and 50 ml of water is added to it. The formed crystalline precipitate is then suctioned off and washed with 100 ml of water. After recrystallization from ethanol, the obtained 1-sulfanylyl-2-imino-3-butyl-imida-

zolidine at 179 - 181°.

EXAMPLE 5

Analogously to example 3a) one obtains from 10 g of 1-sec.butyl-2-amino-2-imidazoline hydrochloride and 15 g of p-acetylamino-benzenesulfochloride 4'-(2-imino-3-sec.butyl-1-imidazolidinylsulfonyl) -acetanilide with m.p. 250 - 251°, which according to example 3b) is hydrolysed to 1-sulfanyl-2-imino-3-sec.butyl-imidazolidine with m.p.

173 - 173.5°.

EXAMPLE 6

a) Dissolve 13.5 g of 1-methyl-2-amino-2-imidazoline hydrochloride in 150 ml of water and add 14 g of sodium hydroxide. Here on

23.4 g of p-acetylaminobenzene sulphochloride in 300 ml of acetone is added to the solution, whereby the reaction mixture heats up and a thick crystal mass precipitates out. The mixture is kept under reflux for 1 hour, cooled and diluted with 250 ml of water. The crystals are filtered off and recrystallized from dimethylformamide-water. The 1-(p-acetamidophenylsulfonyl)-2-imino-3-methylimidazolidine melts at 2 78 - 2 79°.

b) Dissolve 29.6 g of 1-(p-acetamidophenylsulfonyl)-2-imino-3-methyl-imidazolidine in 240 ml of 2-n hydrochloric acid and heat 30

minutes at 80°. After cooling, the solution is stirred into 300 ml of 2N caustic soda. The precipitated crystals are filtered off and recrystallized from methanol/water. The pure 1-sulfanyl-2-imino-3-methyl-imidazolidine melts at 209 - 210°.

EXAMPLE 7

Analogous to example 6 is obtained from 14.9 g of 1-ethyl-2-amino-2-imidazoline hydrochloride in 150 ml of water and 10 g of caustic soda with 23.4 g of p-acetylaminobenzene sulfochloride in 300 ml of acetone 1-(p-acetamido-phenylsulfonyl )-2-imino-3-ethyl-imidazolidine with a cleavage point of 250°, which upon heating for 30 minutes in 2-n hydrochloric acid at 80° is saponified to 1-sulfanyl-2-imino-3-ethylimidazolidine with a melting point of 172 - 173° .

EXAMPLE 8

Analogous to example 6 is obtained from 20.2 g of 3-cyclohexen-1-yl-2-amino-2-imidazoline hydrochloride in 150 ml of water and 10 g of caustic soda with 23.4 g of p-acetamidobenzene sulfochloride in 300 ml of acetone 1-(p -acetamidophenylsulfonyl)-2-imino-3-cyclohexen-1-yl-imidazoli-

dinet, as by heating for 30 minutes in 2-n hydrochloric acid at 80°

saponified to 1-sulfanilyl-2-imino-3-cyclohexen-1-yl-imidazoli-

your dinner. Temp. 172 - 173° (from methanol).

Claims (1)

Process for the preparation of previously unknown, therapeutically active derivatives of the sulfanilamide of the general formula I, where R means a lower alkyl radical with no more than 5 carbon atoms or a monocycloalkyl or monocycloalkenyl radical with no more than 6 carbon atoms, and their addition salts with inorganic and organic acids, characterized by reacting a reactive functional derivative with a sulfonic acid of the general formula II, where X means a residue which by hydrolysis, reduction or reductive cleavage can be transferred to an amino group, optionally in the presence of an acid-binding agent with an amine of the general formula III, where R has the meaning given under formula I, hydrolyzes or reduces the reaction product to convert the group X into the free amino group and optionally transfers the compound obtained with an inorganic or organic acid to an addition salt.