NO122417B - - Google Patents

Description

Process for the production of benzenesulfonylureas with a blood sugar-lowering effect.

The invention relates to a process for the production of benzenesulfonylureas with formula

in which

R means alkylene.with 2-3 carbon atoms,

R<1>means a) alkyl or alkenyl with 3-6 carbon atoms, b) endoalkylenecyclohexyl, endoalkylenecyclohexenyl, encoalkylenecyclohexylmethyl or endoalkylenecyclohexenylmethyl with 1-3 endoalkylene carbon atoms,

c) lower alkyl or dialkylcyclohexyl,

d) cycloalkyl with 5~8 carbon atoms,

e) cyclohexenyl, methylcyclohexenyl,

f) nortricyclyl, adamantyl,

X means hydrogen, low molecular weight alkyl, low molecular weight alkoxy,

halogen,

X' means the same substituents as mentioned for X, further if X

means hydrogen, also -CP^ or -NC^ or

X and X' together mean methylenedioxy,

as well as their salts.

In the above and the following definitions, "lower alkyl" always means that having 1 to H carbon atoms in a straight or branched chain.

R<1> can for example mean propyl, isopropyl, butyl, isobutyl, sec. butyl, straight or branched amyl (pentyl)

or hexyl as well as those to the aforementioned hydrocarbon residues corresponding residues with an ethylenic double bond such as allyl or crotyl.

Particular preference is given within the scope of the invention to such compounds which as R^" contain a cycloaliphatic hydrocarbon residue, optionally substituted with alkyl or bonded via the alkyl to the nitrogen atom. Such residues should be mentioned, for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, ethylcyclohexyl, propyl- and isopropylcyclohexyl, the alkyl groups preferably being in the ^-position both in the cis- and in the trans-position, endomethylenecyclohexyl (2,2,1-bi-cycloheptyl), endoethylene-cyclohexyl (2,2,2-bicyclooctyl), endomethylenecyclohexenyl, endoethylenecyclohexenyl, endomethylenecyclohexylmethyl, endoethylenecyclohexylmethyl, endomethylenecyclohexaenylmethyl or endoethylenecyclohexenylmethyl.

The grouping

means indolino, tetrahydroquinolino.

The aforementioned benzenesulfonylureas can be produced using different methods, which are generally used for the production of compounds of this class. Thus, one can either

a) react amines of the formula R^NHg or their salts with benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters, -ureas, -semicarbazides or -semicarbazones which in the benzene nucleus contain the substituent

or

b) reacts sulfonamides with formula

or their salts with R<1->substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas, or

c) hydrolyzes N-benzenesulfonylisourea ethers, -isothiourea ethers, haloformic amidines or -parabanic acids as in

the benzene ring is substituted with the group

and in the N' position with the group R or

d) in to benzenesulfonylureas of formula I corresponding to benzenesulfony lt iour inst offer replaces the sulfur atom with an oxygen atom,

or

e) hydrogenates to benzenesulfonylureas of formula I corresponding to benzenesulfonylureas, which in the molecule contain olefinic

bindings, or

f) in benzenesulfonylureas of formula

possibly stepwise by acylating it to alkylbenzenesulfonyl-urea f the group neighboring placerté amino group introduces the residue with

. formula

and optionally treating the process products with alkaline agents for salt formation.

Depending on the nature of the links X and R, in some cases one or the other of the aforementioned methods will be unsuitable for the preparation of the individual compounds falling under the general formula. Such relatively rare occurring cases can be easily recognized by professionals and it does not pose any difficulties in such cases with results to use one of the other mentioned synthesis methods.

The mentioned benzenesulfonyl-carbamic acid esters resp. -thiocarbamic acid esters can have a lower alkyl residue or a phenyl residue in the alcohol component. The same applies to the R<1->substituted carbamic acid esters or the corresponding monothiocarbamic acid esters.

As carbamic acid halides, the chlorides are primarily suitable.

The benzenesulfonylureas relevant as starting materials for the method can be unsubstituted or, in particular, twice substituted, on the side of the urea molecule facing away from the sulfonyl group. As these substituents are split off with amines during the reaction, their character can be varied within wide limits. In addition to alkyl, aryl, acyl or heterocyclic substituted benzenesulfonylureas, bis-(benzenesulfonyl)ureas can also be used which may also have a further substituent at one of the nitrogen atoms, e.g. methyl. One can, for example, treat such bis-(benzenesulfonyl)ureas or also N-benzenesulfonyl-N'-acylureas with amines of the formula R^NH2 and heat the formed salts to elevated temperatures, especially those above 100°C.

Furthermore, it is possible to proceed from urine substances with

formula

or from such ureas which are also substituted once or especially twice at the free nitrogen atom and to react these with benzenesulfonamides substituted in the 4-position. Examples of such starting materials are the corresponding N'-acetyl-, N'-nitro-, N'-cyclohexyl-, N^Ct-methyl-cyclohexyl)-, NJN'-diphenyl (since they two phenyl residues can also be substituted directly as well as be connected to each other via a bridge link such as -CI^-, -NH-, -O- or -S-), N^-methyl-t^-phenyl-, N, , N'-dicyclohexylureas as well as R^-carbamoylimidazoles or -triazoles.

The hydrolysis of the benzol-sulfonylparabanic acids, -isourea ethers, -isothiourea ethers or -haloformic acid amidines mentioned as starting materials conveniently takes place in an alkaline medium. Isourea ethers and haloformic acid amidines can also be hydrolysed with good results in an acidic medium.

The replacement of the sulfur atom in the corresponding benzenesulfonyl-thioureas with an oxygen atom can for example be carried out using oxides or salts of heavy metals or also by using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acid. Thereby, a thiourea grouping in the left molecular part or a derivative thereof can be simultaneously transferred into the urea grouping. The thioureas can also be desulphurised by treatment with phosgene or phosphorus pentachloride. As intermediates formed chloroformate amidines resp. -carbodiimides can be transferred into the benzenesulfonylureas by suitable precautions such as saponification or addition of water.

Correspondingly substituted benzenesulfonylureas which contain an unsaturated bond in the molecule can, by hydration, e.g. with molecular hydrogen in the presence of a known hydrogenation catalyst is transferred in the benzenesulfonylureas according to the invention.

The subsequent introduction of the rest

in aminoalkyl-benzenesulfonyl ureas of formula

can be carried out in one as well as in several reaction steps. For example, it is possible to react the aforementioned aminoalkylbenzenesulfonylureas with correspondingly substituted carbamic acid halides, suitably in the presence of tertiary organic bases. However, one can also first treat the aminoalkylbenzenesulfonylureas with phosgene and react the intermediate products formed with correspondingly substituted amines.

The embodiment of the method according to the invention can generally be greatly varied with respect to reaction conditions and adapted to any conditions. For example, the reactions can take place using solvents at room temperature or at an elevated temperature. The benzenesulfonylurea derivatives obtainable by the method according to the invention are valuable drugs which are distinguished by a strong and long-lasting blood sugar-lowering effect. Their blood sugar-lowering effect could e.g. determined on rabbits by feeding the process products in a dose of 10 mg/kg and determining the blood sugar value according to the known method of Hagedorn-Jensen, or with an autoanalyzer over a longer period of time. Thus, it was e.g. found that N-/-4-(g-indolino-carbonamidoethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea in rabbits causes a reduction in blood sugar of 32$, which after 24 hours still amounts to 29% and even after 48 hours still 13% - N-/-4-(g<->indolino-carbonamidoethyl)-benzenesulfonyl7-N'-cyclohexylurea causes, under the specified experimental conditions, even a lowering of blood sugar of J>8%, which after 24 hours still amounts to 20% .

N-/-4-(3-<1,2 , 3,4-tetrahydro-quinolino-carbamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea causes a lowering of blood sugar in rabbits at a dosage of 10 mg/kg after 1 hour around 26%. After 6 hours, the drop in blood sugar still amounts to $10

and after 24 hours 8%.

In relation to this, the oral antidiabetic drug known as N-(4-methyl-benzenesulfonyl)-N'-butyl urea is ineffective in rabbits at doses of less than 25 mg/kg.

The mentioned benzenesulfonylureas should preferably be used for the production of orally administrable preparations with a blood sugar-lowering effect for the treatment of diabetes mellitus and can be applied as such or in the form of their salts, resp.

in the presence of substances that lead to salt formation. For salt formation, alkaline agents such as alkali or alkaline earth hydroxides, carbonates or bicarbonates can be used, for example.

As medicinal preparations, tablets are preferably taken into consideration which, in addition to the process products, contain the usual auxiliary and carrier substances such as talc, starch, milk sugar, tragacanth or magnesium stearate.

A preparation containing these mentioned benzol-sulphonylureas is as active substance, e.g. a tablet or a powder with or without the aforementioned additions, is conveniently brought into a suitable dosage form. The dose must then be chosen which is adapted to the effect of the benzenesulfonylurea used and the desired effect. Appropriately, the dosage per unit approx. 0.5 to 100 mg, preferably 2 to 10 mg, however, it is also possible to use considerably higher or lower dosage units which may have to be divided or be multiplied before application.

Example 1.

N-[-4-(3-indolino-carbamidoethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea f.

17.2 g of 4-(3-indolinocarbamidoethyl)-benzenesulfamide

(m.p. 189-191°C, prepared from 4-(3-aminoethyl)-benzenesulfonamide and indolinocarbonic acid chloride), is suspended in 200 ml of acetone and dissolved in water with the solution of 2 g of sodium hydroxide. To this, 6.5 g of cyclohexyl isocyanate are added while stirring at room temperature and stirred for 2 hours. The portion is then mixed with water, filtered and the filtrate acidified with dilute hydrochloric acid.

The precipitated N-N-4-(3-indolino-carbamidoethyl)-benzenesulfonyl-7-N'-cyclohexylurea is reprecipitated from 1% ammonia and recrystallized from water-ethanol. Temp. 200-202°C.

In an analogous manner, N-(4-(3-indolino-carbamidoethyl)-benzenesulfonyl 7-N'-(4-methyl-cyclohexyl)-urea is obtained with m.p. 184-186°C, and N-[~4-(3-indolino-carbamidoethyl)-benzenesulfonyl7-N'-butylurea with m.p. 193-195°C,

and

N-(4-(3-indolino-carbamidoethyl)-benzenesulfonyl 7-N'-(4-ethylcyclohexyl)-urea with m.p. 179-181°C.

In an analogous way, one would further:

of 4-(Y-indolinocarbonamidopropyl)-benzenesulfonamide (m.p. l6l°C) obtain N-/—4-(Y-indolinocarbonamidopropyl)-benzenesulfonyl7~N'-cyclohexyl-urea with m.p. 155°C (from methanol/water),

of 4-(3-indolinocarbonamidopropyl)-benzenesulfonamide (m.p. 171°C) obtain N-/—4-(3-indolinocarbonamidopropyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 174°C (from methanol/water),

of 4-(3-<1,2,3,4-tetrahydro-quinolino-carbamido>-ethyl)-benzenesulfonamide with m.p. 138-139°C few

N-[<->4-(3-<<>1,2,3,4-tetrahydro-quinolino-carbamido>-ethyl)-benzene-sulfonyl7-N*-cyclohexyl-urea f with m.p. 184-186°C and N-/-4-(3-<1,2,3,4-tetrahydro-quinolino-carbamido>-ethyl)-benzene-sulfonyl7-N'-butyl-urea with m.p. 135-137°C and N-[4-(3-<1,2,3,4-tetrahydroquinolino-carbamido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea with m.p. . 153-155°C,

Example 2.

N-N-4-(3-Indolino-carbamidoethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea.

11.1 g N-/-4-($-indolino-carbamidoethyl)-benzenesulfonyl7-urea (m.p. 189-191°C, prepared by boiling 4-(3-indolino-carbamidoethyl)-benzenesulfonamide with potassium cyanate in 90% ethanol )

boil in 30 ml toluene and 30 ml monomethylglycol with 1.65 g glacial acetic acid and 3 g cyclohexylamine for 5 hours under reflux. It is then evaporated in a vacuum, the residue is reprecipitated from 1# ammonia and recrystallized from water-ethanol. The formed N-(4-(3-indolino-carbamidoethyl)-benzenesulphonyl-7-N'-cyclohexylurea melts at 200-202°C.

Analogously, you get

N-(4-(3-indolino-carbamidoethyl)-benzenesulfonyl 7-N'-(4-methyl-cyclohexyl)-urea with m.p. l84-l86°C and

N-[-4-(3-indolino-carbamidoethyl)-benzenesulfonyl-7-N'-butylurea with m.p. 193-195°C

Example 3.

N-[-4-(3-indolino-carbamidoethyl)-benzenesulfonyl-7-N'-(2,5-endomethylenecyclohexylmethyl)-urea.

10.2 g N-[4-(3-indolino-carbamidoethyl)-benzene-sulfonyl7-N'-(2,5-endomethylene-cyclohexylmethyl)-thiourea

(m.p. 172-174°C, prepared from 4-(3-indolino-carbamidoethyl)-benzenesulfonamide and 2.5 g of endomethylene-cyclohexylmethyl mustard oil by boiling in dioxane in the presence of pot ash) is dissolved in 250 ml of acetone. To this, a solution of 2.8 g of sodium nitrite in 20 ml of water is added and 30 ml of 5-n acetic acid is added dropwise to the mixture while stirring and cooling with ice. The mixture is stirred for 2 hours at room temperature, the sulfur is filtered off and the acetone is removed as best as possible under vacuum. The residue is poured into dilute ammonia, filtered with charcoal, the solution acidified and the precipitate recrystallized from dilute methanol. The formed N-(4-(3-indolino-carbamidoethyl)-benzenesulfonyl-7-N'-(2,5-endomethylene-cyclohexylmethyl)-urea melts at 174-176°C.

Example 4.

N-[<->4-(B-indolinocarbamidoethyl)-benzenesulfoyl7-N'-(2,5-endomethylenecyclohexylmethyl)-urea.

2.5 g of N-/~4-(3-indolinocarbamidoethyl)-benzenesulfonyl7-N'-(2,5-endomethylene-cyclohexylmethyl)-isourea methyl ether (crude product which was formed by desulfurization of N-/ 4-(3- indolino

carbamidoethyl)-benzenesulfonyl7-N' - (2 a 5-endomethylene-cyclohexyl-methyl)-thiourea f with mercuric oxide (HgO) in methanol) is dissolved in 10 ml of dioxane, mixed with 50 ml of 2-n caustic soda and heated for 3 hours on steam bath. After cooling, it is acidified, filtered off with suction and recrystallized from methanol. The formed N-(4-(3-indolinocarbamido-ethyl)-benzenesulfonyl-7-N'-(2,5-endomethylene-cyclohexylmethyl)-urea melts at 173-175°C.

Example 5 -

N-[4-(3-indolinecarbamidoethyl)-benzenesulfonyl-7-N'-(4-methylcyclo-hephesyl)-urea. 1 g N-/-4-(3-indolinocarbamidoethyl)-benzenesulfonyl7-N'-(4-methyl-A,3-cyclohexenyl)-urea (m.p. 168-170°C, prepared from 4-(3-indolinocarbamidoethyl) -benzenesulfonamide and 4-methyl-A3-cyclohexenyl isocyanate) are dissolved in 50 ml of methanol and some dimethylformamide and hydrated in a shaking apparatus in the presence of palladium catalyst at normal pressure and room temperature. After the hydrogen uptake has ended, the catalyst is filtered off, the filtrate is evaporated, the residue is mixed with water, the product is sucked off and recrystallized from ethanol-water. The formed N-[~4-(3-indolinocarbamidoethyl)-benzenesulfonyl 7-N'-(4-methylcyclohexyl)-urea melts at 184-186°C.

Example 6.

N-[4-(3-indolino-carbamidoethyl)-benzenesulfonyl-7-N'-cyclohexylurea.

1.6 g of N-/-4-(3-aminoethyl-benzenesulfonyl)-N'-cyclohexyl-urea are dissolved in 10 ml of pyridine and mixed with 0.9 g of indolinocarbamic acid chloride. The mixture is allowed to stand for \ hour at room temperature, heated for 10 min. on a steam bath, cool, pour into water and slightly acidify. The precipitate is reprecipitated from 1% ammonia and recrystallized from ethanol. N-(4-(3-indolino-carbamidoethyl)-benzenesulfonyl7-N'-cyclohexyl-urea melts at 200-202°C.

Claims (1)

Process for the preparation of benzenesulfonylureas with blood sugar-lowering action and with formula in which R means alkylene with 2-3 carbon atoms, R"<*>" means a) alkyl or alkenyl with 3-6 carbon atoms, b) endoalkylenecyclohexyl, endoalkylenecyclohexenyl, endoalkylenecyclohexylmethyl or endoalkylenecyclohexenylmethyl with 1-3 endoalkylene carbon atoms, c) lower alkyl- or dialkylcyclohexyl, d) cycloalkyl with 5-8 carbon atoms, e) cyclohexenyl, methylcyclohexenyl, f) nortricyclyl, adamantyl, X means hydrogen, low molecular weight alkyl, low molecular weight alkoxy, halogen, X' means the same substituents as mentioned for X, further if X means hydrogen, also -CF^or -NO^or X and X<1> together mean methylenedioxy, as well as their salts, characterized by either a) reacting amines with the formula R^NHg or their salts with benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters . haloformic acid amidines or -parabanic acids which in the benzene nucleus are substituted with the group and in the N' position with the group R or d) i to benzenesulfonylureas of formula I corresponding to benzenesulfonylthioureas f is replacing the sulfur atom with an oxygen atom, or e): hydrogenating to benzenesulfonylureas of formula I corresponding to benzenesulfonylureas, which in the molecule contain olefinic bonds , or f) in benzenesulfonylureas of formula possibly stepwise by acylation of the amino group adjacent to the alkylbenzenesulfonylurea f group introduces the residue with formula and optionally treating the process products with alkaline agents for salt formation.