IL28873A - Benzenesulfonyl ureas and process for their manufacture - Google Patents

Description

HUSH'S • 'ynm mK^TiK-^^ais^ pata BE ZENBSULFOUYL UREAS AND PROCESS FOB THEIR MANUFACTURE Benzenesulfonyl ureas and process for their manufacture ( Pw 5.229 B/aB ) The present invention relates to benzenesul onyl-ureas corresponding to the formula which as such or in the form of their physiologically tolerable salts show hypoglycemic properties and are characterized by a strong hypoglycemic action.

In the formula R represents lower alkyl, preferably methyl or lower alkenyl, X represents hydrogen, fluorine, chlorine or bromine, preferably chlorine, 'lower alkyl, preferably methyl or lower alkoxy, preferably me hoxy, R1 represents endomethylene-cyclohexyl, endomethylene-cyclo- hexenyl, endoethylene-cyclohexyl, endoethylene-cyclohexenyl.

The substituent X is in 4- or preferably in 5-position to the carbonamide group. ■ .'·._, In the above and the following definitions "lower alkyl, alkenyl or alkoxy" always stands for an alkyl, alkenyl or alkoxy group containing 1 to 4 carbon atoms in a straight or branched chain.

According to the above-mentioned definitions R may represent, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, allyl.

In particular R1 may represent 2.5-endomethylenecyclo-hexenyl, 2.5-endomethylenecyclohexyl, 2.5-endoethylenecyclo- for the preparation of said benzenesulfonyl-ureas wherein a) benzenesulfonyl-isocyanates, benzenesulfonyl-carbamic acid esters, benzenesulfonyl-thiolcarbamic acid esters, benzenesulfonyl-carbamic acid halides or benzenesulfonyl- ureas, benzenesulfonyl-semicarbazides or benzenesulfonyl- semicarbazones substituted in p-position by the group X are reacted with R -substituted amines or, if desired, the salts thereof, b) benzenesulfonamides of the formula X 1 or their salts are reacted with R -substituted isocyanates, carbamic acid esters, thiblcarbamic acid esters, carbamic acid halides or ureas, c) correspondingly substituted benzenesulfonyl-isourea ethers, benzene-sulfonyl-isourea esters, benzenesulfonyl- isothiourea ethers, benzenesulfonyl-parabanic acids or benzenesulfonyl-haloformic acid amidines are hydrolyzed, d) correspondingly substituted benzenesulfonyl-halides are reacted with R^-substituted ureas, in particular their alkaline metal salts, e) correspondingly substituted benzenesulfinlc acid halides or, in the presence of acid condensing agents even correspondingly substituted benzenesulfinic acids or their alkaline metal salts, are reacted with hydroxy ureas the to correspondingly substituted carbodiimides water is add^ in correspondingly substituted benzenesulfonyl-thioureas the sulfur atom is exoha ged for an oxygen atom, correspondingly substituted benzenesulfinyl-ureas or ben- zenesulfenyl-ureas are oxidized, corresponding benzenesulfonyl-ureas containing in the molecule unsaturated linkages are hydrogenated, in benzenesulfonyl-ureas of the formula H2 -CH2-CH2-^^-SG2-NH-CO- H-R1 the radical _ is introduced by acylation, if desired in several stages, in correspondingly substituted thiobenzamidoalkyl- benzene-sulfonyl-ureas or -benzenesulfonyl-thioureas the sulfur atom or the sulfur atoms are exchanged by an oxygen atom or oxygen atoms, or compounds of the formula X or their parabanic acid derivatives or compounds of the formula wherein U represents O-lower alkyl, S-lower alkyl or halogen (preferably chlorine) are saponified, and the reaction products are treated with alkaline agents, if the formation of salts is desired.

The above-mentioned benzenesulfonyl-carbamic. acid esters or the benzenesulf on l-thiolcarbamic acid esters may contain or a heterocyclic radical. Since this radical is split off during the reaction, its chemical constitution has no influence on the character of the final product and can therefore vary within wide limits. The same applies to the R1-substituted carbamic acid esters or the corresponding thiolcarbamic acid esters.

As carbamic acid halldes there are suitable, above all, the chlorides.

The benzenesulfonyl-ureas used as starting substances for the process of the invention may be unsubstituted at the side of the urea molecule opposite to the sulfonyl' group or may be mono- or preferably di-substituted. Since these substituents are split off during the reaction with amines, their nature can vary within wide limits. Instead of benzenesulfonyl-ureas substituted by an alkyl, aryl, acyl or heterocyclic radical, there can likewise be used the Bis-(benzenesulfonyl) -ureas, which may carry a further substituent at one nitrogen atom, for example methyl. It is, for example, possible to treat such bis-(benzenesulfonyl) -ureas or N-benzene-sulfonyl-N' -acyl-ureas with amines of the formula R1 H2 and to heat the salts so obtained to an elevated temperature, particularly to a temperature above 100°C.

Furthermore, it is possible to start from ureas of the formula R1- H-C0- H2 or from such ureas which are mono- or, in particular di-substituted at the free nitrogen atom and to . react these with benzenesulfonamides substituted by the grouping X the corresponding Ν' -acetyl- or N† -nitro-ureas, N1 -endomethyl- enecyclohexyl-ureas, N' -endomethylenecyclohexenyl-ureas, N' ,NT -diphenyl-ureas (in which case the two phenyl radicals may be substituted and may be linked with one another directly or by means of a bridge member such as -CH^, -NH- -0- or -S, ) N' -methyl-N1 -phenyl- or Ν' ,Ν' -dicyclohexyl-ureas as well as R- substituted cyclohexyl carbamoyl-imidazoles or triazoles.

Hydrolysis of the mentioned benzenesulfonyl-parabanic acids, benzenesulfonyl-isourea-ethers, benzenesulfonyl-thio- urea-ethers, benzenesulfonyl-isourea-esters or benzenesulfonyl-haloformic acid amidines is suitably carried out in an alkaline medium. Isourea-ethers ad isourea-esters can be hydrolysed successfully in an acid medium, too.

The reaction with the benzenesulfonic halides with R - substituted ureas is suitably carried out by using basic condensing agents such as alkali metals, alkali amides or, preferably, -hydrides in indifferent solvents.

The reaction of the sulfinic acids or sulfinic acid chlorides with hydroxy ureas can suitably be carried out in indifferent solvents. If the sulfinic acids or their alkali metals are used as starting substances, acid condensing agents such as for example thionyl chloride, polyphosphoric acids, anhydrous phosphoric acid or sulfuric acid are added.

The sulfur atom in correspondingly substituted benzene- sulfonyl-thioureas can be replaced by an oxygen atom, in known manner, for example with the aid of oxides or salts of heavy metals or likewise by applying oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid.

Thioureas may also be desulfurized by treating them with phosgene or phosphorus pentachloride. Chloroformic acid anidines or carbodiimides obtained as intermediate products can The oxidation of the benzenesulfinyl- or -sulfenylureas can be carried out with the known oxidizing agents such as for example potassium permanganate in indifferent solvents.

Correspondingly substituted benzenesulfonyl-ureas, containing in the molecule an unsaturated bond, for example can be converted by hydrogenation for example With mo'le'eular hydrogen in the presence of a known hydration "catalys.. in the benzenesulfonyl-ureas according to the present invention.

The acylation of aminoethyl-benzenesulfonyl-ureas may be carried out either in one step, for example, by reaction of a correspondingly substituted benzoic acid halide, or it may be carried out in several stepu. One example of the numerous possibilities of stepwise acylation is the reaction of amino-ethyl-benzenesulfonyl-ureas with 2-methoxy-benzoyl chloride and subsequent introduction of a halogen atom into the benzene nucleus of the benzamido group.

The sulfur atoms in correspondingly substituted thiobenz-amido-ethyl-benzenesulfonyl-ureas or thiobenz - amidoethyl-benzenesulfonyl-thioureas can be replaced by oxygen atoms for example, with the aid of. oxidizing agents such as hydrogen peroxide, sodium peroxide or other peroxide compounds.

Instead of the thiobenzamido-ethyl-benzenesulfonyl-ureas the corresponding thiobenzamidoethyl-benzenesulfonyl-isothio-urea-ethers, isourea-ethers or -esters, -parabanic acids or thiobenzamidoethyl-benzenesulfonyl-haloformic acid amidines can be desulfurized by treatment with oxidizing agents in an acid or alkaline medium whereby simultaneously a desulfuriza- Instead of the thiobenzamido-ethyl-benzene-sulfonyl-thioureas, compounds of the formula X wherein U has the meaning given above, can be converted by treatment with oxidizing agents in an acid or alkaline medium by simultaneous desulfuration and hydrolysis into the corresponding benzamido-ethyl-benzenesulfonyl-ureas.

As regards the reaction conditions, the forms of realizing the process of the invention .may, in general, vary within wide limits and can be adapted to each individual case. For example, the reactions can be carried out with the use of solvents either at room temperature or at an elevated temperature.

According to the nature of the starting substances, in some cases, one or the other mentioned process may yield a desired individual benzenesulfonyl-urea in only small amounts or might be inappropriate. Such relatively rare cases can easily be recognized by experts and it is not difficult to use successfully a method of synthesis other than that described.

As starting substances such compounds are used which contain a benzene nucleus being substituted by the group OR in para-position.

As examples for the part X The preparation of the starting substances may be carried out according to generally known methods. Thus, for example benzenesulfonamides used as starting substances which are substituted in the benzene nucleus by the radical can be obtained by reaction of the corresponding benzene compounds with chloro-sulfonic acid and subsequently with ammonia or by acylation of amino compounds of the formula with corresponding acid chlorides.

The benzenesulfonyl carbamic acid esters and -ureas used The hypoglycemic action of the benzene-sulfonyl-urea derivatives described above could be determined by feeding them to rabbits in doses of.10 mg/kg and determining the blood sugar value according to the known method by Hagedorn-Jensen or by means of an auto-analyzer over a prolonged period of time.

Thus, it was found, for example, that 10 milligrams/kilogram of Ν- 4~-(β- < 2-methoxy-5-bromo-benzamido > -ethyl) -benzene-sulfonyl7-N' -( 2.5-endomethylene-cyclohexyl) -urea provoke, after 3 hours, a lowering of the blood sugar by 35 , after 24 hours 26 and after 48 hours 18 $>.

In the same manner, 10 milligrams of Ν-/4~-(β- < 2-methoxy-5-chlorobenzamido-^ -ethyl) -benzene-sulfonyl7-N' -( 2.5-endomethylene-cyclohexyl) -urea provoke after 3 hours a blood sugar lowering of 32 , after 24 hours of 3 , after 48 hours of 28 %, and even after 7 hours of 14 whereas the known N-/5-methyl-benzene-sulfonyl7-N' -butyl-urea, when administered to rabbits in doses of less than 25 mg/kg, does not provoke a lowering of the blood sugar level.

The strong hypoglycemic action of the "benzenesulfonyl-ureas of the present invention becomes more evident if the dose is further reduced. When Ν- 4"-(β- ' 2-methoxy-5-bromo-benzamido> -ethyl) -benzenesulfonyl7-N' -( 2, 5-eridomethylene-cyclohexyl) -urea is admingtered to rabbits in a dose of 0.01 mg/kg or Ν-/4"-(β-< 2-methoxy-5-chloro-benzamido^ -ethyl) -benzenesulfonyl7-N' -( 2.5-endomethylene-cyclohexyl) -urea is administered to rabbits in a dose of 0.06 mg/kg, or the Ν-/4"-(β- < 2-methoxy-5-methyl-benzamido> -ethyl) -benzensulfonyl7-N† -(2.5-endomethylene-cyclohexyl) -urea is administered to rabbits in a dose of 0.06 mg/kg, a distinct lowering of the blood sugar can still be observed.

The benzenesulfonyl-ureas described are preferably used treatment of diabetes mellitus; they may be used as such or in the form of their physiologically tolerable salts or in the presence of substances which cause such salt formation. For the. formation of salts there may be used, for example, alkaline agents such as alkali metal hydroxides or alkaline earth metal hydroxides, alkali metal carbonates or bicarbonates or alkaline earth metal carbonates or bicarbonates.

The .pharmaceutical preparations are advantageously in the form of tablets containing, in addition to the products of the present invention, the usual pharmaceutically suitable carriers such as talc, starch, lactose, tragacanth or magnesium stearate.

. A pharmaceutical preparation containing one of the aforesaid benzenesulfonyl-ureas as the active substance, for example, a tablet or a powder, with or without the aforesaid carriers, is advantageously brought into a suitable unit dosage form.

The dose chosen should comply with the activity of the benzenesulfonyl-urea used and the desired effect. Advantageously, the dosage per unit amounts to about 0.5 to 100 mg, preferably 2 to 10 mg, but considerably higher or lower dosage units may also be used, which, if desired, are divided or multiplied prior to their administration.

The following Examples serve to illustrate the invention, but they are not intended to limit it thereto.

E x a m p l e 1 Ν-/5-(β- <2-methoxy-5-chlorobenzamido^> -ethyl) -benzenesulfonyl7-N' -( 2.5-endomethylene-cyclohexyl) -urea benzenesulfonyl7-methyl-urethane (melting point 189 - 191°C) after addition-of 1. 2 g 2 , 5-endomethylene-cyclphexylamxne are suspended in 100 ml of dioxane and heated for about 1 hour to 110°C. When cooling, the Ν- ¾"-(β- <2-methoxy-5-chloro-. - - - ' - - t - In analogous manner there are obtained: from Ν-/ -(β- ^2-methoxy-4-chlorobenzamido^ -ethyl) -benzene- sulfony 7-carbamic acid methyl ester (melting point 178 - l80°C) Ν-;/?-(β- ^ -methoxy- -chlorobenzamido ^ -ethyl) -benzene- sulfonyjT-N' -( 2.5-endomethylenecyclohexyl) -urea, melting point 205 - 205°C (from methanol); from Ν-/ί-(β- ^2-ethoxy-5-chlorobenzamido ^-ethyl) -benzene- sulfonyl7-carbamic acid methyl ester (melting point 203 - 205°C) Ν-/5-(β- ^2-ethoxy-5-chlorobenzamido^ -ethyl) -benzenesulfonyl/-N' -( 2.5-endomethylenecyclohexyl) -urea, melting point 158 - l6o°C (from methanol); from Ν-/5-(β- ^2-methoxy-5-bromobenzamido ^-ethyl) -benzenesulfonyl7-carbamic acid methyl ester (melting point 197 - 199°C): Ν-/ί-(β- ^2-methoxy-5-bromobenzamido ^ -ethyl) -benzenesulfonyl7-N' -( 2.5-endomethylenecyclohexyl)-urea, melting point 171 - 172°C (from methanol/dimethylformamide) ; from Ν_ -(β- ^*2-methoxy-5-methylbenzamido^ -ethyl) -benzenesulfonyl7-carbamic acid methyl ester (melting point 175 - 177°C): Ν-/¥-(β- -benzenesulfonyl7-N1 -( 2.5-endomethylenecyclohexyl)-urea, melting point 191 - 193°C (from methanol/dimeth lformamide) ; from Ν-/5-(β- ^2.5-dimethoxy-benzamido^-ethyl) -benzenesulfonyl7-carbamic acid methyl ester (melting point 173 - 175°C): Μ-/5-(β- ^2.5-dimethoxy-benzamido ^-ethyl) -benzenesulfonyl7- from N- 5-( fl- ^2-methoxybenzamido.^-ethyl) -benzenesulfonyl7-carbamic acid methyl ester (melting point 17^· - 176°C): , N- 5-(fl- ^2-methoxybenzamido ^.-ethyl) -benzenesulfon l7-N' -( 2.5-endomethylenecyclohexyl) -urea, melting point 197 - 198°C (from methanol); from Ν- ¥-(β- ^2-methoxy-5-fluorobenzamido^ -ethyl) -benzenesulfonyl/-carbamic acid methyl ester (melting point 171 - 172°C): Ν- 5-(β- ^ -methoxy-5-fluorobenzamido ^-ethyl) -benzenesulfonyl7-N' -( 2.5-endomethylenecyclohexyl) -urea, melting point 206 - 207°C (from methanol/dimethylformamide) .

E x a m p l e 2 N- 5-(fi- ^2-methoxy-5-fluorobenzamido^ -e.thyl) -benzenesulfonyl7-Nr -(2.5-endomethylenecyclohexyl) -urea 6 g of k-(β- ^-methoxy-5-fluorobenzamido^ -ethyl)-benzene-sulfonamide (melting point 167 - l69°C) are dissolved in 8.5 ml of 2N sodium hydroxide solution and 50 ml of acetone, and 2.5 g of 2.5-endomethylenecyclohexyl-isocyanate are added dropwise at 0 - 5°C. Stirring is continued for 3 hours, water and methanol is added, the whole is filtered from the undissolved matter and the filtrate is acidified with dilute hydrochloric acid. The Ν- 5-(β- ^-methoxy-5-fluorobenzamido ^-ethyl) -benzensulfonyl7-N' -(2.5-endomethylenecyclohexyl) -urea which has precipitated, melts after recrystalllzation from methanol/ dimethylformamide at 206 - 207°C.

In analogous manner there is obtained: from -( β- ^-2-n-propoxy-5-chlorobenzamido^-ethyl) -benzenesulfon- ' amide (meltin point 192 - 19^°C): N- 5-(B-^2-n-propoxy-5-chlorobenzamido^. -ethyl) -benzenesul- fonyl7-N' -(2.5-endomethylenecyclohexyl) -urea, melting point 171 - 173°C (from methanol); from 4-(β- ^2-n-propoxy-5-methylbenzamido^-ethyl)-benzenesulfon- amide (melting point 166 - l67°C): Ν- ¥-(β- <^2-n-propoxy-5-methylbenzamido^>-ethyl) -benzene- sulfonyl7-N' -(2.5-endomethylenecyclohexyl) -urea, melting point 148 - 150°C (from methanol),' from 4-(fi-^2-methoxy-5-ethylbenzamido^-ethyl)-be,nzenesu1 fonamide (melting point 193 - 195°C): Ν- ?-(β- ^2-methoxy-5-ethylbenzamido^-ethyl)-benzenesulfonyl7-N' -(2.5-endomethylenecyclohexyl) -urea, melting point l62 - l64°C (from methanol).

E x a m p l e 3 Ν-/5-(β- ^2-methoxy-5-chloro-benzamido^>-ethyl)-benzenesulfonyl7-N' -(2.5-endomethylenecyclohexyl) -urea 2 g of Ν- 5-(β- ^*2-methoxy-5-chloro-benzamido^ -ethyl) -benzenesulfonyl7-N' -(2.5-endomethylenecyclohexyl) -thiourea (prepared by boilingfor several hours 4-(β- <^2-methoxy-5-chloro-benzamido^ -ethyl) -benzenesulfonamide and 2.5-endomethylenecyclohexyl mustard oil in acetone in the presence of potassium carbonate while stirring, melting point 158 - l60°C (from dilute methanol)) are dissolved in about 10 ml of 2N sodium hydroxide solution and 5 nil of dioxane. After addition of 5 ml of hydrogen peroxide of 35 strength, the whole is heated for about 20 minutes in a water bath. After cooling it is acidified. There is obtained a crystalline precipitate which is filtered off with suction, dissolved in ammonia of about 1 strength obtained crude N-^-(B-^2-methoxy-5-chlorobenzamido^-ethyl)-benzene-sulfpnyl7-(2.5-endomethyieneQyclohexyl)-urea melts after recrystallization from methanol at l86 - l88°C.

E x a m p l e 4 N- 5-(S- N' -(2.5-endomethylenecyclohexyl)-urea cf. Example > is dissolved in 50 ml of ethanol. After addition of 0.5 g of mercury oxide and a small amount of potassium carbonate, the whole is heated to 0 - 60°C for 4 hours while stirring. It is filtered, concentrated and crystallized from dilute methanol. The thus obtained Ν- 5-(β- ^2-methoxy-5-chlorobenzamido^ -ethyl) -benzenesulfonyl7-N' -(2.5-endomethylenecyclohexyi) -isourea methyl ether melts at 118 - 120°C. b) 0.1 g of the product obtained according to 4a), is heated in 2 ml of dioxane and 10 ml of concentrated hydrochloric acid for 20 minutes in a vapour bath. The product which is obtained after pouring into water is filtered off with suction and re-crystallized from dilute methanol. The chloro-benzamido^-ethyl) -benzenesulfonyl7-N' -(2.5-endomethyl-eneeyelohexyl) -urea thus prepared melts at 186 - l88°C. The same product is obtained by alkaline saponification of the isourea ether prepared according to 4a) by heating for 1 hour with 2N sodium hydroxide solution in a vapour bath.

E x a m p l e 5 of benzene, 0.4 g of trimethylamine and 1.6 g of 4-(B- ^2-methoxy-5-chlorobenzaLmido^-ethyl) -benzenesulfohic acid chloride are added and heated to boil under reflux for 2 1/2 hours. The hole is concentrated in vacuo, water is added to the residue obtained and it is triturated. The substance crystallizes after abandoning for some time. It is filtered off with suction, washed with water and recrystallized from methanol/ dioxane. The thus obtained 1-/5-(β- ^2-methoxy-5-chloro-benzamidO/ -ethyl) -benzenesulfonyl7-3-( 2.5-endomethylene-cyclo-hexyl)-parabanic acid melts at 227 - 229°C.. b) The product obtained according to 5a) is dissolved in a small amount of dioxane and 2N sodium. hydroxide solution and the solution is heated in a vapour bath for 5 minutes. After coolin it is diluted with water and acidified. The. precipitate obtained of N-/3T-(B-^-methoxy-5-chloro-benzamido^>--ethyl) -benzenesulfonyl7-N' -( 2.5-endomethylenecyclohexyl) -urea melts after recrystallization from methanol/water at 186 - l88°C.

E x a m p l e 6 N- 5-(B- ^2-methoxy-5-chlorobenzamido ^-ethyl) -benzenesulfonyl/-N' -( 2.5-endomethylenecyclohexyl) -urea a) 3. 1 g of M-2.5-endomethylenecyclohexyl-urea are dissolved in pyridine, when introducing 7. g of 4-(β- ^-methoxy-5-chloro-benzamido ^>-ethyl) -benzenesulfinyl chloride slight heating occurs. The clear solution is added after 10 minutes to a mixture of ice water and dilute hydrochloric acid, the precipitate thus formed is filtered off with suction, and stirred with ammonia of 0.5 strength. The amorphous precipitate is dissolved in acetone while hot. When cooling, the Ν- 4-(β- ^2-methoxy-5-chloro-benzamido ^>-ethyl) -benzene-sulfinyl7-N' -( 2.5-endomethylenecyclo:-hexyl)-urea crystallizes, having a melting point of Γ53 - 135°C. in excess is added to the bath. After filtration of the pyrolusite, water and dilute hydrochloric acid is added and the precipitate which has formed is recrystallized. There is obtained Ν-/5-(β- ^2-methoxy-5-chlorobenzamido^ -ethyl)-benzenesulfonyl7-N' -(2.5-endomethylenecyolohexyl)-urea melting at I87 — 189°C.

Claims (2)

1. we claim is: Benzenesulfonyl-ureas corresponding to the formula in which R represents lower alkyl, preferably methyl or lower alkenyl, X represents hydrogen, fluorine, chlorine dr bromine, preferably chlorine, lower alkyl, preferably methyl or lower alkoxy, preferably methoxy in 4- or 5-position to the carbonamide group, R represents endomethylene-cyclohexenyl, endomethylene cyclohexyl, endoethylene-cyclohexyl, endoethylene-cyclo hexenyl, and their salts. A compound as claimed in claim 1, wherein R is methyl, X is chlorine in 5-position and R1 is 2, 5-endomethylene cyclohexyl. A compound as claimed in claim 1, wherein R is methyl, X is bromine in 5-position and R1 is 2.5-endomethylene-cyclohexyl. A compound as claimed in claim 1, wherein R is methyl, X is methyl in 5-position and R1 is 2. -endomethylene-cyclohexyl. A compound as claimed in claim 1, wherein R is methyl, X is chlorine in 4-position and R1 is 2.5-endomethylene cyclohexyl. A compound as claimed in claim 1, wherein R is ethyl, X is hlorine in - osition and R1 is

2. -endometh lene A compound as claimed in claim 1, wherein R is methyl, X is methoxy in 5-POsition and R1 is 2.5-endomethylene-cyclohexyl. A compound as claimed in claim 1, wherein R is methyl, X Xs hydrogen and R1 is 2.5-endomethylene-cyclohexyl. A compound as claimed in claim 1, wherein R is methyl, X is fluorine in 5-position and R1 is 2.5-endomethylene-cyclohexyl. A compound as claimed in claim 1, wherein R is n-propyl, X is chlorine in 5-position and R1 is 2.5-endomethylene-cyclohexyl. A compound as claimed in claim 1, wherein R is n-propyl, X is methyl in 5-position and R1 is 2.5-endomethylene-cyclohexyl . A compound as claimed in claim 1, wherein R is methyl, X is ethyl in 5-position and R1 is 2.5-endomethylene-cyclohexyl. Process for the manufacture of benzenesulfonyl-ureas as claimed in claim 1, in which a) benzenesulfonyl-isocyanates, benzenesulfonyl-carbamic acid esters, benzenesulfonyl-thiolcarbamic acid esters, benzenesulfonyl-carbamic acid halides or benzenesulfonyl-ureas, benzenesulfonyl-semicarbazides or benzenesulfonyl-semicarbazones substituted in p-positio by the group are reacted with R -substituted amines or their salts, b) sulfonamides of the formula or their salts are reacted with R -substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halities or ureas, c) correspondingly substituted benzenesulfonyl-isourea ethers, benzenesulfonyl-isourea esters, benzenesulfonyl-isothiourea ethers, benzenesulfonyl-parabanic acids or benzenesulfonyl-haloformlc acid amidlnes are hydrolyzed, d) correspondingly substituted benzenesulfonyl-halides are reacted with R -substituted ureas, in particular their alkali metal salts, e) correspondingly substituted benzenesulfinic acid halides or, in the presence of acid condensing agents even correspondingly substituted benzenesulfinic acids or their alkali metal salts, are reacted with hydroxy ureas the NH2 group of which being substituted by R1, f) to correspondingly substituted carbodiimides water is added, g) in correspondingly substituted benzenesulfonyl-thioureas the sulfur atom is exchanged for an oxygen atom, h) correspondingly substituted benzenesulfinyl-ureas or benzenesulfenyl-ureas are oxidized, i) corresponding benzenesulfonyl-ureas containing in the molecule unsaturated linkages are hydroger.ated, k) in benzenesulfonyl-ureas of the formula HgNCHgCHg-^^-SOgNHCONH-R1 the radical is introduced by acylation, if desired in several stages, 1) in correspondingly substituted thiobenzamido-alkyl-benzenesulfonyl-ureas or -benzenesulfonyl-thioureas the sulfur atom or the sulfur atoms are exchanged by an oxygen atom or oxygen atoms, or m) compounds of the formula or their parabanic acid derivatives or compounds of the formula wherein U represents O-lower alkyl, S-lower alkyl or halogen (preferably chlorine) are saponified and the reaction products are treated with alkaline agents, if the formation of salts is desired. Process for preparing pharmaceutical compositions which have hypoglycemic action and are suitable for oral administration in the treatment of diabetes mellitus, which comprises bringing into a pharmaceutically suitable dosage unit form benzenesulfonyl-ureas as claimed in claim 1 or salts of such compounds, if desired in admixture or con- unction with a harmaceuticall suitable carrier. 28873/2 Pharmaceutical compositions having hypoglycemic action* which are suitable for oral administration in the treatment o diabetes mellitus, essentially consieting of a compound as claimed in Claim 1 or of a physiologically tolerable Regd. Patent Attorneys P. O. Box 331 16, TEL-AVIV, ISRAEL