DE1443894C - Benzenesulfonylureas, processes for their production and pharmaceutical preparations containing them - Google Patents

Description

- NH-Y -

Z '

substituted benzenesulfonyl isocyanates, carbamic acid esters, thiocarbamic acid esters,

. carbamic acid halides or ureas are reacted with R ¹ -substituted amines or, if appropriate, their salts, with these radicals being protected by esterification in the case of using benzenesulfonyl isocyanates with Z = - OH or --COOH

b) Benzenesulfonamides of the general formula

20th

ZC ₄ -C ₅ -AlkVl, Q-Gj-Cycloalkyl, C ₄ -C ₅ -alkoxy, C ₄ -C ₅ -CyClOaIkOXy, alkylmercapto, alkylsulphinyl, alkylsulphonyl with a low molecular weight alkyl radical; Phenyl, benzyl, benzyloxy; low molecular weight alkanoyl; Aroyl; Trifluoromethyl; a hydroxy, acyloxy, carboxy, carbalkoxy, nitrile or a carbamyl group optionally substituted by low molecular weight alkyl radicals,

Z 'is hydrogen or, if Z = hydroxy or carboxy, also halogen, low molecular weight Alkyl or low molecular weight alkoxy,

Y is a straight or branched C ₁ -C ₃ hydrocarbon radical and

R ^{1 is} a saturated or unsaturated, optionally branched C ₂ -C ₃ -alkyl radical, a C ₄ -C ₈ -alkyl radical interrupted by oxygen or sulfur, a benzyl, phenylethyl, cyclohexylmethyl, cyclohexylethyl radical, one by methyl, ethyl, Propyl, isopropyl, methoxyl, ethoxyl, propoxyl or isopropoxyl substituted cyclohexyl radical, a C ₅ -C ₈ cycloalkyl radical or a saturated or unsaturated cycloalkyl or cycloalk'ylmethyl radical with 4 to 5 ring carbon atoms containing oxygen or sulfur atoms in the ring

means, and their physiologically acceptable salts.

2. Process for the preparation of benzenesulfonylureas according to claim 1, characterized in that that one in a known manner

a) with the group
Z

35

45

50

55

60 SO ₂ -NH-CO-NH-R ¹

substituted isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or converts urea,

c) appropriately substituted benzenesulfonyl halides with ureas, isourea ethers, Isothiourea ethers or parabanic acids and those on this or other route obtained benzenesulfonylisoureaether, benzenesulfonylisothioureaether or benzenesulfonylparabanic acids hydrolyzed,

d) in appropriately substituted benzenesulfonylthioureas the sulfur atom through a . Exchanges oxygen atom,

e) corresponding benzenesulphinyl or benzenesulfenyl ureas are oxidized,

f) in benzenesulfonylureas the general formula

^^ SO ₂ -NH-CO-NH-R ¹

the remainder by acylation
Z

introduces, whereby this process can also take place in several steps,
g) in benzenesulfonylureas of the formula given in the preamble, in which Z represents a hydroxy or carboxy group protected by esterification or a hydroxy group protected by etherification or Z is a carboxy group protected by phthalimide formation to the carbonamide grouping, exposes this by saponification or optionally the Cleaving protecting groups catalytically

and the products of the process are optionally treated with alkaline agents.

3. Pharmaceutical preparations with a blood sugar lowering effect, characterized by a content on a benzenesulfonylurea defined in claim 1 or its physiologically tolerable one Salt.

or optionally their salts with R'-sub-It is known that benzo isulfonyl urea derivatives Have blood sugar-lowering properties and are therefore suitable as antidiabetic agents that can be administered orally are. In particular N- (4-amino-benzenesulfonyl) -N'-n-butyl urea and the N- (4-methyl-benzenesulfonyl) -N'-n-butyl-urea have due to their

good blood sugar-lowering properties and their tolerability in diabetes therapy are of great importance attained. .

CO ^V - NH - Y - * The invention relates to a process for the preparation of benzenesulfonyl ureas of the general formula I.

SO ₇ NH-CO-NH-R ¹

which, as a substance or in the form of their salts, also have blood sugar-lowering properties and which are characterized by a strong and especially long-lasting lowering of the blood sugar level. In the formula means

ZC ₄ -C ₅ alkyl, C ₄ -C ₅ cycloalkyl, C ₄ -C ₅ alkoxy, C ₄ -C ₅ cycloalkoxy; Alkyl mercapto, alkylsufinyl, lower alkyl alkylsulfonyl; Phenyl, benzyl, benzyloxy; lower alkanoyl; Aroyl; Trifluoromethyl; a hydroxy, acyloxy, carboxy, carbalkoxy, nitrile or a carbamyl group which is optionally substituted by lower alkyl radicals,

Z 'is hydrogen or, if Z = hydroxy or carboxy, also halogen, lower alkyl or lower Alkoxy,

Y is a straight or branched C ₁ -C ₃ hydrocarbon radical and

R is a saturated or unsaturated, optionally branched C ₂ -C ₈ -alkyl radical, a C ₄ -C ₈ -alkyl radical interrupted by oxygen or sulfur, a benzyl, phenyethyl, cyclohexylmethyl, cyclohexylethyl radical, one by methyl, ethyl, propyl , Isopropyl, methoxyl, ethoxyl, propoxyl or isopropoxyl-substituted cyclohexyl radical, a C ₅ -C ₈ cycloalkyl radical or a saturated or unsaturated cycloalkyl or cycloalkylmethyl radical with 4 to 5 ring carbon atoms containing oxygen or sulfur atoms in the ring.

The method of the present invention is characterized in that one is known per se wise

a) with the group

NH-Y-

substituted benzenesulfonyl isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas with R ¹ -substituted amines or optionally their salts or reacts
b) Benzenesulfonamides of the general formula

CO-NH-Y

SO ₂ -NH ₂

or, if appropriate, ^{reacts their salts with R 1} -substituted isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas,

c) appropriately substituted benzenesulfonyl halides with ureas, isourea ethers, isothiourea ethers or parabanic acids and the benzenesulfonyl isourea ethers, benzenesulfonyl isothiourea ethers, obtained in this way or in another way or benzenesulfonylparabanic acids hydrolyzed,

d) in appropriately substituted benzenesulfonylthioureas the sulfur atom through a Exchanges oxygen atom,

e) corresponding benzenesulphinyl or benzenesulfenylureas are oxidized,

f) in benzenesulfonylurea of the general formula

H ₂ NY

SO, -NH-CO-NH-

the remainder by acylation
Z

CO-

introduces, whereby this process can also take place in several steps, '

g) in benzenesulfonylureas of the formula given in the preamble, in which Z is a through Hydroxy or carboxy group protected by esterification or one protected by etherification Represents a hydroxyl group or an o-position carboxy group protected by phthalimide formation, exposes this by saponification or, optionally the protective group cleaves off catalytically

and the products of the process are optionally treated with alkaline agents.

Instead of the benzenesulfonyl isocyanates, reaction products of benzenesulfonyl isocyanates can also be used with acid amides, such as caprolactam or butyrolactam, and also with weakly basic amines how to use carbazoles.

When using benzenesulfonyl isocyanates or the above-mentioned reaction products with Acid amides, it is necessary as Z standing hydroxyl groups by esterification or etherification, carboxy groups in a corresponding position by esterification or one in the o-position to the carbonamide group to protect standing carboxy group also by ring closure to the phthalimide derivative.

The benzenesulfonyl carbamic acid esters or thiocarbamic acid esters mentioned can have a low molecular weight alkyl radical or a phenyl radical in the alcohol component. The same applies to the R ¹ -substituted carbamic acid esters or the 'corresponding mono-thiocarbamic acid esters. Under

The embodiments of the method according to the invention can generally with regard to Reaction conditions can be varied widely and adapted to the respective conditions.

For example, the reactions can be carried out using solvents, at room temperature or be carried out at an elevated temperature.

The starting materials used are on the one hand those compounds which one with the group

ok

15th

a low molecular weight or lower alkyl radical in the context of the invention should be such in all cases with no more than 4 carbon atoms apply.

The chlorides are primarily suitable as carbamic acid halides.

The benzenesulfonylureas which may be used as starting materials for the process can be unsubstituted or monosubstituted or disubstituted by other alkyl radicals or aryl radicals on the side of the urea molecule facing away from the sulfonyl group. Instead of benzenesulfonylureas substituted in this way, corresponding N-benzenesulfonyl-N'-acylureas and also bis (benzenesulfonyl) ureas are to be used. One can, for example, such bis (benzenesulfonyl) -ureas or N-benzenesulfonyl-N'-acyl ureas and treated with amines R ¹ NH _2, the obtained salts at elevated temperatures, especially those above 100 ⁰ C heat.

It is also possible to use ureas from all 20 \ - \

common formula. \ _ ρ - CO -

R ¹ —NH-CO —NH _{2 z} /

or acylated ureas of the general formula

_{Dl XTtr} "^ _XTtr . 25 of this formula are - without claim to full-

K JNrt CU INH acyl resistance - the following named:

wherein acyl is preferably a low molecular weight

aliphatic or an aromatic acid residue or CH ₃

denotes the nitro group, or of phenylureas

of the general formula 30 CH-CH, - <f VCO-

R ¹ —NH-CO —NH-C _fi H,

CONH - Y -

contain substituted benzene radical. As examples of the component

--6. ^1Α 5

or of diphenyl ureas of the general formula

^ -NH-CO-N (C ₆ Hj) ₂

where the phenyl radicals can be substituted and can be connected to one another directly or via a bridge member such as - CH ₂ -, - NH -, - O - or - S - or by Ν, Ν-disubstituted ureas of the general formula

R ¹ - NH - CO - NH - R ¹

to go out and this with

CH,

CH, - C

CO-

CH,

CA (n) -

45

CONH - Υ -

-substituted benzenesulfonamides to implement.

The replacement of the sulfur atom by an oxygen atom in the appropriately substituted benzenesulfonyl'thioureas can for example with the help of oxides or salts of heavy metals or also by using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid be performed.

The use of phthalimide compounds where Z = carboxyl in o-position to the carbonamide group is basically possible for all reaction types. The splitting of the phthalimide residue can by Alkali take place; however, it generally occurs already during the reaction or during the work-up of the reaction products one. When using esters or benzyl ethers, a cleavage to the free Connections are made.

CO-

CO-

U ο -r

CO

CH, CO

CO -

OH -CO CH ₃ CH ₃ -CH -CO I.
OH -CO CH ₃ O OCOCH ₃ I.
OH O" -CO COOH

COOH

CO-

COOC ₂ H ₅

CON

CH,

CH,

On the other hand, the starting compounds used are those which, for example, follow ^{as R 1}

; 25 residues contain: ethyl, propyl, isopropyl, butyl, Isobutyl, straight-chain or branched pentyl, hexyl, heptyl or octyl radicals, the benzyl or phenylethyl radical.

If they contain 4 or more carbon atoms, these radicals can optionally be interrupted by oxygen or sulfur atoms, such as, for example, the co-butoxypropyl, ω-ethoxypropyl, cy-propoxypropyl or <o-methoxypropyl radicals or the sulfur compounds corresponding to these. For the purposes of the invention, particular preference is given to those compounds which ^{contain, as R 1,} a cycloaliphatic hydrocarbon radical which is optionally substituted by alkyl or alkoxy. Such radicals are the cyclohexyl radical, methyl, ethyl, propyl or isopropyl, methoxy, ethoxy, propoxy or isopropoxy-cyclohexyl as well as cyclopentyl, cycloheptyl and cyclo-octyl radical

Finally, cycloalkylalkyl radicals such as cyclohexylmethyl or cyclohexylethyl are to be mentioned as suitable substituents, as well as those cycloalkyl or cycloalkylalkyl radicals with 5 or 6 members in which one CH ₂ group has been replaced by an oxygen or sulfur atom, such as

HOOC or

The hypoglycemic effect of the described benzenesulfonyiurea derivatives could thereby found that they were fed to rabbits in doses of 10 mg / kg and the blood sugar level according to the well-known method of Hagedorn-Jensen or determined with an autoanalyzer over a longer period of time.

For example, it was determined that 10 mg / kg N - [4 - (/ S - 2 - carboxy - benzamidoethyl) - benzenesulfo-

• 309 611/97

nyl) - N '- cyclohexylurea after 3 hours. one Causes blood sugar lowering of 5 to 10%, while the well-known N- (4-methyl-benzenesulfonyl) -N'-butylurea at a dose of less than 25 mg / kg in rabbits, no decrease in blood sugar level evokes more.

The strong effectiveness of the products of the process becomes particularly clear if the dose is further reduced. If one administers the N- [4 - (/ 3-2-Hydroxybenzamidoethyl) - benzenesulfonyl] - N '- η - butylurea in a dosage of 2 mg / kg or the N - [4 - (ß - 2 - Hydroxybenzamidoäthyl) - benzenesulfonyl ] -N'-cyclohexylurea in a dose of 0.15 mg / kg in rabbits, a clear drop in blood sugar can still be seen.

The products of the process should preferably be used for the production of orally administrable preparations Blood-sugar-lowering effectiveness for the treatment of diabetes mellitus and can as such or in the form of their salts or in the presence of substances which lead to salt formation will. For salt formation, for example, the following can be used: Alkaline agents such as alkali or Alkaline earth hydroxides, carbonates or bicarbonates. As medical preparations come preferred Tablets into consideration, which in addition to the products of the process, the usual auxiliaries and excipients, such as Contains talc, starch, lactose, tragacanth or magnesium stearate.

example 1

N- [4 - (/? - 4-n-Butoxy-benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexylurea

18.8 g of 4 - (/ 3-4-n-butoxy-benzamido-ethyl) -benzenesulfonamide (melting point 208-209 ⁰ C) are stirred together with 13.8 g of potassium carbonate and 300 ml of acetone 1 hour. It is heated to the boiling point of the acetone. 6.3 g of cyclohexyl isocyanate are then added dropwise at the boiling point of the acetone, and the mixture is stirred for 4 hours with continued boiling. It is concentrated in vacuo, the residue obtained is dissolved in about 2 l of water on the steam bath, filtered and the filtrate is acidified with dilute hydrochloric acid. The residue obtained is taken up in 1% aqueous ammonia and precipitated again by acidifying the filtrate with hydrochloric acid. The thus obtained N - [4 - {ß - 4 - η - butoxy - benzamido - ethyl) -benzenesulfonyl] -W- cyclohexyl - urea melts after recrystallization from methanol / dioxane at 197-199 ° C.

In an analogous manner, from the same 4 - (/ S-4-n-butoxybenzamido-ethyl) -benzenesulfonamide and 4-methyl-cyclohexyl isocyanate, the N- [4 - (/? - 4-n-butoxy-benzamido-ethyl) - benzenesulfonyl] - N '- 4 - methyl - cyclohexyl - urea with a melting point of 202 to 204 ° C (from methanol / dioxane) and using n-butyl isocyanate the N- [4 - (/ S-4-n-butoxy - benzamido ethyl) - benzenesulfonyl] - N '- η - butyl urea of melting point 203 to 205 ⁰ C (from methanol).

Example 2

N- [4 - (/ 9-4-n-Butoxy-benzamido-ethyl) -benzenesulfonyl] -N'-isobutylurea

13.6 g of mercury chloride are dissolved in 120 ml of water. The mixture is added dropwise with stirring 50 ml 2 η sodium hydroxide solution. To the precipitated Queck

Silver oxide is added to 18 g of N- [4 - (/? - 4-n-butoxy-benzamido-ethyl) -benzenesulfonyl] -N'-isobutyl-thiourea (melting point 124 to 126 ° C.), prepared from β - 4 - η - Butoxy - benzamido - ethyl - benzenesulfonamide and isobutyl mustard oil in the presence of potassium carbonate), dissolved in 80 ml of a mixture of equal parts in sodium hydroxide solution and dimethylformamide at a temperature of 40 ^° C. The _{mixture is then stirred for 2} hours at 40 to 50 ^° C., sucks off the mercury sulphide and washes with a little water. The filtrate is clarified with charcoal and acidified with dilute hydrochloric acid. A precipitate of N- [4 - (/ 3-4-n-butoxy-benzamidoethyl) -benzenesulfonyl] -N'-isobutylurea is obtained, which is washed with water and recrystallized from methanol. The melting point is 210 to 212 ° C.

B e is ρ ie I 3

N- [4 - (/? - 4-n-Butoxy-benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexylurea

A mixture of 10 g of N- [4 - (/ S-4-n-butoxy-benzamido - ethyl) - benzenesulfonyl] - urea (melting point 219 to 220 ° C), 300 ml toluene, 30 ml glycol monomethyl ether, 1.7 g of glacial acetic acid and 8.8 g of cyclohexylamine are stirred and refluxed for 5 hours heated. The mixture is concentrated in vacuo and the residue is triturated with alcohol. The one as a raw product obtained Ν- [4- (β-4-η-butoxy - benzamidoethyl) - benzene - sulfonyl] - N '- cyclohexyl - urea is sucked off. The melting point. Lies after recrystallization from dimethylformamide / methanol at 190 to 192 ° C.

Example 4

N- [4 - (/ 9-2-Benzyloxy-benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexylurea

20.5 g of 4 - (β - 2 - benzyloxy - benzamidoethyl) - benzenesulfonamide (melting point 180 to 183 ° C.) are suspended in 250 ml of acetone. Are added to 13.8 g of ground potassium carbonate and heated I ¹ Z reflux for ₂ hours to boiling. 6.25 g of cyclohexyl isocyanate are then added dropwise. After stirring for 7V for ₂ hours at the boiling point of the acetone, this is distilled off in vacuo. The residue is taken up in water, the undissolved material is filtered off, clarified with charcoal and the filtrate is acidified. The resulting crude N - [4 - (ß - 2 - benzyloxy - benzamido - ethyl) benzene sulfonyl] - N '- cyclohexyl - urea melts after recrystallization from methanol at 175 to 177 ° C.

In an analogous manner, using the abovementioned sulfonamide and methyl cyclohexyl isocyanate, N - [4 - (β - 2 - benzyloxy - benzamido - ethyl) - benzenesulfonyl] - N '- 4 - methyl - cyclohexyl urea with a melting point of 165 is obtained to 167 ⁰ C.

Example5

N- [4 - (/ 3-2-Hydroxy-benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexylurea

1 g of the N- [4 - (/ S-2-benzoxy - benzamidoethyl) - benzenesulfonyl] - N '- cyclohexyl urea is dissolved in about 150 ml of methanol. After adding palladium black, it is shaken Solution in a hydrogen duck with hydrogen. After the uptake of hydrogen has ended, the reaction

Solution filtered off from the catalyst and concentrated. The obtained N - [4 - (o - 2 - hydroxy - benzamido - ethyl) -benzenesulfonyl] -W- cyclohexyl - urea melts after recrystallization from methanol at 191 to 193 ° C.

. Example 6

N- [4 - (/ 3-2-Carboxy-benzamido-a-methyl-ethyl) -benzenesulfonyl] -N'-cyclohexylurea

34.4 g of 4 - (/? - Phthalimido - α - methyl - ethyl) - benzenesulfonamide (melting point 165 to 171 ° C.) are dissolved in 500 ml of acetone. 27.6 g of ground potassium carbonate are added and the mixture is heated to the boil for 1 hour with stirring and reflux. Now 12.5 g of cyclohexyl isocyanate are added dropwise. After refluxing for 6 hours and simultaneous stirring, the acetone is distilled off from the reaction mixture and the residue is dissolved in water. Acidification with hydrochloric acid gives a precipitate which is redissolved in 1% ammonia. After filtration and acidification, the N- [4 - (/? - 2-carboxy - benzamido - α - methylethyl) - benzenesulfonyl] _: N'-cyclohexylurea crystallizes out. The melting point of the substance after recrystallization from methanol is 170 to 171 ° C. (Decomp.)

In an analogous manner, using 4- (β- phthalimidoethyl) -benzenesulfonamide (melting point 225 to 227 ° C.), N- [4- (£ -2-carboxy-benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexylurea is obtained from a melting point of 161 to 163 ° C (decomp.) and, using the above-mentioned benzenesulfonamide and isobutyl isocyanate, the N- [4 - (/? - 2-carboxy - benzamido - ethyl) - benzenesulfonyl] - N '- isobutylurea from the melting point 145 to 146 ° C (dec.).

The same compound is obtained if, instead of the phthalimide, the 4 - (/ S-2-carboxy-benzamidoethyl) - benzenesulfonamide using an excess of potassium carbonate in acetone with isobutyl isocyanate implements.

In an analogous manner, from 4 - (^ - 2-carboxy - 4 - chloro - benzamido - ethyl) - benzenesulfonamide and cyclohexyl isocyanate, the N - [4 - (ß - 2 - carboxy-4 - chloro - benzamido - ethyl) - benzenesulfonyl] -N'-cyclohexyl urea with a melting point of 117 to 118 ° C (decomp.), from which 4 - (ß - 2 - carboxy - 4 - chlorobenzamido - ethyl) - benzenesulfonamide and 4 - methylcyclohexyl isocyanate give the N - [4 - (ß - 2 - Carboxy-4 - chloro - benzamido - ethyl) - benzenesulfonyl] - N '- (4 - methyl - cyclohexyl) - urea with a melting point of 109 to 110 ° C (decomp.).

B e i s ρ i e 1 7

N- [4- (yS-3-trifluoromethyl-benzamido-ethyl) -benzenesulfonyl] -N'-cyclohexylurea

18.6 g of 4 - (ß - 3 - trifluoromethyl - benzamido - ethyl) benzenesulfonamide (melting point 145 to 147 ° C, from methanol) are dissolved in 25 ml of 2 η sodium hydroxide solution and 50 ml of acetone and kept at 0 to 5 ° C 6.3 g of cyclohexyl isocyanate were added dropwise. The mixture is stirred for 3 hours, diluted with water and a little methanol, filtered and the filtrate is acidified. The precipitating in crystalline form N - [4 - (ß - 3 - trifluoromethyl - benzamido - ethyl) - benzenesulfonyl] - N '- cyclohexyl - urinary

substance melts after recrystallization from methanol at 160 to 162 ⁰ C.

In an analogous manner, N- [4 - (/? - 3-trifluoromethyl-benzamido-ethyl) -benzenesulfonyl] -W-butylurea with a melting point of 145 to 146 ° C. (from methanol) is obtained; N - [4 - (β - 3 - trifluoromethyl - benzamidoethyl) - benzenesulfonyl] - N '- (4 - methyl - cyclohexyl) urea with a melting point of 176 to 177 ° C. (from methanol).

In an analogous manner, 4 - (/ S-4-cyanobenzamido-ethyl) -benzenesulfonamide (melting point 237 to 238 ° C., from dimethylformamide / water) gives N - [4 - (β- 4-cyano-benzamido-ethyl) ) - benzenesulfonyl] -N'-cyclohexyl - urea with a melting point of 198 ° C (from dimethylformamide / water), the N- [4- (ß-4-cyanobenzamido - ethyl) - benzenesulfonyl] -W- butyl - urea with a melting point of 192 up to, 193 ° C (from methanol), and the N- [4 - (/ 3-4-cyano-benzamido-ethyl) -benzenesulfonyl] - W - (4 - methyl - cyclohexyl) - urea with a melting point of 198 to 199 ° C (from methanol); from the 4 - (ß - 4 - trifluoro - methyl - benzamido - ethyl) - benzenesulfonamide (melting point 216 to 217 ° C), the N - [4 - (ß - 4 - trifluoromethyl - benzamido - ethyl) - benzenesulfonyl] -W - Cyclohexyl urea with a melting point of 205 to 206 ° C (from dimethylformamide / water) and the N- [4 - (/ S-4-trifluoromethyl-benzamidoethyl) -benzenesulfonyl] - N '- (4 - methyl - cyclohexyl) - urea with a melting point of 213 to 214 ° C (from dimethylformamide / water); from the 4 - (ß - 4 - methylsulfonyl - benzamido - ethyl - benzenesulfonamide (melting point 238 to 240 ° C), the N- [4 - (ß- 4- methylsulfonyl - benzamido - ethyl) - benzenesulfonyl] -N'-cyclohexyl - urea with a melting point of 212 ° C (from dimethylformamide / methanol) and the trans N - [4 - (β - 4 - methylsulfonyl - benzamido - ethyl) - benzenesulfonyl] - W - (4 - methyl - cyclohexyl) - urea with a melting point of 210 up to 211 ° C (from dimethylformamide / methanol); from 4 - (/? - 4-benzoxy-benzamidoethyl) - benzenesulfonamide (melting point 242 ° C), from N - [4 - (ß - benzoxy - benzamido - ethyl) - benzenesulfonyl] -W- cyclohexyl urea with a melting point of 218 ° C (from dimethylformamide / water) and the trans N - [4 - (β - 4 - benzoxy - benzamido - ethyl) - benzenesulfonyl] - W - (4 - methyl - cyclohexyl) ) - urea with a melting point of 224 ° C (from dimethylformamide / water).

Example8

N- [4 - (/ 3-4-methylmercapto-benzamido-ethyl) T
benzenesulfonyQ-N'-cyclohexyl urea

40.8 g of N- [4- (jS-4- methylmercapto -benzamidoethyl) -benzenesulfonyl] -methyl urethane (melting point 195 to 197 ° C from dimethylformamide / water) are suspended in 50 ml of xylene and added dropwise at 70 ° C with stirring 10 g of cyclohexylamine are added. The temperature is increased to 120 to 130 ° C., the reaction commencing after a short time with evolution of methanol. After 1 hour it is cooled down. The sulfonylurea formed precipitates and '60 is recrystallized from dimethylformamide / water. The N- [4 - (/? - 4-methylmercapto-benzamido-ethyl) -benzenesulfonyl] -W- cyclohexyl-urea thus obtained melts at 212 to 213 ° C.

The trans-N- [4 - (/? - 4-methylmercapto - benzamido - ethyl) - benzenesulfonyl] -N '- (4 - methyl - cyclohexyl) - urea vom Melting point 213 ° C. (from dimethylformamide / water).

Example 9

N- [4- (y-4 ⁺ -carboxy-benzamido-propyl) -benzenesulfonyl] -N'-cyclohexyl-urea

7 g of N-4- (y-4 ⁺ - carboxy - benzamido - propyl) benzenesulfonamide (melting point 148 to 149 °) are dissolved in 100 ml. Acetone and 19.4 ml 2 η sodium hydroxide solution and stirred and cooled (0 up to 5 ^° C.), 2.5 g of cyclohexyl isocyanate are added dropwise. After the end of the dropwise addition, the mixture is stirred for a further 3 hours and the temperature rises to 20.degree. C. in the process. It is then acidified, the acetone is separated off in vacuo at room temperature and the residue is extracted with 1% ammonia. The urea precipitated with acid is recrystallized from methanol and a little water, melting point 163 to 164 ° C.

Example 10

N- [4- ( ²⁺ -hydroxy-benzamido-methyl) -benzenesulfonyl] -N '- (4-methyl-cyclohexyl) -urea

10 g of N - [4 - (2 ⁺ - hydroxy - benzamido - methyl) benzenesulfonamide (mp 184 ° C.) are dissolved in 80 ml of acetone and 32.5 ml of 2 η sodium hydroxide solution, cooled to 0 to 5 ° C. and 4.6 g of methylcyclohexyl isocyanate are added dropwise with stirring. During 3 hours of stirring, the temperature is allowed to rise to 20 ° C., acidified and the acetone is separated off on a rotary evaporator at room temperature. The residue is extracted with 1% ammonia, the extract is acidified and the precipitate is filtered off with suction. Recrystallize from ethanol / water and get crystals with a melting point of 180 to 18 ° C.

In an analogous manner, the N- [4- (β-2 ⁺ - hydroxy - benzamido) is obtained from the N - [4 - (/? - 2 ⁺ - hydroxy - benzamido '- ethyl) - benzenesulfonamide (mp 207 ° C.) -

20 ethyl) - benzenesulfonyl] - N '- cyclohexyl - urea with a melting point of 193 ° C (from ethanol), the N- [4 - (/? - 2 ⁺ - hydroxy - benzamido - ethyl) - benzenesulfonyl] - N' - ( 4 - methyl - cyclohexyl) - urea with a melting point of 188 ° C (from ethanol / water), the N- [4 - (/? - 2 ⁺ - hydroxy - benzamido - ethyl) - benzenesulfonyl] - N '- η - butyl - urea with a melting point of 152 ° C (from isopropanol / water); from the N- [4 - (/? - ²⁺ - hydroxy - benzamido - propyl) - benzenesulfonamide (mp 196 ° C) the N - [4 - {ß - 2+ - hydroxy - benzamido - propyl) - benzenesulfonyl] - N '- (4 - methyl - cyclohexyl) urea with a melting point of 158 ° C (from ethanol / water); from the N- [4- (y-3 ⁺ -acetoxy-benzamidopropyl) - benzenesulfonamide (F. 137 ⁰ C) the N - [4- {γ - 3 ⁺ - hydroxy - benzamido - propyl) - benzenesulfonyl] - N ' - cyclohexyl - urea of melting point 173 to 174.5 ⁰ C (from ethanol / water).

During the preparation in an alkaline medium, deacetylation of the hydroxyl group took place.

B e i s ρ i e 1 11

N- [4- (ß-4-n-butoxy-benzamidoethyl) -benzenesulfonyl] -N'-isobutylurea

3.8 g of N - [4 - (ß - 4 - η - butoxy - benzamidoethyl) benzenesulfonyl] - N '- isob'utyl - isourea methyl ether (obtained as an oily crude product by reacting N- [4 - (/ S -4-n-butoxy - benzamido - ethyl) -benzenesulfonyl] - N '- isobutyl - thiourea with mercury oxide in methanol) are concentrated with 50 ml. Hydrochloric acid heated on the steam bath for 10 minutes. It is cooled, diluted with water and the N- [4 - (/ S-4-n-butoxy - benzamido - ethyl) - benzenesulfonyl] - N '- isobutyl - urea, which after recrystallization from methanol at 210 to 212 ° C melts.

Claims (1)

Patent claims: 1. Benzenesulfonylureas of the general formula Z ι - NH- " in the IO