DE1445774A1 - Process for the preparation of benzenesulfonylureas - Google Patents

Description

FARBWERKE HOECHST AG. formerly Master Lucius & Brüning

File number: P 14 45 774.0 - Fw 4547 B

Date:

Process for the preparation of benzenesulfonyl ureas

It is known that benzenesulfonyl urea derivatives have blood sugar-lowering properties and are therefore suitable as antidiabetic agents that can be administered orally. In particular, N- (4-Amino-benzenesulfonyl-N ¹ -n-butyl-urea and N- (4-methyl-benzenesulfonyl) -N ^f -ntautylurea have great blood sugar-lowering properties and their tolerability in diabetes therapy Gained importance.

The invention relates to a process for the preparation of benzenesulfonyl ureas of the formula I.

CO-N-Y-

- CO-NH-R

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

Hydrogen, lower alkyl or phenylalkyl,

Z, Z 'is hydrogen, lower alkyl, lower alkoxy or halogen, where Z and Z' are the same or different could be,

Y is a straight or branched hydrocarbon radical with 1 to 3 carbon atoms and

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

The method of the present invention is characterized in that

a) with the group

substituted benzenesulfonyl isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas with R substituted amines or converts their salts, if necessary,

b) benzenesulfonamides of the formula

ORIGINAL INSPECTED 909ötU / 13ö8

ζ-

η -a. . .

CO - N - Y - ('^) - SO ₂ -NH ₂ II

or optionally their salts with R -substituted ones Isocyanates, carbamic acid esters ^ thiocarbamic acid esters, Converts carbamic acid halides or ureas,

c) appropriately substituted benzenesulfonyl halides with R -substituted ureas, isourea ethers, Isothiourea ethers or parabanic acids and the benzenesulfonylisoureaethers obtained in this or other way, -isothiourea ethers or -parabanic acids hydrolyzed,

d) in appropriately substituted benzenesulfonyl thioureas replaces the sulfur atom with an oxygen atom,

e) corresponding benzenesulphinyl or benzenesulfenylureas oxidized,

f) in benzenesulfonylureas of the formula

'00H

SO-NH-CO-NH-R

respectively.

OR ₁₆ WAU INSPECTED

909804/1308

NH-Y- f \ -SO ₂ -NH-CO-NH-R ¹ IV

the phthalimidinoring closes, this process also in several steps, possibly via functional Derivatives of the COOH group or the -CH-OH group take place

t R

or the products of the process are optionally treated with alkaline agents to form salts.

Instead of the benzenesulfonyl isocyanates, reaction products of benzenesulfonyl isocyanates can also be used Acid amides such as caprolactam or * butyrοlactam, also Use with weakly basic amines such as carbazoles.

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 -substituted carbamic acid esters or the corresponding mono-thiocarbamic acid esters. In the context of the invention, a low molecular weight or lower alkyl radical should in all cases apply to one having no more than k carbon atoms.

The chlorides are primarily suitable as carbamic acid halides.

As starting materials of the process in question Benzenesulfonylureas can be attached to the gdr sulfonyl group remote side of the urine of fmolecule unsubstituted or be monosubstituted or disubstituted by preferably lower alkyl radicals or aryl radicals. Instead of in safe way substituted benzenesulfonylureas are

909804/1308 ■ offleiNAL wspected

also corresponding N-benzenesulfonyl-N · acyl ureas and also to use bis (benzenesulfonyl) ureas. One can, for example, such bis (benzenesulfonyl) ureas or N-benzenesulfonyl-N'-acyl ureas with Treat amines R -NH_ and the salts obtained elevated temperatures, especially those above 100 C, heat.

It is also possible to use ureas of the formula R -NH-CO-NH ₂ or acylated ureas of the formula R -NH-CO-NH-acyl, in which acyl is a preferably low molecular weight aliphatic or an aromatic acid radical or the nitro group, or of Phenylureas of the formula R -NH-CO-NH-CgH- or of diphenylureas of the formula R -NH-CO-N (CgH ₁₅ ), where the phenyl radicals are substituted as well as directly or via a bridge member such as -CH ₂ -, - NH-, -0- or -S- can be connected to one another or starting from N, N-disubstituted ureas of the formula R -NH-CO-NH-R and these with

- to implement substituted benzenesulfonamides.

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 by using oxidizing agents such as hydrogen peroxide, sodium peroxide or nitrous acid. The ring closure to the phthalimidine compound, starting of the compounds of the formula XXX or IV, can

909804/1308

for example, by heating this compound to an elevated temperature. The embodiments of the method according to the invention can generally vary widely with regard to the reaction conditions and the respective ratios be adjusted. 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 those compounds which one with the group

contain substituted benzene radical. As examples of the component

of this formula the following are mentioned - without claiming to be exhaustive:

909804/1308

CH

CO-NJL, ° Η -

CO-N-,

On the other hand, the starting compounds used are those which contain, for example, the following radicals as R: ethyl, propyl _f isopropyl, butyl, isobutyl, straight-chain or branched pentyl, hexyl, heptyl or octyl radicals, the benzyl, phenylethyl radical or the phenylpropyl radical.

If they contain k or more carbon atoms, these radicals can optionally be interrupted by oxygen or sulfur atoms, such as, for example, the Ui -butoxylpropyl, tt ^ ethoxypropyl, CcZ-propoxypropyl or £ t> -methoxypr§pyl radicals or these corresponding sulfur compounds. For the purposes of the invention, particular preference is given to those compounds which contain, as R, a cycloaliphatic hydrocarbon radical which is optionally substituted by alkyl or alkoxy. As such are leftovers

909804/1308

INSPECTED

called the Cyelohexylrest; Methyl, ethyl, propyl or Isopropyl, methoxy, ethoxy, propoxy or isopropoxycyclohexyl as well as the cyclopentyl, cycloheptyl and cyclooctyl 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 a CH ₂ group is replaced by an oxygen or sulfur atom, such as

or -

The blood sugar-lowering effect of the benzene sulfonylurea derivatives described could be determined by feeding them to rabbits in doses of 10 mg / kg and the blood sugar level according to the well-known method of Hagedorn-Jensen or with an autoanalyzer for a longer period of time certain.

Thus, for example, determined that 10 mg / kg N- ^ T- (ß-Phthalimidino-Ok-methyl-ethyl) -benzolsulfonyl7-N ^f -cyclohexylharnstoff after 3 hours, a decrease in blood glucose of 14 $, 10 mg / kg N / Jl - (ß-Phthalimidino-ethyl) -benzenesulfonylJ-N 'cyclohexyl-urea after 3 hours a blood sugar reduction of 17 $, 10 mg / kg Ν- / Ϊ- (ß-Phthalimidino-ethyl) -benzenesulfonyl / -lf- 4-methyl-cyclohexylurea after 3 hours a blood sugar decrease of 23%, 10 mg / kg N- _J / ^ - (ß-5-chloro-plithalimidinoethyl) -benzo-sulfonyl / -N '-4-methylcyclohexyl -urea after 3 hours a blood sugar decrease of 22 % _t the corresponding N'-cyclohexylurea such of 35% and the corresponding N'-butylurea such of 30 % and 10 mg / kg H- / K- (ß -3-Ethyl-phthalimidino-ethyl) -benzenesulfonylJ-N '- cyclohexyl-harnet off cause a blood sugar drop of 15 $ after 3 hours, while the well-known N- (4-Me-fchyl-benzene->

9.8 04/130

- ίο -

sulfonyl) -N'-butyl urea at a dosage of Less than 25 mg / kg in rabbits does not lower blood sugar levels evokes more.

The strong effectiveness of the products of the process becomes particularly clear if the dose is further reduced. If the N - ^ - (ß-phthalimidino-ethyl) »benzene sulfonyl7-N ^f cyclohexyl-urea is administered in a dosage of 2 mg / kg, the Ν - ^ / 4 ~ - (ß-phthalimidino-ethyl) -benzenesulfonyl7- N'-4-methyl-cyclohexyl-urea in a dosage of 0.1 mg / kg, the H- / K- (ß-S-chlorophthalimidino-ethyl-benzenesulfonyl / -N'-4-methylcyclohexyl-urea in a dosage of 0.3 mg / kg, the corresponding N'-cyclohexyl urea in a dosage of 0.4 mg / kg or the corresponding N'-butyl urea in a dosage of 1 mg / kg in rabbits, see above there is still a marked decrease in blood sugar.

The process products should preferably be used for manufacture of orally administrable preparations with blood sugar-lowering effectiveness are used for the treatment of diabetes mellitus and can be applied as such vein in the form of their salts or in the presence of substances that lead to salt formation will. 2Just salt formation can be used, for example! Alkaline agents such as alkali or alkaline earth hydroxides, carbonato or bicarbonate. As medical preparations, tablets come into consideration, in addition to the Process products the usual auxiliary and. Carriers such as talc, starch, lactose, tragacanth or magnesium stearate contain.

Example 11

N- ^ T- (ß-phthalimidino-ethyl) -benzenesulfonyl / -N -cyclohexyl harnatoff '

A) 53.6 g of phthalide are dissolved in 500 ml of xylene. While stirring

OMGWAL WSPKTED

'"' ■ ''" ^ ^; ..- - 909804/1308 '".

88.8 g of 4- (ß-aminoethyl) -benzenesulfpnamide sodium admitted. The mixture is heated to the boil for 30 minutes and added dropwise then add 24 g of glacial acetic acid. The xylene is distilled off from this. The residue obtained is dissolved in 1N sodium hydroxide solution, the solution, clarified with charcoal and acidified after filtering. A precipitate is obtained in good yield of 4- (ß-o-hydroxymethyl-benzamidoethyl) -benzenesulfonamide, which is vacuumed off, washed with water and dried. The substance melts at 163-165 ° C.

b) By heating to about 200 ° C for 1 1/2 hours, cooling the Reaction material and recrystallization from methanol are obtained in good yield from the substance prepared under a) 4- (ß-Phthalimidino-ethyl) -benzenesulfonamide, the one Melting point of 251-253 ° C.

c) 15 S of the sulfonamides obtained according to b) are suspended in 250 ml of acetone. The mixture is stirred, 13 g of dry, ground potassium carbonate are added and the mixture is heated to the boil for 1 hour. 0.3 g of cyclohexyl isocyanate are then added dropwise with further stirring and heating. After 6 hours of cooking

breaks the reaction is off, the solvent distilled off in vacuo, the residue is taken up in water, filtered, after treatment with charcoal, and acidified to _"Man: obtained in good yield a precipitate of N- ^ 4 ~ - (ß-Phthalimidino- ethyl) -benzenesulfonyl7-N'-cyclohexylurea. The substance melts after recrystallization .; from methanol at 213-215 ° C. ~ .y. ~ _; .—

Example 2:. ,

N - ^ - (ß-Phthalimidino-Qi-methyl-ethyl) -benzenesulfonyl / ^ - N ¹ -cyclohexyl -urea

a) 20 g of 4- (ß-phthalimidino-OC-methyl) -benzenesulfonamide obtained

909 804/13

from phthalic anhydride and 4- (ol-methyl-ß-aniinoethyl) -benzene-4-sulfonaraid, are dissolved in 280 ml of ethanol. Add 210 ml of conc. Hydrochloric acid and 42 g of tin granules. After heating the batch to boiling temperature for 3 hours is diluted with water. The resulting precipitate of β- (phthalimidino-C ^ -methyl-ethyl) -benzenesulfonamide is sucked off, washes the substance with water and dries. Melting point 244-247 ° C.

b) 11g of the sulfonamides obtained according to a) are in 250 ml Acetone suspended. 8.7 g of potassium carbonate are added and the mixture is refluxed for 1 hour while stirring. To Addition of 4 g of cyclohexyl isocyanate makes the batch 5 1/2 Hours at the boiling point with simultaneous stirring. The acetone is distilled off, the residue dissolved in water. The solution is clarified with charcoal and the filtrate acidified. A good yield is obtained a crystalline precipitate of N- ^ T- (ß-phthalimidino-G £ -methyl-ethyl) -benzenesulfonyl ^ -N'-cyclohexylurea, which is suctioned off and recrystallized from methanol. The substance melts at 198 to 200 ° C.

In an analogous catfish obtained from 4- (ß-Phthalimidino- Oi -oethyläthyl) -benzenesulfonamide and the butylisocyanate N- ^ 4- (ß-Phthalimidines-Ct-methyl-ethyl) -benzolsulfonyl7 ^{N-f-butyl-urea} of melting point 166 - 168 C (from methanol).

Example 3:

N - ^^ + iß-Phthalimidino-ethyl) -benzenesulfonylT-N ¹ -cyclohexylurstoff f

a) 27 g of phthalide are dissolved in 2O _n JD ml of xylene. While stirring, 44.4 g of β-4- (β-aminoethyl) -benzenesulfonanide sodium are added

909804/1308

admitted. The mixture is heated to the boil for 30 minutes, 12 g of glacial acetic acid are added dropwise and the mixture is stirred at the boiling temperature for 1 1/2 hours. The residue obtained after the solvent has been stripped off in vacuo is dissolved in 1N sodium hydroxide solution. It is filtered using charcoal and the filtrate is acidified. A crystalline precipitate of k- (β-o-hydroxymethyl- »benzamidoethyl) -benzenesulfonamide is obtained, which is filtered off with suction, washed with water and dried. The substance melts at 161 - 163 ° C.

g of the sulfonamides obtained under a) are dissolved in 10 ml of 2N sodium hydroxide solution. After adding 50 ml of acetone, the mixture is cooled to about 0 ° C. and 2.5 S cyclohexyl isocyanate is added with stirring. The batch is then stirred for 2 hours at room temperature and diluted with water. The piltrate is filtered and acidified. A crystalline precipitate is obtained, which is filtered off with water. washes and recrystallized from methanol / dimethylformamide.The product obtained: Ν- / Ϊ- (ß-phthalimidino-ethyl) -benzenesulfonyl / -N'-cyclohexylurea melts at 213-215 ° C and gives the product obtained according to Example 1 with Substance no melting point depression,

Example k:

N- / 5- (ß-phthalimidino-ethyl) -benzenesulfonylJ-N -cyclohexyl-urene toff

a) 4.57 g of Ν- / ΪΓ- (ß-phthalimidino-ethyl) -benzenesulf οηνΐ7-Ν · - cyclohexyl-thiourea are dissolved in 250 ml of methanol. Is added with stirring a suspension of 2.2 g of mercuric oxide in 5 ml of methanol and heated ° for 3 1/2 hours while continuing the stirring to approximately 6O ⁰ C. After cooling, the solution is filtered and concentrated. The obtained conc. methanolic solution is carefully mixed with water, whereby a crystalline lower

OWGINAL INSPECTED

90980 4/130 8

- Tk -

blow from N- ^ T- (ß-phthalimidino-ethyl) -benzenesulfonyl-N'-cyclohexyl-isourea methylate. The substance melts after recrystallization from methanol at 139 - 1 ^ 1 ⁰ C.

b) 0 »^ S of the isourea methyl ether obtained under a) are concentrated with 10 ml. Hydrochloric acid heated on the steam bath for 5 minutes. It is cooled, the crystals obtained are filtered off with suction and washed with water. After recrystallization from methanol, N-2 / T- (β-phthalimidino-ethyl-benzo-olsulfony-YZ-N'-cyclohexyl urea with a melting point of 213-215 ° C. is obtained.

Example 5J

N- / 5 "- (ß-Phthalimidino-fte thyl) -benzenesulfonylJ-N« -cyclohexyl urea .

k, 2 g of N-2 ^ 5- (ß-phthalimidino-ethyl) -benzenesulfonyl / carbamic acid -methyleβter (obtained by reacting 4- (ß-phthalimidino-: ethyl) -benzenesulfonamide and chloramic acid methyl ester in acetone in the presence of potassium carbonate (melting point 228-231 ° C.) are suspended in 150 ml of dioxane. After adding 1.1 g of cyclohexylamine, the mixture is refluxed for 11/2 hours. The solvent is then stripped off in vacuo and the residue obtained is recrystallized from methanol. For purification, the filtrate is taken up in dilute aqueous ammonia, filtered and acidified. The received. Precipitate of N - ^ - fß-phthalimidino-ethyl) -benzolauJLfonylT-N'-cyclohexylurea melts after recrystallization from methanol at 213-215 ° C.

Example 6 »

Nj / ΣΓ- (ß-PhthaliiBidino-ae thyl) -benzenesulfonyl7- ^N '-cyclohexyl urea ......

a) 21- / 6 ^: g? 4- {ß-Phthalimidino-ethyl) -benzenesulfonamide are in

909804/1308

Dissolve 200 ml of ethanol. A solution of 11.4 g of potassium cyanate in 15 ml of water is added while shaking. Man heated to boiling for 4 hours on the steam bath under reflux and then distilled the solvent alcohol for the most part off. The residue obtained is dissolved in water. The solution is filtered and acidified. The precipitate obtained is taken up in dilute, approx. 1% ammonia. After acidification one obtains a crystallizate of N- / 4- (ß-phthalimidino-ethyl) -benzenesulfonyl / urea. The substance melts after recrystallization from a mixture of methanol / dimethylformamide at 220 - 222 ° C with decomposition.

3t6 g of the urea obtained according to a) are in 100 ml Toluene suspended. After adding 0.66 g of glacial acetic acid and 1 ι 1 g of cyclohexylamine is heated for 3 1/2 hours in an oil bath reflux to boiling. Let it cool down and stand overnight. The next morning the one that has crystallized out Sucked off precipitate, washed with diisopropyl ether and water and made from a mixture of methanol / dimethylformamide recrystallized. The N- / 4 "- (β-phthalimidino-ftethyl) -benzenesulfonylj-N'-cyclohexylurea obtained in this way in good yield melts at 213-2T5 ° C.

example

N - ^ - (ß-S-chlorophthalimidino-ethylJ-benzenesulfonylJ-N ¹ -cyclohexyl-urinst off. -

11.7 g of 4- (ß-5-chloro-phthalimidiko-ethyl) benzenesulfonamide (prepared by reduction of the corresponding phthalimide derivative, mp I76 - 178 ⁰ C) and 9 g of potassium carbonate $ 2 "■" / - 'are in 150 ml of acetone are heated to boiling for 1 hour with stirring. 4.2 g of cyclohexyl isocyanate are then added dropwise

ORIGINAL INSPECTED

909804/1308

and continue stirring and heating for 4 hours. After concentration ± u vacuum, the residue obtained is mixed with dilute hydrochloric acid and the resulting crystalline paste is filtered off with suction. The substance is dissolved in about 1% ammonia; the filtrate is acidified with dilute hydrochloric acid. The N- / 5 "- (β-5-chloro-phthalimidino-ethyl) -benzenesulfonyl7-N" - cyclohexylurea is obtained in good yield. The substance melts at 151-153 ° C. after recrystallization from isopropanol

Benzenesulfonamide is obtained in an analogous manner from the same and 4-methyl-cyclohexyl-isocyanate the N- ^ 4 ~ - (ß-5-chlorophthalimidinoethyl) -benzenesulfonyl / ^ - N'- (4-methyl-cyclohexyl) -urea with a melting point of 13 ^ - I36 C. Recrystallization from methanol and when using n-butyl isocyanate the N- ^ 4 ~ - (ß-5-chloro-phthalimidino-ethyl) - benzenesulfonyl7-N'-butyl urea. The substance melts after recrystallization from isopropanol at 160-162 ° C.

Example 8: »

N- ^ jT- (Phthalimidino-methyl) -benzenesulfonyl / -N '- cyclohexylurea

15 S b- (phthalimidino-methyl) -benzenesulfonamide (obtained from phthalimidino-methyl-benzene by chlorosulfuration and reaction of the sulfonic acid chloride obtained as intermediates with ammonia, melting point 228-230 C or from 4-ph.thalimidino-methylbenzenesulfonamide by reduction with Tin granules and concentrated hydrochloric acid in ethanol) are boiled in 250 μl acetone in the presence of 13.8 g potassium carbonate with simultaneous stirring and reflux. 6.3 g of cyclohexyl isocyanate are then added dropwise at the boiling point of the acetone while stirring is continued, and stirring and boiling are continued for 6 hours. After standing overnight

909804/1308

is suctioned off and the salt mixture obtained in water solved. The solution is filtered. By acidifying

-nie thyl) -benzenesulfonyl7-N '-cyclohexyl-

urea with a melting point of 203-205 C after recrystallization from methanol.

In an analogous manner, 4- (phthalimidino-methyl) -benzenesulfonamide and 4-methyl-cyclohexyl-isocyanate give N - ^ - (phthalimidino-methyl) -benzenesulfonyl ^ -N ¹ - (4- ethyl-cyclöhexyl) Urea with a melting point of 191 - 193 C (from methanol.

Example 9:

Ν- / ΪΓ- (ß-3-ethyl-phthalimidino-ethyl) -benzenesulphonyl-N »-cyclohexyl ureaff

7.6 g of 4- (ß-3-sthyl-phthalimidino-ethyl) -benzenesulfonamide (melting point 215 - 217 ° C) prepared from 2-ß-phenylethyl-3-ethyl-phthalimidine by sulfo-chlorination and reaction with ammonia) and 6, 2 g of potassium carbonate are added to 100 ml of acetone. The batch is heated to boiling with stirring and reflux for 1 hour. 2.8 g of cyclohexyl isocyanate are then added dropwise and the mixture is stirred for 3 hours at the boiling point. It is dissolved in water, the solution is filtered and the filtrate is acidified with dilute hydrochloric acid. The crystalline precipitate obtained is filtered off with suction and taken up in 1% ammonia. Acidification with acetic acid gives the N- / 4 "- (β-3-ethyl-phthalimldino-ethyl) -benzenesulfonyl7 ~ N 'cyclohexylurea with a melting point of 105-107 ° C in good yield.

Example 10:

N / 4 "- (ß <Phthalimidines ^ -a thyl) -benzolsulf onyiT ^N-1 -cyclohexyl urea

3.9 g of 4- (ß- ^ hthalimidino) -ethyl) -benzenesulfonamide-natriusr and

90.9804 / 1-3 00-

• - U45774

4.5 g of N-cyclohexylcarbamic acid phenyl ester are dissolved in 100 ml of dimethylformamide solved. The mixture is heated to 110 ° C. for 45 minutes cool and pour into approx. 0.5 $ aqueous ammonia. Man filtered from the undissolved material and acidified the filtrate. The precipitated crystalline precipitate of N- / 4 (ß- <PhthalimidinoS-ethyl) -benzenesulfonyl ^ -N'-cyclohexylurea is suctioned off, washed and dried. After recrystallization from methanol / dimethyl / pormamide, the substance melts at 213 - 215 ° C.

Example 111

Ν-2 ^ Γ- (ß- <Phthalimidino ^ -ethyl) -benzenesulfonyl7-N -cyclohexyl-urea

1.90 g of 4- {ß- ^ Phthaliiaidino ^ -äthyl) -benzenesulfonamide-sodium and 1.6 g of N-cyclohexyl-monothiocarbamic acid-S-methyl ester (prepared by methylating sodium N-cyclohexylmonothiocarbamic acid with dimethyl sulfate. Melting point 110 - 112 C) are rubbed together in a mortar and heated to 180 C ^{in an Erlenraeyer's flask 15 1.} The reaction mixture first becomes greasy and then solid again. It is treated with aqueous 0.5% ammonia, the undissolved material is filtered off and acidified. The deposited precipitate is filtered off with suction and purified again by dissolving in dilute ammonia and precipitating with acid. It is filtered off with suction, dried and, after recrystallization from methanol / dimethylformamide, the N- / 5 '- (β- <phthalimidino _< > ethyl) -benzenesulfonyl / -N'-cyclohexylurea with a melting point of 213-215 ° C. is obtained.

Example 12t

N- / 5 "- (ß ^ phthalimidine;> - ethyl) -benzenesulfonyl / -N '-cyclohexylurea

3.9 g of 4- (ß «^ Phthaliraidino / -äthyl) -benzenesulfonamide-sodium

ORIGINAL INSPECTED

909804 / taÖä ^;

<-: <■ U45774

6.0 g of N ^ N-diphenyl-N'-cyclohexylurea and 100 ml of dimethylformamide are heated to 110 ° C. for 45 '. It is allowed to cool, poured into water and mixed with 0.5 % ammonia. After filtering, the piltrate is acidified.

The resulting precipitate is filtered off with suction and again poured into 0.5 $ ammonia. After filtration and acidification of the Filtrates one receives a crystalline precipitate of N- / 4 "- (ß- ^ Phthalimidino> -äthyl) -benzenesulfonyl7-N'-cyclohexylurea, which is vacuumed off, washed and dried first in the air, then in a drying cabinet at 60 C. After recrystallization from methanol / dimethylformamide the substance melts 213-215 ° C.

Example 13:

N- / 4 ~ - (β- ^ phthalimidines)> - ethyl) -benzenesulfonylJ-N'-cyclohexylurea

- «ι

1.1g N- _i / ¥ - (ß- <Phthalimidino> -äthyl) -benzenesulfonyl7-tliiomethyl-urethane (prepared from 4- (ß-phthalimidino-ethyl) -benzenesulfonamide and monothiocarbonic acid S-methyl ester chloride in acetone in the presence of K CO.) Are mixed with 0.25 g of cyclohexylamine. The mixture is heated in an oil bath to 130 ° C and held at that temperature .. JO minutes After cooling, the N / 4 ~ formed is - (Q * - <Phthalimidino ^ ethyl) · ^r benzolsulfonyl7-N -cyclohexyl-urea in dilute Dissolved ammonia and precipitated again by acidifying the filtrate. The substance melts after crystallization from methanol / dimethylformamide at 213-215 ° C.

Example iki

N-r / 4 "- (ß- <Q? Hthalimidino ■ > -äthyl) -benzenesulfonyl7-N »- cyclohexylurea

8 g of 4- (ß- ^ Phthalimidino ^ -äthyl) -benzenesulfonamide are in

OBVGlHAt INSPECTED 9 0 9804/1308

125 ml of acetone with 14 g of potassium carbonate for 1 hour Stirring heated. 3t 5 g of N-cyclohexylcarbamic acid chloride are then added dropwise and stirred for 6 hours at boiling temperature. The acetone is distilled off in vacuo from, the residue is taken up in water and, after filtration, acidifies the filtrate. The obtained filling of N- / 4 ~ - (ß- (Phthalimidino ^ -ethyl) -benzene sulfonyl7-N'-cyclohexylurea is taken up in dilute ammonia and reprecipitated from the filtrate by acidification.

After recrystallization from methanol / dimethylformamide the substance melts at 213 - 15 ° C.

Example 15s

N- / 4 "- (β- <phthalimidino> -ethyl) -benzenesulfonylJ-N'-cyclohexylurea

2.8 g of cyclohexylurea are largely dissolved in 30 ml of pyridine. 6.5 g of 4- (ß- ^ phthalimidino-ethyl) -benzenesulfinic acid chloride (prepared from 4- (ß-ya ± halimidino-ethyl) -benzenesulfinic acid and thionyl chloride with warming) are introduced with stirring and the mixture is stirred for about 1/2 hour after. It is poured onto ice to which hydrochloric acid has been added and filtered off with suction. The crude 4- (β- <phthalimidino ^ -ethyl) -benzenesulfinylZ-N'-cyclohexylurea obtained is dissolved in about 25 ml of dimethylformamide. After adding a little water, potassium permanganate is added in a 3-fold excess in portions and heated on the steam bath. After about 45 minutes, the manganese dioxide formed is filtered off and the filtrate is acidified. The precipitate obtained is taken up in about 1% ammonia. It is filtered and, on acidification, N- / 4 "- (ß- {Phthalimidine ^ -ethyl) -benzenesulfonyl7-N'-cyclohexylurea, which is recrystallized from methanol / dimethylformamide.
Melting point 213-215 ° C.

909804/1308

- τη -

Example 16:

N- / h- (ß-phthalimidino-ethyl) -benzenesulfonyl7-N'-cyclohexylurea

a) Ν - ^ _ ϊ <- (ß-2-Hydroxy-methyl-benzamido-ethyl) -benzenesulfonyl7-N -cyclohexyl-urea

11.1 g of N-4- (β-2-hydroxy-Kie thyl-benzamido-ethyl) -benzenesulfonaraid, prepared according to Example 1a Cx- · and 9 »2 g of potassium carbonate are _{suspended in 150 ml of acetone:} and with stirring 1 Heated to the boil for 1/2 hour. After 2 g of cyclohexyl isocyanate have been added dropwise, stirring is continued for 5 hours at the boiling point. The acetone is distilled off, the residue is dissolved cold in 1% ammonia, filtered and acidified with dilute hydrochloric acid. The Ν - ^ / ¥ - (ß-2-hydroxy-methyl-benzaniido-ethyl) -benzenesulfonyl / -N'-cyclohexylurea thus obtained melts after recrystallization from methanol at 155-157 ° C. decomposition.

b) Ν- / ΖΓ- (ß-phthalimidino-ethyl) -benzenesulfonyl7-H · - cyclohexyl-urine tof f

1 g N - ^ - (ß-o-Hydroxy-methyl-benzamidovethyl) -benzenesulfonyl7 N'-cyclohexyl urea is mixed with 20 ml of 2 η NaOH for 1 hour heated on the steam bath, with salt formation only partially dissolving. One cools down and sucks the undissolved Substance off. It is triturated with dilute hydrochloric acid and recrystallized from methanol. The thus obtained N-j / 5 "- (β-phthalimidino-ethyl) -benzenesulfonyl7-N'-cyclohexyl-urine toff melts at 213 - 215 ° C.

909804/1308

Example 17 »

Ν- / 4- (ß-phthalimidirio-ethyl) -benzenesulfonyl-7-N'-cyclohexyl-haras toff

0.5 g N - ^ / 7- (ß-Phthalimidino-Hihyl) -benzenesulfonyl7-N »-

Cyclohexyl-lüiioharnst off, melting point 217-219 ° C, are dissolved in 1 ml of dioxane and 5 ml of 2N NaOH. 5 ml of 35/6 hydrogen peroxide are added and the mixture is heated on the steam bath for 15 minutes. After cooling, it is filtered and acidified with dilute hydrochloric acid. The Ν- ^ ΣΓ- (ß-phthalimidino-ethyl) -benzene sulfonyl / ⁷ -cyclohexylurea thus obtained melts after recrystallization from methanol at 213 to 215 ° C.

INSPECTED

909804/1308

Claims (2)

Patent claims: wherein Barrel, lower alkyl or phenyl alkyl, Z ^{f is} hydrogen, halogen, lower alkyl or lower alkoxy, where Z and Z * can be the same or different, Y 'is a straight or branched hydrocarbon radical with 1 to 3 carbon atoms and R is a saturated or unsaturated, optionally branched alkyl radical with 2 to 8 carbon atoms, one through Oxygen or sulfur-interrupted alkyl radical with 4 to 8 carbon atoms, a benzyl, phenylethyl, Phenylpropyl, cyclohexylmethyl, cyclohexylethyl radical, one substituted by methyl, ethyl, propyl, isopropyl, methoxyl, ethoxyl, propoxyl or isopropoxyl Cyclohexyl radical, a cycloalkyl radical with 5 to 8 C atoms or a saturated or unsaturated one containing oxygen or sulfur atoms in the ring Cycloalkyl or cycloalkylmethyl radical with 4 to 5 Ring carbon atoms mean and their salts. ORIGINAL INSPECTED 909804/1308 2. Process for the production of benzenesulfonyl ureas according to claim 1, characterized in that one a) with the group substituted benzenesulfonyl isocyanates, carbamic acid esters, thiocarbamic acid esters, carbamic acid halides or ureas with R substituted amines or converts their salts, if necessary, b) benzenesulfonamides of the formula 0 - N - Y or optionally their salts with R-substituted isocyanates, carbamic acid esters, thxocarbamic acid esters, Converts carbamic acid halides or ureas, c) appropriately substituted benzenesulfonyl halides with R-substituted ureas, isourea ethers, isothiourea ethers or parabanic acids and the benzenesulfonylisourea ethers obtained on this or other ¥ ege, -isothiourea ethers or parabanic acids hydrolyzed. 9098G4 / 1308 d) in appropriately substituted benzenesulfonyl thioureas replaces the sulfur atom with an oxygen atom, e) corresponding benzenesulfinyl or benzenesulfeny ureas oxidized, f) in benzenesulfonyl ureas of the formula COOH
Z SO ₂ NH-CO-NH-R the phthalimidinoring closes, this process also can be done in several steps and the products of the process are treated with alkaline agents for salt formation, if necessary. ORIGINAL INSPECTED 4/1308