NO127189B

NO127189B -

Info

Publication number: NO127189B
Application number: NO250870A
Authority: NO
Inventors: Rudi Weyer; Walter Aumueller; Helmut Weber; Karl Muth; Kurt Stach
Original assignee: Hoechst Ag
Priority date: 1967-03-18
Filing date: 1970-06-26
Publication date: 1973-05-21
Also published as: DE1618389A1; DE1618389B2; DE1618389C3

Description

Analogifremgangsmåter for fremstilling av benzen_ Analogous processes for the production of benzene_

sulfonylurinstoffer med blodsukkersenkende virkning. sulfonylureas with blood sugar-lowering effects.

Oppfinnelsen vedrører analogifremgancsmåter til fremstilling av benzensulfonylurinstoffer med blodsukkersenkende virkning og med formel The invention relates to analogous processes for the production of benzenesulfonylureas with a blood sugar-lowering effect and with a formula

hvori in which

R 1 betyr alkyl med 1-3 karbonatorner,5 R 1 means alkyl with 1-3 carbon atoms,5

R betyr R stands for

a) alkyl med 3-6 karbonatorner, a) alkyl with 3-6 carbon atoms,

b) lavere alkyl- eller dialkylcykloheksyl, b) lower alkyl- or dialkylcyclohexyl,

c) cykloalkyl med 5-8 karbonatorner, c) cycloalkyl with 5-8 carbon atoms,

d) cykloheksényl, metylcykloheksenyl, d) cyclohexenyl, methylcyclohexenyl,

X betyr hydrogen, lavere alkyl, lavere alkoksy , halogen, X means hydrogen, lower alkyl, lower alkoxy, halogen,

X' betyr det samme som X, og dessuten når X betyr hydrogen, en ~CP^ eller -N02-gruppe,eller X' means the same as X, and furthermore when X means hydrogen, a ~CP^ or -NO2 group, or

X og X' betyr sammen en metylendipksyjjruppe, og X and X' together mean a methylene dipoxy group, and

Y betyr -CK2"CK2-a -ClKCHjJCHg- eller -CH2. CU( CH^)-, ... Y means -CK2"CK2-a -ClKCHjJCHg- or -CH2. CU(CH^)-, ...

samt salter av de nevnte benzensulfonylurinstoffer?som videreføring av oppfinnelsen ifølge patent nr. 118.606. as well as salts of the aforementioned benzenesulfonylureas? as a continuation of the invention according to patent no. 118,606.

■ I det ovennevnte pg de følgende definisjoner betyr ■ In the above pg the following definitions mean

"lavere alkyl" alltid en alkylgruppe med 1 til 4 karbonatorner i rett eller forgrenet kjede. "lower alkyl" always an alkyl group with 1 to 4 carbon atoms in a straight or branched chain.

R"1" kan eksempelvis bety propyl, isopropyl, butyl, iso-butyl eller sek. butyl. R"1" can for example mean propyl, isopropyl, butyl, iso-butyl or sec. butyl.

Spesielt foretrukket er slike forbindelser som inneholder en cykloalifatisk rest som eventuelt er substituert med alkyl. Som slike rester skal det eksempelvis nevnes cyklppentyl-, cykloheksyl-', cykloheptyl-, cyklooktyl-, metyl-cykloheksyl-, etylcykloheksyl-, propyl- og isopropylcykloheksyl-, idet.alkylgruppene .fortrinnsvis er plassert i 4-stilling såvel i cis- som i transkonfigurasjon. Particularly preferred are such compounds which contain a cycloaliphatic residue which is optionally substituted with alkyl. Examples of such residues include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, ethylcyclohexyl, propyl and isopropylcyclohexyl, the alkyl groups being preferably placed in the 4-position both in cis and in trans configuration.

Analogifremgangsmåtene til fremstilling av de nevnte benzensulfonylurinstoffer er karakterisert' ved'at man enten The analogous methods for producing the aforementioned benzenesulfonylureas are characterized by either

a) omsetter aminer med formel R MH2 eller deres salter med benzensulfonylisocyanater, -karbaminsyreestere, -tiolkarbaminsyreestere, -urinstoffer, -semikarbazider eller -semikarbazoner som i benzenkjernen inneholder substituenten a) reacts amines of formula R MH2 or their salts with benzenesulfonyl isocyanates, -carbamic acid esters, -thiolcarbamic acid esters, -ureas, -semicarbazides or -semicarbazones which in the benzene nucleus contain the substituent

eller or

b) omsetter sulfonamider med formel'b) reacts sulfonamides of formula'

eller deres salter med R^-substituerte isocyanater, k<p.>rhaninsyreestere, tiolkarbam.insyreestere, karbaminsyrehalogenider eller urinstof fer a eller or their salts with R^-substituted isocyanates, cyanic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas or

c) hydrolyserer N-benzensulfonylurinstoffetere, -iso^ tiourinstof fetere , halogenmaursyreamidiner eller -para.bansyrer som_ c) hydrolyzes N-benzenesulfonylurea ethers, -iso^thiourea ethers, haloformic acid amidines or -para.banic acids such as_

i benzenkjernen er substituert, med gruppen in the benzene nucleus is substituted, with the group

og i IV-stilling med gruppen i;1, eller and in IV position with the group i;1, or

d) erstatter svovel atomet i benzer.sul-f onyltiourinstof f er svarende t i% ben zens ulfony lur ins t o f f e r med f orr el I reel c. t oksygenatom,eller e) hydregenerer benzensulfonylurinstoffer svarende tii benzensulf onylurinstof fer med f ori: el I, som i molekylet inneholder d) replaces the sulfur atom in benz.sulfonylthiourea is equivalent to i% benzenesulfonylures with forel I real c. t oxygen atom, or e) hydrogenates benzenesulfonylureas corresponding to benzenesulfonylureas with forel I , which in the molecule contains

<r>mettede bindinger, eller <r>saturated bonds, or

f) innfarer resten f) incurs the remainder

i benzensulfonylurinstoffer med formel in benzenesulfonylureas of formula

ved acylering, by acylation,

og behandler eventuelt fremgan<g>si?.åteproduktene ued alkaliske midler for saltdannelse. and optionally treats the processed food products with alkaline agents for salt formation.

Alt etter naturen av substituentene X og R vil i enkelte tilfelle den ene eller andre av de nevnte fremgangsmåter v?ore uegnet for fremstilling av de under den generelle formel fallende forbindelser. Slike forholdsvis sjeldent opptredende tilfeller kan lett erkjennes av fagfolk og det byr ikke på vanskeligheter i slike, tilfeller med resultat å anvende en av de andre omtalte syntesemetoder. Depending on the nature of the substituents X and R, in some cases one or the other of the methods mentioned will be unsuitable for the preparation of the compounds falling under the general formula. Such relatively rarely occurring cases can be easily recognized by professionals and there are no difficulties in such cases with the result of using one of the other mentioned synthesis methods.

De nevnte benzensulfonyl-karbaminsyreestere resp. -tiolkarbaminsyreestere kan i alkoholkomporientene. ha en -lavere alkylrest eller en fenylrest. Det sa;::!:e gjelder for de R^-substituerte karba-rainsyreestere resp. de tilsvarende rnonotiokarbaminsyreestere. The aforementioned benzenesulfonyl-carbamic acid esters resp. -thiocarbamic acid esters can in the alcohol components. have a -lower alkyl residue or a phenyl residue. This applies to the R 1 -substituted carbaic acid esters resp. the corresponding rnonotiocarbamic acid esters.

Som karbaminsyrehalogenider egner det seg i første rekke kloridene. As carbamic acid halides, the chlorides are primarily suitable.

De som utgangsstoffer for fremgangsmåtene aktuelle benzensulfonylurinstoffer kan ved den side av urinstoffmolekylet som er vendt bort fra sulfonylgruppen være usubstituert eller substituert én eller spesielt to ganger. Da disse substituenter ved reaksjonen lied aminer avspaltes, kan deres karakter varieres innen vide grenser. Ved siden av alkyl-, aryl-, acyl- eller heterocykliske substituerte benzensulfonylurinstoffer kan man også anvende bis-(benzensulfonyl)-urinstoffer som eventuelt ved ét av nitrogenatomene dessuten kan ha en ytterligere substituent, f.eks. metyl. Man kan eksempelvis behandle slike bis - (benzensulf ony 1)-urinstof fer eller også. N-benzensulf onyl-H '-acylurinstof f er med aminer av formel rHjI-^ og oppvarme de dannede salter til forhøyede temperaturer, spesielt slike over 100°C The benzenesulfonylureas in question as starting materials for the methods can be unsubstituted or substituted once or especially twice on the side of the urea molecule facing away from the sulfonyl group. As these substituents are split off in the reaction with amines, 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 - (benzenesulfony 1)-ureas or also. N-benzenesulfonyl-H'-acylureas with amines of the formula rHjI-^ and heating the formed salts to elevated temperatures, especially those above 100°C

Videre er det mulig å gå ut fra urinstoffer med formel Furthermore, it is possible to proceed from urine substances with a formula

I-^N-CO-NHR<1>I-^N-CO-NHR<1>

eller fra urinstoffer som ved det frie nitrogenatom er substituert or from urea substances which have been substituted at the free nitrogen atom

en eller spesielt to ganger og å omsette disse med benzensulfonamider once or especially twice and to react these with benzenesulfonamides

av formelen of the formula

Som slike utgangsstoffer kommer det eksempelvis på tale de tilsvarende M ' -acetyl-, W-nitro-, N ' -cykloheksyl- , N ' - ( 4-mety 1-cykloheksy 1) - , II',N'-difenyl- (idet de to fenylrester også kan være substituert såvel direkte som også være forbundet med hverandre over et broledd som -CKp-, -MH-, -0- eller -S-), fl'-mety1-N'-fenyl-, N' ,N•-dicykloheksyl-urinstoffer såvel som R -karbamoylimidazoler eller -triazoler. . ydrolysen av de som utgangsstoffer nevnte benzensulfon-ylparabansyrer, -isourinstoffetere, -isotiourinstoffetere, eller -halogenrnaursyreamidiner foregår hensiktsmessig i alkalisk medium. Isourinstoffetere og halogenrnaursyreamidiner kan også hydrolyseres med godt resultat i et surt medium. Examples of such starting materials include the corresponding M'-acetyl-, W-nitro-, N'-cyclohexyl-, N'- (4-methyl 1-cyclohexy 1)-, II',N'-diphenyl- ( in that the two phenyl residues can also be substituted directly as well as be connected to each other via a bridge link such as -CKp-, -MH-, -O- or -S-), fl'-methyl-N'-phenyl-, N' ,N•-dicyclohexylureas as well as R -carbamoylimidazoles or -triazoles. . the hydrolysis of the benzenesulfonylparabanic acids, -isourea ethers, -isothiourea ethers, or -halogenauric acid amidines mentioned as starting materials conveniently takes place in an alkaline medium. Isoururic ethers and halogenuric acid amidines can also be hydrolysed with good results in an acidic medium.

Utbyttingen av svovelatomet i benzensulfonyltiourin-stoffer rned et oksygenatom kan eksempelvis utføres ved hjelp av ok-syder eller salter av tungmetaller eller også ved anvendelse av oksydasjonsmiuler som hynrogenperoksyd . natriumneroksyd eller sal-petersyrling.. Derved kan en.i venstre molekyldel befinnende tiourin-stoffgruppe eller et derivat derav sartidig overføres til urinstoff. Tiourinstoffene Iran ogsé' avsvovles ved behandling med fosgen eller fosforpentaklorid. Klormaursyreamioiner resp. -karbcdiimider som dan-nes som mellomprodukter kan veu egnede forholdsregler som forsåpning eller tilleiring av vann overføres i benzensulfonylurinstoffene. The exchange of the sulfur atom in benzenesulfonylthiourea substances with an oxygen atom can be carried out, for example, by means of oxides or salts of heavy metals or also by using oxidizing agents such as hydrogen peroxide. sodium neroxide or nitrous acid. Thereby, a thiourea substance group or a derivative thereof located in the left molecular part can be subtly transferred to urea. The thioureas Iran are also desulphurised by treatment with phosgene or phosphorus pentachloride. Chloroformic acid amioins resp. -carbdiimides which are formed as intermediates can be transferred into the benzenesulfonylureas by suitable precautions such as saponification or addition of water.

benzensulfonylurinstoffer som/ i molekylet inneholder en olefinisk binding kan ved hydrogenering, f.eks. med molekyla-rt hydrogen i nærvær av en kjent hydrogeneringskatalysator overføres i benzensulf onylurinstof f ene . Benzenesulfonylureas which/ in the molecule contain an olefinic bond can by hydrogenation, e.g. with molecular hydrogen in the presence of a known hydrogenation catalyst is transferred into the benzenesulfonyl urea.

Innføring av resten Introduction of the rest

i aminoalkyl-benzensulfonyl-urinstoffer med formel in aminoalkyl-benzenesulfonyl ureas of formula

kan- såvel foretas i ett som også i flere reaksjonstrinn. Eksempelvis er det mulig, å omsette de nevnte aminoalky lbenzensulf onyl-urinstof f er med tilsvarende substituerte karbaminsyrehalogenider, hensiktsmessig i nærvær av tertiære organiske baser. Man kan imidlertid også først behandle aminoalkylbenzensulfonyl-urinstoffene med fosgen og bringe de dannede mellomprodukter til reaksjon med tilsvarende substituerte aminer. 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.

Utførelsesformen av fremgangsmåtene ifølge oppfinnelsen kan generelt varieres sterkt med hensyn til reaksjonsbetingelser og tilpasses forholdene. Eksempelvis kan omsetningene foregå under anvendelse av oppløsningsmidler ved værelsesteniperatur eller ved for-høyet temperatur. De ved fremgangsmåten ifølge oppfinnelsen oppnåe-lige benzensulfonylurinstoffderivater er verdifulle legemidler som ut-merker seg ved en sterk og langvarig blodsukkersenkende virkning. Deres blodsukkersenkende virkning kunne fastslås på Kaniner ved å fore dem med fremgangsmåteprodukter i en dose pa 10/fflg/kg og be-stemte blodsukkerverdién ifølge den kjente metode av Hagerdorn-Jensen, eller med en autoanalyser over et lengre tidsrom. Således ble det f.eks. funnet at N-^~4-(3-<N-metyl-N-fenyl-ureido>-etyl)-benzensulfonyl7-N'-(4-nietyl-cykloneksyl)-urinstoff på kaniner etter 3 timer bevirker en blodsukkersenkning på 30%, som etter 24 timer sogar utgjør 49$ . N-/_—4 - ( 3-<N-4-metylf eny l-M-metylureido>-etyl) -benzensulf ony 1/-N<1->(4-metyl-cykloheksy1)-urinstoff bevirker under de angitte forsøks-betingelser etter 6 timer en blodsukkersenkning på. 32?, som etter 24 timer ennå utgjør 2Jf. og etter 48 timer ennå 25%. På samme måte fører N-/_— 4- ( 3-< 2-klorf enyl-iJ-metylureido>-etyl) -benzensulf ony 17-N ' - cykloheksylurinstoff etter 3 timer tii en blodsukkersenkning på 30%, som etter 24 timer utgjør 39/3. The embodiment of the methods according to the invention can generally be varied greatly with regard to reaction conditions and adapted to the 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 be determined on rabbits by feeding them with process products in a dose of 10/fflg/kg and determining the blood sugar value according to the known method of Hagerdorn-Jensen, or with an auto-analyser over a longer period of time. Thus, it was e.g. found that N-^~4-(3-<N-methyl-N-phenyl-ureido>-ethyl)-benzenesulfonyl7-N'-(4-niethyl-cyclonexyl)-urea in rabbits after 3 hours causes a blood sugar lowering of 30 %, which after 24 hours even amounts to $49. N-/_—4 - (3-<N-4-methylphenyl-M-methylureido>-ethyl)-benzenesulfony 1/-N<1->(4-methyl-cyclohexy1)-urea causes under the indicated experimental conditions after 6 hours a blood sugar reduction of. 32?, which after 24 hours still amounts to 2Cf. and after 48 hours still 25%. Similarly, N-/_— 4-( 3-< 2-chlorophenyl-1J-methylureido>-ethyl)-benzenesulfony 17-N ' - cyclohexylurea after 3 hours leads to a blood sugar lowering of 30%, as after 24 hours amounts to 39/3.

I forhold til dette er det som oralt antidiabetikum kjente N-(4-metyl-benzensulfonyl)-N'-butyl-urinstoff på kaniner uvirk-somt ved doser på mindre enn 25 nig/kg. In relation to this, N-(4-methyl-benzenesulfonyl)-N'-butyl urea, known as an oral antidiabetic, is ineffective in rabbits at doses of less than 25 nig/kg.

Den sterke langvarige blodsukkersenkende virkning av sulfonylurinstoffene som fremstilles ifølge oppfinnelsen er tydelig-gjort av de angitte tall. De i norsk patent nr. 118.606 omtalte forbindelser viser ved en dosering av 10 mg/kg etter 24 timer ikke mer blodsukkersenkende virkning. The strong, long-term blood sugar-lowering effect of the sulfonylureas produced according to the invention is made clear by the indicated figures. The compounds mentioned in Norwegian patent no. 118,606 show no more blood sugar-lowering effect at a dosage of 10 mg/kg after 24 hours.

Således er eksempelvis K10-verdiene (prosentuell senkning av blodsukkerspeilet etter peroral applikasjon av 10 mg/kg på kaniner) av det i norsk patent nr. 118.606 omtalte N-/_<->4-(B-N-fenylureido)-etyl)-benzensulfonyl7-N'-(4-metyl-eykloheksy1)-urinstoff med formel Thus, for example, the K10 values (percentage lowering of the blood sugar level after oral application of 10 mg/kg to rabbits) of the N-/_<->4-(B-N-phenylureido)-ethyl)-benzenesulfonyl mentioned in Norwegian patent no. 118,6067 -N'-(4-methyl-cyclohexyl)-urea of formula

Av den følgende tabell fremgår det at benzensulfony1-urinstoffene fremstilt ifølge oppfinnelsen har en vesentlig bedre blodsukkersenkende virkning. From the following table it appears that the benzenesulfonylureas produced according to the invention have a significantly better blood sugar-lowering effect.

De omtalte benzensulfonylurinstoffer skal- fortrinns- The mentioned benzenesulfonylureas shall preferably

vis tjene til fremstilling av oralt administrerbare preparater med blodsukkersenkende virkning til behandling av diabetes mellitus og kan appliseres som sådanne eller i form av deres salter, resp. i nærvær av stoffer som fører til en saltdannelse. Til saltdannelse kan det eksempelvis anvendes alkaliske midler som alkali- eller jordalkalihydroksyder, -karbonater eller bikarbonater. show serve 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.

Som medisinske preparater kommer det fortrinnsvis i betraktning tabletter som ved siden av fremgangsmåteproduktene inneholder de vanlige hjelpe- og bærestoffer som talkum., stivelse, melkesukker, tragant eller magnesiumstearat. 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.

Et preparat som inneholder de nevnte benzensulfonyl-urinstoffer som virksomt stoff, f.eks. en tablett eller et pulver med eller uten de nevnte tilsetninger, er hensiktsmessig, bragt i en form med bestemt dosering. Som dosis skal det da velges en slik som er tilpasset virkningen av det anvendte benzensulfonylurin-stoff og den ønskede effekt. Hensiktsmessig, utgjør doseringen pr. enhet ca. 0,5 til 100 mg, fortrinnsvis 2 til 10 mg, imidlertid kan det også anvendes betraktelig høyere eller lavere doser som eventuelt må deles resp. mangfoldiggjøres før applisering. A preparation containing the aforementioned benzenesulfonylureas as active substance, e.g. a tablet or a powder with or without the aforementioned additives is appropriate, brought in a form with a specific dosage. 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 considerably higher or lower doses can also be used which may have to be divided or be multiplied before application.

Eksempel 1. Example 1.

N-/__il- (3-<N-fenyl-M-metyl-ureido>-etyl)-benzensulf ony 17-II' - cykloheksy1-urinstoff. N-/__yl-(3-<N-phenyl-M-methyl-ureido>-ethyl)-benzenesulfony 17-II' - cyclohexy1-urea.

8,3 g 't- ( g-<N-f eny l-N-metyl-ureido>-etyl) -benzensulfon-amid (smeltepunkt 156 - 153°, fremstillet ved omsetning av 4-(|3-aminoetyl)-benzensulfonamid med N-fenyl-M-metyl-karbamidsyreklorid) suspenderes i 100 ml aceton og bringes ved tilsetning av 1 g NaOH og vann i oppløsning. Hertil tildrypper man ved va^relsestemperatur under omrøring 3,3 g cykloheksylisocyanat og lar det etteromrøre i 2 timer. Reaksjonsblåndingen..blandes med.vann, filtreres og surgj.øres 8.3 g of t-(g-<N-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide (melting point 156 - 153°, prepared by reaction of 4-(|3-aminoethyl)-benzenesulfonamide with N- phenyl-M-methyl-carbamic acid chloride) is suspended in 100 ml of acetone and brought into solution by adding 1 g of NaOH and water. To this, 3.3 g of cyclohexyl isocyanate are added dropwise at room temperature with stirring and allowed to stir for 2 hours. The reaction mixture is mixed with water, filtered and acidified

med saltsyre. Man'frafiltrerer det utfelte produkt, gjenutfeller fra ca. 1% ammoniakk og får ved omkrystallisering fra vann/etanol N-/_~4-(g-<N-fenyl-N-metylureido>-etyl)-benzensulfonyl7-N' -cyklohek-sylurinstoff med,smeltepunkt 148 - 150°C. with hydrochloric acid. The precipitated product is filtered off, reprecipitated from approx. 1% ammonia and is obtained by recrystallization from water/ethanol N-/_~4-(g-<N-phenyl-N-methylureido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea with, melting point 148 - 150°C .

På analog måte får man: N-/_ 4- ( 3-<N-feny1-N-mety1-ureido>-etyl)-benzensulfonyl7-N '- (4-mety1-cykloheksyl)-urinstoff med smeltepunkt 136-138°C, N-/_ 4 - ( 3-<N-feny1-N-metyl-ureido>-ety1)-benzensulfonyl7-N' - buty 1-urinstoff med smeltepunkt 131-133°C, In an analogous manner, one obtains: N-/_ 4-(3-<N-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl-7-N'-(4-methyl-cyclohexyl)-urea with melting point 136-138° C, N-/_ 4 - (3-<N-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-buty 1-urea with melting point 131-133°C,

fra 4-(g-<N-2-klorfenyl-N-metyl-ureido>-ety1)-benzensulfonamid med smeltepunkt 134-136°C: from 4-(g-<N-2-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 134-136°C:

N-/_ 4- (3-<N-2-klorfenyl-N-metyl-ureido>-etyl) -benzensulfonyl7-N ' - cykloheksyl-urinstoff med smeltepunkt 204-206°C, N-/__4- (g-<N-2-klorfenyl-N-metyl-ureido>-etyl )-benzensulfonyl7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 169-171°C N-/_ 4 - ( B-<N- 2-klor f enyl-N-me ty 1-ure ido>-ety 1) -benzensulf ony l7-N'-isobutyl-urinstoff med smeltepunkt 189-191°C, fra 4-(g-<N-3-klorfeny1-N-mety1-ureido>-ety1)-benzensulfonamid med smeltepunkt 158-l60°C: N-/_ 4- ($- <N-3-klorf eny 1-N-me tyl-ure ido> -etyl)-benzensulf ony 1/-N 1 - cykloheksyl-urinstoff med smeltepunkt l69-170°C, N-/__4-( 6-<N-3-kbrf enyl-N-me ty l-ureido>-etyl)-benzensulf ony l7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 150-152°C, fra 4-(3-<N-4-klorfeny1-N-metyl-ureido>-etyl)-benzensulfonamid med smeltepunkt 168-170°C: N-/_-4- ( 3-<N- 4-klor f eny 1-N-mé ty l-ureido>-etyl)-benzensulf ony l7-N '-cykloheksyl-urinstoff med smeltepunkt 173-175°C, N-/_~4- ( 3-<N-4-klorfenyl-N-mety l-ureido>-etyl-benzensulf onyl7-N' - (4-metyl-cykloheksyl)-urinstoff med smeltepunkt 179-l8l°C, fra 4-(3-<N-4-metylfeny1-N-mety1-ureido>-etyl)-benzensulfonamid med smeltepunkt l63-l65°C: N-/_—4- ( 3_<N-4-metylfenyl-N-metyl-ureido>-etyl )-benzensulfony_l/-N '— cykloheksyl-urinstoff med smeltepunkt l65-l67°C, N-/_—4 - ( 3_ <N-4-me t y lf eny 1-N-me tyl- ureido>-etyl)-benzensulf ony_l/-N ' - N-/_ 4-(3-<N-2-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N ' - cyclohexyl-urea with melting point 204-206°C, N-/__4- (g- <N-2-chlorophenyl-N-methyl-ureido>-ethyl )-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea with melting point 169-171°C N-/_ 4 - ( B-<N- 2-chlorophenyl-N-methyl-1-ureido>-ethyl 1)-benzenesulfonyl 17-N'-isobutyl-urea with melting point 189-191°C, from 4-(g-<N-3-chlorophenyl) -N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 158-160°C: N-/_ 4- ($- <N-3-chloropheny 1-N-methyl-ureido> -ethyl)- benzenesulfony 1/-N 1 - cyclohexyl-urea with melting point l69-170°C, N-/__4-( 6-<N-3-kbrf enyl-N-methyl-ureido>-ethyl)-benzenesulfony l7 -N'-(4-methyl-cyclohexyl)-urea with melting point 150-152°C, from 4-(3-<N-4-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 168-170 °C: N-/_-4-(3-<N-4-chloropheny1-N-methyl-ureido>-ethyl)-benzenesulfonyl 17-N'-cyclohexyl-urea with melting point 173-175 °C, N-/_~4- ( 3-<N-4-chlorophenyl-N-methyl-ureido>-ethyl-benzenesulfonyl7- N' - (4-methyl-cyclohexyl)-urea with melting point 179-181°C, from 4-(3-<N-4-methylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 163-165° C: N-/_—4- ( 3_<N-4-methylphenyl-N-methyl-ureido>-ethyl )-benzenesulfonyl_1/-N '— cyclohexyl-urea with melting point 165-167°C, N-/_— -

(4-metylcykloheksyl)-urirBtoff med smeltepunkt 176-178°C» N-/_—4- ( 3-<N-4-mety lf eny 1-N-me ty 1-ure ido>-etyl)-benzensulf ony 1/-N ' - (4-Methylcyclohexyl)-urine with melting point 176-178°C» 1/-N ' -

(4-etyl-cykloheksyl)-urinstoff med smeltepunkt l63-l65°C, N-/_—4- ( 3_<N- 4-mety lf eny 1-N-me tyl-ure ido>-e tyl)-benzensulf ony]./-N ' - cykloheptyl-urinstoff med smeltepunkt l40-l42°C, . (4-ethyl-cyclohexyl)-urea with melting point 163-165°C, N-/_—4-( 3_<N- 4-methyl lf eny 1-N-methyl-ureido>-ethyl)-benzenesulf ony]./-N ' - cycloheptyl-urea with melting point l40-l42°C, .

N-/_— 4- ( 6-<N-4-mety 1-f eny 1-N-me ty l-ureido>-e tyl) -benzensulf ony 1/-N ' - isobutyl-urinstoff med smeltepunkt 137-139°C, N-/_— 4- ( 6-<N-4-methyl 1-phenyl 1-N-methyl-ureido>-ethyl)-benzenesulfony 1/-N '- isobutyl-urea with melting point 137- 139°C,

N-/_ 4- (3-<N-4-mety lf eny 1-N-me ty 1-ure i do>-etyl) -benzensulf ony 1/-N ' - N-/_ 4-(3-<N-4-methyl lf eny 1-N-methyl 1-ure i do>-ethyl)-benzenesulfony 1/-N ' -

(4-metyl-A3-cykloheksenyl)-urinstoff med smeltepunkt 178-l80°Cj N-/_-4- ( 3-<N-4-metylf enyl-N-metyl-ureido>-etyl )-benzensulfonyl7-N' - (4-methyl-A3-cyclohexenyl)-urea with melting point 178-180°Cj N-/_-4-( 3-<N-4-methylphenyl-N-methyl-ureido>-ethyl )-benzenesulfonyl7-N' -

(A3-cykloheksenyl)-urinstoff med smeltepunkt 150-152°C3(A3-cyclohexenyl)-urea with melting point 150-152°C3

fra 4-(3~<N-3~metylfeny1-N-metyl-ureido>-ety1)-benzensulfonamid med smeltepunkt 136-138°C: from 4-(3~<N-3~methylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 136-138°C:

N-/_ 4- ( 3-<N-3-metylfenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N '-cykloheksyl-urinstoff med smeltepunkt l67-l69°C, N-/_ 4- ( 3-<N-3-metylfenyl-N-metyl-ureido>-etyl)-benzensulfonyl/-N '-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 133-135°C. N-/_ 4 - ( 3-<N- 3-metylf eny 1-N-me ty l-ureido>-etyl) -benzensulf ony 1/ , N ' - isobutyl-urinstoff med smeltepunkt 150-152°C} fra 4-(3-N-<2-metylfeny1-N-metyl-ureido>-etyl)-benzensulfonamid med smeltepunkt 138-l40°C: N-/_ 4- (3-<2-metyl f eny 1-N-me ty l-ureido>- etyl)-benzensulf ony l7-N ' - cykloheksyl-urinstoff med smeltepunkt 197-199°C, N-/_ 4- ( 3-<N-3-methylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N '-cyclohexyl-urea with melting point 167-169°C, N-/_ 4- ( 3 -<N-3-methylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl/-N'-(4-methyl-cyclohexyl)-urea with melting point 133-135°C. N-/_ 4 - ( 3-<N- 3-methylpheny 1-N-methyl-ureido>-ethyl)-benzenesulfony 1/ , N ' - isobutyl-urea with melting point 150-152°C} from 4-(3-N-<2-methylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 138-140°C: N-/_ 4-(3-<2-methyl phenyl 1-N- methy l-ureido>-ethyl)-benzenesulfony l7-N'-cyclohexyl-urea with melting point 197-199°C,

N-/_ 4 - ( 3-<N-2-metylf eny l-N-metyl-ureido>-etyl) -benzensulf onyl7-N ' - N-/_ 4 - (3-<N-2-methylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N' -

(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 171-172°C, (4-methyl-cyclohexyl)-urea with melting point 171-172°C,

fra 4-(3-<N-etyl-N-fenyl-ureido>-etyl)-benzensulfonamid med smeltepunkt 138-l40°C: from 4-(3-<N-ethyl-N-phenyl-ureido>-ethyl)-benzenesulfonamide with melting point 138-140°C:

N-/_ 4- ( 3-<N-etyl-N-f enyl-ureido>-ety 1 )-benzensulfonyl/-N '-cykloheksy 1-urinstoff med smeltepunkt l62-l64°C N-/_-4- (3-<N-et yl-N-f eny l-ureido>-etyl)-benzensulf ony l7-N ' - (4-metyl-cykloheksyl )-urinstoff med smeltepunkt 159_l6l°C N-/_ 4- ( 3-<N-etyl-N-fenyl-ureido->etyl )-benzensulfonyl/-N '-butyl-urinstoff med smeltepunkt l47-l49°C, fra 4-(3-<N-4-metoksyfenyl-N-metyl-ureido>-etyl-benzensulfonamid med smeltepunkt 150-152°C: N-/_ 4- ( 3-<N-4-metoksyf eny l-N-metyl-ureido>-etyl) -benzensulfony]./-N ' - cykloheksyl-urinstoff med smeltepunkt 184-186°C N-/_ 4 - (3-<N-4-metoksyf enyl-N-metyl-ureido->etyl) -benzensulf ony 1/-N ' - (4-metyl-cykloheksyl)-urinstoff med smeltepunkt l88-J30<o>C fra 4 - ( 3-<N-3-nietoksyf eny 1-N-me ty 1-ure ido>-et yl) -benzensulf onamid med smeltepunkt 194-196°C: N-/_ 4- ( 3-<N-3-metoksyf enyl-N-metyl-ureido>-etyl)-benzensulf onyl7-N' - cykloheksyl-urinstoff med smeltepunkt 137-139°C, N-/_ 4- ( 3-<N-ethyl-N-phenyl-ureido>-ethy 1 )-benzenesulfonyl/-N '-cyclohexy 1-urea with melting point l62-164°C N-/_-4- (3 -<N-ethyl-N-phenyl-ureido>-ethyl)-benzenesulfony l7-N ' - (4-methyl-cyclohexyl )-urea with melting point 159_161°C N-/_ 4- ( 3-<N- ethyl-N-phenyl-ureido->ethyl )-benzenesulfonyl/-N '-butyl-urea with melting point 147-149°C, from 4-(3-<N-4-methoxyphenyl-N-methyl-ureido>-ethyl -benzenesulfonamide with melting point 150-152°C: N-/_ 4- ( 3-<N-4-methoxy enyl l-N-methyl-ureido>-ethyl)-benzenesulfony]./-N ' - cyclohexyl-urea with melting point 184 -186°C N-/_ 4 - (3-<N-4-Methoxyphenyl-N-methyl-ureido->ethyl)-benzenesulfony 1/-N ' - (4-methyl-cyclohexyl)-urea with melting point l88-J30<o>C from 4 - ( 3-<N-3-nietoxyf eny 1-N-methy 1-ureido>-et yl) -benzenesulfonamide with melting point 194-196°C: N-/_ 4- (3-<N-3-methoxyphenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with melting point 137-139°C,

N-/_ 4- (3-<N-3-metoksy f eny l-N-metyl-ureido>-etyl)-benzensulf ony l7-N' - N-/_ 4-(3-<N-3-Methoxyphenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl 17-N' -

(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 152-154°C N-/__4- (3-<N-3-metoksy f eny l-N-metyl-ureido>-etyl) -benzensulf ony l7-N' - isobutyl-urinstoff med smeltepunkt 115-117°C (4-methyl-cyclohexyl)-urea with melting point 152-154°C N-/__4- (3-<N-3-methoxyphenyl-N-methyl-ureido>-ethyl)-benzenesulfony l7-N' - isobutyl -urea with a melting point of 115-117°C

fla 4-(3-<N-2-metoksyfenyl-N-metyl-ureido>-etyl)-benzensuifonamid med smeltepunkt 155-157°C: fla 4-(3-<N-2-methoxyphenyl-N-methyl-ureido>-ethyl)-benzenesuifonamide with melting point 155-157°C:

N-/_—4- ( 3-<N-2-metoksyfenyl-N-metyl-ureido>-etyl )-benzensulfonyl7-N ' - cykloheksyl-urinstoff med smeltepunkt 192-194°C N-/_~4- (3-<N-2-metoksyfenyl-N-metyl-ureido>-etyl )-benzensulfonyl7-N ' - (4-metyl-cykloheksyl)-urinstoff med smeltepunkt 178-l80°C N-/__4- ('3-<N-2-metoksyf enyl-N-metyl-ureido>-etyl )-benzensulfonyl7-N ' - isobutyl-urinstoff med smeltepunkt 189-191°C fra 4-(3-<N-3~trifluormetylfeny1-N-mety1-ureido>-etyl)-benzensulfon-amid med smeltepunkt 176-178°C: N-/_ 4- ( 3-<N-3-tri f luormetylf eny l-N-metyl-ureido>-etyl) -benzensulf o-nyl7-N'-cykloheksyl-urinstoff med smeltepunkt l6l-l63°C N-/_ 4- (3- <N- 3-tri f luormetylf eny 1-N-me ty 1-ure ido>-etyl)-benzensulf ony l7-N' - (4-metyl-cykloheksyl')-urinstof f med smeltepunkt 151-153°C N-/_ 4 - ( 3-<N-3~trif luormetylf eny 1-N-me ty 1-ure ido >-etyl)-benzensulf ony l7-N'-isobutyl-urinstoff med smeltepunkt 144-146°C fra 4-(3-<N-4-isopropylfenyl-N-metyl-ureido>-etyl)-benzensulfonamid med smeltepunkt 173-174°C: N-/~4-(3-<N-4-isopropylfenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-cykloheksyl-urinstoff med smeltepunkt 157-159°C N-/_ 4- (3-<N-4-isopropylfenyl-N-metyl-ureido>-etyl)-benzensulfony 1/-N' - (4-metyl-cykloheksyl)-urinstoff med smeltepunkt 164-166°C N-/_ 3-<N-4-isopropylfenyl-N-metyl-ureido>-etyl)-benzensulfony 1/-N'-isobutyl-urinstoff med smeltepunkt 150-152°C, frå 4-(3-<N-5-klor-2-metyl-feny1-N-metyl-ureido>-ety1)-benzensulfon-amid med smeltepunkt 150-152°C: N-/_ 4- (3-<N-5-klor-2-metyl-feny 1-N-mety 1-ureido>-etyl)-benzensulfony 1/-N'-cykloheksyl-urinstoff med smeltepunkt 173-175°C N-/_—4- ( 3-<N-5-klor-2-metyl-f enyl-N-metyl-ureido>-etyl) -benzensulf onyl7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 170-172°C, N-_/~4-(g-<N-5-klor-2-metyl-fenyl-N-metyl-ureido>-etyl)-benzensulfony1/- N'-butyl-urinstoff med smeltepunkt 155-157°C N-/_—4- ( 3-<N-2-methoxyphenyl-N-methyl-ureido>-ethyl )-benzenesulfonyl7-N ' - cyclohexyl-urea with melting point 192-194°C N-/_~4- ( 3-<N-2-methoxyphenyl-N-methyl-ureido>-ethyl )-benzenesulfonyl7-N ' - (4-methyl-cyclohexyl)-urea with melting point 178-180°C N-/__4- ('3-< N-2-Methoxyphenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-isobutylurea with melting point 189-191°C from 4-(3-<N-3-trifluoromethylphenyl-N-methyl-ureido >-ethyl)-benzenesulfonamide with melting point 176-178°C: N-/_ 4-( 3-<N-3-trifluoromethylphenyl-N-methyl-ureido>-ethyl)-benzenesulf o-nyl7-N '-cyclohexyl-urea with a melting point of 161-163°C N-/_ 4- (3-<N- 3-trifluoromethylpheny 1-N-methyl 1-ureido>-ethyl)-benzenesulfony 17-N ' - (4-methyl-cyclohexyl')-urea with melting point 151-153°C N-/_ 4 - ( 3-<N-3~trifluoromethylpheny 1-N-methyl 1-ureido >-ethyl )-benzenesulfony 17-N'-isobutylurea with melting point 144-146°C from 4-(3-<N-4-isopropylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 173-174°C : N-/~4-(3-<N-4-is opropylphenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with melting point 157-159°C N-/_ 4- (3-<N-4-isopropylphenyl-N-methyl-ureido>- ethyl)-benzenesulfony 1/-N' - (4-methyl-cyclohexyl)-urea with melting point 164-166°C N-/_ 3-<N-4-isopropylphenyl-N-methyl-ureido>-ethyl)-benzenesulfony 1/-N'-isobutylurea with melting point 150-152°C, from 4-(3-<N-5-chloro-2-methyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 150-152°C: N-/_ 4-(3-<N-5-chloro-2-methyl-phenyl 1-N-methyl 1-ureido>-ethyl)-benzenesulfony 1/-N'-cyclohexyl- urea with melting point 173-175°C N-/_—4- ( 3-<N-5-chloro-2-methyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-(4 -methyl-cyclohexyl)-urea with melting point 170-172°C, N-_/~4-(g-<N-5-chloro-2-methyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfony1/ - N'-butyl urea with melting point 155-157°C

fra 4- (3-<N-5-.klor-2-metoksy-fenyl-N-metyl-ureido>-etyl )-benzensulfon-amid med smeltepunkt 172-174°C: N- 1_ 4 - (3-<N-5-klor-2-met oks y- f eny 1-N-me ty 1-ure ido> -etyl)-benzensulf o-nyl7-N'-cykloheksyl-urinstoff med smeltepunkt 182-184°C from 4-(3-<N-5-.chloro-2-methoxy-phenyl-N-methyl-ureido>-ethyl )-benzenesulfonamide with melting point 172-174°C: N- 1_ 4 - (3-< N-5-Chloro-2-methoxy-pheny 1-N-methyl 1-ureido>-ethyl)-benzenesulf o-nyl7-N'-cyclohexyl-urea with melting point 182-184°C

N-/_ 4 - ( g-<N-5_klor-2-metoksy-feny1-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 147-149°C. N-/_ 4- (6-<N-5-klor-2-metoksy-f eny1-N-metyl-ureido^-etyl )-benzensulfonyl7-N'-isobutyl-urinstoff med smeltepunkt 150-152°0 N-/_ 4 - (g-<N-5_chloro-2-methoxy-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea with melting point 147-149° C. N-/_ 4-(6-<N-5-chloro-2-methoxy-pheny1-N-methyl-ureido^-ethyl )-benzenesulfonyl7-N'-isobutyl urea melting point 150-152°0

fra 4-(g-<N-4-klor-2-metoksy-fenyr-N-metyl-ureido>-etyl)-benzerisul-fonamid med smeltepunkt 175-177°C: N-/_ 4-(g-<N-4-klor-2-metoksy-fenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-cykloheksyl-urinstoff med smeltepunkt 192-194°C N-/__4- ( g-<N- 4-klor-2-metoksy-f eny l-N-metyl-'ureido>-etyl)-benzensulf ony l7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt l8l-l83°C N-/_ 4- (g-<N-4-klo r- 2-metoksy-f eny 1-N-me ty 1-ure ido>-etyl)-benzensulf o-nylV-N'-isobutyl-urinstoff med smeltepunkt l8l-l83°C from 4-(g-<N-4-chloro-2-methoxy-phenir-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 175-177°C: N-/_ 4-(g-< N-4-chloro-2-methoxy-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with melting point 192-194°C N-/__4- ( g-<N- 4- chloro-2-methoxy-phenyl 1-N-methyl-'ureido>-ethyl)-benzenesulfony 17-N'-(4-methyl-cyclohexyl)-urea with melting point 181-183°C N-/_ 4-(g -<N-4-chloro-2-methoxy-pheny 1-N-methyl 1-ureido>-ethyl)-benzenesulf o-nylV-N'-isobutyl urea with melting point 181-183°C

fra 4-(g-<N-3,4-dimetyl-feny1-N-metyl-ureido>-etyl)-benzensulfonamid med smeltepunkt 154-156°C: from 4-(g-<N-3,4-dimethyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 154-156°C:

N-/_ 4 - ( g-<N- 3,4-dime tyl-f eny l-N-metyl-ureido>-e ty 1)-benzensulf ony l7-N<*->cykloheksyl-urinstoff med smeltepunkt l84-l86°C N-/_ 4- ( g-<N-3,4-dimetyl-f eny 1-N-me ty l-ureido>-etyl)-benzensulf ony l7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 157-159°C, N-/_ 4- ( g-<N-3 ,4-dimetyl-f eny l-N-metyl-ureido>-etyl)-benzensulf ony l7-, N'-isobutyl-urinstoff med smeltepunkt 150-152°C N-/_ 4- ( g-<N-3,4-dime tyl -f eny 1-N-me ty 1-ure ido>-etyl) -benzensulf ony 17-N'-(4-etyl-cykloheksyl)-urinstoff med smeltepunkt 151-153°C, fra 4-(g-<N-3-metoksy-4-mety1-fenyl-N-metyl-ureido>-étyl)-benzensul-fonamid med smeltepunkt 176-177°C: N-/_ 4- ( g-<N-3-met oksy-4-mety 1-f eny 1-N-me ty l-ureido>-etyl )-benzensul-fonyl7-N'-cykloheksyl-urinstoff med smeltepunkt 151-153°C N-/_—g-N-3-met oksy-4-mety 1-f eny 1-N-me ty l-ureido>-etyl)-benzensulf ony l7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 174-176°C N-/_—4- (g-<N-3-met oksy-4-mety 1-f eny 1-N-mety 1-ure ido>-etyl) -benzensulf o-nyl7-N'-butyl-urinstoff med smeltepunkt l60-l62°C, N-/_ 4 - (g-<N-3,4-dimethyl-pheny l-N-methyl-ureido>-e ty 1)-benzenesulfony l7-N<*->cyclohexyl-urea with melting point l84-l86 °C N-/_ 4-( g -<N-3,4-dimethyl-phenyl 1-N-methyl-ureido>-ethyl)-benzenesulfonyl 17-N'-(4-methyl-cyclohexyl) -urea with melting point 157-159°C, N-/_ 4- ( g-<N-3 ,4-dimethyl-phenyl l-N-methyl-ureido>-ethyl)-benzenesulfony l7-, N'-isobutyl- urea with melting point 150-152°C N-/_ 4- ( g-<N-3,4-dimethyl -pheny 1-N-methy 1-ureido>-ethyl) -benzenesulfony 17-N' -(4-ethyl-cyclohexyl)-urea with melting point 151-153°C, from 4-(g-<N-3-methoxy-4-methyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 176-177°C: N-/_ 4- ( g-<N-3-methoxy-4-methyl 1-pheny 1-N-methyl-ureido>-ethyl )-benzenesulfonyl7- N'-cyclohexyl-urea with melting point 151-153°C N'-(4-methyl-cyclohexyl)-urea with melting point 174-176°C N-/_—4-(g-<N-3-methoxy-4-methyl 1-phenyl 1-N-methyl -ure ido>-ethyl) -benzenesulf o-n yl7-N'-butyl urea with a melting point of 160-162°C,

fra 4-(g-<N-2-klor-4-metyl-fenyl-N-metyl-ureido>-etyl)-benzensulfon-amid med smeltepunkt 156-158°C: N-/~4 r-( g-<N-2-klor-4-mety 1-f eny 1-N-me ty l-uréido>-etyl)-benzensulf ony l7-N'-cykloheksyl-urinstoff med smeltepunkt l85-l87°C from 4-(g-<N-2-chloro-4-methyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 156-158°C: N-/~4 r-( g- <N-2-chloro-4-methyl 1-phenyl 1-N-methyl-ureido>-ethyl)-benzenesulfonyl 17-N'-cyclohexyl-urea with melting point 185-187°C

N-/_—4-( g-<N-2-klor-4-metyl-fenyl-N-metyl-ureido>-e.tyl )-benzensulf onyl7-N'-(4-metyl-cykloheksyl)-urinstoff med smeltepunkt l68-170°C N-/<->4-(g-<N-2-klor-4-metyl-fenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-isobutyl-urinstoff med smeltepunkt l82-l84°C N-/_—4-( g -<N-2-chloro-4-methyl-phenyl-N-methyl-ureido>-ethyl )-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea with melting point l68-170°C N-/<->4-(g-<N-2-chloro-4-methyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-isobutyl-urea with melting point l82-l84°C

fra 4-(g-<N-etyl-N-4-klorfenyl-ureido>-etyl)-benzensulfonamid med from 4-(g-<N-ethyl-N-4-chlorophenyl-ureido>-ethyl)-benzenesulfonamide with

smeltepunkt 189-192°C: N-/-4- (B-<N-e ty l-N-4-klorf eny 1-ure ido >-e ty 1)-benzensulf ony ]_7-N ' - cykloheksyl-urinstoff med smeltepunkt 164-166°C N-_/~4-( B-<N-etyl-N-U-klorfenyl-ureido>-etyl )-benzensulfonyl7-N ' - (4-metyl-cykloheksyl)-urinstoff med smeltepunkt l67-l69°C. N- l_ 4- (B-<N-ety1-N-klorfeny1-ureido>-ety1)-benzensulfonyl7-N' - iso-butyl-urinstof f med smeltepunkt 164-166°C, fra 4-(B-<N-4-etoksyfeny1-N-mety1-ureido>-ety1)-benzensulfonamid med smeltepunkt 176-178°C: N-/_~4- (B-<N-4-etoksyf enyl-N-metyl-ureido>-etyl) -benzensulfonyl7-N ' - cykloheksyl-urinstoff med smeltepunkt l69-171°C N-/_ 4 - ( B-<N-4-e t oksy f eny 1-N-me ty 1-ure ido>-etyl) - benzensulf ony 1/-N ' - (4-metyl-cykloheksyl)-urinstoff med smeltepunkt 175-177°C N-/_~"4- (B-<N-4-et oksy f eny 1-N-me ty 1-ure ido>-e tyl)-benzensulf ony 17-N '-isobutyl-urinstoff med smeltepunkt l43-l45°C fra 4-(B-<N-3-etoksy-feny1-N-metyl-ureido>-ety1)-benzensulfonamid med smeltepunkt 177-179°C: N-/_ 4- (B-<N-3-etoksy-f eny 1-N-mety 1-ure i do-e tyl) -benzensulf ony l7-N ' - cykloheksyl-urinstoff med smeltepunkt 139-l4l°C N-/~4-(B-<N-3-etoksy-fenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-(4-metyl-cykbheksyl)-urinstoff med smeltepunkt l49-151°C N-/_ 4 - ( B-<N-3-e t oks y-f eny 1-N-me ty 1-ure ido>-etyl)-benzensulfonyl7-N * - butyl-urinstoff med smeltepunkt 124-126°C fra 4-(B-<N-3-klor-4-metyl-fenyl-N-metyl-ureido>-etyl)-benzensulfon-amid med smeltepunkt 189-192°C: N-/_ 4- ( 3-<N-3~klor-4-mety 1-f eny 1-N-mety 1-ure i do>-etyl) -benzensulf ony 17-N'-cykloheksyl-urinstoff med smeltepunkt l88-190°C. N-/~4-( 3-<N-3-klor-4-mety 1-f eny 1-N-me ty l-ureido>-etyl)-benzensulf ony 1/-N'-(4-metylcykloheksyl)-urinstoff med smeltepunkt 154-156°C, N-/_~4-( 3-<N-3-klo r-4-met y 1-f eny 1-N-me ty 1-ure ido>-etyl)-benzensulf ony l7-N<*->isobutyl-urinstoff med smeltepunkt l62-l64°C N-/_~4- ( B -<N-3-klor-4 -me ty 1-f eny 1-N-met yl-ure ido>-e ty 1)-benzensulf ony l7-N'-(4-etyl-cykloheksyl)-urinstoff med smeltepunkt 145-147°C, fra 4-(B-<N-4-brom-fenyl-N-metyl-ureido>-etyl)-benzensulfonamid med smeltepunkt 177-l8l°C: N-/_ 4 - (B.-<N-4-bromf eny 1-N-metyl-ureido>-etyl)-benzensulfony 1/-N ' - cykloheksyl-urinstoff med smeltepunkt 173-175°C melting point 189-192°C: N-/-4- (B-<N-e ty l-N-4-chloropheny eny 1-ureido >-e ty 1)-benzenesulfony ]__7-N ' - cyclohexyl-urea with melting point 164 -166°C N-_/~4-( B-<N-ethyl-N-U-chlorophenyl-ureido>-ethyl )-benzenesulfonyl7-N ' - (4-methyl-cyclohexyl)-urea with melting point 167-169°C . N-1_ 4- (B-<N-ethy1-N-chlorophenyl-ureido>-ethy1)-benzenesulfonyl7-N' - iso-butyl-urea f with melting point 164-166°C, from 4-(B-<N -4-ethoxyphenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 176-178°C: N-/_~4-(B-<N-4-ethoxyphenyl-N-methyl-ureido>-ethyl ) -benzenesulfonyl7-N ' - cyclohexyl-urea with melting point l69-171°C N-/_ 4 - ( B-<N-4-e toxypheny 1-N-methyl 1-ureido>-ethyl) - benzenesulfony 1/-N ' - (4-methyl-cyclohexyl)-urea with melting point 175-177°C N-/_~"4- (B-<N-4-ethoxy f eny 1-N-methy 1-ureido>-ethyl)-benzenesulfony 17-N'-isobutyl-urea with melting point 143-145°C from 4-(B-<N-3-ethoxy-phenyl-N-methyl-ureido>-ethyl) )-benzenesulfonamide with melting point 177-179°C: N-/_ 4-(B-<N-3-ethoxy-pheny 1-N-methyl 1-ure i do-ethyl)-benzenesulfony l7-N ' - cyclohexyl-urea with melting point 139-141°C N-/~4-(B-<N-3-ethoxy-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl )-urea with melting point l49-151°C N-/_ 4 - ( B-<N-3-e t ox y-f eny 1-N-me ty 1-ure ido> -ethyl)-benzenesulfonyl7-N * - butyl-urea with melting point 124-126°C from 4-(B-<N-3-chloro-4-methyl-phenyl-N-methyl-ureido>-ethyl)-benzenesulfon- amide with melting point 189-192°C: N-/_ 4-( 3-<N-3~chloro-4-methyl 1-pheny 1-N-methyl 1-ure i do>-ethyl)-benzenesulfony 17 -N'-cyclohexylurea with a melting point of 188-190°C. N-[4-(3-<N-3-chloro-4-methyl-phenyl-1-N-methyl-ureido>-ethyl)-benzenesulfonyl]-N'-(4-methylcyclohexyl) -urea with melting point 154-156°C, N-/_~4-( 3-<N-3-chloro-4-methyl 1-pheny 1-N-methyl 1-ureido>-ethyl) -benzenesulfony l7-N<*->isobutyl-urea with melting point l62-l64°C N-/_~4- ( B -<N-3-chloro-4 -methy 1-f eny 1-N-met yl-ureido>-e ty 1)-benzenesulfony l7-N'-(4-ethyl-cyclohexyl)-urea with melting point 145-147°C, from 4-(B-<N-4-bromo-phenyl- N-methyl-ureido>-ethyl)-benzenesulfonamide with melting point 177-181°C: N-/_ 4 - (B.-<N-4-bromopheny 1-N-methyl-ureido>-ethyl)-benzenesulfony 1 /-N ' - cyclohexylurea with melting point 173-175°C

N-_/ 4- (B-<N-4-bromf eny l-N-metyl-ureido>-etyl)-benzensulf ony 1/-N ' - N-_/ 4-(B-<N-4-bromophenyl-N-methyl-ureido>-ethyl)-benzenesulfony 1/-N' -

(4-metyl-cykloheksyl)-urinstoff med smeltepunkt 180-191°C (4-methyl-cyclohexyl)-urea with melting point 180-191°C

N-/_~4-( 3-<N-4-bromf eny 1-N-me ty l-ureido>-etyl) -benzensulf ony 1/-N' - isobutyl-urinstoff med smeltepunkt 156-158°C. N-/_~4-( 3-<N-4-bromopheny 1-N-methyl-ureido>-ethyl)-benzenesulfony 1/-N' - isobutyl-urea with melting point 156-158°C.

Eksempel 2. Example 2.

N-/_~4-( 3-<N-4-klorfeny 1-N-metyl-ureido>-etyl) -benzensulfonyl7-N ' - cykloheksyl- urinstof f. N-/_~4-(3-<N-4-chlorophenyl 1-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea f.

10,6 g 4-(3-<N-4-klorfenyl-M-metyl-ureido>-etyl)-benzensulfonyl-metyl-uretan (smeltepunkt 188-190°C, fremstillet av 4- ( 3-<N-klorfenyl-M-metyl-ureido>-etyl) -benzensulf onamid og klor-maursyremetylester) oppvarmes med 2,5 g cykloheksylamin i oljebad i 1 time ved 130°C. Etter avkjøling gjenutfelles reaksjonsproduktet fra 1% ammoniakk og omkrystalliseres fra vann/etanol. N-/-4-(3-<N-4-klorfeny1-N-mety1-ureido>-ety1)-benzensulfonyl7-N'-cykloheksyl- 10.6 g of 4-(3-<N-4-chlorophenyl-M-methyl-ureido>-ethyl)-benzenesulfonyl-methyl-urethane (melting point 188-190°C, prepared from 4-( 3-<N-chlorophenyl -M-methyl-ureido>-ethyl)-benzenesulfonamide and chloroformic acid methyl ester) are heated with 2.5 g of cyclohexylamine in an oil bath for 1 hour at 130°C. After cooling, the reaction product is reprecipitated from 1% ammonia and recrystallized from water/ethanol. N-(-4-(3-<N-4-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-

urinstof f smelter ved 173-175°C urea f melts at 173-175°C

På analog måte vil man fra 4-(3-<N-4-metylfenyl-N-metylureido>-etyl)-benzensulfony1-metyluretan (smeltepunkt l66-l68°C) In an analogous way, from 4-(3-<N-4-methylphenyl-N-methylureido>-ethyl)-benzenesulfonyl-1-methylurethane (melting point 166-168°C)

få M-/_ 4-(3-<N-4-metyl-fenyl-N-metyl-ureido>-ety 1)-benzensulfonyl/- N '-cykloheksyl-urinstof f med smeltepunkt 165-167"°C. obtain M-/_ 4-(3-<N-4-methyl-phenyl-N-methyl-ureido>-ethy 1)-benzenesulfonyl/- N '-cyclohexyl-urea f with melting point 165-167"°C.

N-/_—4-( 3~<N-4-netylfeny 1-N-metylureido>-etyl) -benzensulfonyl7-N'-cykloheptyl-urinstoff med smeltepunkt l40-l42°C. N-/_—4-( 3~<N-4-Nethylphenyl 1-N-methylureido>-ethyl)-benzenesulfonyl7-N'-cycloheptyl-urea with melting point 140-142°C.

N-/_ 4- ( 3~<N-4-mety lf enyl-N-metyl-ureido>-etyl) -benzensulfonyl7-N ' - cyklopentyl-urinstoff med smeltepunkt 156-158°C. N-/_ 4-(3~<N-4-methyl lf enyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-cyclopentyl-urea with melting point 156-158°C.

Eksempel 3-N-/_ 4- (3-<N-fenyl-N-metyl-ureido>-etyl) -benzensulf onyl7-N ' - (4-metyl-cykloheksyl) - urinstof f. Example 3-N-(4-(3-<N-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea f.

7,5 g N-/_—4-(3-<N-fenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-urinstoff (smeltepunkt l62-l64°C, fremstillet av 4-(3-<N-fenyl-N-metyl-ureido>-etyl)-benzensulfonamid og.kaliumcyanat i 90% 7.5 g N-/_—4-(3-<N-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-urea (melting point 162-164°C, prepared from 4-(3-<N- phenyl-N-methyl-ureido>-ethyl)-benzenesulfonamide and potassium cyanate in 90%

etanol) oppvarmes med 3,5 g 4-metylcykloheksylaminacetat il time under tilbaleLøp.. Deretter inndamper man i vakuum, behandler resi- ethanol) is heated with 3.5 g of 4-methylcyclohexylamine acetate for 1 hour under tilbaleLøp.. It is then evaporated in a vacuum, treated resi-

duet med 1% ammoniakk, filtrerer og utfeller med fortynnet saltsyre. Det dannede N-/~4-(3<N-fenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-(4-metyl-cykloheksyl)-urinstoff omkrystalliseres fra vann-etanol og smelter ved 136-138°C. Eksempel 4. dove with 1% ammonia, filter and precipitate with dilute hydrochloric acid. The formed N-/~4-(3<N-phenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea is recrystallized from water-ethanol and melts at 136-138 °C. Example 4.

N-/~4-(3-<N-metyl-N-fenyl-ureido>-etyl)-benzensulfonyl7-N'-cykloheksyl-urinstoff. ■ N-[4-(3-<N-methyl-N-phenyl-ureido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea. ■

0,5 g N-/—4-(3-<N-metyl-N-fenyl-ureido>-etyl)-benzensulf onyl7-N'-cykloheksyl-tiourinstoff (smeltepunkt 175-176°C, fremstillet av 4-(3—<N-metyl-N-fenyl-ureido>-etyl)-benzensulfonamid og cykloheksylsennepsolje) oppløses i 10 ml aceton. Hertil drypper man en oppløsning av 0,75 g natriumnitrit i 2,5 ml vann og deretter en oppløsning av 0,6 g iseddik og 2,5 ml vann i løpet av 30 minutter. Blandingen etteromrøres i 2 timer ved værelsestemperatur, blandes deretter med vann og reaksjonsproduktet frasuges. Man omkrystalli-serer fra metanol og får N-/~4-(0-<N-metyl-N-fenyl-ureido>-etyl)-benzensulfony17-N'-cykloheksylurinstoff med smeltepunkt l48-l49°C. Eksempel 5. 0.5 g N-/—4-(3-<N-methyl-N-phenyl-ureido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-thiourea (melting point 175-176°C, prepared from 4-( 3-<N-methyl-N-phenyl-ureido>-ethyl)-benzenesulfonamide and cyclohexyl mustard oil) are dissolved in 10 ml of acetone. To this, a solution of 0.75 g of sodium nitrite in 2.5 ml of water and then a solution of 0.6 g of glacial acetic acid and 2.5 ml of water are dripped over the course of 30 minutes. The mixture is stirred for 2 hours at room temperature, then mixed with water and the reaction product is sucked off. It is recrystallized from methanol and gives N-[4-(O-<N-methyl-N-phenyl-ureido>-ethyl)-benzenesulphonyl7-N'-cyclohexylurea with a melting point of 148-149°C. Example 5.

N-/~~4-(3-<N-4-klorfeny1-N-metyl-ureido>-etyl)-benzensulfony17-N'-cykloheksyl- urinstoff. N-[~4-(3-<N-4-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl-17-N'-cyclohexylurea.

1,6 g N-/<->4-(3-aminoetyl)-benzensulfonyl7-N'-cykloheksyl-urinstoff oppvarmes i 10 ml pyridin med 1,1 g N-(4-klorfenyl)-N-metyl-karbamidsyreklorid i 10 minutter på dampbad. Etter avkjøling heller man i vann, surgjør svakt, frasuger fellingen og omkrystalli-serer fra vann-etanol. N-/ 4-(3-<N-4-klorfenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-cykloheksyl-urinstoff smelter ved 173-175°C. Eksempel 6. 1.6 g of N-/<->4-(3-aminoethyl)-benzenesulfonyl7-N'-cyclohexylurea is heated in 10 ml of pyridine with 1.1 g of N-(4-chlorophenyl)-N-methylcarbamic acid chloride in 10 minutes in a steam bath. After cooling, pour into water, slightly acidify, suction off the precipitate and recrystallize from water-ethanol. N-/ 4-(3-<N-4-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea melts at 173-175°C. Example 6.

N-7 4-(6-<N-4-mety1-feny1-N-metylureido>-etyl)-benzen-sulfonylT-N'-( 4- metylcykloheksyl)- urinstoff. N-7 4-(6-<N-4-methyl-phenyl-N-methylureido>-ethyl)-benzenesulfonyl T-N'-(4-methylcyclohexyl)-urea.

2,4 g N-^~4-(3-<N-4-metylfenyl-N-metylureido>-etyl)-benzensulfonyl/-M'(4-metyl-A3-cykloheksenyl)-urinstoff oppløses i 100 ml metanol under oppvarmning og hydrogeneres i nærvær av Pd-kull-katalysator ved normaltrykk til avslutning av hydrogenopptak. Deretter frafiltreres katalysatoren, oppløsningen inndampes og resi-duet omkrystalliseres fra metanol. Det dannede N-/~4-(3-<N-4-metyl-fenyl-M-metylureido>-etyl)-benzensulfonyl7-N'-(4-metylcykloheksyl)-urinstoff smelter ved 176-178°C. 2.4 g of N-^~4-(3-<N-4-methylphenyl-N-methylureido>-ethyl)-benzenesulfonyl/-M'(4-methyl-A3-cyclohexenyl)-urea are dissolved in 100 ml of methanol under heating and is hydrogenated in the presence of a Pd-charcoal catalyst at normal pressure until hydrogen absorption is complete. The catalyst is then filtered off, the solution is evaporated and the residue is recrystallized from methanol. The formed N-[4-(3-<N-4-methyl-phenyl-M-methylureido>-ethyl)-benzenesulfonyl 7-N'-(4-methylcyclohexyl)-urea melts at 176-178°C.

Eksempel 7• ■ Example 7• ■

N-/—4-(3-<N-4-klorfenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-N'-cykloheksyl- urinstoff. N-[-4-(3-<N-4-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea.

0,5 g l-/~4-(3-<M-4-klorfenyl-N-metyl-ureido>-etyl)-benzensulfonyl7-3-cykloheksyl-parabansyre (smeltepunkt 217-219 C, fremstillet av 3-<N-4-klor f eny 1-N-me ty lure ido>-ety 1) -benzensulf o- 0.5 g 1-/~4-(3-<M-4-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl7-3-cyclohexyl-parabanic acid (melting point 217-219 C, prepared from 3-<N -4-chloropheny 1-N-methy lure ido>-ethy 1) -benzenesulf o-

klorid og cykloheksylparabansyre) oppvarmes med 10 ml 1 N natronlut i 10 minutter på dampbad. Man filtrerer og surgjør den avkjølte opp-løsning svakt med saltsyre. Det utfelte N-/_— 4-(g-<N-4-klorfenyl-N-metyl-ureido>-etyl)-benzensulfony1/-N'-cykloheksyl-urinstoff omkrystalliseres fra vann-etanol og smelter ved 173-175°C. chloride and cyclohexylparabanic acid) are heated with 10 ml of 1 N caustic soda for 10 minutes on a steam bath. The cooled solution is filtered and slightly acidified with hydrochloric acid. The precipitated N-/_— 4-(g-<N-4-chlorophenyl-N-methyl-ureido>-ethyl)-benzenesulfonyl/-N'-cyclohexyl-urea is recrystallized from water-ethanol and melts at 173-175° C.

Claims

Analogous methods for the preparation of benzenesulfonyl ureas with blood sugar-lowering action and with formula

in which R means alkyl with 1 to 3 carbon atoms, R"1" means a) alkyl with 3 to 6 carbon atoms, b) cyclohexyl which is substituted, with one or two lower alkyl groups, c) cycloalkyl with 5 to 8 carbon atoms, d) cyclohexenyl, methylcyclohexenyl, X means hydrogen, lower alkyl, lower alkoxy, halogen, X' means the same as X and furthermore, when X means hydrogen, a -CF-j or NO2~ group, or X and X' together mean a methylenedioxy group, and Y means -CH 2 .CH 2 -, -CHCCH 2 ). CH2~ or -CH"2 . CH(CH"3) - as well as their salts, as a continuation of the invention according to patent no. II8,606, characterized by either • a) reacting amines with the formula R"*"NH2 or their salts with benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters, -ureas, -semicarbazides or -semicarbazones which in the benzene ring contain substituents or b) react sulfonamides of formula or their salts with R^-substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas , or c) hydrolyzes N-benzenesulfonylurea ethers, -isothiourea ethers, halornauric 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) replaces the sulfur atom in benzenesulfonylureas corresponding to benzenesulfonylureas of formula I with an oxygen atom? or e) hydrogenates benzenesulfonylureas corresponding to benzenesulfonylureas of formula I, which in the molecule contain unsaturated bonds, or f) introduces the remainder in benzenesulfonylureas of formula by acylation, and optionally treating the process products with alkaline agents for salt formation.