NO126685B

NO126685B -

Info

Publication number: NO126685B
Application number: NO02818/68A
Authority: NO
Inventors: Walter Aumueller; Helmut Weber; Karl Muth; Rudi Weyer
Original assignee: Hoechst Ag
Priority date: 1967-08-10
Filing date: 1968-07-16
Publication date: 1973-03-12
Also published as: FR1598160A; OA02877A; AR193338A1; SU404232A3; IT1053691B; LU56488A1; SU435610A3; SU437277A3; IL30431A; SU460622A3; DK132946B; FI50115B; SU399115A3; CH522609A; IS767B6; SE352345B; CH522615A; SU400086A3; AT321316B; CH506500A

Description

Analogifremgangsmåter til fremstilling av Analogy methods for the production of

benzensulfonylurinstoffer med blodsukkersenkende virkning. benzenesulfonylureas with blood sugar-lowering effects.

Oppfinnelsens gjenstand er analogifremgangsmåter til fremstilling av benzensulfonylurinstoffer med formel The object of the invention is analogous methods for the preparation of benzenesulfonylureas of formula

som eventuelt i form av deres salter har blodsukkersenkende egenskaper og utmerker seg ved en sterk og langvarig senkning av blodsukkerspeil. which, possibly in the form of their salts, have blood sugar-lowering properties and are distinguished by a strong and long-lasting lowering of blood sugar levels.

I formelen betyr: In the formula means:

R<1>R<1>

4,7-endometylen-perhydroindan-5-yl 4,7-endomethylene-perhydroindan-5-yl

som eventuelt er substituert med klor i 6-stilling, 2,6-endometylen-cykloheptyl, which is optionally substituted with chlorine in the 6-position, 2,6-endomethylene-cycloheptyl,

4,4-dimetyl-A -cykloheksenyl, 4,4-dimethyl-A-cyclohexenyl,

A n -cyklopente' nyl,& p -cykloheptenyl,A p-cyklooktenyl, A n -cyclopentenyl, & p -cycloheptenyl, A p -cyclooctenyl,

metyl-cyklopentyl, methylcyclopentyl,

3,3-dimetyi-cyki°Pentyi, 3,3-dimetyi-cyki°Pentyi,

3-etyl-cyklopentyl, 3-ethyl-cyclopentyl,

3-tert.-butyl-cyklopentyl, 3-tert-butyl-cyclopentyl,

2-klor-cyklopentyl, 2-chloro-cyclopentyl,

5-metyl-A <2->cykloheksenyl, og 5-methyl-A <2->cyclohexenyl, and

Z og Z', som er like eller forskjellige, betyr hydrogen, halogen, laverealkyl eller laverealkoksy. Z and Z', which are the same or different, mean hydrogen, halogen, lower alkyl or lower alkoxy.

I ovennevnte og følgende definisjon betyr "lavere alkyl" alltid en alkylgruppe med 1 til 4 C-atomer i rettlinjet eller forgrenet kjede. "Lavere acy.l" betyr en acylrest (organisk syre-rest) med inntil 4 C-atomer, In the above and following definitions, "lower alkyl" always means an alkyl group with 1 to 4 C atoms in a straight or branched chain. "Lower acy.l" means an acyl residue (organic acid residue) with up to 4 C atoms,

Analogifremgangsmåtene ifølge oppfinnelsen er karakterisert ved at The analog methods according to the invention are characterized in that

a) et amin av formel R-^NHg eller et salt derav omsettes med benzensulfonylisocyanater, -karbaminsyreestere, -tiolkarbaminsyreestere, -karbaminsyrehalogenider, -urinstoffer, -semikar-bazider eller semikarbazoner som i para-stilling i benzenkjernen er substituert med en substituent av den generelle formel a) an amine of the formula R-^NHg or a salt thereof is reacted with benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters, -carbamic acid halides, -ureas, -semicarbazides or semicarbazones which are substituted in the para-position of the benzene ring with a substituent of the general formula

b) omsetter benzensulfonamider av formel eller salter derav, med R-^-substituerte isocyanater, karbaminsyreestere, tiolkarbaminsyreestere, karbaminsyrehalogenider eller urinstoffer, eller c) hydrolyserer N-benzensulfonylisourinstoffetere, -isotiourinstoffetere, - isourinstoffestere, - parabansyrer eller -halogenmaursyreamidiner som i benzenkjernen er substituert med b) reacts benzenesulfonamides of formula or salts thereof, with R-^-substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas, or c) hydrolyzes N-benzenesulfonylisourea ethers, -isothiourea ethers, - isourea esters, - parabanic acids or -haloformic acid amidines which are substituted in the benzene ring with

gruppen the group

og i N' -stilling er substituert med and in the N' position is substituted with

gruppen R-^, eller the group R-^, or

d) utveksler svovelatomet i urinstoffresten i benzensulfonyltiourinstoffer svarende til benzensulfonylurinstoffene d) exchanges the sulfur atom in the urea residue in benzenesulfonylthioureas corresponding to the benzenesulfonylureas

av formel I med et oksygenatom, eller of formula I with an oxygen atom, or

e) tilleirer vann til karbodiimider av den generelle formel e) adds water to carbodiimides of the general formula

f) oksyderer benzensulfinyl- henholdsvis benzensulf enylurinstof f er svarende til bensulfonylurinstoffene av formel I, f) oxidises benzenesulfinyl or benzenesulfenyl urea f corresponds to the benzenesulfonylureas of formula I,

eller or

g) innfører, eventuelt trinnvis, rester g) introduces, possibly step by step, residues

i benzensulf onylurinstrf f er av formel in benzenesulfonyl urin strf f is of formula

ved acylering, eller by acylation, or

h) omsetter benzensulfonsyrehalogenider som i para- h) reacts benzenesulfonic acid halides as in para-

stilling er substituert med gruppen position is substituted with the group

med urinstoffer som er substituert med gruppen R-^, eller alkalisalter derav, eller i) omsetter til benzensulfonylurinstoffer av formel I svarende benzensulfinylhalogenider, eller i nærvær av sure kondensasjonsmidler benzensulfinsyrer eller alkalisalter derav med hydrok-syurinstof f er som er substituert med gruppen R-^, eller k) utveksler svovelatomet henholdsvis svovelatomene i tioamidoalkylbenzensulfonylurinstoffer eller -tiourinstoffer svarende til benzensulfonylurinstoffene av formel I med oksygen, eller 1) forsåper forbindelser av formel eller deres parabansyrederivater av formel eller forbindelser av formel with ureas which are substituted with the group R-^, or alkali salts thereof, or i) converts to benzenesulfonylureas of formula I corresponding to benzenesulfinyl halides, or in the presence of acidic condensing agents benzenesulfinic acids or alkali salts thereof with hydroxyureas f are substituted with the group R- ^, or k) exchanges the sulfur atom respectively the sulfur atoms in thioamidoalkylbenzenesulfonylureas or -thioureas corresponding to the benzenesulfonylureas of formula I with oxygen, or 1) saponifies compounds of formula or their parabanic acid derivatives of formula or compounds of formula

hvor U betyr en av gruppene -0—laverealkyl, -S-laverealkyl eller halogen, fortrinnsvis klor, eller where U means one of the groups -O-lower alkyl, -S-lower alkyl or halogen, preferably chlorine, or

m) hydrogenerer til benzensulfonylurinstoffer av formel I svarende forbindelser som i molekylet inneholder en eller flere dobbeltbindinger av ikke-aromatisk karakter, m) hydrogenates to benzenesulfonylureas of formula I corresponding compounds which in the molecule contain one or more double bonds of a non-aromatic character,

og omdanner eventuelt reaksjons produktene til salter med alkaliske midler. and optionally converts the reaction products into salts with alkaline agents.

Alt etter utgangsmaterialenes natur vil i enkelte tilfelle den ene eller andre av de nevnte fremgangsmåter for fremstilling av de individuelle forbindelser som faller under den generelle formel være uegnet eller i det minste nødvendiggjøre forholdsregler til beskyttelse av aktive grupper. Slike forholdsvis sjeldne opptredende tilfeller kan uten vanskelighet erkjennes av fagfolk, og det byr ikke på noen vanskeligheter i slike tilfeller med resultat å anvende en annen av de omtalte synteseveier. Depending on the nature of the starting materials, in some cases one or the other of the aforementioned methods for preparing the individual compounds that fall under the general formula will be unsuitable or at least require precautions to protect active groups. Such relatively rare occurring cases can be recognized without difficulty by experts, and it does not present any difficulties in such cases with the result of using another of the synthesis routes mentioned.

I stedet for benzensulfonyl-isocyanater kan man også anvende omsetningsprodukter av benzensulfonyl-isocyanater med syreamider som kaprolaktam eller butyrolaktam, videre med svakt basiske aminer som karbazoler. Instead of benzenesulfonyl isocyanates, one can also use reaction products of benzenesulfonyl isocyanates with acid amides such as caprolactam or butyrolactam, further with weakly basic amines such as carbazoles.

De nevnte benzensulfony1-karbaminsyreestere resp. -tiolkarbaminsyreestere lean i alkoholkomponenten ha en lavmolekylær alkyl-rest eller en fenylrest. Det ri amme gjelder for de R<1->substituerte karbaminsyreestere resp. tilsvarende tiolkarbaminsyreestere. The aforementioned benzenesulphonyl-carbamic acid esters resp. -thiocarbamic acid esters lean in the alcohol component to have a low molecular weight alkyl residue or a phenyl residue. The same applies to the R<1->substituted carbamic acid esters or corresponding thiolcarbamic acid esters.

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

De som utgangsstoffer for fremgangsmåten aktuelle benzensulfonylurinstoffer kan på den side av urinstoffmolekylet som er vendt bort fra sulfonylgruppen være usubstituert eller substituert en eller spesielt to ganger. Da disse substituenter avspaltes ved reaksjonen med aminene, kan deres karakter varieres innen vide grenser. Ved siden av alkyl-, aryl-, acyl- eller heterocyklisk bustituerte benzensulfonylurinstoffer, kan man også anvende bis-(benzensulf onyl) -urinstoff er , som eventuelt dessuten ved ett av nitrogen-atomene har en ytterligere substituent, f.eks. metyl. Man kan eksempelvis behandle slike bis-(benzensulfonyl)-urinstoffer eller også N-benzensulfonyl-N<*->acylurinstoffer med aminer med formel R^NH^ og oppvarmer de dannede salter til forhøyede temperaturer, spesielt slike over 100°C. The benzenesulfonylureas relevant as starting materials for the method can, on the side of the urea molecule facing away from the sulfonyl group, be unsubstituted or substituted once or especially twice. As these substituents are split off during the reaction with the amines, their character can be varied within wide limits. Next to alkyl-, aryl-, acyl- or heterocyclically substituted benzenesulfonylureas, one can also use bis-(benzenesulfonyl)-ureas, which optionally also have a further substituent at one of the nitrogen atoms, e.g. methyl. One can, for example, treat such bis-(benzenesulfonyl)ureas or also N-benzenesulfonyl-N<*->acylureas with amines of the formula R^NH^ and heat the formed salts to elevated temperatures, especially those above 100°C.

Videre er det mulig å gå ut fra urinstoffer med formel R^-NH-CO-NH^ eller fra slike urinstoffer som ved det fri nitrogenatom dessuten er substituert en eller spesielt to ganger, og å omsette disse med X-CO-NH-Y-substituerte benzensulfonamider. Som slike utgangsstoffer er egnet eksempelvis ved N-nitrogenatomet med R<1->substituerte N'-acetyl eller N'-nitrourinstoffer, N',N'-difenyl-urinstoffer, idet de to fenylrester også substituert kan være for-bundet med hverandre såvel direkte som over et broledd som - CU^-, -NH-, -0- eller -S-, N<*->metyl-N'-fenyl- eller N',N'-dicykloheksyl-urinstoffer såvel som tilsvarende karbamojrl-imidazoler eller -triazoler, endelig også urinstoffer med formel R<1->NH-C0-NH-R<1>. Furthermore, it is possible to start from ureas with the formula R^-NH-CO-NH^ or from such ureas which are additionally substituted once or especially twice at the free nitrogen atom, and to react these with X-CO-NH-Y -substituted benzenesulfonamides. Such starting materials are suitable, for example, at the N-nitrogen atom with R<1->substituted N'-acetyl or N'-nitroureas, N',N'-diphenylureas, since the two phenyl residues can also be substituted and connected to each other both directly and via a bridge link such as - CU^-, -NH-, -O- or -S-, N<*->methyl-N'-phenyl- or N',N'-dicyclohexyl ureas as well as corresponding carbamoyl -imidazoles or -triazoles, finally also ureas of formula R<1->NH-C0-NH-R<1>.

Hydrolysen av de som utgangsstoffer nevnte benzensulf onylparabansyrer, -isourinstoffetere, -isotiourinstoffetere, isourinstoffestere eller -halogenmaursyreamidiner foregår hensiktsmessig i alkalisk medium. Isourinstoffetere og isourinstoffestere kan også hydrolyseres i et surt medium med godt resultat. The hydrolysis of the benzenesulfonylparabanic acids, -isourea ethers, -isothiourea ethers, isourea esters or -haloformic acid amidines mentioned as starting materials conveniently takes place in an alkaline medium. Isourea ethers and isourea esters can also be hydrolysed in an acidic medium with good results.

Omsetningen av benzensulfohalogenidene med R^-substituerte urinstoffer foregår hensiktsmessig under anvendelse av sterkt basiske kondensasjonsmidler som alkalimetaller, alkaliamider eller fortrinnsvis hydrider i indifferente oppløsningsmidler. The reaction of the benzenesulfohalides with R^-substituted ureas conveniently takes place using strongly basic condensing agents such as alkali metals, alkali amides or preferably hydrides in indifferent solvents.

Omsetningen av sulfinsyrene eller sulfinsyre-kloridene med hydroksyurinstoffene kan hensiktsmessig foreå i indifferente oppløsningsmidler. Velger man sulfinsyrene eller deres alkalisalter som utgangsstoffer, så er det nødvendig med sure kondensasjonsmidler, som eksempelvis tionylklorid, polyfosforsyrer, vannfri fosforsyre eller svovelsyre. The reaction of the sulfinic acids or sulfinic acid chlorides with the hydroxyureas can suitably take place in indifferent solvents. If you choose the sulfinic acids or their alkali salts as starting materials, then acidic condensation agents are needed, such as thionyl chloride, polyphosphoric acids, anhydrous phosphoric acid or sulfuric acid.

Svovelatomets erstatning med et oksygenatom i de tilsvarende substituerte benzensulfonyl-tiourinstoffer kan på kjent måte utføres f.eks. ved hjelp av oksyder eller salter av tungmetaller eller også ved anvendelse av oksydasjonsmidler, som hydrogenperoksyd, nåtriumperoksyd eller, salpetersyrling. The replacement of the sulfur atom with an oxygen atom in the correspondingly substituted benzenesulfonyl-thioureas can be carried out in a known manner, e.g. by means of oxides or salts of heavy metals or also by using oxidizing agents, such as hydrogen peroxide, sodium peroxide or, nitric acid.

Tiourinstoffene kan også avsvovles ved behandling med fosgen eller fosforpentaklorid. Som mellomtrinn oppnådde klor-maursyreamidiner resp. -karbodiimider kan ved egnede forholdsregler som forsåpning eller tilleiring av vann overføres i benzensulfonyl-urinstof f ene . The thioureas can also be desulphurised by treatment with phosgene or phosphorus pentachloride. As an intermediate step, chloroformic acid amidines were obtained resp. -carbodiimides can be transferred into benzenesulfonyl urea by suitable precautions such as saponification or addition of water.

Tilsvarende substituerte benzensulfonylurinstoffer som i molekylet har en umettet binding, f.eks. Correspondingly substituted benzenesulfonylureas which have an unsaturated bond in the molecule, e.g.

kan ved hydrogenering f.eks. med molekylært hydrogen overføres i nærvær av en kjent hydrogeneringskatalysator i benzensulfonylurin-stof f ene . can by hydrogenation e.g. with molecular hydrogen is transferred in the presence of a known hydrogenation catalyst into benzenesulfonylureas.

Acyleringen av aminoalkylbenzensulfonyl-urinstoffene kan enten foregå i ett trinn, f.eks. ved omsetning av tilsvarende substituerte syrehalogenider, den kan også utføres i flere trinn. The acylation of the aminoalkylbenzenesulfonylureas can either take place in one step, e.g. by reacting correspondingly substituted acid halides, it can also be carried out in several steps.

Som eksempel på de tallrike muligheter for en trinnvis acylering skal det nevnes omsetningen av aminoalkylbenzensulfonyl-urinstoffer med 2-metoksybBnzoylklorid og den etterfølgende innføring av et halogen-atom i benzenkjernen av benzamido-gruppen. Oksydasjonen av tilsvarende benzensulfinyl- eller -sulfenylurinstoffer lar seg spesielt fordelaktig gjennomføre med permanganat. As an example of the numerous possibilities for a stepwise acylation, mention should be made of the reaction of aminoalkylbenzenesulfonyl ureas with 2-methoxybenzoyl chloride and the subsequent introduction of a halogen atom into the benzene nucleus of the benzamido group. The oxidation of corresponding benzenesulfinyl or -sulfenylureas can be carried out particularly advantageously with permanganate.

Svovelatomets erstatning i tilsvarende substituerte tioamidoalkylbenzensulfonyl-urinstoffer eller -tiourinstoffer med oksygenatomer kan eksempelvis utføres ved hjelp av oksydasjonsmidler som hydrogenperoksyd, nåtriumperoksyd eller andre peroksydforbindelser. The replacement of the sulfur atom in correspondingly substituted thioamidoalkylbenzenesulfonyl ureas or thioureas with oxygen atoms can be carried out, for example, by means of oxidizing agents such as hydrogen peroxide, sodium peroxide or other peroxide compounds.

I stedet for tioamidoalkyl-benzensulfonyl-urin-stoffetere, -isourinstoffetere resp. -estere, -parabansyrer eller Instead of thioamidoalkyl-benzenesulfonyl-urea ethers, -isourea ethers or -esters, -parabanic acids or

-halogenrnaursyreamidiner ved behandling med oksydas jonsmidler i surt -halogenauric acid amidines when treated with oxidizing agents in acid

eller alkalisk miljø med samtidig hydrolytisk frigjøring av sulfonyl-urinstoffgrupperingen avsvovles til amidoalkylbenzensulfonylurinstoffer. or alkaline environment with simultaneous hydrolytic release of the sulfonylurea group is desulfurized to amidoalkylbenzenesulfonylureas.

På samme måte kan i stedet for tioamidoalkylbenzensulfonyl-tiourinstoffer forbindelser med formel Likewise, instead of thioamidoalkylbenzenesulfonyl-thioureas, compounds of formula

hvori U har den ovenfor angitte betydning ved behandling med oksydasjonsmidler i surt eller alkalisk medium under samtidig avsvovling og hydrolyse, omdannes i amidoalkylbenzensulfonylurinstoffer. in which U has the above meaning when treated with oxidizing agents in an acidic or alkaline medium during simultaneous desulphurisation and hydrolysis, is converted into amidoalkylbenzenesulfonylureas.

Utførelsesformen av fremgangsmåten ifølge oppfinnelsen kan generelt varieres sterkt med hensyn til reaksjonsbetingel-ser og tilpasses de eventuelle forhold. Eksempelvis kan omsetningen eventuelt gjennomføres i nærvær av oppløsningsmidler, ved værelsestemperatur eller ved forhøyet temperatur. The embodiment of the method according to the invention can generally be varied greatly with regard to reaction conditions and adapted to the possible conditions. For example, the reaction can possibly be carried out in the presence of solvents, at room temperature or at an elevated temperature.

Den blodsukkersenkende virkning av de omtalte benzensulfonylurinstoffderivater kunne fastslås ved at man foret dem, f.eks. -i form av natriumsalt i doser på 10 mg/kg på normalt er-nærte kaniner, og fastslo blodsukkerverdien etter den kjente metode av Hagedorn Jensen eller med en autanalysør over et lengre tidsrom. The blood sugar-lowering effect of the mentioned benzenesulfonylurea derivatives could be established by feeding them, e.g. - in the form of sodium salt in doses of 10 mg/kg on normally fed rabbits, and determined the blood sugar value according to the known method of Hagedorn Jensen or with an autoanalyzer over a longer period of time.

Således ble det eksempelvis fastslått av 10 mg/kg N-/~4-(p-<2-metoksy-5-metyl-benzamido -etyl)-benzensulfonyl/-N'-(4 »7_ endometylenperhydroindanyl-5)-urinstoff etter 3 timer, bevirker en blodsukkersenkning på 24$- I samme grad bevirker 10 mg N-/ /{-{$- <2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N r-(4,7-endometylen-perhydroindanyl-5)-urinstoff etter 6 timer en blodsukkersenkning på 23$, mens det kjente N-/ 4-mebyl-benzensulfonyl/-N•-butylurinstoff ved en dosering på mindre enn 25 mg/kg på kaniner, ikke mere frem-bringer noen senkning av blodsukkerspeilet. Thus, for example, 10 mg/kg of N-[4-(p-<2-methoxy-5-methyl-benzamido-ethyl)-benzenesulfonyl/-N'-(4»7_ endomethyleneperhydroindanyl-5)-urea was determined after 3 hours, causes a blood sugar lowering of 24$- To the same extent, 10 mg of N-/ /{-{$- <2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N r-(4,7 -endomethylene-perhydroindanyl-5)-urea after 6 hours a blood sugar lowering of 23$, while the known N-/ 4-mebyl-benzenesulfonyl/-N•-butylurea at a dosage of less than 25 mg/kg in rabbits, no more produces some lowering of the blood sugar level.

Videre ble det fastslått av 10 mg N-/ 4-((3- 2-metoksybenzamido>-etyl)-benzensulfonyl/-N * -(4> 7-endometylenpperhydro-indanyl-5)-urinstoff etter 3 timer bevirker en blodsukkersenkning på 40$. Furthermore, it was established that 10 mg of N-/ 4-((3-2-methoxybenzamido>-ethyl)-benzenesulfonyl/-N * -(4> 7-endomethyleneperhydro-indanyl-5)-urea after 3 hours causes a blood sugar lowering of 40$.

Fremgangsmåteproduktene har således en meget sterk blodsukkersenkende virkning med en overordentlig god tålbarhet. The process products thus have a very strong blood sugar-lowering effect with an extremely good tolerability.

De omtalte benzensulfonylurinstoffer skal fortrinnsvis tjene til fremstilling av oralt administrerbare preparater med blodsukkersenkende virkning for behandling av Diabetes mellitus, og'kan anvendes som sådanne eller i form av deres alter resp. i nærvær av stoffer som fører til en saltdannelse. Til saltdannelse kan eksempelvis anvendes alkaliske midler som alkali- eller jord-alkalihydroksyder, -karbonater eller -bikarbonater. The mentioned benzenesulfonylureas should preferably be used for the production of orally administrable preparations with blood sugar-lowering effects for the treatment of diabetes mellitus, and can be used as such or in the form of their alters or 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 fortrinnsvis i betraktning tabletter, som ved siden av fremgangsmåteproduktene inneholder de vanlige hjelpe- og bærestoffer, som talkum, stivelse, melkesukker, tragant eller magnesiumstearat. Tablets are preferably taken into consideration as medical preparations, 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 omtalte benzensulfonylurinstoffer som virksomt stoff, f.eks. en tablett eller et pulver, med eller uten de nevnte tilsetninger, er hensiktsmessig bragt i en egnet dosert form. Som dosis er det da å velge en slik som er tilpasset virkningen av det anvendte benzensulfonylurinstoff 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 før applikasjon må deles resp. mangfordiggjøres. A preparation containing the mentioned benzenesulfonylureas as active substance, e.g. a tablet or a powder, with or without the aforementioned additives, is conveniently brought into a suitable dosage form. As a dose, it is then to choose one that 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 before application or multiply.

Fra norsk patent nr. II8..548 er det kjent acyl-aminoalkylbenzensulfonylurinstoffer med hypoglykemiske .egenskaper. Imidlertid utmerker benzensulfonylurinstoffene fremstilt ifølge oppfinnelsen seg ved en vesentlig lavere grensedose enn forbindelsene ifølge norsk patent nr. II8.548. ( I det norske patent nr. II8.548 er det feilaktig i stedet for 0,08 mg/kg angitt en grenseverdi på 0,008 mg/kg for N-/~4-(p-benzamidoetyl)-benzensulfonyl/-N'(4-etyl-cykloheksyl)-urinstoff. Dette skyldes en trykkfeil som er korrigert i det tilsvarende danske patent nr. II9.O52 samt belgisk patent nr. 654.56I). Acyl-aminoalkylbenzenesulfonylureas with hypoglycaemic properties are known from Norwegian patent no. II8..548. However, the benzenesulfonylureas produced according to the invention are distinguished by a significantly lower limit dose than the compounds according to Norwegian patent no. II8,548. (In the Norwegian patent no. II8,548, instead of 0.08 mg/kg, a limit value of 0.008 mg/kg is erroneously stated for N-/~4-(p-benzamidoethyl)-benzenesulfonyl/-N'(4 -ethyl-cyclohexyl)-urea. This is due to a printing error which has been corrected in the corresponding Danish patent no. II9.052 and Belgian patent no. 654.56I).

I følgende tabell er det oppstillet KG-verdier (KG betyr den minimale dosering av stoffet i mg/kg som er på kaniner ennå bevirker en tydelig målbar senkning av blodsukkerspeilet) av forbindelsene fremstilt ifølge oppfinnelsen. Som det fremgår av disse tall utmerker- benzensulfonylurinstoffene ifølge oppfinnelsen seg ved en vesentlig lavere grensedosis enn for forbindelsen ifølge det norske patent nr. II8.548. Eksempel 1. N-/ 4-( P-<:2-metyoksy-5-klorbenzamido>-etyl) -benzensulf onyl/-N '-(4,7-metano- perhydro- indanyl- 5)- urinstoff. In the following table, KG values are listed (KG means the minimal dosage of the substance in mg/kg which on rabbits still causes a clearly measurable lowering of the blood sugar level) of the compounds produced according to the invention. As can be seen from these figures, the benzenesulfonylureas according to the invention are characterized by a significantly lower limit dose than for the compound according to the Norwegian patent no. II8,548. Example 1. N-[4-(P-<:2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4,7-methano-perhydro-indanyl-5)-urea.

8,5 g N-/ 4~(f3-£2-metoksy-5-klorbenzamido?-etyl) -benzensulf onyl/- metyluretan (s-meltepunkt 189-191°^) suspenderes i 100 ml xylen og oppvarmes ca. 2 timer ved 130°C etter tilsetning av 3>3 g 5-amino_ 4,7-metanofperhydro-indan (kokepunkt 8 mm 96-98°C) (oppnådd ved hydrogenering av dicyklopentadien-bis-nitrosoklorid/RaNi 100°C og 100 Atm. H^) oppløst i 50 ml'xylen, idet den ved reaksjonen dannede metanol avdestillerer. Man avdestillerer xylen i vakuum, derved utfelles det dannede N-/ 4- ((3-^2-metoksy-5-klorbenzamido>-etyl) -benzensulf onyl/- N'-(4>7-metano_Perhydro-indanyl-5)-urinstoff i krystallinsk form. 8.5 g of N-/ 4~(f3-£2-methoxy-5-chlorobenzamido?-ethyl)-benzenesulfonyl/- methylurethane (s-melting point 189-191°^) are suspended in 100 ml of xylene and heated approx. 2 hours at 130°C after addition of 3>3 g of 5-amino_ 4,7-methanofperhydro-indane (boiling point 8 mm 96-98°C) (obtained by hydrogenation of dicyclopentadiene-bis-nitrosochloride/RaNi 100°C and 100 Atm. H^) dissolved in 50 ml of xylene, the methanol formed by the reaction distilling off. The xylene is distilled off in a vacuum, thereby precipitating the formed N-/ 4- ((3-^2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/- N'-(4>7-methano_Perhydro-indanyl-5) -urea in crystalline form.

Det omkrystalliseres fra metano, smeltepunkt 196-198°C. It is recrystallized from methanol, melting point 196-198°C.

På analog måte vil man^ In an analogous way one will^

av N-/ 4-(p-<2-klorbenzamido>-etyl)-benzensulfonyl/-metyl-uretan (smeltepunkt 212-2I5°C) få: of N-/ 4-(p-<2-chlorobenzamido>-ethyl)-benzenesulfonyl/-methyl-urethane (melting point 212-215°C) get:

N-/ 4~(p-^4-klorbenzamido>-etyl)-benzensulfonyl/-N'-(4,7-metano-per-hydroindanyl-5-)urinstoff, smeltepunkt 206-208°C (fra metanol/dioksan), av N-/ 4-( P-^2-metoksybenzamid'o>-etyl) -benzensulf onyl/-metyl-uretan, smeltepunkt 174-176°C, få: N-/ 4- ((3-2-metoksybenzamido-etyl) -benzensulf onyl/-N ' - (4,7-metano-perhydroindanyl-5)-urinstoff, smeltepunkt 195-197°^ (fra metanol), av N-/ 4- ((3-<2-metoksy-5-metylbenzamido >-etyl) -benzensulf onyl/-metyl-uretan, smeltepunkt 175-177°C, få: N-/ 4-(P-^2-metoksy-5-metylbenzamido>-etyl)-benzensulfonyl/-N'-(4,7-metano-perhydro-indanyl-5)-urinstoff, smeltepunkt 208-210°C (fra fort. dioksan), av N-/ 4-"<P-benzamido-etyl>-benzensulf onyl/-metyluretan, smeltepunkt 177-179°C, få: N-/ 4-(p-benzamido-etyl)-benzensulfonyl/-N'-(4,7-metano-perhydro-indanyl-5)-urinstoff, smeltepunkt 2l8-220°C (dekomp.); av N-/~4" ( P~<:3~klorbenzamido>-etyl) -benzensulfonyl7-metylmetan, smeltepunkt 173-175°G, få: N-/~4- ( p-«£3-klorbenzamido>-etyl) - benzensulf onyl/-N ' - (2, 6-endometylen-cykloheptyl)-urinstoff, smeltepunkt l86°-l87°C (fra metanol); N-/ 4~ ( P-^J-klQrbenzamido.^-etyl) -benzensulf onyl/-N ' -cyklopenten-( 2) - yl- urinstoff, smeltepunkt 195-196°^ (fra metanol); N-/ 4~(p-^4-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-(4,7-methano-per-hydroindanyl-5-)urea, melting point 206-208°C (from methanol/dioxane ), of N-/ 4-( P-^2-methoxybenzamide'o>-ethyl)-benzenesulfonyl/-methyl-urethane, melting point 174-176°C, get: N-/ 4- ((3-2- methoxybenzamido-ethyl)-benzenesulfonyl/-N'-(4,7-methano-perhydroindanyl-5)-urea, melting point 195-197°^ (from methanol), of N-/ 4- ((3-<2-methoxy-5-methylbenzamido >-ethyl)-benzenesulfonyl/-methyl-urethane, melting point 175-177°C, get: N-/ 4-(P-^2 -methoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl/-N'-(4,7-methano-perhydro-indanyl-5)-urea, melting point 208-210°C (from cont. dioxane), of N-/ 4-"<P-benzamido-ethyl>-benzenesulfonyl/-methylurethane, melting point 177-179°C, obtain: N-/ 4-(p-benzamido-ethyl)-benzenesulfonyl/-N'-( 4,7-methano-perhydro-indanyl-5)-urea, mp 218-220°C (decomp.); of N-/~4" ( P~<:3~chlorobenzamido>-ethyl)-benzenesulfonyl7-methylmethane, melting point 173-175°G, get: N-/~4- ( p-«£3-chlorobenzamido>-ethyl ) - benzenesulfonyl/-N' - (2, 6-endomethylene-cycloheptyl)-urea, melting point 186°-187°C (from methanol); N-/ 4~ ( P-^J-klQrbenzamido.^-ethyl) -benzenesulfonyl/-N'-cyclopentene-(2)-yl-urea, melting point 195-196°^ (from methanol);

N-/ 4~(p-<3-klorbenzamido ^-etyl)-benzensulfonyl/-N1 -(4,4-dimetylcyklo-heksen-(2)-yl)-urinstoff, smeltepunkt l88°-190°C (fra metanol); N-/ 4~(p-<3-chlorobenzamido ^-ethyl)-benzenesulfonyl/-N1 -(4,4-dimethylcyclohexen-(2)-yl)-urea, melting point 188°-190°C (from methanol );

N-/ 4-((3-<3-klorbenzamido>-etyl) -benzensulf onyl/-N'-cyklophepten-t 2) - yl-urinstoff, smeltepunkt 170°-172°C (fra metanol), og N-/ 4-(P-<3-klorbenzamido>-etyl)-benzensulfonyl/-N'-cyklookten-(2)-yl-urinstoff , smeltepunkt 179°-l8l°C (fra metanol); N-/ 4-((3-<3-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-cyclohepten-t 2 )-yl-urea, melting point 170°-172°C (from methanol), and N- / 4-(P-<3-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-cycloocten-(2)-yl-urea, melting point 179°-181°C (from methanol);

av N-/ 4~(p-^2-metoksy-benzamido>-etyl)-benzensulfonyl/-metyluretan, smeltepunkt 174°-176°C, få: of N-/ 4~(p-^2-methoxy-benzamido>-ethyl)-benzenesulfonyl/-methylurethane, melting point 174°-176°C, obtain:

N-/ 4-((3-«£2-metoksybenzamido>-etyl) -benzensulf onyl/-N ' - ( 2,6-endometylen-cykloheptyl)-urinstoff, smeltepunkt 170°-172°C, (fra metanol), N-/ 4- ((3-<2-metoksybenzamido7-etyl) -benzensulf onyl/-N ' -cyklopenten-2-yl-urinstoff, smeltepunkt 170-172°C, fra metanol),_ N-/ 4-(p-<2-metoksybenzamido>-etyl)-benzensulfonyl/-N'-(4? 4-dimetyl-cykloheksen-2-yl) -urinstof f, smeltepunkt 178°-179°9_, (fr& metanol), N-/ 4- ( P-<-2-metoksybenzamido>-etyl) -benzensulf onyl/-N' -cyklohepten-(2)=yl-urinstoff, smeltepunkt 174°-176°C, fra metanol), og N-/ 4- ((3- <2-metoksy-benzamido7-etyl) -benzensulfonyl/-N ' -cyklookten-(2)-yl-urinstoff, smeltepunkt l68°-170°C, (fra metanol); av N-/ 4-(p-<2-etoksybenzamido?-etyl)-benzensulfonyl/-metyluretan, smeltepunkt 172°-174°C, få: N-/4- ((3-^2-etoksybenzamido>-etyl) -benzensulf onyl/-N ' - (4, 4-dimetyl-cykloheksen-(2)-yl)-urinstoff, smeltepunkt 141°-142°C, (fra metanol), N-/ 4-( p-^2-etoksybenzamido>-etyl) -benzensulf onyl/-N ♦ -cyklohepten-(2)-yl-urinstoff, smeltepunkt l62°-l64°G, (fra metanol); av N-/ 4~ (p-<:2-metoksy-5-klorbenzamido>-etyl) -benzensulf onyl/-met yl-uretan, smeltepunkt l89°-191<0>C, få: N-/ 4-(P-^2-metoksy-5-klorbenzamido?-etyl)-benzensulfonyl/-N'-(2,6-endometylen-cyklohetJtyl)-urinstoff, smeltepunkt 140°-142°C, (fra metanol), N-/ 4-((3-«£2-Methoxybenzamido>-ethyl)-benzenesulfonyl/-N' - (2,6-endomethylene-cycloheptyl)-urea, melting point 170°-172°C, (from methanol) , N-/ 4- ((3-<2-methoxybenzamido7-ethyl)-benzenesulfonyl/-N '-cyclopenten-2-yl-urea, melting point 170-172°C, from methanol),_ N-/ 4- (p-<2-methoxybenzamido>-ethyl)-benzenesulfonyl/-N'-(4?4-dimethyl-cyclohexen-2-yl)-urea f, m.p. 178°-179°9_, (fr& methanol), N- / 4- (P-<-2-methoxybenzamido>-ethyl)-benzenesulfonyl/-N'-cyclohepten-(2)=yl-urea, melting point 174°-176°C, from methanol), and N-/ 4 - ((3-<2-methoxy-benzamido-7-ethyl)-benzenesulfonyl/-N'-cycloocten-(2)-yl-urea, melting point 168°-170°C, (from methanol); of N-/ 4-(p-<2-ethoxybenzamido?-ethyl)-benzenesulfonyl/-methylurethane, melting point 172°-174°C, obtain: N-/4-((3-^2-ethoxybenzamido>-ethyl) -benzenesulfonyl/-N ' - (4, 4-dimethyl-cyclohexen-(2)-yl)-urea, melting point 141°-142°C, (from methanol), N-/ 4-( p-^2- ethoxybenzamido>-ethyl)-benzenesulfonyl/-N ♦ -cyclohepten-(2)-yl-urea, mp 162°-164°G, (from methanol); of N-/ 4~ (p-<:2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-methyl-urethane, melting point l89°-191<0>C, get: N-/ 4-( β-[2-Methoxy-5-chlorobenzamido?-ethyl)-benzenesulfonyl/-N'-(2,6-endomethylene-cyclohexyl)-urea, melting point 140°-142°C, (from methanol),

N-/ 4-(P—^2-metoksy-5-klorbenzamido7-etyl)-benzensulfonyl/-N'-cyklo-panten-(2)-yl-urinstoff, smeltepunkt l88°C-l89°C, (fra metanol), N-/ 4-(P-^2-Methoxy-5-chlorobenzamido7-ethyl)-benzenesulfonyl/-N'-cyclo-panten-(2)-yl-urea, melting point 188°C-189°C, (from methanol ),

N-/ 4- ( p-«^2~metoksy-5-klorbenzamido>-etyl) -benzensulf onyl/-N ' - (4,4~ dimetylcykloheksen-(2)-yl)-urinstoff, smeltepunkt 170°-172°C, (fra metanol), N-/ 4-( p-«^2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N ' - (4,4-dimethylcyclohexen-(2)-yl)-urea, melting point 170°-172 °C, (from methanol),

N-/ 4-(P-<2-metoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N'-cyklo-hepten-(2)-yl-urinstoff, smeltepunkt 142°-144°C, (fra metanol), og N-/ 4-(P-^2-metoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N'-cyklo-okten-(2)-yl-urinstoff, smeltepunkt 171°-172°C, (fra metanol); N-/ 4-(P-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-cyclo-hepten-(2)-yl-urea, melting point 142°-144°C, (from methanol ), and N-/ 4-(P-^2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-cyclo-octen-(2)-yl-urea, melting point 171°-172°C, (from methanol);

av N-/ 4-(P-<2-metoksy-5-met<y>lbenzamido;>-etyl)-benzensulfonyl/-metyl-uretan, smeltepunkt 175°-177°C, få: N-/ 4_(p-<2-metoksy-5-metylbenzamido7-etyl)-benzensulfonyl/-N'-2,6-endometylencykloheptyl)-urinstoff, smeltepunkt l89°-191°C (fra metanol/ dimetylformamid), of N-/ 4-(P-<2-methoxy-5-meth<y>lbenzamido;>-ethyl)-benzenesulfonyl/-methyl-urethane, melting point 175°-177°C, get: N-/ 4_(p -<2-methoxy-5-methylbenzamido7-ethyl)-benzenesulfonyl/-N'-2,6-endomethylenecycloheptyl)-urea, melting point 189°-191°C (from methanol/dimethylformamide),

N-/ 4~ ( p-<:2-metoksy-5-metylbenzamido-7—etyl) -benzensulf onyl/-N ' -cyklopenten-(2)-yl-urinstoff, smeltepunkt 201°-203°C, (fra metanol-dimetylformamid), N-/ 4~ ( p-<:2-methoxy-5-methylbenzamido-7-ethyl)-benzenesulfonyl/-N '-cyclopenten-(2)-yl-urea, melting point 201°-203°C, (from methanol-dimethylformamide),

N-/ 4- ( P-^2-metoksy-5-metylbenzamido >-etylen)-benzensulfonyl/-N'-(454-dimetylcykloheksen-(2)-yl)-urinstoff, smeltepunkt 152°-154°G, N-/ 4-( P-^2-methoxy-5-methylbenzamido >-ethylene)-benzenesulfonyl/-N'-(454-dimethylcyclohexen-(2)-yl)-urea, melting point 152°-154°G,

(fra metanol), (from methanol),

N-/ 4~( P-^2-metoksy-5-metylbenzamido>-etyl)-benzensulfonyl/-N'-cyklo-hepten-(2)-yl-urinstoff, smeltepunkt 177°-178°C , (fra metanol), og N-/ 4_( P-<r2-metoksy-5-metylbenzamido>-etyl) -benzensulf onyl/-N ' -cyklo-okten-(2)-yl-urinstoff, smeltepunkt 178°-l8o°C, (fra metanol-dimetylformamid); N-/ 4~( P-^2-methoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl/-N'-cyclo-hepten-(2)-yl-urea, melting point 177°-178°C , (from methanol ), and N-/ 4_( P-<r2-methoxy-5-methylbenzamido>-ethyl)-benzenesulfonyl/-N'-cyclo-octen-(2)-yl-urea, melting point 178°-180°C, (from methanol-dimethylformamide);

av N-/ 4-(p-^2-metoksy-5-brombenzamidor-etyl)-benzensulfonyl/-metyl-uretan, smeltepunkt 197°-199°C, få: N-/~ 4-(p-<2-metyoksy-5-brombenzamido>-etyl)-benzensulfonyl/-N'-(2,6-endometylencykloheptyl)-urinstoff, smeltepunkt 170°-172°C, (fra metanol), of N-/ 4-(p-^2-methoxy-5-bromobenzamidor-ethyl)-benzenesulfonyl/-methyl-urethane, melting point 197°-199°C, get: N-/~ 4-(p-<2- methoxy-5-bromobenzamido>-ethyl)-benzenesulfonyl/-N'-(2,6-endomethylenecycloheptyl)-urea, melting point 170°-172°C, (from methanol),

N-/ 4- ( P-*2-metoksy-5-brombenzamido;>-etyl) -benzensulf onyl/-N ' -cyklopenten-(2)-yl-urinstoff, smeltepunkt l88°-190°C, (fra metanol), N-/ 4-( P-*2-Methoxy-5-bromobenzamido;>-ethyl)-benzenesulfonyl/-N'-cyclopenten-(2)-yl-urea, melting point 188°-190°C, (from methanol ),

N-/ 4-(P—r2-metoksy-5-brombenzamido?—etyl)-benzensulfonyl/-N'-4,4-dimetylcykloheksen-(2)-yl)-urinstoff, smeltepunkt ll8°-120°C, (fra metanol), N-/ 4-(P—r2-methoxy-5-bromobenzamido?—ethyl)-benzenesulfonyl/-N'-4,4-dimethylcyclohexen-(2)-yl)-urea, melting point ll8°-120°C, ( from methanol),

N-/ 4~ ( P-<2-metoksy-5-brombenzamido->-etyl) -benzensulf onyl/-N ' -cyklo-hepten-(2)-yl-urinstoff, smeltepunkt 142°-144°G, (fra metanol), og N-/ 4- ( P—<:2-metoksy-5-brombenzamido7-etyl) -benzensulf onyl/-N ' -cyklo-okten-(2)-yl-urinstoff,smeltepunkt 175°-176°C, (fra metanol); N-/ 4~ ( P-<2-methoxy-5-bromobenzamido->-ethyl)-benzenesulfonyl/-N '-cyclo-hepten-(2)-yl-urea, melting point 142°-144°G, ( from methanol), and N-[4-(P-<:2-methoxy-5-bromobenzamido-7-ethyl)-benzenesulfonyl/-N'-cyclo-octen-(2)-yl-urea, melting point 175°-176 °C, (from methanol);

av N-/ 4~ ( P—<2-etoksy-5-klorbenzamido-?-etyl) -benzensulf onyl/-metyl-uretan, smeltepunkt 203°-205°C, få: of N-/ 4~ ( P—<2-ethoxy-5-chlorobenzamido-?-ethyl)-benzenesulfonyl/-methyl-urethane, melting point 203°-205°C, obtain:

N-/ 4-( p-<£2-etoksy-5-klorbenzamido7— ety 1) -benzensulfonyl/-N ' - ( 2, G-endometylencykloheptyl)-urinstoff, smeltepunkt 172°-174°C > (Ira metanol); av N-/ 4- ( > 5~dimetylbenzamido7-etyl) -benzensulf onyl/-mety lur et an, smeltepunkt 223°-225°G), få: N-/ 4-(P-<3,5-dimetylbenzamido>-etyl)-benzensulfonyl/-N'-cyklohepten-(-2) -yl-urinstoff, smeltepunkt 196°-198°C, (fra metanol); av N-/ 4- ( p-<2-etoksy-5-f luorbenzarnido>-etyl) -benzensulf onyl/-metyluretan, smeltepunkt 193°-<1>95°C, få: N-/ 4-(P-<2-etoksy-5-fluorbenzamido>-etyl)-benzensulfonyl/-N'-(4,4~ dimetylcykloheksen-(2)-yl)-urinstoff, smeltepunkt 140°-141°C, (fra metanol); av N-/ 4-(p-<2-metoksy-5-metyl-benzamido>-etyl)-benzensulfonyl/-metyl-uretan, få: N_/ 4_(p-<2-metoksy-5-metyl-benzamido>-etyl)-benzensulfonyl/-N'-(2-klorcyklopentyl)-ruinstoff, smeltepunkt 209°-210°C, (fra metanol/DMFA), N-/ 4-( P-<;2-metoksy-5-metyl-benzamido>-etyl) -benzensulfonyl/-N ' - (1-metylcyklopentyl)-urinstoff, smeltepunkt 156°-158°C, (fra metanol), N-/ 4-(6-<2-metoksy-5-metyl-benzamido>-etyl)-benzensulfonyl/-N'-(5-metylcykloheksen-( 2)-yl)-urinstoff, smeltepunkt 171°-173°(-'> (fra metanol), N-/ 4- ( P-<2-metoksy-5-metyl-benzamido>-etyl-benzensulfonyl/-N'-(3~tert. butyl-cyklopentyl)-urinstoff, smeltepunkt 143°_145<0>C> (fra metanol), N-/_~4 - ( P-<r2-metoksy-5-mety 1-benzamido>-etyl—benzensulf onyl/-N ' - ( 3-metylcyklopentyl)-urinstoff, smeltepunkt 151°-153°^> (fra metanol), av N-/ 4-( p-<33 5-dim.etyl-benzamido>-etyl)-benzensulf onyl/-metyluretan, få:_ N-/ 4-( p-<3 5 5-dimetyl-benzamido>-etyl) -benzensulf onyl/-N.r-( 2-klorcyklo-pentyl)-urinstoff, smeltepunkt 207°-209°C, (fra metanol), N-/ 4-(p-<3 > 5_dimetyl-benzamido> - etyl)-benzensulfonyl/-N'-(3-tert. butyl-cyklopentyl)-ruinstoff, smeltepunkt 150°-152°C, (fra metanol), og N-/ 4~( >5-dimetyl-benzamido>-etyl)-benzensulfonyl/-N'-(3-metylcyklopentyl)-urinstoff, smeltepunkt l83°-l85C, (fra metanol); av N-/ 4~( p-<^2-metoksy-benzamido>-etyl) -benzensulf onyl/-metyluretan, få:_ N-/ 4-(P-<2-metoksy-benzamido>-etyl)-benzensulfonyl/-N'-(2-klorcyklo-pentyl)-urinstoff., smeltepunkt l82°-l83°G, (fra metanol), N-/ 4-(P-<2-metoksy-benzamido>-etyl)-benzensulfonyl/-N'-(3tert.butyl-cyklopentyl ) -urinstof f, smeltepunkt 175°-177°G, (fra metanol), N-/ 4~(p-<2-metoksy-benzamido>-etyl)-benzensulfonyl/-N'-(3-metylcyklo-pentyl)-urinstoff, smeltepunkt l64°-l65°C, (fra metanol), av N-/ 4-(p-<2-etoksy-benzamido>-ety1)- benzensulfonyl/-metyluretan, få: N-/ 4-P-^2-etoksy-benzamido>-etyl)-benzensulfonyl/-N'-(3-metylcyklo- N-/ 4-( p-<£2-ethoxy-5-chlorobenzamido7-ethyl 1)-benzenesulfonyl/-N ' - ( 2,G-endomethylenecycloheptyl)-urea, melting point 172°-174°C > (Ira methanol) ; of N-/ 4- ( > 5-dimethylbenzamido7-ethyl)-benzenesulfonyl/-methyl et an, melting point 223°-225°G), get: N-/ 4-(P-<3,5-dimethylbenzamido> -ethyl)-benzenesulfonyl/-N'-cycloheptene-(-2)-yl-urea, mp 196°-198°C, (from methanol); of N-/ 4- ( p-<2-ethoxy-5-fluorbenzanido>-ethyl)-benzenesulfonyl/-methylurethane, melting point 193°-<1>95°C, get: N-/ 4-(P- <2-ethoxy-5-fluorobenzamido>-ethyl)-benzenesulfonyl/-N'-(4,4-dimethylcyclohexen-(2)-yl)-urea, mp 140°-141°C, (from methanol); of N-/ 4-(p-<2-methoxy-5-methyl-benzamido>-ethyl)-benzenesulfonyl/-methyl-urethane, get: N_/ 4_(p-<2-methoxy-5-methyl-benzamido> -ethyl)-benzenesulfonyl/-N'-(2-chlorocyclopentyl)-degradant, melting point 209°-210°C, (from methanol/DMFA), N-/ 4-( P-<;2-methoxy-5-methyl -benzamido>-ethyl)-benzenesulfonyl/-N ' - (1-methylcyclopentyl)-urea, melting point 156°-158°C, (from methanol), N-/ 4-(6-<2-methoxy-5-methyl -benzamido>-ethyl)-benzenesulfonyl/-N'-(5-methylcyclohexen-(2)-yl)-urea, melting point 171°-173°(-'> (from methanol), N-/ 4- ( P- <2-Methoxy-5-methyl-benzamido>-ethyl-benzenesulfonyl/-N'-(3~tert.butyl-cyclopentyl)-urea, melting point 143°_145<0>C> (from methanol), N-/_ ~4 - (P-<r2-methoxy-5-methyl 1-benzamido>-ethyl-benzenesulfonyl/-N' - (3-methylcyclopentyl)-urea, melting point 151°-153°^> (from methanol), of N-/ 4-( p-<33 5-dimethyl-benzamido>-ethyl)-benzenesulfonyl/-methylurethane, get:_ N-/ 4-( p-<3 5 5-dimethyl-benzamido>- ethyl) -benzenesulfonyl/-N.r-(2-chlorocyclopentyl)-urea, melting point 207°-209°C, (from methanol), N-/ 4-(p-<3 > 5_dimethyl-benzamido> - ethyl) -benzenesulfonyl/-N'-(3-tert.butyl-cyclopentyl)-degradant, melting point 150°-152°C, (from methanol), and N-/ 4~(>5-dimethyl-benzamido>-ethyl)- benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea, mp 183°-185C, (from methanol); of N-/ 4~( p-<^2-methoxy-benzamido>-ethyl)-benzenesulfonyl/-methylurethane, get:_ N-/ 4-(P-<2-methoxy-benzamido>-ethyl)-benzenesulfonyl /-N'-(2-Chlorocyclopentyl)-urea., melting point 182°-183°G, (from methanol), N-/ 4-(P-<2-methoxy-benzamido>-ethyl)-benzenesulfonyl/ -N'-(3-tert.butyl-cyclopentyl)-urea f, melting point 175°-177°G, (from methanol), N-/ 4~(p-<2-methoxy-benzamido>-ethyl)-benzenesulfonyl/- N'-(3-methylcyclopentyl)-urea, melting point 164°-165°C, (from methanol), of N-/ 4-(p-<2-ethoxy-benzamido>-ethyl)-benzenesulfonyl/-methylurethane, get: N-/ 4-P-^2-ethoxy-benzamido>-ethyl)-benzenesulfonyl/-N' -(3-methylcyclo-

pentyl)-urinstoff, smeltepunkt 139°-141°C, (fra metanol); pentyl)-urea, mp 139°-141°C, (from methanol);

av N-/ 4-(p-<2-etoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-metyl-uretan, få: N_/ 4_ ((3-<:2-etoksy-5-klorbenzamido>- etyl)-benzensulfonyl/-N♦-(3-tert. butyl-cyklopentyl)-urinstoff, smeltepunkt 152°-153°c> (fra metanol), og of N-/ 4-(p-<2-ethoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-methyl-urethane, get: N_/ 4_ ((3-<:2-ethoxy-5-chlorobenzamido>- ethyl )-benzenesulfonyl/-N♦-(3-tert.butyl-cyclopentyl)-urea, m.p. 152°-153°c> (from methanol), and

N-/ 4-p-^2-etoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N'-(3-metyl-cyklopentyl)-urinstoff, smeltepunkt 144°-146°C, (fra metanol); N-(4-p-[2-ethoxy-5-chlorobenzamido-ethyl)-benzenesulfonyl]-N'-(3-methyl-cyclopentyl)-urea, m.p. 144°-146°C, (from methanol);

Analogt eksempel 1 vil man Analogous to example 1, one will

av N-/ 4-( (3-<:3,4-diklorbenzamido>-etyl) -benzensulfonyl/-metyluretan, få:_ of N-/ 4-((3-<:3,4-dichlorobenzamido>-ethyl)-benzenesulfonyl/-methylurethane, get:_

N-/ 4-(p-^3,4-diklorbenzamido>-etyl)-benzensulfonyl/-N'-(3-metylcyklo-pentyl)-urinstoff, smeltepunkt l80°-l8l°C, (fra metanol); N-/ 4-(p-^3,4-dichlorobenzamido>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea, melting point 180°-181°C, (from methanol);

av N-/ 4-(p-<2-metoksy-5-brom-benzamido>-etyl)-benzensulfonyl/-metyl-uretan, få: of N-/ 4-(p-<2-methoxy-5-bromo-benzamido>-ethyl)-benzenesulfonyl/-methyl-urethane, get:

N-/ 4- ((3-<:2-metoksy-5-brom-benzamido>-etyl) -benzensulfonyl/-N ' -(2-klor-cyklopentyl)-urinstoff, smeltepunkt 191°-193°G, (fra metanol-dimetylformamid), N_/ 4_( p_<2-metoksy-5-brom-benzamido>-etyl)-benzensulfonyl/-N•-(3-tert. butylcyklopentyl)-urinstoff, smeltepunkt 144°-146°C, (fra metanol), N-/ 4-(p-<2-metoksy-5-brom-benzamido>-etyl)-benzensu lfonyl/-N'-(3-metylcjrklopentyl)-urinstoff, smeltepunkt 144°-145°9) (fra metanol); av N-/ 4-P-<3-klor-benzamido>-etyl) -benzensulfonyl/-metyluretan, få: N-/ 4-(p-<3-klor-benzamido>-etyl)-benzensulfonyl/-N'-(2-klorcyklopen-tyl)-urinstoff, smeltepunkt 192°-193°C, (fra metanol), N-/ 4-(p-<3-klor-benzamido>-etyl)-benzensulfonyl/-N♦-(1-metylcyklopen-tyl)_-urinstoff, smeltepunkt 191°-193°C, (fra metanol), N-/ 4- ((3-<:2-methoxy-5-bromo-benzamido>-ethyl)-benzenesulfonyl/-N ' -(2-chloro-cyclopentyl)-urea, melting point 191°-193°G, ( from methanol-dimethylformamide), N_/ 4_( p_<2-methoxy-5-bromo-benzamido>-ethyl)-benzenesulfonyl/-N•-(3-tert.butylcyclopentyl)-urea, melting point 144°-146°C, (from methanol), N-/ 4-(p-<2-methoxy-5-bromo-benzamido>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea, mp 144°-145°9 ) (from methanol); of N-/ 4-P-<3-chloro-benzamido>-ethyl)-benzenesulfonyl/-methylurethane, get: N-/ 4-(p-<3-chloro-benzamido>-ethyl)-benzenesulfonyl/-N' -(2-chlorocyclopentyl)-urea, melting point 192°-193°C, (from methanol), N-/ 4-(p-<3-chloro-benzamido>-ethyl)-benzenesulfonyl/-N♦-( 1-methylcyclopentyl)-urea, melting point 191°-193°C, (from methanol),

N-/ 4- ((3-<3-klor-benzamid>-etyl) -benzensulfonyl/-N ♦ - (3-tert .butyl-cyklopentyl) -urinsotff, smeltepunkt 174°-175°c> (fra metanol), N-/ 4- ((3-<3-chloro-benzamide>-ethyl)-benzenesulfonyl/-N ♦ - (3-tert.butyl-cyclopentyl)-urinsotff, melting point 174°-175°c> (from methanol) ,

N-/ 4-( p-<3-klor-benzamido>--etyl) -benzensulf onyl/-N '-(3-metylcyklopen-tyl)-urinstoff, smeltepunkt l64°-l66°C, (fra metanol), N-/ 4-(p-<3-chloro-benzamido>--ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea, melting point 164°-166°C, (from methanol),

Eksempel 2. N-/ 4~(P-<2-metoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N'-(4,7_ metano- perhydro- indanyl-^)- urinstoff. Example 2. N-[4-(P-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-(4,7_methano-perhydro-indanyl-^)-urea.

En blanding av 10,3 g N_/ 4-(P-<2-metoksy-5-klor-benzamido-etyl)-benzensulfonyl/-urinstoff, 3 00 ml toluen, 30 ml glykolmonometyleter, 1,65 g iseddik og 4>2 g 4»7_metano-perhydro-indanyl-5-amin oppvarmes i 5 timer under tilbakeløp. Deretter inndampes i vakuum, residuet behandles med alkohol, og de dannede krystaller av N-/ 4- ((3-<2-metoksy-5-klor-benzamido>-etyl) -benzensulf onyl/-N ' - A mixture of 10.3 g of N_/ 4-(P-<2-methoxy-5-chloro-benzamido-ethyl)-benzenesulfonyl/-urea, 300 ml of toluene, 30 ml of glycol monomethyl ether, 1.65 g of glacial acetic acid and 4> 2 g of 4,7-methano-perhydro-indanyl-5-amine are heated for 5 hours under reflux. It is then evaporated in vacuo, the residue is treated with alcohol, and the formed crystals of N-/ 4-((3-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N ' -

(4,7-metano-perhydroindanyl-5)-urinstoff omkrystalliseres fra metanol (smeltepunkt 196°-198°C). (4,7-Methano-perhydroindanyl-5)-urea is recrystallized from methanol (melting point 196°-198°C).

Eksempel 3« N-/ 4-(p-^2-metoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N'-(4,7~ metano- perhydro- indanyI5)'- urinstof f. Example 3« N-/ 4-(p-^2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-(4,7~ methano-perhydro-indanyI5)'-urea f.

8,2 g N-/ 4-((3-acetamidoetyl) -benzensulfonyl/-N ' - 8.2 g of N-[4-((3-acetamidoethyl)-benzenesulfonyl]-N'-

(4,7-metano-perhydro-indanyl-5)-urinstoff oppvarmes med en oppløsning av 1,6 g natriumhydroksyd i-30 ml vann i 2 timer under tilbakeløp. (4,7-Methano-perhydro-indanyl-5)-urea is heated with a solution of 1.6 g of sodium hydroxide in 30 ml of water for 2 hours under reflux.

Man lar avkjøle til værelsestemperatur, blander med 20 ml aceton og 1,3 g iseddik, og tilsetter porsjonsvis 4>1 g 2-metoksy-5-klorbenzo-ylklorid. Etter 2 timers etteromrøring ved værelsestemperatur suges det fra utfellingen, behandles med bikarbonatoppløsning, og gjenutfelles deretter fra fortynnet ammoniakk/saltsyre. Det dannede N-/ 4~ ( f3-<2-metoksy-5-klorbenzamido>—etyl) -benzensulf onyl/-N ' - (4,7~ endometylen-perhydro-indanyl-5)-urinstoff smelter etter omkrystallisering fra metanol-dimetylfomamld ved 196°-198°C. Allow to cool to room temperature, mix with 20 ml of acetone and 1.3 g of glacial acetic acid, and add 4>1 g of 2-methoxy-5-chlorobenzoyl chloride in portions. After 2 hours of stirring at room temperature, the precipitate is sucked off, treated with bicarbonate solution, and then reprecipitated from dilute ammonia/hydrochloric acid. The formed N-/ 4~ ( f3-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N ' - (4,7~ endomethylene-perhydro-indanyl-5)-urea melts after recrystallization from methanol -dimethylformamide at 196°-198°C.

Eksempel 4-N-/ 4-(P-<2-metoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N ' -(4> 7-metano- 6- klor- perhydro- indanyI-' 3) - urinstoff. Example 4-N-/4-(P-<2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-(4>7-methano-6-chloro-perhydro-indanyl-'3)-urea .

7,'8 g N-/ 4-( p-/:2-metoksy-5-klorbenzamido>-etyI)-benzensulfonyl/-metyluretan (smeltepunkt l89°-191°C) suspenderes i 50 ml xylen og blandes med 2,7 g 4>7_metano-6-klor-perhydro-indanyl-5-amin (kokepunkt 8 mm 134°-138°C). Man oppvarmer reaksjonsblandingen i 2 timer til kokning, idet det ved reaksjonen dannede metanol avdestilleres, etter avdestillering av xylen i vakuum behandles residuet med sterkt fortynnet natronlut. Man frafUtrerer uoppløst og surgjør filtratet. Det dannede N-/ 4-((i-^2-metoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N *(4,7-metan°-6-klor-perhydro-indanyl-5)-urinstoff suges fra og omkrystalliseres fra vantidig dioksan. Stoffet smelter ved l89°-igi<0>C. 7.8 g of N-[4-(p-/:2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-methylurethane (melting point 189°-191°C) are suspended in 50 ml of xylene and mixed with 2, 7 g of 4>7-methano-6-chloro-perhydro-indanyl-5-amine (boiling point 8 mm 134°-138°C). The reaction mixture is heated to boiling for 2 hours, the methanol formed by the reaction being distilled off, after distilling off the xylene in a vacuum, the residue is treated with highly diluted caustic soda. One filters off undissolved and acidifies the filtrate. The formed N-/ 4-((i-^2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N *(4,7-methane°-6-chloro-perhydro-indanyl-5)-urea is sucked from and recrystallized from anhydrous dioxane The substance melts at l89°-igi<0>C.

Eksempel 5« N-/ 4-( (3-<2-metoksy-5-klorbenzamido>-etyl) -benzensulf onyl/-N '-(4,7-metano- perhydro- indanyl-^)- urinstoff. Example 5 N-[4-((3-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(4,7-methano-perhydro-indanyl-^)-urea.

5 g. 4- ( P-^2-metoksy-5-klorbenzamido-?-etyl) -benzensulfonamid oppløses i '] ml 2n natronlut og 50 ml aceton, og blandes ved 0-5°C dråpevis under omrøring med 2,7 g 3>4 metano-perhydro-indanyl-5-isocyanat. Man lar det etteromrøre i 3 timer, fortynner med vann og metanol, frafiltrerer uoppløst og surgjør filtratet med fortynnet saltsyre. Det utfelte N-/'4-(|3-<2-metoksy-5-klorbenzamido?-etyl)-benzensulfonyl/-N'-(4>7_metano-perhydro-indanyl-5)-urinstoff smelter etter omkrystallisering fra metanol ved ig6°-198 C. 5 g of 4-(β-2-methoxy-5-chlorobenzamido-?-ethyl)-benzenesulfonamide is dissolved in 1 ml of 2N caustic soda and 50 ml of acetone, and mixed at 0-5°C dropwise while stirring with 2.7 g 3>4 methano-perhydro-indanyl-5-isocyanate. It is left to stir for 3 hours, diluted with water and methanol, undissolved filtered off and the filtrate acidified with dilute hydrochloric acid. The precipitated N-/'4-(|3-<2-methoxy-5-chlorobenzamido?-ethyl)-benzenesulfonyl/-N'-(4>7_methano-perhydro-indanyl-5)-urea melts after recrystallization from methanol at ig6°-198 C.

På analog måte vil man Analogously, one will

av 4- ((3-<r3,4-diklorbenzamido>-etyl) -benzensulfonamid, smeltepunkt 171°-172°C, få: N-/ 4-(P-<3,4-diklorbenzamido>-etyl)-benzensulfonyl/N'-cyklohepten-(2)-yl-uronstoff, smeltepunkt 197°-199°C, (fra metanol/dimetylformamid) ; of 4-((3-<r3,4-dichlorobenzamido>-ethyl)-benzenesulfonamide, mp 171°-172°C, get: N-/ 4-(P-<3,4-dichlorobenzamido>-ethyl)-benzenesulfonamide /N'-cyclohepten-(2)-yl-uronic acid, melting point 197°-199°C, (from methanol/dimethylformamide);

av 4-(P—t2-metoksy-5-fluorbenzamido>-etyl)-benzensulfonamid, smeltepunkt 167°-169°C, få: of 4-(P—t2-methoxy-5-fluorobenzamido>-ethyl)-benzenesulfonamide, melting point 167°-169°C, obtain:

N-/ 4~(P-<2-metoksy-5-fluorbenzamido>-etyl)-benzensulfonyl/-N'-cyklo-hepten-(2)-yl-urinstoff, smeltepunkt 157° -159°C, (fra metanol); av 4-(P-<2-etoksy-5-metylbenzamido>-etyl)-benzensulfonamid, smeltep punkt 147°-148°C, få: N-/ 4~(P-<2-etoksy-5-metylbenzamido>-etyl)-benzensulfonyl/-N'-cyklo-hepten-(2)-yl-urinstoff, smeltepunkt l64°-l66°C, (fra metanol/dimetylformamid); N-/ 4~(P-<2-methoxy-5-fluorobenzamido>-ethyl)-benzenesulfonyl/-N'-cyclo-hepten-(2)-yl-urea, melting point 157° -159°C, (from methanol ); of 4-(P-<2-ethoxy-5-methylbenzamido>-ethyl)-benzenesulfonamide, mp 147°-148°C, obtain: N-/ 4~(P-<2-ethoxy-5-methylbenzamido>- ethyl)-benzenesulfonyl/-N'-cyclo-hepten-(2)-yl-urea, mp 164°-166°C, (from methanol/dimethylformamide);

Eksempel 6. N-/ 4-(p-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'-4j7~ metano- perhydro- indanyl- 5)- urinstoff. Example 6. N-[4-(p-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-4j7~ methano-perhydro-indanyl-5)-urea.

lg N-/ 4~(p-<2-metoksy-5-klor-benzamido?-etyl)-benzen-sulfonyl/-N'-4,7-metano-perhydro-indanyl-5)-riourinstoff, smeltepunkt 137°-139°C, oppløses i 100 ml metanol, hvortil man har satt 10 ml dioksan. Man tilsetter 1,1 g kvikksølvoksyd og omrører i 3 timer ved 50°-60°C. Etter frafiltrering av kvikksølvsulfid inndampes i vakuum. Det således dannede N-/ 4~(P-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'-(4,7~metano-perhydro-indanyl-5)-isourinstoffmetyleter suspenderes i 20 ml dioksan og 100 ml konsen-trert saltsyre. Man oppvarmer i 10 minutter på dampbad, heller ut i vann, frasuger utfellingen og omkrystalliserer fra metanol. lg N-/ 4~(p-<2-methoxy-5-chloro-benzamido?-ethyl)-benzenesulfonyl/-N'-4,7-methano-perhydro-indanyl-5)-riourea, melting point 137° -139°C, dissolve in 100 ml of methanol, to which 10 ml of dioxane has been added. 1.1 g of mercuric oxide is added and stirred for 3 hours at 50°-60°C. After filtering off mercuric sulphide, it is evaporated in a vacuum. The thus formed N-/ 4~(P-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-(4,7~methano-perhydro-indanyl-5)-isourea methyl ether is suspended in 20 ml of dioxane and 100 ml of concentrated hydrochloric acid. It is heated for 10 minutes in a steam bath, poured into water, the precipitate is sucked off and recrystallized from methanol.

Det dannede N-/ 4-(P-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'-(4,7-metano-perhydro-indanyl-5)-urinstoff smelter ved 196°-198°C. The formed N-/ 4-(P-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-(4,7-methano-perhydro-indanyl-5)-urea melts at 196° -198°C.

Eksempel 7» N-/ 4-(p-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'(4> 7_ metanoperhydro- indanyl- 5)- urinstoff. 1 g N-/ 4~(P-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'-(4,7-metano^perhydro-indanyl-5)-tiourinstoff, smeltepunkt 137°-139°C, suspenderes i 20 ml 2N natronlut og blandes med 5 ml 5%_1§ hydrogenperoksyd. Example 7» N-/ 4-(p-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'(4>7_methanoperhydro-indanyl-5)-urea. 1 g N-/ 4~(P-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-(4,7-methano^perhydro-indanyl-5)-thiourea, melting point 137° -139°C, suspended in 20 ml of 2N caustic soda and mixed with 5 ml of 5% hydrogen peroxide.

Mann oppvarmer i 15 minutter på dampbad, avkjøler Man heats up for 15 minutes in a steam bath, cools down

og surgjør. Man får en utfelling som man suger fra og vasker med vann. Det således dannede N-/ 4- (P-<2-metoksy-5-klor-benzamido>-etyl) - benzensulfonyl/-N'-(4,7-metano-perhydro-indanyl-5)-urinstoff smelter etter omkrystallisering fra metanol-dioksan ved 196°-198°C. and acidifies. You get a precipitate that you suck off and wash with water. The N-/ 4-(P-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-(4,7-methano-perhydro-indanyl-5)-urea thus formed melts after recrystallization from methanol-dioxane at 196°-198°C.

Samme forbindelse får man ved avsvovling av N-/ 4-([S-<2-metoksy-5-klor-benzamido?-etyl) -benzensulf onyl/-N ' - ( 4,7-metanoperhydro-indanyl-5)-tiourinstoff med kvikksølvoksyd. The same compound is obtained by desulfurization of N-[4-([S-<2-methoxy-5-chloro-benzamido?-ethyl)-benzenesulfonyl]-N'-(4,7-methaneperhydro-indanyl-5)- thiourea with mercuric oxide.

Eksempel 8. N-/ 4- ((3-^2-metoksy-5-klor-benzamido>-etyl) -benzensulf onyl/-N'-(3-met<y>l- c<y>klo<p>ent<y>l)- urinstoff. Example 8. N-/ 4-((3-^2-Methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-(3-meth<y>l- c<y>chloro<p >ent<y>l)- urea.

7,1 g 4-(P-<2-metoksy-5-klorbenzamido>-etyl)-benzensulf insyre og 3 g N-(3-metylcyklopentyl)-N'-hydroksyurinstoff suspenderes i 60 ml dioksan. Hertil drypper man langsomt 2 ml tionylklorid i 20 ml dioksan, oppvarmer blandingen 2 timer ved 60°C, av-kjøler og blander med vann. Den således dannede utfelling suges fra og oppløses i 1% ammoniakk. Oppløsningen filtreres og det etter surgjøring utfelte produkt omkrystalliseres av metanol. Man får N-/ 4-( p-<;2-metoksy-5-klor-benzamido>-etyl) -benzensulfonyl/-N '-(3~ metylcyklopentyl)-urinstoff av smeltepunkt 156-158°C. 7.1 g of 4-(P-(2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonic acid and 3 g of N-(3-methylcyclopentyl)-N'-hydroxyurea are suspended in 60 ml of dioxane. To this end, 2 ml of thionyl chloride is slowly dripped into 20 ml of dioxane, the mixture is heated for 2 hours at 60°C, cooled and mixed with water. The thus formed precipitate is sucked off and dissolved in 1% ammonia. The solution is filtered and the product precipitated after acidification is recrystallized from methanol. N-[4-(p-<;2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-N'-(3-methylcyclopentyl)-urea of melting point 156-158°C is obtained.

Eksempel 9- Example 9-

N-/ 4-( p-*2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'(3-metylcyklopentyl)- urinstoff. N-/ 4-( p -*2-Methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'(3-methylcyclopentyl)-urea.

2,5 g N-/ 4-(p-^2-metoksy-5-klor-tiobenzamido>-etyl)-benzensulf onyl/-N'-(3-metylcyklopentyl)-urinstof L1 oppløses i 15 ml Dissolve 2.5 g of N-/ 4-(p-^2-methoxy-5-chloro-thiobenzamido>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea L1 in 15 ml

2n natronlut og 20 ml dioksan, oppløsningen blande;; med noen dråper 30%-ig hydrogenperoksyd og oppvarmes 15 min. på dampbad. Man fortynner med vann og surgjør med fortynnet saltsyre. Det utskilte N-/ 4-(p-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'-(3-metyleyklopentyl)-urinstoff har et smeltepunkt på 156-158°C ( fra metanol). 2n caustic soda and 20 ml dioxane, the solution mix;; with a few drops of 30% hydrogen peroxide and heated for 15 min. in a steam bath. Dilute with water and acidify with dilute hydrochloric acid. The secreted N-/ 4-(p-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea has a melting point of 156-158°C (from methanol ).

Eksempel 10. N-/ 4-(P-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfonyl/-N'-(3-metylcyklopentyl)- urinstoff. Example 10. N-[4-(P-(2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-N'-(3-methylcyclopentyl)-urea.

6,8 g 4-(P-£2-metoksy-5-klorbenzoamido>-etyl)-benzensulf inylklorid (fremstilt av 4-(P~ 2-metoksy-5-klor-benzamid -etyl)-benzensulfinsyre og tionylklorid) innføres i en suspensjon av 2,8 g 3-metylcyklopentylurinstoff og 30 ml pyridin. Etter 10 minutter has blandingen i 100 ml isvann, som er blandet med 20 ml 2N saltsyre. 6.8 g of 4-(P-£2-methoxy-5-chlorobenzoamido>-ethyl)-benzenesulfinyl chloride (prepared from 4-(P~ 2-methoxy-5-chloro-benzamide -ethyl)-benzenesulfinic acid and thionyl chloride) are introduced in a suspension of 2.8 g of 3-methylcyclopentylurea and 30 ml of pyridine. After 10 minutes, the mixture is poured into 100 ml of ice water, which has been mixed with 20 ml of 2N hydrochloric acid.

Den dannede utfelling behandles med Ufo ammoniakk, residuet oppløses The formed precipitate is treated with Ufo ammonia, the residue is dissolved

i dimetylformamid og oppløsningen blandes under omrøring med en vanndig oppløsning av kaliumpermanganat, inntil brunsten og blander filtratet med vann og saltsyre. Det dannede N-/ 4-(p-<2-metoksy-5~ klor-benzamido>-etyl)-benzensulfonyl/-N *-(3-metylcyklopentyl)-urinstoff omkrystalliseres fra metanol og smelter ved 156-158°C. in dimethylformamide and the solution is mixed with stirring with an aqueous solution of potassium permanganate, until brown, and the filtrate is mixed with water and hydrochloric acid. The formed N-/ 4-(p-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N *-(3-methylcyclopentyl)-urea is recrystallized from methanol and melts at 156-158°C.

Eksempel 11. N-/~4- ((3-<2-metoksy-5-klor-benzamido>-etyl) -benzensulf onyl/-N ' - (3-metylcyklopentyl)- urinstoff. Example 11. N-[4-((3-<2-Methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea.

2,5 g N-/ 4- ((3-^2-metoksy-5-klor-benzamido>-etyl) - benzensulfonyl/-N<*->(3-mety1-2-cyklopenten-1-yl)-urinstoff (smp. 159-l6l°C. Fremstilt av 4-(p-^2-metoksy-5-klor-benzamido>-etyl)-benzensulf onyl/-metyluretan og 3-metyl-2-cyklopenten-l-ylamin)-oppløses i 2.5 g of N-/4-((3-^2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N<*->(3-methyl-2-cyclopenten-1-yl)- urea (m.p. 159-161°C. Prepared from 4-(p-^2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-methylurethane and 3-methyl-2-cyclopenten-1-ylamine) -dissolves in

150 ml metanol og noe dimetylformamid. Man hydrogenerer i nærvær av Pd-C-katalysator ved værelsestemperatur og normaltrykk, inntil hydrogen-opptaket er avsluttet. Katalysatoren frafUtreres, oppløsningsmidlet avdestilleres for det meste under nedsatt trykk, residuet blandes med vann, det utfelte produkt gjenutfelles fra Ufo ammoniakk og omkrystalliserer fra metanol. Det dannede N-/ 4~(P—£2-metoksy-5-klor-benzamido? -etyl)-benzensulfonyl/-N'-(3-metylcyklopentyl)-urinstoff smelter ved 156-158°C. 150 ml of methanol and some dimethylformamide. Hydrogenation is carried out in the presence of a Pd-C catalyst at room temperature and normal pressure, until the hydrogen uptake has ended. The catalyst is filtered off, the solvent is mostly distilled off under reduced pressure, the residue is mixed with water, the precipitated product is reprecipitated from UFO ammonia and recrystallized from methanol. The formed N-[4-(P-[2-methoxy-5-chloro-benzamido?-ethyl)-benzenesulfonyl]-N'-(3-methylcyclopentyl)-urea melts at 156-158°C.

' Eksempel 12. N-/ 4- ( p-<:2-metoksy-5-klor-benzamido>-etyl-benzensulf onyl/-N * - (3-metylcyklopentyl)- urinstoff. Example 12. N-[4-(p-<:2-methoxy-5-chloro-benzamido>-ethyl-benzenesulfonyl]-N*-(3-methylcyclopentyl)-urea.

4)9 g I-( 3-metylcyklC)pentyl)-parabansyre suspenderes i 200 ml benzen. Hertil har man 2,5 g trietylamin og deretter 8,9 g 4~(P-<2-metoksy-5-klor-benzamido>-etyl)-benzensulfoklorid. Blandingen oppvarmes 3 timer under tilbakeløp, filtreres varmt, det avkjølte filtrat blandes med petroleter og det utskilte stoff suges fra, oppvarmes med 50 ml dioksan og 100 ml IN natronlut i 3° minutter på dampbad, oppløsningen filtreres og blandes med vann og saltsyre. Det utskilte N-/ 4~( P-*2-metoksy-5-klor-benzamido;>-etyl)-benzensulfonyl/-N'-(3-metylcyklopentyl)-urinstoff omkrystalliseres fra mentol og smelter ved 156-158°C. 4) 9 g of I-(3-methylcyclC)pentyl)-parabanic acid are suspended in 200 ml of benzene. To this, you have 2.5 g of triethylamine and then 8.9 g of 4~(P-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfochloride. The mixture is heated for 3 hours under reflux, filtered hot, the cooled filtrate is mixed with petroleum ether and the separated substance is sucked off, heated with 50 ml dioxane and 100 ml IN caustic soda for 3° minutes on a steam bath, the solution is filtered and mixed with water and hydrochloric acid. The separated N-/ 4~( P-*2-methoxy-5-chloro-benzamido;>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea is recrystallized from menthol and melts at 156-158°C .

Eksempel 13-N-/~4- ((3— <:2-metoksy-5-klor-benzamido>-etyl) -benzensulf onyl/-N * -(3-metylcyklopentyl)- urinstoff. Example 13-N-[4-((3- <:2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl/-N*-(3-methylcyclopentyl)-urea.

7,1 g 3_metylcyklopentylurinstoff suspenderes i 7.1 g of 3-methylcyclopentylurea are suspended in

100 ml absolutt benzen og blandes med 2,4 g 50% natriumhydrid, Man omrører i 3 timer ved 50°C , blander med 9,7 g 4_(P-<2-metoksy-5~klor-benzamido>-etyl)-benzensulfoklorid i 100 ml absolutt benzen og etter-omrører i 3 timer ved 80°C. Man lar det avkjøle, utryster reaksjonsblandingen flere ganger med vann og surgjør de forenede vanndige ekstrakter med saltsyre. Det utfelte reaksjons produkt gjenutfelles fra lfo ammoniakk og omkrystalliseres fra metanol. N-/ 4- ({3~^2-metoksy-5-klorbenzamido>-etyl)-benzensulfonyl/-N'-(3-metylcyklopentyl)-urinstoff smelter ved 156-158°C. 100 ml of absolute benzene and mix with 2.4 g of 50% sodium hydride. Stir for 3 hours at 50°C, mix with 9.7 g of 4_(P-<2-methoxy-5~chloro-benzamido>-ethyl)- benzene sulphochloride in 100 ml of absolute benzene and after-stirring for 3 hours at 80°C. It is allowed to cool, the reaction mixture is shaken several times with water and the combined aqueous extracts are acidified with hydrochloric acid. The precipitated reaction product is reprecipitated from lfo ammonia and recrystallized from methanol. N-/ 4-({3-^2-Methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-urea melts at 156-158°C.

Eksempel 14» Example 14»

N-/ (3- 5-klor-2-metoksy-benzamido->etyl) -benzensulfonyl/-N '-(3-metyl-cyklopentyl)- urinstoff. N-(3-5-chloro-2-methoxy-benzamido->ethyl)-benzenesulfonyl/-N'-(3-methyl-cyclopentyl)-urea.

2.55 g (=1/200 mol) N-/ 4-(p-<5-klor-2-metoksy-benzamido?-etyl)-benzensulfonyl/-N'-(3-metylcyklopentyl)-tiourinstoff og I.03 g (=l/200 mol) dicykloheksylkarbomiimid oppløses i 20 ml absolutt dioksan og hensettes natten voer. Man blander oppløsningen etter filtrering fra blandet dicykloheksyltiourinstoff med 10 ml vann og oppvarmer 10 minutter på dampbad. Under nedsatt trykk fjernes oppløsningsmidlet. Residuet blandes med toluen og eter og uttrekkes 3 ganger med hver gang 300 ml 0.25%-ig vanndig ammoniakk. Den 2.55 g (=1/200 mol) N-/ 4-(p-<5-chloro-2-methoxy-benzamido?-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-thiourea and 1.03 g (=1/200 mol) dicyclohexylcarbomiimide is dissolved in 20 ml of absolute dioxane and allowed to stand overnight. The solution after filtration from mixed dicyclohexylthiourea is mixed with 10 ml of water and heated for 10 minutes in a steam bath. The solvent is removed under reduced pressure. The residue is mixed with toluene and ether and extracted 3 times with each time 300 ml of 0.25% aqueous ammonia. It

vanndige fase adskilles, filtreres, og filtratet surgjøres med fortynnet saltsyre. Man frasuger, behandler produktet med litt metanol og frasuger igjen. aqueous phase is separated, filtered, and the filtrate acidified with dilute hydrochloric acid. You vacuum, treat the product with a little methanol and vacuum again.

De således dannede N-/ 4_(P-<5~klor-2-metoksy-benzamido>-etyl)-benzensulfonyl/-N'-(3-metylcyklopentyl)-urinstoff omkrystalliseres fra metanol og smelter ved 156-158°C. The thus formed N-/ 4_(P-<5~chloro-2-methoxy-benzamido>-ethyl)-benzenesulfonyl/-N'-(3-methylcyclopentyl)-ureas are recrystallized from methanol and melt at 156-158°C.

Eksempel 15-N-/ 4-( {3- C2.-metoksy-5-klor-benzamido>-etyl) -benzensulf onyl/-N '- ( 3-metylcyklopentyl)- urinstoff. Example 15-N-[4-({3-C2.-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-N'-(3-methylcyclopentyl)-urea.

1.95 S N-/ 4~( |3-^2-metoksy-5-klor-tiobenzamido - 1.95 S N-/ 4~( |3-^2-methoxy-5-chloro-thiobenzamido -

etyl)-benzensulfonyl/-N<*->(3-metylcyklopentyl)-urinstoff oppvarmes med 50 ml metanol, 5 ml dioksan og 2,5 ml metyljodid i 2 timer under tilbakeløp til kokning. Deretter avdestillerer man oppløsningsmidlet og oppløser residuet i fortynnet natronlut. Man oppvarmer kort på ethyl)-benzenesulfonyl/-N<*->(3-methylcyclopentyl)-urea is heated with 50 ml of methanol, 5 ml of dioxane and 2.5 ml of methyl iodide for 2 hours under reflux to boiling. The solvent is then distilled off and the residue dissolved in diluted caustic soda. You heat up briefly

dampbad, filtrerer og surgjør. Det utfelte N-/ 4-((3-<2-metoksy-5-klor-benzamidei-etyl)-benzensulfonyl/-N *-(3-metylcyklopentyl)-urin- steam bath, filters and acidifies. The precipitated N-/ 4-((3-<2-methoxy-5-chloro-benzamidei-ethyl)-benzenesulfonyl/-N *-(3-methylcyclopentyl)-urine-

stoff omkrystalliseres av metanol og smelter ved 156-158°C. substance is recrystallized from methanol and melts at 156-158°C.

Claims

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

where R^" means 4,7-endomethylene-perhydroindan~5-yl which is optionally substituted with chlorine in the 6-position, 2,6-endomethylene-cycloheptyl, 4,4-dimethyl-α o -cyclohexenyl, A 2 -cyclopentenyl, A 2 -cycloheptenyl, A <2->cyclooctenyl, methyl-cyclopentyl, 3,3-dimethyl-cyclopentyl-, 3-ethyl-cyclopentyl, 3-tert-butyl-cyclopentyl, 2-chloro-cyclopentyl, or 5-methyl-A p-cyclohexenyl, and Z and Z', which are the same or different, mean hydrogen, halogen, lower alkyl or lower alkoxy, characterized in that a) an amine of formula R^NI-^ or a salt thereof reacts with benzenesulfonyl isocyanates, -carbamic acid esters, -thiolcarbamic acid esters, -carbamic acid halides, -ureas, -semi-carbazides or semicarbazones which are substituted in the para-position in the benzene nucleus with a substituent of the general formula b) reacts benzenesulfonamides of formula or salts thereof, with R -^-substituted isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas,. or c) hydrolyzes N-benzenesulfonylisourea ethers, -isothiourea ethers, -isourea esters, -parabanic acids or -haloformic acid amidines which are substituted in the benzene nucleus with the group and are substituted in the N' position with the group R-p or dt exchanges the sulfur atom in the urea residue in benzenesulfonylthiourea f corresponds to the benzenesulfonylureas of formula I with an oxygen atom, or e) adds water to carbodiimides of the general formula f) oxidizes benzenesulfinyl or benzenesulfonyl urea corresponds to the benzenesulfonylureas of formula I, or g) introduces, possibly step by step, x the residue in benzenesulfonylureas of formula by acylation, or h) converts benzenesulfonylureas which are substituted in the para position with the group of ureas which are substituted with the group R-^, or alkali salts thereof, or i) converts into benzenesulfonylureas of formula I corresponding to benzenesulfinyl halides or in the presence of acidic condensing agents benzenesulfinic acids or alkali salts thereof with hydroxyureas substituted by the group R^, or k) exchanges the sulfur atom or the sulfur atoms in thioamidoalkylbenzenesulfonylureas or -thioureas corresponding to the benzenesulfonylureas of formula I with oxygen, or 1) saponifies compounds of formula or their parabanic acid derivatives of formula or compounds of formula where U means one of the groups -O-lower alkyl, -S-lower alkyl or halogen, preferably chlorine, or m) hydrogenates to benzenesulfonylureas of formula I corresponding compounds which in the molecule contain one or more double bonds of a non-aromatic character, and transform are possibly the reaction products of salts with alkaline agents.