NO122416B

NO122416B -

Info

Publication number: NO122416B
Application number: NO171025A
Authority: NO
Inventors: H Weber; W Aumueller; R Weyer; K Muth; F Schmidt
Original assignee: Hoechst Ag
Priority date: 1966-12-19
Filing date: 1967-12-18
Publication date: 1971-06-28
Also published as: GB1212695A; AT276433B; MC697A1; CU33297A; AT276425B; DE1568648B2; MY7200014A; CY618A; SU366606A3; DE1568648C3; AT276435B; AT276432B; AT291275B; AT289135B; BE708212A; NL6716110A; LU55101A1; SE344061B; CH509279A; FI45964B

Description

Fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer med sterk og protrahert blodsukkersenkende virkning. Process for the production of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect.

Oppfinnelsens gjenstand er en fremgangsmåte til fremstilling av oralt anvendbare benzolsulfonylurinstoffer med sterk og protrahert blodsukkersenkende virkning og med den generelle formel The object of the invention is a process for the production of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect and with the general formula

samt deres salter, hvori as well as their salts, wherein

R betyr alkyl eller alkenyl med 1-4 C-atomer i alkyl restp. R means alkyl or alkenyl with 1-4 C atoms in the alkyl residue.

alkenyIdelen, fortrinnsvis metyl,the alkenyl moiety, preferably methyl,

R betyrR stands for

a) alkyl eller alkenyl med hver 3-6 karbonatomer,a) alkyl or alkenyl with each 3-6 carbon atoms,

b) fenylalkyl med 1-4 C-atomer i alkyldelen,b) phenylalkyl with 1-4 C atoms in the alkyl part,

c) cykloheksylalkyl med 1-4 C-atomer i alkyldelen, cyklo-heptylmetyl, cykloheptyletyl eller cyklooktylmetyl, d) endoalkylencykloheksyl, endoalkylencykloheksenyl, endoalkylencykloheksylmetyl eller endoalkylencyklo-heksenylmetyl med 1-2 endoalkylenkarbonatomer, e) alkylcykloheksyl med 1-4 C-atomer i alkyldelen, alkoksycykloheksyl med 1-4 C-atomer i alkyldelen, c) cyclohexylalkyl with 1-4 C atoms in the alkyl part, cycloheptylmethyl, cycloheptylethyl or cyclooctylmethyl, d) endoalkylenecyclohexyl, endoalkylenecyclohexenyl, endoalkylenecyclohexylmethyl or endoalkylenecyclohexenylmethyl with 1-2 endoalkylene carbon atoms, e) alkylcyclohexyl with 1-4 C atoms in the alkyl part , alkoxycyclohexyl with 1-4 C atoms in the alkyl part,

f) cykloalkyl 5 til 8 karbonatomer,f) cycloalkyl 5 to 8 carbon atoms,

g) cykloheksenyl, cykloheksenylmetyl,g) cyclohexenyl, cyclohexenylmethyl,

•JCbetyr acyl med 1-4 C-atomer, nitro, trifluormetyl, fenyl eller •JC means acyl with 1-4 C atoms, nitro, trifluoromethyl, phenyl or

benzyl,benzyl,

Y betyr -CH2-CH2-, -CHCCH^-CI^- eller -CH2-CH(CH3)- ellerY means -CH2-CH2-, -CHCCH^-CI^- or -CH2-CH(CH3)- or

deres salter, idet fremgangsmåten erkarakterisert vedat man enten their salts, as the method is characterized by either

a) omsetter benzolsulfonylisocyanater, -karbaminsyreestere, -tiolkarbaminsyreestere, -karbaminsyrehalogenider, -urinstoffer, -semi-karbazider eller -semikarbazoner som i p-stilling er substituert med gruppen a) reacts benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters, -carbamic acid halides, -ureas, -semi-carbazides or -semicarbazones which are substituted in the p-position with the group

med aminer, som er substituert med gruppen R eller deres salter, eller with amines, which are substituted with the group R or their salts, or

b) omsetter sulfonamider med formelb) reacts sulfonamides with formula

eller deres salter med isocyanater, karbaminsyreestere, tiolkarbaminsyreestere, karbaminsyrehalogenider eller urinstoffer som er substituert med gruppen R1 eller c) hydrolyserer N-benzolsulfonylisourinstoffetere, -isourinstoffestere, -isotiourinstoffetere, -parabansyrer eller -halogenmaursyreamidiner, som i benzolkjernen er substituert med gruppen or their salts with isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas which are substituted with the group R1 or c) hydrolyze N-benzenesulfonylisourea ethers, -isourea esters, -isothiourea ethers, -parabanic acids or -haloformic acid amidines, which in the benzene ring are substituted with the group

og i N'-stilling er substituert med gruppen R^ eller and in the N' position is substituted with the group R^ or

d) omsetter benzolsulfonylhalogenider som er substituert med gruppen d) reacts benzenesulfonyl halides which are substituted with the group

med urinstoffer som er substituert med gruppen R"*", spesielt deres with ureas substituted with the group R"*", especially their

alkalisalter, elleralkali salts, or

e) omsetter benzolsulfinsyrehalogenider som er substituert med gruppen e) reacts benzenesulfinic acid halides which are substituted with the group

eller i nærvær av syrekondensasjonsmidler også de tilsvarende substituerte benzolsulfinsyrer eller deres alkalisalter med hydroksyurinstoffer, hvis NR^-gruppe er substituert med R"1", eller or in the presence of acid condensing agents also the corresponding substituted benzenesulfinic acids or their alkali salts with hydroxyureas, whose NR^ group is substituted by R"1", or

f) tilleirer vann til karbodiimider med den generelle formelf) adds water to carbodiimides of the general formula

eller or

g) utveksler svovelatomet i benzolsulfonyl-tiourinstoffer som svarer til benzolsulfonylurinstoffer med formel I med et oksygenatom g) exchanges the sulfur atom in benzenesulfonylthioureas corresponding to benzenesulfonylureas of formula I with an oxygen atom

elleror

h) oksyderer benzolsulfinyl- resp. -sulfenylurinstoffer som svarer til benzolsulfonylurinstoffer med formel I eller h) oxidizes benzenesulfinyl or -sulfenylureas corresponding to benzenesulfonylureas of formula I or

i) hydrerer benzolsulfonylurinstoffer som svarer til benzolsulf onylurinstof f er med formel I og som i molekylet inneholder olefinisk umettede bindinger, eller i) hydrates benzenesulfonylureas which correspond to benzenesulfonylureas of formula I and which in the molecule contain olefinically unsaturated bonds, or

k) i benzolsulfonylurinstoffer med formelk) in benzenesulfonylureas of formula

ved acylering, eventuelt trinnvis på kjent måte innfører resten by acylation, possibly step by step in a known manner introducing the residue

eller or

1) utveksler svovelatomet eller -atomene i tiobenzamido-alkylbenzol-sulfonylurinstoffer eller -tiourinstoffer som svarer til benzolsulf onylurinstof f er med formel I med et oksygenatom resp. oksygenatomer, eller 1) exchanges the sulfur atom or atoms in thiobenzamido-alkylbenzene-sulfonylureas or -thioureas that correspond to benzolsulfonylureas f is of formula I with an oxygen atom resp. oxygen atoms, or

m) forsåper forbindelser med formelm) saponify compounds of formula

eller deres parabansyrederivater eller forbindelser med formel or their parabanic acid derivatives or compounds of formula

idet U hver gang betyr en av gruppene -0- lavmolekylært alkyl-, where U each time means one of the groups -0- low molecular weight alkyl-,

-S- lavmolekylært alkyl eller halogen (fortrinnsvis klor), og eventuelt omsetter dannede forbindelser med en base for saltdannelse. -S- low molecular weight alkyl or halogen (preferably chlorine), and optionally reacts formed compounds with a base for salt formation.

Substituent X befinner seg i 4- eller fortrinnsvis 5-stilling til karbonamidgruppøn. Substituent X is in the 4- or preferably 5-position to the carbonamide group.

Tilsvarende ovennevnte definisjoner kan R eksempelvis bety: metyl, etyl, propyl, iaopropyl, butyl, isobutyl, tert.butyl, allyl. Corresponding to the above definitions, R can mean, for example: methyl, ethyl, propyl, iopropyl, butyl, isobutyl, tert.butyl, allyl.

R<1>kan eksempelvis bety: propyl, isopropyl, butyl, isobutyl, sek.butyl, rettlinjet eller forgrenet amyl (pentyl), heksyl, allyl, videre kommer det som R<1>på tale: benzyl, ot-fenyletyl, 3-fenyletyl. Spesielt foretrukket, er innen oppfinnelsens ramme slike forbindelser som som R<1>inneholder en p^kloalifatisk, eventuelt med alkyl, resp. alkoksy substituert hy&isolea<y>boOTest. Som slike rester skal eksempelvis nevnes: cyklopentyl, cykloheksyl, cykloheptyl, cyklooktyl, metylcykloheksyl, etylcykloheksyl, metoksycykloheksyl, etoksycykloheksyl, idet alkyl- resp. alkoksygruppene kan foreligge i 2-, 3~eller fortrinnsvis i 4-stilling, nemlig såvel i cis- som også i trans-stilling. Cykloheksylmetyl, a- eller g-cykloheksyletyl, endometylencykloheksyl (2,2,1-bicykloheptyl), endoetylencykloheksyl R<1> can mean, for example: propyl, isopropyl, butyl, isobutyl, sec.butyl, straight or branched amyl (pentyl), hexyl, allyl, further R<1> is mentioned: benzyl, o-phenylethyl, 3 -phenylethyl. Particularly preferred, within the scope of the invention, are such compounds which, as R<1>, contain a p^chloroaliphatic, optionally with alkyl, resp. alkoxy substituted hy&isolea<y>boOTest. Examples of such residues should be mentioned: cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, methylcyclohexyl, ethylcyclohexyl, methoxycyclohexyl, ethoxycyclohexyl, as alkyl- or the alkoxy groups can be present in the 2-, 3- or preferably in the 4-position, namely both in the cis- and also in the trans-position. Cyclohexylmethyl, a- or g-cyclohexylethyl, endomethylenecyclohexyl (2,2,1-bicycloheptyl), endoethylenecyclohexyl

(2,2,2-bicyklooktyl), endometylencykloheksenyl, endoetylencyklo-heksenyl, endometylencykloheksylmetyl, endoetylencykloheksylmetyl, endometyléncykloheksenylmetyl eller endoetylencykloheksenylmetyl. (2,2,2-bicyclooctyl), endomethylenecyclohexenyl, endoethylenecyclohexenyl, endomethylenecyclohexylmethyl, endoethylenecyclohexylmethyl, endomethylenecyclohexenylmethyl or endoethylenecyclohexenylmethyl.

De nevnte benzolsulfonyl-karbaminsyreestere, resp. -tiolkarbaminsyreestere kan i alkoholkomponenten ha en alkylrest eller en arylrest eller også en heterocyklisk rest. Da denne rest avspaltes ved reaksjonen har dens kjemiske konstitusjon ingen inn-virkning på sluttproduktets karakter, og kan derfor varieres innen vide grenser. Det samme gjelder for de F^-substituerte karbaminsyreestere, resp. de tilsvarende tiolkarbaminsyreestere. The mentioned benzenesulfonyl-carbamic acid esters, resp. -thiocarbamic acid esters can have an alkyl residue or an aryl residue or also a heterocyclic residue in the alcohol component. As this residue is split off during the reaction, its chemical constitution has no effect on the character of the final product, and can therefore be varied within wide limits. The same applies to the F^-substituted carbamic acid esters, resp. the corresponding thiolcarbamic acid esters.

Som karbaminsyrehalogenider egner det seg i første rekke As carbamic acid halides, it is primarily suitable

kloridene.the chlorides.

De som utgangsstoffer for fremgangsmåten aktuelle Those as starting materials for the procedure in question

benzolsulfonylurinstoffer kan på den side av urinstoffmolekylet som vender bort fra sulfonylgruppen være usubstituert eller være 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 benzenesulfonylureas 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 heterocyclic

substituerte benzolsulfonylurinstoffer kan man også anvende bis-(benzolsulfonyl)-urinstoffer som ved et av nitrogenatomene dessuten substituted benzenesulfonylureas, you can also use bis-(benzenesulfonyl)ureas which, at one of the nitrogen atoms, also

kan ha en ytterligere substituent, f.eks. metyl. Man kan eksempelvis behandle slike bis-(benzolsulfonyl)-urinstoffer eller også N-benzolsulfonyl-N<1->acylurinstoffer med R<1->substituerte aminer og oppvarme may have a further substituent, e.g. methyl. One can, for example, treat such bis-(benzenesulfonyl)ureas or also N-benzenesulfonyl-N<1->acylureas with R<1->substituted amines and heating

de dannede salter til forhøyede temperaturer, spesielt slike over they formed salts at elevated temperatures, especially those above

100°C. 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

eller fra slike urinstoffer som ved det frie nitrogenatom dessuten er en- eller spesielt to-ganger substituert, og å omsette disse med gruppen or from such urea substances which are additionally substituted once or especially twice at the free nitrogen atom, and reacting these with the group

-substituerte benzolsulfonamider. Som slike utgangsstoffer, kommer det eksempelvis på tale N-cykloheksyl- eller N-(4-metyl-cykloheksyl)-urinstoffer, de tilsvarende N<1->acetyl-, N<*->nitro-, N'-cykloheksyl-, Nf<->(4-metyl-cykloheksyl)-, NJN<*->difenyl- (idet de to fenylrester også kan være substituert såvel som forbundet med hverandre direkte eller -substituted benzenesulfonamides. Such starting substances include, for example, N-cyclohexyl or N-(4-methyl-cyclohexyl)-ureas, the corresponding N<1->acetyl-, N<*->nitro-, N'-cyclohexyl-, Nf<->(4-methyl-cyclohexyl)-, NJN<*->diphenyl- (since the two phenyl residues can also be substituted as well as connected to each other directly or

også over et broledd som -CH2~, -NH-, -0- eller -S-), N'-metyl-N'-fenyl-, NJN<*->dicykloheksylurinstoffer såvel som Y-substituerte cyklo-heksylkarbamoylimidazoler eller -triazoler. also over a bridge link such as -CH2~, -NH-, -0- or -S-), N'-methyl-N'-phenyl-, NJN<*->dicyclohexylureas as well as Y-substituted cyclohexylcarbamoylimidazoles or -triazoles .

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

Omsetningen av benzolsulfohalogenider med R^-substituerte urinstoffer foregårhensiktsmessig under anvendelse av sterkt basiske kondensasjonsmidler som alkalimetaller, alkaliamider eller fortrinnsvis -hydrider i indifferente oppløsniirgsmidler. The reaction of benzenesulfohalides with R 1 -substituted ureas conveniently takes place using strongly basic condensing agents such as alkali metals, alkali amides or preferably -hydrides in indifferent solvents.

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

Erstatningen av tiourinstoff med svovelatom med et oksygenatom i de tilsvarende substituerte benzolsulfonyl-tiourinstoffer kan foregå på kjent måte, f.eks., ved hjelp av oksyder eller salter av tungmetaller eller også ved anvendelse av oksydasjonsmidler som hydrogenperoksyd, natriumperoksyd eller salpetersyrling. The replacement of thiourea with a sulfur atom by an oxygen atom in the correspondingly substituted benzenesulfonyl-thioureas can take place in a known manner, for example, by means of oxides or salts of heavy metals or also by the use of oxidizing agents such as hydrogen peroxide, sodium peroxide or nitric acid.

Tiourinstoffene kan også avsvovles ved behandling med fosgen eller fosforpentaklorid. Som mellomtrinn dannede klormaursyre-amidiner, resp. -karbodiimider kan ved egnede forholdsregler som forsåpning eller tilleiring av vann overføres i benzolsulfonylurinstoffene. The thioureas can also be desulphurised by treatment with phosgene or phosphorus pentachloride. As an intermediate step, chloroformate amidines formed, resp. -carbodiimides can be transferred into the benzenesulfonylureas by suitable precautions such as saponification or addition of water.

Oksydasjonen av benzolsulfinyl-resp. sulfenylurinstoffer kan gjennomføres med de kjente oksydasjonsmidler som f.eks. kalium- permanganat i indifferente oppløsningsmidler. The oxidation of benzenesulfinyl-resp. Sulphenylureas can be carried out with the known oxidizing agents such as e.g. potassium permanganate in indifferent solvents.

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

kan ved hydrering, f.eks. med molekylært hydrogen i nærvær av en kjent hydreringskatalysator overføres i benzolsulfonylurinstoffene ifølge oppfinnelsen. can by hydration, e.g. with molecular hydrogen in the presence of a known hydrogenation catalyst is transferred in the benzenesulfonylureas according to the invention.

Acyleringen av aminoalkylbenzolsulfonylurinstoffer kan enten utføres i et trinn, f.eks. ved omsetning av tilsvarende substituerte benzosyrehalogenider, den kan også utføres i flere trinn. The acylation of aminoalkylbenzenesulfonylureas can either be carried out in one step, e.g. by reacting correspondingly substituted benzoic acid halides, it can also be carried out in several steps.

Svovelatomets erstatning i tilsvarende substituerte tio-benzamidoalkylbenzolsulf onylurinstoffer eller -tiourinstoffer med oksygenatomer kan eksempelvis utføres ved hjelp av oksydasjonsmidler som hydrogenperoksyd, natriumperoksyd eller andre peroksydforbindelser. The replacement of the sulfur atom in correspondingly substituted thio-benzamidoalkylbenzenesulfonylureas 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.

Istedenfor tiobenzamidoalkylbenzolsulfonylurinstoffer,Instead of thiobenzamidoalkylbenzenesulfonylureas,

kan også tilsvarende tiobenzamidoalkylbenzolsulfonylisotiourinstoff-etere, -isourinstoffetere, resp. -estere, -parabansyrer eller -halogenmaursyreamidiner avsvovles ved behandling med oksydasjonsmidler i surt eller alkalisk miljø under samtidig hydrolytisk fri-gjøring av sulfonylurinstoffgrupperingen til benzamidoalkylbenzol-sulfonylurinstoffer. can also correspond to thiobenzamidoalkylbenzenesulfonyl isothiourea ethers, isourea ethers, resp. -esters, -parabanic acids or -haloformic amidines are desulphurized by treatment with oxidizing agents in an acidic or alkaline environment with simultaneous hydrolytic release of the sulfonylurea grouping to benzamidoalkylbenzene-sulfonylureas.

kan generelt variere sterkt med hensyn til reaksjonsbetingelsene og tilpasses de eventuelle forhold. Eksempelvis kan omsetningen gjennom-føres i fravær eller nærvær av oppløsningsmidler ved værelsetemperatur eller forhøyet temperatur. can generally vary greatly with regard to the reaction conditions and can be adapted to any conditions. For example, the reaction can be carried out in the absence or presence of solvents at room temperature or elevated temperature.

Alt etter utgangsstoffen.es karakter kan en eller annen av de omtalte fremgangsmåter i enkelte tilfeller gi et ønsket individuelt benzolsulfonylurinstoff bare i små utbytter, og ikke være egnet til dets syntese. I slike forholdsvis sjelden opptredende tilfeller byr det for fagfolk ingen vanskeligheter å syntetisere det ønskede pro-dukt på en annen av de omtalte fremgangsmåter. Depending on the nature of the starting material, one or another of the described methods may in some cases give a desired individual benzenesulfonylurea only in small yields, and not be suitable for its synthesis. In such relatively rarely occurring cases, there are no difficulties for experts in synthesizing the desired product using another of the mentioned methods.

Utgangsstoffenes fremstilling foregår etter generelt kjente metoder. Således kan eksempelvis som utgangsmateriale anvendte benzolsulfonamider som ved benzolkjernen er substituert med resten The production of the starting materials takes place according to generally known methods. Thus, for example, benzenesulfonamides can be used as starting material which have been substituted by the residue at the benzene nucleus

fåes ved omsetning av de tilsvarende benzolforbindelser med klor-sulfonsyre og deretter med ammoniakk, eller ved acylering av amino-forbindelser med formel are obtained by reacting the corresponding benzene compounds with chlorosulfonic acid and then with ammonia, or by acylating amino compounds with the formula

med tilsvarende syreklorider. with corresponding acid chlorides.

Som utgangsmateriale anvendte benzolsulfonyluretaner og -urinstoffer kan eksempelvis fåes av benzolsulfonamider og halogen-maursyrealkylestere, resp. kaliumcyanat (KOCN). Benzenesulfonyl urethanes and ureas used as starting materials can, for example, be obtained from benzenesulfonamides and halogen-formic acid alkyl esters, resp. potassium cyanate (KOCN).

De omtalte benzolsulfonylurinstoffderivaters blodsukkersenkende virkning kunne fastslås ved at man foret dem i doser på 10 mg/kg til kaniner, og bestemte blodsukkerverdien etter den kjente metode av Hagedorn-Jensen eller med en autoanalysør over et lengre tidsrom. The blood sugar-lowering effect of the mentioned benzenesulfonylurea derivatives could be determined by feeding them in doses of 10 mg/kg to rabbits, and determining 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 at 10 mg/kg N-/—4-(3-<2-metoksy-4-trifluormetylbenzamiclo>-etyl)-benzolsulfonyl7-N' - (4-metyl-cykloheksyl)-urinstoff etter 3 !fcimer bevirker en blodsukkersenkning på l6#, som etter 24 timerfisågar utgjør 2535, og først etter 48 timer igjen er sunket til nullveMien. Thus, for example, it was determined that 10 mg/kg N-(4-(3-<2-methoxy-4-trifluoromethylbenzamiclo>-ethyl)-benzenesulfonyl7-N'-(4-methyl-cyclohexyl)-urea after 3 causes a drop in blood sugar of l6#, which after 24 hours amounts to 2535, and only after 48 hours again has it dropped to the zero level.

På samme måte bevirker IQ ag M-/¥-(B-<2-etoksy-5-acetyl-benzamido>-etyl)-benzolsulf onyl7-N'-(|^9jcfj4oyJKl0heksyl)--urin8tof f etter 3 timer en blodsukkersenkning crøsfcpsnt 32g som etter 24 timer ennå utgjør 2135, mens det kjente N-/¥-mefcj?ll)Qnzol8uifonyl7-N'-butylurin- stoff med en dosering på mindre enn 25 mg/kg til kaniner ikke frem-bringer noen senkning av blodsukkerspeilet mer. In the same way, IQ ag M-/¥-(B-<2-ethoxy-5-acetyl-benzamido>-ethyl)-benzenesulfonyl7-N'-(|^9jcfj4oyJKl0hexyl)--urin8tof f after 3 hours causes a blood sugar lowering crøsfcpsnt 32g which after 24 hours still amounts to 2135, while the known N-/¥-mefcj?ll)Qnzol8ufonyl7-N'-butylurea with a dosage of less than 25 mg/kg to rabbits does not produce any further lowering of the blood sugar level .

De omtalte benzolsulfonylurinstoffers sterke virkning blir spesielt tydelig når man ytterligere nedsetter dosen. Administrerer man N-/~~4-({3- ( 2-metoksy-5-acetylbenzamido^-etyl)-benzolsulfonyl7-N»-(4-metyl-cykloheksyl)-urinstoff i en dosering på 0,2 mg/kg, N-/~4-(p-2-metoksy-4-trifluormetylbenzamido-etyl)-benzolsulfonyl7-N,-cykloheksyl-urinstoff i en dosering på 0,1 mg/kg og N-/~4-(P-< 2-metoksy-4-trifluor-metylbenzamido)-etyl)-benzolsulfonyl7-N»-(4-metylcykloheksyl)-urinstoff i en dosering på 0,08 mg/kg på kaniner, så kan det stadig fastslås en tydelig blodsukkersenkning. The strong effect of the mentioned benzenesulfonylureas becomes particularly evident when the dose is further reduced. N-[~4-({3-(2-Methoxy-5-acetylbenzamido^-ethyl)-benzenesulfonyl7-N''-(4-methyl-cyclohexyl)-urea is administered in a dosage of 0.2 mg/kg , N-/~4-(p-2-methoxy-4-trifluoromethylbenzamido-ethyl)-benzenesulfonyl7-N,-cyclohexyl-urea in a dosage of 0.1 mg/kg and N-/~4-(P-< 2-Methoxy-4-trifluoro-methylbenzamido)-ethyl)-benzenesulfonyl7-N»-(4-methylcyclohexyl)-urea in a dosage of 0.08 mg/kg in rabbits, a clear lowering of blood sugar can still be determined.

De omtalte benzolsulfonylurinstoffer skal fortrinnsvis tjene til fremstilling av oralt administrerbare preparater med blodsukkersenkende virkning til behandling av diabetes mellitus og kan applisere som sådan eller i form av deres salter, resp. i nærvær av stoffer som fdrer til en saltdannelse. Til saltdannelse kan det eksempelvis anvendes alkaliske midler som alkali- eller jordalkalihydroksyder, The mentioned benzenesulfonylureas should preferably be used 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, for example, alkaline agents such as alkali or alkaline earth hydroxides can be used,

-karbonater eller -bikarbonater.-carbonates or -bicarbonates.

Som medisinske preparater kommer det fortrinnsvis på tale As medical preparations, it is preferably mentioned

tabletter som ved siden av fremgangsmåteproduktene inneholder de van-lige hjelpe- og bærestoffer som talkum, stivelse, melkesukker, tragant eller magnesiumstearat. tablets 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 benzolsulfonylurinstoffer 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 benzolsulfonylurinstoff og den Ønskede effekt. Hensiktsmessig utgjor doseringen pr. enhet ca. 0,5 til 100 mg, fortrinnsvis 2 til 10 mg, imidlertid kan det også anvendes betraktelig hOyere eller lavere-liggende doseringsenheter som eventuelt fSr applikasjon må oppdeles, resp. deles flere ganger. A preparation containing the mentioned benzenesulfonylureas as active substance, e.g. a tablet or a powder with or without the aforementioned additives is suitably brought into a suitable dosage form. The dose 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. shared several times.

Eksempel_l Example_l

N~/~4-(p-( 2-etoksy-5-acetylbenzainido^-etyl)-benzol3ulfonyl7-Nl-(4-metyleykloheksyD- urinstoff ( trans) N~/~4-(p-(2-ethoxy-5-acetylbenzainido^-ethyl)-benzol3sulfonyl7-Nl-(4-methylcyclohexyD-urea (trans)

8 g 4-(P-^etoksy-5-acetylben*amido^-etyl)-benzolsulfonamid (smp. 197-l<o>,8°C, dannet av 2-etoksy-5-acetylbenzosyre og 4-(p-aminoetyl)-benzolsulfonamid) opplSses i 10,5 ral 2 normal natronlut og 40 ul aceton og blandes dråpevis ved 0 - 5°C under omrSring med 3,1 g 4-metylcyklo-heksylisocyanat (trans). Han lar det etteromrdre i 3 timer ved værelsetemperatur, fortynner med vann og metanol, frafiltrerer uopplOst og surgjOr filtratet med fortynnet saltsyre. Detikrystallinskform dannede N-^~4-(p-{ 2-etoksy-5-acetylbenzamido)-etyl)-benzolsulfonyl7-N»-(4-metylcykloheksyl)-urinstoff (trans) smelter etter omkrystallisering fra metanol ved l62-l64°C. 8 g of 4-(P-^ethoxy-5-acetylben*amido^-ethyl)-benzenesulfonamide (m.p. 197-l<o>.8°C, formed from 2-ethoxy-5-acetylbenzoic acid and 4-(p- aminoethyl)-benzenesulfonamide) is dissolved in 10.5 ral 2 normal caustic soda and 40 ul acetone and mixed dropwise at 0 - 5°C with stirring with 3.1 g of 4-methylcyclohexyl isocyanate (trans). He allows it to stir for 3 hours at room temperature, dilutes with water and methanol, filters off undissolved and acidifies the filtrate with dilute hydrochloric acid. Dicrystalline form formed N-^~4-(p-{ 2-ethoxy-5-acetylbenzamido)-ethyl)-benzenesulfonyl7-N»-(4-methylcyclohexyl)-urea (trans) melts after recrystallization from methanol at 162-164°C .

På analog måte får man N-/~4-(p-{2-etoksy-5~acetylbenzamidQ> - etyl)-benzolsulfonyl7-N,-cykloheksylurinstoff med smp. l6l-l62°C In an analogous manner, one obtains N-[4-(p-{2-ethoxy-5-acetylbenzamideQ>-ethyl)-benzenesulfonyl7-N,-cyclohexylurea with m.p. 161-162°C

(fra metanol).(from methanol).

På analog måte vil manAnalogously, one will

av 4-(P**^2-metoksy-5-propionylbenzamido^-etyl)-benzolsulf on amid (smp. 203- 205°C) få: of 4-(P**^2-methoxy-5-propionylbenzamido^-ethyl)-benzenesulfonamide (m.p. 203-205°C) get:

N-/~4-(p-('2-metoksy-5-propionylbenzamido,^-etyl)-benzol-sulfonyl7-N »-cykloheksyl-urinstoff med smp. 136-138°C (fra metanol) og N-/~4-(p—^2-metoksy-5-propionylbenzamido^-etyl)-benzolsulfonylZ-N1-(4-metylcykloheksyl)-urinstoff (trans) med smp. I37 - 139°C (fra metanol); av 4-(p-( 2-allyoksy-5-acetylbenzamido} -etyl)-benzolsulfonamid (smp. I69 - 171°C) få: N-/~4-(p-^2-allyloksy-5-acetylbenzamid6^-etyl)-benzolsulfonyl7-N,-cykloheksyl-urinstoff med smp. 154 - 155°c (fra metanol) og N-/~4-(p-{2-allyloksy-5-acetylbenzamido) -etyl)-benzolsulfonyl7-N»-(4-metylcykloheksyl)-urinstoff (trans) med smp. I43 - 145°C (fra metanol); av 4-(p-^2-metoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonamid (smp. 172 - 174°C) få: N-/~4-(p-^2-metoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N »-cykloheksyl-urinstoff med smp. 182 - l83°C (fra metanol) og N-/~4-(p-(2-metoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl/-N »-(4-metylcykloheksyl)-urinstoff (trans) med smp. 191 - 193°C (fra metanol); av 4-(p-C2-metoksy-5-fenylbenzamido^-etyl)-benzolsulfonamid (smp. 213-214°C) få: N-^~4-(p-^ 2-metoksy-5-fenylbenzamido^-etyl)-benzolsulfonyl/-N cykloheksyl-urinstoff med smp. 194 - 195°c (fra metanol/dimetylformamid), N-/~4-(p-^ 2-metoksy-5-fenylbenzamidd^-etyl)-benzosulfon yl7-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 189 - 190°C (fra metanol/ dine tylformamid) og H-/~4-(p-«^ 2-metoksy-5-fenylben»amido)~etyl)-benzolsulfonyl7-N»-(4-etylcykloheksyl)-urinstoff (trans) med smp. 183 - l84°C (fra metanol); N-/~4-(p-('2-methoxy-5-propionylbenzamido,^-ethyl)-benzenesulfonyl7-N»-cyclohexyl-urea with m.p. 136-138°C (from methanol) and N-/ ~4-(p-^2-Methoxy-5-propionylbenzamido^-ethyl)-benzenesulfonylZ-N1-(4-methylcyclohexyl)-urea (trans) with mp 137 - 139°C (from methanol); of 4-( p-(2-allyoxy-5-acetylbenzamido}-ethyl)-benzenesulfonamide (m.p. 169 - 171°C) get: N-/~4-(p-^2-allyloxy-5-acetylbenzamide6^-ethyl)-benzenesulfonyl7 -N,-cyclohexyl-urea with mp 154 - 155°c (from methanol) and N-/~4-(p-{2-allyloxy-5-acetylbenzamido)-ethyl)-benzenesulfonyl7-N»-(4- methylcyclohexyl)-urea (trans) with m.p. 143 - 145°C (from methanol); from 4-(p-^2-methoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonamide (m.p. 172 - 174°C) get : N-/~4-(p-^2-methoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl7-N»-cyclohexyl-urea with m.p. 182 - 183°C (from methanol) and N-/~4- (p-(2-methoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl/-N »-(4-methylcyclohexyl)-urea (trans) with mp 191 - 193°C (from methanol); of 4 -(p-C2-methoxy-5-phenylbenzamido^-ethyl)-benzenesulfonamide (m.p. 213-214°C) obtain: N-^~4-(p-^ 2-methoxy-5-phenylbenzamido^-ethyl)-benzenesulfonyl/-N cyclohexyl-urea with m.p. 194 - 195°c (from methanol/dimethylformamide), N-[4-(p-^2-methoxy-5-phenylbenzamidid^-ethyl)-benzosulfonyl 7-N'-(4-methylcyclohexyl)-urea (trans) with m.p. 189 - 190°C (from methanol/ diethylformamide) and H-/~4-(p-«^ 2-methoxy-5-phenylben»amido)~ethyl)-benzenesulfonyl7-N»-(4-ethylcyclohexyl)-urea (trans) with m.p. 183 - 184°C (from methanol);

av 4-(p-^ 2-metoksy-5-benzylbenzamido^-etyl)-benzolsulfonamid (smp.of 4-(p-^2-methoxy-5-benzylbenzamido^-ethyl)-benzenesulfonamide (m.p.

158 - 160°C) få: N-/~4-(P-{ 2-metoksy-5-benzylbenzamido^ -etyl)-benzol-sulfonyl7-N<f->158 - 160°C) get: N-[4-(P-{2-methoxy-5-benzylbenzamido^-ethyl)-benzenesulfonyl7-N<f->

(4-metylcykloheksyl)-urinstoff (trans) med smp. 150 - 151°C (fra metanol); (4-methylcyclohexyl)-urea (trans) with m.p. 150 - 151°C (from methanol);

av 4-(P-{2-metoksy-4-nitrobenzamido^-etyl)-benzol-sulfonamid (smp.of 4-(P-{2-methoxy-4-nitrobenzamido^-ethyl)-benzenesulfonamide (m.p.

207 - 209°C) få: 207 - 209°C) get:

N-/~4-(p-"{2-metoksy-4-nitrobenzamido) -etyl)-benzol-sulfonyl7-N'-cykloheksyl-urinstoff med smp. 196 - 198°C (fra metanol), N-/~4-(p-(2-metoks<y->4-nitrobenzamido)-benzolsulfonylJ-N'-(4-met<y>lcyklo-heksylj-urinstoff (trans) med smp. I97 - 198°C (fra metanol) og N-/~*4-(p~^ 2-metoksy-4-nitrobenzamidq^ -etyl)-benzolsulfonyl7-N<»->(4-etylcykloheksyl)-urinstoff (trans) med smp. 201 - 202°C (fra metanol/ dimetylformamid); av 4-(p-^ 2-etoksy-4-nitrobenzamido)-etyl)-benzolsulfonamid (smp. 213°C) få: N-/~4-(p-^2-etoksy-4-nitrobenzamid<^-et<y>l)-benzolsulfonyl/-N<»->cykloheksyl-urinstoff med smp. 174 - 176°C (fra metanol) og N-/4-(p--^ 2-etoksy-4-nitrobenzamido) -etyl)-benzolsulfonyl/-N'-(4-metylcykloheksyl)-urinstoff (trans) med smp. 195 - 197°C (fra metanol/ dimetylformamid); av 4-(0-{ 2-metoksy-5-nitrpbenzamido^-etyl)-benzolsulfonamid (smp. 174 - 176°C få: N-/~4-(p-{ 2-metoksy-5-nitrobenzamidoJ -etyl)-benzolsulfonyl7-N *-cykloheksyl-urinstoff med smp. 146 - 148°C (fra metanol) og N-/~4-(p-"{2-methoxy-4-nitrobenzamido)-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea with m.p. 196 - 198°C (from methanol), N-/~ 4-(p-(2-methoxy<y->4-nitrobenzamido)-benzenesulfonyl J-N'-(4-meth<y>lcyclohexyl)-urea (trans) with mp 197 - 198°C (from methanol) and N-(p~^ 2-methoxy-4-nitrobenzamideq^ -ethyl)-benzenesulfonyl 7-N<»->(4-ethylcyclohexyl)-urea (trans) with mp 201 - 202°C ( from methanol/dimethylformamide); from 4-(p-^2-ethoxy-4-nitrobenzamido)-ethyl)-benzenesulfonamide (m.p. 213°C) get: N-/~4-(p-^2-ethoxy-4 -nitrobenzamide<^-et<y>l)-benzenesulfonyl/-N<»->cyclohexyl-urea with m.p. 174 - 176°C (from methanol) and N-/4-(p--^ 2-ethoxy- 4-nitrobenzamido)-ethyl)-benzenesulfonyl/-N'-(4-methylcyclohexyl)-urea (trans) with m.p. 195 - 197°C (from methanol/dimethylformamide); of 4-(0-{ 2-methoxy- 5-nitrpbenzamido^-ethyl)-benzenesulfonamide (m.p. 174 - 176°C obtain: N-/~4-(p-{ 2-methoxy-5-nitrobenzamidoJ -ethyl)-benzenesulfonyl7-N*-cyclohexyl-urea with m.p. 146 - 148°C (from methanol) and

av 4-(p-< 2-etoksy-4-trifluormetylbenzamido)-etyl)-benzolsulfonamid (smp. 228 - 229°C) få of 4-(p-< 2-ethoxy-4-trifluoromethylbenzamido)-ethyl)-benzenesulfonamide (m.p. 228 - 229°C) get

N-/~4~(p-^2-etoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N<»->N-/~4~(p-^2-ethoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl7-N<»->

(p-fenyletyl)-urinstoff med smp. 148 - 149°C (fra metanol), N-/~4-(p-^ 2-etoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N »-cykloheksylmetyl-urinstoff med smp. 194 -195°C (fra metanol), (p-phenylethyl)-urea with m.p. 148 - 149°C (from methanol), N-/~4-(p-^ 2-ethoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl7-N»-cyclohexylmethyl-urea with m.p. 194 -195°C (from methanol),

N-/~4-(P"^ 2-etoksy-4-t^ifluo^metylbenzamido^-etyl)-benzolsulfonyl7-N,-cykloperoksyl-urinstoff med smp. 143 - 144°C (fra metanol), N-/~4-(p-^ 2-etoksy-4-trifluormetylbenzamido)-etyl)-benzolsulfonyl7-N»-(4-isopropoksycykloheksyl)-urinstoff med smp. I84 - l85°C (fra metanol),, N-/~4-(p-{2-etoksy-4-trifluormetylbenzamido>-etyl)-benzolsulfonyl7-N n-heksylurinstoff med smp. I73 - 174°C (fra metanol) og N-/~4-(p-{2-etoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N,-cyklo-heptyl-urinstoff med smp. 162 -l64°C (fra metanol) N-/~4-(P"^ 2-ethoxy-4-trifluoro^methylbenzamido^-ethyl)-benzenesulfonyl7-N,-cycloperoxyl-urea with m.p. 143 - 144°C (from methanol), N-/ ~4-(p-^ 2-ethoxy-4-trifluoromethylbenzamido)-ethyl)-benzenesulfonyl7-N'-(4-isopropoxycyclohexyl)-urea with m.p. 184 - 185°C (from methanol),, N-/~4 -(p-{2-ethoxy-4-trifluoromethylbenzamido>-ethyl)-benzenesulfonyl7-N n-hexylurea with m.p. 173 - 174°C (from methanol) and N-/~4-(p-{2-ethoxy- 4-Trifluoromethylbenzamido^-ethyl)-benzenesulfonyl 7-N,-cycloheptyl-urea with mp 162 -164°C (from methanol)

av 4-(p-<2-metoksy-5-trifluormetylbenzamido^-etyl)-benzolsulfonamidof 4-(p-<2-methoxy-5-trifluoromethylbenzamido^-ethyl)-benzenesulfonamide

(smp. 190°C) få: N-/^4-(p-^2-metoksy-5-trifluormetylben2amido^-etyl)-benzolsulfonyl7-N »-cykloheksyl-urinstoff med smp. 106°C (Zers.) (fra metanol), N-/~4~(P-C2-metoksy-5-trifluormetylbenzamidq^-etyl)-benzolsiilfonyl7-Nr-butyl-urinstoff med smp. 123 - 125°C (fra metanol), N-/ 4"(P^2-metoksy-5-t^ifluormetylbenzamido^-etyl)-benzol3ulfonyl7-N,-(4-metylcykloheksyl)-urinstoff (trans) med smp. 168 - 170°C (fra metanol) og N-/~4-(P-{ 2-metoksy-5-trifluormetylbenzamido^-etyl-benzolsulfonyl7-N »-cykloheptyl-urinstoff med smp. 104 - 106°C (fra metanol) av 4-(p-^2-etoksy-5-trifluormetylbenzamido^-etyl)-benzolsulfonamid (smp. 200°C) få: N-/~4-(p-^2-etoksy-5-trifluormetylbenzamido)-etyl)-benzolsulfonyl/-N »-cykloheksyl-urinstoff med smp. 140 - 142°C (fra metanol) og N~/~4~(P-(2-etoksy-5~trifluormetylbenzamido)> -etyl)-benzolsulf ony.l7~N,-(4-metylcykloheksyl)-urinstoff (trans) med smp. 170 - 171°C (fra metanol), N-/~4-(p-f 2-metoksy-5-nitrobenzamido^ -etyl)-benzolsulfonylJ-N »-(4-metylcykloheksyl)-urinstoff (trans) med smp. 163 - l64°C (fra metanol); av 4~(P~^2-etoksy-5-nitrobenzamido)-etyl)-benzolsulfonamid (smp. 178 - 180°C) få: N-^4~(P-^"etoksy-5~nitr°benzamido^-etyl)-benzolsulfonyl7-H,-(4-metyl-cykloheksyD-urinstoff (trans) med smp. I69 -170°C (fra metanol); (m.p. 190°C) obtain: N-[4-(p-2-methoxy-5-trifluoromethylbenzamido-ethyl)-benzenesulfonyl-7-N]-cyclohexyl-urea with m.p. 106°C (Zers.) (from methanol), N-/~4~(P-C2-Methoxy-5-trifluoromethylbenzamideq^-ethyl)-benzenesiylfonyl7-N-butyl-urea m.p. 123 - 125°C (from methanol), N-/ 4"(P^2-methoxy-5-trifluoromethylbenzamido^-ethyl)-benzol3ulfonyl7-N,-(4-methylcyclohexyl)-urea (trans) with m.p. 168 - 170°C (from methanol) and N-/~4-(P-{ 2-methoxy-5-trifluoromethylbenzamido^-ethyl-benzenesulfonyl7-N»-cycloheptyl-urea with m.p. 104 - 106°C (from methanol ) of 4-(p-^2-ethoxy-5-trifluoromethylbenzamido^-ethyl)-benzenesulfonamide (m.p. 200°C) obtain: N-/~4-(p-^2-ethoxy-5-trifluoromethylbenzamido)-ethyl )-benzenesulfonyl/-N»-cyclohexylurea with mp 140-142°C (from methanol) and N~/~4~(P-(2-ethoxy-5-trifluoromethylbenzamido)>-ethyl)-benzenesulfony. l7~N,-(4-methylcyclohexyl)-urea (trans) with m.p. 170 - 171°C (from methanol), N-/~4-(p-f 2-methoxy-5-nitrobenzamido^ -ethyl)-benzenesulfonylJ- N»-(4-methylcyclohexyl)-urea (trans) with mp 163 - 164°C (from methanol); of 4~(P~^2-ethoxy-5-nitrobenzamido)-ethyl)-benzenesulfonamide (mp 178 - 180°C) obtain: N-^4~(P-^"ethoxy-5~nitr°benzamido^-ethyl)-benzenesulfonyl7-H,-(4-methyl-cyclohexyD-urea (trans) with m.p. I6 9 -170°C (from methanol);

av 4-(p-^ 2-etoksy-4«trifluormetyl-benzamido^-etyl)-benzolsulfonamid (smp. 228 - 229°C) fås of 4-(p-^2-ethoxy-4'trifluoromethyl-benzamido^-ethyl)-benzenesulfonamide (m.p. 228 - 229°C) is obtained

N-/~4-(p-( 2-etoksy-4-triflKoraetylbenzamldo^-etyl)-benzolsulfonyl7-Ny<->cykloheksyl-urinstoff med sap« 172 - 174°C (fra metanol), N-/~4-(p- { 2-etoksy-4-trif Imorssetylbeniamido) -etyl)-benzolsulfony^~N»-butylurinstoff med smp. 151 - 153°C ffra metanol), N-/~4- (p-(2-etoksy-4-trif Iwoffissfey Iboassaoide^-etyl) -benzolsulf onyl7«=M (4-metylcykloheksyl)-urinstioff StraaaJ m©å smp. 185 - l86°Cog av 4"(P-^-n-Propoksy-5-ac©fcylfoQrasaE&åe$«=ofeyl)=b©azolsulfonamid(smp. 201 - 202°C) få: H-/~4-(p-^2-n-propoksy-5-ac©tylb®aaaai^©^°@feyl|»bønBol8ulfonyl7-II»-(4~Btetylcykloheksyl)«»urinstoff f tråas) eiæd tmp<> 121 » 123°C (fra metanol) av 4-0- f 2-n-butoksy-5-acstylb@aaaialfåd^ «=@tyl)-b©asolsulfonamid (smp. N-/~4-(p-(2-Ethoxy-4-triflKoraethylbenzamldo^-ethyl)-benzenesulfonyl7-Ny<->cyclohexyl-urea with sap« 172 - 174°C (from methanol), N-/~4- (p-{2-ethoxy-4-trif Imorcetylbeniamido)-ethyl)-benzenesulfony^~N»-butylurea with m.p. 151 - 153°C from methanol), N-/~4- (p-(2-ethoxy-4-trif Iwoffissfey Iboassaoid^-ethyl)-benzenesulfonyl7«=M (4-methylcyclohexyl)-urinthioff StraaaJ m©å m.p. . 185 - 186°C and of 4"(P-^-n-Propoxy-5-ac©fcylfoQrasaE&åe$«=opheyl)=b©azolesulfonamide (m.p. 201 - 202°C) get: H-/~4-( p-^2-n-propoxy-5-ac©tylb®aaaai^©^°@feyl|»bönBol8ulfonyl7-II»-(4~Btetylcyclohexyl)«»urea f tråas) eiæd tmp<> 121 » 123°C ( from methanol) of 4-O- f 2-n-butoxy-5-acstylb@aaaialfåd^ «=@tyl)-b©azolesulfonamide (m.p.

187 - 188°G) få: 187 - 188°G) get:

N-/~4-(p- K 2-n-butoksy-5-acetylbenzamido^ -etyl)-benzolsulfonyl/-N *-cykloheksyl-urinstoff med smp. 169 - 170°C ( fra metanol); N-/~4-(p-K 2-n-butoxy-5-acetylbenzamido^-ethyl)-benzenesulfonyl/-N *-cyclohexyl-urea with m.p. 169 - 170°C (from methanol);

Eksem£el_2 Example_2

N-/~4~(P-(2-metoksy-5-acetylbenzamido^-etyl)-benzolsulfonyl7~N<f->(4-metylcykloheksyl)- urinstoff ( trans), N-/~4~(P-(2-methoxy-5-acetylbenzamido^-ethyl)-benzenesulfonyl7~N<f->(4-methylcyclohexyl)-urea (trans),

8,7 g N-/~4-(p-<2-metoksy-5-acetylbenzamido}-etyl)-benzolsulfonyl7-metyluretan (smp. I90 - 192°C)dannet av 4-(p-<2-metoksy-5-acetylbenzamido}-etyl)-benzolsulfonamid (smp. 206 - 208°C) ved omsetning med klormaursyremetylester) suspenderes i 100 ml dioksan og oppvamres etter tilsetning av 2,3 g metylcykloheksylamin (trans) enog-enhalv time ved 110 C, idet den ved reaksjonen dannede metanol destil-lerer av. Ved tilsetning av litt vann til den avkjSlte reaksjonsblanding fås det ovennevnte sulfonylurinstoff krystallinsk. Etter omkrystallisering fra metanol utgjSr smeltepunktet 155 - 157°C. 8.7 g of N-/~4-(p-<2-methoxy-5-acetylbenzamido}-ethyl)-benzenesulfonyl-7-methylurethane (m.p. 190 - 192°C) formed from 4-(p-<2-methoxy- 5-acetylbenzamido}-ethyl)-benzenesulfonamide (m.p. 206 - 208°C) by reaction with chloroformic acid methyl ester) is suspended in 100 ml of dioxane and heated after the addition of 2.3 g of methylcyclohexylamine (trans) for one and a half hours at 110 C, the methanol formed by the reaction distills off. By adding a little water to the cooled reaction mixture, the above-mentioned sulfonylurea is obtained crystalline. After recrystallization from methanol, the melting point is 155 - 157°C.

På analog måte får man: N-/~<4>-(p-<'2-metoksy-5-acetylbenzamidoj)-et<y>l)-benzolsulfonyl7-N'-cykloheksyl-urinstoff med smp, 162 - 163°C (fra metanol) og N-/_4-(p-(2-metoksy-5-acetylbenzamid^-etyl)-benzolsulfonyl7-Nf-butyl-urinstoff med smp. 158 - l60°C (fra metanol) og In an analogous manner, one obtains: N-[<4>-(p-<'2-methoxy-5-acetylbenzamidoyl)-et<y>l)-benzenesulfonyl7-N'-cyclohexyl-urea with mp, 162 - 163° C (from methanol) and N-/_4-(p-(2-methoxy-5-acetylbenzamide^-ethyl)-benzenesulfonyl7-Nf-butyl-urea with m.p. 158 - 160°C (from methanol) and

N-/~4-(p-^ 2-metoksy-5-acetylbenzamido)—etyl)-benzolsulfonyl7-N»<->isobutyl-urinstoff med smp. l60 - l62°C (fra metanol); N-/~4-(p-^ 2-methoxy-5-acetylbenzamido)-ethyl)-benzenesulfonyl7-N»<->isobutylurea with m.p. 160 - 162°C (from methanol);

av N-/~4-(Pc"^2-iBetoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-metyluretan (smp. I90 - 192°C) får man of N-/~4-(Pc"^2-iBethoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl-7-methylurethane (m.p. 190 - 192°C) gives

N-/"~4~(p-< 2-metoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N»<->butyl-urinstoff med smp. I59 - l6l°C (fra metanol), N-/"~4~(p-< 2-methoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl7-N"<->butyl-urea with m.p. 159 - 161°C (from methanol),

N-/""4~(P-^ 2-metoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N»-(4-metoksy-cykloheksyl)-urinstoff med smp. 170 - 172°C (fra metanol), N-/~4-(P-^2«»metoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N,-n«heksyl»urinstoff med smp. I47 - 148°C ( fra metanol), H-^~4» (p-^S-metoksy-4-trifluormetylbenzamido} -etyl )-benzolsulf onyl7-N »-(3«aøtylcykloheksyl)-urinstoff med smp. 158 - l60°C (fra metanol) og &~Z4™(P°^ 2-metoksy-4-trifluormetylbenzamido^-etyl)-benzolsulfonyl7-N»<->N-/""4~(P-^ 2-methoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl7-N»-(4-methoxy-cyclohexyl)-urea with m.p. 170 - 172°C (from methanol), N-/~4-(P-^2«»methoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl7-N,-n«hexyl»urea with m.p. 147 - 148°C (from methanol), H-^~4» (p-^S-methoxy-4-trifluoromethylbenzamido}-ethyl )-benzenesulfonyl7-N»-(3-methylcyclohexyl)-urea with m.p. 158 - 160°C (from methanol) and &~Z4™(P°^ 2-methoxy-4-trifluoromethylbenzamido^-ethyl)-benzenesulfonyl7-N»<->

(2j,5-©ndometylencykloheksyl)-urinstoff med smp. 146 - 148°C (fra meta-a©l)j (2j,5-©ndomethylenecyclohexyl)-urea with m.p. 146 - 148°C (from meta-al©l)j

Ekoempol 3Ekoempol 3

IS-/4<->(p-< 2-me toksy-5-ace tyl-benzamido^-etyl )-benzolsulfonyl7-N»- (p-f en yl- IS-/4<->(p-< 2-me toxy-5-acetyl-benzamido^-ethyl )-benzenesulfonyl7-N»- (p-phenyl-

etyl )- urinstoff.ethyl )- urea.

a) 2,7 g N-_~4-(p-^ 2-metoksy-5-acetyl-benzamido^-etyl)-benzol-sulfony__7-N '-(p-fenyl-etyl)-tiourinstoff opploses i en blanding av a) 2.7 g of N-_~4-(p-^ 2-methoxy-5-acetyl-benzamido^-ethyl)-benzene-sulfony__7-N '-(p-phenyl-ethyl)-thiourea are dissolved in a mixture of

150 ml metanol og 40 ml dimetylformamid. Man tilsetter 1,08 g kvikk-solvoksyd og omrorer under oppvarmning ved 60°C i I5time. Etter frafiltrering av dannet kvikksSlvsulfid blander man med vann. Man får en utfelling av N-_~4-(p~^ 2-metoksy-5-acetylbenzamido>-etyl)-benzolsulfo-ny_7-N»<->(p-fenyletyl)-isourinstoff-metyleter som harpiks. 150 ml of methanol and 40 ml of dimethylformamide. 1.08 g of mercury sol oxide is added and stirred while heating at 60°C for 15 hours. After filtering off the mercury sulphide formed, it is mixed with water. A precipitate of N-_~4-(p~^ 2-methoxy-5-acetylbenzamido>-ethyl)-benzenesulfonyl-7-N»<->(p-phenylethyl)-isourea methyl ether is obtained as a resin.

b) Den ifolge punkt a) dannede harpiks opploses i litt dioksan. Man tilsetter 2n natronlut og oppvarmer i 25 minutter på dampbad. Etter b) The resin formed according to point a) is dissolved in a little dioxane. Add 2N caustic soda and heat for 25 minutes in a steam bath. After

avkjoling fortynner man med vann og surgjor. Den dannede krystallinske utfelling av N-_~4-(p-<' 2-metoksy-5-acetyl-benzamido^-etyl)-benzolsulfo-ny_7_N,-(p-fenyletyl)-urinstoff smelter etter omkrystallisering fra metanol ved 144 - 146°C. cooling is diluted with water and acidified. The formed crystalline precipitate of N-_~4-(p-<' 2-methoxy-5-acetyl-benzamido^-ethyl)-benzenesulfonyl_7_N,-(p-phenylethyl)-urea melts after recrystallization from methanol at 144 - 146°C.

<Eksempel>__ <Example>__

N-_~4-(p-{ 2-metoksy-5-acetyl)-benzamido-etyl)-benzolsulfony_7-N,-( P- fenyl- etyl)- urinstoff. N-_~4-(p-{2-Methoxy-5-acetyl)-benzamido-ethyl)-benzenesulfony_7-N,-(P-phenyl-ethyl)-urea.

6,5 S N-_~4-(0-<2-metoksy-5-acetyl>-benzamido-etyl)-benzol-sulfony_7-N»<->(p-fenyletyl)-tiourinstoff (fremstilt ved koking av sulfon-amidet med fenyletyl-sennepolje i aceton i nærvær av kaliumkarbonat, smp. 195 - 197°C under spaltning fra fortynnet metanol) suspenderes i 250 ml aceton. Det tilsettes 2,07 g natriumnitrit opplSst i litt vann. Under omroring og isavkjoling tildrypper man nu 20 ml 5n eddiksyre og etteromrorer i 2^ time ved værelsetemperatur. Etter filtrering og ace-tonets avdestillering opploser man i fortynnet ammoniakk, filtrerer over kull og surgjor filtratet. Man får en forst seig utfelling av N-_~4-(p- { 2-metoksy-5-acetyl) -benzamidoetyl)-benzolsulfony_7~N»-(p-fenyletyD-urinstoff, som man krystalliserer fra metanol.Det således rensede stoff smelter ved 144 - 146°C. 6.5 S N-_~4-(0-<2-methoxy-5-acetyl>-benzamido-ethyl)-benzene-sulfony_7-N»<->(p-phenylethyl)-thiourea (prepared by boiling sulfone -amide with phenylethyl mustard oil in acetone in the presence of potassium carbonate, mp 195 - 197°C during cleavage from dilute methanol) is suspended in 250 ml of acetone. 2.07 g of sodium nitrite dissolved in a little water is added. While stirring and ice-cooling, 20 ml of 5N acetic acid is now added dropwise and stirred for 2^ hours at room temperature. After filtration and the acetone has been distilled off, dissolve in dilute ammonia, filter over charcoal and acidify the filtrate. An initially tough precipitate of N-_~4-(p-{2-methoxy-5-acetyl)-benzamidoethyl)-benzenesulfony_7~N»-(p-phenylethylD-urea) is obtained, which is crystallized from methanol. The thus purified substance melts at 144 - 146°C.

Eksem£el__Example__

N-_~"4-(p- ^2-etoksy-5-acetyl-benzamido^ -etyl)-benzolsulfony_7-N<f>-cykloheksyl- urinstoff. N-_~"4-(p-^2-ethoxy-5-acetyl-benzamido^-ethyl)-benzenesulfony_7-N<f>-cyclohexyl-urea.

4>1 g4(P- f 2-etoksy-5-acetyl-benzamid6^-etyl)-benzolsulfoil-amid-natrium og 4»4g N-cykloheksyl-karbamidsyrefenylester opploses i 100 ml dimetylformamid. Man oppvarmer i 45 minutter ved 110°C, blander reaksjonsblandingen etter avkjoling med 0,5 %- ig vandig ammoniakk, filtrerer og surgjSr filtratet. Den utfelte utfelling suges fra og omkrystalliseres fra metanol. Det dannede N-_~4-(P- K 2-etoksy-5-acetyl-benzaraido>-et<y>l)-benzolsulfonyl/-N»-cykloheksyl-urinstoff smelter ved 4>1 g of 4(P-f 2-ethoxy-5-acetyl-benzamide-6-ethyl)-benzenesulfoyl-amide-sodium and 4-4 g of N-cyclohexyl-carbamic acid phenyl ester are dissolved in 100 ml of dimethylformamide. It is heated for 45 minutes at 110°C, the reaction mixture is mixed after cooling with 0.5% aqueous ammonia, filtered and the filtrate acidified. The precipitate formed is suctioned off and recrystallized from methanol. The formed N-_~4-(P-K 2-ethoxy-5-acetyl-benzarado>-eth<y>1)-benzenesulfonyl/-N»-cyclohexyl urea melts at

161-162°C. 161-162°C.

Eksempel 6. Example 6.

N-_ 4-(3-<2-metoksy-5-propionyl-benzamido>-etyl)-benzolsulfony_7-N'-cykloheksyl- urinstoff. N-_ 4-(3-<2-Methoxy-5-propionyl-benzamido>-ethyl)-benzenesulfony_7-N'-cyclohexyl-urea.

4,1 g 4-(3-<2-metoksy-5-propionyl-benzamido>-etyl)-benzolsulfonamidnatrium oppvarmes med 5 >9 g NjN^difenyl-N^cykloheksylurinstoff i 100 ml dimetylformamid i 45 minutter ved 110°C. Etter avkjøling behandler man med ca. 0,5/2-ig ammoniakk, filtrerer og surgjør filtratet. Den dannede utfelling gjenutfelles en gang fra 0,5^-ig ammoniakk og omkrystalliseres deretter fra metanol. N-_ 4- ( f5-<2-metoksy-5-propionyl-benzamido>-etyl)-benzolsulf onyl7-. N'-cykloheksylurinstoff smelter ved 136-138°C. 4.1 g of 4-(3-<2-methoxy-5-propionyl-benzamido>-ethyl)-benzenesulfonamide sodium is heated with 5 >9 g of NjN^diphenyl-N^cyclohexylurea in 100 ml of dimethylformamide for 45 minutes at 110°C. After cooling, treat with approx. 0.5/2-ig ammonia, filter and acidify the filtrate. The precipitate formed is reprecipitated once from 0.5% ammonia and then recrystallized from methanol. N-_ 4-( f5-<2-methoxy-5-propionyl-benzamido>-ethyl)-benzenesulfonyl7-. N'-cyclohexylurea melts at 136-138°C.

Eksempel 7»Example 7»

a) N-/—4-(3-2-metoksy-5_trifluormetyl-tiobenzamido-etyl)-benzolsulf onyl7- N' - cykloheksyl- urinstoff. 5 g 4-(3-2-metoksy-5-trifluormetyl-tiobenzamido-etyl)-benzolsulfonamid (smp. 155-157°C, fremstilt av 4-(B-2-metoksy-5-trifluormetylbenzamido-etyl)-benzolsulfonamid og fosforpentasulfid i nærvær av pyridin), 3,3 g kaliumkarbonat og 100 ml aceton oppvarmes i 2 timer under omrøring og tilbakeløp til kokning. a) N-(3-2-methoxy-5-trifluoromethyl-thiobenzamido-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea. 5 g of 4-(3-2-methoxy-5-trifluoromethyl-thiobenzamido-ethyl)-benzenesulfonamide (m.p. 155-157°C, prepared from 4-(B-2-methoxy-5-trifluoromethyl-benzamido-ethyl)-benzenesulfonamide and phosphorus pentasulphide in the presence of pyridine), 3.3 g of potassium carbonate and 100 ml of acetone are heated for 2 hours with stirring and refluxed to boiling.

Deretter tildrypper man 1,6 g cykloheksylisocyanat og omrører i 4 timer ved koketemperatur. Under nedsatt trykk avdestilleres oppløsningsmidlet, residuet behandles med fortynnet saltsyre og produktet frasuges. Det i godt utbytte dannede N-/~~4-(g-2-metoksy-5-trifluormetyl-tiobenzamido-etyl)-benzolsulfonyl7-N'-cykloheksylurinstoff gjenutfelles to ganger av meget fortynnet (ca. 0,25?5-ig)vandig ammoniakk/fortynnet saltsyre qg smelter etter omkrystallisering fra isopropanol ved 120-122°C. 1.6 g of cyclohexyl isocyanate are then added dropwise and stirred for 4 hours at boiling temperature. Under reduced pressure, the solvent is distilled off, the residue is treated with dilute hydrochloric acid and the product is suctioned off. The N-[~~4-(g-2-methoxy-5-trifluoromethyl-thiobenzamido-ethyl)-benzenesulfonyl7-N'-cyclohexylurea formed in good yield is reprecipitated twice from very dilute (approx. 0.25 µg )aqueous ammonia/diluted hydrochloric acid qg melts after recrystallization from isopropanol at 120-122°C.

b) 2 g N-/—4-(3~2-metoksy-5-trifluormetyl-tiobenzamido-etyl ) -benzolsulf onyl7-N' -cykloheksyl-urinstoff oppløses i 100 ml b) Dissolve 2 g of N-[-4-(3~2-methoxy-5-trifluoromethyl-thiobenzamido-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea in 100 ml

metanol, det tilsettes 10 g metyljodid og man oppvarmer 2 timer under tilbakeløp til kokning. Oppløsningsmidlet avdestilleres i vakuum og det oljeaktige utfelte N-/—4-(g-2-metoksy-5-trifluormetyl-s-metyl-tiobenzamido-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff oppvarmes med 2-n natronlut. Etter noen minutter surgjøres det. Det således dannede N-/—4-(8-2-metoksy-5~trifluormetyl-benzamido-etyl )-benzolsulfonyl7-N'-cykloheksyl-urinstoff omkrystalliseres fra metanol og smelter ved 106°C under spaltning. methanol, 10 g of methyl iodide are added and heated for 2 hours under reflux until boiling. The solvent is distilled off in vacuo and the oily precipitated N-(g-2-methoxy-5-trifluoromethyl-s-methyl-thiobenzamido-ethyl)-benzenesulfonyl 7-N'-cyclohexyl urea is heated with 2-n caustic soda. After a few minutes it is acidified. The thus formed N-(8-2-methoxy-5-trifluoromethyl-benzamido-ethyl)-benzenesulfonyl-7-N'-cyclohexylurea is recrystallized from methanol and melts at 106°C with decomposition.

Eksempel 8. Example 8.

N-/—4-(g-2-metoksy-5-trifluormetyl-benzamido-etyl)-benzolsulfonyl7-N'- cykloheksyl- urinstoff. N-[-4-(g-2-methoxy-5-trifluoromethyl-benzamido-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea.

1,5 g N-/—4-(g-2-metoksy-5_trifluormetyl-tiobenzamido-etyl )-benzolsulfonyl7-N'-cykloheksyl-urinstoff oppløses i 10 ml dioksan. Man blander oppløsningen med 10 ml 2-n natronlut og 5 ml hydrogenperoksiyd og oppvarmer i 15 minutter på dampbad. Det fortynnes med vann, frafUtreres og filtratet surgjøres med fortynnet saltsyre. 1.5 g of N-[-4-(g-2-methoxy-5-trifluoromethyl-thiobenzamido-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-urea are dissolved in 10 ml of dioxane. The solution is mixed with 10 ml of 2-n caustic soda and 5 ml of hydrogen peroxide and heated for 15 minutes in a steam bath. It is diluted with water, filtered off and the filtrate acidified with dilute hydrochloric acid.

Det i godt utbytte dannede N-<_>4-(g-2-metoksy-5-trifluormetyl-benzamido-etyl)-benzolsulfonyl7-N'-cykloheksylurinstoff suges fra. Det smelter etter omkrystallisering fra metanol ved 106°C under spaltning. The N-<_>4-(g-2-methoxy-5-trifluoromethyl-benzamido-ethyl)-benzenesulfonyl7-N'-cyclohexylurea formed in good yield is sucked off. It melts after recrystallization from methanol at 106°C during decomposition.

Eksempel 9. Example 9.

N-/~~4- (g^^-metoksy-S^rifluormetyl-benzamido^etyl ^benzolsulf onyl/- N'- cykloheksyl- urinstoff. 5 g N-/—4-(g-<2-metoksy-5-triflurometyl-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyltiourinstoff oppløses i 400 ml tørr tetrahydrofuran. Under omrjiring innfører man ved værelse-' temperatur fosgen i overskudd og lar det innvirke i 2 timer. Deretter blåser man tørr nitrogen gjennom oppløsningen og inndamper i vakuum til ca. 50 ml volum. Man blander med 400 ml tørr toluol og overskytende trimetylamin og koker opp. Etter avkjøling blir ved tilsetning av vann og noen natronlut under omrøring det dannede, N-/~4- (g^^-methoxy-S^rifluoromethyl-benzamido^ethyl ^benzenesulfonyl/- N'- cyclohexyl- urea. 5 g N-/—4-(g-<2-methoxy-5 -trifluoromethyl-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylthiourea is dissolved in 400 ml of dry tetrahydrofuran. Under stirring, phosgene is introduced in excess at room temperature and allowed to act for 2 hours. Dry nitrogen is then blown through the solution and evaporates in vacuum to a volume of approx. 50 ml. It is mixed with 400 ml of dry toluene and excess trimethylamine and brought to a boil. After cooling, by adding water and some caustic soda while stirring, the product formed,

ikke isolerte N-/—4-(B-<2-metoksy-5_trifluormetyl-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-karbodiimid under vanntilleiring overført til N-/—4-(g-<2-metoksy-5-trifluormetyl-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff. Man får sulfonylurin-stoffer ved uttrekning av den organiske fase med fortynnet lut og surgjøring med saltsyre som utfelling, som man frasuger, behandler med sterkt fortynnet ammoniakk og igjen frigjør fra ammoniakkoppløs-ningen med en syre. Stoffet smelter etter omkrystallisering fra metanol ved 106°C. unisolated N-/—4-(B-<2-methoxy-5_trifluoromethyl-benzamido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-carbodiimide under water precipitation transferred to N-/—4-(g-<2-methoxy- 5-Trifluoromethyl-benzamido>-ethyl)-benzenesulfonyl 7-N'-cyclohexylurea. Sulfonylureas are obtained by extracting the organic phase with dilute lye and acidifying with hydrochloric acid as a precipitate, which is suctioned off, treated with highly diluted ammonia and again released from the ammonia solution with an acid. The substance melts after recrystallization from methanol at 106°C.

Eksempel 10. Example 10.

N.-/~ 4-(8-<2-etoksy-5-acetyl-benzamido>-etyl)-benzolsulf onyl7-N' - cykloheksyl- urinstoff. N.-/~ 4-(8-<2-ethoxy-5-acetyl-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexyl-urea.

Man suspenderer 16,3 g N-/T4-aminoetyl)-benzolsulfonyl7-N'-cykloheksyl-urinstoff i 130 ml kloroform. Etter tilsetning av 9 g pyridin tilsetter man en oppløsning av 10,5 g 2-etoksy-5~acetyl-benzosyre-klorid og oppvarmer under omrøring det hele i 6 timer ved 40°C. Derpå inndamper man i vakuum og uttrekker det dannede residuet med ca. 1%- xg ammoniakk. Etter surgjøring av den ammoniakkalske oppløsning og etter omkrystallisering fra metanol får man N-/—4-(g<-><8-etoksy-5-acetyl-benzamido>-etyl)-benzolsulfonyl7-N'-cyklo-heksylurinstof f av smp. l6l-l62°C. 16.3 g of N-((T4-aminoethyl)-benzenesulfonyl7-N'-cyclohexylurea is suspended in 130 ml of chloroform. After adding 9 g of pyridine, a solution of 10.5 g of 2-ethoxy-5-acetyl-benzoic acid chloride is added and the whole is heated with stirring for 6 hours at 40°C. It is then evaporated in a vacuum and the residue formed is extracted with approx. 1%-xg ammonia. After acidification of the ammoniacal solution and after recrystallization from methanol, N-/-4-(g<-><8-ethoxy-5-acetyl-benzamido>-ethyl)-benzenesulfonyl7-N'-cyclohexylurea is obtained of m.p. . 161-162°C.

Eksempel 11. Example 11.

N-/~4-(g<-><2-metoksy-5-trifluormetylbenzamido>-etyl)-benzolsulfonyl7-N'-( 4- metylcykloheksyl)- urinstoff. a) 2)2 g 4-metyl-cykloheksylurinstoff oppløses i 30 ml pyridin, ved innføring av 4,2 g 4-/~~f5-(2-metoksy-5_trifluormetyl)-etyl7-benzolsulfinsyrekldrid(fremstilt av 4-/—3-(2-metoksy-5-trifluormetyl)-etyl7-benzolsulfinsyre smp. 125°C under spaltning og tionylklorid) opptrer lett oppvarmning. Den klar eoppløsning has etter 10 min. i en blanding av isvann og fortynnet saltsyre og det frasuges N-/<->4-(6-<2-metoksy-5_trifluormetylbenzamido>-benzolsulf inyl7-N '-(4-metylcykloheksyl)-urinstoff. b) 1 g av ovennevnte urinstoff oppløses i 20 ml dimetylformamid og oksyderes varmt med en vandig kaliumpermanganatoppløs-ning. Etter brunstenens frafiltrering blandes med vann og fortynnet saltsyre og den dannede utfelling omkrystalliseres fra metanol. Man får N-/~4-(e-<2-metoksy-5-trifluormetylbenzamido>-etyl)-benzolsulf onyl7-N' -(4-metylcykloheksyl)-urinstof f med smp. l68-170°C. Eksempel 12. N.-/~4-.( B-<2-metoksy-5-trif luormetylbenzamido>-etyl)-benzolsulf onyl7-N'-( metylcykloheksyl)- urinstoff. N-[4-(g<-><2-methoxy-5-trifluoromethylbenzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)-urea. a) 2) 2 g of 4-methyl-cyclohexylurea is dissolved in 30 ml of pyridine, by introducing 4.2 g of 4-[~f5-(2-methoxy-5-trifluoromethyl)-ethyl7-benzenesulfinic acid chloride (prepared from 4-/-3 -(2-methoxy-5-trifluoromethyl)-ethyl7-benzenesulfinic acid m.p. 125°C under cleavage and thionyl chloride) slight heating occurs. The clear solution is obtained after 10 min. in a mixture of ice water and dilute hydrochloric acid and N-/<->4-(6-<2-methoxy-5-trifluoromethylbenzamido>-benzolsulfinyl7-N'-(4-methylcyclohexyl)-urea is sucked off. b) 1 g of the above urea is dissolved in 20 ml of dimethylformamide and oxidized hot with an aqueous potassium permanganate solution. After the brownstone has been filtered off, it is mixed with water and dilute hydrochloric acid and the formed precipitate is recrystallized from methanol. N-[4-(e-<2-methoxy-5-trifluoromethylbenzamido>-ethyl)-benzenesulfonyl7-N'-(4-methylcyclohexyl)-urea is obtained with m.p. l68-170°C. Example 12. N.-(4-.(B-<2-methoxy-5-trifluoromethylbenzamido>-ethyl)-benzenesulfonyl-7-N'-(methylcyclohexyl)-urea.

2,9 g 4-/—g-(2-metoksy-5-trifluormetylbenzamido)-etyl7-benzolsulfinsyre og 1,7 g N-4-metyl-cykloheksyl-N'-hydroksy-urinstoff utrøres i 20 ml dioksan med 40 g polyfosforsyre i riv-skål. Den seigtflytende masse blandes etter 3 timer med isvann og den utfelte utfelling ekstraheres med 0, 5%- ig ammoniakk. Man filtrerer med dyrekull og surgjør filtratet med fortynnet saltsyre. Etter utfellingens omkrystallisering fra metanol får man N-<_>4-(&-<2-metoksy-5-trifluormetylbenzamido>-etyl)-benzolsulfonyl7-N'-(4-metylcykloheksyl)-urinstoff av smp. l68-170°C. 2.9 g of 4-(2-methoxy-5-trifluoromethylbenzamido)-ethyl7-benzenesulfinic acid and 1.7 g of N-4-methyl-cyclohexyl-N'-hydroxyurea are stirred in 20 ml of dioxane with 40 g polyphosphoric acid in grate bowl. After 3 hours, the viscous mass is mixed with ice water and the resulting precipitate is extracted with 0.5% ammonia. Filter with animal charcoal and acidify the filtrate with dilute hydrochloric acid. After recrystallization of the precipitate from methanol, N-<_>4-(&-<2-methoxy-5-trifluoromethylbenzamido>-ethyl)-benzenesulfonyl 7-N'-(4-methylcyclohexyl)-urea of m.p. l68-170°C.

Eksempel 13. Example 13.

N-£<r>4-(e-<2-metoksy-5-trifluormetyl-benzamido>-etyl)-benzolsulfonyl7-N*" cykloheksyl- urinstoff. N-£<r>4-(ε-<2-methoxy-5-trifluoromethyl-benzamido>-ethyl)-benzenesulfonyl 7-N*" cyclohexylurea.

2,6 g N-/~4-(g-<2-metoksy-5-trifluormetyl-benzamido-etyl)-benzolsulfonyl7-N'-(A3-cykloheksenyl)-urinstoff (smp. 171-173°C, fremstilt av 4-(3-< 2-metoksy-5-trifluormetyl-benzamido>-etyl)-benzolsulfonamid og A3-cykloheksenylisocyanat) hydreres i 2.6 g of N-[4-(g-<2-methoxy-5-trifluoromethyl-benzamido-ethyl)-benzenesulfonyl7-N'-(A3-cyclohexenyl)-urea (m.p. 171-173°C, prepared by 4-(3-<2-methoxy-5-trifluoromethyl-benzamido>-ethyl)-benzenesulfonamide and A3-cyclohexene isocyanate) are hydrated in

200 ml metanol og ca. 5 ml dimetylformamid i nærvær av en palladiumkatalysator med normalt trykk og værelsetemperatur under rysting inntil avsluttet hydrogenopptak. Man frasuger katalysatoren, avdestillerer oppløsningsmidlet best mulig under nedsatt trykk og blander residuet med vann. Det utfelte N-/_— 4-(3-<2-metoksy-5~ trifluormetyl-benzamido>-etyl)-benzolsulfonyl7-N'-cykloheksyl- 200 ml of methanol and approx. 5 ml of dimethylformamide in the presence of a palladium catalyst at normal pressure and room temperature with shaking until complete hydrogen absorption. The catalyst is sucked off, the solvent is distilled off as best as possible under reduced pressure and the residue is mixed with water. The precipitated N-[_— 4-(3-<2-methoxy-5-trifluoromethyl-benzamido>-ethyl)-benzenesulfonyl-7-N'-cyclohexyl-

urinstoff omkrystalliseres fra metanol. Smp. l63-l65°C.urea is recrystallized from methanol. Temp. 163-165°C.

Eksempel 14. Example 14.

N-/—4-(fi-<2-metoksy-5-t r if luormetyl-benzamido>-et yl)-benzolsulf onyl7-N'- cykloheksylurinstoff. N-[-4-(fi-<2-methoxy-5-trifluoromethyl-benzamido>-ethyl)-benzenesulfonyl-7-N'-cyclohexylurea.

7,1 g N-cykloheksylurinstoff oppløses i 250 ml absolutt7.1 g of N-cyclohexylurea is dissolved in 250 ml of absolute

benzol. Etter tilsetning av 2,4 g 50#-ig natriumhydrid etteromrører man i 2\ time ved 70°C. Nå tilsetter man under god omrøring en suspensjon av 10,14 g N-4-(3-2-metoksy-5-trifluormetylbenzamidoetyl)-benzol-sulfoklorid, smp. 98-100°C, i 100 ml absolutt benzol og etteromrører i 4 timer under en temperatur på 70 til 80°C. Man avkjøler, blander med vann og adskiller den vandige alkaliske fase og uttrekker ennå to ganger med fortynnet natronlut. De forenede alkaliske oppløsninger surgjøres med fortynnet saltsyre, suges fra og vaskes med vann. Det i godt utbytte dannede N-/—4-(3-<2-metoksy-5-trifluormetyl-benzamido>-etyl)-benzolsulfony_7-N'-cykloheksyl- benzene. After adding 2.4 g of 50% sodium hydride, stirring is continued for 2 hours at 70°C. A suspension of 10.14 g of N-4-(3-2-methoxy-5-trifluoromethylbenzamidoethyl)-benzene sulphochloride is now added with good stirring, m.p. 98-100°C, in 100 ml of absolute benzene and after stirring for 4 hours under a temperature of 70 to 80°C. It is cooled, mixed with water and the aqueous alkaline phase is separated and extracted twice more with diluted caustic soda. The combined alkaline solutions are acidified with dilute hydrochloric acid, sucked off and washed with water. The N-/-4-(3-<2-methoxy-5-trifluoromethyl-benzamido>-ethyl)-benzenesulfony_7-N'-cyclohexyl-

urinstoff gjenutfelles fra fortynnet (ca. 0,25#-ig) vandig ammoniakk/ fortynnet saltsyre og smelter etter omkrystallisering fra metanol ved 163-165°C urea is re-precipitated from dilute (approx. 0.25#-ig) aqueous ammonia/ dilute hydrochloric acid and melts after recrystallization from methanol at 163-165°C

Claims

Process for the preparation of orally usable benzenesulfonylureas with a strong and prolonged blood sugar-lowering effect and with the general formula

as well as their salts, wherein R means alkyl or alkenyl with 1-4 C atoms in alkyl or alkenyl- moiety, preferably methyl, B?~ means a) alkyl or alkenyl with each 3-6 carbon atoms, b) phenylalkyl with 1-4 C atoms in the alkyl part, c) cyclohexylalkyl with 1-4 C atoms in the alkyl part, cycloheptylmethyl, cycloheptylethyl or cyclooctylmethyl, d) endoalkylenecyclohexyl, endoalkylenecyclohexenyl, endoalkylenecyclohexylmethyl or endoalkylenecyclohexenylmethyl with 1 to 2 endoalkylene carbon atoms, e) alkylcyclohexyl with 1-4 C atoms in the alkyl part, alkoxycyclohexyl with 1-4 C atoms in the alkyl part, f) cycloalkyl with 5 to 8 carbon atoms, g) cyclohexenyl, cyclohexenylmethyl, X means acyl with 1-4 C atoms, nitro, trifluoromethyl, phenyl or benzyl, Y means -CH2 -CH2 -, -CHCCH-j)-CH_- or -CH2-CH(CH-5)- or their salts, characterized by either) converting benzenesulfonyl isocyanates, -carbamic acid esters, -thiocarbamic acid esters, -carbamic acid halides, - ureas, -semi-carbazides or -semicarbazones which are substituted in the p-position with the group

with amines, which are substituted by the group R^" or their salts, orb) reacts sulfonamides of formula

or their salts with isocyanates, carbamic acid esters, thiolcarbamic acid esters, carbamic acid halides or ureas which are substituted with the group R-1- orc) hydrolyze N-benzenesulfonylisourea ethers, -isourea esters, -isothiourea ethers, -parabanic acids or -haloformic acid amidines, which in the benzene nucleus are substituted with the group

and in the N' position is substituted with the group R <1> or d) reacts benzenesulfonyl halides which are substituted with the group

which is substituted with the group of ureas which are substituted with the group R"*", especially their alkali salts, or e) reacts benzolsulfinic acid halides which are substituted with the group

or in the presence of acid condensation agents also the corresponding substituted benzenesulfinic acids or their alkali salts with hydroxyureas, whose NHg group is substituted with R <1> , or f) adds water to carbodiimides of the general formula

. or g) exchanges the sulfur atom in benzenesulfonylthioureas corresponding to benzenesulfonylureas of formula I with an oxygen atom or h) oxidizes benzenesulfinyl or -sulfenylureas corresponding to benzenesulfonylureas of formula I or i) hydrates benzenesulfonylureas which correspond to benzenesulfonylureas of formula I and which in the molecule contain olefinically unsaturated bonds, ork) in benzenesulfonylureas of formula

by acylation, possibly step by step in a known manner introducing the residue

or 1) exchanges the sulfur atom or atoms in thiobenzamido-alkylbenzene-sulfonylureas or -thioureas that correspond to benzolsulfonylureas f is of formula I with an oxygen atom resp. oxygen atoms, orm) saponify compounds with formula

or their parabanic acid derivatives or compounds of formula

where U each time means one of the groups -0- low molecular weight alkyl-, -S- low molecular weight alkyl or halogen (preferably chlorine), and optionally reacts formed compounds with a base to form a salt.