NO124373B - - Google Patents

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NO124373B
NO124373B NO2971/70A NO297170A NO124373B NO 124373 B NO124373 B NO 124373B NO 2971/70 A NO2971/70 A NO 2971/70A NO 297170 A NO297170 A NO 297170A NO 124373 B NO124373 B NO 124373B
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ethyl
imino
phenylsulfonyl
imidazolidine
amino
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NO2971/70A
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Norwegian (no)
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H Dietrich
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Ciba Geigy Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/46—Nitrogen atoms not forming part of a nitro radical with only hydrogen atoms attached to said nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Analogifremgangsmåte for fremstilling av nye terapeutisk virksomme derivater av p-aminoalkyl-benzensulfonamid. Analogy method for the production of new therapeutically active derivatives of p-aminoalkyl-benzenesulfonamide.

Nærværende oppfinnelse vedrører en fremgangsmåte The present invention relates to a method

for fremstilling av nye terapeutiske virksomme for the production of new therapeutic agents

derivater av p-aminoalkylbenzensulfonamid. derivatives of p-aminoalkylbenzenesulfonamide.

Det er funnet at p-substituerte fenylsulfonyl-2-imino-imidazolidiner med den generelle formel I, It has been found that p-substituted phenylsulfonyl-2-imino-imidazolidines of the general formula I,

hvor R, betyr en. eventuell forgrenet alkylrest med where R, means a. any branched alkyl residue with

1- - 6- karbonatomert en- allylrest, en cykloalkyl- 1- - 6- carbon atomized en- allyl residue, a cycloalkyl-

hhv. cykloalkenylrest: med S - a karbonatomer, respectively cycloalkenyl radical: with S - a carbon atoms,

R 2 "hydrogen, én etyl- eller en metylgruppe, R 2 "hydrogen, one ethyl or one methyl group,

R3 en eventuelt forgrenet alkylgruppe med 1-6 R3 an optionally branched alkyl group with 1-6

karbonatomer, en cykloalkyl- hhv. cykloalkenylgruppe med hoyst 8 karbonatomer, en alkenylgruppe med 3-5 karbonatomer, en fenylgruppe, carbon atoms, a cycloalkyl or cycloalkenyl group with at most 8 carbon atoms, an alkenyl group with 3-5 carbon atoms, a phenyl group,

R. hydrogen, en eventuelt forgrenet alkylgruppe med R. hydrogen, an optionally branched alkyl group with

1 - 6-karbonatomer, en f enylgruppe, 1 - 6 carbon atoms, a phenyl group,

og R^ tilsammen en polymetylenkjede med 4-7 karbonatomer, som.-kan være avbrutt av et oksygenatom, X oksygen eller svovel og and R^ together a polymethylene chain with 4-7 carbon atoms, which can be interrupted by an oxygen atom, X oxygen or sulfur and

m 2 eller 3, m 2 or 3,

såvel som deres addisjonssalter med uorganiske eller organiske syrer oppviser en hypoglykemisk virkning på varmblodsdyr. as well as their addition salts with inorganic or organic acids exhibit a hypoglycemic effect on warm-blooded animals.

I forbindelsene med den generelle formel I kan R^ f.eks-., ha f olgende betydninger: som alkylgruppe metyl- ,. etyl- , prppyl- , isopropyl-, butyl-,~sek.butyl-, tert.butyl-, isobutyl-, pentyl-, isopentyl-, 2^2-dimetyl-propyl-, 1-metyl-butyl-, 1-etyl-propyl- eller 1,2-dimetyl-prppylgruppen,. eller en heksyl-, metyl—pentyl— ^ dimetyl-butyl-, etyl-butylgruppe; som cyklo-alkylgruppe eyklopentylgruppen, som- eventuelt kan være substituert med alkylrester med 1 - 3 karbonatomer, cykloheksyl-gruppen, som kan være substituert med etyl eller metyl, og eventuelt den meÆ metyl substituerte cykloheptylgruppen, såvel som cyklooktylgruppen; som cykloalkenylgruppe 2-cyklopenten-l-yl-, 2-cykloheksen-l-yl-, 3-cykloheksen-l-yl-, 2-metyl-2-cykloheksen-l-yl-,.3-cyklohepten-l-yl-gruppen, eller en In the compounds of the general formula I, R^ can, for example, have the following meanings: as alkyl group methyl-,. ethyl-, propyl-, isopropyl-, butyl-, ~sec.butyl-, tert.butyl-, isobutyl-, pentyl-, isopentyl-, 2^2-dimethyl-propyl-, 1-methyl-butyl-, 1- the ethyl-propyl or 1,2-dimethyl-propyl group,. or a hexyl, methyl-pentyl-, dimethyl-butyl, ethyl-butyl group; as cycloalkyl group the cyclopentyl group, which may optionally be substituted with alkyl residues with 1 - 3 carbon atoms, the cyclohexyl group, which may be substituted with ethyl or methyl, and optionally the meÆ methyl substituted cycloheptyl group, as well as the cyclooctyl group; as cycloalkenyl group 2-cyclopenten-1-yl-, 2-cyclohexen-1-yl-, 3-cyclohexen-1-yl-, 2-methyl-2-cyclohexen-1-yl-,.3-cyclohepten-1-yl -group, or one

cyklooktenylgruppe. cyclooctenyl group.

Substituenten. står for de samme som under R^ nevnte alkylgrup-pene, cykloalkyl- hhv. cykloalkenylgruppene, og alkenylgruppen står for allyl-, 1-metyl-ally1-, 2-metyl-allyl-, 2- hhv. 3-butenyl- eller 2-, 3- hhv. 4-pentenylgruppen. The substituent. stand for the same as the alkyl groups mentioned under R^, cycloalkyl or the cycloalkenyl groups, and the alkenyl group stands for allyl-, 1-methyl-allyl-, 2-methyl-allyl-, 2- or 3-butenyl- or 2-, 3- or the 4-pentenyl group.

Efter fremgangsmåten ifolge oppfinnelsen fremstilles forbindelser med den generelle formel.I, idet man omsetter en forbindelse med den generelle formel II, . According to the method according to the invention, compounds of the general formula I are prepared by reacting a compound of the general formula II.

hvor R , R2 og m har den under formel I angitte where R , R 2 and m have the under formula I indicated

betydning, importance,

med et isocyanat hhv. isotiocyanat med den generelle formel III, with an isocyanate or isothiocyanate of the general formula III,

hvor R^ og X har den under formel I angitte betydning, eller med et reaksjonsdyktig derivat av en karbaminsyre hhv. tiokarbaminsyre med den generelle formel IV, where R^ and X have the meaning given under formula I, or with a reactive derivative of a carbamic acid or thiocarbamic acid of the general formula IV,

hvor R^, R^ og X har den under formel I angitte where R^, R^ and X have the under formula I indicated

betydning, importance,

og overforer de erholdte reaksjonsprodukter, om onsket, i saltet til en uorganisk eller organisk syre. and transfers the obtained reaction products, if desired, in the salt to an inorganic or organic acid.

Som reaksjonsdyktige derivater av en karbamin- hhv. tiokarbaminsyre med den generelle formel IV, kommer i betraktning f.eks. halogenider, fortrinnsvis klorider, de lavere alkylestere, fortrinnsvis metyl- eller etylester^ fenylester, amider, de lavere mono- hhv. dialkylamider, fortrinnsvis R-metyl- og N,N-dimetylamidene^ difenyl-amidene, videre N-acylamidene som f.eks. acetylamidene og benzoylamidene. As reactive derivatives of a carbamine or thiocarbamic acid with the general formula IV, comes into consideration e.g. halides, preferably chlorides, the lower alkyl esters, preferably methyl or ethyl esters, phenyl esters, amides, the lower mono- or dialkyl amides, preferably the R-methyl and N,N-dimethyl amides, the diphenyl amides, further the N-acyl amides such as e.g. the acetylamides and the benzoylamides.

Omsetningen skjer f .eks. ved romtemperatur eller ved oppvarmning, i et inert organisk opplpsningsmiddel. Som slike kommer f.eks. folgende^ i betraktnings hydrokarboner, som benzen,, toluen eller xylen; eter, som dietyleter, dioksan eller tetrahydrofuran; klorerte hydrokarboner som metylenklorid; og lavere ketoner som aceton eller metyletylketon. Reaksjonen kan vanligvis gjennom-fares uten tilsetning av kondensasjonsmidler. Om onsket kan slike midler, f.eks, alkalimetallalkoholater og alkalimetall-hydroksyder imidlertid tilsettes. The turnover takes place e.g. at room temperature or upon heating, in an inert organic solvent. As such, e.g. the following^ in consideration of hydrocarbons, such as benzene, toluene or xylene; ether, such as diethyl ether, dioxane or tetrahydrofuran; chlorinated hydrocarbons such as methylene chloride; and lower ketones such as acetone or methyl ethyl ketone. The reaction can usually be carried out without the addition of condensing agents. However, if desired, such agents, for example, alkali metal alcoholates and alkali metal hydroxides, can be added.

Omsetningen av et halogenid av en karbaminsyre, hhv. tiokarbaminsyre med den generelle formel IV skjer ifolge oppfinnelsen fortrinnsvis i nærvær av et syrebindende middel. Som sådant kan anvendes uorganiske baser eller salter, som f.eks. et alkalihydroksyd, -acetat, -hydrogenkarbonat, -karbonat og -fosfat, som natriumhydroksyd, -acetat, -hydrogenkarbonat, -karbonat og -fosfat eller de tilsvarende kaliumforbindelsene. Videre kan anvendes kalsiumoksyd,.-karbonat, såvel som -fosfat og magnesiumkarbonat. I stedet for uorganiske baser eller salter egner seg også organiske baser, som f.eks. pyridin, trimetyl-eller trietylaminr diisopropylamin, eller kollidin. Disse kan, tilsatt i overskudd, også anvendes som løsningsmiddel. The reaction of a halide of a carbamic acid, resp. According to the invention, thiocarbamic acid with the general formula IV takes place preferably in the presence of an acid-binding agent. As such, inorganic bases or salts can be used, such as e.g. an alkali hydroxide, acetate, hydrogen carbonate, carbonate and phosphate, such as sodium hydroxide, acetate, hydrogen carbonate, carbonate and phosphate or the corresponding potassium compounds. Furthermore, calcium oxide,.-carbonate, as well as -phosphate and magnesium carbonate can be used. Instead of inorganic bases or salts, organic bases are also suitable, such as e.g. pyridine, trimethyl or triethylamine, diisopropylamine, or collidine. These can, added in excess, also be used as a solvent.

I stedet for aminer med den generelle formel II, kan det ifolge oppfinnelsen ved omsetningen med et karbamin- hhv. tiokarbamin-syreklorid også anvendes N-alkalimetallderivater av disse forbindelser, som f.eks. natrium-, kalium- eller litiumderivater. Instead of amines with the general formula II, according to the invention, the reaction with a carbamine or thiocarbamic acid chloride, N-alkali metal derivatives of these compounds are also used, such as e.g. sodium, potassium or lithium derivatives.

Utgangsforbindelsene med den generelle formel II er på sin side nye forbindelser og kan f.eks. fremstilles idet man omsetter et reaksjonsdyktig derivat av en sulfonsyre med den generelle formel V, The starting compounds with the general formula II are in turn new compounds and can e.g. is prepared by reacting a reactive derivative of a sulfonic acid with the general formula V,

hvor R står for en enkel alkyl- hhv. arylrest, f.eks. where R stands for a simple alkyl or aryl residue, e.g.

en metyl-, hhv. en fénylgruppe og a methyl-, respectively a phenyl group and

m har den under formel I angitte betydning, m has the meaning given under formula I,

med 2-amino-2-imidazolin-derivater med den generelle formel VI, with 2-amino-2-imidazoline derivatives of the general formula VI,

hvor R^ og R^ har den under formel I angitte where R^ and R^ have the one indicated under formula I

betydning, importance,

og til slutt foretaes en hydrolytisk avspaltning av acylbeskyt-telsesgruppen (R-CO-) . Den intermediært erholdte og av formel II avledede N-acylforbindelsen er heller ikke tidligere blitt beskrevet i litteraturen. and finally a hydrolytic removal of the acyl protecting group (R-CO-) is carried out. The N-acyl compound obtained intermediately and derived from formula II has also not previously been described in the literature.

Som reaksjonsdyktige derivater av en sulfonsyre med den generelle formel V kommer i betraktning halogenider, fortrinnsvis klorider og anhydrider med den generelle formel Va, hvor R- har den under formel V angitte betydning. As reactive derivatives of a sulfonic acid with the general formula V, halides, preferably chlorides and anhydrides with the general formula Va, where R- has the meaning given under formula V, come into consideration.

Anhydrider med den generelle formel Va kan på enkel måte erholdes ved omsetning av tilsvarende substituerte sulfonsyrehalogenider med salter av tilsvarende substituerte sulfonsyrer. Anhydrides of the general formula Va can be obtained in a simple way by reacting correspondingly substituted sulfonic acid halides with salts of correspondingly substituted sulfonic acids.

Efter en annen fremgangsmåte kommer man frem til utgangsstoffer med den generelle formel II, idet man. omsetter substituerte p-(aminoalkyl)-benzensulfonamider (fremstilt analogt E. Miller, J.Amer. Chem.Soc.62, 2101 (1940)) med den generelle, formel VII, Following another method, starting materials with the general formula II are arrived at, as reacts substituted p-(aminoalkyl)-benzenesulfonamides (prepared analogously to E. Miller, J. Amer. Chem. Soc. 62, 2101 (1940)) with the general formula VII,

hvor m har deri under formel I angitte betydning, where m has the meaning given therein under formula I,

med substituerte N-(2-bromalkyl)-cyanamider i alkalisk medium. with substituted N-(2-bromoalkyl)-cyanamides in alkaline medium.

Fremstillingen av utgangsforbindelsene med den generelle formel III og den generelle formel IV skjer ifolge de ålment kjente fremstillingsmetodene for isocyanater hhv. isotiocyanater og karbaminsyrederivater} hhv. tiokarbaminsyrederivater. The preparation of the starting compounds with the general formula III and the general formula IV takes place according to the widely known preparation methods for isocyanates or isothiocyanates and carbamic acid derivatives} respectively. thiocarbamic acid derivatives.

De: nye aktivstoffene eller de farmasdytisk aksepterbare saltene av disse kan administreres peroralt eller parenteralt. For saltdannelse kan anvendes fysiologisk egnede uorganiske eller organiske syrer, som f.eks. saltsyre, bromhydrogensyre, svovel-syre, fosforsyre, metansulfonsyre, eddiksyre, melkesyre, ravsyre, vinsyre og maleinsyre, men også blodsukkersendendé sulfonyl-urinstoffer kan anvendes, som f.eks. p-toluensulfonyl-butyl-urinstoff, p-klorbenzen-sulfonyl-propyl-urinstoff og p-[2-(2-metoksy-5-klor-benzamido)-etyl]-fenylsulfonyl-cykloheksyl-urinstoff. De daglige doser ligger mellom 10 og 400 mg/kg varmblodsdyr. Egnede doseenhetsformer som dragéer eller tabletter inneholder fortrinnsvis 10-200 mg av et aktivstoff ifolge oppfinnelsen, hvorved aktivstoffinnholdet utgjor 20 - 80 vektsprosent. The: new active substances or the pharmaceutically acceptable salts thereof can be administered orally or parenterally. Physiologically suitable inorganic or organic acids can be used for salt formation, such as e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulphonic acid, acetic acid, lactic acid, succinic acid, tartaric acid and maleic acid, but also blood sugar-sending sulphonylureas can be used, such as e.g. p-toluenesulfonyl-butyl urea, p-chlorobenzenesulfonyl-propyl urea and p-[2-(2-methoxy-5-chloro-benzamido)-ethyl]-phenylsulfonyl-cyclohexyl urea. The daily doses are between 10 and 400 mg/kg warm-blooded animals. Suitable dosage unit forms such as dragées or tablets preferably contain 10-200 mg of an active substance according to the invention, whereby the active substance content amounts to 20-80% by weight.

De efterfolgende eksempler forklarer nærmere fremstillingen av de nye forbindelser med den generelle formel I og av hittil ikke beskrevne mellomprodukter. De er dog på ingen måte de eneste utforelsesformer for de samme. Temperaturene er angitt i Celsiusgrader. The following examples explain in more detail the preparation of the new compounds of the general formula I and of previously undescribed intermediates. However, they are by no means the only embodiments of the same. The temperatures are indicated in degrees Celsius.

EKSEMPEL 1 EXAMPLE 1

a) 39,8 g. l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin^dihydroklorid loses i 100 ml vann og basen a) 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine^dihydrochloride are dissolved in 100 ml of water and the base

frigjøres med 150 ml 2-n natronlut. Det ekstraheres 3 ganger med 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlbsningen tilsettes 8,5 g n-propyl-isocyanat og roreSr 1 time. Derefter inndampes reaksjonsblandingen i vakuum.og det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-n-propylureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin smelter ved 164 - 166°. b) Ut gangsma teri alet l-[p-(2-amino-etyl)-f enylsulf onyl]-2-imino-3-butyl-imidazolidin-dihydroklorid fåes ifolge to fremgangsmåter: 1) 36,65 g l-[p-(2-acetamino-etyl)-fenylsulfonylJ-2-imino-3-butyl-imidazolidin loses i 370 ml 2-n saltsyre, og losningen kokes 6 timer ved tilbakelop. Losningen inndampes i vakuum til torrhet og den erholdte olje loses i alkohol. Ved avkjoling utkrystalliserer l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-butyI-imidazolidin-dihydroklorid med smp. 231 - 233°. is released with 150 ml of 2-n caustic soda. It is extracted 3 times with 250 ml of methylene chloride. 8.5 g of n-propyl isocyanate is added to the sodium sulfate-dried methylene chloride solution and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-n-propylureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine melts at 164 - 166°. b) The starting material l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine dihydrochloride is obtained according to two methods: 1) 36.65 g of l-[p -(2-acetamino-ethyl)-phenylsulfonyl-2-imino-3-butyl-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is evaporated in vacuo to dryness and the oil obtained is dissolved in alcohol. On cooling, 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine dihydrochloride with m.p. 231 - 233°.

Dette l-[p-(2-acetamido-etyl)-fenylsulfonyl]-2-imino-3-butyl-imidazolidin kan fremstilles på folgende måte: I en losning av 8,5 g natriumhydroksyd i 85 ml vann tilsettes 17,8 g l-butyl-2-imino-imidazolidin-hydroklorid. Til den erholdte klare losning tilsettes en opplesning av 26,6 g p-(2-acetamidoetylNbenzensulfoklorid i lOO ml aceton, hvorved en temperaturhoyning inntrer. Blandingen oppvarmes til slutt 1/2 time ved 90° og derpå inndampes den i vakuum til torrhet. Den tilbakeværende rest omkrystalliseres i eddikester. Det rene l.[p-C>-acetamido-etyl)-fenylsulfonyl]-2-imino-3-butyl-imidazolidin smelter ved 130 - 131°. This 1-[p-(2-acetamido-ethyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine can be prepared in the following way: In a solution of 8.5 g of sodium hydroxide in 85 ml of water, 17.8 g are added 1-butyl-2-imino-imidazolidine hydrochloride. To the clear solution obtained is added a portion of 26.6 g of p-(2-acetamidoethyl Nbenzenesulfochloride in 100 ml of acetone, whereby a temperature rise occurs. The mixture is finally heated for 1/2 hour at 90° and then evaporated in vacuo to dryness. the remaining residue is recrystallized in acetic ester The pure 1.[p-C>-acetamido-ethyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine melts at 130 - 131°.

De i de folgende eksempler for fremstilling av utgangsmaterialer benyttede I-[p-(2-acetamido-etyl)-fenylsulfonyl]-2-imino-imidazolidiner erholdes på analog måte ved omsetning av p-(2-acetamido-etyl)-benzensulfoklorid med tilsvarende substituerte 2-imino-imidazolidiner. 2) En blanding av lOO ml dimetylsulfoksyd, 11,2 g pulverisert kaliumhydroksyd, 23,65 g p-(2-amino-etyl)-benzensulfonamid-hydroklorid flit.: E. Miller et al, J. Amer,Chem,Soc.62, 2101, The I-[p-(2-acetamido-ethyl)-phenylsulfonyl]-2-imino-imidazolidines used in the following examples for the preparation of starting materials are obtained in an analogous manner by reacting p-(2-acetamido-ethyl)-benzenesulfochloride with correspondingly substituted 2-imino-imidazolidines. 2) A mixture of 100 ml dimethyl sulfoxide, 11.2 g powdered potassium hydroxide, 23.65 g p-(2-amino-ethyl)-benzenesulfonamide hydrochloride flt.: E. Miller et al, J. Amer, Chem, Soc. 62, 2101,

(1940)] og 16 g N-(2-klor-etyl)-N-butyl-cyanamid oppvarmes i oljebad og holdes 1 time ved 110° under roring. Efter avkjoling heller man på vann. Den erholdte uklare losning stilles alkalisk med konsentrert natronlut, mettes med natriumklorid og ekstraheres 3 ganger med metylenklorid. Den organiske fasen torkes over natriumsulfat, filtreres og inndampes. Den erholdte olje (frie basen) loses i alkohol og stilles sur med mettet alkoholisk saltsyre. Ved avkjoling og eventuell utspedning med eter utfelles l-[p-(2-aminoetyl)-fenylsulfonyl]-2-imino-3-butyl-imidazolidin-dihydroklorid med smp. 231 - 233°. (1940)] and 16 g of N-(2-chloro-ethyl)-N-butyl-cyanamide are heated in an oil bath and kept for 1 hour at 110° with stirring. After cooling, pour on water. The cloudy solution obtained is made alkaline with concentrated caustic soda, saturated with sodium chloride and extracted 3 times with methylene chloride. The organic phase is dried over sodium sulphate, filtered and evaporated. The obtained oil (free base) is dissolved in alcohol and acidified with saturated alcoholic hydrochloric acid. On cooling and possible dilution with ether, 1-[p-(2-aminoethyl)-phenylsulfonyl]-2-imino-3-butyl-imidazolidine dihydrochloride is precipitated with m.p. 231 - 233°.

EKSEMPEL 2 EXAMPLE 2

Analogt eksempel 1 erholdes: Analogous to example 1, the following is obtained:

fra 38,4 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-isopropyl-imidazolidin-dihydroklorid og 12,5 g cykloheksylisocyanat 1- [p-(2-cykloheksyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-isopropyl-imidazolidin med smp. 158 - 159°. from 38.4 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isopropyl-imidazolidine dihydrochloride and 12.5 g of cyclohexylisocyanate 1-[p-(2-cyclohexyl-ureido) -ethyl)-phenylsulfonyl]-2-imino-3-isopropyl-imidazolidine with m.p. 158 - 159°.

fra 42,5 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-2-n-butyl-4-etyl-imidazolidin-dihydroklorid og 12,5 g cykloheksyliso- from 42.5 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-2-n-butyl-4-ethyl-imidazolidine dihydrochloride and 12.5 g of cyclohexyliso-

cyanat l-[p-(2-(cykloheksyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-4-etyl-imidazolidin med smp. 98 - 99°. cyanate 1-[p-(2-(cyclohexyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-4-ethyl-imidazolidine with m.p. 98 - 99°.

fra 43,7 g l-[p-(2-amino-propyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidinr-dihydroklorid og 12,5 g cykloheksyl- from 43.7 g of 1-[p-(2-amino-propyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine n-dihydrochloride and 12.5 g of cyclohexyl-

isocyanat l-[p-(2-(cykloheksyl-ureido)-propyl)-fenylsulfonyl]-2- imino-3-cykloheksyl-imidazolidin med smp. 201 - 202°. isocyanate l-[p-(2-(cyclohexyl-ureido)-propyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 201 - 202°.

EKSEMPEL 3 EXAMPLE 3

Ved å gå ut fra 39,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n.butyl-imidazolidin-dihydroklorid erholdes analogt eksempel 1: a) med 8,5 g isopropyl-isocyanat l-[p-(2-(3-isopropyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin, Starting from 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n.butyl-imidazolidine dihydrochloride is obtained analogously to example 1: a) with 8.5 g isopropyl isocyanate 1-[p-(2-(3-isopropyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine,

smp. 151 - 152° (fra eddikester). m.p. 151 - 152° (from acetic acid).

b) med 9,9 g n-butyl-isocyanat 1-[p-(2-(3-n-butyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin med smp. 158 - b) with 9.9 g of n-butyl isocyanate 1-[p-(2-(3-n-butyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine with m.p. 158 -

159° (i eddikester). 159° (in vinegar).

c) med 11,5 g n-butyl-isotiocyanat l-[p-(2-(3-n-butyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin c) with 11.5 g of n-butyl isothiocyanate 1-[p-(2-(3-n-butyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine

med smp. 183 - 184°. (i eddikester). with m.p. 183 - 184°. (in vinegar).

d) med 11,1 g cyklopentyl-isocyanat l-[p-(2-(3-cyklopentyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin med d) with 11.1 g of cyclopentyl isocyanate 1-[p-(2-(3-cyclopentyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine with

smp. 176 - 177° (i eddikester). m.p. 176 - 177° (in vinegar).

e) med 11,9 g fenyl-isocyanat l-[p-(2-(3-fenylureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-hemihydrat med smp. e) with 11.9 g of phenyl isocyanate 1-[p-(2-(3-phenylureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine hemihydrate with m.p.

210 - 211° (i eddikester). 210 - 211° (in vinegar).

f) med 13,5 g fenyl-isotiocyanat l-[p-(2-(3-fenyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin inne- f) with 13.5 g of phenyl isothiocyanate 1-[p-(2-(3-phenyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine inside

holdende 1/4 mol vann med smp. 195 - 196° (i eddikester). holding 1/4 mol of water with m.p. 195 - 196° (in vinegar).

EKSEMPEL 4 EXAMPLE 4

a) 38,4 g l-[p-(2-amino-etyl>-fenylsulfonyl]-2-^imino-3-n-propyl-imidazolidin-dihydroklorid loses i 100 ml vann og a) Dissolve 38.4 g of 1-[p-(2-amino-ethyl>-phenylsulfonyl]-2-^imino-3-n-propyl-imidazolidine dihydrochloride in 100 ml of water and

basen frigjores med 150 ml 2-n natronlut. Den ekstraheres 3 the base is released with 150 ml of 2-n caustic soda. It is extracted 3

ganger med 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridldsning tilsettes 12,5 g cykloheksyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum, times with 250 ml of methylene chloride. 12.5 g of cyclohexyl isocyanate is added to the sodium sulfate-dried methylene chloride solution and stirred for 1 hour. The reaction mixture is then evaporated in vacuo,

og den krystallinske tiIbakeværende rest omkrystalliseres i eddikester. Det erholdte l-[p-(2-(3-cykloheksyl-ureido)- . etyl)-fenylsulfonyl]-2-imino-3-n-propyl-imidazolidin smelter ved 185 - 186°. and the crystalline residue remaining is recrystallized in acetic acid. The obtained 1-[p-(2-(3-cyclohexyl-ureido)-.ethyl)-phenylsulfonyl]-2-imino-3-n-propyl-imidazolidine melts at 185-186°.

b). Utgangsmaterialet l-[p-(2-amino-etyl)-fenyl-sulfonyl]-2-imino-3-propyl-imidazolidin-dihydroklorid fremstilles ifolge b). The starting material 1-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-propyl-imidazolidine dihydrochloride is prepared as follows

to fremgangsmåter: two methods:

1) 35,2 g l-[p-(2-acetamino-etyl)-fenyl-sulfonyl]-2-imino-3-propyl-imidazolidin loses i 370 ml 2-n saltsyre og oppløsningen kokes 6 timer ved tilbakelop. Oppløsningen inndampes i vakuum til torrhet og den erholdte olje loses i alkohol. Ved avkjoling utkrystalliserer l-[p^(2-amino-etyl)-benzen-sulfonyl]-2-imino-3-propyl-imidazolidin-dihydroklorid med smp. 255 - 256°. 2) En blanding av 100 ml dimetylsulfoksyd, 11,2 g pulverisert kaliumhydroksyd, 2 3,65 g p-(2-amino-etyl)-fenyl-sulfonamid-hydroklorid [lit.: E. Miller et al, J.Amer,Chem.Soc. 62, 2101, 1) 35.2 g of 1-[p-(2-acetamino-ethyl)-phenyl-sulfonyl]-2-imino-3-propyl-imidazolidine are dissolved in 370 ml of 2-n hydrochloric acid and the solution is refluxed for 6 hours. The solution is evaporated in vacuo to dryness and the oil obtained is dissolved in alcohol. On cooling, 1-[p^(2-amino-ethyl)-benzene-sulfonyl]-2-imino-3-propyl-imidazolidine dihydrochloride crystallizes out with m.p. 255 - 256°. 2) A mixture of 100 ml of dimethyl sulfoxide, 11.2 g of powdered potassium hydroxide, 2 3.65 g of p-(2-amino-ethyl)-phenyl-sulfonamide hydrochloride [lit.: E. Miller et al, J. Amer, Chem.Soc. 62, 2101,

(1940)] og 16 g N-(2-klor-etyl)-N-propyl-cyanamid oppvarmes (1940)] and 16 g of N-(2-chloro-ethyl)-N-propyl-cyanamide are heated

i oljebad og holdes 1 time ved 110° under roring. Efter avkjoling heller man på vann. Den erholdte uklare losning stilles alkalisk med konsentrert natronlut, mettes med• natriumklorid og ekstraheres tre ganger med metylenklorid. in an oil bath and kept for 1 hour at 110° while stirring. After cooling, pour on water. The cloudy solution obtained is made alkaline with concentrated caustic soda, saturated with sodium chloride and extracted three times with methylene chloride.

Den organiske fasen torkes over natriumsulfat, filtreres og inndampes. Den erholdte olje (frie base) loses i alkohol og stilles sur med mettet alkoholisk saltsyre. Ved avkjoling og eventuell utspedning med eter utfelles l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-propyl-imidazolidin-dihydroklorid med smp. 255 - 256°. The organic phase is dried over sodium sulphate, filtered and evaporated. The obtained oil (free base) is dissolved in alcohol and acidified with saturated alcoholic hydrochloric acid. On cooling and possible dilution with ether, 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-propyl-imidazolidine dihydrochloride is precipitated with m.p. 255 - 256°.

EKSEMPEL 5 EXAMPLE 5

a) 39,8 g l-[p- (2-amino-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin-dihydroklorid loses i 100 ml vann, og basen a) 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water, and the base

frigjores med 150 ml 2-n natronlut. Den ekstraheres 3 ganger med 250 ml metylenklorid.. Den med natriumsulfat torkedé metylenkloridlosningen tilsettes 8,5 g n-propyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum, og det krystallinske residum omkrystalliseres i eddikester. is released with 150 ml of 2-n caustic soda. It is extracted 3 times with 250 ml of methylene chloride. To the methylene chloride solution dried with sodium sulfate, 8.5 g of n-propyl isocyanate is added and stirred for 1 hour. The reaction mixture is then evaporated in vacuo, and the crystalline residue is recrystallized in acetic acid.

Det erholdte l-[p-(2-(3-n-propyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin smelter ved 154 - 156°. The obtained 1-[p-(2-(3-n-propyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine melts at 154-156°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin-dihydroklorid-monohydrat erholdes b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride monohydrate is obtained

ifolge to fremgangsmåter: according to two methods:

1) 36,65 g l-[p- (2-acetamino-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin loses i 370 ml 2-n saltsyre, og opp-løsningen kokes 6 timer ved tilbakelop. Oppløsningen inndampes i vakuum til torrhet, og den erholdte olje loses i alkohol. Ved avkjoling utkrystalliseres l-[p-(2-aminoétyl)-benzensulfonyl]-2-imino-3-isobutyl—imidazolidin-dihydroklorid-monohydrat med smp. 151 - 152°. 21 En blanding av 1O0 ml dimetylsulf oksyd, 11,2 g pulverisert kaliumhydroksyd, 23,65 g p- (2-amino-etyl')-benze<n->sulfonamid-hydroklorid [lit.: E. Miller et al, J. Amer.,Chem. Soc. 62, 2101, 1) 36.65 g of 1-[p-(2-acetamino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine are dissolved in 370 ml of 2-n hydrochloric acid, and the solution is refluxed for 6 hours. The solution is evaporated in vacuo to dryness, and the resulting oil is dissolved in alcohol. On cooling, 1-[p-(2-aminoethyl)-benzenesulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride monohydrate with m.p. 151 - 152°. 21 A mixture of 100 ml of dimethyl sulfoxide, 11.2 g of powdered potassium hydroxide, 23.65 g of p-(2-amino-ethyl')-benzene<n->sulfonamide hydrochloride [lit.: E. Miller et al, J .Amer.,Chem. Soc. 62, 2101,

(1940)] og 20,5 g N-(2-brometyl)-N-isobutyl-cyanamid (1940)] and 20.5 g of N-(2-bromomethyl)-N-isobutylcyanamide

oppvarmes i oljiebad og holdes 1 time ved 110° under roring. heated in an oil bath and kept for 1 hour at 110° while stirring.

Efter avkjoling helles på vann. Den erholdte uklare opplosning stilles alkalisk med konsentrert natronlut r mettes med natriumklorid og ekstraheres tre ganger med metylenklorid. After cooling, pour on water. The cloudy solution obtained is made alkaline with concentrated caustic soda, saturated with sodium chloride and extracted three times with methylene chloride.

Den organiske fasen torkes over natriumsulfat, filtreres og inndampes. Den erholdte olje (frie base} loses i alkohol og stilles sur med mettet alkoholisk saltsyre. Ved avkjoling og eventuell utspedning med eter utfelles l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-isobu tyl-imidazolidin-dihydroklorid-monohydrat med smp. 151 - 152°. The organic phase is dried over sodium sulphate, filtered and evaporated. The obtained oil (free base} is dissolved in alcohol and acidified with saturated alcoholic hydrochloric acid. Upon cooling and possible dilution with ether, l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl is precipitated -imidazolidine dihydrochloride monohydrate with mp 151 - 152°.

EKSEMPEL 6 EXAMPLE 6

På analog måte ifolge eksempel 4 erholdes ved å gå ut fra 39,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin-dihydroklorid med 12,5 g cykloheksylisocyanat l-[p-(2-(3-cykloheksyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin med smp. 1.71 - 172,5° (i eddikester). In an analogous manner according to example 4, starting from 39.8 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride is obtained with 12.5 g of cyclohexyl isocyanate l -[p-(2-(3-cyclohexyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine with m.p. 1.71 - 172.5° (in vinegar).

EKSEMPEL 7 EXAMPLE 7

a) 41,0 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid loses i lOO ml vann og a) 41.0 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride is dissolved in 100 ml of water and

basen frigjores med 150 ml 2-n natronlut. Den ekstraheres 3' ganger med 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes 5,7 g metyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum og det krystallinske residum omkrystalliseres i eddikester. Det the base is released with 150 ml of 2-n caustic soda. It is extracted 3 times with 250 ml of methylene chloride. 5.7 g of methyl isocyanate is added to the methylene chloride solution dried with sodium sulfate and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. The

erholdte l-[p-(2-(3-metyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin smelter ved 129 - 130°. obtained 1-[p-(2-(3-methyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine melts at 129 - 130°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid erholdes ifolge b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride is obtained according to

to fremgangsmåter: two methods:

1) 37,8 g l-[p-(2-acetamino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin loses i 370 ml 2-n saltsyre og losningen kokes 6 timer ved tilbakelop. Opplosningen inndampes så i vakuum til torrhet og den erholdte olje loses i alkohol. Ved avkjoling krystalliserer l-[p-(2-amino-etyl)-benzen-sulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid med smp. 2 70° ut. 2) En blanding av 100 ml dimetylsulfoksyd, 11,2 g pulverisert kaliumhydroksyd, 23,65 g p-(2-amino-etyl)-fenylsulfonamid-hydroklorid [lit.: E. Miller et al, J.Amer.Chem.Soc.62, 2101, 1) 37.8 g of 1-[p-(2-acetamino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine are dissolved in 370 ml of 2-n hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuo to dryness and the oil obtained is dissolved in alcohol. On cooling, 1-[p-(2-amino-ethyl)-benzenesulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride crystallizes with m.p. 2 70° out. 2) A mixture of 100 ml of dimethyl sulfoxide, 11.2 g of powdered potassium hydroxide, 23.65 g of p-(2-amino-ethyl)-phenylsulfonamide hydrochloride [lit.: E. Miller et al, J.Amer.Chem.Soc .62, 2101,

(1940)] og 17,2 g N-(2-klor-etyl)-N-cyklopentyl-cyanamid oppvarmes under roring 1 time i oljebad på 110°. Efter avkjoling heller man på vann. Den erholdte uklare opplosning stilles alkalisk med konsentrert natronlut, mettes med natriumklorid og ekstraheres tre ganger med metylenklorid. De organiske faser torkes over natriumsulfat, filtreres og inndampes. Den erholdte olje (frie base) loses i alkohol og stilles sur med mettet alkoholisk saltsyre. Efter avkjoling og eventuell utspedning med eter utfelles l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid med smp. 2 70° (spaltning). (1940)] and 17.2 g of N-(2-chloro-ethyl)-N-cyclopentyl-cyanamide are heated with stirring for 1 hour in an oil bath at 110°. After cooling, pour on water. The cloudy solution obtained is made alkaline with concentrated caustic soda, saturated with sodium chloride and extracted three times with methylene chloride. The organic phases are dried over sodium sulphate, filtered and evaporated. The obtained oil (free base) is dissolved in alcohol and acidified with saturated alcoholic hydrochloric acid. After cooling and possibly diluting with ether, 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride is precipitated with m.p. 2 70° (cleavage).

' EKSEMPEL 8 ' EXAMPLE 8

Utgående fra 41,0 g l-[p- (2-amino-etyl)-fenyl-sulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid oppnåes analogt eksempel 7: a) med 9,9 g n-butyl-isocyanat l-[p-(2-(3-n-butyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. Starting from 41.0 g of 1-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride is obtained analogously to example 7: a) with 9.9 g of n-butyl -isocyanate 1-[p-(2-(3-n-butyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p.

134 - 136° (i eddikester). 134 - 136° (in vinegar).

EKSEMPEL 9 EXAMPLE 9

a) 42,4 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid opploses i lOO ml vann a) Dissolve 42.4 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride in 100 ml of water

og basen frigjores med 150 ml 2-n natronlut. Det ekstraheres 3 ganger med 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosningen tilsettes 9,9 g n-butyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum og det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-n-butyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyi-imidazolidin smelter ved 161,5 - 162°. and the base is released with 150 ml of 2-n caustic soda. It is extracted 3 times with 250 ml of methylene chloride. 9.9 g of n-butyl isocyanate is added to the methylene chloride solution dried with sodium sulfate and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-n-butyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine melts at 161.5 - 162°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid oppnåes b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride is obtained

ifolge to fremgangsmåter: according to two methods:

1) 39,2 g l-[p-(2-acetamino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin loses i 370 ml 2-^n saltsyre og losningen kokes 6 timer ved tilbakelop. Losningen inndampes i vakuum til torrhet og den erholdte olje loses i alkohol. 1) 39.2 g of 1-[p-(2-acetamino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine are dissolved in 370 ml of 2-n hydrochloric acid and the solution is refluxed for 6 hours. The solution is evaporated in vacuo to dryness and the oil obtained is dissolved in alcohol.

Ved avkjoling utkrystalliserer l-[p-(2-amino-etyl)-fenyl-sulf onyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid med smp. 247 - 250°. 2) En blanding av 100 ml dimetylsulfoksyd, 11,2 g pulverisert kaliumhydroksyd, 23,65 g p- (2-amino-etyl)-benzensulfonamid-hydroklorid [lit.: E. Miller et al. J.Amer.Chem.Soc.62, 2101, On cooling, 1-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride crystallizes out with m.p. 247 - 250°. 2) A mixture of 100 ml of dimethyl sulfoxide, 11.2 g of powdered potassium hydroxide, 23.65 g of p-(2-amino-ethyl)-benzenesulfonamide hydrochloride [lit.: E. Miller et al. J. Amer. Chem. Soc. 62, 2101,

(1940)] og 23,1 g N-(2-brom-etyl)-N-cykloheksyl-cyanamid oppvarmes i oljebad og holdes 1 time ved 110° under roring. Efter avkjoling heller man på vann. Den erholdte uklare losning stilles alkalisk med konsentrert natronlut, mettes med natriumklorid og ekstraheres tre ganger med metylenklorid. De organiske faser torkes over natriumsulfat, filtreres og inndampes. Den erholdte olje (frie base) loses i alkohol og stilles sur med mettet alkoholisk saltsyre. Ved avkjoling og eventuell utspedning med eter utfelles I-[p-(2-amino-etyl)-fenyl-sulf onyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid med smp. 247 - 250°. (1940)] and 23.1 g of N-(2-bromoethyl)-N-cyclohexylcyanamide are heated in an oil bath and kept for 1 hour at 110° with stirring. After cooling, pour on water. The cloudy solution obtained is made alkaline with concentrated caustic soda, saturated with sodium chloride and extracted three times with methylene chloride. The organic phases are dried over sodium sulphate, filtered and evaporated. The obtained oil (free base) is dissolved in alcohol and acidified with saturated alcoholic hydrochloric acid. On cooling and possibly diluting with ether, I-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride is precipitated with m.p. 247 - 250°.

EKSEMPEL 10 EXAMPLE 10

Utgående fra 42,4 g l-[p-(2-amino-etyl)-fenyl-sulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid oppnås analogt eksempel 9. Starting from 42.4 g of 1-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride is obtained analogously to example 9.

a) med 11,5 g n-butyl-isotiocyanat l-[p-(2-(3-n-butyl-2-tio-ureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin a) with 11.5 g of n-butyl isothiocyanate 1-[p-(2-(3-n-butyl-2-thio-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine

med smp. 186 - 187° (i eddikester); with m.p. 186 - 187° (in vinegar);

b) med 11,9 g fenyl-isocyanat l-[p-(2-(3-fenyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med b) with 11.9 g of phenyl isocyanate 1-[p-(2-(3-phenyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with

smp. 210,5 - 212° (i eddikester); m.p. 210.5 - 212° (in vinegar);

c) med 13,5 g fenyl-isotiocyanat l-[p-(2-(3-fenyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med c) with 13.5 g of phenyl isothiocyanate 1-[p-(2-(3-phenyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with

smp. 188 - 189° (i eddikester). m.p. 188 - 189° (in vinegar).

EKSEMPEL 11 EXAMPLE 11

43,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-(4-metylcyklo-heksyl)-imidazolidin-dihydroklorid opploses i 100 ml vann og basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosningen tilsettes 8,5 g n-propyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum og det krystallinske residum omkrystalliseres i eddikester. 1- [p-(2-(3-n-propyl-ureido)-etyl)-fenylsulfonyl]-2-imino-(4-metylcykloheksyl)-imidazolidin, inneholder 1/4 mol vann og smelter ved 162,5 - 163°. 43.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-(4-methylcyclohexyl)-imidazolidine dihydrochloride are dissolved in 100 ml of water and the base is released with 150 ml of 2- n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. 8.5 g of n-propyl isocyanate is added to the methylene chloride solution dried with sodium sulfate and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1- [p-(2-(3-n-propyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-(4-methylcyclohexyl)-imidazolidine, contains 1/4 mole of water and melts at 162.5 - 163 °.

Utgangsmaterialet l-[p-(2-amino-etyl)-benzensulfonyl]-2-imino-3-(4-metyl-cykloheksyl)-imidazolidin-dihydroklorid oppnåes ifolge to fremgangsmåter: a) 40,7 g l-[p-(2-acetamino-etyl)-fenyl-sulfonyl]-2-imino-3-(4-metyl-cykloheksyl)-imidazolidin loses i 370 ml 2-n saltsyre The starting material l-[p-(2-amino-ethyl)-benzenesulfonyl]-2-imino-3-(4-methyl-cyclohexyl)-imidazolidine dihydrochloride is obtained according to two methods: a) 40.7 g of l-[p- (2-acetamino-ethyl)-phenyl-sulfonyl]-2-imino-3-(4-methyl-cyclohexyl)-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid

og losningen kokes 6 timer ved tilbakelop. Losningen inndampes så i vakuum til torrhet og den erholdte oljej opploses i alkohol. Ved avkjoling utkrystalliserer l-[p-(2-amino-etyl)-benzen-sulfonyl]-2- imino-3-(4-metyl-cykloheksyl)-imidazolidin-dihydroklorid med and the solution is boiled for 6 hours at reflux. The solution is then evaporated in vacuo to dryness and the oil obtained is dissolved in alcohol. On cooling, 1-[p-(2-amino-ethyl)-benzenesulfonyl]-2-imino-3-(4-methyl-cyclohexyl)-imidazolidine dihydrochloride crystallizes out with

ee

smp. 260° (under spaltning). m.p. 260° (during cleavage).

b) En blanding av lOO ml dimetylsulfoksyd, 11,2 g pulverisert kaliumhydroksyd, 23,65. g. p-(2-amino-etyl)-benzen-sulfonamid-hydroklorid [lit.: E. Miller et al, J.Amer.Chem.Soc. 62, 2101, b) A mixture of 100 ml of dimethylsulfoxide, 11.2 g of powdered potassium hydroxide, 23.65. g. p-(2-amino-ethyl)-benzenesulfonamide hydrochloride [lit.: E. Miller et al, J.Amer.Chem.Soc. 62, 2101,

(1940)] og 200 g 2-klor-etyl-(4-metyl-cykloheksyl)-cyanamid oppvarmes i- oljebad og holdes 1 time ved 110° under roring. (1940)] and 200 g of 2-chloro-ethyl-(4-methyl-cyclohexyl)-cyanamide are heated in an oil bath and kept for 1 hour at 110° with stirring.

Efter avkjoling heller man på vann. Den erholdte uklare After cooling, pour on water. It obtained unclear

losning stilles alkalisk med konsentrert natronlut, mettes med natriumklorid og ekstraheres tre ganger med metylenklorid. solution is made alkaline with concentrated caustic soda, saturated with sodium chloride and extracted three times with methylene chloride.

De organiske faser torkes med natriumsulfat, filtreres og inndampes. Den erholdte olje (frie base) loses i alkohol og stilles sur med mettet alkoholisk saltsyre. Ved- avkjoling og eventuell utspedning med eter utfelles l-[p-(2-amino-etyl)-benzen-sulf onyl]-2-imino-3-(4-metyl-cykloheksyl)-imidazolidin-dihydroklorid med smp. 260° (under spaltning). The organic phases are dried with sodium sulphate, filtered and evaporated. The obtained oil (free base) is dissolved in alcohol and acidified with saturated alcoholic hydrochloric acid. On cooling and possible dilution with ether, 1-[p-(2-amino-ethyl)-benzene-sulfonyl]-2-imino-3-(4-methyl-cyclohexyl)-imidazolidine dihydrochloride is precipitated with m.p. 260° (during cleavage).

EKSEMPEL 12 EXAMPLE 12

Utgående fra 49,8 g 1-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-(4-metylcykloheksyl)-imidazolidin-dihydroklorid oppnåes analogt eksempel 11: a) med 11,5 g n-butyl-isotiocyanat l-[p-(2-(3-n-butyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-(4-metylcykloheksyl)-imidazolidin med smp. 170 - 171°' (i eddikester); b) med 12,5 g cykloheksyl-isocyanat l-[p-(2-(3-cykloheksyl-ureido)-etyl)-f eny1sulfony1]-2-imino-3-(4-me ty1cykloheksy1)-imidazolidin med smp. 179 - 182° (i eddikester); c) med 11,9 g fenyl-isocyanat l-[p-(2-(3-fenyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-(4-metylcykloheksyl)-imidazolidin med smp. 213 - 214° (i eddikester); d) med 13,5 g f enyl-isotiocyanat l-[p-(2-(3-f enyl-2.-tio-ureido)-etyl)-fenylsulfonyl]-2-imino-3-(4-metyl-cykloheksyl)-imidazolidin med smp. 181,5 - 182,5° (i eddikester). Starting from 49.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-(4-methylcyclohexyl)-imidazolidine dihydrochloride is obtained analogously to example 11: a) with 11.5 g n -butyl isothiocyanate 1-[p-(2-(3-n-butyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-(4-methylcyclohexyl)-imidazolidine with m.p. 170 - 171°' (in vinegar); b) with 12.5 g of cyclohexyl isocyanate 1-[p-(2-(3-cyclohexyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-(4-methylcyclohexyl)-imidazolidine with m.p. 179 - 182° (in vinegar); c) with 11.9 g of phenyl isocyanate 1-[p-(2-(3-phenyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-(4-methylcyclohexyl)-imidazolidine with m.p. 213 - 214° (in vinegar); d) with 13.5 g of phenyl isothiocyanate 1-[p-(2-(3-phenyl-2.-thio-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-(4-methyl-cyclohexyl )-imidazolidine with m.p. 181.5 - 182.5° (in vinegar).

• * • *

EKSEMPEL 13 EXAMPLE 13

Analogt eksempel 11 oppnåes: Analogous to example 11, the following is obtained:

fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 7,7 g etyl-isotiocyanat l~[p-(2-(3-etyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imirio-3-cykloheksyl-imidaz01idin med smp. 140°. fra 42,3 g 1-[p-(2-amino-etyl)-fenylsulfonylJ-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 7,3 g metyl-isotiocyanat l-[p- (2-t3-metyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. 187 - 188°. fra 40,9 g 1-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid og 7,7 g etyl-isotiocyanat 1-[p-(2-(3-etyl-2-tioureido)-etyl-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. 178°. fra 40,9 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid og 7,3 g- metylisotio-cyanat l-[p- (2- (3-metyl-2-tioureido)-etyl)-f-enylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. 179°. fra 39,7 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid og 13,7 g cyklopentylisotio-cyanat 1-[p-(2-(3-cyklopentyl-2-tioureido)-etyl)-fenylsulfonyl]-2- imino-3-n-butyl-imidazolidin med smp. 206 - 207°. fra 35,5 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-metyl-imidazolidin-dihydroklorid og 11,5 g n-butyl-isotiocyanat l-[p-(2- (3-n-butyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-metyl-imidazolidln med smp. 174,5 - 176°. fra 38,1 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-allyl-imidazolidin-dihydroklorid og 11,5 g n-butyl-isotiocyanat l-[p-(2-(3-n-butyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3- allyl-imidazolidin med smp. 170 - 172°. fra 42,5 g 1-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-(1,2-dimetyl-butyl)-imidazolidin-dihydroklorid og 8,7 g etyl-isotiocyanat l-[p-(2-(3-etyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-(1,2-dimetyl-butyl)-imidazolidin med smp. 122,5 - 124°. fra 40,9 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid og 10,1 g n-propylisotio-cyanat l-[p-(2-(3-n-propyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. 184,5 - 185°. fra 40,9 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid og 10,1 g isopropylisotio-cyanat l-[p-(2-(3-isopropyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. 196 - 197°. fra 40,9 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-iminb-3-cyklopentyl-imidazolidin-dihydroklorid og 11,5 g n-butyl-isotiocyanat l-[p-(2-(3-n-butyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. 179 - 180°. fra 40,9 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid og 11,5 g sek.butyl-isotiocyanat l-[p-(2-(3-sek.butyl-2-tioureido)-etyl)-fenyl-sulf onyl] -2-imino-3-cyklopentyl-imidazolidin med smp. 191 - 192°: fra 40,9 g 1-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid og 11,5 g tert.butyl-isotiocyanat l-[p- (2-(3-tert.butyl-2-tioureido)-etyl)-fenyl-sulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. 190 - from 42.3 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 7.7 g of ethyl isothiocyanate 1~[p-(2-(3 -ethyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imirio-3-cyclohexyl-imidazolidine with m.p. 140°. from 42.3 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl J-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 7.3 g of methyl isothiocyanate 1-[p-(2-t3-methyl -2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 187 - 188°. from 40.9 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride and 7.7 g of ethyl isothiocyanate 1-[p-(2-(3 -ethyl-2-thioureido)-ethyl-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine with mp 178° from 40.9 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2 -imino-3-cyclopentyl-imidazolidine dihydrochloride and 7.3 g of methyl isothiocyanate 1-[p-(2-(3-methyl-2-thioureido)-ethyl)-f-enylsulfonyl]-2-imino-3 -cyclopentyl-imidazolidine with m.p. 179° from 39.7 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride and 13.7 g of cyclopentyl isothio -cyanate 1-[p-(2-(3-cyclopentyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine with mp 206 - 207° from 35.5 g l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-methyl-imidazolidine dihydrochloride and 11.5 g of n-butyl isothiocyanate l-[p-(2-(3-n- butyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-methyl-imidazolidin with mp 174.5 - 176° from 38.1 g of 1-[p-(2-amino-ethyl)- phenylsulfonyl]-2-imino-3-allyl-imidazolidine dihydrochloride and 11.5 g of n-butyl isothiocyanate 1-[p-(2-(3-n-butyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-allyl-imidazolidine with m.p. 170 - 172°. from 42.5 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-(1,2-dimethyl-butyl)-imidazolidine dihydrochloride and 8.7 g of ethyl isothiocyanate l- [p-(2-(3-ethyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-(1,2-dimethyl-butyl)-imidazolidine with m.p. 122.5 - 124°. from 40.9 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride and 10.1 g of n-propyl isothiocyanate l-[p-(2- (3-n-propyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p. 184.5 - 185°. from 40.9 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride and 10.1 g of isopropyl isothiocyanate 1-[p-(2-(3 -isopropyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p. 196 - 197°. from 40.9 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-iminb-3-cyclopentyl-imidazolidine dihydrochloride and 11.5 g of n-butyl isothiocyanate l-[p-(2- (3-n-butyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p. 179 - 180°. from 40.9 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride and 11.5 g of sec-butyl isothiocyanate l-[p-(2- (3-sec.butyl-2-thioureido)-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p. 191 - 192°: from 40.9 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride and 11.5 g of tert-butyl isothiocyanate l-[ p-(2-(3-tert.butyl-2-thioureido)-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p. 190 -

191° (spaltning). 191° (decomposition).

fra 40,9 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid og 12,9 g isopentylisotio- from 40.9 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride and 12.9 g of isopentyl isothio-

cyanat l-[p-(2-(3-isopentyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp.196 - 197°. cyanate 1-[p-(2-(3-isopentyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p. 196 - 197°.

fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 10,1 g n-propyl-isotio- from 42.3 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 10.1 g of n-propyl-isothio-

cyanat l-[p-(2-(3-n-propyl-2-tioureido)-etyl)-fenylsulfonyl]-2- cyanate l-[p-(2-(3-n-propyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-

imino-3-cykloheksyl-imidazolidin med smp. 174 - 175°. imino-3-cyclohexyl-imidazolidine with m.p. 174 - 175°.

fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonylj-2-imino-3-cyklc~ heksyl-imidazolidin-dihydroklorid og 10,1 g isopropyliso- from 42.3 g of 1-[p-(2-amino-ethyl)-phenylsulfonylj-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 10.1 g of isopropyliso-

tiocyanat l-[p-(2-(3-isopropyl-2-tioureido)-etyl)-fenylsulfonyl]-2- imino-3-cykloheksyr-imidazolidin med smp. 186 - 187°. thiocyanate 1-[p-(2-(3-isopropyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyr-imidazolidine with m.p. 186 - 187°.

fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 9,9 g cyklopropylisotiocyanat l-[p-(2-(3-cyklopropyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3- cykloheksyl-imidazolidin med smp. 116,5 - 118°. from 42.3 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 9.9 g of cyclopropyl isothiocyanate l-[p-(2-(3-cyclopropyl -2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 116.5 - 118°.

fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 11,5 g sek.butyl-isotiocyanat l-[p-(2-(3-sek.butyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. from 42.3 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 11.5 g of sec-butyl isothiocyanate l-[p-(2- (3-sec.butyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p.

186 - 187°. . fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 11,5 g tert.butyl-isotiocyanat 1-[p-(2-(3-tert.butyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. 186 - 187°. . from 42.3 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 11.5 g of tert.butyl isothiocyanate 1-[p-(2- (3-tert.butyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p.

201 - 202°. 201 - 202°.

fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazOlidin-dihydroklorid og 12,9 g isopentyl-isotiocyanat l-[p-(2-(3-isopentyl-2-tioureido)-etyl)-f enylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. 193,5-194,5°. from 42.3 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazOlidine dihydrochloride and 12.9 g of isopentyl isothiocyanate l-[p-(2-(3 -isopentyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 193.5-194.5°.

fra 42,3 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin.-dihydroklorid og 14,3 g n-heksyl-isotiocyanat l-[p-(2-(3-n-heksyl-2-tioureido)-etyl)-fenyl-sulf onyl] -2-imino-3-cykloheksyl-imidazolidin med smp. 172,5 - 173. from 42.3 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidin.-dihydrochloride and 14.3 g of n-hexyl isothiocyanate l-[p-(2 -(3-n-hexyl-2-thioureido)-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 172.5 - 173.

fra 42,1 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksen-3-yl-imidazolidin-dihydroklorid og 11,5 g n-butyl-isotiocyanat l-[p-(2- (3-n-butyl-2-tioureido)-etyl)-fenyl-sulf onyl]-2-imino-3-cykloheksen-3-yl-imidazolidin med smp. from 42.1 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexen-3-yl-imidazolidine dihydrochloride and 11.5 g of n-butyl isothiocyanate l-[p -(2-(3-n-butyl-2-thioureido)-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclohexen-3-yl-imidazolidine with m.p.

149 - 151°. 149 - 151°.

fra 43,7 g l-[p-(2-amino-etyl)-fenyl-sulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 8,7 g etyl-isotiocyanat l-[p-(2-(3-etyl-2-tioureido)-propyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. 162 - 163°. from 43.7 g of l-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 8.7 g of ethyl isothiocyanate l-[p-(2- (3-ethyl-2-thioureido)-propyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 162 - 163°.

EKSEMPEL 14 EXAMPLE 14

a) 41,1 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-4-metyl-imidazolidin-dihydroklorid loses i 100 ml vann a) Dissolve 41.1 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-4-methyl-imidazolidine dihydrochloride in 100 ml of water

og basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 8,5 g n-propyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum og den krystallinske rest omkrystalliseres i eddikester. l-[p-(2-(3-n-propyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-4-metyl-imidazolidin smelter ved 109 - 112°. and the base is released with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 8.5 g of n-propyl isocyanate and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-n-propyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-4-methyl-imidazolidine melts at 109 - 112°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-butyl-4-metyl-imidazolidin-dihydroklorid fåes ifolge b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-butyl-4-methyl-imidazolidine dihydrochloride is obtained according to

folgende fremgangsmåte: following procedure:

38,0 g l-[p-(2-acetamino-etyl)-fenylsulfonyl]-2-imino-3-butyl-4-metyl-imidazolidin loses i 370 ml 2-n saltsyre og opplosningen kokes 6 timer ved tilbakelop. Losningen inndampes så i vakuum til torrhet og den erholdte olje loses i alkohol. Ved avkjoling utkrystalliserer l-[p-(2-amino-etyl)-fenyl-sulfonyl]-2-imino-3-butyl-4-metyl-imidazolidin-dihydroklorid med smp. 240° (spaltning). 38.0 g of 1-[p-(2-acetamino-ethyl)-phenylsulfonyl]-2-imino-3-butyl-4-methyl-imidazolidine are dissolved in 370 ml of 2-n hydrochloric acid and the solution is refluxed for 6 hours. The solution is then evaporated in vacuo to dryness and the oil obtained is dissolved in alcohol. On cooling, 1-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-butyl-4-methyl-imidazolidine dihydrochloride with m.p. 240° (cleavage).

EKSEMPEL 15 EXAMPLE 15

Utgående fra 41,1 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-4-metyl-imidazolidin-dihydroklorid oppnåes analogt eksempel 14 med 12,5 g cykloheksyl-isocyanat l-[p-(2-(3-cykloheksyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-4-metyl-imidazolidin med smp. 137 - 138° (i eddikester). Starting from 41.1 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-4-methyl-imidazolidine dihydrochloride is obtained analogously to example 14 with 12.5 g of cyclohexyl- isocyanate l-[p-(2-(3-cyclohexyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-4-methyl-imidazolidine with m.p. 137 - 138° (in vinegar).

EKSEMPEL 16 EXAMPLE 16

a) 41,1 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-5-metyl-imidazolidin-dihydroklorid loses i 100 ml vann a) Dissolve 41.1 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-5-methyl-imidazolidine dihydrochloride in 100 ml of water

og basen frigjores med 150 ml 2-n natronlut. Det ekstraheres and the base is released with 150 ml of 2-n caustic soda. It is extracted

med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 11,3 g isoamyl-isocyanat og ror.es 1 time. Derefter inndampes reaksjonsblandingen i vakuum og det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-isoamyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-5-metyl-imidazolidin smelter ved 117 - 118°. with 3 times 250 ml of methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 11.3 g of isoamyl isocyanate and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-isoamyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-5-methyl-imidazolidine melts at 117 - 118°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-butyl-5-metyl-imidazolidin-dihydroklorid fremstilles b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-butyl-5-methyl-imidazolidine dihydrochloride is prepared

analogt 14 b) fra 38,0 g l-[p-(2-acetamino-etyl)-fenylsulfonyl]-2- imino-3-butyl-5-metyl-imidazolidin-dihydroklorid, smp. analogous to 14 b) from 38.0 g of 1-[p-(2-acetamino-ethyl)-phenylsulfonyl]-2-imino-3-butyl-5-methyl-imidazolidine dihydrochloride, m.p.

255 - 257°. 255 - 257°.

EKSEMPEL 17 EXAMPLE 17

39.7 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-propyl-5-metyl-imidazolidin-dihydroklorid loses i 100 ml vann og basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 39.7 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-propyl-5-methyl-imidazolidine dihydrochloride are dissolved in 100 ml of water and the base is released with 150 ml of 2-n caustic soda . It is extracted with 3

ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 11,1. g cyklopentyl-isocyanat og : rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum times 250 ml methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 11.1. g cyclopentyl isocyanate and: stirred for 1 hour. The reaction mixture is then evaporated in vacuo

og det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-cyklopentyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3- n-propyl-5-metyl.-imidazolidin smelter ved 137 - 138°. and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-cyclopentyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-propyl-5-methyl.-imidazolidine melts at 137 - 138°.

Utgangsmaterialet l-[p-(2-amino-etyl)-benzensulfonyl]-2-imino-3-propyl-5-metyl-imidazolidin-dihydroklorid oppnåes som folger: 36,6 g l-[p- (2-acetamino-etyl)-fenyl-sulfonyl]-2-iraino-3-propyl-5-metyl-imidazolidin opploses i 370 ml 2-n saltsyre og. losningen kokes 6 timer ved tilbakelop. Losningen inndampes så i vakuum til torrhet og den erholdte olje opploses i alkohol. Ved avkjoling utkrystalliserer l-[p-(2-amino-etyl)-benzen-sulfonyl]-2"-imino-3-propyl-5-metyl-imidazolidin-dihydroklorid med smp. 241 - 242°. The starting material l-[p-(2-amino-ethyl)-benzenesulfonyl]-2-imino-3-propyl-5-methyl-imidazolidine dihydrochloride is obtained as follows: 36.6 g of l-[p-(2-acetamino- ethyl)-phenyl-sulfonyl]-2-iraino-3-propyl-5-methyl-imidazolidine is dissolved in 370 ml of 2-n hydrochloric acid and. the solution is boiled for 6 hours at reflux. The solution is then evaporated in vacuo to dryness and the oil obtained is dissolved in alcohol. On cooling, 1-[p-(2-amino-ethyl)-benzene-sulfonyl]-2"-imino-3-propyl-5-methyl-imidazolidine dihydrochloride with mp 241 - 242° crystallizes out.

EKSEMPEL 18 EXAMPLE 18

39.8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-propyl-5-metyl-imidazolidin-dihydroklorid loses i lOO ml vann og basen 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-propyl-5-methyl-imidazolidine dihydrochloride are dissolved in 100 ml of water and the base

frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 is released with 150 ml of 2-n caustic soda. It is extracted with 3

ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes 12,5 g cykloheksyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i. times 250 ml methylene chloride. 12.5 g of cyclohexyl isocyanate is added to the sodium sulfate-dried methylene chloride solution and stirred for 1 hour. The reaction mixture is then evaporated in

vakuum og det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-cykloheksyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-propyl-5-metyl-imidazolidin smelter ved 99,5 - 100,5°. vacuum and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-cyclohexyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-propyl-5-methyl-imidazolidine melts at 99.5 - 100.5°.

Utgangsmaterialet, l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-propyl-5-metyl-imidazolidin-dihydroklorid, fremstilles analogt eksempel 17. The starting material, 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-propyl-5-methyl-imidazolidine dihydrochloride, is prepared analogously to example 17.

EKSEMPEL 19 EXAMPLE 19

a) 39,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid loses i 100 ml vann og basen a) Dissolve 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride in 100 ml of water and the base

frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 14 g 4-cykloheks-3-enyl-isotiocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum og det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-cykloheks-3-enyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin smelter ved 182 183°. is released with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 14 g of 4-cyclohex-3-enyl isothiocyanate and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-cyclohex-3-enyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine melts at 182 183°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid oppnåes ifolge de i b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride is obtained according to the

eksempel lb) angitte forskrifter. example lb) specified regulations.

EKSEMPEL 20 EXAMPLE 20

39,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin-dihydroklorid loses i 100 ml vann og basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes 9,9 g n-butyl-isocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum bg det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-n-butyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin smelter ved 144 - 144,5°. 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride are dissolved in 100 ml of water and the base is released with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. 9.9 g of n-butyl isocyanate is added to the sodium sulfate-dried methylene chloride solution and stirred for 1 hour. The reaction mixture is then evaporated in a vacuum so that the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-n-butyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine melts at 144 - 144.5°.

Utgangsmaterialet, l-[p-(2-amino-etyl)-fenyl-sulfonyl]-2-imino-3-isobutyl-imidazolidin-dihydroklorid fremstilles analogt eksempel 5 b). The starting material, 1-[p-(2-amino-ethyl)-phenyl-sulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride is prepared analogously to example 5 b).

EKSEMPEL . 21 EXAMPLE . 21

a) 41,O g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid loses i lOO ml vann og a) 41.0 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride is dissolved in lOO ml of water and

basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 14,1 g cykloheksyl-isotiocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum og den krystalline rest omkrystalliseres i eddikester. l-[p-(2-(3-cykloheksyl-2-tioureido).-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin smelter ved 21S - 216°. the base is released with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 14.1 g of cyclohexyl isothiocyanate and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-cyclohexyl-2-thioureido).-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine melts at 21S - 216°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl |-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid oppnåes efter b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl |-2-imino-3-cyclopentyl-imidazolidine dihydrochloride is obtained after

de i eksempel 7 b) angitte forskrifter. the regulations specified in example 7 b).

EKSEMPEL 22 EXAMPLE 22

a) 42,4 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid loses i lOO ml vann og a) 42.4 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride are dissolved in 100 ml of water and

basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes 12,7 g cyklopentyl-isotiocyanat og rores 1 time. Derefter inndampes reaksjonsblandingen i vakuum og det krystallinske residum omkrystalliseres i eddikester. l-[p-(2-(3-cyklopentyl-2-tioureido)-etyl)-f enylsulfonyl]-2-imino-3-cykloheksyl-imi-dazolidin smelter ved 206 - 207°. the base is released with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. 12.7 g of cyclopentyl isothiocyanate are added to the sodium sulfate-dried methylene chloride solution and stirred for 1 hour. The reaction mixture is then evaporated in vacuo and the crystalline residue is recrystallized in acetic acid. 1-[p-(2-(3-cyclopentyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine melts at 206 - 207°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid oppnåes efter b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride is obtained after

de i eksempel 9 b) angitte forskrifter. the regulations specified in example 9 b).

EKSEMPEL 23 EXAMPLE 23

Utgående fra 42,4 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid oppnåes analogt Starting from 42.4 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride is obtained analogously

eksempel 2 2: example 2 2:

a) med 14 g cykloheks-3-enyl-isotiocyanat l-[p-(2-(3-cyklo-heks-3-enyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. 208,5 - 209,5° (i eddikester); b) med 14 g cykloheksyl-isotiocyanat l-[p-(2-(3-cykloheksyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. 214 - 215° (i eddikester). a) with 14 g of cyclohex-3-enyl isothiocyanate 1-[p-(2-(3-cyclohex-3-enyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl- imidazolidine with m.p. 208.5 - 209.5° (in vinegar); b) with 14 g of cyclohexyl isothiocyanate 1-[p-(2-(3-cyclohexyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 214 - 215° (in vinegar).

EKSEMPEL 24 EXAMPLE 24

a) 39,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid loses i 100 ml vann og a) Dissolve 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride in 100 ml of water and

basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 20 g trietylamin. Derefter drypper man til ved romtemperatur opplosningen av 23,2 g difenyl-karbaminsyreklorid i lOO ml metylenklorid og rorer i 4 timer ved romtemperatur. Derefter vasker man det to ganger med 30 ml vann. Den vandige fase ekstraherer man to ganger med 100 ml metylenklorid. De forenede metylenklorid- the base is released with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 20 g of triethylamine. The solution of 23.2 g of diphenylcarbamic acid chloride in 100 ml of methylene chloride is then added dropwise at room temperature and stirred for 4 hours at room temperature. It is then washed twice with 30 ml of water. The aqueous phase is extracted twice with 100 ml of methylene chloride. The United Methylene Chloride-

faser gir efter torkningen med natriumsulfat, filtreringen og inndampningen l-[p-(2-(3-difenyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidinet, som omkrystallisert i eddik- phases give after drying with sodium sulfate, filtration and evaporation the l-[p-(2-(3-diphenyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine, which is recrystallized in acetic

ester smelter ved 96,5 - 98°. ester melts at 96.5 - 98°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid oppnåes efter de b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride is obtained after the

i eksempel lb) angitte forskrifter. in example lb) stated regulations.

EKSEMPEL' 25 EXAMPLE' 25

a) 39,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid loses.i lOO ml vann og basene a) 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride are dissolved in 100 ml of water and the bases

frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 is released with 150 ml of 2-n caustic soda. It is extracted with 3

ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 20 g trietylamin. Derefter drypper man til ved romtemperatur opplosningen av 14,8 g piperidino-karbonylklorid i 100 ml metylenklorid og rorer i 4 ti mer ved romtemperatur. Derefter vasker man det med to ganger 30 ml times 250 ml methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 20 g of triethylamine. The solution of 14.8 g of piperidinocarbonyl chloride in 100 ml of methylene chloride is then added dropwise at room temperature and stirred for 4 hours more at room temperature. It is then washed twice with 30 ml

vann. Den vandige fase ekstraherer man to ganger med lOO ml metylenklorid. De forenede metylenkloridfaser gir efter torkning med natriumsulfat, filtrering og Inndampning l-[p-(2-(3-pi.peridino-karbamido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin, som omkrystallisert i eddikester smelter ved 179,5 - 180,5°. water. The aqueous phase is extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases give after drying with sodium sulfate, filtration and evaporation 1-[p-(2-(3-pi.peridino-carbamido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine, as recrystallized in acetic acid melts at 179.5 - 180.5°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid oppnåes efter de i b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride is obtained according to the

eksempel lb) angitte forskrifter. example lb) specified regulations.

EKSEMPEL 26 EXAMPLE 26

a) 39,8 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidin-dihydroklorid loses i 100 ml vann og a) Dissolve 39.8 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride in 100 ml of water and

basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med the base is released with 150 ml of 2-n caustic soda. It is extracted with

3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med .20 g trietylamin. Derefter drypper man til ved romtemperatur opplosningen av 9,8 g dimetyl-karbaminsyreklorid i 100 ml metylenklorid og rorer i 4 timer ved romtemperatur. Derefter vasker man det med to ganger 30 ml vann. Den vandige fase ekstraherer man to ganger med lOO ml metylenklorid. De forenede metylenkloridfaser gir efter torkningen med natriumsulfat, filtreringen og inndampningen 1-[p-(2-(3-dimetyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-isobutyl-imidazolidlnet, som omkrystallisert i eddikester smelter ved 132 - 135°. 3 times 250 ml of methylene chloride. The sodium sulfate-dried methylene chloride solution is added with .20 g of triethylamine. The solution of 9.8 g of dimethylcarbamic acid chloride in 100 ml of methylene chloride is then added dropwise at room temperature and stirred for 4 hours at room temperature. It is then washed twice with 30 ml of water. The aqueous phase is extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases give, after drying with sodium sulfate, filtration and evaporation, 1-[p-(2-(3-dimethyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine, which recrystallized in ethyl acetate melts at 132 - 135°.

b) Utgangsmaterialet l-[p- (,2-an i no-etyl)-f enylsulf onyl]-2-imino-3-isobutyl-imidazolidin-dihydroklorid oppnåes efter b) The starting material 1-[p-(,2-an i no-ethyl)-phenylsulfonyl]-2-imino-3-isobutyl-imidazolidine dihydrochloride is obtained after

de i eksempel 5b) angitte forskrifter. the regulations specified in example 5b).

EKSEMPEL 2 7 EXAMPLE 2 7

Analogt eksempel 2 8 oppnåes: Analogous to example 2 8 is obtained:

fra 39,6 g 1-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid og 15,0 g morfolinokarbonyl-klorid l-[p-(2-morfolino-karbamido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin med smp. 176 - 177°. from 39.6 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride and 15.0 g of morpholinocarbonyl chloride 1-[p-(2- morpholino-carbamido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine with m.p. 176 - 177°.

fra 42,5 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin-dihydroklorid og 13,9 g N-n-butyl-N-metylamino-karbonylklorid l-[p-(2- (3-n-butyl-3-metyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-cykloheksyl-imidazolidin med smp. 134 - 136°. from 42.5 g of l-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride and 13.9 g of N-n-butyl-N-methylamino-carbonyl chloride l-[p -(2-(3-n-butyl-3-methyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclohexyl-imidazolidine with m.p. 134 - 136°.

fra 39,6 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid og 13,9 g N-n-butyl-N-metyl-amino-karbonylklorid l-[p-(2-(3-n-butyl-3-metyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin med smp. 136 - 137°. from 39.6 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride and 13.9 g of N-n-butyl-N-methyl-amino-carbonyl chloride 1-[p-(2-(3-n-butyl-3-methyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine with m.p. 136 - 137°.

EKSEMPEL 28 EXAMPLE 28

a) 41,0 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid loses i 100 ml vann og a) Dissolve 41.0 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride in 100 ml of water and

basen frisettes med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. I den med natriumsulfat torkede the base is freed with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. In the with sodium sulfate dried

metylenkloridlosning drypper man til ved romtemperatur opplosningen av 23,2 g difenylkarbaminsyreklorid i lOO ml metylenklorid og rorer i 4 timer ved romtemperatur. Derefter vasker man det med to ganger 30 ml vann. Den vandige fase ekstraherer man to ganger med 100 ml metylenklorid. De forenede metylen-kloridf aser gir efter torkningen med natriumsulfat, filtrering og inndampning l-[p-(2-(3-difenyl-ureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-hydroklorid, som omkrystal-li sert i eddikester smelter ved 209 - 210°. methylene chloride solution is added dropwise at room temperature to the solution of 23.2 g of diphenylcarbamic acid chloride in lOO ml methylene chloride and stirred for 4 hours at room temperature. It is then washed twice with 30 ml of water. The aqueous phase is extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases give after drying with sodium sulfate, filtration and evaporation 1-[p-(2-(3-diphenyl-ureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine hydrochloride, which recrystallised in acetic acid melts at 209 - 210°.

b) Utgangsmaterialet l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin-dihydroklorid oppnåes efter b) The starting material 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine dihydrochloride is obtained after

de i eksempel 7b) angitte forskrifter. the regulations specified in example 7b).

EKSEMPEL 2 9 EXAMPLE 2 9

39,7 g l-[p-(2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid loses i 100 ml vann og basen frigjores med 150 ml 2-n natronlut. Det ekstraheres med 3 ganger 250 ml metylenklorid. Den med natriumsulfat torkede metylenkloridlosning tilsettes med 20 g trietylamin. Derefter drypper man til ved romtemperatur opplosningen av 15 g 1-morfolinyl-karbonylklorid i 100 ml metylenklorid og rorer i 4 timer ved 39.7 g of 1-[p-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride are dissolved in 100 ml of water and the base is released with 150 ml of 2-n caustic soda. It is extracted with 3 times 250 ml of methylene chloride. The sodium sulfate-dried methylene chloride solution is added with 20 g of triethylamine. The solution of 15 g of 1-morpholinylcarbonyl chloride in 100 ml of methylene chloride is then added dropwise at room temperature and stirred for 4 hours at

romtemperatur. Derefter vasker man det med to ganger 30 ml vann. Den vandige fase ekstraherer man to ganger med 10O ml metylenklorid. De forenede metylenkloridfaser gir efter torkning med natriumsulfat, filtrering og inndampning l-[p-(2-(1-morfolinyl-karbonamido)-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidinet, som omkrystallisert i eddikester smelter ved 176 - 177°. room temperature. It is then washed twice with 30 ml of water. The aqueous phase is extracted twice with 100 ml of methylene chloride. The combined methylene chloride phases give, after drying with sodium sulfate, filtration and evaporation, 1-[p-(2-(1-morpholinyl-carbonamido)-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine, which is recrystallized from ethyl acetate melts at 176 - 177°.

Utgangsmaterialet, 1-fp- (2-amino-etyl)-fenylsulfonyl]-2-imino-3-n-butyl-imidazolidin-dihydroklorid, oppnåes efter de i eksempel lb)r angitte forskrifter. The starting material, 1-fp-(2-amino-ethyl)-phenylsulfonyl]-2-imino-3-n-butyl-imidazolidine dihydrochloride, is obtained according to the instructions given in example lb)r.

EKSEMPEL 30 EXAMPLE 30

5 g l-[p-(2-(3-etyl-2-tioureido)-etyl)-fenylsulfonyl]-2-imino-3-cyklopentyl-imidazolidin med smp. 178° loses under svak oppvarmning i 100 ml 2-n saltsyre. Efter avkjoling med isvann, skiller l-[p-(2- (3-etyI-2-tioureido)-etyl)-fenylsulfonyl}-2-imino-3-cyklopentyl-imidazolidin-hydrokloridet med smp. 5 g of 1-[p-(2-(3-ethyl-2-thioureido)-ethyl)-phenylsulfonyl]-2-imino-3-cyclopentyl-imidazolidine with m.p. 178° is dissolved under gentle heating in 100 ml of 2-n hydrochloric acid. After cooling with ice water, separate the 1-[p-(2-(3-ethyl-2-thioureido)-ethyl)-phenylsulfonyl}-2-imino-3-cyclopentyl-imidazolidine hydrochloride with m.p.

166 - 168° seg ut. 166 - 168° out.

Claims (1)

Analogifremgangsmåte for fremstilling av nye terapeutisk virksomme derivater av p-aminoalkyl-benzensulfonamid med den generelle formel I,Analogous process for the preparation of new therapeutically active derivatives of p-aminoalkylbenzenesulfonamide of the general formula I, hvor R^ betyr en eventuelt forgrenet alkylrest med 1-6 karbonatomer, en allylrest, en cykloalkyl-hhv. cykloalkenylrest med 5 - 8 karbonatomer, R 2 hydrogen, en etyl- eller en metylgruppe, R^ en eventuelt forgrenet alkylgruppe med 1-6 karbonatomer, en cykloalkyl- hhv. cykloalkenylgruppe med hoyst 8 karbonatomer, en alkenylgruppe med 3-5 karbonatomer, en fenylgruppe, R 4 hydrogen, en eventuelt forgrenet alkylgruppe med 1-6 karbonatomer, en fenylgruppe, R^ og R^ tilsammen en polymetylenkjede med 4-7 karbonatomer, som kan være avbrutt av et oksygenatom, X oksygen eller svovel, og m 2 eller 3, såvel som deres addisjonssalter med uorganiske eller organiske syrer, karakterisert ved at man omsetter en forbindelse med den generelle formel II, hvor R^, R „ og ra har den under formel I angitte betydning, med et isocyanat hhv. isotiocyanat med den generelle formel III, hvor R^ og X har den under formel I angitte betydning, eller med et reaksjonsdyktig derivat av en karbaminsyre hhv. tiokarbaminsyre med den generelle formel IV, hvor R3, R4 og X har den under formel I angitte betydning, og overforer de erholdte reaksj onsprodukter, om onsket r i saltet til en uorganisk eller organisk syre. Anførte publikasjoner: Ålment tilgjengelig norsk patentsøknad nr. 968/69where R^ means an optionally branched alkyl residue with 1-6 carbon atoms, an allyl residue, a cycloalkyl or cycloalkenyl radical with 5 - 8 carbon atoms, R 2 hydrogen, an ethyl or a methyl group, R^ an optionally branched alkyl group with 1-6 carbon atoms, a cycloalkyl or cycloalkenyl group with at most 8 carbon atoms, an alkenyl group with 3-5 carbon atoms, a phenyl group, R 4 hydrogen, an optionally branched alkyl group with 1-6 carbon atoms, a phenyl group, R^ and R^ together a polymethylene chain with 4-7 carbon atoms, which can be interrupted by an oxygen atom, X oxygen or sulfur, and m 2 or 3, as well as their addition salts with inorganic or organic acids, characterized by reacting a compound with the general formula II, where R^, R„ and ra have the meaning indicated under formula I, with an isocyanate or isothiocyanate with the general formula III, where R^ and X have the meaning given under formula I, or with a reactive derivative of a carbamic acid or thiocarbamic acid of the general formula IV, where R3, R4 and X have the meaning given under formula I, and transfers the reaction products obtained, if desired, into the salt of an inorganic or organic acid. Listed publications: Generally available Norwegian patent application no. 968/69
NO2971/70A 1969-08-08 1970-07-31 NO124373B (en)

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CH1208569A CH513874A (en) 1969-08-08 1969-08-08 Process for the preparation of new derivatives of p- (aminoalkyl) -benzenesulfonamide

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CH (2) CH518287A (en)
DE (1) DE2039419C3 (en)
DK (1) DK125854B (en)
ES (1) ES382540A1 (en)
FI (1) FI52461C (en)
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GB (1) GB1313578A (en)
IE (1) IE34445B1 (en)
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DE1218154B (en) * 1964-04-20 1966-06-02 Bayer Ag Process for the preparation of copolymers of trioxane
US3538085A (en) * 1966-03-24 1970-11-03 Geigy Chem Corp 1-phenylsulfonyl-2-imino-imidazolidines and hexahydropyrimidines
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FR2068476B1 (en) 1973-12-21
ZA705468B (en) 1971-04-28
PL80964B1 (en) 1975-08-30
CH518287A (en) 1972-01-31
BE754597A (en) 1971-02-08
GB1313578A (en) 1973-04-11
FR2068476A1 (en) 1971-08-27
DE2039419B2 (en) 1978-01-05
DK125854B (en) 1973-05-14
NL7011391A (en) 1971-02-10
NL167423C (en) 1981-12-16
AT303750B (en) 1972-12-11
ES382540A1 (en) 1972-12-01
IE34445L (en) 1971-02-08
CH513874A (en) 1971-10-15
IL35080A (en) 1973-11-28
NL167423B (en) 1981-07-16
CA925089A (en) 1973-04-24
BG17961A3 (en) 1974-03-05
FI52461B (en) 1977-05-31
FI52461C (en) 1977-09-12
US3725430A (en) 1973-04-03
DE2039419C3 (en) 1978-09-14
IE34445B1 (en) 1975-05-14
SE367408B (en) 1974-05-27
DE2039419A1 (en) 1971-02-18
IL35080A0 (en) 1970-10-30
BG17544A3 (en) 1973-11-10

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