NO742418L

NO742418L -

Info

Publication number: NO742418L
Application number: NO742418A
Authority: NO
Inventors: H Wilkens; J Gmuender
Original assignee: Sandoz Ag
Priority date: 1973-07-11
Filing date: 1974-07-03
Publication date: 1975-02-10
Also published as: JPS5037772A; NL7409118A; IL45223A0; DD112757A5; ZA744451B; DE2431356A1; CS170116B2; HU168306B; FI201874A; AU7107374A; DK354674A; SE7408790L; BE817503A; FR2236494A1

Description

Fremgangsmåte for fremstilling av nye heterocykliske forbindelser. Process for the production of new heterocyclic compounds.

Foreliggense oppfinnelse vedrorer en fremgangsmåte for fremstilling av.nye forbindelser med formel I The present invention relates to a method for the production of new compounds with formula I

hvori R1står for hydrogen eller en CHR^R^-gruppe, hvori R^og wherein R 1 stands for hydrogen or a CHR^R^ group, wherein R^ and

R^står for hydrogen eller lavere alkyl,R^ stands for hydrogen or lower alkyl,

R2 betyr hydrogen, en lavere alkylgruppe, en cykloalkylgruppe medR 2 means hydrogen, a lower alkyl group, a cycloalkyl group with

5 eller 6 karbonatomer eller en fenylalkylgruppe med 7 til 9 karbonatomer, som eventuelt i fenylresten ytterligere er substituert med halogen, en lavere alkyl-, lavere alkoksy- eller trifluormetyl-resten, og 5 or 6 carbon atoms or a phenylalkyl group with 7 to 9 carbon atoms, which optionally in the phenyl residue is further substituted with halogen, a lower alkyl, lower alkoxy or trifluoromethyl residue, and

R^ betyr hydrogen, en primær eller sekundær lavere alkylgruppe,R^ means hydrogen, a primary or secondary lower alkyl group,

en cykloalkylgruppe med 3 til 6 karbonatomer, en fenylalkylgruppe med 7 til 9 karbonatomer som på karbonatomet ved siden av nitrogenatomet som den er bundet til, bærer minst et hydrogenatom og idet fenylresten eventuelt er substituert med halogen, lavere alkyl, lavere alkoksy, eller trifluormetylresten, allyl-, hydroksy- eller aminogruppen, eller en NRgR^-gruppe, hvori Rg og R^står for lavere alkyl, og idet substituentene R^, R2og R^ikke alle samtidig betyr hydrogen og, hvis R^står for alkyl, allyl, cykloalkyl eller den ovenfor definerte, eventuelt substituerte fenylalkylgruppe, betyr R2hydrogen, og syreaddisjonssalter derav. a cycloalkyl group with 3 to 6 carbon atoms, a phenylalkyl group with 7 to 9 carbon atoms which, on the carbon atom next to the nitrogen atom to which it is bound, carries at least one hydrogen atom and with the phenyl radical optionally substituted with halogen, lower alkyl, lower alkoxy, or the trifluoromethyl radical, the allyl, hydroxy or amino group, or a NRgR^ group, in which Rg and R^ stand for lower alkyl, and since the substituents R^, R2 and R^ do not all at the same time mean hydrogen and, if R^ stands for alkyl, allyl, cycloalkyl or the above-defined, optionally substituted phenylalkyl group, means R2hydrogen, and acid addition salts thereof.

Står R.J for en gruppe CHR^R^, så inneholder denne spesielt 1 tilIf R.J stands for a group CHR^R^, then this in particular contains 1 more

3 karbonatomer' og står foretrukket for metyl.3 carbon atoms' and preferably stands for methyl.

R2står foretrukket for hydrogen.. Står R2 for lavere alkyl, så, inneholder"denne foretrukket 1 til h, spesielt 1 eller 2 karbonatomer. R2 preferably stands for hydrogen. If R2 stands for lower alkyl, this preferably contains 1 to h, especially 1 or 2 carbon atoms.

Hvis'symbolet R^står for cykloalkyl med 3 til 6 karbonatomer, betyr dette foretrukket cyklopropyl. If the symbol R^ stands for cycloalkyl with 3 to 6 carbon atoms, this preferably means cyclopropyl.

Rg og Rr7 inneholder foretrukket 1 til h, spesielt 1 eller 2 karbonatomer-. Rg and Rr7 preferably contain 1 to h, especially 1 or 2 carbon atoms.

Hvis R2, R^jR^og/eller R^står for lavere alkyl, inneholder deIf R 2 , R 2 , R 2 and/or R 2 represent lower alkyl, they contain

1 til k, spesielt 1 eller 2 karbonatomer.1 to k, especially 1 or 2 carbon atoms.

Hvis R2 og/eller R^betyr substituert fenylalkyl, inneholder de mulig forekommende lavere alkyl og/eller alkoksysubstituenter foretrukket 1 til<!>+, spesielt 1 eller 2 karbonatomer. Særlig egnet som lavere alkylsubstituent er metylgruppen, spesielt egnet som lavere ålkoksysubstituent er metoksygruppen. Mulig forekommende halogensubstituenter på en fenylalkylrest R2eller R^er fluor, klor, brom, foretrukket klor eller brom, spesielt klor. If R 2 and/or R 4 means substituted phenylalkyl, the possibly occurring lower alkyl and/or alkoxy substituents preferably contain 1 to <!>+, especially 1 or 2 carbon atoms. Particularly suitable as a lower alkyl substituent is the methyl group, particularly suitable as a lower alkyl oxy substituent is the methoxy group. Possible halogen substituents on a phenylalkyl radical R 2 or R 1 are fluorine, chlorine, bromine, preferably chlorine or bromine, especially chlorine.

Hvis R2betyr fenylalkyl og fenylresten er substituert, er denne foretrukket monosubstituert. If R 2 means phenylalkyl and the phenyl radical is substituted, this is preferably monosubstituted.

Hvis R^betyr fenylalkyl og fenylresten er substituert, er denne foretrukket mono- eller disubstituert. If R₁ means phenylalkyl and the phenyl residue is substituted, this is preferably mono- or disubstituted.

Spesielt foretrukket er forbindelser med formel I, hvori R^står for hydrogen. Particularly preferred are compounds of formula I, in which R^ stands for hydrogen.

Det særegne ved fremgangsmåten i henhold til oppfinnelsen er at The peculiarity of the method according to the invention is that

a) forbindelser med formel IIa) compounds of formula II

hvori R^og R2har den ovennevnte betydning, og Rg står for en wherein R 1 and R 2 have the above meaning, and R 2 stands for one

lavere alkylrest, omsettes med forbindelser med formel IIIlower alkyl residue, is reacted with compounds of formula III

hvori R^ har den ovennevnte betydning, eller wherein R^ has the above meaning, or

b) for fremstilling av forbindelser med formel Ia b) for the preparation of compounds of formula Ia

I IN

hvori R1og R2 har den ovennevnte betydning og R^betyr hydrogen, en primær eller sekundær lavere alkylgruppe, en cykloalkylgruppe med 3 til 6 karbonatomer, en fenylalkylgruppe med 7 til 9 karbonatomer, som på karbonatomet ved siden av nitrogenatomet, som den er bundet til, bærer minst - yA- hydrogenatom og idet fenylresten eventuelt er substituert med halogen, lavere alkyl, lavere alkoksy eller trifluormetylresten, eller betyr allylgruppen, idet R1, R2og R^ ikke alle samtidig betyr hydrogen, og, hvis R^ står for alkyl, allyl, cykloalkyl eller det ovenfor definerte, eventuel substituerte fenylalkyl, betyr R2hydrogen, omsettes forbindelser med formel IV wherein R 1 and R 2 have the above meaning and R 2 is hydrogen, a primary or secondary lower alkyl group, a cycloalkyl group of 3 to 6 carbon atoms, a phenylalkyl group of 7 to 9 carbon atoms, as on the carbon atom adjacent to the nitrogen atom to which it is attached, carries at least - yA- hydrogen atom and the phenyl residue is optionally substituted with halogen, lower alkyl, lower alkoxy or the trifluoromethyl residue, or means the allyl group, as R1, R2 and R^ do not all simultaneously mean hydrogen, and, if R^ stands for alkyl, allyl, cycloalkyl or the above-defined, optionally substituted phenylalkyl, means R2hydrogen, compounds of formula IV are reacted

hvori R^ har den ovennevnte betydning, med forbindelser med forme] wherein R^ has the above meaning, with compounds of the form]

V V

hvori R2og R^ har den ovennevnte betydning og R^q står for lavere alkyl, in which R2 and R^ have the above meaning and R^q stands for lower alkyl,

og de erholdte forbindelser med formel I utvinnes som base eller som syreaddisjonssalter. and the obtained compounds of formula I are recovered as base or as acid addition salts.

Rg og R^q står foretrukket for metyl.Rg and R^q preferably stand for methyl.

Fra de fri baser lar seg på kjent måte.syreaddisjonssalter frem-stille og omvendt. From the free bases, acid addition salts can be prepared in a known manner and vice versa.

Omsetningene i henhold til oppfinnelsen (fremgangsmåten a) henhv. The sales according to the invention (method a) respectively

b)) kan gjennomfores under de for fremstilling av analoge guanidiner kjente reaksjonsbetingelser. Hensiktsmessig skjer omsetningene i b)) can be carried out under the reaction conditions known for the production of analogous guanidines. Appropriately, the sales take place in

henhold til oppfinnelsen i nærvær av en mineralsyre som saltsyre, bromhydrogensyre, jodhydrogensyre eller svovelsyre. according to the invention in the presence of a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid or sulfuric acid.

Foretrukket arbeider man i nærvær av minst en ekvivalent mineralsyre, regnet på forbindelsene med formel II eller IV, men forbindelsene med formel II eller III (fremgangsmåte a)) eller IV eller V (fremgangsmåten b)) anvendes hensiktsmessig i delvis uprotonert form. Preferably, one works in the presence of at least one equivalent of mineral acid, based on the compounds of formula II or IV, but the compounds of formula II or III (method a)) or IV or V (method b)) are suitably used in partially unprotonated form.

Fremgangsmåten a) kan f.eks. gjennomfores ved at forbindelsene med formel II, f.eks. som syreaddisjonssalt, omsettes med forbindelsene med formel III. Denne omsetning gjennomfores foretrukket ved forhoyet temperatur, eventuelt i autoklav, men kan også skje i et under reaksjonsbetingelsene inert, polart løsningsmiddel, f.eks. en blanding av vann med dimetylformamid eller en lavere alkanol, ved normaltrykk og romtemperatur eller forhoyet temperatur. Hvis kondensasjonen gjennomfores uten løsningsmiddel og med hoyt-kokende forbindelser med formel III, kan det for raskere fjernelse av alkylmerkaptanet anordnes et vakuum (ca. 12 Torr). The procedure a) can e.g. is carried out by the compounds of formula II, e.g. as an acid addition salt, is reacted with the compounds of formula III. This reaction is preferably carried out at an elevated temperature, possibly in an autoclave, but can also take place in a polar solvent that is inert under the reaction conditions, e.g. a mixture of water with dimethylformamide or a lower alkanol, at normal pressure and room temperature or elevated temperature. If the condensation is carried out without solvent and with high-boiling compounds of formula III, a vacuum (approx. 12 Torr) can be arranged for faster removal of the alkyl mercaptan.

Reaksjonsvarigheten-er avhengig av reaksjonsbetingelsene (temperatur og trykk). The reaction duration depends on the reaction conditions (temperature and pressure).

Ved fremgangsmåten b) går man f.eks. frem på den måte at forbindelsene med formel IV i et under reaksjonsbetingelsene inert løsningsmiddel, f.eks. i en lavere alkanol som isopropanol, med romtemperatur og under omroring tilsettes et mineralsurt salt, foretrukket hydrojodidet, hydrobromidet eller hydrokloridet av In method b), one goes, e.g. in such a way that the compounds of formula IV in a solvent that is inert under the reaction conditions, e.g. in a lower alkanol such as isopropanol, at room temperature and with stirring, a mineral acid salt, preferably the hydroiodide, hydrobromide or hydrochloride of

en forbindelse med formel V. Blandingen oppvarmes til koking under tilbakelop i lengre tid og det frigjorte alkylmerkaptan fjernes foretrukket ved g-jennomledning av en inert gass, f.eks. nitrogen. Deretter inndampes til torrhet. Etter en annen utforelsesmåte for denne fremgangsmåte kan omsetningen gjennomfores uten løsnings-middel i nærvær av en ekvivalent mineralsyre i smelte, eventuelt a compound of formula V. The mixture is heated to boiling under reflux for a longer time and the liberated alkyl mercaptan is preferably removed by passing through an inert gas, e.g. nitrogen. Then evaporated to dryness. According to another embodiment of this method, the reaction can be carried out without solvent in the presence of an equivalent mineral acid in melt, optionally

i autoklav.in an autoclave.

De etter de foregående beskrevne fremgangsmåter fremstilte guanidinforbindelser med formel I kan isoleres på vanlig måte og renses etter kjente metoder. The guanidine compounds of formula I prepared according to the previously described methods can be isolated in the usual way and purified according to known methods.

De som utgangsprodukt anvendte forbindelser med formel II kan f.eks. fremstilles på folgende måte: Forbindelsene med formel Ila The compounds of formula II used as starting product can e.g. are produced in the following way: The compounds of formula Ila

hvori R^og Rg har den ovennevnte betydning og R^ står for en lavere alkylgruppe, en cykloalkylgruppe med 5 eller 6 karbonatomer eller en fenylalkylgruppe med 7 til 9 karbonatomer, som eventuelt i fenylresten ytterligere er substituert med halogen, en lavere alkoksy-, lavere alkyl- eller trifluormetylresten, kan f.eks. fremstilles ved at forbindelser med formel IV, hvori R^ har den ovennevnte betydning, omsettes med forbindelser med formel VI hvori Rp har den ovennevnte betydning, til forbindelsene med formel VII hvori R1og R^ har den ovennevnte betydning, og disse forbindelser overfores ved omsetning med alkyljodider til forbindelsene med formel Ila. Forbindelsene med formel Ilb hvori R.Jog Rg har den. ovennevnte betydning, kan fremstilles ved at forbindelser med formel IV omsettes med N-benzoylisotiocyanat eller en blanding av ammoniumrodanid og benzoylklorid til forbindelser med formel VIII hvori har den ovennevnte betydning, forbindelsene med formel VIII hydrolyseres til forbindelser med formel IX hvori R^har den ovennevnte betydning, og forbindelsene med formel IX omsettes med alkyljodider til forbindelsene med formel Ilb. Forbindelsen med formel IXa kan også fremstilles ved at 1-amino-1,2,6,7,8,8a-heksahydrobenz (c,d)indol med formel IVa in which R^ and Rg have the above meaning and R^ stands for a lower alkyl group, a cycloalkyl group with 5 or 6 carbon atoms or a phenylalkyl group with 7 to 9 carbon atoms, which optionally in the phenyl residue is further substituted with halogen, a lower alkoxy, lower the alkyl or trifluoromethyl residue, can e.g. are prepared by reacting compounds of formula IV, in which R^ has the above-mentioned meaning, with compounds of formula VI in which Rp has the above-mentioned meaning, to the compounds of formula VII in which R1 and R^ have the above-mentioned meaning, and these compounds are transferred by reaction with alkyl iodides to the compounds of formula IIa. The compounds of formula Ilb in which R.Jog Rg has it. meaning above, can be prepared by reacting compounds of formula IV with N-benzoyl isothiocyanate or a mixture of ammonium rhodanide and benzoyl chloride to compounds of formula VIII in which has the above meaning, the compounds of formula VIII are hydrolysed to compounds of formula IX in which R has the above meaning significance, and the compounds of formula IX are reacted with alkyl iodides to the compounds of formula Ilb. The compound of formula IXa can also be prepared by 1-amino-1,2,6,7,8,8a-hexahydrobenz (c,d)indole of formula IVa

omsettes med tiourinstoff. is reacted with thiourea.

Utg.angsforbindelsene med formel IV kan f.eks. erholdes ved hjelp av de i det folgende beskrevne fremgangsmåter: The starting compounds with formula IV can e.g. obtained using the methods described below:

For fremstilling av 1 -amino-1 ,2,6,7?8,8a-heksahydrobenz (c,d) indol med formel IVa kan 1-nitroso-1,2,6,7,8,8a-heksahydrobenz (cd)indol reduseres, f.eks. ved hjelp av sink i maursyre. Forbindelsen 1-metylamino-1,2,6,7,8,8a-heksahydrobenz(cd)indol med formel IVb kan f.eks. fremstilles ved at forbindelser med formel X For the preparation of 1-amino-1,2,6,7?8,8a-hexahydrobenz (c,d)indole of formula IVa, 1-nitroso-1,2,6,7,8,8a-hexahydrobenz (cd) indole is reduced, e.g. using zinc in formic acid. The compound 1-methylamino-1,2,6,7,8,8a-hexahydrobenz(cd)indole with formula IVb can e.g. is produced by compounds of formula X

hvori R^betyr en lavere alkylrest, reduseres. Forbindelsene med formel X kan på sin side utvinnes av forbindelsen med formel IVa ved omsetning med en .-lavere alkylester av klormaursyre. in which R^ means a lower alkyl residue, is reduced. The compounds of formula X can in turn be recovered from the compound of formula IVa by reaction with a .-lower alkyl ester of chloroformic acid.

Forbindelsene med formel IVcThe compounds of formula IVc

hvori R^ har den ovennevnte betydning og R^ står for lavere alkyl, kan fremstilles f.eks. ved at 1-amino-1,2,6,7,8,8a-heksahydrobenz (cd)indol med formel IVa kondenseres med aldehyder eller ketoner og det erholdte hydrazon reduseres. De som utgangsprodukt anvendte isotiouronium-forbindelser med formel V kan f.eks. fremstilles fra tiourinstoffene med formel XI hvori Rg og R^ har den ovennevnte betydning, ved omsetning med alkylhalogenider med formel XII in which R^ has the above meaning and R^ stands for lower alkyl, can be prepared, e.g. in that 1-amino-1,2,6,7,8,8a-hexahydrobenz (cd)indole of formula IVa is condensed with aldehydes or ketones and the resulting hydrazone is reduced. The isothiouronium compounds of formula V used as starting product can e.g. is prepared from the thioureas of formula XI in which Rg and R^ have the above meaning, by reaction with alkyl halides of formula XII

hvori R^q har den ovennevnte betydning og Hal står for et halogen-atom, fortrinnsvis jod. in which R^q has the above meaning and Hal stands for a halogen atom, preferably iodine.

Forbindelsene med formel I og deres syreaddisjonssalter, i det folgende kort betegnet som nye substanser, er tidligere ikke beskrevet i litteraturen. De utmerker seg ved interessante farmakodynamiske egenskaper og kan folgelig anvendes som medisiner. De har spesielt salidiuretisk aktivitet som vises ved dyreforsok, f.eks. med rotter (metoden til E. Flttckiger for undersøkelse av den renale virksomhet) med doser på omtrent 1 til 10 mg/kg per os. The compounds of formula I and their acid addition salts, hereinafter briefly referred to as new substances, have not previously been described in the literature. They are distinguished by interesting pharmacodynamic properties and can therefore be used as medicines. They have particularly salidiuretic activity which is shown in animal experiments, e.g. with rats (the method of E. Flttckiger for examination of the renal activity) with doses of approximately 1 to 10 mg/kg per os.

På grunn av deres salidiuretiske virkninger kan de nye substanser anvendes som salidiuretika. Due to their salidiuretic effects, the new substances can be used as salidiuretics.

De doser som anvendes varierer selvfolgelig etter typen av substans-en, tilforselsmåten og den tilstand som skal behandles. Generelt oppnås dog tilfredsstillende resultater med en dose på omtrent 0,1 til omtrent 10 mg/kg kroppsvekt. Denne dose kan om nodvendig tilfores i 2 til h deldoser. For storre pattedyr ligger dagsdosen ved 5 til 50 mg. For orale tilforsler inneholder deldosene omtrent 1 til omtrent 20 mg av de nye substanser ved siden av faste eller flytende bæresubstanser. The doses used naturally vary according to the type of substance, the method of administration and the condition to be treated. In general, however, satisfactory results are obtained with a dose of about 0.1 to about 10 mg/kg body weight. If necessary, this dose can be administered in 2 to 1 hour sub-doses. For larger mammals, the daily dose is 5 to 50 mg. For oral supplies, the partial doses contain about 1 to about 20 mg of the new substances in addition to solid or liquid carrier substances.

Som medisin kan de nye forbindelser med den alminnelige formelAs medicine, they can create new compounds with the general formula

I henhv. deres vannloselige, fysiologisk tålbare syreaddisjonssalter tilfores alene eller i passende preparatformer. In resp. their water-insoluble, physiologically tolerable acid addition salts are administered alone or in suitable preparation forms.

Foretrukne representanter for denne forbindelsesklasse er forbindelsene med formel Ib Preferred representatives of this compound class are the compounds of formula Ib

hvori Rg"<5>"står for hydrogen eller lavere alkyl og R^ betyr hydrogen, hydroksy, lavere alkyl, cykloalkyl med 3 til 6 karbonatomer eller en fenylalkylgruppe med 7 til 9 karbonatomer, som ved C-atomet ved siden av N-atomet som den er bundet til, bærer minst 1 hydrogenatom og idet fenylresten eventuelt er mono- eller disubstituert med klor, metyl, metoksy eller trifluormetylresten, og idet substituentene R-1 og R?<1>ikke begge samtidig betyr hydrogen, og hvis R^ II står for en alkyl-, cykloalkyl-gruppe eller står for den ovenfor definerte, eventuelt substituerte fenylalkylgruppe , betyr R^1 hydrogen; wherein Rg"<5>"is hydrogen or lower alkyl and R^ means hydrogen, hydroxy, lower alkyl, cycloalkyl of 3 to 6 carbon atoms or a phenylalkyl group of 7 to 9 carbon atoms, as at the C atom next to the N atom to which it is bound, carries at least 1 hydrogen atom and the phenyl residue is optionally mono- or disubstituted with chlorine, methyl, methoxy or the trifluoromethyl residue, and the substituents R-1 and R?<1> do not both simultaneously mean hydrogen, and if R^ II stands for an alkyl, cycloalkyl group or stands for the above-defined, optionally substituted phenylalkyl group, R^1 means hydrogen;

Særlig foretrukket er 2-cyklopropyl-1 - (1 ,2,6 ,7 ,8,8a-heksahydrobenz (cd)indol-l-yl)guanidin og 1 — Cl,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-2-C<l>+-metoksyfenetyl)guanidin og deres syreaddis jons salter. Particularly preferred are 2-cyclopropyl-1-(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)guanidine and 1-Cl,2,6,7,8,8a-hexahydrobenz( cd)indol-1-yl)-2-C<l>+ -methoxyphenethyl)guanidine and their acid addition salts.

Hvis fremstillingen av de anvendte utgangsmaterialer ikke er beskrevet, er disse kjente eller kan fremstilles etter kjente metoder henhv. analogt med de her beskrevne eller analogt med i og for seg kjente fremgangsmåter. If the production of the starting materials used is not described, these are known or can be produced according to known methods or analogously to those described here or analogously to methods known per se.

I de folgende eksempler, som skal illustrere oppfinnelsen, er alle temperaturangivelser i °C, uten korreksjoner. In the following examples, which will illustrate the invention, all temperature indications are in °C, without corrections.

Eksempel 1 ; 1 - (1__J2_j6_27ji8jl8a-heksahydrobenz (cd) indol-1_-yl)-1 -Example 1; 1 - (1__J2_j6_27ji8jl8a-hexahydrobenz (cd) indol-1_-yl)-1 -

8 g 1-(1 ,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-1,2-dimetyl-isotiourinstof f-hydrojodid opptas i 250 ml ammoniakkmettet isopropanol under forsiktig oppvarming. Det filtreres til klarhet og filtratet oppvarmes i en autoklav i 6 timer ved hjelp av et oljebad på 150°C. Etter avkjoling og inndamping i vakuum opptas resten i alkohol. Etter tilsetning av etanolisk saltsyre til sur reaksjon koker man med aktivkull. Etter fjernelse av aktivkullet ved filtrering inndampes filtratet under vakuum. En varm ekstrakt av inndampningsresten med 1 N saltsyre innstilles alkalisk med vandig natriumhydroksyd. Etter avkjoling til romtemperatur ekstraheres den utskilte base flere ganger med kloroform. De forenede kloro-formekstrakter inndampes etter torring med natriumsulfat under vakuum. Resten loses i vann under tilsetning av saltsyre (til pH 6) under oppvarming. Det filtreres til klarhet og filtratet får stå for krystallisasjon. Hydrokloridet av den i overskriften nevnte forbindelse smelter ved 295 til 296°C (spalting). 8 g of 1-(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)-1,2-dimethyl-isothiourea f-hydroiodide are taken up in 250 ml of ammonia-saturated isopropanol while gently heating. It is filtered until clear and the filtrate is heated in an autoclave for 6 hours using an oil bath at 150°C. After cooling and evaporation in a vacuum, the residue is taken up in alcohol. After adding ethanolic hydrochloric acid to an acidic reaction, it is boiled with activated charcoal. After removing the activated carbon by filtration, the filtrate is evaporated under vacuum. A hot extract of the evaporation residue with 1 N hydrochloric acid is made alkaline with aqueous sodium hydroxide. After cooling to room temperature, the separated base is extracted several times with chloroform. The combined chloroform extracts are evaporated after drying with sodium sulphate under vacuum. The remainder is dissolved in water with the addition of hydrochloric acid (to pH 6) while heating. It is filtered until clear and the filtrate is allowed to crystallize. The hydrochloride of the title compound melts at 295 to 296°C (decomposition).

Utgangsmaterial:Starting material:

a) ' 1,2,6,7?8,8a-heksahydro-1-nitrosobenz(cd)indol reduseres med sink i maursyre til 1 -amino-1 ,2,6,758,8a-heksahydrobenz(cd)indol a) 1,2,6,7?8,8a-hexahydro-1-nitrosobenz(cd)indole is reduced with zinc in formic acid to 1-amino-1,2,6,758,8a-hexahydrobenz(cd)indole

(smeltepunkt 60 - 62°C).(melting point 60 - 62°C).

b) Ved omsetning av den ovennevnte amino-forbindelse med klor-maursyreetylester erholdes 1,2,6,7,8,8a-heksahydrobenz(cd)indol-1-karbaminsyreetylester (smeltepunkt 163 - 165°C) som reduseres med litiumalujniniumhydrid i tetrahydrofuran til 1,2,6,7,8,8a-heksahydro-1-metylaminobenz(cd)indol (smeltepunkt av det noytrale 1,5-naftalendisulfonat 262 til 26h°C). b) When reacting the above-mentioned amino compound with chloroformic acid ethyl ester, 1,2,6,7,8,8a-hexahydrobenz(cd)indole-1-carbamic acid ethyl ester is obtained (melting point 163 - 165°C), which is reduced with lithium aluminum hydride in tetrahydrofuran to 1,2,6,7,8,8a-hexahydro-1-methylaminobenz(cd)indole (melting point of the neutral 1,5-naphthalenedisulfonate 262 at 26h°C).

c) Omsetning av den ovennevnte forbindelse med en blanding av ammoniumrodanid og benzoylklorid i tetrahydrofuran gir 1-benzoyl-3-(heksahydro-1-metylaminobenz(cd)indol-l-yl)tiourinstoff, som ved -forsåpning med natriumhydroksyd og påfolgende metylering med metyljodid overfores i 1 -(1,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-1,2-dimetylisotiourinstoff-hydrojodid og anvendes videre i rå tilstand. c) Reaction of the above compound with a mixture of ammonium rhodanide and benzoyl chloride in tetrahydrofuran gives 1-benzoyl-3-(hexahydro-1-methylaminobenz(cd)indol-1-yl)thiourea, which by saponification with sodium hydroxide and subsequent methylation with methyl iodide is transferred into 1 -(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)-1,2-dimethylisothiourea hydroiodide and further used in the crude state.

Eksempel 2: liili^^iZjS^Sa^eksahydrobenz^cd.)indol=1 =v]>2= Example 2: liili^^iZjS^Sa^exahydrobenz^cd.)indole=1 =v]>2=

hydroksyguanidinhydroxyguanidine

En blanding av 5,8 g hydroksylamin-hydroklorid og 3,33 g natriumhydroksyd i 50 ml isopropanol oppvarmes i 1 time til koking under tilbakelop under nitrogenatmosfære. Etter fjernelse av koksaltet ved filtrering av den avkjolte losning tilsettes filtratet i sulfoneringskolbe under nitrogen 6,26 g 1 -(1,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-2-metylisotiourinstoff-hydrojodid og oppvarmes 1 5 timer under omroring til koking under tilbakelop. Etter inndamping loses resten i 20 ml alkohol og tilsettes omtrent 15 ml 2 N hydrogenjodid til svak sur reaksjon. For avfarging kokes losningen opp med aktivkull, tilsettes omtrent 20 ml vann og får stå for krystallisasjon. Hydrojodidet av den i overskriften nevnte forbindelse smelter ved 200 - 202°C (spalting). A mixture of 5.8 g of hydroxylamine hydrochloride and 3.33 g of sodium hydroxide in 50 ml of isopropanol is heated for 1 hour to reflux under a nitrogen atmosphere. After removing the coke salt by filtering the cooled solution, the filtrate is added to the sulphonation flask under nitrogen 6.26 g of 1-(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)-2-methylisothiourea- hydroiodide and heated for 15 hours with stirring to boiling under reflux. After evaporation, the residue is dissolved in 20 ml of alcohol and approximately 15 ml of 2 N hydrogen iodide is added to a slightly acidic reaction. For decolourisation, the solution is boiled with activated charcoal, approximately 20 ml of water is added and allowed to crystallize. The hydroiodide of the compound mentioned in the title melts at 200 - 202°C (decomposition).

Utg ang smaterial:Output material:

Ved omsetning av 1-amino-1,2,6,7,8,8a-heksahydrobenz(cd)indol med tiourinstoff erholdes 1-(1,2,6,7,8,8a-heksahydrobenz(cd)indol-l-yl) tiourinstoff med smeltepunkt 2^-0 - 258°C (karakteristiske IR-bånd ved 1520 og 1580 cm-<1>).By reacting 1-amino-1,2,6,7,8,8a-hexahydrobenz(cd)indole with thiourea, 1-(1,2,6,7,8,8a-hexahydrobenz(cd)indole-1- yl) thiourea with melting point 2^-0 - 258°C (characteristic IR bands at 1520 and 1580 cm-<1>).

Metylering av denne forbindelse med metyljodid gir 1 -(1,2,6,7,8,8a- heksahydrobenz (cd) indol-1 -yl) -2-metylisotiourinstoff -hydrojodid med smeltepunkt 220 - 222°C (spalting). Methylation of this compound with methyl iodide gives 1 -(1,2,6,7,8,8a-hexahydrobenz (cd)indol-1 -yl)-2-methylisothiourea -hydroiodide with melting point 220 - 222°C (decomposition).

Eksempel 3: liilj2i6i7j8i8a=heksahydrobenz_(cd) indol=1 -yl)-2-hydroksy=3imetylguanidin Example 3: liylj2i6i7j8i8a=hexahydrobenz_(cd)indole=1-yl)-2-hydroxy=3imethylguanidine

Det gås frem analogt med eksempel 2, ved å gå ut fra 1 -(1,2,6,7,8, 8a-heksahydrobenz(cd)indol-1-yl)-2,3-dimetylisotiourinstoff-hydrojodid og den i overskriften nevnte forbindelse med smeltepunkt 155 til 157°C (fra isopropanol)- erholdes. The procedure is analogous to example 2, starting from 1 -(1,2,6,7,8, 8a-hexahydrobenz(cd)indol-1-yl)-2,3-dimethylisothiourea hydroiodide and the one in the title said compound with a melting point of 155 to 157°C (from isopropanol) is obtained.

Utgangsmaterial:Starting material:

Ved omsetning av 1-amino-1,2,6,7,8,8a-heksahydrobenz(cd)indol med metylisotiocyanat erholdes 1-(1,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-3-metyltiourinstoff med smeltepunkt 181 - 183°C (spalting). Metylering av denne forbindelse med metyljodid gir 1 -(1 ,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-2,3-dimetylisotiourinstoff (smeltepunkt av hydrojodidet 120 - 1 22°C). By reacting 1-amino-1,2,6,7,8,8a-hexahydrobenz(cd)indole with methyl isothiocyanate, 1-(1,2,6,7,8,8a-hexahydrobenz(cd)indole-1- yl)-3-methylthiourea with melting point 181 - 183°C (decomposition). Methylation of this compound with methyl iodide gives 1 -(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)-2,3-dimethylisothiourea (melting point of the hydroiodide 120 - 122°C).

Eksempel h: 3-ben.zyl-l - (i ^Sj^^jiSjSa^heksahydrobenz^cd) indol-Example h: 3-ben.zyl-l - (i ^Sj^^jiSjSa^hexahydrobenz^cd) indole-

Man går frem analogt med eksempel 2 ved å gå ut fra 3-benzyl-1-(1,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-2-metylisotiourinstoff-hydrojodid (smeltepunkt av det noytrale 1,5-naftalendisulfonat av den i overskriften nevnte forbindelse er 168 - .170°C - fra alkohol). One proceeds analogously to example 2 by starting from 3-benzyl-1-(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)-2-methylisothiourea hydroiodide (melting point of the neutral 1,5-naphthalenedisulfonate of the compound mentioned in the title is 168 - 170°C - from alcohol).

Utgangsprodukter:Output products:

• a) 3-benzyl-1-(1,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)tiourinstoff (smeltepunkt 167 - 171°C - fra metanol) fra 1-amino-1,2,6,7, 8,8a-heksahydrobenz(cd)indol og benzylisotiocyanat. • a) 3-benzyl-1-(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)thiourea (melting point 167 - 171°C - from methanol) from 1-amino-1 ,2,6,7,8,8a-hexahydrobenz(cd)indole and benzyl isothiocyanate.

b) 3-benzyl-1-(l,2,6,7,8,8a-heksahydrobenz(cd)indol-1^yl)-2- metylisotiourinstoff-hydrojodid (amorft) - fra 3-bénzyl-1 -(1,2,6, 7,8,8a-heksahydrobenz(cd)indol-1-yl)tiourinstoff og metyljodid. b) 3-benzyl-1-(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1^yl)-2-methylisothiourea hydroiodide (amorphous) - from 3-bénzyl-1-(1 ,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)thiourea and methyl iodide.

Eksempel 5: 2=C;yklo£ro£yl=1 - (ij^éj^jS^Sa^heksahydrobenz^cd)Example 5: 2=C;cyclo£ro£yl=1 - (ij^éj^jS^Sa^hexahydrobenz^cd)

En blanding av 1,,88g 1 - (1 ,2,6 ,7 ,8,8a-heksahydrobenz (cd)indol-l -yl)-2-metylisotiourinstoff-hydrojodid og 0,35 ml cyklopropylamin i 20 ml isopropanol oppvarmes under nitrogen i 19 timer til koking under tilbakelop, idet det etter V, 8 henhv. 12 timer hver gang tilfores ytterligere 0,35 ml cyklopropylamin. Etter inndamping ekstraheres resten mellom 2N natriumhydroksyd og eter. Eterlosningene vaskes med vann, forenes og torres med magnesiumsulfat. Etter fjernelse av torremidlet ved filtrering inndampes filtratet og resten loses i alkohol. Etter forsiktig tilsetning av 1 mol vandig 1,5 naftalen-disulfonsyre til sur reaksjon lar man blandingen stå for krystallisering. Krystallene avsuges på filter og omkrystalliseres fra alkohol/vann. Det noytrale 1,5-naftalendisulfonat av den i overskriften nevnte forbindelse har et smeltepunkt på 280 - 282°C (spalting). Hydrojodidet smelter ved 182 - 18!+°C. A mixture of 1,88 g of 1-(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)-2-methylisothiourea hydroiodide and 0.35 ml of cyclopropylamine in 20 ml of isopropanol is heated under nitrogen for 19 hours to boil under reflux, since after V, 8 respectively. Every 12 hours, a further 0.35 ml of cyclopropylamine is added. After evaporation, the residue is extracted between 2N sodium hydroxide and ether. The ether solutions are washed with water, combined and dried with magnesium sulphate. After removing the drying agent by filtration, the filtrate is evaporated and the residue is dissolved in alcohol. After careful addition of 1 mol of aqueous 1.5 naphthalene-disulfonic acid to an acidic reaction, the mixture is allowed to crystallize. The crystals are sucked off on a filter and recrystallized from alcohol/water. The neutral 1,5-naphthalenedisulfonate of the compound mentioned in the title has a melting point of 280 - 282°C (decomposition). The hydroiodide melts at 182 - 18!+°C.

Aanalogt med eksempel 5 erholdesAnalogous to example 5 is obtained

Eksempel 1 5: 2= C3^=dimetoksyf ene tyl) Z1 = Cli2J6J7J8i8a=heksahydro= Example 1 5: 2= C3^=dimethoxy ene tyl) Z1 = Cli2J6J7J8i8a=hexahydro=

benz_(cd)indol =1 -yl)-guanidinbenz_(cd)indole =1 -yl)-guanidine

En blanding av 9,38 g 1 -(1,2,6,7,8,8a-heksahydrobenz(cd)indol-1-yl)-2-metylisotiourinstoff-hydro;jodid og ^,53 g homoveratrylamin settes ned i et oljebad med 100°C. Temperaturen okes i lopet av 2 timer til 150°C. Deretter utoves i lopet av -g- time et vakuum på ca. 15 Torr. En losning av resten i 50 ml alkohol kokes opp med aktivkull, inndampes til ca. 25 ml og tilsettes 60 ml 50% KOH. A mixture of 9.38 g of 1 -(1,2,6,7,8,8a-hexahydrobenz(cd)indol-1-yl)-2-methylisothiourea hydro;iodide and .53 g of homoveratrylamine is placed in a oil bath with 100°C. The temperature is increased over the course of 2 hours to 150°C. A vacuum of approx. 15 Torr. A solution of the residue in 50 ml of alcohol is boiled with activated charcoal, evaporated to approx. 25 ml and add 60 ml of 50% KOH.

Det utfelte produkt ekstraheres tre ganger med eter. Etter torring med magnesiumsulfat inndampes eterekstrakten. En losning av resten i alkohol tilsettes eterisk saltsyre til sur reaksjon, kokes opp med aktivkull, konsentreres noe og tilsettes abs. eter til begynnende uklarhet. De utfelte krystaller frafUtreres og omkrystalliseres fra alkohol/abs. eter. Hydrokloridet av den i overskriften nevnte forbindelse smelter ved 183 - 185°C. The precipitated product is extracted three times with ether. After drying with magnesium sulfate, the ether extract is evaporated. To a solution of the residue in alcohol, ethereal hydrochloric acid is added to an acidic reaction, boiled with activated carbon, concentrated somewhat and abs. ether to incipient obscurity. The precipitated crystals are filtered off and recrystallized from alcohol/abs. ether. The hydrochloride of the compound mentioned in the title melts at 183 - 185°C.

Analogt med eksempel 15 erholdes:Analogous to example 15, the following is obtained:

Eksempel 22: 2ibenzyl-1_-_0 iii^ i2i^ i§^^^ I^ 2^^ i^ l^^ 2lz-; (fremgangsmåte b) Example 22: 2ibenzyl-1_-_0 iii^ i2i^ i§^^^ I^ 2^^ i^ l^^ 2lz-; (method b)

En homogen blanding av 1,7^ g 1-amino-1,2,6,7,8,8a-heksahydrobenz (cd)indol og 3,08 g 1-benzyl-2-metylisotiourinstoff-hydrojodid oppvarmes i en rundkolbe ved hjelp av et oljebad på 150 - 160°C så lenge under leilighetsvis utovelse av et vakuum, til metyl-merkaptan-utviklingen er avsluttet. Etter avkjolingen opploses resten i alkohol og kokes opp med aktivkull. Etter fjernelse av aktivkullet ved filtrering tilsettes filtratet forsiktig petrol-eter. Etter noen tid frafiltreres krystallene og omkrystalliseres flere ganger fra alkohol/petroleter. Etter torring i hoyvakuum i 16 timer ved 70°G erholdes hydrojodidet av den i overskriften nevnte forbindelse med smeltepunkt 170 - 171°C. A homogeneous mixture of 1.7 g of 1-amino-1,2,6,7,8,8a-hexahydrobenz(cd)indole and 3.08 g of 1-benzyl-2-methylisothiourea hydroiodide is heated in a round-bottomed flask using of an oil bath at 150 - 160°C until the methyl mercaptan evolution has ended, with occasional extension of a vacuum. After cooling, the residue is dissolved in alcohol and boiled with activated charcoal. After removing the activated carbon by filtration, the filtrate is carefully added to petroleum ether. After some time, the crystals are filtered off and recrystallized several times from alcohol/petroleum ether. After drying in a high vacuum for 16 hours at 70°G, the hydroiodide of the compound mentioned in the title with a melting point of 170 - 171°C is obtained.

Analogt med eksempel 22 erholdes:Analogous to example 22, the following is obtained:

Claims

1. Procedure for the preparation of new compounds of formula IN

in which R1 stands for hydrogen or a CHR^ R^ -group, in which R^ and R^ stand for hydrogen or lower alkyl, R2 means hydrogen, a lower alkyl group, a cycloalkyl group with 5 or 6 carbon atoms or a phenylalkyl group with 7 to 9 carbon atoms, which optionally in the phenyl residue is further substituted with halogen, a lower alkyl, lower alkoxy or the trifluoromethyl residue, and R^ means hydrogen, a primary or secondary lower alkyl group, a cycloalkyl group with 3 to 6 carbon atoms, a phenylalkyl group with 7 to 9 carbon atoms, which on the carbon atom next to the nitrogen atom to which it is bound, carries at least 1 hydrogen atom and with the phenyl residue optionally substituted with halogen, lower alkyl, lower alkoxy or the trifluoromethyl residue, the allyl, hydroxy or amino group, or an ERgR^ group, in which Rg and R^ stand for lower alkyl, and since the substituents R^ , Rg and R^ do not all at the same time mean hydrogen and, if R^ stands for for alkyl, allyl, cycloalkyl or the optionally substituted phenylalkyl group defined above, Rg means hydrogen, and acid addition salts thereof, characterized by ata) Compounds of formula II

in which IL and Rg have the above meaning and Rg stands for a lower alkyl residue, is reacted with compounds of formula III

in which R^ has the above-mentioned meaning, orb) for the preparation of compounds of formula Ia

wherein R^ and Rg have the above meaning and R^ means hydrogen, a primary or secondary lower alkyl group, a cycloalkyl group of 3 to 6 carbon atoms, a phenylalkyl group of 7 to 9 carbon atoms atoms, which on the carbon atom next to the nitrogen atom to which it is bonded, carries at least 1 hydrogen atom and the phenyl residue is optionally further substituted with halogen, lower alkyl, lower alkoxy or the trifluoromethyl residue, or means the allyl group, with R^ , Rg and R^ not all at the same time mean hydrogen and, if R^ stands for alkyl, allyl, cycloalkyl or the above-defined, optionally substituted phenylalkyl, Rg means hydrogen, compounds of formula IV are reacted

wherein R^ has the above meaning, with compounds of formula V

in which Rg and R^ have the above meaning and R^q stands for lower alkyl, and the obtained compounds of formula I are recovered in the form of a base or as acid addition salts.

2. Process as stated in claim 1, characterized in that 2-cyclopropyl-1-(1,2,6,7,8,8a-hexahydrobenz (cd)indol-1-yDguanidine is produced.

3. Process as set forth in claim 1, characterized in that 1-(1,2,6,7,8,8a-hexahydrobenz (cd)indol-1-yl)-2-(^-methoxy enethylDguanidine is produced.