NO120580B - - Google Patents

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NO120580B
NO120580B NO159442A NO15944265A NO120580B NO 120580 B NO120580 B NO 120580B NO 159442 A NO159442 A NO 159442A NO 15944265 A NO15944265 A NO 15944265A NO 120580 B NO120580 B NO 120580B
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chloro
solution
phenyl
isoquinoline
general formula
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NO159442A
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Norwegian (no)
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H Ott
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Sandoz Ag
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Priority claimed from US388237A external-priority patent/US3369290A/en
Priority claimed from US478351A external-priority patent/US3383760A/en
Application filed by Sandoz Ag filed Critical Sandoz Ag
Priority to NO325469A priority Critical patent/NO123392B/no
Publication of NO120580B publication Critical patent/NO120580B/no

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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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  • Ceramic Engineering (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Nitrogen Condensed Heterocyclic Rings (AREA)
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Description

Fremgangsmåte for fremstilling av nye, terapeutisk aktive benzodiazepin-derivater. Process for the production of new, therapeutically active benzodiazepine derivatives.

Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling The present invention relates to a method for production

av nye,•terapeutisk aktive forbindelser med den alminnelige formel I of new,•therapeutically active compounds with the general formula I

hvori R1og R 2 hver betyr hydrogen eller metoksygruppen, R^ og R^står hver for hydrogen eller metylgruppen, Rg står for hydrogen eller en alkylgruppe med 1 - h karbonatomer og X står for hydrogen, klor eller trifluormetylgruppen, eventuelt deres optisk aktive henholdsvis cis- eller trans-isomere former og/eller deres syreaddisjonssalter. Forbindelsene med den alminnelige formel I har, når R^ = R^= H eller R^= R^_ = CH^ i det minste et og når R^ og R^ikke er like endog to asymmetriske karbonatomer. De ved fremgangsmåten i henhold til forbindelsen fremstillbare forbindelser med den alminnelige formel I kan oppdeles i sine optisk aktive enkelt-komponenter henholdsvis deres cis- henholdsvis trans-isomere former. De optisk aktive forbindelser med den alminnelige formel I henholdsvis de cis- henholdsvis trans-isomere former av forbindelsene med den alminnelige formel I kan dog også etter den lenger ute beskrevne fremgangsmåte fremstilles fra deres optisk aktive henholdsvis deres cis- henholdsvis trans-isomere mellomforbindelser. I henhold til oppfinnelsen kan forbindelsene med den alminnelige formel I, eventuelt deres optisk aktive henholdsvis cis- eller trans-isomere former og/eller deres syreaddisjonssalter fremstilles ved at eventuelt optisk aktive henholdsvis cis- eller trans-isomere forbindelser med den alminnelige formel II in which R1 and R2 each means hydrogen or the methoxy group, R^ and R^ each stand for hydrogen or the methyl group, Rg stands for hydrogen or an alkyl group with 1 - h carbon atoms and X stands for hydrogen, chlorine or the trifluoromethyl group, optionally their optically active respectively cis - or trans-isomeric forms and/or their acid addition salts. The compounds with the general formula I have, when R^ = R^= H or R^= R^_ = CH^ at least one and when R^ and R^ are not equal even two asymmetric carbon atoms. The compounds with the general formula I which can be prepared by the method according to the compound can be divided into their optically active single components and their cis and trans isomeric forms respectively. The optically active compounds with the general formula I respectively the cis- and trans-isomeric forms of the compounds with the general formula I can, however, also be prepared from their optically active and their cis- and trans-isomeric intermediate compounds according to the method described further on. According to the invention, the compounds with the general formula I, optionally their optically active, respectively cis- or trans-isomeric forms and/or their acid addition salts can be prepared by optionally optically active, respectively cis- or trans-isomeric compounds with the general formula II

hvori R.j - R^, Rg og X har den ovennevnte betydning og A står for hydrogen eller et lavere alkyl, underkastes en ringslutning, derved erholdte raeemiske forbindelser med den alminnelige formel I in which R.j - R.sub., R.sub.g and X have the above-mentioned meaning and A represents hydrogen or a lower alkyl, is subjected to a ring closure, thereby obtaining raemic compounds of the general formula I

oppdeles eventuelt i sine optisk aktive former henholdsvis erholdte blandinger av diastereomere forbindelser med den alminnelige formel I oppdeles eventuelt i sine cis- eller trans-isomere former og de således erholdte eventuelt optisk aktive henholdsvis cis- eller trans-isomere forbindelser med den alminnelige formel I overfores derettter eventuelt i sine syreaddisjonssalter. optionally divided into their optically active forms respectively obtained mixtures of diastereomeric compounds with the general formula I are optionally divided into their cis- or trans-isomeric forms and the thus obtained optionally optically active respectively cis- or trans-isomeric compounds with the general formula I are transferred and optionally in its acid addition salts.

Ringslutningen av forbindelsene med den alminnelige formel II, hvori A står for lavere alkyl, gjennomfores fortrinnsvis ved oppvarming enten i nærvær av natrium-p-metoksyetanolat i p-metoksyetanol .'. eller også i tert-butanol eller isoamylalkohol i lopet av 1 til 6 timer ved 100 - 130°C eller ved oppvarming i iseddik. Hvis det gås ut fra forbindelser med den alminnelige formel II, hvori A står for hydrogen, gjennomfores ringslutningen ved oppvarming ved temperaturer mellom 120 og 200°C i 10 - 60 minutter. The cyclization of the compounds of the general formula II, in which A stands for lower alkyl, is preferably carried out by heating either in the presence of sodium p-methoxyethanolate in p-methoxyethanol.' or also in tert-butanol or isoamyl alcohol over the course of 1 to 6 hours at 100 - 130°C or by heating in glacial acetic acid. If the starting point is compounds with the general formula II, in which A stands for hydrogen, the ring closure is carried out by heating at temperatures between 120 and 200°C for 10 - 60 minutes.

De etter den ovennevnte fremgangsmåte fremstillbare, eventuelt optisk aktive henholdsvis cis- eller trans-isomere forbindelser med den alminnelige formel I kan deretter isoleres, f.eks. ved krystallisering fra et egnet organisk løsningsmiddel eller ved utfelling av basen som hydroklorid fra deres losning i et organisk løsningsmiddel ved hjelp av gassformet hydrogenklorid og renses ved omkrystallisering. De fri baser erholdes fra deres salter, f.eks. ved alkalisering av deres vandige losninger. De således erholdte, eventuelt optisk aktive henholdsvis cis- eller trans-isomere forbindelser med den'alminnelige formel I kan deretter overfores i sine syreaddisjonssalter. The optionally optically active or cis- or trans-isomeric compounds with the general formula I which can be prepared according to the above-mentioned method can then be isolated, e.g. by crystallization from a suitable organic solvent or by precipitation of the base as hydrochloride from their solution in an organic solvent by means of gaseous hydrogen chloride and purified by recrystallization. The free bases are obtained from their salts, e.g. by alkalization of their aqueous solutions. The thus obtained, optionally optically active or cis- or trans-isomeric compounds of the general formula I can then be converted into their acid addition salts.

(De her'beskrevne forbindelser med de alminnelige formler II og XII kan - i likhet med forbindelsene med den alminnelige formel (The compounds described here with the general formulas II and XII can - like the compounds with the general formula

I - opptre enten i racemisk form henholdsvis i form av blandinger av diastereomere forbindelser eller.i optisk aktive henholdsvis i cis- henholdsvis trans-isomere former og tilsvarende anvendes for videre omsetning. For enkelthetsskyld sammenfattes dog disse forbindelser under det generelle begrep forbindelser med den alminnelige formel II og forbindelser med den alminnelige formel I - appear either in racemic form or in the form of mixtures of diastereomeric compounds or in optically active or in cis- or trans-isomeric forms and correspondingly used for further reaction. For the sake of simplicity, however, these compounds are summarized under the general term compounds with the general formula II and compounds with the general formula

XII). XII).

Forbindelsene med den alminnelige formel II hvori A står for lavere alkyl, kan fremstilles ved at forbindelser med den alminnelige formel XII The compounds with the general formula II in which A stands for lower alkyl can be prepared by compounds with the general formula XII

hvori R^ - R^, R^ og X har den ovennevnte betydning, omsettes med en lavere klor- eller bromeddiksyrealkylester, fordelaktig i nærvær av et syrebindende middel (f.eks. koking av de to komponenter i en alkoholisk losning av et trialkylamin i 1 - 2 timer). Ved wherein R^ - R^, R^ and X have the above meaning, is reacted with a lower chloro or bromoacetic acid alkyl ester, advantageously in the presence of an acid binding agent (e.g. boiling the two components in an alcoholic solution of a trialkylamine in 1 - 2 hours). By

hydrolyse av forbindelser med den alminnelige formel II, hvori A står for lavere alkyl, f.eks. ved oppvarming i en vandig eller vandig alkoholisk losning av et alkalimetallhydroksyd, kommer man frem til forbindelser med den alminnelige formel II, hvori A står for hydrogen. hydrolysis of compounds of the general formula II, in which A stands for lower alkyl, e.g. by heating in an aqueous or aqueous alcoholic solution of an alkali metal hydroxide, compounds of the general formula II are obtained, in which A stands for hydrogen.

Forbindelsene med den alminnelige formel XII kan fremstilles på folgende måte: The compounds with the general formula XII can be prepared in the following way:

Man kondenserer et amin med den alminnelige formel IV An amine with the general formula IV is condensed

hvori R.j - R^ har den ovennevnte betydning, enten med en o-amino-benzosyreester med den alminnelige formel IXa, hvori R^og X har den ovennevnte betydning og R står for en alkylgruppe med 1 - h karbonatomer (f.eks. ved oppvarming av en ekvimolar blanding ved 150 - 200 C, fortrinnsvis i vakuum eller ved oppvarming i et inert organisk løsningsmiddel, som dioksan, toluen eller xylen, under tilbakelop) eller med et isatosyre-anhydrid med den alminnelige formel IXb hvori R^og X har den ovennevnte betydning (omsetningen forlbper allerede ved romtemperatur i et inert organisk losningsmiddel, som f.eks. tetrahydrofuran, dioksan, dimetylformamid eller dimetyl-sulfoksyd, under karbondioksydutvikling. Omsetningen kan gjores fullstendig ved en kvarters oppvarming i vannbad). De således erholdte o-amino-benzosyreamider med den alminnelige formel X hvori R 1 - R^, R^og X har den ovennevnte betydning, underkastes f.eks. ved koking i xylen, i nærvær av fosforpentoksyd eller i fosforoksyklorid en ringslutning etter Bischler-Napieralski til forbindelser med den alminnelige formel XI.' hvori<R>^<->R^_, Rg og X har den ovennevnte betydning, idet den aromatiske aminogruppe på forhånd hensiktsmessig ved innforing av en tosyl-, benzensulfonyl-, mesyl- eller liknende beskyttelsesgrupper skal beskyttes. Disse beskyttelsesgrupper kan innfores ved en omsetning, som forloper analogt omsetningen etter Schotten-Baumann, og kan etter foretatt•ringslutning på nytt avspaltes, hensiktsmessig ved hydrolyse, f.eks. ved 2-15 timers henstand i konsentrert svovelsyre ved romtemperatur. De således erholdte 3A"dihydro-isokinoliner med den alminnelige formel XI reduseres fortrinnsvis ved hjelp av natriumborhydrid i kokende etanol i 1 - 3 timer eller også f.eks. ved katalyttisk hydrering i eddiksyre, i nærvær av en platina-eller nikkel-katalysator eller ved kjemisk reduksjon, f.eks. med sink, tinn eller jern i saltsyre, til de tilsvarende 1,2,3,^-tetrahydroisokinoliner med den alminnelige formel XII. Tetrahydro-isokinolin-derivater med den alminnelige formel VIII (d.v.s. forbindelser med den alminnelige formel XIL hvori RA står for hydrogen), hvori PL - R^_ og X har den ovennevnte betydning, kan fremstilles ved hjelp av folgende fremgangsmåte: De ved kondensasjon av et amin med den alminnelige formel IV med et o-nitro-benzoylklorid med den alminnelige formel V hvori X har den ovennevnte betydning, i et alkalisk reaksjons-middel, f.eks. i en losning av naferiumhydroksyd i vann/tetrahydrofuran eller i en losning av natriumhydroksyd i vann/dioksan fremstilte forbindelser med den alminnelige formel VI in which R.j - R^ has the above-mentioned meaning, either with an o-amino-benzoic acid ester of the general formula IXa, in which R^ and X have the above-mentioned meaning and R stands for an alkyl group with 1-h carbon atoms (e.g. by heating an equimolar mixture at 150 - 200 C, preferably in vacuum or by heating in an inert organic solvent, such as dioxane, toluene or xylene, under reflux) or with an isatoic anhydride of the general formula IXb in which R^ and X have the above meaning (the reaction already proceeds at room temperature in an inert organic solvent, such as tetrahydrofuran, dioxane, dimethylformamide or dimethyl sulfoxide, with carbon dioxide evolution. The reaction can be completed by heating in a water bath for fifteen minutes). The thus obtained o-amino-benzoic acid amides with the general formula X in which R 1 - R 1 , R 1 and X have the above-mentioned meaning, are subjected to e.g. by boiling in xylene, in the presence of phosphorus pentoxide or in phosphorus oxychloride a ring closure according to Bischler-Napieralski to compounds of the general formula XI.' wherein<R>^<->R^_, Rg and X have the above-mentioned meaning, the aromatic amino group being suitably protected in advance by introducing a tosyl, benzenesulfonyl, mesyl or similar protective groups. These protective groups can be introduced by a reaction, which proceeds analogously to the reaction according to Schotten-Baumann, and can be cleaved off again after ring closure, suitably by hydrolysis, e.g. by standing for 2-15 hours in concentrated sulfuric acid at room temperature. The thus obtained 3A"dihydro-isoquinolines with the general formula XI are preferably reduced using sodium borohydride in boiling ethanol for 1 - 3 hours or also, for example, by catalytic hydrogenation in acetic acid, in the presence of a platinum or nickel catalyst or by chemical reduction, e.g. with zinc, tin or iron in hydrochloric acid, to the corresponding 1,2,3,^-tetrahydroisoquinolines of the general formula XII. Tetrahydro-isoquinoline derivatives of the general formula VIII (i.e. compounds with the general formula XIL in which RA stands for hydrogen), in which PL - R^_ and X has the above-mentioned meaning, can be prepared by means of the following procedure: They by condensation of an amine of the general formula IV with an o-nitro-benzoyl chloride with the general formula V in which X has the above-mentioned meaning, in an alkaline reaction medium, for example in a solution of sodium hydroxide in water/tetrahydrofuran or in a solution of sodium hydroxide in water/dioxane prepared compounds with d the general formula VI

hvori R1- R^og X har den ovennevnte betydning, underkastes - som beskrevet ovenfor - en ringslutning etter Bischler-Napieralski in which R1-R^ and X have the above-mentioned meaning, are subjected - as described above - to a ring closure according to Bischler-Napieralski

og de således erholdte 3,^-dihydro-isokinoliner med den alminnelige and the 3,3-dihydro-isoquinolines thus obtained with the usual

formel VII formula VII

hvori - Ru og X har den ovennevnte betydning, reduseres fordelaktig ved hjelp av natriumborhydrid sammen med en palladium-kull-katalysator til 1 ,2,3,if-tetrahydro-isokinoliner med den alminnelige formel VIII. Forbindelsene med den alminnelige formel XII kan også fremstilles ved at forbindelser med den alminnelige formel XIII hvori R^- R^har den ovennevnte betydning, oppvarmes med forbindelser med den alminnelige formel XIV hvori X har den ovennevnte betydning og Hal står for klor eller brom, i 2 - 6 timer under tilbakelopskjoler, fortrinnsvis i nærvær av tinnklorid eller titantetraklorid til koking, idet et overskudd av forbindelser med den alminnelige formel XIII er fordelaktig, og således kommer man frem til forbindelser med den alminnelige formel XV hvori R.j - R^, X og Hal har den ovennevnte betydning, hvilke deretter omsettes med forbindelser med den alminnelige formel XVI wherein - Ru and X have the above meaning, are advantageously reduced by means of sodium borohydride together with a palladium-charcoal catalyst to 1,2,3,if-tetrahydro-isoquinolines of the general formula VIII. The compounds with the general formula XII can also be prepared by heating compounds with the general formula XIII in which R^-R^ has the above-mentioned meaning, with compounds of the general formula XIV in which X has the above-mentioned meaning and Hal stands for chlorine or bromine, for 2 - 6 hours under reflux, preferably in the presence of stannous chloride or titanium tetrachloride for boiling, since an excess of compounds of the general formula XIII is advantageous, and thus one arrives at compounds of the general formula XV in which R.j - R^, X and Hal has the above meaning, which are then reacted with compounds of the general formula XVI

hvori Rg har den ovennevnte betydning, i 2 - 12 timer ved 50 - 60°C i nærvær av kopper-pulver og kopperklorid, idet forbindelser med den alminnelige formel XI dannes, hvilke - som ovenfor beskrevet - kan omsettes videre til forbindelser med den alminnelige formel XII. in which Rg has the above-mentioned meaning, for 2 - 12 hours at 50 - 60°C in the presence of copper powder and copper chloride, as compounds with the general formula XI are formed, which - as described above - can be converted further into compounds with the general formula XII.

De ved hjelp av de ovennevnte fremgangsmåter, fremstillbare forbindelser med den alminnelige formel XII kan på kjent måte oppdeles i sine optisk aktive komponenter henholdsvis blandinger av diastereomere forbindelser med den alminnelige formel XII kan oppdeles i sine cis- eller trans-isomere former. The compounds with the general formula XII, which can be prepared using the above-mentioned methods, can in a known manner be divided into their optically active components, respectively mixtures of diastereomeric compounds with the general formula XII can be divided into their cis- or trans-isomeric forms.

Ved hjelp av fremgangsmåten i henhold til oppfinnelsen fremstillbare forbindelser med den alminnelige formel I henholdsvis deres optisk aktive henholdsvis cis- eller trans-isomere former er ved romtemperatur krystalliserte substanser som ved: hjelp av organiske eller uorganiske syrer kan overfores i sine syreaddisjonssalter. For dette kommer f.eks. som organiske syrer i betraktning fumar-syre, maursyre, eddiksyre, sitronsyre, maleinsyre, vinsyre, metan-sulfonsyre eller salicylsyre og som uorganiske syrer kommer i betraktning saltsyre og svovelsyre. By means of the method according to the invention, compounds with the general formula I or their optically active or cis- or trans-isomeric forms are at room temperature crystallized substances which can be converted into their acid addition salts by means of: organic or inorganic acids. For this, e.g. as organic acids in consideration fumaric acid, formic acid, acetic acid, citric acid, maleic acid, tartaric acid, methanesulphonic acid or salicylic acid and as inorganic acids come into consideration hydrochloric and sulfuric acid.

De ved fremgangsmåten i henhold til oppfinnelsen fremstillbare for bindelser med den alminnelige formel I henholdsvis deres optisk aktive henholdsvis cis- eller trans-isomere former og deres salter utmerker seg ved beroligende virkning på sentralnervesystemet. Virkningen på sentralnervesystemet manifesterer seg ved farma-kologiske undersøkelser i en nedsettelse av bevegelsesaktiviteten i mus, en krampelosende virkning, i en vekselvirkning med hekso-barbital henholdsvis ved amfetaminantagonisme og ved hemming av The compounds with the general formula I or their optically active or cis- or trans-isomeric forms and their salts, which can be prepared by the method according to the invention, and their salts are distinguished by their calming effect on the central nervous system. The effect on the central nervous system manifests itself in pharmacological investigations in a reduction of movement activity in mice, an anticonvulsant effect, in an interaction with hexobarbital respectively by amphetamine antagonism and by inhibition of

spinalreflekser. En del av forbindelsene viser også blodtrykks-senkende og betenneIseshemmende virkning (se lenger nede). spinal reflexes. Some of the compounds also show blood pressure-lowering and anti-inflammatory effects (see below).

Av de i eksemplene nevnte forbindelser viser alle, med unntagelse av 2-klor-12,13-dimetoksy-5-metyl-5,6,7,9,10,1 kb-heksahydro-isokinolo/2,1 -d/benzo/"1 ,lt/diazepin-6-on en beroligende virkning på sentralnervesystemet og kan derfor anvendes som sedativa, sovemidler, beroligende midler, angstfordrivere, muskelavspennere og antikonvulsiva. Of the compounds mentioned in the examples, all, with the exception of 2-chloro-12,13-dimethoxy-5-methyl-5,6,7,9,10,1 kb-hexahydro-isoquinolo/2,1-d/benzo /"1,lt/diazepin-6-one has a calming effect on the central nervous system and can therefore be used as sedatives, sleeping aids, sedatives, anxiolytics, muscle relaxants and anticonvulsants.

2-klor—12,13-dimetoksy-5-metyl-5,6,7,9,10,1^b-heksahydro-isokinolo /2,1-d/benzo/"1 ,^7diazepin-6-on utmerker seg ved særlig verdifulle antidepressive egenskaper og kan derfor finne anvendelse som antidepressivum. 2-Chloro-12,13-dimethoxy-5-methyl-5,6,7,9,10,1^b-hexahydro-isoquinolo/2,1-d/benzo/"1,^7diazepin-6-one excels characterized by particularly valuable antidepressant properties and can therefore find use as an antidepressant.

De folgende forbindelser utmerker seg ved betenneIseshemmende virkning, nemlig 5-metyl-5)6,7,9,10,1 ifb-heksahydro-isokinolo/2,1 - d/benzo/"1 ,^7diazepin-6-on, (-)-2-klor-5-metyl-5,6,7,9,10,1*fb-heksahydro-isokinolo/2,1 -d/benzo/1 ,lt7diazepin-6-on, (+)-2-klor-5-metyl- 5,6,7,9,10,1 ¥b-heksahydro-isokinolo/2,1 -d/benzo/"1 ,^/diazepin-6-on, 2-klor-5-metyl-5,6,7,9,10, l^-bjheksahydro-isokinolo/^, 1 -d7 benzo/1 ,lf7diazepih-6-on, 2-trifluor-metyl-5-metyl-5,6,7,9,10,1 Vb-heksahydro-isokinolo/2,1 -d7benzo/"1 ,lt/diazepin-6-on og cis-2-klor-5,10-dimetyl-5,6,7,9,10,1 Vb-heksahydro-isokinolo/2,1-d/behzo/1 , k7 diazepin-6-on. The following compounds are distinguished by their anti-inflammatory effect, namely 5-methyl-5)6,7,9,10,1-ifb-hexahydro-isoquinol/2,1-d/benzo/"1,^7diazepin-6-one, ( -)-2-chloro-5-methyl-5,6,7,9,10,1*fb-hexahydro-isoquinolo/2,1 -d/benzo/1 ,lt7diazepin-6-one, (+)-2 -chloro-5-methyl- 5,6,7,9,10,1 ¥b-hexahydro-isoquinolo/2,1 -d/benzo/"1 ,^/diazepin-6-one, 2-chloro-5- methyl-5,6,7,9,10, 1^-bjhexahydro-isoquinolo/^, 1 -d7 benzo/1 ,lf7diazepih-6-one, 2-trifluoro-methyl-5-methyl-5,6,7, 9,10,1 Vb-hexahydro-isoquinolo/2,1-d7benzo/"1,lt/diazepin-6-one and cis-2-chloro-5,10-dimethyl-5,6,7,9,10, 1 Vb-hexahydro-isoquinolo/2,1-d/behzo/1 , k7 diazepin-6-one.

En blodtrykksenkende virkning viser også forbindelsene 2-klor-5-metyl-5,6,7,9,10,1^-b-heksahydro-isokinolo/2,1-d/benzo/l ,Vdiazepin-6-on, ( + )-2-klor-5-metyl-5,6,7,9,10, l^-b-heksahydro-isokinolo/2, 1 -dj7 benzo//! ,1t7diazepin-6-on, 5-metyl-5,6,7,9,10,iVb-heksahydro-isokinolo/2,1- d/ benzof\ ,^7diazepin-6-on, 2-klor-5,10,10-trimetyl- A blood pressure-lowering effect is also shown by the compounds 2-chloro-5-methyl-5,6,7,9,10,1^-b-hexahydro-isoquinolo/2,1-d/benzo/l ,Vdiazepin-6-one, ( + )-2-chloro-5-methyl-5,6,7,9,10, 1^-b-hexahydro-isoquinolo/2, 1 -dj7 benzo//! ,1t7diazepin-6-one, 5-methyl-5,6,7,9,10,iVb-hexahydro-isoquinolo/2,1- d/ benzof\ ,^7diazepin-6-one, 2-chloro-5,10 ,10-trimethyl-

5,6,7,9,10,1 lfb-heksahydro-i sokinolo/2,1 -d/benzo/1 , Vdiazepin- 5,6,7,9,10,1 lfb-hexahydro-i soquinolo/2,1-d/benzo/1 , Vdiazepine-

6-on og cis-2-klor-5,10-dimetyl-5,6,7,9,10,1<l>fb-heksahydro-isokinolo/2,1 -d/benzo/i ,1t7diazepin-6-on. 6-one and cis-2-chloro-5,10-dimethyl-5,6,7,9,10,1<l>fb-hexahydro-isoquinolo/2,1 -d/benzo/i ,1t7diazepin-6- Wed.

Utover dette utmerker 2-trifluormetyl-5-metyl-5,6,7,9,10,1<l>fb-heksahydro-isokinolo/2,1-d/benzo/*1 ,lt7diazepin-6-on seg ved analgetisk virkning. In addition to this, 2-trifluoromethyl-5-methyl-5,6,7,9,10,1<l>fb-hexahydro-isoquinolo/2,1-d/benzo/*1 ,lt7diazepin-6-one excels in analgesic effect.

Den daglig tilforte dose skal utgjore 25 til 200 mg, og for (+)-2-klor-5-metyl-5,6,7,9,10,1 tfb-heksahydro-isokinolo/2,1-d7benzo-£\ ,1t7diazepin-6-on særlig 25 til 150 mg. The daily added dose should amount to 25 to 200 mg, and for (+)-2-chloro-5-methyl-5,6,7,9,10,1 tfb-hexahydro-isoquinolo/2,1-d7benzo-£\ ,1t7diazepin-6-one especially 25 to 150 mg.

De nye forbindelser kan anvende.s som legemiddel alene eller i tilsvarende legemiddelformer for oral eller parenteral tilforsel. The new compounds can be used as drugs alone or in corresponding drug forms for oral or parenteral administration.

I den utstrekning de anvendte utgangsforbindelser med formeler To the extent that they used output compounds with formulas

IV, V, IXa, IXb, XIII og XIV er ukjent, kan de fremstilles på IV, V, IXa, IXb, XIII and XIV are unknown, they can be produced on

i og for seg kjent måte. Forbindelsen med formel XII hvori R1- R^_, R^ og X står for hydrogen, er kjent fra J.Gen. Chem. in and of itself known manner. The compound of formula XII in which R1-R^_, R^ and X stand for hydrogen is known from J.Gen. Chem.

(U.S.S.R.) ia,^91-6(19<>>+3). (U.S.S.R.) ia,^91-6(19<>>+3).

I de etterfølgende eksempler, som skal illustrere utforelsen av fremgangsmåten, er alle temperaturangivelser i °C og er korrigert. In the following examples, which shall illustrate the implementation of the method, all temperature indications are in °C and have been corrected.

Eksempel 1; 5, 6, 7, 9, 10, 1 ^- b- heksahydro- isokinolo/ 2, 1 - d7- benzo/ 1 , h7 Example 1; 5, 6, 7, 9, 10, 1 ^- b- hexahydro-isoquinolo/ 2, 1 - d7- benzo/ 1 , h7

diazepin- 6- on. diazepin-6-one.

En blanding bestående av 2 g 1 -(2-amino-fenyl)-1,2,3,^-tetrahydro-isokinolin, 3 g etylbromacetat, 1 g trietylamin i 10 cm^ etanol, oppvarmes i 2% time til koking under tilbakelop. Losningen inndampes deretter til torrhet, resten loses i 20 cm<J>etanol og 10 cm^ 2N vandig natriumhydroksyd-losning og den således erholdte losning oppvarmes i 1 time ved 60°C. Etter tilsetning av 10 cm^ 2N saltsyre avdampes etylalkoholen i vakuum idet 1-(2-aminc-fenyl)-2-karboksymetyl-1 ,2,3j^-tetrahydro-isokinolin med smeltepunkt 100 - 130°C (uskarpt) utkrystalliseres. b) 5i§jiZi9 i10 i2!+b-heksahy^r^--isoMnolo/2_ 1 6-on. A mixture consisting of 2 g of 1-(2-amino-phenyl)-1,2,3,^-tetrahydro-isoquinoline, 3 g of ethyl bromoacetate, 1 g of triethylamine in 10 cm^ of ethanol, is heated for 2% hour to boiling under reflux . The solution is then evaporated to dryness, the residue is dissolved in 20 cm3 ethanol and 10 cm3 2N aqueous sodium hydroxide solution and the solution thus obtained is heated for 1 hour at 60°C. After the addition of 10 cm 2 of 2N hydrochloric acid, the ethyl alcohol is evaporated in a vacuum, while 1-(2-aminophenyl)-2-carboxymethyl-1,2,3j^-tetrahydro-isoquinoline with a melting point of 100 - 130°C (blurred) crystallizes out. b) 5i§jiZi9 i10 i2!+b-hexahy^r^--isoMnolo/2_ 1 6-one.

Det rå 1 -(2-amino-fenyl)-2-karboksymetyl-1,2,3, h-tetrahydro-isokinolin oppvarmes i 30 min. ved 160°C. Den krystalline rest omkrystalliseres deretter fra etanol Idet den i overskriften nevnte forbindelse erholdes. The crude 1-(2-amino-phenyl)-2-carboxymethyl-1,2,3,h-tetrahydro-isoquinoline is heated for 30 min. at 160°C. The crystalline residue is then recrystallized from ethanol to obtain the compound mentioned in the title.

Under anvendelse av den ovenfor beskrevne fremgangsmåte og tilsvarende utgangsforbindelser kan 5-metyl-5,6,7,9,10,1 Vb-heksahydro-isokinolo/2,1-d7benzo/l ,!t7diazepin-6-on med smeltepunkt 260 - 262°C fremstilles. Using the method described above and corresponding starting compounds, 5-methyl-5,6,7,9,10,1 Vb-hexahydro-isoquinolo/2,1-d7benzo/l,!t7diazepin-6-one with melting point 260 - 262°C is produced.

Eksempel 2: 2- klor- 5, 6, 7, 9, 10, 1 Vb- heksahydro- isokinolo/ 2, 1- d7 Example 2: 2- chloro- 5, 6, 7, 9, 10, 1 Vb- hexahydro- isoquinolo/ 2, 1- d7

benzo/ 1 , 1t7diazepin- 6- on. benzo/ 1 , 1t7diazepin- 6- one.

a) ?lI§l£§2§5Zi2l§2nitro-5-klor=benzamid. a) ?lI§l£§2§5Zi2l§2nitro-5-chloro=benzamide.

En losning av 6 g 2-nitro-5-klor-benzoylklorid i 6 cm^ dioksan A solution of 6 g of 2-nitro-5-chloro-benzoyl chloride in 6 cm^ of dioxane

tilsettes dråpevis under sterk roring i lopet av 30 min. en blanding av 3 g (3 -fenetylamin og 1 g natriumhydroksyd i 15 cm^ vann og 5 ctti^ dioksan ved 35 - h0°C. Deretter rores ennå i 30 min. is added dropwise with vigorous stirring over the course of 30 min. a mixture of 3 g of (3-phenethylamine and 1 g of sodium hydroxide in 15 cm^ of water and 5 cm^ of dioxane at 35 - h0°C. Then stir again for 30 min.

Ved tilsetning av mer vann krystalliserer den i overskriften nevnte forbindelse ut, hvilken omkrystalliseres fra etylacetat/dietyleter. Det således erholdte N-(6-fenetyl)-2-nitro-5-klor-benzamid krystal- When more water is added, the compound mentioned in the title crystallizes out, which is recrystallized from ethyl acetate/diethyl ether. The thus obtained N-(6-phenethyl)-2-nitro-5-chloro-benzamide crystal

liserer i hvite prismer med smeltepunkt 102 - 10<1>+°C. dissolves in white prisms with melting point 102 - 10<1>+°C.

k) "l ii?=nitro-5-klor-f enyl)-2J^=dihydro=isok'inolin. k) "1 ii?=nitro-5-chloro-phenyl)-2J^=dihydro=isoquinoline.

Til den varme losning av 1 g N-(p-fenetyl)-2-nitro-5-klor-benzamid i 5 cm^ xylen-tilsettes 2 g fosforpentoksyd og den dannede blanding oppvarmes i 5 timer til koking under tilbakelop. Deretter avdampes det organiske losningsmidde1 i vakuum og den klebrige rest spaltes ved hjelp av isblandet vann. Det erholdte vandige skikt ekstraheres med dietyleter idet det ikke omsatte utgangsmaterial gjenvinnes. Deretter gjores det vandige skikt alkalisk ved hjelp av konsentrert natronlut. Det derved utfallende krystalline produkt frafiltreres og omkrystalliseres fra dietyleter/pentan. To the hot solution of 1 g of N-(p-phenethyl)-2-nitro-5-chloro-benzamide in 5 cm^ of xylene, 2 g of phosphorus pentoxide are added and the resulting mixture is heated for 5 hours to reflux. The organic solvent 1 is then evaporated in a vacuum and the sticky residue is split using ice-mixed water. The aqueous layer obtained is extracted with diethyl ether while the unreacted starting material is recovered. The aqueous layer is then made alkaline using concentrated caustic soda. The resulting crystalline product is filtered off and recrystallized from diethyl ether/pentane.

Det således erholdte 1 -(2-nitro-5-kbr-fenyl)-3dihydro-isokinolin krystalliserer i gule prismer med smeltepunkt 1 2h - 125°C. The thus obtained 1-(2-nitro-5-kbr-phenyl)-3dihydro-isoquinoline crystallizes in yellow prisms with melting point 1 2h - 125°C.

c) . 1 - (2=am^no-5-klor-f enyl)-1 _12i3i'+-tetrahydro-isokinolin. c) . 1 - (2=amino-5-chloro-phenyl)-1_12i3i'+-tetrahydro-isoquinoline.

10 g 1 -(2-nitro-5-klor-fenyl)-3dihydroisokinolin loses i hO ml Dissolve 10 g of 1-(2-nitro-5-chloro-phenyl)-3-dihydroisoquinoline in 10 ml

metanol og 20 cm^ dioksan og til den således erholdte losning tilsettes 0,5 g palladium-kull-katalysator (10$ palladium) i 50 cm^ metanol og 15 cm^ vann. Denne blanding tilsettes i lopet av h- 5 min. ved 50 - 60°C en losning av 7 g natriumborhydrid i 50 cm^ metanol. Deretter spaltes overskudd av natriumborhydrid ved tilsetning av eddiksyre og katalysatoren frafiltreres. Ved tilsetning av 2N vandig natriumhydroksyd-losning gjores blandingen alkalisk og for-tynnes deretter med vann hvorved 1 -(2-amino-5-klor-fenyl)-1,2,3 tetrahydro-isokinolin utkrystalliseres. Etter omkrystallisering fra metanol/vann smelter forbindelsen ved 135 - 136°C. d) 1 - (2-amino-5-klor-f enyl)-2-karbok syrne tyl-1 i^^^tetrahydro-isokinolin. methanol and 20 cm^ of dioxane and to the thus obtained solution is added 0.5 g of palladium-charcoal catalyst (10% palladium) in 50 cm^ of methanol and 15 cm^ of water. This mixture is added over the course of h - 5 min. at 50 - 60°C a solution of 7 g of sodium borohydride in 50 cm^ of methanol. The excess sodium borohydride is then decomposed by adding acetic acid and the catalyst is filtered off. By adding 2N aqueous sodium hydroxide solution, the mixture is made alkaline and then diluted with water, whereby 1-(2-amino-5-chloro-phenyl)-1,2,3-tetrahydro-isoquinoline crystallizes out. After recrystallization from methanol/water, the compound melts at 135 - 136°C. d) 1-(2-Amino-5-chloro-phenyl)-2-carboxylic acid ethyl-1 in^^^tetrahydro-isoquinoline.

En blanding bestående av 5 g 1 -(2-amino-5-klor-fenyl)-1,2,35^-tetrahydro-isokinolin, h g etylbromacetat, 2,5 g trietylamin og 1 g natriumjodid i 100 cm^ etanol oppvarmes i 2 timer til koking under tilbakelop. Deretter inndampes reaksjonsblandingen til torrhet og resten loses i 150 cm^ etanol og h0 cm^ 2N vandig natriumhydroksyd-losning. Den erholdte losning oppvarmes i 3 timer ved 60°C. Deretter avdampes alkoholen i vakuum hvorved det ikke om satte utgangsmaterial utfelles. Etter frafiltrering tilsettes hO cm^ 2N saltsyre til filtratet hvorved reaksjonsproduktet faller ut i fine hvite krystaller. Etter omkrystallisering fra etanol erholdes 1 -(2-amino-5-klor-fenyl)-2-karboksymetyl-1,2,3 tetrahydro-isokinolin med smeltepunkt 163 - 165°C.e) §z^i°£z5i§jZi2il Qil^ 2z^^^ I^ 2ziS2^ i^ 2l2^ ilz^^^ 2fliil dia.zep_in=6-on. A mixture consisting of 5 g of 1-(2-amino-5-chloro-phenyl)-1,2,35^-tetrahydro-isoquinoline, 1 g of ethyl bromoacetate, 2.5 g of triethylamine and 1 g of sodium iodide in 100 cm^ of ethanol is heated in 2 hours to boil under reflux. The reaction mixture is then evaporated to dryness and the residue dissolved in 150 cm^ of ethanol and h0 cm^ of 2N aqueous sodium hydroxide solution. The solution obtained is heated for 3 hours at 60°C. The alcohol is then evaporated in a vacuum, whereby no solid starting material is precipitated. After filtering off, h0 cm^ 2N hydrochloric acid is added to the filtrate whereby the reaction product precipitates out in fine white crystals. After recrystallization from ethanol, 1 -(2-amino-5-chloro-phenyl)-2-carboxymethyl-1,2,3 tetrahydro-isoquinoline with melting point 163 - 165°C is obtained.e) §z^i°£z5i§jZi2il Qil^ 2z^^^ I^ 2ziS2^ i^ 2l2^ ilz^^^ 2fliil dia.zep_in=6-on.

Det rå 1-(2-amino-5-klor-fenyl)-2-karboksymetyl-1,2,3,^-tetrahydro-isokinolin oppvarmes i 30 min. ved 170°C. Deretter omkrystalliseres det krystalline råprodukt fra etanol og derved erholdes 2-klor-5,6,7,9,10,1 Vb-heksahydro-isokinolo/2,1-d/benzo £\ j^diazepin-å-on med smeltepunkt 220 - 222 C. The crude 1-(2-amino-5-chloro-phenyl)-2-carboxymethyl-1,2,3,^-tetrahydro-isoquinoline is heated for 30 min. at 170°C. The crystalline crude product is then recrystallized from ethanol and thereby 2-chloro-5,6,7,9,10,1 Vb-hexahydro-isoquinolo/2,1-d/benzo £\ j^diazepin-å-one with a melting point of 220 - 222 C.

Eksempel 3: 2- klor- 5- metyl- 5, 6, 7, 9, 10, 1^ b- heksahydro- isokinolo Example 3: 2- chloro- 5- methyl- 5, 6, 7, 9, 10, 1^ b- hexahydro- isoquinolo

/ 2, 1- d7benzo/~ 1 , 1t7diazepin- 6- on. / 2, 1- d7benzo/~ 1 , 1t7diazepin-6-one.

a) N-(gfenetyl)-2-metylamino=5-klor-benzamid. a) N-(gphenethyl)-2-methylamino=5-chloro-benzamide.

En blanding bestående av 2 g 5-klor-N-metyl-isatosyreanhydrid og A mixture consisting of 2 g of 5-chloro-N-methyl isatoic anhydride and

3 g P-fenetylamin i 10 cm^ dioksan oppvarmes i 15 min. på vannbad, hvorved det finner sted sterk karbondioksyd-utvikling. Ved tilsetning av vann til den erholdte losning utfelles N-(p-f ene tyl)-2-metylamino-5-klor-benzamid med smeltepunkt 129 - 131°C 3 g of P-phenethylamine in 10 cm^ of dioxane are heated for 15 min. on a water bath, whereby strong carbon dioxide evolution takes place. When water is added to the resulting solution, N-(p-phenyl)-2-methylamino-5-chloro-benzamide with a melting point of 129 - 131°C is precipitated

b) N-(g-fene<tyl>)^<2-mety>ltosylamino=5iklor=benzamid. b) N-(g-phen<tyl>)^<2-methyl>ltosylamino=5ichloro=benzamide.

Til en losning av 1 g N-(p-fenetyl)-2-metylamino-5-klbr-benzamid To a solution of 1 g of N-(p-phenethyl)-2-methylamino-5-klbr-benzamide

i 5 cm^ pyridin tilsettes 1 g p-toluensulfonsyreklorid og den erholdte blanding oppvarmes i 1-g- time ved 60°C. Deretter inndampes i vakuum, 3 cm^ aceton og 1 cm^ vann tilsettes og den således erholdte reaksjonsblanding rystes i 30 min. Etter avdamping av aceton tilsettes etylacetat og det organiske skikt ekstraheres med fortynnet saltsyre, deretter med vann, såvel som en vandig natriumbikarbonat-losning. Deretter torres det organiske skikt over natriumsulfat og inndampes deretter til torrhet, idet N-(p-fenetyl)-2-metyltosylamino-5-klor-benzamid blir tilbake som en oljeaktig rest. c) IzL ^iBÉjYi^sylamiriO;; 5zklor=f enyl) -Sj^-dihydro-isokinolin-hydroklorid. 1 g of p-toluenesulphonic acid chloride is added to 5 cm^ of pyridine and the resulting mixture is heated for 1-g hour at 60°C. It is then evaporated in a vacuum, 3 cm^ of acetone and 1 cm^ of water are added and the reaction mixture thus obtained is shaken for 30 min. After evaporation of acetone, ethyl acetate is added and the organic layer is extracted with dilute hydrochloric acid, then with water, as well as an aqueous sodium bicarbonate solution. The organic layer is then dried over sodium sulfate and then evaporated to dryness, with N-(p-phenethyl)-2-methyltosylamino-5-chlorobenzamide remaining as an oily residue. c) IzL ^iBÉjYi^sylamiriO;; 5zchloro=phenyl)-Sj^-dihydro-isoquinoline hydrochloride.

Det ovenfor erholdte rå tosylat loses i 10 cm^ xylen og til den erholdte losning tilsettes h g fosforpentoksyd. Den erholdte reaksjonsblanding oppvarmes til koking under tilbakelopskjoler i 15 timer, deretter avdampes xylenet i vakuum og den klebrige rest spaltes ved tilsetning av is. Den vandige blanding gjores alkalisk ved konsentrert vandig natriumhydroksyd-losning og ekstraheres deretter med metylenklorid. Etter torring og fjerning av det organiske løsningsmiddel loses den oljeaktige rest i dietyleter og derfra utfelles ved innføring av torr hydrogenkloridgass 1 -(2-metyltosylamino-5-klor-fenyl)-3,1+-dihydro-isokinolin-hydroklorid med smeltepunkt 2^-0 - 2*f1 °C. The crude tosylate obtained above is dissolved in 10 cm^ of xylene and 1 g of phosphorus pentoxide is added to the solution obtained. The resulting reaction mixture is heated to boiling under reflux for 15 hours, then the xylene is evaporated in vacuum and the sticky residue is split by adding ice. The aqueous mixture is made alkaline by concentrated aqueous sodium hydroxide solution and then extracted with methylene chloride. After drying and removal of the organic solvent, the oily residue is dissolved in diethyl ether and from there is precipitated by introducing dry hydrogen chloride gas 1-(2-methyltosylamino-5-chloro-phenyl)-3,1+-dihydro-isoquinoline hydrochloride with melting point 2^ -0 - 2*f1 °C.

d)lli§z!!?etyl<a>mino-2=<kl>^^ d)lli§z!!?ethyl<a>mino-2=<kl>^^

Til 1 g 1 -(2-metyltosylamino-5-klor-fenyl)-3, K-dihydro-isokinolin-hydroklorid tilsettes etterhvert h g konsentrert svovelsyre under kjbling og den derved erholdte losning hensettes over natten ved romtemperatur. Deretter helles losningen ut på is, innstilles alkalisk ved tilsetning av natriumhydroksyd og den nå alkaliske losning ekstraheres med metylenklorid. Etter torring avdampes det organiske løsningsmiddel og derved erholdes 1 -(2-metylamino-5-klor-fenyl)^3,^-dihydro-isokinolin som en oljeaktig rest. e) 1=(2-metYlamino-5-klor-fe<nyl>)-1^2^3^^-tetrahydro-isokinolin. To 1 g of 1 -(2-methyltosylamino-5-chloro-phenyl)-3,K-dihydro-isoquinoline hydrochloride, 1 g of concentrated sulfuric acid is gradually added with stirring and the resulting solution is allowed to stand overnight at room temperature. The solution is then poured onto ice, made alkaline by the addition of sodium hydroxide and the now alkaline solution is extracted with methylene chloride. After drying, the organic solvent is evaporated and thereby 1-(2-methylamino-5-chloro-phenyl)^3,^-dihydro-isoquinoline is obtained as an oily residue. e) 1=(2-methylamino-5-chloro-phenyl)-1^2^3^^-tetrahydro-isoquinoline.

En losning av 1 g rått 1-(2-metylamino-5-klorfenyl)-3,l4—dihydro-isokinolin i 8 cm^ eddiksyre hydreres etter tilsetning av 0,05 g platinakatalysator i en hydrogenatmosfære ved romtemperatur og normaltrykk. Deretter frafiltreres katalysatoren, filtratet inndampes i vakuum, resten loses i metylenklorid og denne losning ekstraheres med fortynnet vandig natronlut. Etter torring og inndamping av det organiske skikt tilsettes pentan hvorved 1-(2-metylamino-5-klor-fenyl)-1,2,3tetrahydro-isokinolin utkrystalliseres i hvite prismer med smeltepunkt ^ h^ - 1<1>+3°C. f) 1 - (2-me tylamino- 5-^ loT- fenyl)- 2-^& rlpo^ s^ me tyl-1 jj^jj^j-jtejtr aj-hydro^isokinolin. En blanding bestående av 8 g 1 -(2-metylamino-5-klor-fenyl)- 1,2, 3, h-tetrahydro-isokinolin, 10 g etylbromacetat og 6,5 g trietylamin i 75 cm^ etanol oppvarmes i 2 timer til koking under tilbakelop. Den erholdte losning inndampes til torrhet, resten loses i 80cm^ etanol og 32 cm^ 2N vandig natriumhydroksyd-losning og denne losning oppvarmes i 1 time ved 60°C. Etanol avdampes deretter i vakuum idet en mindre andel av utgangsproduktet utkrystalliseres. Dette frafiltreres og til filtratet tilsettes 32 cm^ 2N saltsyre, hvorved 1 -(2-metylamino-5-klor-fenyl)-2-karboksy-metyl-1 ,2,3,*+-tetrahydro-isokinolin faller ut. g) 2-klor-^iSS^yl^^^iSjilQil^frlk^ £liiZ É-i§5§EiD-l§;on. A solution of 1 g of crude 1-(2-methylamino-5-chlorophenyl)-3,14-dihydro-isoquinoline in 8 cm 3 of acetic acid is hydrogenated after the addition of 0.05 g of platinum catalyst in a hydrogen atmosphere at room temperature and normal pressure. The catalyst is then filtered off, the filtrate is evaporated in vacuo, the residue is dissolved in methylene chloride and this solution is extracted with dilute aqueous caustic soda. After drying and evaporating the organic layer, pentane is added whereby 1-(2-methylamino-5-chloro-phenyl)-1,2,3tetrahydro-isoquinoline crystallizes out in white prisms with melting point ^ h^ - 1<1>+3°C . f) 1 - (2-methylamino-5-[loT-phenyl)-2-^& rlpo^ s^ methyl-1 jj^jj^j-jtejtr aj-hydro^isoquinoline. A mixture consisting of 8 g of 1-(2-methylamino-5-chloro-phenyl)-1,2,3,h-tetrahydro-isoquinoline, 10 g of ethyl bromoacetate and 6.5 g of triethylamine in 75 cm^ of ethanol is heated for 2 hours for boiling under reflux. The obtained solution is evaporated to dryness, the residue is dissolved in 80 cm^ of ethanol and 32 cm^ of 2N aqueous sodium hydroxide solution and this solution is heated for 1 hour at 60°C. Ethanol is then evaporated in a vacuum, with a smaller proportion of the starting product crystallising out. This is filtered off and 32 cm 2 2N hydrochloric acid is added to the filtrate, whereby 1-(2-methylamino-5-chloro-phenyl)-2-carboxy-methyl-1,2,3,*+-tetrahydro-isoquinoline precipitates out. g) 2-chloro-^iSS^yl^^^iSjilQil^frlk^ £liiZ É-i§5§EiD-l§;one.

Det rå 1 - (2-metylamino-5-klor-f enyl)-2-karboksymetyl-1 ,2,3,*+-tetrahydro-isokinolin oppvarmes i 1 time ved 1<1>+0°C. Det erholdte råprodukt loses i dietyleter og ved innledning av torr hydrogenkloridgass utfelles 2-klor-5-metyl-5,6,7,9,10,l^b-heksahydro-isokinolo/2,1-d7benzo/l ,^diazepin-6-on-hydroklorid med smeltepunkt 267 - 270°C. The crude 1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-1,2,3,*+-tetrahydro-isoquinoline is heated for 1 hour at 1<1>+0°C. The crude product obtained is dissolved in diethyl ether and, upon introduction of dry hydrogen chloride gas, 2-chloro-5-methyl-5,6,7,9,10,l^b-hexahydro-isoquinol/2,1-d7benzo/l,^diazepine- 6-one hydrochloride with melting point 267 - 270°C.

Den fri base erholdes fra den vandige losningen av hydrokloridet ved tilsetning av natriumhydroksyd. Etter omkrystallisering fra etanol/vann smelter 2-klor-5-metyl-5,6,7,9,10,l^b-heksahydro-isokinolo/2,1-d7benzo/l ,1t7diazepin-6-on ved 95 - 97°C. The free base is obtained from the aqueous solution of the hydrochloride by addition of sodium hydroxide. After recrystallization from ethanol/water, 2-chloro-5-methyl-5,6,7,9,10,l^b-hexahydro-isoquinolo/2,1-d7benzo/l,1t7diazepin-6-one melts at 95 - 97 °C.

Under anvendelse av den ovenfor beskrevne fremgangsmåte og tilsvarende utgangsforbindelser erholdes 2-klor-5-etyl-5,6,7,9,10,iVb-heksahydro-i sokinolo/2,1 -d7benzo//l ,1±/diazepin-6-on med smeltepunkt 173 - ^^C, såvel som 2-klor-5-propyl-5,6,7,9,10,1^-b-heksahydro-isokinolo/2,1 -d/benzo/l ,!+/diazepin-6-on med smeltepunkt 187 - 190 C. Using the method described above and corresponding starting compounds, 2-chloro-5-ethyl-5,6,7,9,10,iVb-hexahydro-i soquinolo/2,1-d7benzo//l,1±/diazepine- 6-one with melting point 173 - ^^C, as well as 2-chloro-5-propyl-5,6,7,9,10,1^-b-hexahydro-isoquinolo/2,1-d/benzo/l , !+/diazepin-6-one with melting point 187 - 190 C.

Eksempel h: (-)- 2- klor- 5- me tyl- 5, 6, 7, 9. 10, 1 Vb- heksahydro- i sokinolo Example h: (-)- 2- chloro- 5- methyl- 5, 6, 7, 9. 10, 1 Vb- hexahydro- i soquinolo

/ 2, 1 - d/ benzo/ l , 1t7diazepin- 6- on- hydroklorid. / 2, 1 - d/ benzo/ l , 1t7diazepin- 6- one- hydrochloride.

a) Spalting av det_racemiske 1 -(2-metylamino-5-klor-fenyl)-1^2^3j h-tetrahydro-isokinolin i sine optiske antipoder. a) Cleavage of the racemic 1-(2-methylamino-5-chloro-phenyl)-1^2^3j h-tetrahydro-isoquinoline into its optical antipodes.

Til en losning av 8,25 g d-vinsyre i 100 cm^ etanol tilsettes en losning av 15 g (+)-1-(2-metylamino-5-klor-fenyl)-1,2,3,V-tetrahydro-isokinolin i 200 cm^ etanol og 100 cm^ metylenklorid. Ved konsentrerlng av denne blanding faller bare tartratet av (+)-basen ut. Bunnfallet frafiltreres og basen settes i frihet fra sitt salt ved fordeling av saltet mellom metylenklorid og fortynnet vandig natriumhydroksyd-losning. Den organiske fase torres og losningsmidlet fjernes i vakuum. Ved omkrystallisering av den tilbakeblivende rå base fra etanol erholdes (+)-i-(2-metylamino-5-klor-fenyl)-1,2,3,lf-tetrahydro-isokinolin , Æ7^6= + 27'3° To a solution of 8.25 g of d-tartaric acid in 100 cm^ of ethanol is added a solution of 15 g of (+)-1-(2-methylamino-5-chloro-phenyl)-1,2,3,V-tetrahydro- isoquinoline in 200 cm^ of ethanol and 100 cm^ of methylene chloride. When concentrating this mixture, only the tartrate of the (+)-base precipitates. The precipitate is filtered off and the base is set free from its salt by partitioning the salt between methylene chloride and dilute aqueous sodium hydroxide solution. The organic phase is dried and the solvent is removed in vacuo. Upon recrystallization of the remaining crude base from ethanol, (+)-i-(2-methylamino-5-chloro-phenyl)-1,2,3,1f-tetrahydro-isoquinoline is obtained, Æ7^6= + 27'3°

(c = 2 i etanol). Filtratet fra tartratet av (+)-basen inndampes til torrhet i vakuum og resten fordeles mellom metylenklorid og fortynnet vandig natriumhydroksyd-losning. Deretter torres den organiske fase og losningsmidlet fjernes i vakuum. Resten, som i det vesentlige består av (-)-basen overfores på den samme måte som ovenfor beskrevet ved tilsetning av 1-vinsyre i 1-tartratet. (c = 2 in ethanol). The filtrate from the tartrate of the (+)-base is evaporated to dryness in vacuo and the residue is distributed between methylene chloride and dilute aqueous sodium hydroxide solution. The organic phase is then dried and the solvent is removed in vacuo. The remainder, which essentially consists of the (-)-base, is transferred in the same way as described above by adding 1-tartaric acid to the 1-tartrate.

Den på den samme måte som (+)~baseh fra sitt tartrat frigitte (-)-1-(2-metylamino-5-klor-fenyl)-1,2,3 , k-tetrahydro-i sokinolin-base har Æ/jjfø = - 27,8° ( c = 2 i etanol). The (-)-1-(2-methylamino-5-chloro-phenyl)-1,2,3 , k-tetrahydro-i soquinoline base released in the same way as (+)~baseh from its tartrate has Æ/ jjfø = -27.8° ( c = 2 in ethanol).

<k>) <k>)

^trahydro=isokinolin. ^trahydro=isoquinoline.

En blanding bestående av 8 g (+)-1-(2-metylamino-5-klor-fenyl)-1 ,2,3,lf-tetrahydro-isokinolin, 10 g etylbromacetat og 6,5 g trietylamin i 75 cm^ etanol oppvarmes i 2 fcimer til koking under tilbakelop. Den erholdte losning inndampes deretter til torrhet, resten loses i 80 cm^ etanol og 32 cm^ 2N vandig natriumhydroksyd-losning og denne losning oppvarmes i 1 time ved 60°C. Alkoholen avdampes deretter i vakuum, hvorved en liten andel utgangsmaterial utkrystalliseres og deretter frafiltreres. Ved tilsetning av 32 cm^ 2N saltsyre til den nevnte vandig-alkaliske losning faller (+)-1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-1,2,3, h-tetrahydro-isokinolin ut med /ct/<2>^ = + 6<>>+,5<0>(c = 1,3 i etanol). A mixture consisting of 8 g of (+)-1-(2-methylamino-5-chloro-phenyl)-1,2,3,1f-tetrahydro-isoquinoline, 10 g of ethyl bromoacetate and 6.5 g of triethylamine in 75 cc of ethanol heat for 2 fcim to boiling under reflux. The resulting solution is then evaporated to dryness, the residue is dissolved in 80 cm^ ethanol and 32 cm^ 2N aqueous sodium hydroxide solution and this solution is heated for 1 hour at 60°C. The alcohol is then evaporated in a vacuum, whereby a small proportion of the starting material is crystallized and then filtered off. By adding 32 cm^ of 2N hydrochloric acid to the aforementioned aqueous-alkaline solution, (+)-1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-1,2,3,h-tetrahydro-isoquinoline precipitates with /ct/<2>^ = + 6<>>+.5<0>(c = 1.3 in ethanol).

°) llll^iklor^metyl;;^ JZ^2il9jil^l^eksahydroIisokinolo^2_11;:d7 °) llll^ichloro^methyl;;^ JZ^2il9jil^l^hexahydroIisoquinolo^2_11;:d7

^§&5°Zlj!tZ^ia5®£i2l6-on-hydroklorid. ^§&5°Zlj!tZ^ia5®£i2l6-one hydrochloride.

Det i eksempel h b) erholdte (+)-1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-1 ,2,3,*+-tetrahydro-isokinolin oppvarmes i 1 time ved 1MD°C. Deretter loses råproduktet i aceton og torr hydrogenkloridgass innledes. Derved utfelles hydrokloridet av (-)-2-klor-5-metyl-5,6,7,9,10,1Vb-heksahydro-isokinolo/2,1-47benzo/l , kj diazepin-6-on. 3- 7^^ = - 313° (c = 2 i vann). Den fri base erholdes fra den vandige losning av hydrokloridet ved tilsetning av natriumhydroksyd bg omkrystallisering av det erholdte bunn-fall fra etanol og vann. The (+)-1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-1,2,3,*+-tetrahydro-isoquinoline obtained in example h b) is heated for 1 hour at 1MD°C. The crude product is then dissolved in acetone and dry hydrogen chloride gas is introduced. Thereby the hydrochloride of (-)-2-chloro-5-methyl-5,6,7,9,10,1Vb-hexahydro-isoquinolo/2,1-47benzo/l , kj diazepin-6-one is precipitated. 3- 7^^ = - 313° (c = 2 in water). The free base is obtained from the aqueous solution of the hydrochloride by addition of sodium hydroxide bg recrystallization of the precipitate obtained from ethanol and water.

Eksempel 5: ( +)- 2- klor- 5- metyl- 5, 6. 7, 9, 10. 1 * fb- heksahydro- isokinolo/ 2. 1 - d7benzo/ 1 . tt7diazepin- 6- on. a) (-)-1 -(2-me tylamino-5-klor-fenyl)-2-karbok synre tyl-1 2223 1k- i£tlaky^£2~isokinolin. En blanding bestående av 6 g (-)-1-(2-metylamino-5-klor-fenyl-1,2,3, h-tetrahydro-isokinolin, 8 g etylbromacetat og h g trietylamin i 3^ cm^ etanol oppvarmes i 90 min. til koking under tilbakelop. Den således erholdte svakt gule losning avkjoles deretter til 60°C og hertil tilsettes i lopet av 15 min. langsomt 1<*>+ cm^ vann, hvorved grove krystaller utfelles. Krystallene frafiltreres og vaskes med vann. Det erholdes (-)-1-(2-metylamino-5-klor-fenyl)-2-karbetoksyrnetyl-1,2,3, k-tetrahydro-isokinolin med smeltepunkt 10<l>* - 106°C (hvite prismer). b) lill^klor^metyl-^é^ ^22-5°/liliZ§^a?2Ein-i§i22-' 1 g (-)-i_(2-metylamino-5-klor-fenyl)-2-karbetoksymetyl-1,2,3,^-tetrahydra-isokinolin oppvarmes i iseddik til koking og det organiske løsningsmiddel avdestilleres i lopet av \ til 3 timer ved atmosfæretrykk. Etter fjerning av den resterende andel av det flyktige løsningsmiddel i vakuum tilsettes etanol hvorved (+)-2-klor-5-metyl-5,6,7,9,10,1Vb-heksahydro-i sokinolo/2,l-d7benzo Example 5: (+)-2-chloro-5-methyl-5,6.7,9,10.1*fb-hexahydro-isoquinolo/2.1-d7benzo/1. tt7diazepin- 6-one. a) (-)-1 -(2-Methylamino-5-chloro-phenyl)-2-carboxymethyl-1 2223 1k- i£tlaky^£2~isoquinoline. A mixture consisting of 6 g of (-)-1-(2-methylamino-5-chloro-phenyl-1,2,3, h-tetrahydro-isoquinoline, 8 g of ethyl bromoacetate and h g of triethylamine in 3^ cm^ of ethanol is heated at 90 min. to boiling under reflux. The slightly yellow solution thus obtained is then cooled to 60°C and to this is slowly added over 15 min. 1<*>+ cm^ of water, whereby coarse crystals are precipitated. The crystals are filtered off and washed with water. There is obtained (-)-1-(2-methylamino-5-chloro-phenyl)-2-carbethoxymethyl-1,2,3,k-tetrahydro-isoquinoline with melting point 10<l>* - 106°C (white prisms) . b) lill^chloro^methyl-^é^ ^22-5°/liliZ§^a?2Ein-i§i22-' 1 g (-)-i_(2-methylamino-5-chloro-phenyl)-2- carbethoxymethyl-1,2,3,^-tetrahydra-isoquinoline is heated in glacial acetic acid to boiling and the organic solvent is distilled off over the course of \ to 3 hours at atmospheric pressure. After removal of the remaining portion of the volatile solvent in vacuo, ethanol is added whereby (+)-2-chloro-5-methyl-5,6,7,9,10,1Vb-hexahydro-i soquinolo/2,1-d7benzo

^",lt/diazepin-6-on med smeltepunkt 190 - 195°C utkrystalliseres. ^",lt/diazepin-6-one with melting point 190 - 195°C is crystallized.

a1) ( = ) = 1 z (2-metylamino:^::klorIf enyl):2Ikarboksvmetyl=1 ^2^3^ a1) ( = ) = 1 z (2-methylamino:^::chloroIfenyl):2Icarboxyvmethyl=1 ^2^3^

5®5r§ty^T2li§2 ki n2ii n' 5®5r§ty^T2li§2 ki n2ii n'

En blanding bestående av 8 g (-)-1-(2-metylamino-5-klor-fenyl)-1,2,3,^-tetrahydro-isokinolin, 10 g etylbromacetat og 6,5 g dietylamin oppvarmes i 75 ccm etanol til koking i 2 timer. Deretter inndampes losningen til torrhet, resten loses i 80 ccm etanol, hertil tilsettes 32 ccm av en 2N vandig natriumhydroksyd-losnin<g>og den erholdte losning holdes i 1 time ved 60°C. Deretter avdampes alkohol i vakuum hvorved- små andeler utgangsmaterial utkrystalliseres. Etter at disse er fjernet ved frafiltrering tilsettes den resterende losning 32 ccm 2N saltsyre hvorved (-)-1-(2-metylamino-5-klor-fenyl)-karboksy-metyl-1,2,3,*+-tetrahydro-isokinolin med foj^^ = - 6k (c = 1,5 1 etanol) utkrystalliseres. A mixture consisting of 8 g of (-)-1-(2-methylamino-5-chloro-phenyl)-1,2,3,^-tetrahydro-isoquinoline, 10 g of ethyl bromoacetate and 6.5 g of diethylamine is heated in 75 ccm of ethanol to boil for 2 hours. The solution is then evaporated to dryness, the residue is dissolved in 80 ccm of ethanol, 32 ccm of a 2N aqueous sodium hydroxide solution is added to this and the resulting solution is kept for 1 hour at 60°C. The alcohol is then evaporated in a vacuum whereby small portions of the starting material crystallize out. After these have been removed by filtration, 32 ccm of 2N hydrochloric acid is added to the remaining solution, whereby (-)-1-(2-methylamino-5-chloro-phenyl)-carboxy-methyl-1,2,3,*+-tetrahydro-isoquinoline with foj^^ = - 6k (c = 1.5 1 ethanol) is crystallized.

<b>1^ Itlz^klor^^me^yl^^ <b>1^ Itlz^chlor^^me^yl^^

Det etter den ovenstående fremgangsmåte erholdte rå (-)-1-(2-metylamino-5-klor-fenyl)-2-karboksymetylr172737V-tetrahydro-isokinolin oppvarmes i 1 time ved 1<1>+0°C. Deretter loses råproduktet i aceton og torr hydrogenkloridgass fores gjennom losningen. Derved utfelles (+)-2-klor-5-metyl-5,6,7,9,10,1^b-heksahydro-isokinolo/2,1-d/benzo/lj^t/diazepin-é-on-hydroklorid med Æ</>^6<=><+>310° (c = 2 i vann). The crude (-)-1-(2-methylamino-5-chloro-phenyl)-2-carboxymethylr172737V-tetrahydro-isoquinoline obtained according to the above procedure is heated for 1 hour at 1<1>+0°C. The crude product is then dissolved in acetone and dry hydrogen chloride gas is fed through the solution. This precipitates (+)-2-chloro-5-methyl-5,6,7,9,10,1^b-hexahydro-isoquinolo/2,1-d/benzo/lj^t/diazepin-é-one- hydrochloride with Æ</>^6<=><+>310° (c = 2 in water).

Eksempel 6; 2- klor- 12113- dimetoksy- 5- metyl- 5?6T7. 9. 10. 1 hb - Example 6; 2- chloro- 12113- dimethoxy- 5- methyl- 5?6T7. 9. 10. 1 hb -

heksahydro- isokinolo/ 2. 1- d7benzoZ1 .^/ diazepln- é- on. hexahydro- isoquinolo/ 2. 1- d7benzoZ1 .^/ diazepln- é- one.

a) N-(homoyeratryl)-2-metylamino-^klor-benzamid. a) N-(homoeryatryl)-2-methylamino-^chloro-benzamide.

En blanding bestående av 1 g 5-klor-N-metyl-isatosyreanhydrid A mixture consisting of 1 g of 5-chloro-N-methyl isatoic anhydride

og 1 g homoveratrylamin i h cm^ dioksan oppvarmes i 15 min. på vannbad, hvorved det finner sted en sterk karbondioksyd-utvikling. Til den erholdte losning tilsettes vann hvorved N-(homoveratryl-2-metylamino-5-klor-benzamid med smeltepunkt 96 - 98°C utfelles. and 1 g homoveratrylamine in h cm^ dioxane are heated for 15 min. on a water bath, whereby a strong carbon dioxide evolution takes place. Water is added to the solution obtained, whereby N-(homoveratryl-2-methylamino-5-chloro-benzamide with a melting point of 96 - 98°C is precipitated).

<b>) !?;1^2<m>2Y2£<a>^<y>]:2z?i<m>2iZii2§Yiami2-2i^i^i25zE2&5<am>i^« <b>) !?;1^2<m>2Y2£<a>^<y>]:2z?i<m>2iZii2§Yiami2-2i^i^i25zE2&5<am>i^«

Til losningen av h g N-(homoveratryl)-3-metylamino-5-klor-benzamid For the solution of h g N-(homoveratryl)-3-methylamino-5-chloro-benzamide

i 1.2 cm^ pyridin tilsettes 3 g p-toluensulfonsyreklorid og den erholdte blanding oppvarmes i 1,5 time ved 60°C. Deretter tilsettes 12 cm aceton og h cm^ vann til den således behandlede 3 g of p-toluenesulfonic acid chloride are added to 1.2 cm^ of pyridine and the resulting mixture is heated for 1.5 hours at 60°C. 12 cm of acetone and 1 cm of water are then added to the mixture thus treated

blanding 'og det hele rystes i 30 min. Etter inndamping til et lite volum tilsettes etylacetat og den organiske fase ekstraheres med fortynnet saltsyre og en vandig natriumhydroksyd-losning. Deretter torres den organiske fase og losningsmidlet fjernes. Som amorf rest erholdes tosylatet av N-(homoveratryl)-2-metylamino-5-klor-benzamid. mixture 'and the whole thing is shaken for 30 min. After evaporation to a small volume, ethyl acetate is added and the organic phase is extracted with dilute hydrochloric acid and an aqueous sodium hydroxide solution. The organic phase is then dried and the solvent is removed. The tosylate of N-(homoveratryl)-2-methylamino-5-chloro-benzamide is obtained as an amorphous residue.

°) lll2rmetyltosylamino-^-klor-fenyl) °) lll2rmethyltosylamino-^-chloro-phenyl)

isokinolin. isoquinoline.

Det etter eksempel 6b) erholdte rå tosylat ioses i 5 ca^ varm xylen og til den erholdte reaksjonsblanding tilsettes 6 g fosforpentoksyd. Denne blanding oppvarmes i 15 timer til koking under tiibakelop. Deretter fjernes xylen i vakuum og den klebrige rest spaltes ved tilsetning av is. Den dannede vandige blanding gjores alkalisk med konsentrert vandig natriumhydroksyd-lbsning og ekstraheres med etylacetat. Den organiske fase ekstraheres deretter med fortynnet saltsyre. Den vandige fase gjores på samme The crude tosylate obtained according to example 6b) is dissolved in 5 g of warm xylene and 6 g of phosphorus pentoxide are added to the reaction mixture obtained. This mixture is heated for 15 hours to boiling under a ten-bake run. The xylene is then removed in a vacuum and the sticky residue is split by adding ice. The resulting aqueous mixture is made alkaline with concentrated aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic phase is then extracted with dilute hydrochloric acid. The aqueous phase is done in the same way

måte som beskrevet ovenfor alkalisk o.g ekstraheres med metyleri-klorid. Etter avdamping av det organiske løsningsmiddel érholdes 1-(2-metyltosylamino-5-klor-f enyl)-6,7-dimetoksy-3,l4—dihydro-isokinolin som amorf rest., d) Ir(2-metylamino-5-klor-fenyl) isokinolin. manner as described above alkaline and extracted with methyl chloride. After evaporation of the organic solvent, 1-(2-methyltosylamino-5-chloro-phenyl)-6,7-dimethoxy-3,14-dihydro-isoquinoline is retained as an amorphous residue, d) Ir(2-methylamino-5- chloro-phenyl) isoquinoline.

En lbsning av 1 g av det etter eksempel 6 c) erholdte råprodukt A solution of 1 g of the crude product obtained according to example 6 c).

i 2,5 g konsentrert saltsyre hensettes over natten ved romtemperatur. Deretter tilsettes løsningen isolandet ,vann og natriumhydroksyd og det derved utfallende, smorjeaktige bunnfall ekstraheres med metylenklorid. Losningsmidlet avdampes dere.tter og resten omkrystalliseres fra etanol. Det således erholdte 1-(2-metylamino-5-klor-fenyj)-6,7-dimetoksy-3,lf-dihydro-isokinolin smelter ved 110 - 112°C. e) 1-(2^5e tylamino^^klor^f enyl2:612-^imetoksy-1 ^g^^ilt-Setrahydro-isokinolin. in 2.5 g of concentrated hydrochloric acid is left overnight at room temperature. Next, the isolated solution, water and sodium hydroxide are added and the resulting, buttery precipitate is extracted with methylene chloride. The solvent is then evaporated and the residue is recrystallized from ethanol. The thus obtained 1-(2-methylamino-5-chloro-phenyl)-6,7-dimethoxy-3,1f-dihydro-isoquinoline melts at 110 - 112°C. e) 1-(2^5e ethylamino^^chloro^phenyl2:612-^imethoxy-1^g^^oxyl-Setrahydro-isoquinoline.

En losning av 1 g 1-(2-metylamino-5-klor-fenyl)-6,7-dimetoksy-3,<l>+- dihydro-isokinolin i 8 cm^ eddiksyre rystes ved romtemperatur i en hydrogenatmosfære og i nærvær av 0,05 g platina-katalysator ved atmosfæretrykk. Deretter frafiltreres katalysatoren og filtratet inndampes i vakuum. Resten fordeles mellom metylenklorid og fortynnet vandig natriumhydroksyd-losning. Den organiske losning torres og befris deretter for løsningsmiddel*Den oljeaktige rest omkrystalliseres fra etylacetat/dietylete». Det således erholdte 1-(2-metylamino-5-klor-fenyl)-6,7-dimetoksy-1,2,3, h-tetrahydro-isokinolin smelter ved 14-5 - 1^7°C. f) 1 - (2-metylamino-5;klor-f enyl)i^karboksymetyl-é^^i^imetoks^ l^g^^il+r tetrahydro-isokinolin. A solution of 1 g of 1-(2-methylamino-5-chloro-phenyl)-6,7-dimethoxy-3,<l>+- dihydro-isoquinoline in 8 cm^ of acetic acid is shaken at room temperature in a hydrogen atmosphere and in the presence of 0.05 g platinum catalyst at atmospheric pressure. The catalyst is then filtered off and the filtrate is evaporated in a vacuum. The remainder is distributed between methylene chloride and dilute aqueous sodium hydroxide solution. The organic solution is dried and then freed from solvent* The oily residue is recrystallized from ethyl acetate/diethyl ether. The thus obtained 1-(2-methylamino-5-chloro-phenyl)-6,7-dimethoxy-1,2,3,h-tetrahydro-isoquinoline melts at 14-5 - 1^7°C. f) 1 - (2-methylamino-5;chloro-phenyl)i^carboxymethyl-e^^i^imethox^ 1^g^^yl+r tetrahydro-isoquinoline.

En blanding bestående av 1 g 1 -(2-metylamino-5-klor-fenyl)-6,7-dimetoksy-1,2,3, h-tetrahydro-isokinolin, 1 g etylbromacetat, 0,6 g trietylamin og 0,1 g natrium;)odid i 8 cm^ etanol oppvarmes i 2 timer til koking under tilbakelop. Den således erholdte losning inndampes deretter til torrhet i vakuum og resten loses i 10 cm^ etanol og 3 cm^ 2N vandig natriumhydroksyd-losning. Den således erholdte løsning oppvarmes deretter i 1 time ved 60°C. Deretter fjernes alkohol i vakuum, hvorved små mengder utgangsforbindelser utkrystalliseres. Disse frafiltreres, til filtratet tilsettes så 3 cm^ 2N saltsyre og det derved utfallende 1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-6,7-dimetoksy-1,2,3 A*tetrahydro-isokinolin frafiltreres. A mixture consisting of 1 g of 1 -(2-methylamino-5-chloro-phenyl)-6,7-dimethoxy-1,2,3,h-tetrahydro-isoquinoline, 1 g of ethyl bromoacetate, 0.6 g of triethylamine and 0, 1 g of sodium hydroxide in 8 cm3 of ethanol is heated for 2 hours to boiling under reflux. The solution thus obtained is then evaporated to dryness in vacuo and the residue is dissolved in 10 cm^ of ethanol and 3 cm^ of 2N aqueous sodium hydroxide solution. The solution thus obtained is then heated for 1 hour at 60°C. Alcohol is then removed in a vacuum, whereby small amounts of starting compounds crystallize out. These are filtered off, 3 cm^ 2N hydrochloric acid is then added to the filtrate and the resulting 1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-6,7-dimethoxy-1,2,3 A*tetrahydro-isoquinoline is filtered out.

6) 2-klor-12J13=dimetoksy=^Imetyl-^i6 6) 2-Chloro-12H13=dimethoxy=^Imethyl-^i6

isokinolo i/^ gl2i§Z^®2-52^1i!tZ^i§5§£iSz§i o2» isoquinolo i/^ gl2i§Z^®2-52^1i!tZ^i§5§£iSz§i o2»

Det etter eksempel 6 f) erholdte 1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-6,7-dimetosky-1>2,3,4~tetrahydro-isokinolin oppvarmes i 1 time ved 150°C. Deretter omkrystalliseres råproduktet fra etylacetat og det erholdes på denne måte 2-klor-12,13-dimetoksy-5- metyl-5j6,7j9j10>14b-heksahydro-i sokinoloZ2,1-d7benzo/1,4/diazepin 6- on med smeltepunkt 175 - 177°C. The 1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-6,7-dimethosky-1>2,3,4~tetrahydro-isoquinoline obtained according to example 6 f) is heated for 1 hour at 150°C . The crude product is then recrystallized from ethyl acetate and 2-chloro-12,13-dimethoxy-5-methyl-5j6,7j9j10>14b-hexahydro-i soquinoloZ2,1-d7benzo/1,4/diazepine 6-one with melting point 175 - 177°C.

Eksempel 7; 2- trif luormetvl- 5- me tyl- 5. 6. 7. 9. 10, 1 U- b- heksahydro-isokinolo/ 2, 1- d7banzo/* 1 A/ diazepin- 6- on- hydroklorid. a) l:l?ikior^2zili£iu2rm2£^^ hydroklorid. Example 7; 2- trifluormetvl- 5- methyl- 5. 6. 7. 9. 10, 1 U- b- hexahydro-isoquinol/ 2, 1- d7banzo/* 1 A/ diazepin- 6- one- hydrochloride. a) l:l?ikior^2zili£iu2rm2£^^ hydrochloride.

En blanding bestående av 8 cm^ tinriklorid, 10 g fenetylklorid og A mixture consisting of 8 cm^ of tin trichloride, 10 g of phenethyl chloride and

13 g 2-klor-5-trifluormetyl-benzonitril oppvarmes i 5 timer under tilbakelopskjoler. Under sterk avkjøling (tørris/aceton) tilsettes den avkjølte blanding en 25$ vandig natriumhydroksyd-losning til alkalisk reaksjon av losningen. Deretter ekstraheres den blakke losning 3 ganger med etylacetat, den organiske fase filtreres, denne vaskes med vann og deretter med en mettet koksalt-losning, torres så over natriumsulfat og det organiske løsnings-middel avdampes i vakuum. Resten loses i metylenklorid og løsning-en mettes med tørr hydrogenklorid-gass. Etter tilsetning av dietyleter og avkjøling til 0°C utfelles 1-(2-klor-5-trifluormetyl-fenyl)-3,4-dihydro-isokinolin-hydroklorid med smeltepunkt 212 - 214°C. Forbindelsen kan renses ved sublimering ved 100°C og 0,5 mm Hg trykk. 13) lii §rmetylamino-^= trif luorme tyl En blanding bestående av 35 g 1-(2-klor-5-trifluormetyl-fenyl)-3,4-dihydro-isokinolin-hydroklorid, 1,7 g kopperklorid, 1,7 g kopperpulver i 500 cm^ flytende metylamin oppvarmes i en autoklav ved 55 - 60°C og holdes i 12 timer ved denne temperatur. Det erholdte omsetningsprodukt avkjøles deretter og metylaminet avdampes ved romtemperatur. Resten løses i 500 cm^ metylenklorid, filtreres og filtratet vaskes 2 ganger med vann. Etter tørring over natriumÉulfat og avdamping av det organiske løsningsmiddel erholde s 1 - (2-me tylamino- 5- triftuorme tyl- f enyl) - 3,4- dihydr o-isokinolin som en svakt gul olje. c) lli2Im£tliami?2l£ltEi£ luormetyl-f enyl)-1 ^2^3^*+-tetrahydro-isokinolin. 13 g of 2-chloro-5-trifluoromethyl-benzonitrile are heated for 5 hours under reflux. Under strong cooling (dry ice/acetone), a 25% aqueous sodium hydroxide solution is added to the cooled mixture for alkaline reaction of the solution. The clear solution is then extracted 3 times with ethyl acetate, the organic phase is filtered, this is washed with water and then with a saturated sodium chloride solution, then dried over sodium sulphate and the organic solvent is evaporated in vacuo. The residue is dissolved in methylene chloride and the solution is saturated with dry hydrogen chloride gas. After addition of diethyl ether and cooling to 0°C, 1-(2-chloro-5-trifluoromethyl-phenyl)-3,4-dihydro-isoquinoline hydrochloride with melting point 212 - 214°C is precipitated. The compound can be purified by sublimation at 100°C and 0.5 mm Hg pressure. 13) lii §rmethylamino-^= trifluoromethyl A mixture consisting of 35 g of 1-(2-chloro-5-trifluoromethyl-phenyl)-3,4-dihydro-isoquinoline hydrochloride, 1.7 g of copper chloride, 1.7 g of copper powder in 500 cm^ liquid methylamine is heated in an autoclave at 55 - 60°C and kept for 12 hours at this temperature. The reaction product obtained is then cooled and the methylamine is evaporated at room temperature. The residue is dissolved in 500 cm^ of methylene chloride, filtered and the filtrate is washed twice with water. After drying over sodium sulfate and evaporating the organic solvent, s 1 - (2-methylamino-5-trifluoromethyl-phenyl)-3,4-dihydro-isoquinoline is obtained as a pale yellow oil. c) lli2Im£tliami?2l£ltEi£ luoromethyl-phenyl)-1 ^2^3^*+-tetrahydro-isoquinoline.

En blanding bestående av 30 g 1-(2-metylamino-5-trifluormetyl-fenyl)-3,4-dihydro-isokinolin og 8 g natriumborhydrid, oppvarmes i 400 cm^ 95$ etanol i 2 timer til koking under tilbakeløp. Den erholdte losning avkjøles og behandles med 2N saltsyre for spalting av overskudd av natriumborhydrid. Deretter innstilles alkalisk med 2N vandig natriumhydroksyd-losning og losningen inndampes ved avdamping av losningsmidlet i vakuum til 100 cm^. Denne ekstraheres 3 ganger- med etylacetat. Den organiske fase vaskes deretter to ganger med mettet koksaltløsning, og borres aå over natriumsulfat. Ved avdamping av losningsmidlet i vakuum og omkrystallisering fra etanol erholdes 1-(2-metylamino-5-trifluormetyl-fenyl)-1,2,3,4-tetrahydro-isokinolin med smeltepunkt 125 - 129°C A mixture consisting of 30 g of 1-(2-methylamino-5-trifluoromethyl-phenyl)-3,4-dihydro-isoquinoline and 8 g of sodium borohydride is heated in 400 cc of 95% ethanol for 2 hours to reflux. The solution obtained is cooled and treated with 2N hydrochloric acid to split the excess of sodium borohydride. It is then made alkaline with a 2N aqueous sodium hydroxide solution and the solution is evaporated by evaporating the solvent in a vacuum to 100 cm 2 . This is extracted 3 times with ethyl acetate. The organic phase is then washed twice with saturated sodium chloride solution, and filtered again over sodium sulphate. By evaporating the solvent in vacuo and recrystallization from ethanol, 1-(2-methylamino-5-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinoline with melting point 125 - 129°C is obtained

1 J2J3Jl+-tetrahydro=isokinolin. 1 J2J3Jl+-tetrahydro=isoquinoline.

En blanding bestående av 1 g 1 -(2-metylamino-5-trifluormetyl-fenyl)-1,2,3,4-tetrahydro-isokinolin, 1 g etylbromacetat og 0,7 g trietylamin i 30 cm^ etanol oppvarmes til koking i 5 timer under tilbakelbp. Deretter fjernes losningsmidlet i vakuum, resten loses i metylenklorid, metylenklorid-losningen vaskes med vann, torres så over natriumsulfat og befris tilslutt i vakuum for løsningsmiddel. Den oljeaktige rest destilleres ved 130°C og 0,5 mm trykk og destillatet omkrystalliseres fra pentan. Det således erholdte 1-(2-metylamino-5-trifluormetyl-fenyl)-2-karbetoksymetyl-1,2,3,4-tetrahydro-isokinolin smelter -ved 80 - 82°C.. A mixture consisting of 1 g of 1-(2-methylamino-5-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinoline, 1 g of ethyl bromoacetate and 0.7 g of triethylamine in 30 cm^ of ethanol is heated to boiling in 5 hours during return. The solvent is then removed in vacuum, the residue is dissolved in methylene chloride, the methylene chloride solution is washed with water, then dried over sodium sulfate and finally freed of solvent in vacuum. The oily residue is distilled at 130°C and 0.5 mm pressure and the distillate is recrystallized from pentane. The thus obtained 1-(2-methylamino-5-trifluoromethyl-phenyl)-2-carbethoxymethyl-1,2,3,4-tetrahydro-isoquinoline melts at 80 - 82°C.

e) 2-trif luorme tyl-^-me ty 1-^6^ e) 2-trif luorme tyl-^-me ty 1-^6^

En losning av 0,1 g metallisk natrium i 200 cm^ absolutt 2-metoksyetanol tilsettes 10 g 1-(2-metylamino-5-trifluormetyl-fenyl)-2-karbetoksynretyl-1,2,3,4-tetrahydro-isokinolin og det hele oppvarmes i 1 time til koking under tilbakelop. Deretter avdestilleres losningsmidlet i vakuum og resten loses i metylenklorid. A solution of 0.1 g of metallic sodium in 200 cm^ of absolute 2-methoxyethanol is added to 10 g of 1-(2-methylamino-5-trifluoromethyl-phenyl)-2-carbethoxynretyl-1,2,3,4-tetrahydro-isoquinoline and it is all heated for 1 hour until boiling under reflux. The solvent is then distilled off in a vacuum and the residue is dissolved in methylene chloride.

Den organiske fase vaskes 2 ganger med vann, torres så over natriumsulfat og tilslutt fjernes losningsmidlet i vakuum, hvorved det blir tilbake en svakt brunaktig olje. Oljen loses i etylacetat og losningen mettes med torr hydrogenkloridgass. Ved avkjøling faller hydrokloridet av 2-trifluormetyl-5-metyl-5,6,7,9,10,l4b-heksahydro-isokinolo/2,1 -d/~benzo£) ,4/diazepin-6-on-hydroklorid med smeltepunkt 221 - 225°C ut. The organic phase is washed twice with water, then dried over sodium sulphate and finally the solvent is removed in vacuo, whereby a slightly brownish oil remains. The oil is dissolved in ethyl acetate and the solution is saturated with dry hydrogen chloride gas. On cooling, the hydrochloride of 2-trifluoromethyl-5-methyl-5,6,7,9,10,14b-hexahydro-isoquinolo/2,1-d/~benzo£),4/diazepin-6-one hydrochloride falls with melting point 221 - 225°C out.

Eksempel 8: 2- klor- 5. 10. 10- tr ime tyl- 5. 6. 7. 9. 10. 14- b- heksahydr o-isokinolo/ 2. 1- d7benzo/* 1 . lt7diazepin- 6- on. Example 8: 2- chloro- 5. 10. 10-trime tyl- 5. 6. 7. 9. 10. 14- b- hexahydr o-isoquinolo/ 2. 1- d7benzo/* 1 . lt7diazepin- 6-one.

a) N-( 2-me tyl-2-fenyl-pr^pyl}-2Iare;t^lam^ a) N-(2-methyl-2-phenyl-propyl}-2Iare;t^lam^

En blanding bestående av 2 g 5-klor-N-metyl-isatosyre-anhydrid og A mixture consisting of 2 g of 5-chloro-N-methyl isatoic anhydride and

1,5 g 2-metyl-2-fenyl-propylamin oppvarmes i 10 em^ dioksan i 15 min. på vannbad hvorved det finner sted en sterk karbondioksyd-utvikling. Til den erholdte losning tilsettes vann hvorved N-(2-metyl-2-fenyl-propyl)-2-metylamino-5-klor-benzamid med smeltepunkt 126 - 127°C utfelles. b) N-(2-metyl-2-fenyl-grogyl)-2-metyltosylamino-5-klor-benzamid. 1.5 g of 2-methyl-2-phenyl-propylamine is heated in 10 em^ dioxane for 15 min. on a water bath whereby a strong carbon dioxide evolution takes place. Water is added to the solution obtained, whereby N-(2-methyl-2-phenyl-propyl)-2-methylamino-5-chloro-benzamide with a melting point of 126 - 127°C is precipitated. b) N-(2-methyl-2-phenyl-grogyl)-2-methyltosylamino-5-chloro-benzamide.

Til en losning av 0,85 g N-(2-metyl-2-fenyl-propyl)-2-metylamino-5-klor-benzamid i 2,5 cm^ pyridin tilsettes 1 g p-toluensulfonsyreklorid og den således erholdte blanding oppvarmes i 1-£ time ved 60°C. Deretter inndampes i vakuum, det tilsettes 3 cm^ aceton og 1 cm^ vann og den således erholdte blanding rystes i 30 min. Etter avdamping av aceton tilsettes etylacetat og det organiske skikt ekstraheres med fortynnet saltsyre og vandig natriumbikarbonat-losning. To a solution of 0.85 g of N-(2-methyl-2-phenyl-propyl)-2-methylamino-5-chloro-benzamide in 2.5 cm^ of pyridine, 1 g of p-toluenesulfonic acid chloride is added and the mixture thus obtained is heated for 1-£ hour at 60°C. It is then evaporated in a vacuum, 3 cm^ of acetone and 1 cm^ of water are added and the mixture thus obtained is shaken for 30 min. After evaporation of acetone, ethyl acetate is added and the organic layer is extracted with dilute hydrochloric acid and aqueous sodium bicarbonate solution.

Den organiske fase torres over natriumsulfat og losningsmidlet fjernes deretter ved avdamping. Det erholdes en oljeaktig rest som utkrystalliseres ved henstand i 5 cm^ dietyleter. Det derved erholdte N-(2-metyl-2-fenyl-propyl)-2-metyltosylamino-5-klor-benzamid smelter ved 127 - 130°C. c) 1 - (2-metyltosylamino=^-klor=f enyl)-4J4-dimetyl-3Jl4;dihydro-i SoMnolin-hjrdr oklor id . The organic phase is dried over sodium sulphate and the solvent is then removed by evaporation. An oily residue is obtained which is crystallized on standing in 5 cm^ of diethyl ether. The N-(2-methyl-2-phenyl-propyl)-2-methyltosylamino-5-chloro-benzamide thus obtained melts at 127 - 130°C. c) 1 - (2-methyltosylamino=^-chloro=phenyl)-4H4-dimethyl-3H14;dihydro-iSoMnoline-hydrochloroid.

10 g av det etter eksempel 8 b) erholdte N-(2-metyl-2-fenyl-propyl)-2-metyltosylamino-5-klor-benzamid tilsettes til 75 cm^ fosforoksyklorid og den erholdte blanding oppvarmes i 15 timer til koking under tilbakelop. Deretter avfc^oles blandingen til romtemperatur (20°C) og inndampes i vakuum. Den erholdte rest loses i 300 cm^ metylenklorid. Denne losning vaskes forst med en iskold 1N vandig natriumhydroksyd-losning (2 vaskinger med tilnærmet 120 cm<J>natriumhydroksyd-losning), deretter med vann og deretter med mettet, vandig natriumklorid-løsning. Den således vaskede, organiske fase torres over natriumsulfat og befris for løsningsmiddel i vakuum. Resten loses i 60 cm aceton og den således erholdte losning mettes med torr hydrogenklorid-gass. Deretter inndampes i vakuum til det halve volum, det tilsettes 30 cm<J>dietyleter hvorved 1 -(2-metyl-tosylamino-5-klor-fenyl)-4,4-dimetyl-3,4-dihydro-isokinolin-hydroklorid med smeltepunkt 260°C (spalting) faller ut. 10 g of the N-(2-methyl-2-phenyl-propyl)-2-methyltosylamino-5-chloro-benzamide obtained according to example 8 b) is added to 75 cm^ of phosphorus oxychloride and the mixture obtained is heated for 15 hours to boiling under backflow. The mixture is then cooled to room temperature (20°C) and evaporated in vacuo. The residue obtained is dissolved in 300 cc of methylene chloride. This solution is first washed with an ice-cold 1N aqueous sodium hydroxide solution (2 washes with approximately 120 cm<J> of sodium hydroxide solution), then with water and then with saturated, aqueous sodium chloride solution. The thus washed organic phase is dried over sodium sulphate and freed from solvent in a vacuum. The residue is dissolved in 60 cm of acetone and the solution thus obtained is saturated with dry hydrogen chloride gas. It is then evaporated in vacuo to half the volume, 30 cm<J>diethyl ether is added, whereby 1 -(2-methyl-tosylamino-5-chloro-phenyl)-4,4-dimethyl-3,4-dihydro-isoquinoline hydrochloride with melting point 260°C (decomposition) precipitates.

d) IzC^^metylamino-5-klor-fenyl)-4^4 d) IzC^^methylamino-5-chloro-phenyl)-4^4

Til 6,8 g 1-(2-metyltosylamino-5-klor-fenyl)-4,4-dimetyl-3,4-dihydro-isokinolin-hydroklorid tilsettes langsomt 15 cm^ konsentrert svovelsyre under avkjøling og den erholdte løsning hensettes ved romtemperatur over natten. Deretter uthelles denne løsning på is, innstilles alkalisk ved tilsetning av natriumhydroksyd og den alkaliske losning ekstraheres msd metylenklorid. Løsningen tørres og befris for organisk løsningsmiddel. Det erholdte 1 - (2-metylamino-5-klor-f enyl).-4,4-dimetyl-3,4-dihydro-isokinolin smelter ved 125 - 128°C. e) lii?i!!?§£Zi§mi£2i£r^i2£i£§nyl)-4^isokinolin. 16 g 1 -(2-metylamino-5-klor-fenyl)-4,4-dimetyl-3,4-dihydro-isokinolin suspenderes i 200 cm^ 95$ etanol, til suspensjonen tilsettes 3j5g natriumborhydrid og den erholdte blanding oppvarmes i 1 time til koking under tilbakelop. Deretter avkjøles til romtemperatur og syres med 2N saltsyre. Deretter innstilles til pH 9 med 2N vandig natronlut, inndampes til 1/3 av volumet i vakuum og den således konsentrerte løsning ekstraheres 2 ganger med hver gang 150 cm^ etylacetat. De organiske faser vaskes deretter med vann og mettet vandig natriumklorid-løsning, tørres over natriumsulfat og befris for løsningsmiddel i vakuum. Den oljeaktige rest krystalliseres fra dietyleter/pentan. Det således erholdte 1 -(2-metylamino-5-klor-fenyl)-4,4-dimetyl-1,2,3,4-tetrahydro-isokinolin smelter ved 110 - 112°C. f) 1 Z I?I™Stvlamin2l?Z^i2£z£ enyl)-2-karboksyme tyl-^^—diine tyl-Ijgj^^V^tetrahydro-isokinolin. 10 g 1-(2-metylamino-5-klor-f enyl)-4,4-dimetyl-1 ,2,3,4-tetrahydro-isokinolin loses i 90 cm<J>etanol og den erholdte losning tilsettes 10 g metylbromacetat og 7 g trietylamin. Den erholdte blanding oppvarmes i 4 timer under tilbakeløpskjøler og deretter avdampes losningsmidlet. Resten blandes med 200 cm^ etylacetat og 100 cm^ vann, fasene skilles og den vandige fase ekstraheres 2 ganger med hver gang 100 cm<J>etylacetat. De organiske faser forenes og vaskes med vann såvel som mettet vandig natriumklorid-losning. Den således behandlede organiske fase torres over natriumsulfat og deretter avdampes det organiske løsningsmiddel i vakuum. Resten omkrystalliseres i 75 cmJ av en blanding av benzen og pentan (1:1). De utfallende krystaller frafiltreres. Det således erholdte 1 -(2-metylamino-5-klor-fenyl)-2-karbometoksymetyl-4 ,4- dimetyl-1,2,3,4-tetrahydro-isokinolin smelter ved 111 - 113°C. 2 g av denne forbindelse loses i 10 cm^ etanol, den erholdte losning tilsettes 10 cm<J>1N vandig natriumhydroksyd-losning og den erholdte blanding oppvarmes i 1 time under tilbakelop. Deretter avkjøles løsningen til romtemperatur og tilsettes 10 cm^ 1N saltsyre. De utfallende krystaller frafiltreres og tørres. Det således erholdte 1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-4,4-dimetyl-1 ,2,3,4-tetrahydro-isokinolin smelter ved 2.1.2 - 216°C. To 6.8 g of 1-(2-methyltosylamino-5-chloro-phenyl)-4,4-dimethyl-3,4-dihydro-isoquinoline hydrochloride, 15 cm^ of concentrated sulfuric acid are slowly added while cooling and the resulting solution is allowed to stand at room temperature over the night. This solution is then poured onto ice, made alkaline by the addition of sodium hydroxide and the alkaline solution is extracted with methylene chloride. The solution is dried and freed from organic solvent. The obtained 1-(2-methylamino-5-chloro-phenyl).-4,4-dimethyl-3,4-dihydro-isoquinoline melts at 125-128°C. e) lii?i!!?§£Zi§mi£2i£r^i2£i£§nyl)-4^isoquinoline. 16 g of 1-(2-methylamino-5-chloro-phenyl)-4,4-dimethyl-3,4-dihydro-isoquinoline are suspended in 200 cm^ 95$ of ethanol, 3j5g of sodium borohydride are added to the suspension and the resulting mixture is heated for 1 hour to boil under reflux. Then cool to room temperature and acidify with 2N hydrochloric acid. The pH is then adjusted to 9 with 2N aqueous caustic soda, evaporated to 1/3 of the volume in a vacuum and the thus concentrated solution is extracted twice with 150 cm^ of ethyl acetate each time. The organic phases are then washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and freed of solvent in vacuo. The oily residue is crystallized from diethyl ether/pentane. The thus obtained 1-(2-methylamino-5-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline melts at 110 - 112°C. f) 1 Z I?I™Stvlamin2l?Z^i2£z£ enyl)-2-carboxymethyl-^^—diine ethyl-Ijgj^^V^tetrahydro-isoquinoline. 10 g of 1-(2-methylamino-5-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline are dissolved in 90 cm<J>ethanol and 10 g of methyl bromoacetate are added to the resulting solution and 7 g of triethylamine. The resulting mixture is heated for 4 hours under a reflux condenser and then the solvent is evaporated. The residue is mixed with 200 cc of ethyl acetate and 100 cc of water, the phases are separated and the aqueous phase is extracted twice with 100 cc of ethyl acetate each time. The organic phases are combined and washed with water as well as saturated aqueous sodium chloride solution. The thus treated organic phase is dried over sodium sulphate and then the organic solvent is evaporated in vacuo. The residue is recrystallized in 75 cmJ of a mixture of benzene and pentane (1:1). The precipitated crystals are filtered off. The thus obtained 1-(2-methylamino-5-chloro-phenyl)-2-carbomethoxymethyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline melts at 111 - 113°C. 2 g of this compound are dissolved in 10 cm3 of ethanol, 10 cm<J>1N aqueous sodium hydroxide solution is added to the resulting solution and the resulting mixture is heated for 1 hour under reflux. The solution is then cooled to room temperature and 10 cm^ 1N hydrochloric acid is added. The precipitated crystals are filtered off and dried. The thus obtained 1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline melts at 2.1.2 - 216°C.

S) ^klor-^IQjIQ-trimetyl^^ S) ^chloro-^IQjIQ-trimethyl^^

/^^l^d^benzo^jVydiazenin-é-on. /^^l^d^benzo^jVydiazenin-é-one.

2 g 1-(2-metylamino-r5-klor-fenyl)-2-karboksymetyl-4,4-dimetyl-1 ,2,3,4-tetrahydro-isokinolin oppvarmes i 4-0 min. ved 200 C. Deretter omkrystalliseres resten fra en blanding av 5 cm^ metylenklorid og10 cm^ dietyleter, hvorved 2-klor-5?}0,10-trimetyl-5,6,7,9,10,l4b-heksahydro-isokinolo/2,1-d/benzo/l ,4_/diazepin-6-on med smeltepunkt 190 - 194°C erholdes. 2 g of 1-(2-methylamino-β-chloro-phenyl)-2-carboxymethyl-4,4-dimethyl-1,2,3,4-tetrahydro-isoquinoline are heated for 4-0 min. at 200 C. The residue is then recrystallized from a mixture of 5 cm^ methylene chloride and 10 cm^ diethyl ether, whereby 2-chloro-5?}0,10-trimethyl-5,6,7,9,10,14b-hexahydro-isoquinolo/ 2,1-d/benzo/l,4-/diazepin-6-one with melting point 190 - 194°C is obtained.

Eksempel 9: cis- og trans- 2- klor- 5. 10- dimetyl- 5, 6. 7, 9. 10. 14b-heksahydro- isokinoloZ2, 1 - d/ benzo/ 1, 4_ 7diazepin- 6- on. Example 9: cis- and trans-2-chloro-5.10-dimethyl-5,6.7,9.10.14b-hexahydro-isoquinoloZ2,1-d/benzo/1,4_7diazepin-6-one.

En blanding bestående av 2 g 5-klor-N-metyl-isatosyreanhydrid og A mixture consisting of 2 g of 5-chloro-N-methyl isatoic anhydride and

1,6 g 2-fenylpropylamin oppvarmes i 10 cm^ dioksan i 15 min. på vannbad hvorved det finner sted en sterk karbondioksyd-utvikling. Til den erholdte losning tilsettes vann hvorved N-(2-fenylpropyl)-2-metylamino-5-klor-benzamid med smeltepunkt 100 - 103°C utfelles. 1.6 g of 2-phenylpropylamine is heated in 10 cm^ of dioxane for 15 min. on a water bath whereby a strong carbon dioxide evolution takes place. Water is added to the solution obtained, whereby N-(2-phenylpropyl)-2-methylamino-5-chloro-benzamide with a melting point of 100 - 103°C is precipitated.

b) N-(2-fenylgropyl)-2-metyltosylamino-5-klor-benzamid. b) N-(2-phenylgropyl)-2-methyltosylamino-5-chloro-benzamide.

Til en losning av 0,8 g N-(2-fenylpropyl)-2-metylamino-5-klor-benzamid i 2,5 cm<J>pyridin tilsettes 1 g p-toluensulfonsyreklorid og den således erholdte blanding oppvarmes i 1-g- time ved 60°C. Deretter inndampes i vakuum, 3 cm aceton og 1 cm^ vann tilsettes To a solution of 0.8 g of N-(2-phenylpropyl)-2-methylamino-5-chloro-benzamide in 2.5 cm<J>pyridine, 1 g of p-toluenesulfonic acid chloride is added and the mixture thus obtained is heated in 1-g - hour at 60°C. It is then evaporated in a vacuum, 3 cm of acetone and 1 cm^ of water are added

og den således erholdte reaksjonsblanding rystes i 30 min. Etter avdamping av aceton tilsettes etylacetat og det organiske skikt ekstraheres med fortynnet saltsyre og en vandig natriumbikarbonat-losning. Den organiske fase torres deretter over natriumsulfat og inndampes til torrhet. Det.erholdes N-(2-fenylpropyl)-2-metyltosylamino-5-klor-benzamid med smeltepunkt 89 - 91°0 (spalting). and the reaction mixture thus obtained is shaken for 30 min. After evaporation of acetone, ethyl acetate is added and the organic layer is extracted with dilute hydrochloric acid and an aqueous sodium bicarbonate solution. The organic phase is then dried over sodium sulphate and evaporated to dryness. N-(2-phenylpropyl)-2-methyltosylamino-5-chloro-benzamide with melting point 89 - 91°C (cleavage) is obtained.

c)llii-metvltosylamino^^klor-fe<ri>Y<l>^-^-<metyl->^j^-dihydro-iso-^i2-2ii2z^Y§S2iSi2ri§« c)llii-metvltosylamino^^chloro-fe<ri>Y<l>^-^-<methyl->^j^-dihydro-iso-^i2-2ii2z^Y§S2iSi2ri§«

Til 4-3 cm f osf oroksyklorid tilsettes 10 g av det etter eksempel To 4-3 cm of phosphorus oxychloride, add 10 g of it according to the example

9 b) erholdte N-(2-fenylpropyl)-2-metylamino-5-klorbenzamid og den erholdte blanding oppvarmes i 15 timer under tilbakelop. Deretter avkjoles til romtemperatur og inndampes i vakuum. Den erholdte rest loses i 300 cmJ metylenklorid. Den således fremstilte organiske losning vaskes forst med en iskold 1N vandig natriumhydroksyd-losning (2 vaskinger med tilnærmet 120 cm^ natriumhydroksyd-losning), deretter med vann og til slutt med en mettet, vandig natriumklorid-losning. Den således vaskede losning torres over natriumsulfat og losningsmidlet avdampes deretter i vakuum. Resten loses i 60 cm^ aceton og losningen mettes med torr hydrogenklorid-gass. Deretter reduseres volumet av losningen til halv-parten ved inndamping og tilsettes 30 cm<J>dietyleter. Derved faller 1 -(2-metyltosylamino~5-klorfenyl)-4—metyl-3,4-dihydro-isokinolin-hydroklotid'.med smeltepunkt 254°C ut. d) 1 - (2-metylamino-5-klor-f enyl)-4-metyl-3_14-dihydro-isokinolin. 9 b) obtained N-(2-phenylpropyl)-2-methylamino-5-chlorobenzamide and the resulting mixture is heated for 15 hours under reflux. It is then cooled to room temperature and evaporated in a vacuum. The residue obtained is dissolved in 300 cmJ of methylene chloride. The organic solution thus prepared is first washed with an ice-cold 1N aqueous sodium hydroxide solution (2 washes with approximately 120 cm 3 of sodium hydroxide solution), then with water and finally with a saturated, aqueous sodium chloride solution. The thus washed solution is dried over sodium sulphate and the solvent is then evaporated in a vacuum. The residue is dissolved in 60 cm3 of acetone and the solution is saturated with dry hydrogen chloride gas. The volume of the solution is then reduced to half by evaporation and 30 cm<J>diethyl ether is added. Thereby 1-(2-methyltosylamino-5-chlorophenyl)-4-methyl-3,4-dihydro-isoquinoline-hydroclotide' with a melting point of 254°C falls out. d) 1-(2-methylamino-5-chloro-phenyl)-4-methyl-3-14-dihydro-isoquinoline.

Til 46 g av det etter eksempel 9 c) erholdte 1-(2-metyltosylamino-5-klor-fenyl)-4-metyl-3,4-dihydro-isokinolin-hydroklorid tilsettes langsomt 100 cm-1 konsentrert svovelsyre under avkjoling og den således erholdte losning hensettes over natten ved romtemperatur. Denne losning uthelles deretter på is og gjores alkalisk med natriumhydroksyd. Den alkaliske losning ekstraheres med metylenklorid, den organiske losning torres og det organiske løsnings-middel avdampes. Som rest erholdes 1 -(2-metylamino-5-klor-fenyl)-4-metyl-3,4-dihydro-isokinolin med smeltepunkt 108 - 110°C.<e>) 2isz_°ÉL££a£s-1 - (2=me^yl^ tetrahydro-isokinolin.. 18,5 g 1 -(2-metylamino-5-klor-fenyl)-4-metyl-3,4-dihydro-isokinolin suspenderes i 200 cm^ 95$ etanol og til den erholdte suspensjon tilsettes 7 g natriumborhydrid. Den erholdte blanding oppvarmes deretter i 1 time under tilbakelop. Deretter avkjoles til romtemperatur og syres med 2N saltsyre. Etter tilsetning av 2N vandig natriumhydroksyd-losning, hvorved det innstilles til pH-verdi 9 inndampes i vakuum til 1/3 av volumet og den således konsentrerte losning ekstraheres 2 ganger med hver gang 150 cm^ etylacetat. De forente organiske faser vaskes med vann og mettet natriumklorid-losning torres over natriumsulfat og inndampes deretter i vakuum, hvorved det blir tilbake en oljeaktig rest. Denne omkrystalliseres fra dietyleter/pentan hvorved det erholdes 14 g cis-1-(2-metylamino-5-klor-fenyl)-4-metyl-1,2,3,4-tetrahydro-isokinolin med smeltepunkt 142 - 144°C og 2,2 g av den tilsvarende trans-isomer med smeltepunkt 81 - 84°C (etter omkrystallisering fra dietyleter/pentan). f) cis- og trans-1-(2-metylamino-5-klor-fenyl)-2-karbometoksy-™2tyl=4^me^yl:1 ^g^^^te^r^hyd^ 2 g av det etter eksempel 9 e) erholdte cis-1-(2-metylamino-5-klor-fenyl)-4-metyl-1,2,3,4-tetrahydro-isokinolin loses i 20 cm^ abs. etanol og den således erholdte losning tilsettes 1,7 g metylbromacetat og 2 g trietylamin. Den erholdte blanding oppvarmes til koking i 4 timer under tilbakelbp og deretter avdampes losningsmidlet. Resten blandes med 200 cwr1 etylacetat og 100 cm<J>vann. Fasene skilles, den vandige fase ekstraheres 2 ganger med hver To 46 g of the 1-(2-methyltosylamino-5-chloro-phenyl)-4-methyl-3,4-dihydro-isoquinoline hydrochloride obtained according to example 9 c) is slowly added 100 cm-1 of concentrated sulfuric acid while cooling and the solution obtained in this way is left overnight at room temperature. This solution is then poured onto ice and made alkaline with sodium hydroxide. The alkaline solution is extracted with methylene chloride, the organic solution is dried and the organic solvent is evaporated. As a residue, 1 -(2-methylamino-5-chloro-phenyl)-4-methyl-3,4-dihydro-isoquinoline with melting point 108 - 110°C is obtained.<e>) 2isz_°ÉL££a£s-1 - (2=me^yl^ tetrahydro-isoquinoline.. 18.5 g of 1 -(2-methylamino-5-chloro-phenyl)-4-methyl-3,4-dihydro-isoquinoline is suspended in 200 cm^ 95% ethanol and to the suspension obtained, 7 g of sodium borohydride is added. The mixture obtained is then heated for 1 hour under reflux. It is then cooled to room temperature and acidified with 2N hydrochloric acid. After the addition of 2N aqueous sodium hydroxide solution, whereby it is adjusted to a pH value of 9, it is evaporated in vacuum to 1/3 of the volume and the thus concentrated solution is extracted 2 times with each time 150 cm^ of ethyl acetate. The combined organic phases are washed with water and saturated sodium chloride solution is dried over sodium sulfate and then evaporated in vacuo, leaving an oily residue. This is recrystallized from diethyl ether/pentane whereby 14 g of cis-1-(2-methylamino-5-chloro-phenyl)-4-methyl-1,2,3,4-tetrahydro-isoquinol is obtained in with melting point 142 - 144°C and 2.2 g of the corresponding trans isomer with melting point 81 - 84°C (after recrystallization from diethyl ether/pentane). f) cis- and trans-1-(2-methylamino-5-chloro-phenyl)-2-carbomethoxy-™2ethyl=4^methyl^yl:1 ^g^^^te^r^hyd^ 2 g of the according to example 9 e) cis-1-(2-methylamino-5-chloro-phenyl)-4-methyl-1,2,3,4-tetrahydro-isoquinoline obtained is dissolved in 20 cm^ abs. ethanol and to the solution thus obtained, 1.7 g of methyl bromoacetate and 2 g of triethylamine are added. The resulting mixture is heated to boiling for 4 hours under reflux and then the solvent is evaporated. The residue is mixed with 200 ml of ethyl acetate and 100 cm<J> of water. The phases are separated, the aqueous phase is extracted 2 times with each

gang 100 cm- 1 etylacetat, de organiske faser forenes og vaskes med vann og deretter med en mettet vandig natriumklorid-losning. Den organiske fase torres deretter over natriumsulfat og inndampes i vakuum. Ved tilsetning av 75 cm-<3>av en blanding av benzen og pentan (1:1) til den resterende organiske losning utkrystalliseres cis-1-(2-metylamino-5-klor-fenyl)-2-karbometoksymetyl-4-metyl-1,2,3,4-tetrahydro-isokinolin med smeltepunkt 111 - 113°C. Den tilsvarende trans-forbindelse med smeltepunkt 99 - 102°C erholdes etter den ovenfor beskrevne fremgangsmåte hvis man går ut fra trans-1 -(2-metylamino-5-klor-fenyl)-4-metyl-1,2,3,4-tetrahydro-isokinolin. times 100 cm-1 ethyl acetate, the organic phases are combined and washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is then dried over sodium sulphate and evaporated in vacuo. By adding 75 cm-<3> of a mixture of benzene and pentane (1:1) to the remaining organic solution, cis-1-(2-methylamino-5-chloro-phenyl)-2-carbomethoxymethyl-4-methyl is crystallized -1,2,3,4-tetrahydro-isoquinoline with melting point 111 - 113°C. The corresponding trans-compound with a melting point of 99 - 102°C is obtained according to the method described above if one starts from trans-1-(2-methylamino-5-chloro-phenyl)-4-methyl-1,2,3,4 -tetrahydro-isoquinoline.

S) Si^zlzl ?i5§tYia!?in2i5i^i2Ii£§£Zi2i2-k S) Si^zlzl ?i5§tYia!?in2i5i^i2Ii£§£Zi2i2-k

<l>i<2i3>a<Z/zt§tr§>^<Z§?!2li>^<2i?iD-2iiS->i <l>i<2i3>a<Z/zt§tr§>^<Z§?!2li>^<2i?iD-2iiS->i

2 g av det etter eksempel 9 f) erholdte cis-1-(2-metylamino-5-klor-fenyl)-2-karbometoksymetyl-4-metyl-1,2,3,4-tetrahydro-isokinolin loses i 10 cm~ > etanol og den erholdte losning blandes med 10 cm-<3>' 1N vandig natriumhydroksyd-losning. Blandingen oppvarmes deretter i 1 time til koking under tilbakelop, avkjoles deretter til romtemperatur og tilsettes .10 cm<J>1N saltsyre. De derved ut-skilte krystaller frafiltreres og torres. Det således erholdte cis-1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-4-metyl-1,2,3,4-tetrahydro-isokinolin smelter ved 260 - 266°C. h) cis-2-klor=^a<10->dimetyl<->^i<6>17i9i12i<l4>^ //2a1-d7benzo^a47diazepin-6-on. 2 g av det etter eksempel 9g) erholdte cis-1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-4-metyl-1,2,3,4-tetrahydro-isokinolin oppvarmes i 40 min. ved 200°C. Råproduktet omkrystalliseres deretter fra en blanding bestående av 5 cm-o 3 metylenklorid og 10 cm-<3>' dietyleter, hvorved cis-2-klor-5,10-dimetyl-5,6,7,9,10,14b-heksahydro-i sokinolo/2,1-d/benzo/T ,4_7diazepin-6-on med smeltepunkt 179 - 181°C erholdes. 2 g of the cis-1-(2-methylamino-5-chloro-phenyl)-2-carbomethoxymethyl-4-methyl-1,2,3,4-tetrahydro-isoquinoline obtained according to example 9 f) is dissolved in 10 cm~ > ethanol and the solution obtained is mixed with 10 cm-<3>' 1N aqueous sodium hydroxide solution. The mixture is then heated to reflux for 1 hour, then cooled to room temperature and .10 cm<J>1N hydrochloric acid is added. The crystals thus separated are filtered off and dried. The thus obtained cis-1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-4-methyl-1,2,3,4-tetrahydro-isoquinoline melts at 260 - 266°C. h) cis-2-chloro=^a<10->dimethyl<->^i<6>17i9i12i<l4>^ //2a1-d7benzo^a47diazepin-6-one. 2 g of the cis-1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-4-methyl-1,2,3,4-tetrahydro-isoquinoline obtained according to example 9g) is heated for 40 min. at 200°C. The crude product is then recrystallized from a mixture consisting of 5 cm-o 3 methylene chloride and 10 cm-<3>' diethyl ether, whereby cis-2-chloro-5,10-dimethyl-5,6,7,9,10,14b-hexahydro -i soquinolo/2,1-d/benzo/T,4_7diazepin-6-one with melting point 179 - 181°C is obtained.

i) trans-2=klor-5l10-dimetyl-5i6l7i9i10A14b=heksahydro=isokinolo i) trans-2=chloro-5l10-dimethyl-5i6l7i9i10A14b=hexahydro=isoquinolo

£A1 -djbenzo/l iH/diazepin-å-on. £A1 -djbenzo/l iH/diazepin-å-one.

10 g av trans-1-(2-metylamino-5-klor-fenyl)-2-karbometoksymetyl-4-metyl-1,2,3,4-tetrahydro-isokinolin loses i en losning av 0,1 g natrium i 100 car' metoksyetanol og den således erholdte losning oppvarmes i 1 time under tilbakelbp. Deretter avkjoles til romtemperatur og losningsmidlet avdampes i vakuum. Den krystalline rest loses i 150 cm<J>metylenklorid og den således erholdte losning ekstraheres 2 ganger med hver gang 50 cm 3 vann. Den således vaskede organiske losning torres over natriumsulfat og inndampes deretter ved avdamping av losningsmidlet til 30 cm . Deretter tilsettes 100 cn<r>dietyleter. De derved dannede krystaller frafiltreres og vaskes med dietyleter. Det således erholdte trans-2-klor-5,1 O-dimetyl-5,6,7,9,10,1 4b-heksahydro-isokinolo/2,1 -d/benzo-/l,47diazepin-6-on smelter ved 187-189°C. På den samme måte erholdes fra den cis-isomere av den etter eksempel 9 f) fremstilte forbindelse den cis-isomere av den i overskriften nevnte forbindelse med smeltepunkt 179-181°C. 10 g of trans-1-(2-methylamino-5-chloro-phenyl)-2-carbomethoxymethyl-4-methyl-1,2,3,4-tetrahydro-isoquinoline are dissolved in a solution of 0.1 g of sodium in 100 car' methoxyethanol and the solution thus obtained are heated for 1 hour under reflux. It is then cooled to room temperature and the solvent is evaporated in a vacuum. The crystalline residue is dissolved in 150 cm<J>methylene chloride and the solution thus obtained is extracted twice with each time 50 cm 3 of water. The thus washed organic solution is dried over sodium sulphate and then evaporated by evaporation of the solvent to 30 cm. Then 100 cn<r>diethyl ether is added. The crystals thus formed are filtered off and washed with diethyl ether. The trans-2-chloro-5,1 O-dimethyl-5,6,7,9,10,1 4b-hexahydro-isoquinolo/2,1-d/benzo-/1,47diazepin-6-one thus obtained melts at 187-189°C. In the same way, the cis-isomer of the compound prepared according to example 9 f) is obtained from the cis-isomer of the compound mentioned in the title with a melting point of 179-181°C.

Claims (2)

1. Fremgangsmåte for fremstilling av nye, terapeutisk aktive benzodiazepinderivater med den alminnelige formel I 1. Process for the production of new therapeutically active compounds benzodiazepine derivatives of the general formula I hvori IL og Rp hver står for hydrogen eller metoksy-gruppen, R^og R^står hver for hydrogen eller metylgruppen, Rg står for hydrogen eller en alkyl-gruppe med 1 - 4 karbonatomer og X står for hydrogen, klor eller trifluormetyl-gruppen, eventuelt deres optisk aktive henhv. cis- eller trans-isomere former og/eller deres syreaddisjonssalter,karakterisert vedat eventuelt optisk aktive henhv. cis- eller trans-isomere forbindelser med den alminnelige formel II in which IL and Rp each stand for hydrogen or the methoxy group, R^ and R^ each stand for hydrogen or the methyl group, Rg stands for hydrogen or an alkyl group with 1 to 4 carbon atoms and X stands for hydrogen, chlorine or the trifluoromethyl group , possibly their optically active or cis- or trans-isomeric forms and/or their acid addition salts, characterized in that any optically active or cis- or trans-isomeric compounds of the general formula II hvori R 1 - R^, R^og X har den ovennevnte betydning og A står for hydrogen eller lavere alkyl, underkastes en ringslutning, derved erholdte racemiske forbindelser med den alminnelige formel I oppdeles eventuelt i sine optisk aktive former henhv. erholdte blandinger av diastereomere forbindelser med den alminnelige formel I oppdeles eventuelt i sine cis- eller trans-isomere former og de således erholdte, eventuelt optisk aktive henhv. cis- eller trans-isomere forbindelser med den alminnelige formel I overfores deretter eventuelt i sine syreaddisjonssalter.in which R 1 - R^, R^ and X have the above-mentioned meaning and A stands for hydrogen or lower alkyl, is subjected to a ring closure, thus obtained racemic compounds with the general formula I are optionally divided into their optically active forms respectively. obtained mixtures of diastereomeric compounds with the general formula I are optionally divided into their cis- or trans-isomeric forms and the thus obtained, optionally optically active or cis- or trans-isomeric compounds of the general formula I are then optionally transferred into their acid addition salts. 2. Fremgangsmåte som angitt i krav 1, for fremstilling av (+)-2-klor-5-metyl-5,6,7,9,10,14b-heksahydro-isokinoloZ2,1-d7-benzo/1j^/diazepin-å-on,karakterisert vedat (-)-1-(2-metylamino-5-klor-fenyl)-2-karboksymetyl-1 ,2,3,4-tetrahydro-isokinolin oppvarmes og det erholdte sluttprodukt overfores deretter eventuelt i sine syreaddisjonssalter.2. Process as stated in claim 1, for the production of (+)-2-chloro-5-methyl-5,6,7,9,10,14b-hexahydro-isoquinoloZ2,1-d7-benzo/1j^/diazepine -å-one, characterized in that (-)-1-(2-methylamino-5-chloro-phenyl)-2-carboxymethyl-1,2,3,4-tetrahydro-isoquinoline is heated and the resulting end product is then possibly transferred into its acid addition salts.
NO159442A 1964-08-07 1965-08-23 NO120580B (en)

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