NO750263L

NO750263L -

Info

Publication number: NO750263L
Application number: NO750263A
Authority: NO
Inventors: H Ott; R Sueess
Original assignee: Sandoz Ag
Priority date: 1974-02-05
Filing date: 1975-01-29
Publication date: 1975-09-01
Also published as: DK136189B; CA1055944A; FR2259611A1; GB1497723A; NL7501159A; PH11824A; SE7500859L; BE825124A; DD117216A5; DK136189C; HU169923B; NZ176550A; ATA79975A; ES434406A1; AU7784375A; DE2503156A1; JPS50108297A; FR2259611B1; GB1497722A; FI750205A

Description

Foreliggende oppfinnelse vedrorer en fremgangsmåte for fremstilling av nye heterocykliske forbindelser med formel I, The present invention relates to a method for the production of new heterocyclic compounds of formula I,

hvori in which

R, står for en i 8- eller 9-stillingen av benzonaftyridin-skjeKettet3 tilknyttet rest av rekken hydrogen, alkoksy med 1-4 karbonatomer eller hydroksy, og R, stands for one in the 8- or 9-position of the benzonaphthyridine chain3 associated with the rest of the series hydrogen, alkoxy with 1-4 carbon atoms or hydroxy, and

enten either

]*2 betyr hydrogen, alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, benzyloksy, hydroksy, halogen, nitro, amino, dimetylaminogruppen, eller en NHCOR5-gruppe, hvori Rr står for hydrogen eller alkyl med 1-4 karbonatomer, ]*2 means hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, the dimethylamino group, or an NHCOR5 group, in which Rr stands for hydrogen or alkyl of 1-4 carbon atoms ,

og R^og R^står for hydrogen, eller and R^ and R^ stand for hydrogen, or

R2betyr alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, benzyloksy, hydroksy, halogen eller nitro, R2 denotes alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy, halogen or nitro,

R^betyr alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, benzyloksy, hydroksy eller klor og R^means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy or chlorine and

R 4 betyr hydrogen, eller R 4 means hydrogen, or

R2, R^og R4betyr alkoksy med 1-4 karbonatomer eller benzyloksy, eller R 2 , R 4 and R 4 mean alkoxy with 1-4 carbon atoms or benzyloxy, or

R2, R^og R^ betyr alkyl med 1-4 karbonatomer, eller R2, R^ and R^ mean alkyl with 1-4 carbon atoms, or

R2, R2og R^betyÉ hydroksy, R 2 , R 2 and R 2 are hydroxy,

idet, hvis en av restene R2, R3og R^står for benzyloksy, betyr R^ hydrogen eller alkoksy med 1-4 karbonatomer, hvis R^betyr en i^ 9-stillingen tilknyttet hydroksygruppe, ingen av restene R2, R^eller R^betyr alkoksy med 1-4 karbonatomer, og når en av restene R2eller R^ betyr benzyloksy eller alkoksy med 1-4 karbonatomer, står den annen rest R2 eller R^ ikke for hydroksy, wherein, if one of the residues R2, R3 and R^ stands for benzyloxy, R^ means hydrogen or alkoxy with 1-4 carbon atoms, if R^ means a hydroxy group attached to the 9-position, none of the residues R2, R^ or R^ means alkoxy with 1-4 carbon atoms, and when one of the residues R2 or R^ means benzyloxy or alkoxy with 1-4 carbon atoms, the other residue R2 or R^ does not stand for hydroxy,

og syreaddisjonssalter derav. and acid addition salts thereof.

Mulige forekommende alkyl- eller alkoksy substit\ienter av 6-fenylresten inneholder spesielt I1 eller 2, foretrukket 1 karbonatom. Possible occurring alkyl or alkoxy substituents of the 6-phenyl residue in particular contain I1 or 2, preferably 1 carbon atom.

Står R^for alkoksy med 1-4 karbonatomer, inneholder den spesielt «Ineller 2, foretrukket 1 karbonatom. If R^ stands for alkoxy with 1-4 carbon atoms, it especially contains "In" or 2, preferably 1 carbon atom.

Hvis R5står for alkyl med 1-4 karbonatomer, utgjor? denne rest spesielt metyl, etyl eller en ce-forgrenet alkylrest som isopropyl eller tert.-butyl. If R5 stands for alkyl with 1-4 carbon atoms, make up? this residue in particular methyl, ethyl or a C-branched alkyl residue such as isopropyl or tert-butyl.

Står resten R2for halogen, utgjor denne fluor, klor eller brom, foretrukket fluor eller klor. If the residue R2 stands for halogen, this is fluorine, chlorine or bromine, preferably fluorine or chlorine.

Som det ses av formlene står hydrogenatomene i 4a-, 6- og 10b-stillingen av benzonaftyridinskjeléttet i cis-stilling. As can be seen from the formulas, the hydrogen atoms in the 4a, 6 and 10b positions of the benzonaphthyridine skeleton are in the cis position.

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

a) Forbindelser.med formel II, a) Compounds of formula II,

hvori Rg står x 8- eller 9-stillingen av benzonaftyridinskjelettet in which Rg stands for x the 8- or 9-position of the benzonaphthyridine skeleton

og betyr hydrogen, alkoksy med 1-4 karbonatomer, hydroksy eller en under reaksjonsbetingelsene spaltbar etergruppe, og R^, R<*>and means hydrogen, alkoxy with 1-4 carbon atoms, hydroxy or an ether group that can be split under the reaction conditions, and R^, R<*>

og R* har den for R^, R^ 0( 3 R4angitte betydning, reduseres eller and R* has the meaning specified for R^, R^ 0( 3 R4, is reduced or

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

hvori enten in which either

R^1 betyr hydrogen, alkyl med 1-4 karbonatomer, alkoksy med R^1 means hydrogen, alkyl with 1-4 carbon atoms, alkoxy with

1-4 karbonatomer, hydroksy, halogen, nitro, amino, dimetylaminogruppen eller en gruppe NHCOR,-, hvori R,, har den ovennevnte betydning, og 1-4 carbon atoms, hydroxy, halogen, nitro, amino, the dimethylamino group or a group NHCOR,-, in which R,, has the above meaning, and

II 11 II 11

R^ og R4 betyr hydrogen, eller R 1 and R 4 mean hydrogen, or

R*1 betyr alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, hydroksy, halogen eller nitro, R*1 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxy, halogen or nitro,

Rj1 betyr alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, hydroksy eller klor og Rj1 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxy or chlorine and

R^1betyr hydrogen, eller R^1 means hydrogen, or

R^1, R^1 og betyr alkoksy med 1-4 karbonatomer, eller R^1, R^1 and means alkoxy with 1-4 carbon atoms, or

vR'21/ og R4"<1>betyr alkyl med 1-4 karbonatomer, eller vR'21/ and R4"<1> means alkyl with 1-4 carbon atoms, or

II II II II II II

R2 , R^og R^står for hydroksygruppen, R2 , R^ and R^ stand for the hydroxy group,

idet, hvis hydroksygruppen står i 9-stillingen, ingen av restene rJ1, R?1 eller R^1 betyr alkoksy med 1-4 karbonatomer, og når in that, if the hydroxy group is in the 9-position, none of the residues rJ1, R?1 or R^1 means alkoxy with 1-4 carbon atoms, and when

II II II II

en av restene R~eller R_ betyr alkoksy med 1-4/karbonatomer, står den annen rest'R2 II c el' ler x R^ II ikke for hydroksy, behandles forbindelser med formel III, one of the residues R~ or R_ means alkoxy with 1-4/carbon atoms, the other residue'R2 II c or' ler x R^ II does not stand for hydroxy, compounds with formula III are treated,

hvori enten in which either

R^<11>betyr hydrogen, alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, benzyloksy, hydroksy, halogen, nitro, aminq, dimetylaminogruppen eller en NHCOR5-gruppe, hvori R5har den ovennevnte betydning, og R^<11>means hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amineq, the dimethylamino group or an NHCOR5 group, in which R5 has the above meaning, and

R^<11>og R^<11>står for hydrogen, eller R^<11> and R^<11> stand for hydrogen, or

R211 betyr alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, benzyloksy, hydroksy, halogen eller nitro, R211 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy, halogen or nitro,

R^11 betyr alkyl med 1-4 karbonatomer, alkoksy med 1-4 karbonatomer, benzyloksy, hydroksy eller klor og R^11 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy or chlorine and

<R>^<11>betyr hydrogen, eller <R>^<11>means hydrogen, or

1*2 I3" /' R311 °9R<411>betyr alkoksy med 1-4 karbonatomer eller * benzyloksy, 1*2 I3" /' R311 °9R<411> means alkoxy with 1-4 carbon atoms or * benzyloxy,

eller or

R111 ,R?<11>^ og R^<11>betyr alkyl med^ 1-4 karbonatomer, eller R^11, R^11 0<3 R^11 står for hydroksygruppen, og R111 ,R?<11>^ and R^<11>mean alkyl with^ 1-4 carbon atoms, or R^11, R^11 0<3 R^11 stands for the hydroxy group, and

R^betyr en under reaksjonsbetingelsene spaltbar eterrest, R^means an ether residue that can be split under the reaction conditions,

under betingelsene for en eterspalting, under the conditions of an ether cleavage,

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

De etter de i det foregående beskrevne fremgangsmåter fremstilte oktahydrobenzo^c/^/I,6/naftyridinderivater kan isoleres på The octahydrobenzo^c/^/I,6/naphthyridine derivatives prepared according to the methods described above can be isolated on

vanlig måte og renses etter kjente metoder. in the usual way and cleaned according to known methods.

Fra de fri baser lar seg på kjrent måte syreaddisjonssalter utvinne og omvendt. Acid addition salts can easily be extracted from the free bases and vice versa.

Står Rg for en i 8- eller 9-stillingen av benzonaftyridinskjelettet under reaksjonsbetingelsene spaltbar etergruppe, så utgjor denne gruppe foretrukket en hydrogenolytisk, spesielt en i i nærvær av en metallkatalysator, som platina eller palladium, spaltbar etergruppe. If Rg stands for an ether group cleavable in the 8- or 9-position of the benzonaphthyridine skeleton under the reaction conditions, this group preferably forms a hydrogenolytically, especially one in the presence of a metal catalyst, such as platinum or palladium, cleavable ether group.

Eksempler på slike grupper R^ er benzyloksygruppen, i fenylringen substituerte eller i a-stilling alkylerte benzyloksygrupper. Examples of such groups R 1 are the benzyloxy group, benzyloxy groups substituted in the phenyl ring or alkylated in the a-position.

Reduksjonen av 5/6-dobbeltbindingen i forbindelsene med formel The reduction of the 5/6 double bond in the compounds of formula

II (fremgangsmåten a) kan gjennomfores analogt med i isokinolin-kjemien kjente metoder. De kan fæeks. gjennomfores ved hjelp av komplekse alkalimetallhydrider i et egnet løsningsmiddel, f.eks. natriumborhydrid i metanol eller etanol eller litiumaluminium-hydrid i eter, tetxahydrofuran, dio.ksan, dimetoksyetan og så . videre. Man arbeider foretrukket ved forhoyét temperatur, f.eks. mellom omtrent 50 og 100°C. Reaksjonens varighet utgjor fra noen minutter til noen timer. Anvender man disse reaksjonsbetingelser velges hensiktsmessig slike forbindelser med formel II som utgangsmaterial hvori R^betyr hydrogen, alkoksy med 1-4 karbonatomer eller hydroksy. Reduksjonsproduktene isoleres og renses analogt med kjente metoder, f.eks. etter spalting av overskudd av reduksjonsmiddel og det dannede kompleks ved utrysting mellom en vandig losning og et dermed ikke blandbart organisk losningsmiddel som kloroform eller etylacetat. II (method a) can be carried out analogously to methods known in isoquinoline chemistry. They can, for example. carried out using complex alkali metal hydrides in a suitable solvent, e.g. sodium borohydride in methanol or ethanol or lithium aluminum hydride in ether, tetxahydrofuran, dioxane, dimethoxyethane and so on. further. One prefers to work at an elevated temperature, e.g. between approximately 50 and 100°C. The duration of the reaction ranges from a few minutes to a few hours. If these reaction conditions are used, such compounds of formula II are suitably chosen as starting material in which R^ means hydrogen, alkoxy with 1-4 carbon atoms or hydroxy. The reduction products are isolated and purified analogously with known methods, e.g. after cleavage of excess reducing agent and the complex formed by shaking between an aqueous solution and a thus immiscible organic solvent such as chloroform or ethyl acetate.

Reduksjonen kan også skje ved katalytisk hydrering, f.eks. The reduction can also take place by catalytic hydration, e.g.

over platinaoksyd eller palladium i et under reaksjonsbetingelsene -inert losningsmiddel, f.eks. en lavere alkanol som etanol. Foretrukket arbeider man ved romtemperatur og under normalt eller forhoyet trykk. De heksahydrobenzo^/c7/^ > 67naf tyridin-,' 3 derivater som skal reduseres anvendes foretrukket som fri base. over platinum oxide or palladium in a solvent inert under the reaction conditions, e.g. a lower alkanol such as ethanol. It is preferred to work at room temperature and under normal or increased pressure. The hexahydrobenzo^/c7/^ > 67naf tyridine-,' 3 derivatives to be reduced are preferably used as free base.

Under de siste betingelser overfores mulig forekommende i forbindelsene med formel II tilstedeværende benzyloksygrupper og/eller under disse betingelser spaltbare etergrupper R^ i Under the latter conditions, any benzyloxy groups present in the compounds of formula II and/or ether groups cleavable under these conditions R^ are transferred into

hydroksygrupper. Som<*>spaltbar etergruppe R velges" da hydroxy groups. As<*>cleavable ether group R is chosen" then

. hensiktsmessig benzyloksygruppen,. og som katalysator velges. > hensiktsmessig palladium. . suitably the benzyloxy group,. and as a catalyst is chosen. > appropriate palladium.

Dertil vil under betingelsene for en katalytisk hydrering en mulig forekommende nitrogruppe reduseres til aminogruppe eller, hvis det i reaksjonsblandingen også er tilstede formaldehyd, In addition, under the conditions of a catalytic hydrogenation, a possible nitro group will be reduced to an amino group or, if formaldehyde is also present in the reaction mixture,

til dimetylaminogruppen. For fremstilling av forbindelser med formel I hvori R2betyr nitrogruppen, anvendes folgelig hensiktsmessig komplekse hydrider ved anvendelse av fremgangsmåten a. to the dimethylamino group. For the preparation of compounds of formula I in which R2 denotes the nitro group, complex hydrides are therefore suitably used when using method a.

Etter avsluttet hydrogenopptagning frafiltreres katalysatoren, filtratet inndampes til torrhet og den som rest tilbakeblivende rå oktahydro-forbindelse renses etter kjente metoder. Reduksjonen av 5/6-dobbeltbindingen skjer i allefall stereo-spesifikt. Det dannes forbindelser med formel I hvori hydrogenatomene i stilling 4a, 6 og 10b alle står i cis-stilling til hverandre. After completion of hydrogen uptake, the catalyst is filtered off, the filtrate is evaporated to dryness and the remaining crude octahydro compound is purified according to known methods. The reduction of the 5/6 double bond is in any case stereo-specific. Compounds of formula I are formed in which the hydrogen atoms in positions 4a, 6 and 10b are all in the cis position to each other.

Fremgangsmåten b) utgjor en eterspalting. Den kan skje analogt med foreterspaltingen analoge forbindelser kjente metoder. Method b) constitutes an ether cleavage. It can take place analogously to the ether cleavage of analogous compounds using known methods.

Således kan man f.eks. gjennomfore eterspaltingen med Lewis-syrer, f.eks. med bortribromid eller aluminiumklorid. Man arbeider, foretrukket i et under reaksjonsbetingelsene inert organisk losningsmiddel, f.eks. i et halogenert hydrokarbon som metylenklorid eller karbontetraklorid eller et aromatisk hydrokarbon som toluen eller benzen. Temperaturen utgjor omtrent -80 "til 70°C. Thus, one can e.g. carry out the ether cleavage with Lewis acids, e.g. with boron tribromide or aluminum chloride. One works, preferably in an organic solvent that is inert under the reaction conditions, e.g. in a halogenated hydrocarbon such as methylene chloride or carbon tetrachloride or an aromatic hydrocarbon such as toluene or benzene. The temperature is about -80" to 70°C.

Eterspaltingen kan også skje ved hjelp av sterke miheralsyrer, f.eks. bromhydrogen- eller jodhydrogensyre. Fordelaktig arbeider man ved forhoyet temperatur, f.eks. mellom omtrent 50 og 150°C, f.eks. ved koketemperaturen for'reaksjonsblandingen. Eventuelt anvendes et under reaksjonsbetingelsene inert losningsmiddel. The ether cleavage can also take place with the help of strong miheralic acids, e.g. hydrobromic or hydroiodic acid. It is advantageous to work at an elevated temperature, e.g. between about 50 and 150°C, e.g. at the boiling temperature of the reaction mixture. If necessary, a solvent inert under the reaction conditions is used.

En etergruppe i 8-stillingen, av benzonaftyridinskjelettet kan spaltes selektivt uten spalting av mulig forekommende alkoksy-grupper på den ikke-kondenserte fenylring, idet spaltingen gjennomfores med mineralsyrer under mildere betingelser, f.eks. med fortynnet mineralsyre ved forhoyet. temperatur, f.eks. med fortynnet bromhydrogensyre ved omtrent 80 til 150°C. An ether group in the 8-position of the benzonaphthyridine skeleton can be selectively cleaved without cleavage of any possible alkoxy groups on the non-condensed phenyl ring, the cleavage being carried out with mineral acids under milder conditions, e.g. with diluted mineral acid at the top. temperature, e.g. with dilute hydrobromic acid at about 80 to 150°C.

Står de grupper som skal spaltes for hydrogenolytisk spaltbare etergrupper, som f.eks. benzyloksygruppen, overfores de Do the groups to be cleaved stand for hydrogenolytically cleavable ether groups, such as e.g. the benzyloxy group, they are transferred

hensiktsmessig ved katalytisk hydrering i nærvær av en palladium-katalysator til hydroksygrupper. Man arbeider foretrukket i et under reaksjonsbetingelsene inert organisk losningsmiddel, f.eks. i en lavere alkanol som metanol, i etylacetat eller i iseddik. Temperaturen utgjor mellom omtrent 20 og 100°C. Man conveniently by catalytic hydrogenation in the presence of a palladium catalyst to hydroxy groups. One preferably works in an organic solvent that is inert under the reaction conditions, e.g. in a lower alkanol such as methanol, in ethyl acetate or in glacial acetic acid. The temperature is between approximately 20 and 100°C. Mon

arbeider under normalt eller forhoyet trykk, foretrukket normaltrykk, en mulig forekommende alkoksygruppe i 8- eller 9-stillingen av benzonaftyridinskjelettet blir under disse betingelser ikke spaltet. En mulig forekommende nitrogruppe reduseres til aminogruppen. working under normal or elevated pressure, preferably normal pressure, a possible alkoxy group in the 8- or 9-position of the benzonaphthyridine skeleton is not cleaved under these conditions. A possible nitro group is reduced to the amino group.

Eterspaltingen av forbindelsene med formel III hvori R*11 star for NHCORg, gjennomfores hensiktsmessig under katalytiske betingelser. R^står da foretrukket for benzyloksy. The ether cleavage of the compounds of formula III in which R*11 stands for NHCORg is conveniently carried out under catalytic conditions. R^ then preferably stands for benzyloxy.

Forbindelsene med formel II er enten kjente eller kan fremstilles analogt med kjente metoder. The compounds of formula II are either known or can be prepared analogously by known methods.

Fremstillingen av forbindelser med formel II som inneholder en aminogruppe skjer foretrukket ved å gå ut fra de tilsvarende nitro^forbindelser med formel II, f.eks. ved selektiv reduksjon med nasgerende hydrogen, f.eks. med jernspon i en vandig syre, eventuelt i et under reaksjonsbetingelsene inert losningsmiddel. F.eks. i en lavere alkanol som etanol, foretrukket ved forhoyet temperatur, f.eks. ved koketemperaturen. The preparation of compounds of formula II which contain an amino group is preferably carried out starting from the corresponding nitro compounds of formula II, e.g. by selective reduction with nascent hydrogen, e.g. with iron filings in an aqueous acid, possibly in a solvent inert under the reaction conditions. E.g. in a lower alkanol such as ethanol, preferably at an elevated temperature, e.g. at the boiling temperature.

For fremstilling av forbindelser med formel II som inneholder For the preparation of compounds of formula II which contain

en acylaminogruppe behandler man foretrukket en aminogruppe-inneholdende forbindelse med formel II med acyleringsmidler, f.eks. med karboksylsyreklorider eller-anhydrider i nærvær av et syrebindende middel som f .eks. pyr^din,' eventuelt i et under reaksjonsbetingelsene inert losningsmiddel og ved forhoyet temperatur. an acylamino group, an amino group-containing compound of formula II is preferably treated with acylating agents, e.g. with carboxylic acid chlorides or anhydrides in the presence of an acid binding agent such as e.g. pyridine, optionally in a solvent inert under the reaction conditions and at an elevated temperature.

For fremstilling av forbindelser med formel II, som inneholder en dimetylaminogruppe, kan man f.eks. reduktivt metylere en aminogruppe-inneholdende forbindelse med formel II med formaldehyd og maursyre som reduksjonsmiddel (Leuckart-Wallach-Reaksjon). For the preparation of compounds of formula II, which contain a dimethylamino group, one can e.g. reductively methylate an amino group-containing compound of formula II with formaldehyde and formic acid as reducing agent (Leuckart-Wallach-Reaction).

De ovrige forbindelse med formel II kan f.eks. fremstilles ved ringslutning av det tilsvarende eis-4-benzoylamino-l-metyl-3-fenylpiperidin etter Bischler-Napieralski.) The other compounds with formula II can e.g. is prepared by cyclization of the corresponding is-4-benzoylamino-1-methyl-3-phenylpiperidine according to Bischler-Napieralski.)

Forbindelsene med formel III er enten kjente eller kan fremstilles analogt med kjente metoder henhv..under hensyntagen til de for fremstilling av -forbindelsene med formel I og II beskrevne metoder. The compounds of formula III are either known or can be prepared analogously with known methods or, taking into account the methods described for the preparation of the compounds of formula I and II.

Forbindelsene med formel I og deres farmakologisk tålbare syreaddisjonssalter utmerker seg ved interessante egenskaper og kan folgelig finne anvendelse som medisin. The compounds of formula I and their pharmacologically tolerable acid addition salts are distinguished by interesting properties and can consequently find application as medicine.

Således bevirker forbindelsene f.eks. i narkotisert katt og narkotisert marsvin (Kbnzett-Rossler-metoden) en hemming av den ved histamin induserte bronkospasmus. På grunn av denne aktivitet kan forbindelsene anvendes ved pppstruktive luftvei-sykdommer f.eks. astmabronkiale, bronkitider med spastiske komponenter og postoperativ atelektase. Den daglige dose ligger ved omtrent 35 til 700 mg. Denne dose kan om nodvendig tilfores i 2 til* 4 deldoser eller også som retardform. Thus, the compounds cause e.g. in anesthetized cat and anesthetized guinea pig (Kbnzett-Rossler method) an inhibition of the histamine-induced bronchospasm. Because of this activity, the compounds can be used in obstructive airway diseases, e.g. bronchial asthma, bronchitis with spastic components and postoperative atelectasis. The daily dose is approximately 35 to 700 mg. This dose can, if necessary, be given in 2 to* 4 partial doses or also as a slow-release form.

Forbindelsene kan videre tilfores ved inhalering, f.eks. under anvendelse av forstovere, fordampere og aerosoler, f.eks. som h% spraypreparat. The compounds can further be administered by inhalation, e.g. using vaporizers, vaporizers and aerosols, e.g. as h% spray preparation.

Disse bronkolytiske egenskaper fremtrer spesielt ved de forbindelser med formel I hvori R., står for hydroksy eller metoksy. Spesielt interessante har forbindelsene med formel .1, hvori R^står for hydroksy i 8-stillingen eller metoksy i 9-stillingen av benzonaftyridinskjelettet vist seg. Foretrukket er spesielt cis-9-metoksy-2-metyl-6-fenyl-1,2,3,4,4a,5,6,10b-oktahydrobenzo/57/I/§7naftyridin og cis-8-hydroksy-2-metyl-69 fenyl-1,2,3,4,4a,5,6,I0b-oktahydrobenzo/c7/l/67naf tyridam. These broncholytic properties appear especially in the compounds of formula I in which R. stands for hydroxy or methoxy. Particularly interesting have been the compounds of formula 1, in which R^ stands for hydroxy in the 8-position or methoxy in the 9-position of the benzonaphthyridine skeleton. Particularly preferred are cis-9-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo/57/I/§7naphthyridine and cis-8-hydroxy-2- methyl-69 phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo/c7/1/67naf tyridam.

Således utmerker den sistnevnte forbindelse seg spesielt ved et interessant virkningsspektrum. Den hemmer i narkotisert katt og narkotisert marsvin likeledes den ved acetylcholin induserte bronkospasmus (Kbnzett-Rossler-metoden). Thus, the latter compound is particularly distinguished by an interesting spectrum of action. It also inhibits bronchospasm induced by acetylcholine in anesthetized cats and guinea pigs (Kbnzett-Rossler method).

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

I, henhv. deres vannloselige, fysiologisk tålbare syreaddisjonssalter tilfores alene eller i egnede preparatformer. Fremstillingen av disse preparatformer, f.eks. av tabletter eller spraypreparater, kan skje analogt ved kjente metoder. In, respectively their water-insoluble, physiologically tolerable acid addition salts are administered alone or in suitable preparation forms. The production of these preparation forms, e.g. of tablets or spray preparations, can be done analogously by known methods.

I den utstrekning fremstillingen av de nodvendige utgangs-materialér ikke er beskrevet, er disse kjente eller kan fremstilles etter kjente metoder henhv. analogt med de her To the extent that the production of the necessary starting materials is not described, these are known or can be produced according to known methods or analogous to those here

o o

beskrevne eller analogt med de i og for seg kjente metoder. described or analogously to the per se known methods.

I de^etterfolgende eksempler som skal illustrere oppfinnelsen, In the following examples to illustrate the invention,

er alle temperaturangivelser i °C uten korreksjon. are all temperature indications in °C without correction.

Eksempel 1: §is-§z^}y^£2]5sy-2-metyl-6-f enyl-1^2L3^414aL5i_6i_10b-oktahydrobenzo/c7/I/67naftyridin (fremgangsmåte a) Example 1: §is-§z^}y^£2]5sy-2-methyl-6-phenyl-1^2L3^414aL5i_6i_10b-octahydrobenzo/c7/I/67naphthyridine (method a)

.2 g Gis-8-hydroksy-2-metyl-6-f enyl-1, 2, 3, 4, 4a,l_0b-heksahydro-benzo/c7/I/67naftyridin (smeltepunkt av dihydrobromidet 268-271°C) loses i 20 ml metai ol og hydrogeneres etter tilsetning av 0,1 g platinaoksyd ved romtemperatur og normaltrykk i en hydrogenatmosfære. Etter avsluttet hydrogenopptagning frafiltreres katalysatoren og filtratet inndampes til torrhet i vakuum. Inndampningsresteh loses i vann, innstilles alkalisk med kalium-karbonat, ekstraheres 3 ganger med metylenklorid, de organiske faser torres og inndampes til torrhet, resten loses i alkohol og ved tilsetning av et lite overskudd av maleinsyre krystalliserer bishydrogenmaleinatet av den i overskriften nevnte forbindelse (smeltepunkt 196^.197§C_,~ j_\ .2 g Gis-8-hydroxy-2-methyl-6-phenyl-1, 2, 3, 4, 4a,1_0b-hexahydro-benzo/c7/1/67naphthyridine (melting point of the dihydrobromide 268-271°C) is dissolved in 20 ml of methanol and hydrogenated after adding 0.1 g of platinum oxide at room temperature and normal pressure in a hydrogen atmosphere. After completion of hydrogen absorption, the catalyst is filtered off and the filtrate is evaporated to dryness in a vacuum. The evaporation residue is dissolved in water, made alkaline with potassium carbonate, extracted 3 times with methylene chloride, the organic phases are dried and evaporated to dryness, the residue is dissolved in alcohol and by adding a small excess of maleic acid, the bishydrogen maleate of the compound mentioned in the title crystallizes (melting point 196^.197§C_,~ j_\

Eksempel 2 : £is-8-hydroksy-2-metyl-6-f eny^-1^2^3_L4^4^L5L6^10b-oktahydrobenzo/c7/I/67naftyridin (fremgangsmåte a) 1 g eis-8-hydroksy-2-metyl-6-fenyl-1,2,3,4,4a,10b-heksahydro-benzo/c7/I,67naftyridin (smeltepunkt av dihydrobromidet 268-271°C) loses i 10 ml etanol, tilsettes 0,1 g natriumborhydrid og denne reaksjonslosning kokes under tilbakelop i 30 minutter. Example 2 : £is-8-hydroxy-2-methyl-6-pheny^-1^2^3_L4^4^L5L6^10b-octahydrobenzo/c7/I/67naphthyridine (method a) 1 g isis-8-hydroxy -2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydro-benzo/c7/1,67naphthyridine (melting point of the dihydrobromide 268-271°C) is dissolved in 10 ml of ethanol, add 0.1 g of sodium borohydride and this reaction solution is boiled under reflux for 30 minutes.

Overskudd av natriumborhydrid spaltes ved tilsetning av fortynnet saltsyre, losningen inndampes, innstilles sterkt alkalisk med fortynnet natriumhydroksyd og denne alkaliske vandige losning ekstraheres med metylenklorid."Etter torring og avdamping av den organiske fase loses resten i etanol,og bishydrogenmaleinatet av den i overskriften nevnte forbindelse krystalliserer ved tilsetning av maleinsyre (smeltepunkt 196-197°C). Excess sodium borohydride is decomposed by adding dilute hydrochloric acid, the solution is evaporated, made strongly alkaline with dilute sodium hydroxide and this alkaline aqueous solution is extracted with methylene chloride." After drying and evaporation of the organic phase, the residue is dissolved in ethanol, and the bishydrogen maleate of the compound mentioned in the title crystallizes upon addition of maleic acid (melting point 196-197°C).

Eksempel 3 ; Sis-8-metoksy-2-metyl-6-f enylz- L- L- L- L-- L- L- L- 9?2z Example 3; Sis-8-methoxy-2-methyl-6-phenylz- L- L- L- L-- L- L- L- 9?2z

oktahydrobenzo/c7/I,6/naftyridin octahydrobenzo/c7/I,6/naphthyridine

Det gås frem analogt med eksempel 1 eller 2 og erholdes ved reduksjon av cis-8-metoksy-2-metyl-6-fenyl-1,2,3,4,4a,10b-. heksahydrobenzo/cZ/I,67naftyridin (smeltepunkt av bishydrogen- Proceed analogously to example 1 or 2 and obtain by reduction of cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-. hexahydrobenzo/cZ/I,67naphthyridine (melting point of bishydrogen-

\J— ~ "o \J— ~ "o

maleinatet 146 til 147 C fra etanol) den i overskriften nevnte forbindelse, som krystalliseres som bishydrogenmaleinat med smeltepunkt 144 til 145°C fra etanol. the maleate 146 to 147°C from ethanol) the compound mentioned in the title, which crystallizes as bishydrogen maleate with melting point 144 to 145°C from ethanol.

cis-8-metoksy-2-metyl-6-fenyl-1,2,3,4,4a,10b-heksahydrobenzo /c7/I767naftyridin ble fremstilt ved addisjon av 3-amino-2-p-metoksyfenyl-propionsyreetylester til akrylsyreetylester, reduktiv metylering av 2-p-metoksyf enyl-3, 3 ,'-iminodipropionsyre-dietylester (smeltepunkt av hydrogenoksalatet 152°C) med formaldehyd til 2-p-metoksymetyl-N-metyl^3,31-iminodipropionsyre - dietylester, omsetning av den sistnevnte forbindelse til 3-kar-betoksy-5-(p-metoksyfenyl)-l-metyl-4-piperidon (smeltepunkt av hydrokloridet: 180 til 182°C), som ved hydrolyse og etter-følgende dekarboksylering ble overfort til 3-p-metoksyfenyl-l-metyl-4-piperidon (smeltepunkt av hydrogenoksalatet 137 til 138°C). Det således erholdte piperidon ble omsatt med hydroksyl-amin til 3-p-metoksyfenyl-l-metyl-4-piperidonoksim (smeltepunkt 121 til 122°C), oksimet ble hydrogenert med Raney-Nickel til 4-amino-3-p-metoksyfenyl-l-metyl-piperidin (blanding av de to diastereoisomere), aminoforbiridelsen ble behandlet medbenzoyl-klorid, fra reaksjonsblåndingen ble cis-4-benzoylamino-3-p-metoksyf enyl-l-metyl-piperidin (smeltepunkt 164 til 165°C) isolert og det sistnevnte amid ble ringsluttet ved hjelp av fosforoksyklorid til det onskede benzonaftyridin. cis-8-Methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo /c7/1767naphthyridine was prepared by addition of 3-amino-2-p-methoxyphenyl-propionic acid ethyl ester to acrylic acid ethyl ester, reductive methylation of 2-p-methoxy enyl-3, 3,'-iminodipropionic acid diethyl ester (melting point of the hydrogen oxalate 152°C) with formaldehyde to 2-p-methoxymethyl-N-methyl^3,31-iminodipropionic acid - diethyl ester, conversion of the latter compound to 3-carbethoxy-5-(p-methoxyphenyl)-1-methyl-4-piperidone (melting point of the hydrochloride: 180 to 182°C), which by hydrolysis and subsequent decarboxylation was transferred to 3- p-Methoxyphenyl-1-methyl-4-piperidone (melting point of the hydrogen oxalate 137 to 138°C). The thus obtained piperidone was reacted with hydroxylamine to 3-p-methoxyphenyl-1-methyl-4-piperidone oxime (melting point 121 to 122°C), the oxime was hydrogenated with Raney-Nickel to 4-amino-3-p-methoxyphenyl -1-methyl-piperidine (mixture of the two diastereoisomers), the amino derivative was treated with benzoyl chloride, from the reaction mixture cis-4-benzoylamino-3-p-methoxyphenyl-1-methyl-piperidine (m.p. 164 to 165°C) isolated and the latter amide was ring-closed with phosphorus oxychloride to the desired benzonaphthyridine.

Eksempel 4: £is=6-^4-aminofenyl|-9-metoks Example 4: £is=6-^4-aminophenyl|-9-methoxy

- L - L - 2kl2^ahydroben i_ 67-naf tyridin - L - L - 2kl2^ahydroben i_ 67-naf tyridine

Det gås frem som i eksempel 1 eller 2 og erholdes ved reduksjon av cis-6-(4-aminof enyl )-9-metoksy-2-metyl-l, 2, 3, 4, 4a, 10b-heksa-hydrobenzo/c7/I,67naftyridin (olje— råprodukt) den i overskriften nevnte forbindelser, som krystalliseres som trihydro-klorid med smeltepunkt 289 - 291°C fra etanol. Proceed as in example 1 or 2 and obtain by reduction of cis-6-(4-aminophenyl)-9-methoxy-2-methyl-1, 2, 3, 4, 4a, 10b-hexa-hydrobenzo/c7 /1,67naphthyridine (oil—crude product) the compound mentioned in the title, which crystallizes as trihydrochloride with melting point 289 - 291°C from ethanol.

Det som utgangsprodukt anvendte cis-6-ft-aminofenyl)-9-metoksy-2-metyl-l,2,3,4,4a,10b-heksahydrobenzo/c7/I/67-naftyridin ble fremstilt på folgende måte: til en varm losning av 2 g cis-9-metoksy-2-metyl-6-(4-nitrofenyl)-l,2,3,4,4a,10b-heksahydrobenzé /c7/I/§7-naftyridin (olje - rådprodukt fra etylacetat) i 40 ml etanol og 13 ml vann ble 2,7 g jernspon tilsatt."I lopet av .40 minutter tildryppes en blanding av 13 ml etanol, 3 ml vann og 0,7 ml 2 N saltsyre i varm tilstand dertil og reaksjonsblandingen kokes enda i 3 timer under tilbakelop. Nå tilsettes 1 ral 2 N NaOH, det filtreres<p>g filtratet inndampes i vakuum. Resten loses i kloroform, losningen torres over natriumsulfat, filtreres og inndampes i vakuum, og den erholdte viskose olje videreforarbeides uten rensing. The cis-6-ft-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo[c7/1/67]-naphthyridine used as starting product was prepared in the following way: to a hot solution of 2 g of cis-9-methoxy-2-methyl-6-(4-nitrophenyl)-1,2,3,4,4a,10b-hexahydrobenzé /c7/1/§7-naphthyridine (oil - crude product from ethyl acetate) in 40 ml of ethanol and 13 ml of water, 2.7 g of iron filings were added."Over the course of 40 minutes, a mixture of 13 ml of ethanol, 3 ml of water and 0.7 ml of 2 N hydrochloric acid is added dropwise thereto in a warm state and the reaction mixture boiled for a further 3 hours under reflux. Now 1 ral of 2 N NaOH is added, the filtrate is filtered<p>and evaporated in vacuo. The residue is dissolved in chloroform, the solution is dried over sodium sulfate, filtered and evaporated in vacuum, and the viscous oil obtained is further processed without cleansing.

Eksempel 5; cis-^ii^-acetamidof^ Y^ z^ Z^-^ lS^ YZ- Z^^ y^ Z- i.- j-^. j. Example 5; cis-^ii^-acetamidof^ Y^ z^ Z^-^ lS^ YZ- Z^^ y^ Z- i.- j-^. j.

4, 4a L5^6, 10b-oktahydrobenzo/c7/I L67naf tyridin 4, 4a L5^6, 10b-octahydrobenzo/c7/I L67naf tyridine

Det gås frem analogt med eksempel 1 eller 2 og erholdes ved reduksjon av cis-6-(4-acetamidofenyl)-9-metoksy-2-metyl-l,2,3,4, 4a,10b-heksahydrobenzo/c7/I,§7naftyridin den i overskriften nevnte forbindelse ismeltepurakt av dihydrokloridet 294-296°C)-fra etanol). Proceed analogously to example 1 or 2 and obtain by reduction of cis-6-(4-acetamidophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo/c7/I, §7naphthyridine the compound mentioned in the heading is melting puract of the dihydrochloride 294-296°C)-from ethanol).

Det som utgangsmaterial anvendte cis-6-(4-acetamido-fenyl)-9-metoksy-2-metyl-l, 2, 3, 4, 4a, 10b-heksahydrob'enzo/c7/I/ 67naf tyridin erholdes fra cis-6-4-amino-fenyl)-9-metoksy-2-metyl-l,2,3,4,4a, 10b-heksahydrobenzo/c7/I,67naftyridin ved henstand over natten ved romtemperatur i nærvær av eddiksyreanhydrid og pyr-ridin. The cis-6-(4-acetamido-phenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo/c7/I/67naf tyridine used as starting material is obtained from cis- 6-4-amino-phenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo/c7/1,67naphthyridine by standing overnight at room temperature in the presence of acetic anhydride and pyridine .

Det erholdte råprodukt (skum) videreforarbeides direkte. The obtained raw product (foam) is further processed directly.

Eksempel 6: cis-6-^4-dimetylaminofenyl2-9-metoksy-2-metyl-1^2 Example 6: cis-6-^4-dimethylaminophenyl2-9-methoxy-2-methyl-1^2

-L-L--L-' Éii0b-oktahydrobenzo/c7/I L67naf tyridin -L-L--L-' Éii0b-octahydrobenzo/c7/I L67naf tyridine

Det gås frem analogt med eksempel 1 eller 2 og erholdes ved reduksjon av cis-6-(4-dimetylaminofenyl)-9-metoksy-2-metyl-1,2,3,4,4a,I0b-heksahydrobenzo/c7/l,§7naftyridin den i overskriften nevnte forbindelse (smeltepunkt av dihydrokloridet 275-277°C). Proceed analogously to example 1 or 2 and obtain by reduction of cis-6-(4-dimethylaminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo/c7/l, §7naphthyridine the compound mentioned in the title (melting point of the dihydrochloride 275-277°C).

Det som utgangsprodukt anvendte; cis-6-(4-dimetylaminofenyl)-9-metoksy-2-metyl-1,2,3,4,4a,10b-heksahydrobenzo/c7/I,§7 naftyridin erholdes etter Leuckart-Wallach fra cis-6-(4-aminofenyl)-9-metoksy-2-metyl-l,2,3,4,4a,10b-heksahydrobenzo /c//I.f67naftyridin ved reduktiv dimetylering med formaldehyd og maursyre. Det erholdte råprodukt videreforarbeides direkte. The starting product used; cis-6-(4-dimethylaminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo/c7/I,§7 naphthyridine is obtained according to Leuckart-Wallach from cis-6-( 4-aminophenyl)-9-methoxy-2-methyl-1,2,3,4,4a,10b-hexahydrobenzo /c//I.f67naphthyridine by reductive dimethylation with formaldehyde and formic acid. The obtained raw product is further processed directly.

Eksempel 4<0;>Ei5~§Z^ydE2]S?yz§zÉ52ZizizO}?tyizii.ii.^i.ii.i?:i.§' 6_L10b-oktahydrobenzo/c7/T/§7n^ftyridin (fremgangsmåte b) 2 g av cis-8-metoksy-6-fenyl-2-metyl-l,2,3,4,4a,5,6,lOb-oktahydro-benzo/c7/I,6_7naf tyridin-bis-hydrogenmaleinat (smeltepunkt 144-145°C fra etanol) overfores på vanlig måte i den fri base. Denne^ kokes under tilbakelop med 20 ml 60% bromhydrogensyre i 2 timer. Den etter avdamping i vakuum til torrhet resulterende .rest omkrystallas eres fra alkohol. Bishydrogenmaleinatet av den overskriften nevnte forbindelse har et smeltepunkt på 196-197°C. Example 4<0;>Ei5~§Z^ydE2]S?yz§zÉ52ZizizO}?tyizii.ii.^i.ii.i?:i.§' 6_L10b-octahydrobenzo/c7/T/§7n^ftyridine (method b) 2 g of cis-8-methoxy-6-phenyl-2-methyl-1,2,3,4,4a,5,6,10b-octahydro-benzo/c7/1,6_7naf tyridine-bis-hydrogen maleate ( melting point 144-145°C from ethanol) is transferred in the usual way into the free base. This^ is boiled under reflux with 20 ml of 60% hydrobromic acid for 2 hours. The resulting residue after evaporation in vacuum to dryness is recrystallized from alcohol. The bishydrogen maleate of the title compound has a melting point of 196-197°C.

Eksempel 41; . Sis-6-_(4-hydroksyffnyll-g-metoksy-g-mety^-l^^S^^ Example 41; . Sis-6-_(4-hydroxyphenyl-g-methoxy-g-methyl^-1^^S^^

_4a,_5, 6,10^-2ktahydrobenzo/c7/I767naf tyridin _4a,_5, 6,10^-2ktahydrobenzo/c7/1767naf tyridine

(fremgangsmåte b) (method b)

5 g cis-6-(4-benzyloksyfenyl)-9-metoksy-2-metyl-l,2,3, 4, 4a, 5, 6, 10b-oktahydrobenzo/c77I/67naftyridin loses i 50 ml etanol og hydrogeneres etter tilsetning av 5 g palladium (10% på aluminium-oksyd) ved romtemperatur og normaltrykk i en hydrogenatmosfære til avsluttet hydrogenopptagning. Dihydrokloridet av den således erholdte i overskriften nevnte forbindelse har et smeltepunkt på 312-315°C.(fra etanol). 5 g of cis-6-(4-benzyloxyphenyl)-9-methoxy-2-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo/c77I/67naphthyridine are dissolved in 50 ml of ethanol and hydrogenated after addition of 5 g of palladium (10% on aluminum oxide) at room temperature and normal pressure in a hydrogen atmosphere until complete hydrogen uptake. The dihydrochloride of the compound mentioned in the title thus obtained has a melting point of 312-315°C. (from ethanol).

Claims

1. Process for the preparation of new heterocyclic compounds of formula I,

in which R^ stands for one in the 8- or 9-position of the benzonaphthyridine shell associated with the rest of the series hydrogen, alkoxy with 1-4 carbon atoms or hydroxy, and either R2 means hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, the dimethylamino group, or an NHCOR^ group, in which R,- stands for hydrogen or alkyl with 1-4 carbon atoms, and R^ and R^ stand for hydrogen, or. R2 denotes alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy, halogen or nitro, R3 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy or chlorine and R^ means hydrogen, or R 2 , R^ and R^ mean alkoxy with 1-4 carbon atoms or benzyloxy, or R2, R^ and R^ mean alkyl with 1-4 carbon atoms, or R2, R^ and R^ mean hydroxy, wherein, if one of the residues R2, R^ and R^ stands for benzyloxy, means R^hydrogen or alkoxy with 1-4 carbon atoms, if R^means a hydroxy group attached to the 9-position, none of the residues R2, R^or R^means alkoxy with 1-4 carbon atoms, and when one of the residues R2 or R^means benzyloxy or alkoxy with 1-4 carbon atoms, the other residue R2 or R^ does not stand for hydroxy, and acid addition salts thereof, characterized by a) Compounds of formula II,

in which R& is in the 8- or 9-position of the benzonaphthyridine skeleton and means hydrogen, alkoxy with 1-4 carbon atoms, hydroxy or an ether group that can be split under the reaction conditions, and R^, Rg and R^ have the meanings given for R2, R3 and R4, are reduced or b) for the preparation of compounds of formula Ia,

in which either

R^1 means hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxy, halogen, nitro, amino, the dimethylamino group or a group NHCORj, in which R 5 has the above-mentioned meaning, and

R<*1> and R^<1> mean hydrogen, or

R*1 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxy, halogen or nitro,

R*1 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, hydroxy or chlorine and

R^<1> means hydrogen, or R2~I/ R3*°^R4^ ^ether alkoxy with 1-4 carbon atoms, or R2~I'' R3*°®R4J ketyr alkyl with 1-4 carbon atoms, or R^<1>/Rj1 and R^1 stands for the hydroxy group, in that, if the hydroxy group is in the 9-position, none of the residues rE1, R*1 or R^<1> means alkoxy with 1-4 carbon atoms, and when II II one of the residues R» or R_ means alkoxy with 1-4 carbon atoms , the other residue R2 II or R^ II does not stand for hydroxy, is treated compounds of formula III,

in which either R^11 means hydrogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy, halogen, nitro, amino, the dimethylamino group or an NHCOR^ group, in which R^ has the above meaning, and R^11 and R^11 stand for hydrogen, or <K>2means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy, halogen or nitro,- • •- •• Rg11 means alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, benzyloxy, hydroxy or chlorine and R^11 means hydrogen, or R^11/ R^11 °9R^11 means alkoxy with 1-4 carbon atoms or benzyloxy, or DIII „III'' means alkyl with 1-4 carbon atoms, or 2 ' 3 ^ 4 DIII _,III _iii .. _ , , , R2, Rg and R^ stand for the hydroxy group, and R7 means an ether residue that can be split under the reaction conditions, under the conditions for an ether cleavage, and the thus obtained compounds of formula I are recovered as a base or as acid addition salts.

2. Method as stated in claim 1, characterized in that cis-8-hydroxy-2-methyl-6-phenyl-1,2,3,4,4a,5,6,10b-octahydrobenzo/c7/1/67 naphthyridine is prepared .