NO166528B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE NAPHALAND AND INDANDER DERIVATIVES. - Google Patents

Abstract

Naphthalene and indane derivatives of the formula <IMAGE> in which the substituents have the meaning given in the description, their enantiomers, their diastereomers and their acid addition salts with inorganic or organic acids which have useful pharmacological properties, in particular a heart rate-reducing action. The novel compounds can be prepared by processes known per se.

Description

I EP-A-O.177.960 er det allerede beskrevet tetrahydro-naftalener som i 2-stilling er substituert med en hydroksygruppe som eventuelt er substituert med en acylrest. Disse forbindelsene har en utpreget kalsium-antagonistisk virkning og kan derfor benyttes som legemidler, spesielt for bekjempelse eller forhindring av angina pectoris, ischemi, arytmier og høyt blodtrykk. EP-A-0.177.960 has already described tetrahydro-naphthalenes which are substituted in the 2-position with a hydroxy group which is optionally substituted with an acyl residue. These compounds have a pronounced calcium-antagonistic effect and can therefore be used as pharmaceuticals, especially for combating or preventing angina pectoris, ischaemia, arrhythmias and high blood pressure.

Det har nå overraskende vist seg at nye naftalen- og indanderivater med formel It has now surprisingly been shown that new naphthalene and indane derivatives of formula

og deres syreaddisjonssalter, spesielt deres fysiologisk akseptable syreaddisjonssalter med uorganiske eller organiske syrer, oppviser andre verdifulle farmakologiske egenskaper, spesielt en hjertefrekvens-senkende virkning og en nedsettende virkning på hjertets C^-behov. and their acid addition salts, especially their physiologically acceptable acid addition salts with inorganic or organic acids, exhibit other valuable pharmacological properties, in particular a heart rate-lowering effect and a depressing effect on the C₂ demand of the heart.

Foreliggende oppfinnelse angår således fremstillingen av The present invention thus relates to the production of

nye tetrahydronaftalen- og indanderivater med den ovenfor angitte formel I, og deres syreaddisjonssalter, spesielt ved farmasøytisk bruk, deres fysiologisk akseptable syreaddisjonssalter med uorganiske eller organiske syrer. new tetrahydronaphthalene and indane derivatives of the above formula I, and their acid addition salts, especially for pharmaceutical use, their physiologically acceptable acid addition salts with inorganic or organic acids.

I den ovenfor angitte formel I har symbolene følgende betydninger: In the above formula I, the symbols have the following meanings:

n tallet 1 eller 2, n the number 1 or 2,

A er en karbonylgruppe og R7 et hydrogenatom eller A is a carbonyl group and R7 is a hydrogen atom or

A en gruppe med formel -CH-, hvor R8 utgjør et hydrogenatom, eller en hydroksy-gruppe, og R7 utgjør et hydrogenatom eller sammen med R8 utgjør en ytterligere binding, A a group of formula -CH-, where R8 constitutes a hydrogen atom, or a hydroxy group, and R7 constitutes a hydrogen atom or together with R8 constitutes an additional bond,

E er en rettkjedet alkylengruppe med 3 eller 4 karbonatomer, E is a straight-chain alkylene group with 3 or 4 carbon atoms,

G er en rettkjedet alkylengruppe med 2-5 karbonatomer, G is a straight-chain alkylene group with 2-5 carbon atoms,

R2 er hydrogen eller en alkyl- eller alkoksygruppe, R 2 is hydrogen or an alkyl or alkoxy group,

R2 er en alkoksy- eller alkylgruppe, R 2 is an alkoxy or alkyl group,

R3 er en alkylgruppe med 1-3 karbonatomer, R3 is an alkyl group with 1-3 carbon atoms,

R4 er et hydrogenatom, en alkyl-, amino-, alkanoylamino-, alkoksykarbonylamino-, alkylsulfonylamino-, bis(alkylsulfonyl)-amino-, cyano-, eller alkylsulfonylgruppe, eller en hydroksy-gruppe som eventuelt er substituert med en alkyl-, fenylalkyl-, 2-hydroksyetyl-, alkylsulfonyl-, cyanoalkyl-, hydroksykarbonylalkyl-, alkoksykarbonylalkyl-, trifluormetyl- eller trifluormetylsulfonylgruppe, R4 is a hydrogen atom, an alkyl, amino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, bis(alkylsulfonyl)amino, cyano, or alkylsulfonyl group, or a hydroxy group which is optionally substituted with an alkyl, phenylalkyl -, 2-hydroxyethyl, alkylsulfonyl, cyanoalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, trifluoromethyl or trifluoromethylsulfonyl group,

R5 er et hydrogen- eller halogenatom, en alkyl-, hydroksy-, alkoksy-, nitro-, cyano- eller trifluormetylgruppe, og Rg er et hydrogen- eller halogenatom eller en alkoksygruppe, hvor alle tidligere nevnte alkyl- eller alkoksygrupper hver inneholder 1-3 karbonatomer, og de tidligere nevnte alkanoyl-grupper hver inneholder 2 eller 3 karbonatomer. R5 is a hydrogen or halogen atom, an alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group, and Rg is a hydrogen or halogen atom or an alkoxy group, where all previously mentioned alkyl or alkoxy groups each contain 1- 3 carbon atoms, and the previously mentioned alkanoyl groups each contain 2 or 3 carbon atoms.

Foretrukne forbindelser med formel I er imidlertid slike hvor However, preferred compounds of formula I are those where

n er tallet 1 eller 2, n is the number 1 or 2,

A er en karbonylgruppe og R7 et hydrogenatom eller A is a carbonyl group and R7 is a hydrogen atom or

A er en gruppe med formel A is a group with formula

hvor R8 betyr et hydrogenatom where R 8 means a hydrogen atom

eller en hydroksygruppe og R7 et hydrogenatom eller R7 og R8 sammen utgjør en ytterligere binding, or a hydroxy group and R7 a hydrogen atom or R7 and R8 together constitute a further bond,

E er n-propylengruppen, E is the n-propylene group,

G er etylen- eller n-propylengruppen, G is the ethylene or n-propylene group,

Ri er en metyl- eller metoksygruppe, R 1 is a methyl or methoxy group,

R2 er et hydrogenatom eller en metoksygruppe, R2 is a hydrogen atom or a methoxy group,

R3 er metylgruppen, R3 is the methyl group,

R4 er et hydrogenatom, en hydroksy-, metoksy-, cyano-, cyano-metoksy-, hydroksykarbonylmetoksy-, metoksykarbonylmetoksy-, etoksykarbonylmetoksy-, metyl-, amino-, acetylamino-, metoksy-karbonylamino-, metylsulfonyloksy-, trifluormetylsulfonyloksy-, benzyloksy-, metylsulfonylamino- eller bis(metylsulfonyl)aminogruppe, R4 is a hydrogen atom, a hydroxy-, methoxy-, cyano-, cyano-methoxy-, hydroxycarbonylmethoxy-, methoxycarbonylmethoxy-, ethoxycarbonylmethoxy-, methyl-, amino-, acetylamino-, methoxycarbonylamino-, methylsulfonyloxy-, trifluoromethylsulfonyloxy-, benzyloxy -, methylsulfonylamino or bis(methylsulfonyl)amino group,

R5 er et hydrogen-, klor- eller bromatom, en metoksy- eller nitrogruppe og R5 is a hydrogen, chlorine or bromine atom, a methoxy or nitro group and

R6 er et hydrogen-, klor- eller bromatom, samt deres enantiomerer, diastereomerer og syreaddisjonssalter. R 6 is a hydrogen, chlorine or bromine atom, as well as their enantiomers, diastereomers and acid addition salts.

Spesielt foretrukne forbindelser med formel I er slike hvor Ri til R3, A, E, G og n er som foran definert, Particularly preferred compounds of formula I are those where Ri to R3, A, E, G and n are as defined above,

R4 er en metoksygruppe, R4 is a methoxy group,

R5 er en metoksygruppe og R5 is a methoxy group and

R6 er et hydrogenatom, samt deres enantiomerer, diastereomerer og syreaddisjonssalter. R 6 is a hydrogen atom, as well as their enantiomers, diastereomers and acid addition salts.

I henhold til oppfinnelsen oppnås de nye forbindelser etter følgende fremgangsmåter: a) For fremstilling av forbindelser med formel I, hvor R7 og Rg hver er et hydrogenatom eller sammen utgjør en ytterligere According to the invention, the new compounds are obtained by the following methods: a) For the preparation of compounds of formula I, where R7 and Rg are each a hydrogen atom or together form an additional

binding: binding:

omsetning av en forbindelse med formel turnover of a compound of formula

hvor where

Ri, R2, n og E er som innledningsvis definert, Ri, R2, n and E are as initially defined,

Ai er en gruppe med formel Ai is a group with formula

hvor R8 betyr et hydrogenatom where R 8 means a hydrogen atom

og R7 utgjør et hydrogenatom eller R7 og Rg sammen utgjør en ytterligere binding, og and R7 constitutes a hydrogen atom or R7 and Rg together constitute a further bond, and

X utgjør en nukleofil utgående gruppe, så som et halogenatom eller en sulfonyloksygruppe, f.eks. et klor-, brom- eller jodatom, en metansulfonyloksy-, p-toluensulfonyloksy- eller etoksysulfonyloksygruppe, X constitutes a nucleophilic leaving group, such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy, p-toluenesulfonyloxy or ethoxysulfonyloxy group,

med et amin med formel with an amine of formula

hvor where

R3 til R6 og G er som innledningsvis definert. R3 to R6 and G are as initially defined.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding som aceton, dietyleter, metylformamid, dimetylformamid, dimetylsulfoksyd, benzen, klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran, dioksan eller i et overskudd av en av utgangsforbindelsene med formel II og/eller III og eventuelt i nærvær av et syrebindende The reaction is conveniently carried out in a solvent or a solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of one of the starting compounds of formula II and/or III and optionally in the presence of an acid binder

middel, f.eks. et alkoholat som kalium-tert-butylat, et alkalihydroksyd som natrium- eller kaliumhydroksyd, et alkalikarbonat som kaliumkarbonat, et alkaliamid som natriumamid, et alkalihydrid som natriumhydrid,, en tertiær organisk base som trietylamin eller pyridin, hvor de sistnevnte samtidig også kan tjene som oppløsningsmiddel, eller en katalysator som kaliumjodid, avhengig av reaktiviteten av den nukleofilt utskiftbare rest, ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 50 og 120°C, f.eks. ved kokepunktet for det anvendte agent, e.g. an alcoholate such as potassium tert-butylate, an alkali hydroxide such as sodium or potassium hydroxide, an alkali carbonate such as potassium carbonate, an alkali amide such as sodium amide, an alkali hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, where the latter can also serve as solvent, or a catalyst such as potassium iodide, depending on the reactivity of the nucleophilically exchangeable residue, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 120°C, e.g. at the boiling point of the substance used

oppløsningsmiddel. Omsetningen kan imidlertid også utføres uten oppløsningsmiddel. Spesielt gunstig er det å utføre omsetningen i nærvær av en tertiær organisk base eller i et overskudd av det anvendte amin med formel III. solvent. However, the reaction can also be carried out without a solvent. It is particularly advantageous to carry out the reaction in the presence of a tertiary organic base or in an excess of the amine of formula III used.

b) Omsetning av en forbindelse med formel b) Reaction of a compound with formula

hvor where

n, A, E, Ri til R3 og R7 er som innledningsvis definert, med en forbindelse med formel n, A, E, R 1 to R 3 and R 7 are as initially defined, with a compound of formula

hvor where

R4 til Rg og G er som innledningsvis definert og R4 to Rg and G are defined as initially and

Y utgjør en nukleofil utgående gruppe, så som et halogenatom eller en sulfonyloksygruppe, f.eks. et klor-, brom- eller jodatom, en metansulfonyloksy-, p-toluensulfonyloksy- eller etoksysulfonyloksygruppe. Y constitutes a nucleophilic leaving group, such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy, p-toluenesulfonyloxy or ethoxysulfonyloxy group.

Omsetningen utføres hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding som aceton, dietyleter, metylformamid, dimetylformamid, dimetylsulfoksyd, benzen, klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran, dioksan eller i et overskudd av en av utgangsforbindelsene med formel IV og/eller V, og eventuelt i nærvær av et syrebindende middel, f.eks. et alkoholat som kalium-tert-butylat, et alkalihydroksyd som natrium- eller kaliumhydroksyd, et alkalikarbonat som kaliumkarbonat, et alkaliamid som natriumamid, et alkalihydrid som natriumhydrid, en tertiær organisk base som trietylamin eller pyridin, hvor de sistnevnte samtidig også kan tjene som oppløsningsmiddel, eller en katalysator som kaliumjodid, avhengig av reaktiviteten av den nukleofilt utskiftbare rest, ved temperaturer mellom 0 og 150°C, fortrinnsvis ved temperaturer mellom 50 og 120°C, f.eks. ved kokepunktet for det anvendte oppløsningsmiddel. Omsetningen kan imidlertid også utføres uten oppløsningsmiddel. Spesielt gunstig er det å utføre omsetningen i nærvær av en tertiær organisk base eller i et overskudd av det anvendte amin med formel IV. The reaction is conveniently carried out in a solvent or a solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxane or in an excess of one of the starting compounds of formula IV and/or V, and optionally in presence of an acid-binding agent, e.g. an alcoholate such as potassium tert-butylate, an alkali hydroxide such as sodium or potassium hydroxide, an alkali carbonate such as potassium carbonate, an alkali amide such as sodium amide, an alkali hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, where the latter can simultaneously also serve as a solvent , or a catalyst such as potassium iodide, depending on the reactivity of the nucleophilically exchangeable residue, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 120°C, e.g. at the boiling point of the solvent used. However, the reaction can also be carried out without a solvent. It is particularly advantageous to carry out the reaction in the presence of a tertiary organic base or in an excess of the amine of formula IV used.

c) For fremstilling av forbindelser med formel I, hvor c) For the preparation of compounds of formula I, where

A utgjør en gruppe med formel A constitutes a group with formula

hvor R8 betyr et hydrogenatom where R 8 means a hydrogen atom

eller en hydroksygruppe: or a hydroxy group:

reduksjon av en forbindelse med formel reduction of a compound of formula

hvor where

n og til R6 er som innledningsvis definert, n and to R6 are as initially defined,

A2 er en karbonylgruppe og R7 et hydrogenatom eller A2 is a carbonyl group and R7 is a hydrogen atom or

A2 er en gruppe med formel A2 is a group with formula

hvor Rg utgjør et hydrogenatom where Rg constitutes a hydrogen atom

eller en hydroksygruppe, og R7 er et hydrogenatom, or a hydroxy group, and R7 is a hydrogen atom,

E' har de for E, og G' de for G, innledningsvis nevnte betydninger, hvor imidlertid en metylengruppe nabostilt til =N-R3-gruppen, i restene E eller G må være erstattet med en karbonylgruppe. E' has the meanings for E, and G' those for G, initially mentioned, where, however, a methylene group adjacent to the =N-R3 group, in the residues E or G must be replaced by a carbonyl group.

Reduksjonen utføres fortrinnsvis med et metallhydrid som litiumaluminiumhydrid eller diboran eller med et kompleks av boran og en tioeter, f.eks. med boran-dimetylsulfid-kompleks, eventuelt i nærvær av en Lewis-syre som bortrifluorid, i et egnet oppløsningsmiddel som dietyleter eller tetrahydrofuran, ved temperaturer mellom 0 og 80°C, fortrinnsvis ved oppløsnings-midlets kokepunkt, f.eks. ved temperaturer mellom 35 og 65°C. The reduction is preferably carried out with a metal hydride such as lithium aluminum hydride or diborane or with a complex of borane and a thioether, e.g. with borane-dimethylsulphide complex, optionally in the presence of a Lewis acid such as boron trifluoride, in a suitable solvent such as diethyl ether or tetrahydrofuran, at temperatures between 0 and 80°C, preferably at the boiling point of the solvent, e.g. at temperatures between 35 and 65°C.

Betyr A2 i en anvendt forbindelse med formel VI, en karbonylgruppe eller R8 en hydroksygruppe, gjennomføres reduksjonen for fremstilling av forbindelser med formel I, hvor R8 utgjør et hydrogenatom, fortrinnsvis i nærvær av en Lewis-syre, f.eks. boran-dimetylsulfid-kompleks i nærvær av bortrifluorid, eller If A2 in a compound of formula VI used is a carbonyl group or R8 a hydroxy group, the reduction is carried out to produce compounds of formula I, where R8 constitutes a hydrogen atom, preferably in the presence of a Lewis acid, e.g. borane-dimethylsulfide complex in the presence of boron trifluoride, or

betyr A2 i en anvendt forbindelse med formel VI, karbonylgruppen eller R8 en hydroksygruppe, utføres reduksjonen for fremstilling av forbindelser med den generelle formel I, hvor R8 utgjør en hydroksygruppe, fortrinnsvis med litiumaluminiumhydrid. d) For fremstilling av forbindelser med formel I, hvor A utgj ør karbonylgruppen: means A2 in an used compound of formula VI, the carbonyl group or R8 a hydroxy group, the reduction is carried out to prepare compounds of the general formula I, where R8 constitutes a hydroxy group, preferably with lithium aluminum hydride. d) For the preparation of compounds of formula I, where A is the carbonyl group:

oksydasjon av en forbindelse med formel oxidation of a compound of formula

hvor where

n, E, G og % til R5 er som innledningsvis definert. n, E, G and % to R5 are as initially defined.

Oksydasjonen foretas fortrinnsvis med et oksydasjonsmiddel som kaliumpermanganat, barium-manganat, kalium-di-kromat eller med et keton i nærvær av en base (Oppenauer-metode), f.eks. med aceton/aluminiumisopropylat eller benzofenon/kalium-tert-butylat, i et egnet oppløsningsmiddel som vann, vann/dioksan, iseddik, vann/eddiksyre eller toluen, ved temperaturer mellom 0 og 150°C. Oksydasjonen med et uorganisk oksydasjonsmiddel, utføres fortrinnsvis ved temperaturer mellom 0 og 50°C, og oksydasjonen etter Oppenauer fortrinnsvis ved reaksjonsblandingens kokepunkt, f.eks. ved temperaturer mellom 50 og 115°C. e) For fremstilling av forbindelser med formel I, hvor R4 er en alkanoylamino-, alkoksykarbonyl-amino-, alkylsulfonylamino-, bis(alkylsulfonyl)amino-, alkoksy-, hydroksykarbonylalkoksy-, alkoksykarbonylalkoksy-, fenylalkoksy-, trifluormetoksy-, cyanoalkoksy-, alkylsulfinyloksy- eller trifluormetylsulfonyl-oksygruppe: The oxidation is preferably carried out with an oxidizing agent such as potassium permanganate, barium manganate, potassium dichromate or with a ketone in the presence of a base (Oppenauer method), e.g. with acetone/aluminium isopropylate or benzophenone/potassium tert-butylate, in a suitable solvent such as water, water/dioxane, glacial acetic acid, water/acetic acid or toluene, at temperatures between 0 and 150°C. The oxidation with an inorganic oxidizing agent is preferably carried out at temperatures between 0 and 50°C, and the oxidation according to Oppenauer preferably at the boiling point of the reaction mixture, e.g. at temperatures between 50 and 115°C. e) For the preparation of compounds of formula I, where R 4 is an alkanoylamino-, alkoxycarbonyl-amino-, alkylsulfonylamino-, bis(alkylsulfonyl)amino-, alkoxy-, hydroxycarbonylalkoxy-, alkoxycarbonylalkoxy-, phenylalkoxy-, trifluoromethoxy-, cyanoalkoxy-, alkylsulfinyloxy or trifluoromethylsulfonyloxy group:

omsetning av en forbindelse med formel turnover of a compound of formula

hvor where

R^ til R3, R5 til R7, A, E, G og n er som innledningsvis definert og 9 R^ to R3, R5 to R7, A, E, G and n are as initially defined and 9

Rg er en hydroksy-, amino- eller alkylaminogruppe med 1-3 karbonatomer, Rg is a hydroxy, amino or alkylamino group with 1-3 carbon atoms,

med en forbindelse med formel with a compound of formula

hvor where

Z er en nukleofil utgående gruppe, så som et halogenatom, Z is a nucleophilic leaving group, such as a halogen atom,

f.eks. et klor-, brom- eller jodatom og R10 betyr en alkyl-, alkanoyl-, alkoksykarbonyl-, hydroksykarbonylalkyl-, alkoksykarbonylalkyl-, alkylsulfonyl-, fenylalkyl-, trifluormetyl-eller cyanoalkylgruppe, hvor hver av de ovennevnte alkyl- og alkoksy-deler inneholder 1 til 3 karbonatomer, eller hvor alkanoyl-delen inneholder 2 eller 3 karbonatomer. e.g. a chlorine, bromine or iodine atom and R10 means an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulfonyl, phenylalkyl, trifluoromethyl or cyanoalkyl group, where each of the above alkyl and alkoxy moieties contains 1 to 3 carbon atoms, or where the alkanoyl moiety contains 2 or 3 carbon atoms.

Omsetningen foretas hensiktsmessig i et oppløsningsmiddel eller en oppløsningsmiddelblanding som metylenklorid, kloroform, tetraklormetan, eter, tetrahydrofuran, dioksan, benzen, toluen, acetonitril eller dimetylformamid, eventuelt også i nærvær av et syreaktiverende middel eller et vanntiltrekkende middel, f.eks. i nærvær av klormaursyreetylester, tionylklorid, fosfortriklorid, fosforpentoksyd, N,N'-dicykloheksylkarbodiimid, N,N'-dicykloheksylkarbodiimid/N-hydroksysuccinimid, N,N'-karbonyldiimidazol eller N,N'-tionyldiimidazol, og eventuelt i nærvær av en uorganisk base som natriumkarbonat, eller en tertiær organiske base som trietylamin eller pyridin, idet de to sistnevnte også samtidig kan tjene som oppløsningsmiddel, ved temperaturer mellom -25 og 250°C, fortrinnsvis ved temperaturer mellom -10°C og kokepunktet for det anvendte oppløsningsmiddel. f) For fremstilling av forbindelser med formel I, hvor R7 og R8 sammen utgjør en ytterligere binding: The reaction is suitably carried out in a solvent or a solvent mixture such as methylene chloride, chloroform, tetrachloromethane, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally also in the presence of an acid activating agent or a water-attracting agent, e.g. in the presence of chloroformate ethyl ester, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole, and optionally in the presence of an inorganic base such as sodium carbonate, or a tertiary organic base such as triethylamine or pyridine, the latter two also simultaneously serving as a solvent, at temperatures between -25 and 250°C, preferably at temperatures between -10°C and the boiling point of the solvent used. f) For the preparation of compounds of formula I, where R7 and R8 together form a further bond:

dehydratisering av en forbindelse med formel dehydration of a compound of formula

hvor where

n, E, G og R^ til R7 er som innledningsvis definert. n, E, G and R^ to R7 are defined as initially.

Dehydratiseringen utføres hensiktsmessig i et oppløsnings-middel som aceton, metanol, etanol, tetrahydrofuran eller dioksan og fortrinnsvis i nærvær av en syre, som saltsyre eller svovelsyre, fortrinnsvis i nærvær av en syre i en alkohol, så som metanolisk saltsyre, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur. The dehydration is suitably carried out in a solvent such as acetone, methanol, ethanol, tetrahydrofuran or dioxane and preferably in the presence of an acid, such as hydrochloric or sulfuric acid, preferably in the presence of an acid in an alcohol, such as methanolic hydrochloric acid, at temperatures between 0 and 50°C, preferably at room temperature.

Ved de beskrevne omsetninger kan eventuelt forekommende reaktive grupper som hydroksy-, amino- eller iminogrupper, beskyttes med vanlige beskyttelsesgrupper, som avspaltes igjen etter omsetningen. In the reactions described, reactive groups that may occur, such as hydroxy, amino or imino groups, can be protected with normal protective groups, which are cleaved off again after the reaction.

Som beskyttelsesrest for en hydroksygruppe kommer trimetyl-silyl-, acetyl-, benzoyl-, benzyl- eller tetrahydropyranyl-gruppen, og som beskyttelsesrest for en imino- eller aminogruppe, acetyl-, benzoyl-, etoksykarbonyl- eller benzylgruppen i betraktning. As a protective residue for a hydroxy group, the trimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl group, and as a protective residue for an imino or amino group, the acetyl, benzoyl, ethoxycarbonyl or benzyl group comes into consideration.

Den eventuelt påfølgende avspaltning av en benyttet beskyttelsesrest skjer fortrinnsvis hydrolytisk i et vandig oppløsningsmiddel, f.eks. i vann, isopropanol/vann, tetrahydrofuran/vann eller dioksan/vann, i nærvær av en syre som saltsyre eller svovelsyre, eller i nærvær av en alkalibase som natrium-hydroksyd eller kaliumhydroksyd, ved temperaturer mellom 0 og 100°C, fortrinnsvis ved reaksjonsblandingens kokepunkt. Avspaltningen av en benzylrest skjer imidlertid fortrinnsvis hydrogenolytisk, f.eks. med hydrogen i nærvær av en katalysator, så som palladium/kull, i et oppløsningsmiddel som metanol, etanol, eddiksyreetylester eller iseddik, eventuelt under tilsetning av en syre, så som saltsyre, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur, og under et hydrogentrykk på 1-7 bar, fortrinnsvis 3-5 bar. The possibly subsequent cleavage of a used protective residue preferably takes place hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulfuric acid, or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100°C, preferably at the reaction mixture's boiling point. However, the cleavage of a benzyl residue preferably takes place hydrogenolytically, e.g. with hydrogen in the presence of a catalyst, such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid, such as hydrochloric acid, at temperatures between 0 and 50°C, preferably at room temperature, and under a hydrogen pressure of 1-7 bar, preferably 3-5 bar.

Oppnår man under fremgangsmåtene i henhold til oppfinnelsen, en forbindelse med formel I, hvor R4 utgjør en benzyloksygruppe, kan forbindelsen overføres i den tilsvarende hydroksyforbindelse ved debenzylering. If, during the methods according to the invention, a compound of formula I is obtained, where R 4 constitutes a benzyloxy group, the compound can be transferred into the corresponding hydroxy compound by debenzylation.

Debenzyleringen utføres fortrinnsvis i et oppløsningsmiddel som vann, vann/etanol, metanol, iseddik, eddiksyreetylester eller dimetylformamid, med hydrogen i nærvær av en hydrerings-katalysator, som Raney-nikkel, platina eller palladium/kull, ved temperaturer mellom 0 og 50°C, fortrinnsvis ved romtemperatur . The debenzylation is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst, such as Raney nickel, platinum or palladium/charcoal, at temperatures between 0 and 50°C , preferably at room temperature.

Oppnådde forbindelser med formel I, som har minst et chiralt sentrum, kan ved hjelp av vanlige metoder spaltes i deres diastereomerer, eksempelvis ved søylekromatografi, og i deres enantiomerer, eksempelvis ved søylekromatografi på en chiral fase eller ved krystallisasjon med optisk aktive syrer, f.eks. med D- eller L-monometyl-vinsyre, D- eller L-diacetyl-vinsyre, D- eller L-vinsyre, D- eller L-melkesyre, D- eller L-kamfersyre, D- eller L-dibenzoyl-vinsyre, D- eller L-kamfer-sulfonsyre eller D- eller L-kamfansyre. Obtained compounds of formula I, which have at least one chiral center, can be resolved using common methods into their diastereomers, for example by column chromatography, and into their enantiomers, for example by column chromatography on a chiral phase or by crystallization with optically active acids, e.g. e.g. with D- or L-monomethyltartaric acid, D- or L-diacetyltartaric acid, D- or L-tartaric acid, D- or L-lactic acid, D- or L-camphoric acid, D- or L-dibenzoyltartaric acid, D - or L-camphor sulphonic acid or D- or L-camphanic acid.

De oppnådde forbindelser med formel I lar seg dessuten overføre i deres syreaddisjonssalter, ved tale om farmasøytisk anvendelse, i deres fysiologisk akseptable syreaddisjonssalter, med uorganiske eller organiske syrer. Syrer som herunder kommer i betraktning er eksempelvis saltsyre, hydrogenbromidsyre, svovelsyre, fosforsyre, eddiksyre, melkesyre, sitronsyre, vinsyre, ravsyre, maleinsyre, fumarsyre eller oksalsyre. The obtained compounds of formula I can also be transferred in their acid addition salts, when speaking of pharmaceutical use, in their physiologically acceptable acid addition salts, with inorganic or organic acids. Acids that come into consideration below are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid, fumaric acid or oxalic acid.

Utgangsforbindelsene med formel II til X er dels kjent fra litteraturen eller kan oppnås etter kjente fremgangsmåter. The starting compounds of formulas II to X are partly known from the literature or can be obtained by known methods.

For eksempel oppnås en utgangsforbindelse med den generelle formel II ved reduksjon av en tilsvarende karbonsyre med formel For example, a starting compound with the general formula II is obtained by reduction of a corresponding carboxylic acid with formula

hvor where

, R2, E og n er som innledningsvis definert, eller ved reduksjon av en tilsvarende ester til den tilsvarende alkohol og påfølgende omsetning med et halogeneringsmiddel, f.eks. fosfortribromid eller hydrogenbromid. Den nødvendige karboksylsyre med formel XI oppnår man ved Michael-addisjon av en tilsvarende acylester til en forbindelse med formel , R2, E and n are as initially defined, or by reduction of a corresponding ester to the corresponding alcohol and subsequent reaction with a halogenating agent, e.g. phosphorus tribromide or hydrogen bromide. The required carboxylic acid of formula XI is obtained by Michael addition of a corresponding acyl ester to a compound of formula

hvor where

Rl • R2 0<3 n er som innledningsvis definert og Rl • R2 0<3 n is as initially defined and

Rll utgjør et hydrogenatom eller en lavere alkoksygruppe. Den nødvendige forbindelse XII for dette formål, oppnår man ved omsetning av et tilsvarende keton med en maursyreester eller et dialkylkarbonat i nærvær av en sterk base, så som et alkali-alkoholat eller et alkalihydrid. R 11 represents a hydrogen atom or a lower alkoxy group. The necessary compound XII for this purpose is obtained by reacting a corresponding ketone with a formic acid ester or a dialkyl carbonate in the presence of a strong base, such as an alkali alcoholate or an alkali hydride.

En utgangsforbindelse med formel IV oppnår man eksempelvis ved omsetning av en karboksylsyre med formel XI med et tilsvarende amin i nærvær av N,N'-karbonyldiimidazol og påfølgende reduksjon av det oppnådde amid. A starting compound of formula IV is obtained, for example, by reacting a carboxylic acid of formula XI with a corresponding amine in the presence of N,N'-carbonyldiimidazole and subsequent reduction of the resulting amide.

En utgangsforbindelse med formel VI, VII, VIII og X oppnår man ved omsetning av en tilsvarende u-halogenforbindelse med et tilsvarende amin. A starting compound of formula VI, VII, VIII and X is obtained by reacting a corresponding u-halogen compound with a corresponding amine.

Som allerede nevnt innledningsvis, oppviser de nye forbindelser med formel I og deres fysiologisk akseptable syreaddisjonssalter med uorganiske eller organiske syrer verdifulle farmakologiske egenskaper, spesielt ved at de har få sentraltvirkende bivirkninger, en spesiell hjertefrekvens-senkende virkning samt en nedsettelse av hjertets 02-behov. As already mentioned at the outset, the new compounds of formula I and their physiologically acceptable acid addition salts with inorganic or organic acids exhibit valuable pharmacological properties, especially in that they have few centrally acting side effects, a special heart rate-lowering effect and a reduction in the heart's 02 demand.

Eksempelvis ble forbindelsene For example, the connections were

A = 6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metyl- A = 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methyl-

amino)-propyl]-1-okso-l,2,3,4-tetrahydronaftalen, amino)-propyl]-1-oxo-1,2,3,4-tetrahydronaphthalene,

B = 6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metyl-amino)-propyl]-1,2,3,4-tetrahydronaftalen-hydroklorid og B = 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methyl-amino)-propyl]-1,2,3,4-tetrahydronaphthalene hydrochloride and

C = 5,6-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metyl-amino)-propyl]-1-hydroksy-indan C = 5,6-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methyl-amino)-propyl]-1-hydroxy-indane

undersøkt på deres biologiske egenskaper på følgende måte: examined for their biological properties as follows:

Virkning på hjertefrekvensen hos rotter: Effect on heart rate in rats:

Virkningen av testsubstansene ble for hver dose undersøkt med henblikk på hjertefrekvensen på to rotter med en gjennom-snittsvekt på 250-300 g. I den anledning ble rottene anestetisert med pentobarbital (50 mg/kg i.p. og 10 mg/kg s.c). Testsubstansene ble injisert i vandige oppløsninger (0,1 ml/100 g) The effect of the test substances was examined for each dose with regard to the heart rate of two rats with an average weight of 250-300 g. On this occasion, the rats were anesthetized with pentobarbital (50 mg/kg i.p. and 10 mg/kg s.c.). The test substances were injected in aqueous solutions (0.1 ml/100 g)

i vena jugularis. in the jugular vein.

Blodtrykket ble målt via en kanyle i A. carotis, og hjertefrekvensen ble registrert fra et EKG avledet med nål-elektrode (II. eller III. avledning). Dyrenes hjertefrekvens i kontrollperioden lå mellom 350 og 400 slag/minutt (S/min). Blood pressure was measured via a cannula in the carotid artery, and heart rate was recorded from an ECG derived with a needle electrode (II. or III. lead). The animals' heart rate during the control period was between 350 and 400 beats/minute (S/min).

Den etterfølgende tabell inneholder de fundne verdier: The following table contains the values found:

Forbindelsene fremstillet i henhold til oppfinnelsen, oppviser ingen toksiske bivirkninger i terapeutiske doser. Således kunne toksiske bivirkninger på mus heller ikke iakttas ved intravenøs injeksjon av substans A og C i en høyere dose (10 mg/kg), bortsett fra en svak sederende virkning. The compounds produced according to the invention show no toxic side effects in therapeutic doses. Thus, toxic side effects on mice could not be observed either by intravenous injection of substances A and C in a higher dose (10 mg/kg), apart from a weak sedative effect.

På grunn av deres farmakologiske egenskaper er de nye forbindelsene egnet til behandling av sinus tachykardier av forskjellig opprinnelse og til profylakse og terapi av ischemiske hj ertesykdommer. Due to their pharmacological properties, the new compounds are suitable for the treatment of sinus tachycardias of various origins and for the prophylaxis and therapy of ischemic heart diseases.

Den nødvendige dosering for å oppnå en ønsket virkning utgjør 0,03 til 0,4 mg/kg legemsvekt, fortrinnsvis 0,07 til 0,25 mg/kg legemsvekt, gitt én til to ganger per dag. Til dette formål innarbeides forbindelser med formel I samt deres fysiologisk akseptable syreaddisjonssalter med uorganiske eller organiske syrer, eventuelt i kombinasjon med andre virkestoffer, sammen med ett eller flere inerte vanlige bæremidler og/eller fortynningsmidler, f.eks. maisstivelse, melkesukker, rørsukker, mikrokrystallinsk cellulose, magnesiumstearat, polyvinyl-pyrrolidon, sitronsyre, vinsyre, vann, vann/etanol, vann/- glycerol, vann/sorbitol, vann/polyetylenglykol, propylenglykol, karboksymetylcellulose eller fettholdige substanser som hardfett eller egnede blandinger av disse, i vanlige galeniske tilberedninger, som tabletter, drasjéer, kapsler, pulvere, suspensjoner, dråper, ampuller, safter eller stikkpiller. The necessary dosage to achieve a desired effect is 0.03 to 0.4 mg/kg body weight, preferably 0.07 to 0.25 mg/kg body weight, given once to twice per day. For this purpose, compounds of formula I and their physiologically acceptable acid addition salts with inorganic or organic acids are incorporated, possibly in combination with other active substances, together with one or more inert usual carriers and/or diluents, e.g. corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/- glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures of these, in usual galenic preparations, such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or suppositories.

De etterfølgende eksempler skal belyse oppfinnelsen nærmere. The following examples shall illustrate the invention in more detail.

Eksempel A Example A

6. 7- dimetoksy- l- okso- l. 2. 3. 4- tetrahydronaftalen- 2- karbaldehYd 6. 7- dimethoxy- l- oxo- l. 2. 3. 4- tetrahydronaphthalene- 2- carbaldeHyd

187,5 g (0,909 mol) 6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen ble suspendert i 4,0 liter dietyleter og under omrøring omsatt med 123,4 g (1,1 mol) kalium-tert.-butylat. Etter 30 minutter ble 89 ml (1,1 mol) maursyreetylester dråpevis tilsatt til det resulterende bunnfall. Etter 5 timer ble den blåligrøde suspensjon tilsatt 1 liter vann. Vannfasen ble fraskilt og surgjort med konsentrert saltsyre, hvorved det utfeltes et gult bunnfall. Den saltsure fase ble ekstrahert 3 x med metylenklorid, tørket over magnesiumsulfat og inndampet i vakuum. 187.5 g (0.909 mol) of 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene was suspended in 4.0 liters of diethyl ether and, while stirring, reacted with 123.4 g (1.1 mol) potassium tert-butylate. After 30 minutes, 89 ml (1.1 mol) of ethyl formic acid was added dropwise to the resulting precipitate. After 5 hours, the bluish-red suspension was added to 1 liter of water. The water phase was separated and acidified with concentrated hydrochloric acid, whereby a yellow precipitate is precipitated. The hydrochloric acid phase was extracted 3x with methylene chloride, dried over magnesium sulfate and evaporated in vacuo.

Utbytte: 186,2 g (87,4% av det teoretiske). Yield: 186.2 g (87.4% of the theoretical).

Smeltepunkt: 153-154°C. Melting point: 153-154°C.

Eksempel B Example B

3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-propionsvre- metvlester 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-propionic acid methyl ester

En blanding av 128,8 g (0,55 mol) 6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-karbaldehyd, 125 ml (1,38 mol) akrylsyremetylester og 82,5 ml (0,6 mol) trietylamin ble kokt under tilbakeløpskjøling i 6 timer. Den ble deretter inndampet i vakuum og den oppnådde rest kromatografert over 1600 g aluminiumoksyd (nøytral, aktivitet II-III) med metylenklorid og deretter kromatografert med økende andeler etanol (inntil 1%). Utbytte: 144,5 g (90% av det teoretiske). A mixture of 128.8 g (0.55 mol) 6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carbaldehyde, 125 ml (1.38 mol) acrylic acid methyl ester and 82.5 ml (0.6 mol) of triethylamine was boiled under reflux for 6 hours. It was then evaporated in vacuo and the residue obtained chromatographed over 1600 g of alumina (neutral, activity II-III) with methylene chloride and then chromatographed with increasing proportions of ethanol (up to 1%). Yield: 144.5 g (90% of the theoretical).

Smeltepunkt: 104-106°C. Melting point: 104-106°C.

Eksempel C Example C

3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-propionsvre 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-propionic acid

169 g (0,578 mol) 3-(6,7-dimetoksy-l,2,3,4-tetrahydro-naftalen-2-yl)-propionsyremetylester ble suspendert i 1,5 liter 8% natronlut og kokt under tilbakeløpskjøling i 90 minutter. Deretter ble blandingen helt på is og surgjort med konsentrert saltsyre. Det resulterende bunnfall ble frafiltrert under sug. Utbytte: 152,1 g (94,5% av det teoretiske). 169 g (0.578 mol) of 3-(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propionic acid methyl ester was suspended in 1.5 liters of 8% caustic soda and boiled under reflux for 90 minutes . The mixture was then poured onto ice and acidified with concentrated hydrochloric acid. The resulting precipitate was filtered off under suction. Yield: 152.1 g (94.5% of the theoretical).

Smeltepunkt: 156-158°C. Melting point: 156-158°C.

Eksempel D Example D

3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N-( 2 -( 3. 4- dimetoksyfenvl)- etyl)- N- metyl- propionsyreamid 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(3.4-dimethoxyphenyl)-ethyl)-N-methyl- propionic acid amide

8,35 g (0,03 mol) 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-propionsyreamid ble suspendert i 120 ml etylacetat og under omrøring i 60 minutter tilsatt 4,86 g (0,03 mol) N,N'-karbonyldiimidazol. Til denne suspensjon ble det tilsatt 5,86 g (0,030 mol) N-metyl-homoveratrylamin, oppløst i 30 ml etylacetat. Etter 1 time ble det ekstrahert med 2x8% natronlut. Den organiske fase ble tørket over magnesiumsulfat og inndampet i vakuum. 8.35 g (0.03 mol) of 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-propionic acid amide was suspended in 120 ml of ethyl acetate and with stirring for 60 minutes added 4.86 g (0.03 mol) N,N'-carbonyldiimidazole. To this suspension was added 5.86 g (0.030 mol) of N-methyl homoveratrylamine, dissolved in 30 ml of ethyl acetate. After 1 hour, it was extracted with 2x8% caustic soda. The organic phase was dried over magnesium sulfate and evaporated in vacuo.

Utbytte: 12,4 g (91% av det teoretiske). Yield: 12.4 g (91% of theoretical).

Rf-verdi: 0,8 (aluminiumoksyd, nøytral; elueringsmiddel: 3% etanol i metylenklorid). Rf value: 0.8 (alumina, neutral; eluent: 3% ethanol in methylene chloride).

Eksempel E Example E

3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N-( 2-( 4- benzyloksvfenvl)- etyl)- N- metyl- propionsvreamid 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4-benzyloxyphenyl)-ethyl)-N-methyl- propionamide

Fremstillet analogt med Eksempel D fra 3-(6,7-dimetoksy-l-okso-l, 2 ,3,4-tetrahydronaftalen-2-yl)-propionsyre, N,N'-karbonyldiimidazol og N-metyl-(2-(4-benzyloksyfenyl)-etylamin. Utbytte: 91% av det teoretiske. Prepared analogously to Example D from 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-propionic acid, N,N'-carbonyldiimidazole and N-methyl-(2- (4-Benzyloxyphenyl)-ethylamine Yield: 91% of theory.

Smeltepunkt: 126-128°C. Melting point: 126-128°C.

Eksempel F Example F

3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N-( 2- f4- nitrofenyl)- etyl)- N- metyl- propionsvreamid 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-f4-nitrophenyl)-ethyl)-N-methyl-propion amide

Fremstillet analogt med Eksempel D fra 3-(6,7-dimetoksy-l-okso-l ,2,3,4-tetrahydronaftalen-2-yl)-propionsyre, N,N'-karbonyldiimidazol og N-metyl-2-(4-nitrofenyl)-etylamin. Utbytte: 87,8% av det teoretiske. Prepared analogously to Example D from 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-propionic acid, N,N'-carbonyldiimidazole and N-methyl-2-( 4-nitrophenyl)ethylamine. Yield: 87.8% of the theoretical.

Smeltepunkt: 128-130°C. Melting point: 128-130°C.

Eksempel G Example G

3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N-( 2-( 4- aminofenyl)- etyl)- N- metyl- propionsyreamid 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4- aminophenyl)-ethyl)- N- methyl- propionic acid amide

10,0 g (0,023 mol) 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N-(2-(4-nitrofenyl)-etyl)-N-metyl)-propionsyreamid i 120 ml metanol ble hydrert i 2 timer ved romtemperatur i nærvær av 1,0 g 10% palladium/kull under et hydrogentrykk på 5 bar. Deretter ble katalysatoren frafiltrert under sug og metanolen avdestillert i vakuum. 10.0 g (0.023 mol) 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4-nitrophenyl)-ethyl)- N-methyl)-propionic acid amide in 120 ml of methanol was hydrogenated for 2 hours at room temperature in the presence of 1.0 g of 10% palladium/charcoal under a hydrogen pressure of 5 bar. The catalyst was then filtered off under suction and the methanol distilled off in a vacuum.

Utbytte: 9,3 g (100% av det teoretiske). Yield: 9.3 g (100% of theoretical).

Rf-verdi: 0,4 (aluminiumoksyd, nøytral; elueringsmiddel: 3% etanol i metylenklorid). Rf value: 0.4 (alumina, neutral; eluent: 3% ethanol in methylene chloride).

Eksempel H Example H

5. 6- dimetoksy- l- okso- indan- 2- karbaldehvd 5. 6- dimethoxy- l- oxo- indan- 2- carbald hvd

Fremstillet analogt med Eksempel A fra 5,6-dimetoksy-l-okso-indan. Prepared analogously to Example A from 5,6-dimethoxy-1-oxo-indane.

Utbytte: 81% av det teoretiske. Yield: 81% of the theoretical.

Smeltepunkt: 145-147°C. Melting point: 145-147°C.

Eksempel I Example I

3-( 5. 6- dimetoksy- l- okso- indan- 2- yl)- propionsyre- metylester 3-(5.6-dimethoxy-l-oxo-indan-2-yl)- propionic acid methyl ester

Fremstillet fra 5,6-dimetoksy-l-okso-indan-2-karbaldehyd og akrylsyre-metylester, analogt med Eksempel B. Prepared from 5,6-dimethoxy-1-oxo-indan-2-carbaldehyde and acrylic acid methyl ester, analogously to Example B.

Utbytte: 38% av det teoretiske. Yield: 38% of the theoretical.

Smeltepunkt: 59-62°C. Melting point: 59-62°C.

Eksempel K Example K

3-( 5. 6- dimetoksy- l- okso- indan- 2- yl)- propionsyre 3-(5.6-dimethoxy-l-oxo-indan-2-yl)-propionic acid

Fremstillet fra 3-(5,6-dimetoksy-l-okso-indan-2-yl)-propionsyre-metylester, analogt med Eksempel C. Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2-yl)-propionic acid methyl ester, analogously to Example C.

Utbytte: 60% av det teoretiske. Yield: 60% of the theoretical.

Smeltepunkt: 146-148°C. Melting point: 146-148°C.

Eksempel L Example L

3-(5,6-dimetoksy-l-okso-indan-2-yl)-N-(2-(3,4-dimetoksy-fenyl)- etvl)- N- metylpropionsyreamid 3-(5,6-dimethoxy-1-oxo-indan-2-yl)-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-N-methylpropionic acid amide

Fremstillet fra 3-(5,6-dimetoksy-i-okso-indan-2-yl)-propionsyre og N-metylhomoveratrylamin, analogt med Eksempel D. Utbytte: 83% av det teoretiske. Prepared from 3-(5,6-dimethoxy-i-oxo-indan-2-yl)-propionic acid and N-methylhomoveratrylamine, analogously to Example D. Yield: 83% of the theoretical.

Rf-verdi: 0,48 (aluminiumoksyd N; metylenklorid +2% etanol) Rf value: 0.48 (alumina N; methylene chloride +2% ethanol)

Eksempel M Example M

6. 7- dimetoksy- 2-( 3- metylaminopropyl)- 1. 2. 3. 4- tetrahydronaftalen 6. 7- dimethoxy- 2-( 3- methylaminopropyl)- 1. 2. 3. 4- tetrahydronaphthalene

a) 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N- metylpropionsyreamid a) 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methylpropionic acid amide

8,35 g (0,03 mol) 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-propionsyre ble suspendert i 120 ml etylacetat og under omrøring i 30 minutter ved 50°C tilsatt 4,86 g (0,03 mol) N,N'-karbonyldiimidazol. Til denne suspensjon ble det i løpet av 3 0 minutter ledet inn 4,65 g (0,15 mol) metylamin. Deretter ble omrøringen fortsatt i 30 minutter til, hvorpå bunnfallet suget av og vasket med kald etylacetat. Utbytte: 6,9 g (79% av det teoretiske). 8.35 g (0.03 mol) of 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-propionic acid was suspended in 120 ml of ethyl acetate and with stirring for 30 minutes at 50°C added 4.86 g (0.03 mol) N,N'-carbonyldiimidazole. 4.65 g (0.15 mol) of methylamine were introduced into this suspension over 30 minutes. Stirring was then continued for another 30 minutes, after which the precipitate was suctioned off and washed with cold ethyl acetate. Yield: 6.9 g (79% of theoretical).

Smeltepunkt: 160-161°C. Melting point: 160-161°C.

Beregnet: C, 65,96; H, 7,27; N, 4,81 Calcd: C, 65.96; H, 7.27; N, 4.81

Funnet: C, 66,15; H, 7,29; N, 4,96 Found: C, 66.15; H, 7.29; N, 4.96

b) 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen b) 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene

6,7 g (0,023 mol) 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N-metyl-propionsyreamid ble suspendert i 80 ml tetrahydrofuran. Deretter ble 3,26 g (0,023 mol) bortrifluorid-eterat tilsatt under nitrogen og det hele oppvarmet til 60°C. Ved denne temperatur ble 5,8 ml (0,058 mol) boran-dimetylsulf idkompleks (10 molar oppløsning) dryppet inn, hvorpå blandingen ble kokt i 5 timer under tilbakeløpskjøling. Den avkjølte reaksjonsblanding ble dråpevis tilsatt metanol, og deretter ble 10 ml metanolisk saltsyre tilsatt og kokingen fortsatt under tilbakeløpskjøling i 2 timer. Reaksjonsblandingen ble etter fordampning av oppløsningsmidlet tatt opp i 2 molar natronlut og utristet med etylacetat. De organiske fasene ble 6.7 g (0.023 mol) of 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-methyl-propionic acid amide was suspended in 80 ml of tetrahydrofuran. Then 3.26 g (0.023 mol) of boron trifluoride etherate was added under nitrogen and the whole heated to 60°C. At this temperature, 5.8 ml (0.058 mol) of borane-dimethylsulfide complex (10 molar solution) was added dropwise, after which the mixture was boiled for 5 hours under reflux. Methanol was added dropwise to the cooled reaction mixture, and then 10 ml of methanolic hydrochloric acid was added and the boiling continued under reflux for 2 hours. After evaporation of the solvent, the reaction mixture was taken up in 2 molar sodium hydroxide solution and shaken out with ethyl acetate. The organic phases were

tørket over magnesiumsulfat og inndampet i vakuum, hvorpå residuet ble renset over aluminiumoksyd (nøytral, aktivitet II-III) med metylenklorid og økende andeler metanolisk ammoniakk. Utbytte: 33% av det teoretiske. dried over magnesium sulfate and evaporated in vacuo, after which the residue was purified over aluminum oxide (neutral, activity II-III) with methylene chloride and increasing proportions of methanolic ammonia. Yield: 33% of the theoretical.

Rf-verdi: 0,15 (aluminiumoksyd, nøytral, elueringsmiddel: 3% etanol i metylenklorid). Rf value: 0.15 (alumina, neutral, eluent: 3% ethanol in methylene chloride).

Eksempel N Example N

6. 7- dimetoksy- 2-( 3- brompropyl- l)- 1. 2. 3. 4- tetrahydronaftalen 6. 7- dimethoxy- 2-( 3- bromopropyl-1)- 1. 2. 3. 4- tetrahydronaphthalene

a) 3-(6,7-dimetoksy-l,2,3,4-tetrahydronaftalen-2-yl)-propanol- 1 a) 3-(6,7-dimethoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-propanol-1

Fremstillet analogt med Eksempel Mb fra 3-(6,7-dimetoksy-l-okso-l, 2 ,3,4-tetrahydronaftalen-2-yl)-propionsyre. Prepared analogously to Example Mb from 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-propionic acid.

Utbytte: 84% av det teoretiske, Yield: 84% of the theoretical,

Rf-verdi: 0,4 (kiselgel-ferdigplater Macherey-Nagel, Polygram, elueringsmiddel: 3% etanol i metylenklorid). Rf value: 0.4 (silica gel ready plates Macherey-Nagel, Polygram, eluent: 3% ethanol in methylene chloride).

b) 6,7-dimetoksy-2-(3-brompropyl-l)-1,2,3,4-tetrahydro-naftalen b) 6,7-dimethoxy-2-(3-bromopropyl-1)-1,2,3,4-tetrahydro-naphthalene

3,8 g (0,0152 mol) 3-(6,7-dimetoksy-l,2,3,4-tetrahydro-naftalen-2-yl)-propanol-1 ble oppløst i 40 ml toluen. Deretter ble 1,57 ml (0,0167 mol) fosfortribromid oppløst i 5 ml toluen tilsatt dråpevis i løpet av 30 minutter. Blandingen ble omrørt videre ved romtemperatur i 1 time, hvorpå den ble tilsatt vann under iskjøling og deretter ekstrahert 3 ganger med etylacetat. De samlede organiske fasene ble tørket over magnesiumsulfat, filtrert og inndampet i vakuum. 3.8 g (0.0152 mol) of 3-(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propanol-1 was dissolved in 40 ml of toluene. Then 1.57 ml (0.0167 mol) of phosphorus tribromide dissolved in 5 ml of toluene was added dropwise over 30 minutes. The mixture was stirred further at room temperature for 1 hour, after which water was added under ice-cooling and then extracted 3 times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and evaporated in vacuo.

Utbytte: 4,4 g (92% av det teoretiske). Yield: 4.4 g (92% of theoretical).

Rf-verdi: 0,9 (kiselgel-ferdigplater, Macherey-Nagel, elueringsmiddel: metylenklorid). Rf value: 0.9 (silica gel ready plates, Macherey-Nagel, eluent: methylene chloride).

Eksempel 1 Example 1

6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl1- 1- hydroksy- l. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1- hydroxy- l. 2. 3. 4- tetrahydronaphthalene

Til 1,60 g (0,042 mol) litiumaluminiumhydrid i 150 ml tørr tetrahydrofuran ble det dråpevis tilsatt 9,6 g (0,021 mol) 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetrahydronaftalen-2-yl)-N-(2-(3,4-dimetoksy-fenyl)-etyl)-N-metyl-propionsyreamid, oppløst i 50 ml tørr tetrahydrofuran. Blandingen ble deretter kokt under tilbakeløpskjøling i 1 time, og så under kjøling med isvann tilsatt 1,6 ml vann, 1,6 ml 15% natronlut og 5 ml vann. Bunnfallet ble frafiltrert under sug og vasket med tetrahydrofuran, hvorpå filtratet ble inndampet i vakuum. To 1.60 g (0.042 mol) of lithium aluminum hydride in 150 ml of dry tetrahydrofuran, 9.6 g (0.021 mol) of 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalene- 2-yl)-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-N-methyl-propionic acid amide, dissolved in 50 ml of dry tetrahydrofuran. The mixture was then boiled under reflux for 1 hour, and then under cooling with ice water added 1.6 ml of water, 1.6 ml of 15% caustic soda and 5 ml of water. The precipitate was filtered off under suction and washed with tetrahydrofuran, after which the filtrate was evaporated in vacuo.

Utbytte: 5,0 g (50% av det teoretiske). Yield: 5.0 g (50% of the theoretical).

Olje, Rf-verdi: 0,61 (aluminiumoksyd, elueringsmiddel: 3% etanol i metylenklorid). Oil, Rf value: 0.61 (alumina, eluent: 3% ethanol in methylene chloride).

Beregnet: C, 70,40; H, 8,41; N, 3,16 Calculated: C, 70.40; H, 8.41; N, 3.16

Funnet: C, 70,26; H, 8,33; N, 3,05 Found: C, 70.26; H, 8.33; N, 3.05

Eksempel 2 Example 2

6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahvdronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

Til en oppløsning av 2,73 g (0,006 mol) 3-(6,7-dimetoksy-l-okso-l, 2 ,3,4-tetrahydronaftalen-2-yl)-N-(2-(3,4-dimetoksy-fenyl)-etyl)-N-metyl-propionsyreamid i 30 ml absolutt tetrahydrofuran ble det under nitrogen dråpevis tilsatt 0,74 ml (0,006 mol) bortrifluorid-eterat og deretter 1,5 ml (0,015 mol) borandimetylsulfidkompleks (10 molar oppløsning). Blandingen ble deretter kokt i 6 timer under tilbakeløpskjøling. Den avkjølte reaksjonsblandingen ble dråpevis tilsatt metanol og deretter tilsatt 5 ml metanolisk saltsyre og kokt under tilbakeløpskjøling i ytterligere 2 timer. Metanol og tetrahydrofuran ble avdestillert og residuet etter tilsetning av vann, nøytralisert med 2 molar natronlut. Det bløtaktige bunnfall ble ekstrahert med metylenklorid. Den organiske fase ble tørket over magnesiumsulfat, inndampet i vakuum og det oppnådde residuum renset over 120 g aluminiumoksyd (nøytral, aktivitet II-III) med metylenklorid og deretter med økende andeler etanol (inntil 0,5%). Fra en oppløsning i aceton ble hydrokloridet utfelt med metanolisk saltsyre. To a solution of 2.73 g (0.006 mol) 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-N-methyl-propionic acid amide in 30 ml of absolute tetrahydrofuran, 0.74 ml (0.006 mol) of boron trifluoride etherate and then 1.5 ml (0.015 mol) of borane dimethyl sulphide complex (10 molar solution ). The mixture was then boiled for 6 hours under reflux. Methanol was added dropwise to the cooled reaction mixture and then 5 ml of methanolic hydrochloric acid was added and boiled under reflux for a further 2 hours. Methanol and tetrahydrofuran were distilled off and the residue after addition of water, neutralized with 2 molar caustic soda. The soft precipitate was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, evaporated in vacuo and the obtained residue purified over 120 g of alumina (neutral, activity II-III) with methylene chloride and then with increasing proportions of ethanol (up to 0.5%). From a solution in acetone, the hydrochloride was precipitated with methanolic hydrochloric acid.

Utbytte: 1,24 g (44,6% av det teoretiske). Yield: 1.24 g (44.6% of the theoretical).

Smeltepunkt: 143-145°C. Melting point: 143-145°C.

Beregnet: C, 67,29; H, 8,25; N, 3,02 Calculated: C, 67.29; H, 8.25; N, 3.02

Funnet: C, 67,16; H, 8,18; N, 3,07 Found: C, 67.16; H, 8.18; N, 3.07

Eksempel 3 Example 3

6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl1- 1- okso- l. 2. 3. 4- tetrahvdronaftalen- hvdroklorid 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1- oxo- l. 2. 3. 4- tetrahydronaphthalene- hydrochloride

En blanding av 4,43 g (0,01 mol) 6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-1,2,3,4-tetrahydronaftalen, 2,80 g (0,025 mol) kalium-tert.-butylat, 9,10 g (0,05 mol) benzofenon og 100 ml toluen ble kokt under tilbakeløpskjøling i 4 timer. Den avkjølte reaksjonsblanding ble vasket 2 x med vann og deretter ekstrahert 3 x med 1% saltsyre. Saltsyrefåsene ble samlet og nøytralisert med konsentrert natronlut. Det smørje-aktige bunnfall ble ekstrahert med metylenklorid. Den organiske fase ble tørket over magnesiumsulfat, inndampet i vakuum og renset over 300 g aluminiumoksyd (nøytral, aktivitet II-III) med metylenklorid og deretter med økende andeler etanol (inntil 0,5%). Hydrokloridet ble utfelt fra en oppløsning i aceton med metanolisk saltsyre. A mixture of 4.43 g (0.01 mol) of 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1 ,2,3,4-tetrahydronaphthalene, 2.80 g (0.025 mol) of potassium tert-butylate, 9.10 g (0.05 mol) of benzophenone and 100 ml of toluene were refluxed for 4 hours. The cooled reaction mixture was washed 2x with water and then extracted 3x with 1% hydrochloric acid. The hydrochloric acid phases were collected and neutralized with concentrated caustic soda. The smear-like precipitate was extracted with methylene chloride. The organic phase was dried over magnesium sulfate, evaporated in vacuo and purified over 300 g of aluminum oxide (neutral, activity II-III) with methylene chloride and then with increasing proportions of ethanol (up to 0.5%). The hydrochloride was precipitated from a solution in acetone with methanolic hydrochloric acid.

Utbytte: 1,7 g (35,6% av det teoretiske). Yield: 1.7 g (35.6% of the theoretical).

Smeltepunkt: 160-162°C. Melting point: 160-162°C.

Beregnet: C, 65,33; H, 7,59; N, 2,93 Calculated: C, 65.33; H, 7.59; N, 2.93

Funnet: C, 65,40; H, 7,50; N, 2,77 Found: C, 65.40; H, 7.50; N, 2.77

Eksempel 4 Example 4

6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet analogt med Eksempel 2 fra 3-(6,7-dimetoksy-l-okso-l ,2,3,4-tetrahydronaftalen-2-yl)-N-(2-(4-benzyloksyfenyl)-etyl)-N-metyl-propionsyreamid. Prepared analogously to Example 2 from 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4-benzyloxyphenyl)-ethyl)-N- methyl propionic acid amide.

Utbytte: 21% av det teoretiske. Yield: 21% of the theoretical.

Smeltepunkt: 171-173°C. Melting point: 171-173°C.

Beregnet: C, 72,99; H, 7,90; N, 2,75 Calculated: C, 72.99; H, 7.90; N, 2.75

Funnet: C, 73,10; H, 8,07; N, 2,71 Found: C, 73.10; H, 8.07; N, 2.71

Eksempel 5 Example 5

6,7-dimetoksy-2-[3-((2-(4-aminofenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahvdronaftalen- dihydroklorid 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene- dihydrochloride

Fremstillet analogt med Eksempel 2 fra 3-(6,7-dimetoksy-l-okso-l, 2 ,3,4-tetrahydronaftalen-2-yl)-N-(2-(4-aminofenyl)-etyl)-N-metyl-propionsyreamid. Prepared analogously to Example 2 from 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-N-(2-(4-aminophenyl)-ethyl)-N- methyl propionic acid amide.

Utbytte: 320 mg (23% av det teoretiske). Yield: 320 mg (23% of the theoretical).

Smeltepunkt: > 220°C. Melting point: > 220°C.

Beregnet: C, 63,29; H, 7,97; N, 6,15 Calculated: C, 63.29; H, 7.97; N, 6.15

Funnet: C, 63,10; H, 7,91; N, 6,08 Found: C, 63.10; H, 7.91; N, 6.08

Eksempel 6 Example 6

6,7-dimetoksy-2-[3-((2-(4-nitrofenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((2-(4-nitrophenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene

En blanding av 1,0 g (0,0038 mol) 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen, 0,87 g (0,038 mol) 2-(4-nitrofenyl)etylbromid og 1,1 ml (0,008 mol) trietylamin ble kokt under tilbakeløpskjøling i 2 timer. Den avkjølte reaksjonsblanding ble oppløst i en blanding av 2 molar natronlut og metylenklorid. Den organiske fase ble fraskilt, vasket med vann, tørket over magnesiumsulfat, inndampet i vakuum og renset over 120 g aluminiumoksyd (nøytral, aktivitet II-III) med metylenklorid og deretter med økende andeler etanol (inntil 0,8%). A mixture of 1.0 g (0.0038 mol) 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene, 0.87 g (0.038 mol) 2-(4- nitrophenyl)ethyl bromide and 1.1 ml (0.008 mol) of triethylamine were refluxed for 2 hours. The cooled reaction mixture was dissolved in a mixture of 2 molar caustic soda and methylene chloride. The organic phase was separated, washed with water, dried over magnesium sulfate, evaporated in vacuo and purified over 120 g of alumina (neutral, activity II-III) with methylene chloride and then with increasing proportions of ethanol (up to 0.8%).

Utbytte: 210 mg (16% av det teoretiske). Yield: 210 mg (16% of the theoretical).

Olje, Rf-verdi: 0,69 (aluminiumoksyd, elueringsmiddel: 2% Oil, Rf value: 0.69 (alumina, eluent: 2%

etanol i metylenklorid). ethanol in methylene chloride).

Beregnet: C, 69,88; H, 7,82; N, 6,79 Calcd: C, 69.88; H, 7.82; N, 6.79

Funnet: C, 69,87; H, 7,61; N, 6,67 Found: C, 69.87; H, 7.61; N, 6.67

Eksempel 7 Example 7

6,7-dimetoksy-2-[3-((2-(4-acetaminofenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahvdronaftalen- hvdroklorid 6,7-dimethoxy-2-[3-((2-(4-acetaminophenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene- hydrochloride

0,76 g (0,002 mol) 6,7-dimetoksy-2-[3-((2-(4-aminofenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen og 0,3 ml (0,0022 mol) trietylamin ble oppløst 10 ml metylenklorid og under omrøring dråpevis tilsatt 0,16 ml (0,0022 mol) acetyl-klorid. Etter 30 minutter ble det tilsatt vann, hvorpå den vandige fase ble ekstrahert 3 x med metylenklorid. Den organiske fase ble tørket over magnesiumsulfat og inndampet i vakuum. Fra en oppløsning av det oppnådde residuum i aceton ble hydrokloridet utfelt med eterisk saltsyre. 0.76 g (0.002 mol) of 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and 0, 3 ml (0.0022 mol) of triethylamine was dissolved in 10 ml of methylene chloride and, with stirring, 0.16 ml (0.0022 mol) of acetyl chloride was added dropwise. After 30 minutes, water was added, after which the aqueous phase was extracted 3 x with methylene chloride. The organic phase was dried over magnesium sulfate and evaporated in vacuo. From a solution of the obtained residue in acetone, the hydrochloride was precipitated with ethereal hydrochloric acid.

Utbytte: 0,25 g (27% av det teoretiske). Yield: 0.25 g (27% of the theoretical).

Smeltepunkt: 129-131°C. Melting point: 129-131°C.

Beregnet: C, 67,73; H, 8,09; N, 6,08; Cl, 7,69 Calculated: C, 67.73; H, 8.09; N, 6.08; Cl, 7.69

Funnet: C, 67,60; H, 8,45; N, 5,89; Cl, 7,73 Found: C, 67.60; H, 8.45; N, 5.89; Cl, 7.73

Eksempel 8 Example 8

6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene

9,1 g (0,019 mol) 6,7-dimetoksy-2-[3-((2-(4-benzyloksy-fenyl) -etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen i 100 ml iseddik, ble hydrert i nærvær av 1,2 g 10% palladium/- kull i 5 timer ved romtemperatur under 5 bar hydrogen. Deretter ble katalysatoren frafiltrert og iseddikken avdestillert i vakuum. Det oppnådde residuum ble tilsatt 10% natronlut og ekstrahert 3 x med etylacetat. Den organiske fase ble tørket over magnesiumsulfat og inndampet i vakuum. 9.1 g (0.019 mol) 6,7-dimethoxy-2-[3-((2-(4-benzyloxy-phenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene in 100 ml of glacial acetic acid was hydrated in the presence of 1.2 g of 10% palladium/charcoal for 5 hours at room temperature under 5 bar of hydrogen. The catalyst was then filtered off and the glacial acetic acid distilled off in vacuum. The obtained residue was added to 10% caustic soda and extracted 3 times with ethyl acetate. The organic phase was dried over magnesium sulfate and evaporated in vacuo.

Utbytte: 6,1 g (83% av det teoretiske). Yield: 6.1 g (83% of the theoretical).

Smeltepunkt: 90-91°C. Melting point: 90-91°C.

Beregnet: C, 75,16; H, 8,67; N, 3,65 Calculated: C, 75.16; H, 8.67; N, 3.65

Funnet: C, 75,00; H, 8,79; N, 3,73 Found: C, 75.00; H, 8.79; N, 3.73

Eksempel 9 Example 9

6,7-dimetoksy-2-[3-((2-(4-metansulfonyloksyfenyl)-etyl)-metyl-amino) - propyl1- 1. 2. 3. 4- tetrahydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-methanesulfonyloxyphenyl)-ethyl)-methyl-amino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

0,96 g (0,0025 mol) 6,7-dimetoksy-2-[3-((2-(4-hydroksy-fenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen ble oppløst i 5 ml pyridin og under omrøring dråpevis tilsatt 0,27 ml (0,0035 mol) metansulfonsyreklorid. Etter 1 time ble det tilsatt 10% natronlut. Den vandige fase ble ekstrahert 3 x med metylenklorid. Den organiske fase ble tørket over magnesiumsulfat, inndampet i vakuum og renset over 80 g aluminiumoksyd (nøytral, aktivitet II-III) med metylenklorid. Det oppnådde residuum ble tatt opp i eter og hydrokloridet utfelt med eterisk saltsyre. 0.96 g (0.0025 mol) 6,7-dimethoxy-2-[3-((2-(4-hydroxy-phenyl)-ethyl)-methylamino)-propyl]-1,2,3,4- tetrahydronaphthalene was dissolved in 5 ml of pyridine and, with stirring, 0.27 ml (0.0035 mol) methanesulfonic acid chloride was added dropwise. After 1 hour, 10% caustic soda was added. The aqueous phase was extracted 3x with methylene chloride. The organic phase was dried over magnesium sulfate, evaporated in vacuo and purified over 80 g of aluminum oxide (neutral, activity II-III) with methylene chloride. The residue obtained was taken up in ether and the hydrochloride precipitated with ethereal hydrochloric acid.

Utbytte: 0,38 g (31% av det teoretiske). Yield: 0.38 g (31% of theoretical).

Smeltepunkt: 145-146°C. Melting point: 145-146°C.

Beregnet: C, 60,29; H, 7,29; N, 2,81; S, 6,44; Cl, 7,12 Funnet: C, 60,35; H, 7,38; N, 2,85; S, 6,27; Cl, 7,39 Calculated: C, 60.29; H, 7.29; N, 2.81; S, 6.44; Cl, 7.12 Found: C, 60.35; H, 7.38; N, 2.85; S, 6.27; Cl, 7.39

Eksempel 10 Example 10

6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahvdronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet analogt med Eksempel 6 fra 6,7-dimetoksy-2-(3-bromfenyl)-1,2,3,4-tetrahydronaftalen og N-metyl-(4-benzyloksy-fenyl) -etylamin. Prepared analogously to Example 6 from 6,7-dimethoxy-2-(3-bromophenyl)-1,2,3,4-tetrahydronaphthalene and N-methyl-(4-benzyloxy-phenyl)-ethylamine.

Utbytte: 43% av det teoretiske. Yield: 43% of the theoretical.

Smeltepunkt: 171-173°C. Melting point: 171-173°C.

Eksempel 11 Example 11

6,7-dimetoksy-2-[3-((2-(4-trifluormetansulfonyloksyfenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydro-naf talen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-trifluoromethanesulfonyloxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydro-naphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen og trifluormetansulfonsyreklorid, analogt med Eksempel 9. Utbytte: 69% av det teoretiske. Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and trifluoromethanesulfonic acid chloride, analogously to Example 9. Yield : 69% of the theoretical.

Smeltepunkt: 135-137°C. Melting point: 135-137°C.

Beregnet: C, 54,39; H, 6,03; N, 2,54; Cl, 6,42; S, 5,81 Funnet: C, 54,34; H, 6,28; N, 2,74; Cl, 6,69; S, 6,05 Calculated: C, 54.39; H, 6.03; N, 2.54; Cl, 6.42; S, 5.81 Found: C, 54.34; H, 6.28; N, 2.74; Cl, 6.69; S, 6.05

Eksempel 12 Example 12

6,7-dimetoksy-2-[3-((2-(4-cyanometoksyfenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahydronaftalen- hydrogentartrat 6,7-dimethoxy-2-[3-((2-(4-cyanomethoxyphenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene- hydrogen tartrate

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen og kloracetonitril, analogt med Eksempel 16. Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and chloroacetonitrile, analogously to Example 16.

Utbytte: 31% av det teoretiske. Yield: 31% of the theoretical.

Smeltepunkt: 63-68°C. Melting point: 63-68°C.

Beregnet: C, 62,92; H, 7,04 ; N, 4,89 Calcd: C, 62.92; H, 7.04; N, 4.89

Funnet: C, 62,64; H, 7,01; N, 4,80 Found: C, 62.64; H, 7.01; N, 4.80

Eksempel 13 Example 13

6,7-dimetoksy-2-[3-((2-(4-trifluormetoksyfenyl)-etyl)-metyl-amino)- propyl1- 1. 2. 3. 4- tetrahydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-trifluoromethoxyphenyl)-ethyl)-methyl-amino)- propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen og 2-(4-trifluormetoksyfenyl)-etylbromid, analogt med Eksempel 6. Prepared from 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene and 2-(4-trifluoromethoxyphenyl)-ethyl bromide, analogously to Example 6.

Utbytte: 50% av det teoretiske. Yield: 50% of the theoretical.

Smeltepunkt: 124-125°C. Melting point: 124-125°C.

Beregnet: C, 61,53; H, 6,82; N, 2,87; Cl, 7,27 Calculated: C, 61.53; H, 6.82; N, 2.87; Cl, 7.27

Funnet: C, 61,43; H, 7,03; N, 2,85; Cl, 7,55 Found: C, 61.43; H, 7.03; N, 2.85; Cl, 7.55

Eksempel 14 Example 14

6,7-dimetoksy-2-[3-((2-(4-metansulfonylaminofenyl)-etyl)-metylamino)- propyl1- 1. 2. 3. 4- tetrahydronaftalen- hydroklorid Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-aminofenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen og metansulfonsyreklorid, analogt med Eksempel 7. 6,7-dimethoxy-2-[3-((2-(4-methanesulfonylaminophenyl)-ethyl)-methylamino)- propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride Prepared from 6,7-dimethoxy-2- [3-((2-(4-aminophenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and methanesulfonic acid chloride, analogously to Example 7.

Utbytte: 30% av det teroetiske. Yield: 30% of the teroethical.

Smeltepunkt: 177-179°C. Melting point: 177-179°C.

Beregnet: C, 60,40; H, 7,50; N, 5,64 Calculated: C, 60.40; H, 7.50; N, 5.64

Funnet: C, 60,60; H, 7,61; N, 5,70 Found: C, 60.60; H, 7.61; N, 5.70

Eksempel 15 Example 15

6,7-dimetoksy-2-[3-((2-(4-metoksykarbonylaminofenyl)-etyl)-metylamino)- propyl]- 1. 2. 3. 4- tetrahydronaftalen- hydrogenfumarat 6,7-dimethoxy-2-[3-((2-(4-methoxycarbonylaminophenyl)-ethyl)-methylamino)- propyl]- 1. 2. 3. 4- tetrahydronaphthalene- hydrogen fumarate

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-aminofenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen og klormaursyremetylester, analogt med Eksempel 7. Prepared from 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and chloroformic acid methyl ester, analogously to Example 7.

Utbytte: 23% av det teoretiske. Yield: 23% of the theoretical.

Smeltepunkt: 156-160°C (dekomp.). Melting point: 156-160°C (decomp.).

Beregnet: C, 64,73; H, 7,24; N, 5,03 Calculated: C, 64.73; H, 7.24; N, 5.03

Funnet: C, 65,03; H, 7,08; N, 5,20 Found: C, 65.03; H, 7.08; N, 5.20

Eksempel 16 Example 16

6,7-dimetoksy-2-[3-((2-(4-etoksykarbonylmetoksyfenyl)-etyl)-metylamino)- propyl1- 1. 2. 3. 4- tetrahvdronaftalen- hvdroklorid 6,7-dimethoxy-2-[3-((2-(4-ethoxycarbonylmethoxyphenyl)-ethyl)-methylamino)- propyl1- 1. 2. 3. 4- tetrahydronaphthalene- hydrochloride

En blanding av 1,15 g (0,003 mol) 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydro-naftalen, 0,34 g (0,003 mol) kalium-tert.-butylat og 10 ml dimetylsulfoksyd ble oppvarmet i 1 time til 50°C. Deretter ble 0,5 g (0,003 mol) bromeddiksyreetylester tilsatt og blandingen oppvarmet igjen til 50°C i 1 time. Den avkjølte reaksjonsblandingen ble tilsatt vann og ekstrahert med etylacetat. Den organiske fase ble tørket over magnesiumsulfat, inndampet i vakuum og renset over 60 g kiselgel (32-63 lm, Fa. Woelm) med metylenklorid og deretter med økende andeler etanol (inntil 3%). Hydrokloridet ble utfelt med metanolisk saltsyre fra en oppløsning i aceton. A mixture of 1.15 g (0.003 mol) of 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydro -naphthalene, 0.34 g (0.003 mol) of potassium tert-butylate and 10 ml of dimethylsulfoxide were heated for 1 hour at 50°C. Then 0.5 g (0.003 mol) bromoacetic acid ethyl ester was added and the mixture was heated again to 50°C for 1 hour. The cooled reaction mixture was added to water and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate, evaporated in vacuo and purified over 60 g of silica gel (32-63 lm, Fa. Woelm) with methylene chloride and then with increasing proportions of ethanol (up to 3%). The hydrochloride was precipitated with methanolic hydrochloric acid from a solution in acetone.

Utbytte: 0,2 g (13% av det teoretiske). Yield: 0.2 g (13% of the theoretical).

Smeltepunkt: 134-136°C. Melting point: 134-136°C.

Beregnet: C, 66,45; H, 7,97; N, 2,77; Cl, 7,01 Calcd: C, 66.45; H, 7.97; N, 2.77; Cl, 7.01

Funnet: C, 66,31; H, 7,91; N, 2,74; Cl, 7,15 Found: C, 66.31; H, 7.91; N, 2.74; Cl, 7.15

Eksempel 17 Example 17

6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl1- 1. 2- dihydronaftalen- hvdroklorid 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1. 2- dihydronaphthalene hydrochloride

5,0 g (0,011 mol) 6,7-dimetoksy-2-[3-((2-(3,4-dimetoksy-fenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydro-naftalen ble oppløst i 40 ml aceton og tilsatt metanolisk saltsyre. Blandingen ble omrørt ved romtemperatur i 30 minutter og deretter dråpevis tilsatt eter inntil en lett blakking oppsto, og igjen omrørt i 30 minutter. Det utfelte bunnfall ble frafiltrert under sug og tørket. 5.0 g (0.011 mol) 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxy-phenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2, 3,4-tetrahydro-naphthalene was dissolved in 40 ml of acetone and methanolic hydrochloric acid was added. The mixture was stirred at room temperature for 30 minutes and then ether was added dropwise until a slight clouding occurred, and again stirred for 30 minutes. The precipitate was filtered off under suction and dried.

Utbytte: 4,8 g (92% av det teoretiske). Yield: 4.8 g (92% of theoretical).

Smeltepunkt: 171-172°C. Melting point: 171-172°C.

Beregnet: C, 67,59; H, 7,85; N, 3,03 Calculated: C, 67.59; H, 7.85; N, 3.03

Funnet: C, 67,51; H, 8,06; N, 3,27 Found: C, 67.51; H, 8.06; N, 3.27

Eksempel 18 Example 18

6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl1- 1- hvdroksv- indan 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1- hydroxyvindan

Fremstillet fra 3-(5,6-dimetoksy-l-okso-indan-2-yl)-N-(2-(3,4-dimetoksyfenyl)-etyl)-N-metylpropionsyreamid, analogt med Eksempel 1. Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2-yl)-N-(2-(3,4-dimethoxyphenyl)-ethyl)-N-methylpropionic acid amide, analogously to Example 1.

Utbytte: 58% av det teoretiske. Yield: 58% of the theoretical.

Smeltepunkt: 83-85°C. Melting point: 83-85°C.

Beregnet: C, 69,90; H, 8,11; N, 3,26 Calculated: C, 69.90; H, 8.11; N, 3.26

Funnet: C, 69,18; H, 8,19; N, 3,13 Found: C, 69.18; H, 8.19; N, 3.13

Eksempel 19 Example 19

5.6- dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl1- 1- okso- indan 5.6- dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1- oxo-indane

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(3,4-dimetoksy-fenyl)etyl)-metylamino)-propyl]-l-hydroksy-indan og benzofenon, analogt med Eksempel 3. Prepared from 5,6-dimethoxy-2-[3-((2-(3,4-dimethoxy-phenyl)ethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 3.

Utbytte: 16% av det teoretiske. Yield: 16% of the theoretical.

Smeltepunkt: 98-100°C. Melting point: 98-100°C.

Beregnet: C, 64,71; H, 7,39; N, 3,02 Calculated: C, 64.71; H, 7.39; N, 3.02

Funnet: C, 64,80; H, 7,39; N, 2,95 Found: C, 64.80; H, 7.39; N, 2.95

Eksempel 20 Example 20

6.7- dimetoksy-2-[3-((2-(4-hydroksykarbonylmetoksyfeny1)-etyl)-metylamino)- propyl1- 1. 2. 3. 4- tetrahydronaftalen 6.7- dimethoxy-2-[3-((2-(4-hydroxycarbonylmethoxyphenyl)-ethyl)-methylamino)- propyl1- 1. 2. 3. 4- tetrahydronaphthalene

En oppløsning av 700 mg (0,014 mol) 6,7-dimetoksy-2-[3-((2-(4-etoksykarbonylmetoksyfenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen i 10 ml metanol ble dråpevis tilsatt 4,1 ml 0,1N natronlut, omrørt ved romtemperatur i 25 minutter og tilslutt tilsatt 4,1 ml 0,1N saltsyre. Oppløsningen ble ekstrahert flere ganger med etylacetat, og etter tørking av de samlede organiske faser over magnesiumsulfat, inndampet i vakuum. Residuet ble tatt opp med litt metylenklorid og filtrert, hvorpå filtratet ble inndampet til tørrhet. A solution of 700 mg (0.014 mol) of 6,7-dimethoxy-2-[3-((2-(4-ethoxycarbonylmethoxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene in 10 ml of methanol was added dropwise to 4.1 ml of 0.1N caustic soda, stirred at room temperature for 25 minutes and finally 4.1 ml of 0.1N hydrochloric acid was added. The solution was extracted several times with ethyl acetate and, after drying the combined organic phases over magnesium sulphate, evaporated in vacuo. The residue was taken up with a little methylene chloride and filtered, after which the filtrate was evaporated to dryness.

Utbytte: 240 mg (36% av det teoretiske). Yield: 240 mg (36% of the theoretical).

Smeltepunkt: 71°C. Melting point: 71°C.

Beregnet: C, 70,72; H, 7,99; N, 3,17 Calculated: C, 70.72; H, 7.99; N, 3.17

Funnet: C, 70,49; H, 7,74; N, 3,06 Found: C, 70.49; H, 7.74; N, 3.06

Eksempel 21 Example 21

6,7-dimetoksy-2-[3-((2-(4-N,N-bis-metansulfonylamino)-fenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydro-naftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-N,N-bis-methanesulfonylamino)-phenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydro-naphthalene - hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-aminofenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen og metansulfonsyreklorid, analogt med Eksempel 14. Prepared from 6,7-dimethoxy-2-[3-((2-(4-aminophenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydronaphthalene and methanesulfonic acid chloride, analogously to Example 14.

Utbytte: 15% av det teoretiske. Yield: 15% of the theoretical.

Smeltepunkt: 106-108°C (dekomp.) Melting point: 106-108°C (decomp.)

Beregnet: C, 54,29; H, 6,83; N, 4,87 Calculated: C, 54.29; H, 6.83; N, 4.87

Funnet: C, 54,10; H, 6,77; N, 4,62 Found: C, 54.10; H, 6.77; N, 4.62

Eksempel 22 Example 22

6,7-dimetoksy-2-[3-((3-(4-bromfenyl)-propyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahvdronaftalen- hydrogenfumarat 6,7-dimethoxy-2-[3-((3-(4-bromophenyl)-propyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene- hydrogen fumarate

Fremstillet fra 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen og 3-(4-bromfenyl)-1-brompropan, analogt med Eksempel 6. Prepared from 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene and 3-(4-bromophenyl)-1-bromopropane, analogously to Example 6.

Utbytte: 35% av det teoretiske. Yield: 35% of the theoretical.

Smeltepunkt: 59°C Melting point: 59°C

Beregnet: C, 60,42; H, 6,65; N, 2,43 Calculated: C, 60.42; H, 6.65; N, 2.43

Funnet: C, 60,10; H, 6,43; N, 2,40 Found: C, 60.10; H, 6.43; N, 2.40

Eksempel 23 Example 23

6,7-dimetoksy-2-[3-((3-(4-cyanofenyl)-propyl)-metylamino)-propyl1- 1, 2. 3. 4- tetrahvdronaftalen- hvdrogenfumarat 6,7-dimethoxy-2-[3-((3-(4-cyanophenyl)-propyl)-methylamino)-propyl1- 1, 2. 3. 4- tetrahydronaphthalene hydrogen fumarate

Fremstillet fra 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen og 3-(4-cyanofenyl)-1-brompropan, analogt med Eksempel 6. Prepared from 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene and 3-(4-cyanophenyl)-1-bromopropane, analogously to Example 6.

Utbytte: 58% av det teoretiske. Yield: 58% of the theoretical.

Smeltepunkt: fra 57°C dekomponering. Melting point: from 57°C decomposition.

Beregnet: C, 68,94; H, 7,33; N, 5,36 Calcd: C, 68.94; H, 7.33; N, 5.36

Funnet: C, 68,71; H, 7,15; N, 5,20 Found: C, 68.71; H, 7.15; N, 5.20

Eksempel 24 Example 24

6,7-dimetoksy-2-[3-((2-(4-metylsulfonylfenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahvdronaftalen 6,7-dimethoxy-2-[3-((2-(4-methylsulfonylphenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen og 2-(4-metylsulfonylfenyl)-1-brometan, analogt med Eksempel 6. Prepared from 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene and 2-(4-methylsulfonylphenyl)-1-bromoethane, analogously to Example 6.

Utbytte: 10,4% av det teoretiske. Yield: 10.4% of the theoretical.

Olje, Rf-verdi: 0,63 (aluminiumoksyd, elueringsmiddel: 3% etanol i metylenklorid). Oil, Rf value: 0.63 (alumina, eluent: 3% ethanol in methylene chloride).

Beregnet: C, 67,32; H, 7,85; N, 3,14 Calculated: C, 67.32; H, 7.85; N, 3.14

Funnet: C, 67,14; H, 7,98; N, 3,25 Found: C, 67.14; H, 7.98; N, 3.25

Eksempel 25 Example 25

6,7-dimetoksy-2-[3-((3-(4-metoksyfenyl)-propyl)-metylamino)-propvl1- 1. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((3-(4-methoxyphenyl)-propyl)-methylamino)-propvl1- 1. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen og 3-(4-metoksyfenyl)-1-brompropan, analogt med Eksempel 6. Prepared from 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene and 3-(4-methoxyphenyl)-1-bromopropane, analogously to Example 6.

Utbytte: 68,7% av det teoretiske. Yield: 68.7% of the theoretical.

Smeltepunkt: <3>9°C Melting point: <3>9°C

Beregnet: C, 75,87; H, 8,82; N, 3,40 Calculated: C, 75.87; H, 8.82; N, 3.40

Funnet: C, 75,69; H, 8,94; N, 3,59 Found: C, 75.69; H, 8.94; N, 3.59

Eksempel 26 Example 26

6,7-dimetoksy-2-[3-((2-fenyletyl)-metylamino)-propyl]-1. 2. 3. 4- tetrahvdronaftalen 6,7-Dimethoxy-2-[3-((2-phenylethyl)-methylamino)-propyl]-1. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 2-fenyl-l-kloretan og 6,7-dimetoksy-2-(3-metylaminopropyl)-1,2,3,4-tetrahydronaftalen, analogt med Eksempel 6. Prepared from 2-phenyl-1-chloroethane and 6,7-dimethoxy-2-(3-methylaminopropyl)-1,2,3,4-tetrahydronaphthalene, analogously to Example 6.

Utbytte: 42% av det teoretiske. Yield: 42% of the theoretical.

Olje, Rf-verdi: 0,42 (aluminiumoksyd, elueringsmiddel: 2% etanol i metylenklorid). Oil, Rf value: 0.42 (alumina, eluent: 2% ethanol in methylene chloride).

Beregnet: C, 78,43; H, 9,05; N, 3,81 Calculated: C, 78.43; H, 9.05; N, 3.81

Funnet: C, 78,63; H, 9,29; N, 3,66 Found: C, 78.63; H, 9.29; N, 3.66

Eksempel 27 Example 27

5,6-dimetoksy-2-[3-((4-benzyloksyfenyl)-etyl)-metylamino)-propyl1- 1- hydroksv- indan 5,6-dimethoxy-2-[3-((4-benzyloxyphenyl)-ethyl)-methylamino)-propyl1- 1- hydroxyswindane

Fremstillet fra 3-(5,6-dimetoksy-l-okso-indan-2-yl)-N-(2-(4-benzyloksyfenyl)-etyl)-N-metyl-propionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2-yl)-N-(2-(4-benzyloxyphenyl)-ethyl)-N-methyl-propionic acid amide and lithium aluminum hydride, analogously to Example 1.

Utbytte: 90% av det teoretiske. Yield: 90% of the theoretical.

Smeltepunkt: 80-83°C. Melting point: 80-83°C.

Beregnet: C, 75,76; H, 7,84; N, 2,95 Calculated: C, 75.76; H, 7.84; N, 2.95

Funnet: C, 75,58; H, 8,01; N, 2,79 Found: C, 75.58; H, 8.01; N, 2.79

Eksempel 28 Example 28

6,7-dimetoksy-2-[3-((2-(4-(2-hydroksyetoksy)-fenyl)-etyl)-metylamino)- propyl1- 1. 2. 3. 4- tetrahydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-(2-hydroxyethoxy)-phenyl)-ethyl)-methylamino)- propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-etoksykarbonyl-metoksyfenyl) -etyl)-metylamino)-propyl]-1,2,3,4-tetrahydro-naf talen og litiumaluminiumhydrid, analogt med Eksempel 1. Utbytte: 43% av det teoretiske. Prepared from 6,7-dimethoxy-2-[3-((2-(4-ethoxycarbonyl-methoxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydro-naphthalene and lithium aluminum hydride, analog with Example 1. Yield: 43% of the theoretical.

Smeltepunkt: 141-143°C. Melting point: 141-143°C.

Beregnet: C, 67,30; H, 8,25; N, 3,02; Cl, 7,64 Calculated: C, 67.30; H, 8.25; N, 3.02; Cl, 7.64

Funnet: C, 67,20; H, 8,28; N, 3,04; Cl, 7,65 Found: C, 67.20; H, 8.28; N, 3.04; Cl, 7.65

Eksempel 29 Example 29

6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl]- 1- hydroksy- l. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]- 1- hydroxy- 1. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetra-hydronaf talen-2-yl)-N-(2-(4-benzyloksyfenyl)-etyl)-N-metyl-propionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Utbytte: 53,6% av det teoretiske. Prepared from 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetra-hydronaphthalen-2-yl)-N-(2-(4-benzyloxyphenyl)-ethyl)-N-methyl -propionic acid amide and lithium aluminum hydride, analogously to Example 1. Yield: 53.6% of the theoretical.

Smeltepunkt: 75°C. Melting point: 75°C.

Beregnet: C, 70,77; H, 7,66; N, 2,66 Calculated: C, 70.77; H, 7.66; N, 2.66

Funnet: C, 71,00; H, 7,52; N, 2,56 Found: C, 71.00; H, 7.52; N, 2.56

Eksempel 30 Example 30

6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]- 1- hydroksy- l. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]- 1- hydroxy- 1. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og hydrogen, analogt med Eksempel 8. Prepared from 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrogen, analogous to Example 8.

Utbytte: 47,5% av det teoretiske. Yield: 47.5% of the theoretical.

Smeltepunkt: 97°C. Melting point: 97°C.

Beregnet: C, 72,15; H, 8,33; N, 3,51 Calculated: C, 72.15; H, 8.33; N, 3.51

Funnet: C, 72,14; H, 8,43; N, 3,53 Found: C, 72.14; H, 8.43; N, 3.53

Eksempel 31 Example 31

6,7-dimetoksy-2-[3-((2-(4-metansulfonyloksyfenyl)-etyl)-metylamino)- propyl1- 1- hydroksv- l. 2. 3. 4- tetrahvdronaftalen 6,7-dimethoxy-2-[3-((2-(4-methanesulfonyloxyphenyl)-ethyl)-methylamino)- propyl1- 1- hydroxy-l. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og metansulfonsyreklorid, analogt med Eksempel 9. Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and methanesulfonic acid chloride, analogous to Example 9.

Utbytte: 16,7% av det teoretiske. Yield: 16.7% of the theoretical.

Olje, Rf-verdi: 0,4 (aluminiumoksyd, elueringsmiddel: 5% etanol i metylenklorid). Oil, Rf value: 0.4 (alumina, eluent: 5% ethanol in methylene chloride).

Beregnet: C, 62,87; H, 7,39; N, 2,93; S, 6,71 Calcd: C, 62.87; H, 7.39; N, 2.93; S, 6.71

Funnet: C, 62,05; H, 7,50; N, 2,75; S, 6,88 Found: C, 62.05; H, 7.50; N, 2.75; S, 6.88

Eksempel 32 Example 32

6,7-dimetoksy-2-[3-((2-(4-tri fluormetansulfonyloksyfeny1)-et yl)- metylamino)- propyl]- 1- hvdroksv- l. 2. 3. 4- tetrahvdronaftalen 6,7-dimethoxy-2-[3-((2-(4-trifluoromethanesulfonyloxyphenyl)-ethyl)- methylamino)- propyl]- 1- hydroxy-l. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og trifluormetansulfonsyreklorid, analogt med Eksempel 9. Utbytte: 54,8% av det teoretiske. Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and trifluoromethanesulfonic acid chloride, analogous to Example 9. Yield: 54.8% of the theoretical.

Smeltepunkt: 119°C Melting point: 119°C

Beregnet: C, 56,49; H, 6,07; N, 2,63; S, 6,03 Calculated: C, 56.49; H, 6.07; N, 2.63; S, 6.03

Funnet: C, 56,36; H, 6,01; N, 2,49; S, 6,86 Found: C, 56.36; H, 6.01; N, 2.49; S, 6.86

Eksempel 33 Example 33

6,7-dimetoksy-2-[3-((2-(4-etoksykarbonylmetoksyfenyl)-etyl)-metylamino)- propyl1- 1- hydroksv- l. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((2-(4-ethoxycarbonylmethoxyphenyl)-ethyl)-methylamino)- propyl1- 1-hydroxyl. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og bromeddiksyreetylester, analogt méd Eksempel 9. Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and bromoacetic acid ethyl ester, analogously to Example 9.

Utbytte: 29% av det teoretiske. Yield: 29% of the theoretical.

Olje, Rf-verdi: 0,2 (aluminiumoksyd, elueringsmiddel: 3% etanol i metylenklorid). Oil, Rf value: 0.2 (alumina, eluent: 3% ethanol in methylene chloride).

Beregnet: C, 69,25; H, 8,09; N, 2,88 Calcd: C, 69.25; H, 8.09; N, 2.88

Funnet: C, 69,00; H, 7,93; N, 2,63 Found: C, 69.00; H, 7.93; N, 2.63

Eksempel 34 Example 34

6,7-dimetoksy-2-[3-((2-(4-hydroksykarbonylmetoksyfenyl)-etyl)-metylamino)- propyl]- 1- hydroksy- l. 2. 3. 4- tetrahydronaftalen 6,7-dimethoxy-2-[3-((2-(4-hydroxycarbonylmethoxyphenyl)-ethyl)-methylamino)- propyl]- 1- hydroxy- 1. 2. 3. 4- tetrahydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og bromeddiksyreetylester/natronlut, analogt med Eksempel 20. Utbytte: 37% av det teoretiske. Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and bromoacetic acid ethyl ester/sodium lye, analogous to Example 20. Yield: 37% of the theoretical.

Smeltepunkt: 92°C Melting point: 92°C

Beregnet: C, 68,25; H, 7,71; N, 3,06 Calculated: C, 68.25; H, 7.71; N, 3.06

Funnet: C, 68,58; H, 7,63; N, 2,92 Found: C, 68.58; H, 7.63; N, 2.92

Eksempel 35 Example 35

6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl1- 1- okso- l. 2. 3. 4- tetrahydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl1- 1-oxo- l. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og kalium-tert.-butylat/benzofenon, analogt med Eksempel 3. Utbytte: 26% av det teoretiske. Prepared from 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and potassium tert. -butylate/benzophenone, analogously to Example 3. Yield: 26% of the theoretical.

Smeltepunkt: 191°C Melting point: 191°C

Beregnet: C, 71,04; H, 7,31; N, 2,67; Cl, 6,76 Calculated: C, 71.04; H, 7.31; N, 2.67; Cl, 6.76

Funnet: C, 71,12; H, 7,24; N, 2,61; Cl, 6,87 Found: C, 71.12; H, 7.24; N, 2.61; Cl, 6.87

Eksempel 36 Example 36

6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl]- 3. 4- dihydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]- 3. 4- dihydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og saltsyre, analogt med Eksempel 17. Prepared from 6,7-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid, analogous to Example 17.

Utbytte: 18,6% av det teoretiske. Yield: 18.6% of the theoretical.

Smeltepunkt: 185°C Melting point: 185°C

Beregnet: C, 73,28; H, 7,54; N, 2,76; Cl, 6,98 Calculated: C, 73.28; H, 7.54; N, 2.76; Cl, 6.98

Funnet: C, 73,66; H, 7,20; N, 2,78; Cl, 7,43 Found: C, 73.66; H, 7.20; N, 2.78; Cl, 7.43

Eksempel 37 Example 37

6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl1- 3, 4- dihydronaftalen 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl1- 3, 4- dihydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-hydroksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og saltsyre, analogt med Eksempel 17. Prepared from 6,7-dimethoxy-2-[3-((2-(4-hydroxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid, analogous to Example 17.

Utbytte: 65% av det teoretiske. Yield: 65% of the theoretical.

Olje, Rf-verdi: 0,83 (aluminiumoksyd, elueringsmiddel: 5% etanol i metylenklorid). Oil, Rf value: 0.83 (alumina, eluent: 5% ethanol in methylene chloride).

Beregnet: C, 75,56; H, 8,19; N, 3,67 Calculated: C, 75.56; H, 8.19; N, 3.67

Funnet: C, 75,29; H, 8,10; N, 3,62 Found: C, 75.29; H, 8.10; N, 3.62

Eksempel 38 Example 38

6,7-dimetoksy-2-[3-((2-(4-metansulfonyloksyfenyl)-etyl)-metylamino)- propyl1- 3. 4- dihydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(4-methanesulfonyloxyphenyl)-ethyl)-methylamino)- propyl1- 3. 4- dihydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-metansulfonyl-oksyfenyl) -etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydro-naftalen og saltsyre, analogt med Eksempel 17. Utbytte: 42,8% av det teoretiske. Prepared from 6,7-dimethoxy-2-[3-((2-(4-methanesulfonyl-oxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydro-naphthalene and hydrochloric acid, analogous to Example 17. Yield: 42.8% of the theoretical.

Smeltepunkt: 81°C (sintrer fra 59°C). Melting point: 81°C (sinters from 59°C).

Beregnet: C, 58,41; H, 7,06; N, 2,72; Cl, 6,89; S, 6,24 Funnet: C, 58,60; H, 7,07; N, 2,54; Cl, 7,00; S, 6,37 Calculated: C, 58.41; H, 7.06; N, 2.72; Cl, 6.89; S, 6.24 Found: C, 58.60; H, 7.07; N, 2.54; Cl, 7.00; S, 6.37

Eksempel 39 Example 39

6,7-dimetoksy-2-[3-((2-(4-trifluormetansulfonyloksyfenyl)-etyl)- metylamino)- propyll- 3. 4- dihydronaftalen 6,7-dimethoxy-2-[3-((2-(4-trifluoromethanesulfonyloxyphenyl)-ethyl)- methylamino)- propyl- 3. 4- dihydronaphthalene

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-trifluormetan-sul f onyloksyf enyl) -etyl)-metylamino)-propyl]-l-hydroksy-1,2,3,4-tetrahydronaftalen og saltsyre» analogt med Eksempel,17. Utbytte: 77% av det teoretiske. Olje, Rf-verdi: 0,92 (aluminiumoksyd, elueringsmiddel: 3% etanol i metylenklorid). Prepared from 6,7-dimethoxy-2-[3-((2-(4-trifluoromethane-sulfonyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and hydrochloric acid" analogous to Example, 17. Yield: 77% of the theoretical. Oil, Rf value: 0.92 (alumina, eluent: 3% ethanol in methylene chloride).

Beregnet: C, 58,47; H, 5,89; N, 2,73; S, 6,24 Calculated: C, 58.47; H, 5.89; N, 2.73; S, 6.24

Funnet: C, 58,61; H, 5,88; N, 2,54; S, 6,75 Found: C, 58.61; H, 5.88; N, 2.54; S, 6.75

Eksempel 40 Example 40

5,6-dimetoksy-2-[3-((2-(4-metoksyfenyl)-etyl)-metylamino)-propyl]- 1- hvdroksy- indan- oksalat 5,6-dimethoxy-2-[3-((2-(4-methoxyphenyl)-ethyl)-methylamino)-propyl]- 1- hydroxy-indane- oxalate

Fremstillet fra 3-(5,6-dimetoksy-l-okso-indan-2-yl)-N-(2-(4-metoksyfenyl)-etyl)-N-metylpropionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2-yl)-N-(2-(4-methoxyphenyl)-ethyl)-N-methylpropionic acid amide and lithium aluminum hydride, analogously to Example 1.

Utbytte: 90% av det teoretiske. Yield: 90% of the theoretical.

Smeltepunkt: 80-83°C. Melting point: 80-83°C.

Beregnet: C, 63,79; H, 7,21; N, 2,86 Calcd: C, 63.79; H, 7.21; N, 2.86

Funnet: C, 63,55; H, 7,31; N, 3,02 Found: C, 63.55; H, 7.31; N, 3.02

Eksempel 41 Example 41

5,6-dimetoksy-2-[3-((2-(4-metoksyfenyl)-etyl)-metylamino)-propyl1- 1- okso- indan- hvdroklorid 5,6-Dimethoxy-2-[3-((2-(4-Methoxyphenyl)-ethyl)-methylamino)-propyl1- 1- oxo-indan- hydrochloride

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(4-metoksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og benzofenon, analogt med Eksempel 13. Prepared from 5,6-dimethoxy-2-[3-((2-(4-methoxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 13.

Utbytte: 21% av det teoretiske. Yield: 21% of the theoretical.

Smeltepunkt: 193-194°C. Melting point: 193-194°C.

Beregnet: C, 66,42; H, 7,43; N, 3,23; Cl, 8,17 Calculated: C, 66.42; H, 7.43; N, 3.23; Cl, 8.17

Funnet: C, 66,30; H, 7,58; N, 3,39; Cl, 8,30 Found: C, 66.30; H, 7.58; N, 3.39; Cl, 8.30

Eksempel 42 Example 42

5,6-dimetoksy-2-[3-((2-)4-benzyloksyfenyl)-etyl)-metylamino)-propyl]- 1- hvdroksy- indan 5,6-dimethoxy-2-[3-((2-)4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]- 1- hydroxyindan

Fremstillet fra 3-(5,6-dimetoksy-l-okso-indan-2-yl)-N-(2-(4-benzyloksyfenyl)-etyl)-N-metylpropionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2-yl)-N-(2-(4-benzyloxyphenyl)-ethyl)-N-methylpropionic acid amide and lithium aluminum hydride, analogously to Example 1.

Utbytte: 90% av det teoretiske. Yield: 90% of the theoretical.

Smeltepunkt: 80-83°C. Melting point: 80-83°C.

Beregnet: C, 75,76; H, 7,84; N, 2,95 Calculated: C, 75.76; H, 7.84; N, 2.95

Funnet: C, 75,58; H, 8,07; N, 2,79 Found: C, 75.58; H, 8.07; N, 2.79

Eksempel 43 Example 43

5,6-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl1- 1- okso- indan- hvdroklorid 5,6-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl1- 1- oxo-indan- hydrochloride

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og benzofenon, analogt med Eksempel 3. Prepared from 5,6-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 3.

Utbytte: 12% av det teoretiske. Yield: 12% of the theoretical.

Smeltepunkt: 189-191°C. Melting point: 189-191°C.

Beregnet: C, 70,64; H, 7,11; N, 2,75; Cl, 6,95 Calculated: C, 70.64; H, 7.11; N, 2.75; Cl, 6.95

Funnet: C, 70,50; fl, 7,22; N, 2,83; Cl, 7,20 Found: C, 70.50; fl, 7.22; N, 2.83; Cl, 7.20

Eksempel 44 Example 44

5,6-dimetoksy-2-[3-((2-(4-metylfenyl)-etyl)-metylamino)-propyl1- 1- hydroksy- indan 5,6-dimethoxy-2-[3-((2-(4-methylphenyl)-ethyl)-methylamino)-propyl1- 1- hydroxy- indan

Fremstillet fra 3-(5,6-dimetoksy-l-okso-indan-2-yl)-N-(2-(4-metylfenyl)-etyl)-N-metylpropionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(5,6-dimethoxy-1-oxo-indan-2-yl)-N-(2-(4-methylphenyl)-ethyl)-N-methylpropionic acid amide and lithium aluminum hydride, analogously to Example 1.

Utbytte: 83% av det teoretiske. Yield: 83% of the theoretical.

Smeltepunkt: 89-90°C. Melting point: 89-90°C.

Beregnet: C, 75,16; H, 8,67; N, 3,65 Calculated: C, 75.16; H, 8.67; N, 3.65

Funnet: C, 74,96; H, 8,65; N, 3,58 Found: C, 74.96; H, 8.65; N, 3.58

Eksempel 45 Example 45

5,6-dimetoksy-2-[3-((2-(4-metylfenyl)-etyl)-metylamino)-propyl1- 1- okso- indan- hydroklorid 5,6-dimethoxy-2-[3-((2-(4-methylphenyl)-ethyl)-methylamino)-propyl1- 1- oxo-indan hydrochloride

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(4-metylfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og benzofenon, analogt med Eksempel 3. Prepared from 5,6-dimethoxy-2-[3-((2-(4-methylphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 3.

Utbytte: 19% av det teoretiske. Yield: 19% of the theoretical.

Smeltepunkt: 193-194°C. Melting point: 193-194°C.

Beregnet: C, 68,96; H, 7,72; N, 3,35; Cl, 8,48 Calcd: C, 68.96; H, 7.72; N, 3.35; Cl, 8.48

Funnet: C, 68,86; H, 7,72; N, 3,45; Cl, 8,63 Found: C, 68.86; H, 7.72; N, 3.45; Cl, 8.63

Eksempel 46 Example 46

4-metyl-2-[3-((2-(3,5-dimetoksyfenyl)-etyl)-metylamino)-propyl]- 1- hvdroksy- indan- oksalat 4-methyl-2-[3-((2-(3,5-dimethoxyphenyl)-ethyl)-methylamino)-propyl]- 1- hydroxy-indane- oxalate

Fremstillet fra 3-(4-metyl-l-okso-indan-2-yl)-N-(2-(3,5-dimetoksyfenyl)-etyl)-N-metylpropionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(4-methyl-1-oxo-indan-2-yl)-N-(2-(3,5-dimethoxyphenyl)-ethyl)-N-methylpropionic acid amide and lithium aluminum hydride, analogously to Example 1.

Utbytte: 90% av det teoretiske. Yield: 90% of the theoretical.

Smeltepunkt: 82-83°C. Melting point: 82-83°C.

Beregnet: C, 65,94; H, 7,45; N, 2,96 Calcd: C, 65.94; H, 7.45; N, 2.96

Funnet: C, 66,03; H, 7,55; N, 3,05 Found: C, 66.03; H, 7.55; N, 3.05

Eksempel 47 Example 47

4-metyl-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl1- 1- okso- indan 4-methyl-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1- oxo-indane

Fremstillet fra 4-metyl-2-[3-((2-(3,5-dimetoksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og benzofenon, analogt med Eksempel 3. Prepared from 4-methyl-2-[3-((2-(3,5-dimethoxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 3.

Eksempel 48 Example 48

4-metyl-2-[3-((2-fenyletyl)-metylamino)-propyl]-1-hydroksy-indan- oksalat 4-methyl-2-[3-((2-phenylethyl)-methylamino)-propyl]-1-hydroxy-indan-oxalate

Fremstillet fra 3-(4-metyl-l-okso-indan-2-yl)-N-(2-fenyletyl)-N-metylpropionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(4-methyl-1-oxo-indan-2-yl)-N-(2-phenylethyl)-N-methylpropionic acid amide and lithium aluminum hydride, analogously to Example 1.

Utbytte: 90% av det teoretiske. Yield: 90% of the theoretical.

Smeltepunkt: 88-90°C. Melting point: 88-90°C.

Beregnet: C, 69,71; H, 7,56; N, 3,39 Calcd: C, 69.71; H, 7.56; N, 3.39

Funnet: C, 69,57; H, 7,63; N, 3,31 Found: C, 69.57; H, 7.63; N, 3.31

Eksempel 49 Example 49

4-metyl-2-[3-((2-fenyletyl)-metylamino)-propyl]-3-okso-indan- fumarat 4-methyl-2-[3-((2-phenylethyl)-methylamino)-propyl]-3-oxo-indane fumarate

Fremstillet fra 4-metyl-2-[3-((2-fenyletyl)-metylamino)-propyl]-1-hydroksy-indan og benzofenon, analogt med Eksempel 3. Utbytte: 5% av det teoretiske. Prepared from 4-methyl-2-[3-((2-phenylethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 3. Yield: 5% of the theoretical.

Smeltepunkt: 118-121°C. Melting point: 118-121°C.

Beregnet: C, 71,37; H, 7,14; N, 3,20 Calculated: C, 71.37; H, 7.14; N, 3.20

Funnet: C, 71,19; H, 7,33; N, 3,31 Found: C, 71.19; H, 7.33; N, 3.31

Eksempel 50 Example 50

4-metyl-2-[3-((2-(3,4,5-trimetoksyfenyl)-etyl)-metylamino)-propyl " I - 1 - hydroksy- indan 4-methyl-2-[3-((2-(3,4,5-trimethoxyphenyl)-ethyl)-methylamino)-propyl " I - 1 - hydroxy-indane

Fremstillet fra 3-(4-metyl-l-okso-indan-2-yl)-N-(2-(3,4,5-trimetoksyfenyl)-etyl)-N-metylpropionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(4-methyl-1-oxo-indan-2-yl)-N-(2-(3,4,5-trimethoxyphenyl)-ethyl)-N-methylpropionic acid amide and lithium aluminum hydride, analogously to Example 1.

Utbytte: 85% av det teoretiske. Yield: 85% of the theoretical.

Smeltepunkt: 75-77°C. Melting point: 75-77°C.

Beregnet: C, 64,40; H, 7,41; N, 2,78 Calculated: C, 64.40; H, 7.41; N, 2.78

Funnet: C, 64,49; H, 7,38; N, 3,09 Found: C, 64.49; H, 7.38; N, 3.09

Eksempel 51 Example 51

4-metyl-2-[3-((2-(3,4,5-trimetoksyfenyl)-etyl)-metylamino)-propyl1- 1- okso- indan 4-methyl-2-[3-((2-(3,4,5-trimethoxyphenyl)-ethyl)-methylamino)-propyl1- 1- oxo-indane

Fremstillet fra 4-metyl-2-[3-((2-(3,4,5-trimetoksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og benzofenon, analogt med Eksempel 3. Prepared from 4-methyl-2-[3-((2-(3,4,5-trimethoxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 3.

Eksempel 52 Example 52

5,6-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl1- inden- hvdroklorid 5,6-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl-1- indene-hydrochloride

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(4-benzyloksy-fenyl) -etyl) -metylamino) -propyl] -1-hydroksy-indan og saltsyre, analogt med Eksempel 17. Prepared from 5,6-dimethoxy-2-[3-((2-(4-benzyloxy-phenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and hydrochloric acid, analogously to Example 17.

Utbytte: 88% av det teoretiske. Yield: 88% of the theoretical.

Smeltepunkt: 181-183°C. Melting point: 181-183°C.

Beregnet: C, 72,93; H, 7,34; N, 2,84; Cl, 7,18 Calculated: C, 72.93; H, 7.34; N, 2.84; Cl, 7.18

Funnet: C, 72,50; H, 7,39; N, 2,62; Cl, 7,32 Found: C, 72.50; H, 7.39; N, 2.62; Cl, 7.32

Eksempel 53 Example 53

5,6-dimetoksy-2-[3-((2-(4-metoksyfenyl)-etyl)-metylamino)-propyl1- inden- hydroklorid 5,6-dimethoxy-2-[3-((2-(4-methoxyphenyl)-ethyl)-methylamino)-propyl-1-indene- hydrochloride

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(4-metoksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og saltsyre, analogt med Eksempel 17. Prepared from 5,6-dimethoxy-2-[3-((2-(4-methoxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and hydrochloric acid, analogously to Example 17.

Utbytte: 68% av det teoretiske. Yield: 68% of the theoretical.

Smeltepunkt: 188-190°C. Melting point: 188-190°C.

Beregnet: C, 68,96; H, 7,72; N, 3,35; Cl, 8,48 Calcd: C, 68.96; H, 7.72; N, 3.35; Cl, 8.48

Funnet: C, 68,86; H, 7,72; N, 3,25; Cl, 8,68 Found: C, 68.86; H, 7.72; N, 3.25; Cl, 8.68

Eksempel 54 Example 54

5,6-dimetoksy-2-[3-((2-(4-metylfenyl)-etyl)-metylamino)-propyl1- inden- hvdroklorid 5,6-dimethoxy-2-[3-((2-(4-methylphenyl)-ethyl)-methylamino)-propyl-1- indene-hydrochloride

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(4-metylfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og saltsyre, analogt med Eksempel 17. Prepared from 5,6-dimethoxy-2-[3-((2-(4-methylphenyl)-ethyl)-methylamino)-propyl]-1-hydroxyindane and hydrochloric acid, analogously to Example 17.

Utbytte: 72% av det teoretiske. Yield: 72% of the theoretical.

Smeltepunkt: 205-207°C. Melting point: 205-207°C.

Beregnet: C, 71,71; H, 8,02; N, 3,48; Cl, 8,82 Calculated: C, 71.71; H, 8.02; N, 3.48; Cl, 8.82

Funnet: C, 71,63; H, 8,04; N, 3,48; Cl, 8,94 Found: C, 71.63; H, 8.04; N, 3.48; Cl, 8.94

Eksempel 55 Example 55

7-metyl-2-[3-((2-(3,5-dimetoksyfenyl)-etyl)-metylamino)-propyl]- inden- oksalat 7-methyl-2-[3-((2-(3,5-dimethoxyphenyl)-ethyl)-methylamino)-propyl]- indene-oxalate

Fremstillet fra 4-metyl-2-[3-((2-(3,5-dimetoksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og saltsyre, analogt med Eksempel 17. Prepared from 4-methyl-2-[3-((2-(3,5-dimethoxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxyindane and hydrochloric acid, analogously to Example 17.

Utbytte: 37% av det teoretiske. Yield: 37% of the theoretical.

Smeltepunkt: 133-134°C. Melting point: 133-134°C.

Beregnet: C, 68,55; H, 7,30; N, 3,07 Calcd: C, 68.55; H, 7.30; N, 3.07

Funnet: C, 68,43; H, 7,45; N, 3,17 Found: C, 68.43; H, 7.45; N, 3.17

Eksempel 56 Example 56

7- metvl- 2- r3-(( 2- fenyletyl)- metylamino)- propyll- inden- fumarat 7- methyl- 2- r3-(( 2- phenylethyl)- methylamino)- propyl- indene- fumarate

Fremstillet fra 4-metyl-2-[3-((2-fenyletyl)-metylamino)-propyl]-1-hydroksy-indan og saltsyre, analogt med Eksempel 17. Utbytte: 33% av det teoretiske. Prepared from 4-methyl-2-[3-((2-phenylethyl)-methylamino)-propyl]-1-hydroxy-indane and hydrochloric acid, analogously to Example 17. Yield: 33% of the theoretical.

Smeltepunkt: 124-126°C. Melting point: 124-126°C.

Beregnet: C, 74,08; H, 7,41; N, 3,32 Calculated: C, 74.08; H, 7.41; N, 3.32

Funnet: C, 73,83; H, 7,38; N, 3,52 Found: C, 73.83; H, 7.38; N, 3.52

Eksempel 57 Example 57

7-metyl-2-[3-((2-(3,4,5-trimetoksyfenyl)-etyl)-metylamino)-propvl1- inden- oksalat 7-methyl-2-[3-((2-(3,4,5-trimethoxyphenyl)-ethyl)-methylamino)-propvl1- indene-oxalate

Fremstillet fra 4-metyl-2-[3-((2-(3,4,5-trimetoksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og saltsyre, analogt med Eksempel 17. Prepared from 4-methyl-2-[3-((2-(3,4,5-trimethoxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and hydrochloric acid, analogously to Example 17.

Utbytte: 28% av det teoretiske. Yield: 28% of the theoretical.

Smeltepunkt: 102-104°C (dekomp.). Melting point: 102-104°C (decomp.).

Beregnet: C, 66,78; H, 7,27; N, 2,88 Calcd: C, 66.78; H, 7.27; N, 2.88

Funnet: C, 66,59; H, 7,48; N, 2,62 Found: C, 66.59; H, 7.48; N, 2.62

Eksempel 58 Example 58

5.6- dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propvl]- 1- okso- indan- hydroklorid 5.6- dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propvl]- 1- oxo-indane- hydrochloride

Fremstillet fra 5,6-dimetoksy-2-[3-((2-(4-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-indan og benzofenon, analogt med Eksempel 3. Prepared from 5,6-dimethoxy-2-[3-((2-(4-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-indane and benzophenone, analogously to Example 3.

Utbytte: 12% av det teoretiske. Yield: 12% of the theoretical.

Smeltepunkt: 189-191°C. Melting point: 189-191°C.

Beregnet: C, 70,64; H, 7,11; N, 2,75; Cl, 6,95 Calculated: C, 70.64; H, 7.11; N, 2.75; Cl, 6.95

Funnet: C, 70,50; H, 7,22; N, 2,83; Cl, 7,10 Found: C, 70.50; H, 7.22; N, 2.83; Cl, 7.10

Eksempel 59 Example 59

6.7- dimetoksy-3-[3-((2-(3-benzyloksyfenyl)-etyl)-metylamino)-propvl]- 1. 2- dihydronaftalen- hvdroklorid 6.7- dimethoxy-3-[3-((2-(3-benzyloxyphenyl)-ethyl)-methylamino)-propyl]- 1. 2- dihydronaphthalene- hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(3-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydro-l-hydroksy-naftalen og saltsyre, analogt med Eksempel 17. Prepared from 6,7-dimethoxy-2-[3-((2-(3-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4-tetrahydro-1-hydroxy-naphthalene and hydrochloric acid, analogous to Example 17.

Utbytte: 23% av det teoretiske. Yield: 23% of the theoretical.

Smeltepunkt: 133-134°C. Melting point: 133-134°C.

Beregnet: C, 73,28; H, 7,54; N, 2,76; Cl, 6,98 Calculated: C, 73.28; H, 7.54; N, 2.76; Cl, 6.98

Funnet: C, 73,12; H, 7,46; N, 2,89; Cl, 7,07 Found: C, 73.12; H, 7.46; N, 2.89; Cl, 7.07

Eksempel 60 Example 60

6,7-dimetoksy-2-[3-((2-(4-metansulfonyloksyfenyl)-etyl)-metylamino)-propyl]-1-okso-l,2,3,4-tetrahydro-naftalen-hydroklorid 6,7-dimethoxy-2-[3-((2-(4-methanesulfonyloxyphenyl)-ethyl)-methylamino)-propyl]-1-oxo-1,2,3,4-tetrahydro-naphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(4-metansulfonyl-oksyf enyl) -etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydronaftalen og benzofenon, analogt med Eksempel 3. Utbytte: 53% av det teoretiske. Prepared from 6,7-dimethoxy-2-[3-((2-(4-methanesulfonyl-oxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydronaphthalene and benzophenone , analogous to Example 3. Yield: 53% of the theoretical.

Smeltepunkt: 183°C. Melting point: 183°C.

Beregnet: C, 58,64; H, 6,69; N, 2,73; Cl, 6,92; S, 6,26 Funnet: C, 58,48; H, 6,93; N, 2,68; Cl, 7,22; S, 6,50Calculated: C, 58.64; H, 6.69; N, 2.73; Cl, 6.92; S, 6.26 Found: C, 58.48; H, 6.93; N, 2.68; Cl, 7.22; S, 6.50

Eksempel 61 Example 61

6,7-dimetoksy-2-[3-((2-(3-metansulfonyloksyfenyl)-etyl)-metyl-amino)- propyl]- 1- okso- l. 2. 3. 4- tetrahydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(3-methanesulfonyloxyphenyl)-ethyl)-methyl-amino)- propyl]- 1- oxo- l. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(3-metansulfonyloksy-fenyl) -etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydro-naftalen og benzofenon, analogt med Eksempel 3. Prepared from 6,7-dimethoxy-2-[3-((2-(3-methanesulfonyloxy-phenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydro-naphthalene and benzophenone, analogous to Example 3.

Utbytte: 28% av det teoretiske. Yield: 28% of the theoretical.

Smeltepunkt: 81°C (sintrer fra 66°C). Melting point: 81°C (sinters from 66°C).

Beregnet: C, 58,64; H, 6,69; N, 2,74 Calculated: C, 58.64; H, 6.69; N, 2.74

Funnet: C, 58,56; H, 6,83; N, 2,69 Found: C, 58.56; H, 6.83; N, 2.69

Eksempel 62 Example 62

6,7-dimetoksy-2-[3-((2-(3-benzyloksyfenyl)-etyl)-metylamino)-propyl]- 1- okso- l. 2. 3. 4- tetrahvdronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(3-benzyloxyphenyl)-ethyl)-methylamino)-propyl]- 1- oxo- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(3-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydro-naftalen og benzofenon, analogt med Eksempel 3. Prepared from 6,7-dimethoxy-2-[3-((2-(3-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydro-naphthalene and benzophenone, analogous to Example 3.

Utbytte: 27% av det teoretiske. Yield: 27% of the theoretical.

Smeltepunkt: 170°C. Melting point: 170°C.

Beregnet: C, 71,04; H, 7,31; N, 2,67; Cl, 6,77 Calculated: C, 71.04; H, 7.31; N, 2.67; Cl, 6.77

Funnet: C, 70,20; H, 7,31; N, 2,64; Cl, 6,68 Found: C, 70.20; H, 7.31; N, 2.64; Cl, 6.68

Eksempel 63 Example 63

6,7-dimetoksy-2-[3-((2-(3-hydroksyfenyl)-etyl)-metylamino)-propvl1- 1- hvdroksv- l, 2. 3, 4- tetrahvdronaftalen- oksalat 6,7-dimethoxy-2-[3-((2-(3-hydroxyphenyl)-ethyl)-methylamino)-propyl-1- hydroxy-1, 2, 3, 4- tetrahydronaphthalene- oxalate

Fremstillet fra 6,7-dimetoksy-2-[3-((2-(3-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1-hydroksy-l,2,3,4-tetrahydro-naftalen og hydrogen i nærvær av palladium/kull, analogt med Eksempel 8. Prepared from 6,7-dimethoxy-2-[3-((2-(3-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1-hydroxy-1,2,3,4-tetrahydro-naphthalene and hydrogen in presence of palladium/coal, analogously to Example 8.

Utbytte: 84% av det teoretiske. Yield: 84% of the theoretical.

Smeltepunkt: 77°C Melting point: 77°C

Beregnet: C, 63,79; H, 7,21; N, 2,86 Calcd: C, 63.79; H, 7.21; N, 2.86

Funnet: C, 63,57; H, 7,40; N, 2,68 Found: C, 63.57; H, 7.40; N, 2.68

Eksempel 64 Example 64

6,7-dimetoksy-2-[3-((2-(3-hydroksyfenyl)-etyl)-metylamino)-propyl1- 1. 2. 3. 4- tetrahydronaftalen- hydroklorid 6,7-dimethoxy-2-[3-((2-(3-hydroxyphenyl)-ethyl)-methylamino)-propyl1- 1. 2. 3. 4- tetrahydronaphthalene hydrochloride

Fremstillet fra 6,7-dimetoksy-3-[3-((2-(3-benzyloksyfenyl)-etyl)-metylamino)-propyl]-1,2-dihydronaftalen og hydrogen i nærvær av palladium/kull i etanol som oppløsningsmiddel, analogt med Eksempel 8. Prepared from 6,7-dimethoxy-3-[3-((2-(3-benzyloxyphenyl)-ethyl)-methylamino)-propyl]-1,2-dihydronaphthalene and hydrogen in the presence of palladium/charcoal in ethanol as solvent, analogous to Example 8.

Utbytte: 65% av det teoretiske. Yield: 65% of the theoretical.

Smeltepunkt: sintrer fra 72°C. Melting point: sinters from 72°C.

Beregnet: C, 68,64; H, 8,16; N, 3,34; Cl, 8,44 Calculated: C, 68.64; H, 8.16; N, 3.34; Cl, 8.44

Funnet: C, 68,50; H, 7,95; N, 3,02; Cl, 8,84 Found: C, 68.50; H, 7.95; N, 3.02; Cl, 8.84

Eksempel 65 Example 65

6,7-dimetoksy-2-[3-((2-(3-benzyloksyfenyl)-etyl)-metylamino)-propyl1- 1- hvdroksy- l. 2. 3. 4- tetrahvdronaftalen- oksalat 6,7-dimethoxy-2-[3-((2-(3-benzyloxyphenyl)-ethyl)-methylamino)-propyl1- 1- hydroxy- 1. 2. 3. 4- tetrahydronaphthalene- oxalate

Fremstillet fra 3-(6,7-dimetoksy-l-okso-l,2,3,4-tetra-hydronaf talen-2 -yl) -N-(2-(3-benzyloksyfenyl)-etyl)-N-metyl-propionsyreamid og litiumaluminiumhydrid, analogt med Eksempel 1. Prepared from 3-(6,7-dimethoxy-1-oxo-1,2,3,4-tetra-hydronaphthalen-2-yl)-N-(2-(3-benzyloxyphenyl)-ethyl)-N-methyl -propionic acid amide and lithium aluminum hydride, analogous to Example 1.

Utbytte: 51% av det teoretiske. Yield: 51% of the theoretical.

Smeltepunkt: 108°C (dekomp.). Melting point: 108°C (decomp.).

Beregnet: C, 68,37; H, 7,13; N, 2,42 Calculated: C, 68.37; H, 7.13; N, 2.42

Funnet: C, 68,09; H, 7,08; N, 2,38 Found: C, 68.09; H, 7.08; N, 2.38

Claims (3)

1. Analogifremgangsmåte for fremstilling av nye terapeutisk aktive naftalen- og indanderivater med formel hvor n er tallet 1 eller 2, A er en karbonylgruppe <p>g R7 et hydrogenatom eller A en gruppe med formel hvor Rg utgjør et hydrogenatom, eller en hydroksy-gruppe, og R7 utgjør et hydrogenatom eller sammen med Rg utgjør en ytterligere binding, E er en rettkjedet alkylengruppe med 3 eller 4 karbonatomer, G er en rettkjedet alkylengruppe med 2-5 karbonatomer, R 2 er hydrogen eller en alkyl- eller alkoksygruppe, R2 er en alkoksy- eller alkylgruppe, R3 er en alkylgruppe med 1-3 karbonatomer, R4 er et hydrogenatom, en alkyl-, amino-, alkanoylamino-, alkoksykarbonylamino-, alkylsulfonylamino-, bis(alkylsulfonyl)-amino-, cyano-, eller alkylsulfonylgruppe, eller en hydroksy-gruppe som eventuelt er substituert med en alkyl-, fenylalkyl-, 2-hydroksyetyl-, alkylsulfonyl-, cyanoalkyl-, hydroksykarbonylalkyl-, alkoksykarbonylalkyl-,.trifluormetyl- eller trifluormetylsulfonylgruppe, R5 er et hydrogen- eller halogenatom, en alkyl-, hydroksy-, alkoksy-, nitro-, cyano- eller trifluormetylgruppe, og R6 er et hydrogen- eller halogenatom eller en alkoksygruppe, hvor alle tidligere nevnte alkyl- eller alkoksygrupper hver inneholder 1-3 karbonatomer, og de tidligere nevnte alkanoyl- grupper hver inneholder 2 eller 3 karbonatomer, samt deres syreaddisjonssalter, karakterisert ved at a) for fremstilling av forbindelser med formel I, hvor R7 og R8 hver er et hydrogenatom eller sammen utgjør en ytterligere binding, en forbindelse med formel hvor R^, R2, n og E er som ovenfor angitt, A^ er en gruppe med formel hvor Rg betyr et hydrogenatom og R7 utgjør et hydrogenatom eller R7 og Rg sammen utgjør en ytterligere binding, og X utgjør en nukleofil utgående gruppe, så som et halogenatom eller en sulfonyloksygruppe, omsettes med et amin med formel hvor R3 til R5 og G er som ovenfor angitt, b) en forbindelse med formel i hvor n, A, E, R-l til R 3 og R7 er som ovenfor angitt, omsettes med en forbindelse med formel hvor R4 til R6 og G er som ovenfor angitt og Y utgjør en nukleofil utgående gruppe, så som et halogenatom eller en sulfonyloksygruppe, c) for fremstilling av forbindelser med formel I, hvor Ra I A utgjør en gruppe med formel -CH-, hvor Rg betyr et hydrogenatom eller en hydroksygruppe, en forbindelse med formel hvor n og R-± til Rg er som ovenfor angitt, A2 er en karbonylgruppe og R7 et hydrogenatom eller A2 er en gruppe med formel hvor Rg utgjør et hydrogenatom eller en hydroksygruppe, og R7 er et hydrogenatom, E' har de for E, og G' de for G, ovenfor angitte betydninger, hvor imidlertid en metylengruppe nabostilt til =N-R3~gruppen i restene E eller G må være erstattet med en karbonylgruppe, reduseres, eller d) for fremstilling av forbindelser med formel I, hvor A utgjør karbonylgruppen, en forbindelse med formel hvor n, E, G og R^ til R6 er som ovenfor angitt, oksyderes, eller e) for fremstilling av forbindelser med formel I, hvor R4 er en alkanoylamino-, alkoksykarbonylamino-, alkylsulfonylamino-, bis(alkylsulfonyl)amino-, alkoksy-, hydroksykarbonylalkoksy-, alkoksykarbonylalkoksy-, fenylalkoksy-, trifluormetoksy-, cyanoalkoksy-, alkylsulfonyloksy- eller trifluormetylsulfonyl-oksygruppe, en forbindelse med formel hvor Ri til R3, R5 til R7, A, E, G og n er som ovenfor angitt og Rg er en hydroksy-, amino- eller alkylaminogruppe med 1-3 karbonatomer, omsettes med en forbindelse med formel hvor Z er en nukleofil utgående gruppe, så som et halogenatom, og R10 betyr en alkyl-, alkanoyl-, alkoksykarbonyl-, hydroksykarbonylalkyl-, alkoksykarbonylalkyl-, alkylsulfonyl-, fenylalkyl-, trifluormetyl-, eller cyanoalkylgruppe, hvor hver av de ovennevnte alkyl- og alkoksy-deler inneholder 1 til 3 karbonatomer, eller hvor alkanoyl-delen inneholder 2 eller 3 karbonatomer, eller f) for fremstilling av forbindelser med formel I, hvor R7 og R8 sammen utgjør en ytterligere binding, en forbindelse med formel hvor n, E, G og R^ til R7 er som ovenfor angitt, dehydratiseres, hvorpå en beskyttelsesgruppe benyttet under omsetningene a) til f) for beskyttelse av reaktive grupper, deretter om nødvendig avspaltes, og en således oppnådd forbindelse med formel I, hvor R4 utgjør en benzyloksygruppe, om ønskes, overføres i den tilsvarende hydroksyforbindelse ved debenzylering, og/eller en således oppnådd forbindelse med formel I overføres i sine syreaddisjonssalter, spesielt i sine fysiologisk akseptable syreaddisjonssalter, med uorganiske eller organiske syrer.1. Analogy method for the preparation of new therapeutically active naphthalene and indane derivatives with formula where n is the number 1 or 2, A is a carbonyl group <p>g R7 is a hydrogen atom or A a group with formula where Rg constitutes a hydrogen atom, or a hydroxy group, and R7 constitutes a hydrogen atom or together with Rg constitutes a further bond, E is a straight-chain alkylene group with 3 or 4 carbon atoms, G is a straight-chain alkylene group with 2-5 carbon atoms, R 2 is hydrogen or an alkyl or alkoxy group, R 2 is an alkoxy or alkyl group, R3 is an alkyl group with 1-3 carbon atoms, R4 is a hydrogen atom, an alkyl, amino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, bis(alkylsulfonyl)amino, cyano, or alkylsulfonyl group, or a hydroxy group which is optionally substituted with an alkyl, phenylalkyl -, 2-hydroxyethyl, alkylsulfonyl, cyanoalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, trifluoromethyl or trifluoromethylsulfonyl group, R 5 is a hydrogen or halogen atom, an alkyl, hydroxy, alkoxy, nitro, cyano or trifluoromethyl group, and R 6 is a hydrogen or halogen atom or an alkoxy group, where all previously mentioned alkyl or alkoxy groups each contain 1- 3 carbon atoms, and the previously mentioned alkanoyl- groups each containing 2 or 3 carbon atoms, as well as their acid addition salts, characterized in that a) for the preparation of compounds of formula I, where R7 and R8 are each a hydrogen atom or together form a further bond, a compound with formula where R 1 , R 2 , n and E are as indicated above, A 2 is a group of formula where Rg means a hydrogen atom and R7 forms a hydrogen atom or R7 and Rg together form a further bond, and X constitutes a nucleophilic leaving group, such as a halogen atom or a sulfonyloxy group, is reacted with an amine of formula where R 3 to R 5 and G are as indicated above, b) a compound of formula in which n, A, E, R-1 to R 3 and R 7 are as indicated above, is reacted with a compound of formula where R4 to R6 and G are as indicated above and Y constitutes a nucleophilic leaving group, such as a halogen atom or a sulfonyloxy group, c) for the preparation of compounds of formula I, where Raw IN A constitutes a group of formula -CH-, where Rg means a hydrogen atom or a hydroxy group, a compound with formula where n and R-± to Rg are as stated above, A2 is a carbonyl group and R7 is a hydrogen atom or A2 is a group with formula where Rg constitutes a hydrogen atom or a hydroxy group, and R7 is a hydrogen atom, E' has the meanings given for E, and G' those for G, above, where, however, a methylene group adjacent to the =N-R3~ group in the residues E or G must be replaced by a carbonyl group, be reduced, or d) for the preparation of compounds of formula I, where A constitutes the carbonyl group, a compound with formula where n, E, G and R^ to R6 are, as indicated above, oxidized, or e) for the preparation of compounds of formula I, where R4 is an alkanoylamino-, alkoxycarbonylamino-, alkylsulfonylamino-, bis(alkylsulfonyl)amino-, alkoxy-, hydroxycarbonylalkoxy-, alkoxycarbonylalkoxy-, phenylalkoxy-, trifluoromethoxy-, cyanoalkoxy, alkylsulfonyloxy or trifluoromethylsulfonyloxy group, a compound with formula where Ri to R3, R5 to R7, A, E, G and n are as indicated above and Rg is a hydroxy, amino or alkylamino group with 1-3 carbon atoms, is reacted with a compound of formula where Z is a nucleophilic leaving group, such as a halogen atom, and R 10 means an alkyl, alkanoyl, alkoxycarbonyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, alkylsulfonyl, phenylalkyl, trifluoromethyl, or cyanoalkyl group, wherein each of the above alkyl- and alkoxy parts contain 1 to 3 carbon atoms, or where the alkanoyl part contains 2 or 3 carbon atoms, or f) for the preparation of compounds of formula I, where R7 and R8 together form a further bond, a compound with formula where n, E, G and R^ to R7 are as indicated above, are dehydrated, whereupon a protective group used during reactions a) to f) for protection of reactive groups, is then cleaved off if necessary, and a thus obtained compound of formula I, where R4 constitutes a benzyloxy group, if desired, is transferred in the corresponding hydroxy compound by debenzylation, and/or a thus obtained compound of formula I is transferred in its acid addition salts, especially in its physiologically acceptable acid addition salts, with inorganic or organic acids. 2. Fremgangsmåte ifølge krav 1, for fremstilling av 6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl]-1-okso-l,2,3,4-tetrahydronaftalen og dets syreaddisjonssalter, karakterisert ved anvendelsen av tilsvarende utgangsforbindelser.2. Process according to claim 1, for the production of 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl]-1-oxo-1,2, 3,4-tetrahydronaphthalene and its acid addition salts, characterized by the use of corresponding output connections. 3. Fremgangsmåte ifølge krav 1, for fremstilling av 6,7-dimetoksy-2-[3-((2-(3,4-dimetoksyfenyl)-etyl)-metylamino)-propyl]-1,2,3,4-tetrahydronaftalen og dets syreaddisjonssalter, karakterisert ved anvendelsen av tilsvarende utgangsforbindelser.3. Method according to claim 1, for the production of 6,7-dimethoxy-2-[3-((2-(3,4-dimethoxyphenyl)-ethyl)-methylamino)-propyl]-1,2,3,4- tetrahydronaphthalene and its acid addition salts, characterized by the use of corresponding starting compounds.