NO144212B

NO144212B - ANALOGY PROCEDURE FOR THE PREPARATION OF PHARMACOLOGICALLY ACTIVE ARYLAL CYLAMINES

Info

Publication number: NO144212B
Application number: NO760766A
Authority: NO
Inventors: Wolfgang Eberlein; Eberhard Kutter; Joachim Heider; Volkhard Austel; Rudolf Kadatz; Willi Diederen; Juergen Daemmgen; Walter Kobinger; Christian Lillie
Original assignee: Thomae Gmbh Dr K
Priority date: 1975-03-06
Filing date: 1976-03-05
Publication date: 1981-04-06
Also published as: DK92876A; ES445812A1; YU98082A; JPS6139305B2; YU98182A; IL49150A; NO144212C; SE7602856L; JPS51113866A; SU620209A3; FR2302733B1; IE42962B1; DK138792C; NO760766L; GR60053B; IL49150A0; DK138792B; LU74479A1; YU55076A; SE418398B

Description

Denne oppfinnelse angår fremstilling av nye substituerte arylalkylaminer med den generelle formel I This invention relates to the preparation of new substituted arylalkylamines with the general formula I

hvo r which r

R^ betyr et.hydrogenatom, en lavere alkylgruppe eller en fenyl- R^ means a hydrogen atom, a lower alkyl group or a phenyl

gruppe, group,

1*2 betyr et hydrogenatom eller en metoksygruppe, 1*2 means a hydrogen atom or a methoxy group,

R 3 betyr et hydrogenatom eller en metoksygruppe eller sammen R 3 means a hydrogen atom or a methoxy group or together

med R2 en metylendioksy- eller etylendioksygruppe, with R2 a methylenedioxy or ethylenedioxy group,

R^ og R,., som kan være like eller forskjellige, betyr hydrogen- R^ and R,., which may be the same or different, mean hydrogen-

atomer eller 1-3 C alkylgrupper, atoms or 1-3 C alkyl groups,

Rg betyr et hydrogenatom eller en 1-3 c alkoksygruppe, Rg means a hydrogen atom or a 1-3 C alkoxy group,

R^ betyr en 1-3 C alkoksygruppe eller sammen med Rg en metylen- R^ means a 1-3 C alkoxy group or together with Rg a methylene-

dioksy- eller etylendioksygruppe, dioxy or ethylenedioxy group,

X betyr en karbonyl- eller sulfonylgruppe, og X means a carbonyl or sulfonyl group, and

n betyr tallet 2 eller 3, n means the number 2 or 3,

og deres fysilogisk forlikelige syreaddisjonssalter med uorgan- and their physiologically compatible acid addition salts with inorganic

iske eller organiske syrer. ic or organic acids.

Alkylrestene som er nevnt som betydninger ved definisjonen The alkyl residues mentioned as meanings by the definition

av R4 og R,. , er særlig en metyl-, etyl-, propyl- eller isopro-pylgruppe, og alk"oksyrestene som er nevnt som betydning for restene of R4 and R1. , is in particular a methyl, ethyl, propyl or isopropyl group, and alk"oxy acids which are mentioned as meaning for the residues

Rg og R^, er særlig en metoksy-, etoksy-, propoksy- eller iso-propoksygruppe. Rg and R^ are in particular a methoxy, ethoxy, propoxy or iso-propoxy group.

Forbindelsene med den ovenfor angitte generelle formel I og syreaddisjonssaltene derav er i besittelse av verdifulle farmakologiske egenskaper, særlig en hjertefrekvenssenkende virkning. The compounds of the general formula I indicated above and the acid addition salts thereof possess valuable pharmacological properties, in particular a heart rate lowering effect.

De nye forbindelser med den generelle formel I fremstilles The new compounds of the general formula I are prepared

i henhold til oppfinnelsen som følger: according to the invention as follows:

a) omsetning av en forbindelse med den generelle formel II a) conversion of a compound of the general formula II

hvor where

R^, R2, R^, X og n er som ovenfor angitt, og R^, R2, R^, X and n are as indicated above, and

Z betyr en utgående gruppe så som et klor-, brom- eller jodatom, en alkylsulfonyloksy- eller arylsulfonyloksygruppe, med et fenyletylamin med den generelle formel III Z means a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group, with a phenylethylamine of the general formula III

hvor where

R^ , R,. , Rg og R^ er som ovenfor angitt. R^ , R,. , Rg and R^ are as indicated above.

Omsetningen utføres eventuelt i et oppløsningsmiddel, f.eks. i metanol, eter, tetrahydrofuran, metylformamid, dimetylformamid, dimetylsulfoksyd eller benzen, og hensiktsmessig alt efter reaktiviteten av resten Z ved temperaturer mellom -50 og 250°C. Det er fordelaktig med nærvær av et syrebindende middel, f.eks. et alkoholat, et alkali-hydroksyd eller en tertiær organisk base så som trietylamin eller pyridin, eller en reaksjonsakselrator så som kaliumjodid. b) For fremstilling av forbindelser med den generelle formel I hvor R^ betyr et hydrogenatom og X en karbonylgruppe: The reaction is optionally carried out in a solvent, e.g. in methanol, ether, tetrahydrofuran, methylformamide, dimethylformamide, dimethylsulfoxide or benzene, and appropriately depending on the reactivity of the residue Z at temperatures between -50 and 250°C. It is advantageous to have an acid binding agent, e.g. an alcoholate, an alkali hydroxide or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide. b) For the preparation of compounds of the general formula I where R^ means a hydrogen atom and X a carbonyl group:

Reduksjon av en forbindelse med den generelle formel IV Reduction of a compound of the general formula IV

hvor where

R^, Rg» R4, Rg, Rg, R^ og n er som ovenfor angitt. R^, Rg» R4, Rg, Rg, R^ and n are as indicated above.

Reduksjonen foretaes fortrinnsvis i et oppløsningsmiddel The reduction is preferably carried out in a solvent

så som iseddik, vann eller etanol, hensiktsmessig med nacerendé hydrogen, f.eks. med sink-iseddik, tinn-saltsyre eller tinn(II}-klorid-saltsyre eller med katalytisk aktivert hydrogen ved temperaturer mellom 0 og 250°C, fortrinnsvis mellom 50 og 100°C. such as glacial acetic acid, water or ethanol, suitably with nacerendé hydrogen, e.g. with zinc glacial acetic acid, stannous hydrochloric acid or stannous chloride hydrochloric acid or with catalytically activated hydrogen at temperatures between 0 and 250°C, preferably between 50 and 100°C.

c) Omsetning av et ftalimidin med den generelle formel V c) Reaction of a phthalimidine with the general formula V

hvor where

R^, Rj, R^, R^, X og n er som ovenfor angitt, med en aralkyl-forbindelse med den generelle formel VI R^, Rj, R^, R^, X and n are as indicated above, with an aralkyl compound of the general formula VI

hvor where

, Rg og R^ er som ovenfor angitt, og , Rg and R^ are as stated above, and

Z betyr en utgående gruppe så som et klor-, brom- eller jodatom, en alkylsulfonyloksy- eller arylsulfonyloksygruppe. Z means a leaving group such as a chlorine, bromine or iodine atom, an alkylsulfonyloxy or arylsulfonyloxy group.

Omsetningen utføres eventuelt i et oppløsningsmiddel, f.eks. i aceton, dimetylformamid, dimetylsulfoksyd, klorbenzen eller metylenklorid, og hensiktsmessig alt efter reaktiviteten av resten Z ved temperaturer mellom 0 og 150°C. Det er fordelaktig med et nærvær av et syrebindende middel så som et alkoholat, et alkalihydroksyd, et alkalikarbonat eller en tertiær organisk base så som trietylamin eller pyridin, eller en reaksjonsakselrator så som kaliumjodid. The reaction is optionally carried out in a solvent, e.g. in acetone, dimethylformamide, dimethylsulfoxide, chlorobenzene or methylene chloride, and appropriately depending on the reactivity of the residue Z at temperatures between 0 and 150°C. It is advantageous in the presence of an acid binding agent such as an alcoholate, an alkali hydroxide, an alkali carbonate or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide.

d) Omsetning av et lH-ftalimidin med den generelle formel VII d) Reaction of a 1H-phthalimidine of the general formula VII

hvor where

R^, R^, R 3 og X er som ovenfor angitt, med et alkylamin med den generelle formel VIII R 1 , R 1 , R 3 and X are as indicated above, with an alkylamine of the general formula VIII

hvor where

R4, Rg, Rg, R7 og n er som ovenfor angitt, og R4, Rg, Rg, R7 and n are as indicated above, and

Omsetningen utføres eventuelt i et oppløsningsmiddel, f.eks. i aceton, dimetylformamid, dimetylsulfoksyd eller metanol, og hensiktsmessig alt efter reaktiviteten av resten Z ved temperaturer mellom 0 og 150°C. Det er fordelaktig med nærvær av et syrebindende middel som f.eks. et alkoholat, et alkali-hydroksyd, et alkaliamid eller en tertiær organisk base så som trietylamin eller pyridin, eller en reaksjonsakselrator så som kaliumjodid. e) For fremstilling av forbindelser med den generelle formel I hvor X betyr en karbonylgruppe: Omsetning av et benzylhalogenid med den generelle formel IX The reaction is optionally carried out in a solvent, e.g. in acetone, dimethylformamide, dimethylsulfoxide or methanol, and appropriately depending on the reactivity of the residue Z at temperatures between 0 and 150°C. It is advantageous to have an acid-binding agent such as e.g. an alcoholate, an alkali hydroxide, an alkali amide or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide. e) For the preparation of compounds of the general formula I where X means a carbonyl group: Reaction of a benzyl halide of the general formula IX

hvor where

R til R^ er som ovenfor angitt, og R to R^ are as indicated above, and

Hal betyr et klor-, brom- eller jod atom, med et amin med den generelle formel X Hal means a chlorine, bromine or iodine atom, with an amine of the general formula X

hvor where

R^ til R^ og n er som ovenfor angitt, og påfølende hydrolyse R^ to R^ and n are as indicated above, and susceptible to hydrolysis

av det erholdte 1-imino-ftalimidin. of the 1-imino-phthalimidine obtained.

Omsetningen utføres eventuelt i et oppløsningsmiddel, f.eks. i aceton, etanol, dimetylformamid, dimetylsulfoksyd eller The reaction is optionally carried out in a solvent, e.g. in acetone, ethanol, dimethylformamide, dimethylsulfoxide or

metylenklorid, og hensiktsmessig ved forhøyet temperatur, f.eks. ved temperaturer mellom 50 og 150°C. Det er fordelaktig med nærvær av et syrebindende middel, som f.eks. et alkoholat, et alkali-hydroksyd, et alkalikarbonat eller en tertiær organiske base så som trietylamin eller pyridin, eller en reaksjonsakselerator så som kaliumjodid. methylene chloride, and suitably at elevated temperature, e.g. at temperatures between 50 and 150°C. It is advantageous to have an acid-binding agent, such as e.g. an alcoholate, an alkali hydroxide, an alkali carbonate or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide.

Den påfølgende hydrolyse utføres hensiktsmessig i nærvær av en base så som kaliumkarbonat eller i nærvær av en syre så som saltsyre i et vandig medium så som etanol/vann eller dioksan/ vann, og ved temperaturer mellom 50°C og det anvendte oppløs-ningsmiddels koketemperatur. f) For fremstilling av forbindelser med den generelle formel I hvor X betyr en karbonylgruppe: Omsetning av et benzylhalogenid med den generelle formel XI The subsequent hydrolysis is conveniently carried out in the presence of a base such as potassium carbonate or in the presence of an acid such as hydrochloric acid in an aqueous medium such as ethanol/water or dioxane/water, and at temperatures between 50°C and the boiling point of the solvent used . f) For the preparation of compounds of the general formula I where X means a carbonyl group: Reaction of a benzyl halide of the general formula XI

hvor where

R-^ til R^ er som ovenfor angitt. R-^ to R^ are as indicated above.

Hal betyr et klor-, brom- eller jodatom, og Hal means a chlorine, bromine or iodine atom, and

Y betyr en utgående gruppe så som et klor-, brom eller jodatom, en metoksy- eller fenoksygruppe, med et amin med den generelle formel X Y means a leaving group such as a chlorine, bromine or iodine atom, a methoxy or phenoxy group, with an amine of the general formula X

hvor where

R^ til R^ og n er som ovenfor angitt. R^ to R^ and n are as indicated above.

Omsetningen utføres eventuelt i et oppløsningsmiddel, f.eks. i aceton, dimetylformamid, dimetylsulfoksyd eller metylenklorid, og hensiktsmessig ved forhøyede temperaturer, f.eks. ved temperaturer mellom 50 og 150°C. Det er fordelaktig med nærvær av et syrebindende middel så som et alkoholat, et alkali-hydroksyd, et alkalikarbonat eller en tertiær organisk base så som trietylamin eller pyridin, eller en reaksjonsakselerator så som kaliumjodid. The reaction is optionally carried out in a solvent, e.g. in acetone, dimethylformamide, dimethylsulfoxide or methylene chloride, and suitably at elevated temperatures, e.g. at temperatures between 50 and 150°C. It is advantageous in the presence of an acid binding agent such as an alcoholate, an alkali hydroxide, an alkali carbonate or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide.

Herunder kan det in situ dannede benzamidderivat med den generelle formel XII Below, the in situ formed benzamide derivative of the general formula XII

hvor where

til R^ er som ovenfor angitt, to R^ is as stated above,

en av restene A eller B har en av de ovenfor for Hal eller Y nevnte betydninger, og den annen av restene A eller B betyr en gruppe med formelen one of the residues A or B has one of the meanings mentioned above for Hal or Y, and the other of the residues A or B means a group with the formula

hvor where

R 4 til R^ og n er som ovenfor angitt, eventuelt isoleres og derefter omsettes videre. R 4 to R 4 and n are as indicated above, optionally isolated and then reacted further.

g) Omsetning av et ftalimidin-aldehyd med den generelle formel g) Reaction of a phthalimidine aldehyde with the general formula

XIII XIII

hvor where

R^, R2, R^ X og n er som ovenfor angitt, eller et acetal derav, med et amind med den generelle formel III R 1 , R 2 , R 2 , X and n are as indicated above, or an acetal thereof, with an amine of the general formula III

hvor where

R. til R^ er som ovenfor angitt, i nærvær av katalytisk aktivert hydrogen. R. to R.sub.3 are as indicated above, in the presence of catalytically activated hydrogen.

Den reduktive aminering foretaes med hydrogen i nærvær en hydrogeneringskatalysator, f.eks. med hydrogen i nærvær av palladium/kull ved hydrogentrykk på 5 atmosfærer, i et oppløs-ningsmiddel så som metanol, etanol eller dioksan og ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20 og 80°C. The reductive amination is carried out with hydrogen in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium/charcoal at a hydrogen pressure of 5 atmospheres, in a solvent such as methanol, ethanol or dioxane and at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.

h) Omsetning av en karbonylforbindelse med den generelle formel XIV h) Reaction of a carbonyl compound of the general formula XIV

hvor where

Rg til R^ er som ovenfor angitt, eller et acetal eller ketal derav, med et ftalimidin med den generelle formelV Rg to R^ are as indicated above, or an acetal or ketal thereof, with a phthalimidine of the general formula V

d H R_ d H R_

hvor where

R^ til R^, X og n er som ovenfor angitt, i nærvær av katalytisk aktivert hydrogen. R^ to R^, X and n are as above, in the presence of catalytically activated hydrogen.

Den reduktive aminering med hydrogen i nærvær av en hydrogeneringskatalysator, f.eks. med hydrogen i nærvær av pal-ladium/kull ved et hydrogentrykk på 5 atmosfærer, i et oppløs-, ningsmiddel så som metanol, etanol eller dioksan og ved temperaturer mellom 0 og 100°C, fortrinnsvis ved temperaturer mellom 20 og 80°C. The reductive amination with hydrogen in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium/charcoal at a hydrogen pressure of 5 atmospheres, in a solvent such as methanol, ethanol or dioxane and at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.

Hvis man ved fremgangsmåtene a) til h) får en forbindelse med den generelle formel I hvor R^ betyr et hydrogenatom, kan denne alkyleres ved alkylering, f.eks. ved omsetning med et tilsvarende alkylhalogenid eller dialkylsulfat, eller metyleres ved omsetning med formaldehyd/maursyre. If a compound of the general formula I is obtained by methods a) to h) where R 1 means a hydrogen atom, this can be alkylated by alkylation, e.g. by reaction with a corresponding alkyl halide or dialkyl sulfate, or is methylated by reaction with formaldehyde/formic acid.

De erholdte forbindelser med den generelle formel I kan omdannes til de fysiologisk forlikelige salter derav med uorgan-iske eller organiske syrer. Som syrer anvendes hensiktsmessig saltsyre, fosforsyre, bromhydrogensyre, svovelsyre, melkesyre, vinsyre eller maleinsyre. The obtained compounds of the general formula I can be converted into the physiologically compatible salts thereof with inorganic or organic acids. Suitable acids are hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, lactic acid, tartaric acid or maleic acid.

Forbindelsene med de generelle formler II til XIV, som anvendes som utgangsmaterialer, kan fremstilles ved i og for seg kjente fremgangsmåter. Således får man f.eks. et ftalimidin med den generelle formel V eller et lH-ftalimidin med den generelle formel VII ved reduksjon av et tilsvarende ftalimid med sinkstøv i iseddik og eventuelt påfølgende alkylering. The compounds with the general formulas II to XIV, which are used as starting materials, can be prepared by methods known per se. Thus, you get e.g. a phthalimidine of the general formula V or a 1H-phthalimidine of the general formula VII by reduction of a corresponding phthalimide with zinc dust in glacial acetic acid and optionally subsequent alkylation.

Et benzylhalogenid med den generelle formel IX resp. XI A benzyl halide of the general formula IX or XI

får man fortrinnsvis ved halogenering av et tilsvarende toluen, f.eks. med N-bromsuccinimid i karbontetraklorid, eventuelt under tilsetning av en radikalstarter så som dibenzoylperOksyd og/eller under UV-bestråling. is preferably obtained by halogenation of a corresponding toluene, e.g. with N-bromosuccinimide in carbon tetrachloride, optionally with the addition of a radical initiator such as dibenzoyl peroxide and/or under UV irradiation.

Som nevnt innledningsvis oppviser de nye forbindelser As mentioned at the beginning, they show new connections

med den generelle formel I og deres syreaddisjonssalter verdi- with the general formula I and their acid addition salts value-

fulle farmakologiske egenskaper, ved siden av en mild blodtrykks-senkende virkning særlig en selektiv hjertefrekvenssenkende virkning. full pharmacological properties, in addition to a mild blood pressure-lowering effect, in particular a selective heart rate-lowering effect.

Som eksempler ble de følgende forbindelser undersøkt med hensyn til sine biologiske egenskaper: A = 5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-pro pyl)-ftalimidin-hydroklorid, As examples, the following compounds were examined for their biological properties: A = 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-pro pyl)-phthalimidine hydrochloride,

B = 5,6-dimetoksy-2-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-1,2-benzisotiazolin-l,1-dioksyd-hydroklorid, B = 5,6-dimethoxy-2-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide hydrochloride,

C = 5,6-metylendioksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylaminoj-propyl)-ftalimidin-hydroklorid, C = 5,6-methylenedioxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylaminoj-propyl)-phthalimidine hydrochloride,

D = 5,6-dimetoksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino] -propyl)-ftalimidin-hydroklorid, og D = 5,6-dimethoxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride, and

E = 5,6-etylendioksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino]-propyl)-ftalimidin-hydroklorid. E = 5,6-ethylenedioxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride.

1. Virkning på hjertefrekvensen hos narkotiserte marsvinunger: På marsvinunger i uretan-narkose ble hjertefrekvensen registrert med elektrokardiogram. Prøyeforbindelsene ble til-ført i stigende doser mellom 0,5 og 20 mg/kg i.v. 1. Effect on the heart rate in anesthetized guinea pigs: On guinea pigs in urethane anesthesia, the heart rate was recorded with an electrocardiogram. The bait compounds were added in increasing doses between 0.5 and 20 mg/kg i.v.

Den følgende tabell inneholder forandringene i hjertefrekvensen . The following table contains the changes in heart rate.

2. Virkning på hjertefrekvensen hos forkammere fra marsvinunger: Isolerte, spontant slående forkammere fra marsvinunger av begge kjønn med en kroppsvekt på 300 - 400 g, ble undersøkt i et organisk bad i tyrode-oppløsning. Næringsoppløsningen ble til- ført karbogen (95% 02 + 5% C02) og holdt konstant ved 30°C. Kon-traksjonen ble. registrert isometrisk ved hjelp av et streknings-målebånd på en Grass-polygraf. Prøveforbindelsene ble satt til det organiske bad slik at man fikk sluttfortynninger på 10 5 g/ml. 2. Effect on heart rate in guinea pig atria: Isolated, spontaneously beating guinea pig atria of both sexes with a body weight of 300 - 400 g were examined in an organic bath in tyrode solution. The nutrient solution was passed carbogen (95% 02 + 5% C02) and kept constant at 30°C. The contraction was. recorded isometrically using a stretch-measuring tape on a Grass polygraph. The test compounds were added to the organic bath so that final dilutions of 10 5 g/ml were obtained.

5 forkammere pr. forbindelse. 5 atria per connection.

I den følgende tabell er angitt den prosentvise reduksjon av hjertefrekvensen som middelverdi av 5 forkammere ved en for-bindelseskonsentrasjon på 10 ^ g/ml. In the following table, the percentage reduction of the heart rate as the mean value of 5 atria at a compound concentration of 10 µg/ml is given.

3. Akutt toksisitet: 3. Acute toxicity:

Den akutte toksisitet av prøveforbindelsene ble bestemt på mus (observasjonstid: 14 dager) efter oral resp. intravenøs administrering. LD5ø ble beregnet på grunnlag av den prosentvise mengde dyr som døde efter de forskjellige doser i løpet av observas jonstiden (se J. Pharmacol. exp. Therap. 9ji, 99 (1949)): The acute toxicity of the test compounds was determined in mice (observation time: 14 days) after oral resp. intravenous administration. The LD50 was calculated on the basis of the percentage of animals that died after the various doses during the observation period (see J. Pharmacol. exp. Therap. 9ji, 99 (1949)):

For farmasøytisk anvendelse kan forbindelsene med den generelle formel I og deres fysiologisk forlikelige syreaddisjonssalter, eventuelt i kombinasjon med andre aktive stoffer, innarbeides i de vanlige galeniske tilberedelsesformer så som tabelétter, dragéer, pulver, suspensjoner, oppløsninger eller stikkpiller. Enkeltdosen utgjør 20 - 300 mg, fortrinnsvis 25 - 200 mg. For pharmaceutical use, the compounds of the general formula I and their physiologically compatible acid addition salts, possibly in combination with other active substances, can be incorporated into the usual galenic preparation forms such as tablets, dragees, powders, suspensions, solutions or suppositories. The single dose amounts to 20 - 300 mg, preferably 25 - 200 mg.

De følgende eksempler skal tjene til å illustrere oppfinnelsen ytterligere: EKSEMPEL 1 2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]propyl)-ftalimidin-hydroklorid a) 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] propyl)- ftalimid 5,04 g (0,02 mol) 1-[2-(3,4-dimetoksy-fenyl)-etyl-metyl amino]-3-amino-propan og 2,06 g (0,02 mol) ftalsyreanhydrid oppløses i 100 ml iseddik og oppvarmes i 4 timer under tilbake-løpskjøling. Derefter inndamper man i vakuum, opptar residuet i kloroform og utvasker kloroformoppløsningert sukssesivt med mettet natriumhydrogenkarbonatoppløsning og vann. Efter tørring over natriumsulfat avdestillerer man oppløsningsmidlet og får den ønskede forbindelse som amorft produkt. The following examples shall serve to further illustrate the invention: EXAMPLE 1 2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]propyl)-phthalimidine hydrochloride a) 2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]propyl) - phthalimide 5.04 g (0.02 mol) 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methyl amino]-3-amino-propane and 2.06 g (0.02 mol) of phthalic anhydride are dissolved in 100 ml of glacial acetic acid and heated for 4 hours under reflux. It is then evaporated in vacuo, the residue is taken up in chloroform and the chloroform solution is successively washed out with saturated sodium bicarbonate solution and water. After drying over sodium sulfate, the solvent is distilled off and the desired compound is obtained as an amorphous product.

Utbytte: 6,1 g (79,8% av det teoretiske), Yield: 6.1 g (79.8% of the theoretical),

R^-verdi (benzen/aceton = 1/1) : 0,4.. R^-value (benzene/acetone = 1/1) : 0.4..

b) 2N- (' 3- 2 - ( 3 , 4- dimetoksy) - fenyletyl- metylamino] propyl) - f tal-imidin- hydroklorid b) 2N-(3-2-(3,4-dimethoxy)-phenylethyl-methylamino]propyl)-phthalimidine hydrochloride

6,1 g (159 mol) 2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino] propyl)-ftalimid, oppløst i 80 ml iseddik, tilsettes 10 g sinkstøv og reduseres ved 3 timers kokning under tilbakeløps-kjøling. For å fraskille sinkstøvet filtreres den ennu varme opp-løsning, og filtratet inndampes i vakuum. Derefter oppløses residuet i kloroform, og kloroformfasen utristes med mettet natrium-karbonatoppløsning og vann, tørres med natriumsulfat og inndampes. Råproduktet renses ved kromatografi på silikagel (kloroform/metanol = 19/1). Ved felling fra eterisk saltsyre får man hydrokloridet, som efter oppslutning i etylacetat har et smeltepunkt på 146 - 148°C. 6.1 g (159 mol) of 2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino] propyl)-phthalimide, dissolved in 80 ml of glacial acetic acid, 10 g of zinc dust are added and reduced by boiling for 3 hours under reflux cooling. To separate the zinc dust, the still warm solution is filtered, and the filtrate is evaporated in a vacuum. The residue is then dissolved in chloroform, and the chloroform phase is decanted with saturated sodium carbonate solution and water, dried with sodium sulphate and evaporated. The crude product is purified by chromatography on silica gel (chloroform/methanol = 19/1). Precipitation from ethereal hydrochloric acid gives the hydrochloride, which after digestion in ethyl acetate has a melting point of 146 - 148°C.

Utbytte: 2,25 g (35% av det teoretiske). Yield: 2.25 g (35% of the theoretical).

EKSEMPEL 2 EXAMPLE 2

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

a) 5, 6- dimetoksy- 2N- ( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino]-propyl)- ftalimid a) 5, 6- dimethoxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]-propyl)-phthalimide

Fremstilt analogt med eksempel la ved kondensation av 4,5-dimetoksy-ftalsyreanhydrid med 1-[2-( 3,4-dimetoksy-fenyl)-etyl-metylamino]-3-amino-propan i iseddik. Prepared analogously to example la by condensation of 4,5-dimethoxyphthalic anhydride with 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3-amino-propane in glacial acetic acid.

Smeltepunkt: 91 - 93°C. Melting point: 91 - 93°C.

b) 5, 6- dimetoksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] - propyl)- ftalimidin- hydroklorid b) 5, 6- dimethoxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- propyl)- phthalimidine- hydrochloride

Fremstilt analogt med eksempel lb ved reduksjon av 5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]propyl) - Prepared analogously to example 1b by reduction of 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]propyl) -

ftalimid med sinkstøv i iseddik. phthalimide with zinc dust in glacial acetic acid.

Smeltepunkt: 170 - 172°C. Melting point: 170 - 172°C.

EKSEMPEL 3 EXAMPLE 3

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletylamino]-propyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine hydrochloride

a) 5, 6- dimetoksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletylamino]-propyl)- ftalimid a) 5, 6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimide

Fremstilt analogt med eksempel la ved kondensasjon av 4,5-dimetoksy-ftalsyreanhydrid med 1-[2-(3,4-dimetoksy-fenyl)-etyl-amino]-3-amino-propan i iseddik. Prepared analogously to example la by condensation of 4,5-dimethoxyphthalic anhydride with 1-[2-(3,4-dimethoxy-phenyl)-ethyl-amino]-3-amino-propane in glacial acetic acid.

Rj-verdi (kloroform/metanol = 9/1) : 0,2 5 Rj value (chloroform/methanol = 9/1) : 0.2 5

b) 5, 6- dimetoksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletylamino]- propyl)-ftalimidin- hydroklorid b) 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethylamino]-propyl)-phthalimidine hydrochloride

Fremstilt analogt med eksempel lb ved reduksjon av 5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletylamino]propyl)-ftalimid med sinkstøv i iseddik. Prepared analogously to example 1b by reduction of 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethylamino]propyl)-phthalimide with zinc dust in glacial acetic acid.

Smeltepunkt: 207 - 209°C. Melting point: 207 - 209°C.

EKSEMPEL 4 EXAMPLE 4

5g (12,1 mol) av forbindelsen erholdt ifølge eksempel 3 oppvarmes i en blanding av 1,38 g (30 mmol) maursyre og 1,5 g 5g (12.1 mol) of the compound obtained according to example 3 is heated in a mixture of 1.38 g (30 mmol) formic acid and 1.5 g

(20 mmol) formalin i 1 time til 100°C. Efter avkjøling gjøres reaksjonsoppløsningen alkalisk ved tilsetning av 2 n natronlut, ekstraheres med kloroform og kloroformfasen vaskes med vann, tørres og inndampes i vakuum. Man kromatograferer residuet på silikagel (kloroform/metanol = 45/1), inndamper hovedfraksjonen og utfeller basen fra eterisk saltsyre som hydroklorid. Smeltepunkt: 170 - 172°C. (20 mmol) formalin for 1 hour at 100°C. After cooling, the reaction solution is made alkaline by adding 2 N sodium hydroxide solution, extracted with chloroform and the chloroform phase is washed with water, dried and evaporated in vacuo. The residue is chromatographed on silica gel (chloroform/methanol = 45/1), the main fraction is evaporated and the base is precipitated from ethereal hydrochloric acid as hydrochloride. Melting point: 170 - 172°C.

EKSEMPEL 5 EXAMPLE 5

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-n-propylamino]-propyl)-ftalimidin-hydrklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-n-propylamino]-propyl)-phthalimidine hydrochloride

En oppløsning av 25 g (5,5 mmol.) 5,6-dimetoksy-2N- (3-[2-(3,4-dimetoksy)fenyletylamino]propyl)-ftalimidin i 110 ml aceton oppvarmes Under tilbakeløpskjøling i 6 timer efter tilsetning av 20 ml 1-brompropan og 5 g kaliumkarbonat. Efter av-kjøling frafiltreres fast materiale, og filtratet inndampes. Residuet opptaes i eter, uoppløselige stoffer frafiltreres på A solution of 25 g (5.5 mmol.) of 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)phenylethylamino]propyl)-phthalimidine in 110 ml of acetone is heated Under reflux for 6 hours after addition of 20 ml of 1-bromopropane and 5 g of potassium carbonate. After cooling, solid material is filtered off, and the filtrate is evaporated. The residue is taken up in ether, insoluble substances are filtered off

ny, og hydrokloridet utfelles fra eterisk saltsyre efter inndampning. new, and the hydrochloride is precipitated from ethereal hydrochloric acid after evaporation.

Smelteupunkt: 120 - 122°C (aceton/metanol). Melting point: 120 - 122°C (acetone/methanol).

EKSEMPEL 6 EXAMPLE 6

2N- (2-[2- (3,4-dimetoksy)-fenyletyl-metylamino]-etyl)-ftalimidin-hydroklorid 2N-(2-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimidine hydrochloride

3,81 g (15 mmol) N-(2-brometyl)-ftalimid oppvarmes under tilbakeløpskjøling sammen med 6 g 3,4-dimetoksyfenyletyl-N-metylamin i 40 ml xylen i 10 timer. Det oljeaktige residuum som oppnåes efter inndampning i vakuum, overføres til den ønskede forbindelse analogt med eksempel lb ved reduksjon med sinkstøv i iseddik . 3.81 g (15 mmol) of N-(2-bromomethyl)-phthalimide are heated under reflux together with 6 g of 3,4-dimethoxyphenylethyl-N-methylamine in 40 ml of xylene for 10 hours. The oily residue obtained after evaporation in a vacuum is transferred to the desired compound analogously to example 1b by reduction with zinc dust in glacial acetic acid.

Smeltepunkt: 149 - 151°C. Melting point: 149 - 151°C.

EKSEMPEL 7 EXAMPLE 7

2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]propyl)-3-fenyl-ftalimidin 2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]propyl)-3-phenyl-phthalimidine

1.75 g (5,3 mmol) N-(3-brompropyl)-3-fenyl-ftalimidin oppvarmes under tilbakeløpskjøling i 10 timer med 2,06 g (10,6 mmol) 3,4-dimetoksyfenyletyl-N-metylamin i 30 ml xylen. Efter avkjøling inndamper man og kromatograferer på silikagel (kloroform/metylalkohol = 19/1). Man får basen som en høyviskøs olje. R^-verdi (kloroform/metanol = 19/1): 0,4. 1.75 g (5.3 mmol) N-(3-bromopropyl)-3-phenyl-phthalimidine is heated under reflux for 10 hours with 2.06 g (10.6 mmol) 3,4-dimethoxyphenylethyl-N-methylamine in 30 ml xylene. After cooling, evaporate and chromatograph on silica gel (chloroform/methyl alcohol = 19/1). The base is obtained as a highly viscous oil. R^ value (chloroform/methanol = 19/1): 0.4.

EKSEMPEL 8 EXAMPLE 8

3-fenyl-5-klor-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-1,2-benzisotiazolin-l,1-dioksyd-hydroklorid 3-phenyl-5-chloro-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide hydrochloride

3 g (9,3 mmol) N-(3-klorpropyl)-3-fenyl-5-klor-l,2-benzisotiazolin-1,1-dioksyd oppvarmes under tilbakeløpskjøling i 5 timer sammen med 3 g 3,4-dimetoksyfenyletyl-N-metylamin og en spatelspiss kaliumjodid i en oppløsning av 30 ml dimetylformamid og 5 ml trietylamin. Derefter inndamper man til tørr-het, opptar residuet i kloroform og utvasker den organiske fase flere ganger med vann. Efter tørring inndamper man og kromatograferer residuet på silikagel (kloroform/metanol = 40/1). Ved felling med eterisk saltsyre får man hydrokloridet som amorft produkt. R^-verdi (kloroform/metanol = 19/1) : 0,5. 3 g (9.3 mmol) of N-(3-chloropropyl)-3-phenyl-5-chloro-1,2-benzisothiazoline-1,1-dioxide are heated under reflux for 5 hours together with 3 g of 3,4-dimethoxyphenylethyl -N-methylamine and a spatula tip of potassium iodide in a solution of 30 ml of dimethylformamide and 5 ml of triethylamine. The mixture is then evaporated to dryness, the residue is taken up in chloroform and the organic phase is washed out several times with water. After drying, the residue is evaporated and chromatographed on silica gel (chloroform/methanol = 40/1). When precipitated with ethereal hydrochloric acid, the hydrochloride is obtained as an amorphous product. R^ value (chloroform/methanol = 19/1) : 0.5.

C27H31C1N204S • HC1 (551,54) C27H31C1N204S • HC1 (551.54)

EKSEMPEL 9 EXAMPLE 9

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-1,2-benzisotiazolin-l,1-dioksyd-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide hydrochloride

a) 2- metyl- 4, 5- dimetoksy- benzensulfoklorid a) 2- methyl- 4, 5- dimethoxy- benzene sulphochloride

Til 15,2 g (0,1 mol) 3,4-dimetoksy-toluen settes lang-somt dråpevis under omrøring og avkjøling ved ca. -10°C 23,2 g (0,2 mol) klorsulfonsyre. Efter avsluttet tilsetning lar man det hele oppvarmes til romtemperatur og omrører videre til hyd-rogenklorid-utviklingen opphører. Reaksjonsblandingen helles på is, og det utskilte sulfoklorid ekstraheres med eter. Man vasker den organiske fase suksessivt med natriumbikarbonatopp-løsning og vann og inndamper til tørrhet i vakuum. Som residuum blir det tilbake en uklar olje som stivner efter avkjøling. Rf-verdi (benzen) : 0,5. To 15.2 g (0.1 mol) 3,4-dimethoxy-toluene is slowly added dropwise while stirring and cooling at approx. -10°C 23.2 g (0.2 mol) chlorosulfonic acid. After the addition has been completed, the whole is allowed to warm to room temperature and stirred further until hydrogen chloride development ceases. The reaction mixture is poured onto ice, and the separated sulphochloride is extracted with ether. The organic phase is washed successively with sodium bicarbonate solution and water and evaporated to dryness in vacuo. A cloudy oil remains as a residue, which solidifies after cooling. Rf value (benzene) : 0.5.

b) 2- metyl- 4, 5- dimetoksybenzehsulfonamid b) 2-methyl-4,5-dimethoxybenzesulfonamide

18 g (0,07 mol) av forbindelsen erholdt ifølge eksempel 18 g (0.07 mol) of the compound obtained according to example

9a suspenderes i 200 ml konsentrert ammoniakk og omrøres i 4 timer ved romtemperatur. Man avsuger, eftervasker med vann og får det ønskede sulfonamid som amorft produkt efter tørring. Rf-verdi (benzen/aceton = 1/1) : 0,6. 9a is suspended in 200 ml of concentrated ammonia and stirred for 4 hours at room temperature. One extracts, washes with water and obtains the desired sulfonamide as an amorphous product after drying. Rf value (benzene/acetone = 1/1) : 0.6.

c) 5, 6- dimetoksy- l, 2- benzisotiazolin- 3- on- l, 1- dioksyd c) 5, 6-dimethoxy-1,2-benzisothiazolin-3-one-1,1-dioxide

16 g (0,09 mol) 2-metyl-4,5-dimetoksy-benzensulfonamid 16 g (0.09 mol) of 2-methyl-4,5-dimethoxy-benzenesulfonamide

oppløses i 500 ml 5%ig natronlut og oppvarmes til kokning i 2 dissolve in 500 ml of 5% caustic soda and heat to boiling for 2

timer efter tilsetning av 39,6 g (0,25 mol) kaliumpermanganat. hours after the addition of 39.6 g (0.25 mol) of potassium permanganate.

Efter avkjøling filtrerer man over celite og utfeller det øns- After cooling, filter over celite and precipitate the desired

kede produkt ved tilsetning av konsentrert saltsyre. ked product by adding concentrated hydrochloric acid.

Rf-verdi (benzen/aceton = 3/1) -.0,2-0,4.. Rf value (benzene/acetone = 3/1) -.0.2-0.4..

d) 5, 6- dimetoksy- l, 2- benzisotiazolin- l, 1- dioksyd d) 5, 6- dimethoxy-1, 2- benzisothiazoline-1, 1- dioxide

7 g (288 mmol) av forbindelsen erholdt ifølge eksempel 7 g (288 mmol) of the compound obtained according to example

9c, oppvarmes under tilbakeløpskjøling i 2 timer med 3,3 g (865 9c, heated under reflux for 2 hours with 3.3 g (865

mmol) litiumaluminiumhydrid i 400 ml tetrahydrofuran. Efter av-kjøling spalter man overskudd av litiumaluminiumhydrid ved tilsetning av etylacetat, fortynner med vann og tilsetter 2 n salt- mmol) of lithium aluminum hydride in 400 ml of tetrahydrofuran. After cooling, the excess of lithium aluminum hydride is split by adding ethyl acetate, diluted with water and 2 n salt

syre for å oppløse aluminiumhydroksyd-bunnfallet. Reaksjons-oppløsningen ekstraheres med etylacetat, og den organiske fase vaskes med vann og tørres. Man inndamper i vakuum, oppslutter residuet i eter og avsuger forbindelsen. acid to dissolve the aluminum hydroxide precipitate. The reaction solution is extracted with ethyl acetate, and the organic phase is washed with water and dried. Evaporate in a vacuum, dissolve the residue in ether and aspirate the compound.

e) N-( 3- klorpropyl)- 5, 6- dimetoksy- l, 2- benzisotiazolin- l, 1- e) N-(3- chloropropyl)- 5, 6- dimethoxy- 1, 2- benzisothiazoline- 1, 1-

dioksyd dioxide

2,4 g (10, mmol) av forbindelsen erholdt ifølge eksempel 2.4 g (10, mmol) of the compound obtained according to example

9d, oppløses i en blanding av 15 ml 2,5%ig natronlut og 30 ml etanol og oppvarmes i 8 timer under tilbakeløpskjøling efter tilsetning av 10 ml 3-brom-l-klorpropan. Man inndamper reaksjonsvol-umet til halvparten, fortynner med vann og ekstraherer med kloroform. Efter tørring av den organiske fase inndamper man i vakuum og får det ønskede produkt som en høyviskøs olje. 9d, is dissolved in a mixture of 15 ml of 2.5% caustic soda and 30 ml of ethanol and heated for 8 hours under reflux after the addition of 10 ml of 3-bromo-1-chloropropane. The reaction volume is evaporated to half, diluted with water and extracted with chloroform. After drying the organic phase, it is evaporated in a vacuum and the desired product is obtained as a highly viscous oil.

R^-verdi (kloroform/metanol = 19/1) : 0,8. R^ value (chloroform/methanol = 19/1) : 0.8.

f) 5, 6- dimetoksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino]-propyl)- 1, 2- benzisotiazolin- l, 1- dioksyd- hydroklorid f) 5, 6- dimethoxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- propyl)- 1, 2- benzisothiazoline- 1, 1- dioxide- hydrochloride

Fremstilt analogt med eksempel 8 ved omsetning av N-(3-klorpropyl)-5,6-dimetoksy-l,2-benzisotiazolin-l,1-dioksyd med 3,4-dimetoksyfenyletyl-N-metylamin. Prepared analogously to example 8 by reacting N-(3-chloropropyl)-5,6-dimethoxy-1,2-benzisothiazoline-1,1-dioxide with 3,4-dimethoxyphenylethyl-N-methylamine.

Smeltepunkt: 196 - 198°C (aceton). Melting point: 196 - 198°C (acetone).

EKSEMPEL 10 EXAMPLE 10

5,6-metylendioksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metyl-amino]-propyl)-ftalimidin-hydroklorid 5,6-methylenedioxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methyl-amino]-propyl)-phthalimidine hydrochloride

a) 4, 5- metylendioksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] - propyl)- ftalimid a) 4, 5- methylenedioxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- propyl)- phthalimide

3,5 g (18 mmol) 4,5-metylendioksy-ftalsyreanhydrid og 4,5 g (18 mmol) 1-[2-(3,4-dimetoksy-fenyl)-etylmetylamino]-3-aminopropan oppvarmes i 2 timer under tilbakeløpskjøling i 100 ml iseddik. Derefter inndamper man i vakuum, opptar residuet i 3.5 g (18 mmol) of 4,5-methylenedioxyphthalic anhydride and 4.5 g (18 mmol) of 1-[2-(3,4-dimethoxy-phenyl)-ethylmethylamino]-3-aminopropane are heated for 2 hours under reflux in 100 ml glacial acetic acid. It is then evaporated in a vacuum, the residue taken up in

kloroform og vasker kloroformoppløsningen suksessivt med mettet natriumhydrogenkarbonatoppløsning og vann. Efter tørring over natriumsulfat avdestillerer man oppløsningsmidlet og får den chloroform and washing the chloroform solution successively with saturated sodium bicarbonate solution and water. After drying over sodium sulphate, the solvent is distilled off and obtained

ønskede forbindelse som amorft produkt. desired compound as amorphous product.

Utbytte: 4,8 g (63% av det teoretiske), Yield: 4.8 g (63% of the theoretical),

R^-verdi (kloroform/metanol = 9/1) : 0,6. R^ value (chloroform/methanol = 9/1) : 0.6.

b) 5, 6- metylendioksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] - propyl)- ftalimidin- hydroklorid b) 5, 6- methylenedioxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- propyl)- phthalimidine- hydrochloride

4,8 g (11 mmol) 5,6 metylendioksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-ftalimid, oppløst i 40 ml iseddik, tilsettes 5 g sinkstøv og oppvarmes i 2 timer under tilbakeløps-kjøling. Efter avsluttet reaksjon frafiltreres sinkstøvet fra den varme oppløsning, og filtratet inndampes i vakuum. Derefter oppvarmes residuet i kloroform, og kloroformfasen utristes med mettet natriumkarbonatoppløsning og vann, tørres med natriumsulfat og inndampes. Man oppløser residuet i kloroform, og ved tilsetning av eterisk saltsyre utfelles hydrokloridet som har et smeltepunkt på 237 - 239°C. 4.8 g (11 mmol) 5,6 methylenedioxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimide, dissolved in 40 ml of glacial acetic acid, add 5 g of zinc dust and heated for 2 hours under reflux cooling. After completion of the reaction, the zinc dust is filtered off from the hot solution, and the filtrate is evaporated in a vacuum. The residue is then heated in chloroform, and the chloroform phase is extracted with saturated sodium carbonate solution and water, dried with sodium sulfate and evaporated. The residue is dissolved in chloroform, and when ethereal hydrochloric acid is added, the hydrochloride precipitates, which has a melting point of 237 - 239°C.

Utbytte: 1,5 g (30% av det teoretiske) Yield: 1.5 g (30% of the theoretical)

EKSEMPEL 11 EXAMPLE 11

5,6-etylendioksy-2N-(3-[2-(3,4^dimetoksy)-fenyletyl-metylamino]-propyl)-ftalimidin-hydroklorid 5,6-ethylenedioxy-2N-(3-[2-(3,4^dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

a) 4, 5- etylendioksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] - propyl- ftalimid a) 4, 5- ethylenedioxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- propyl- phthalimide

Fremstilt analogt med eksempel 10a ved kondensation av 4,5-etylendioksy-ftalsyreanhydrid med 1-[2-(3,4-dimetoksy-fenyl) - etyl-metylamino]-3-amino-propan i iseddik. Prepared analogously to example 10a by condensation of 4,5-ethylenedioxyphthalic anhydride with 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3-amino-propane in glacial acetic acid.

R^-verdi (kloroform/metanol = 9/1): 0,5. R^ value (chloroform/methanol = 9/1): 0.5.

b) 5, 6- etylendioksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] - propyl)- ftalimidin- hydroklorid b) 5, 6- ethylenedioxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- propyl)- phthalimidine- hydrochloride

Fremstilt analogt med eksempel 10b ved reduksjon av 4,5-etylendioksy-2N-(3-[2-(3,4-dimetoksy)-fenyletylmetylamino]-propyl)-ftalimid med sinkstøv i iseddik. Prepared analogously to example 10b by reduction of 4,5-ethylenedioxy-2N-(3-[2-(3,4-dimethoxy)-phenylethylmethylamino]-propyl)-phthalimide with zinc dust in glacial acetic acid.

Smeltepunkt: 208 - 210°C. Melting point: 208 - 210°C.

EKSEMPEL 12 EXAMPLE 12

5,6-metylendioksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino] -propyl)-ftalimidin-hydroklorid 5,6-methylenedioxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

• a) 4, 5- metylendioksy- 2N-{ 3-[ 2-( 3, 4- metylendioksy^- fenyletyl-metylamino] - propyl)- ftalimid • a) 4, 5- methylenedioxy- 2N-{ 3-[ 2-( 3, 4- methylenedioxy^- phenylethyl-methylamino]- propyl)-phthalimide

2,7 g (10 mmol) 4,5-metylendioksy-N-(3-klorpropyl)-ftalimid og 1,8 g (10 mmol) 3,4-metylendioksy-fenyletyl-N-metylamin oppløses i 20 ml klorbenzen og oppvarmes i 8 timer under tilbake-løpskjøling efter tilsetning av 2,8 g (20 mmol) pulverisert kaliumkarbonat. Derefter filtreres oppløsningen og inndampes til tørrhet i vakuum. Man kromatograferer residuet på silikagel (kloroform/metanol = 19/1) og får efter inndampning hovedfraksjonen på 2,1 g (51% av det teoretiske) av den ønskede forbindelse. R^-verdi (kloroform/metanol = 9/1): 0,6. 2.7 g (10 mmol) of 4,5-methylenedioxy-N-(3-chloropropyl)-phthalimide and 1.8 g (10 mmol) of 3,4-methylenedioxy-phenylethyl-N-methylamine are dissolved in 20 ml of chlorobenzene and heated for 8 hours under reflux after adding 2.8 g (20 mmol) of powdered potassium carbonate. The solution is then filtered and evaporated to dryness in vacuo. The residue is chromatographed on silica gel (chloroform/methanol = 19/1) and after evaporation the main fraction of 2.1 g (51% of the theoretical) of the desired compound is obtained. R^ value (chloroform/methanol = 9/1): 0.6.

b) 5, 6- metylendioksy- 2N-( 3-[ 2-( 3, 4- metylendioksy)- fenyletyl-metylamino] - propyl)- ftalimidin- hydroklorid b) 5, 6- methylenedioxy- 2N-( 3-[ 2-( 3, 4- methylenedioxy)- phenylethyl- methylamino]- propyl)- phthalimidine- hydrochloride

Fremstilt analogt med eksempel 10b ved reduksjon av 4,5-metylendioksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino]-propyl)-ftalimid med sinkstøv i iseddik. Prepared analogously to example 10b by reduction of 4,5-methylenedioxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide with zinc dust in glacial acetic acid.

Smeltepunkt: 206 - 208°C. Melting point: 206 - 208°C.

EKSEMPEL 13 EXAMPLE 13

5,6-etylendioksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino] -propyl)-ftalimidin-hydroklorid 5,6-ethylenedioxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

a) 4, 5- etylendioksy- 2N-( 3-[ 2-( 3, 4- metylendioksy)- fenyletyl-metylamino] - propyl- ftalimid a) 4, 5- ethylenedioxy- 2N-( 3-[ 2-( 3, 4- methylenedioxy)- phenylethyl- methylamino]- propyl- phthalimide

Fremstilt analogt med eksempel 12a ved omsetning av 4,5-etylendioksy-N-(3-klorpropyl)-ftalimid med 3,4-metylendioksy-f enyletyl-.N-metylamin i klorbenzen i nærvær av;'kaliumkarbonat. R^-verdi (kloroform/metanol) = 9/1): 0,5. Prepared analogously to example 12a by reacting 4,5-ethylenedioxy-N-(3-chloropropyl)-phthalimide with 3,4-methylenedioxy-phenylethyl-.N-methylamine in chlorobenzene in the presence of potassium carbonate. R^ value (chloroform/methanol) = 9/1): 0.5.

b) 5, 6- etylendioksy- 2N-( 3-[ 2-( 3, 4- metylendioksy)- fenyletyl-metylamino] - propyl)- ftalimidin- hydroklorid b) 5, 6- ethylenedioxy- 2N-( 3-[ 2-( 3, 4- methylenedioxy)- phenylethyl- methylamino]- propyl)- phthalimidine- hydrochloride

Fremstilt analogt med eksempel 10b ved reduksjon av 4,5-etylendioksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino]-propyl)-ftalimid med sinkstøv i iseddik. Prepared analogously to example 10b by reduction of 4,5-ethylenedioxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide with zinc dust in glacial acetic acid.

Smeltepunkt: 180 - 18 2°C Melting point: 180 - 18 2°C

EKSEMPEL 14 EXAMPLE 14

5,6-dimetoksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino]-propyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

a) 4, 5- dimetoksy- 2N-( 3-[ 2-( 3, 4- metylendioksy)- fenyletyl- metylamino] - propyl)- ftalimid a) 4, 5- dimethoxy- 2N-( 3-[ 2-( 3, 4- methylenedioxy)- phenylethyl- methylamino]- propyl)- phthalimide

Fremstilt analogt med eksempel 12a ved omsetning av 4,5-dimetoksy-N-(3-klorpropyl)-ftalimid med 3,4-metylendioksy-fenyletyl-N-metylamin i klorbenzen i nærvær av klaiumkarbonat. Rf-verdi (kloroform/metanol = 19/1): 0,7. Prepared analogously to example 12a by reacting 4,5-dimethoxy-N-(3-chloropropyl)-phthalimide with 3,4-methylenedioxy-phenylethyl-N-methylamine in chlorobenzene in the presence of clay carbonate. Rf value (chloroform/methanol = 19/1): 0.7.

b) 5, 6- dimetoksy- 2N-( 3-[ 2-( 3, 4- metylendioksy)- fenyletyl- metylamino] - propyl)- ftalimidin- hydroklorid b) 5, 6- dimethoxy- 2N-( 3-[ 2-( 3, 4- methylenedioxy)- phenylethyl- methylamino]- propyl)- phthalimidine- hydrochloride

Fremstilt analogt med eksempel 10b ved reduksjon av 4,5-dimetoksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino]-propyl)-ftalimid med sinkstøv i iseddik. Prepared analogously to example 10b by reduction of 4,5-dimethoxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimide with zinc dust in glacial acetic acid.

Smeltepunkt: 235 - 237°C. Melting point: 235 - 237°C.

EKSEMPEL 15 EXAMPLE 15

5,6-etylendioksy-2-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-1,2-benzisothiazolin-l,1-dioksyd-hydroklorid 5,6-ethylenedioxy-2-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide hydrochloride

Fremstilt analogt med eksempel 12a ved omsetning av N-(3-klorpropyl)-5,6-etylendioksy-l,2-benzisothiazolin-l,1-dioksyd med 3,4-dimetoksy-fenyletyl-N-metylamin. Prepared analogously to example 12a by reacting N-(3-chloropropyl)-5,6-ethylenedioxy-1,2-benzisothiazoline-1,1-dioxide with 3,4-dimethoxy-phenylethyl-N-methylamine.

R^-verdi (kloroform/metanol = 9/1): 0,6. R^ value (chloroform/methanol = 9/1): 0.6.

EKSEMPEL 16 EXAMPLE 16

3-metyl-5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino] -propyl)-ftalimidin-hydroklorid 3-methyl-5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

Fremstilt analogt med eksempel 12a ved omsetning av 3-metyl-5., 6-dimetoksy-N- (3-klorpropyl) -ftalimidin med 3 ,4-dimetoksy-fenyletyl-N-metylamin i klorbenzen i nærvær av kaliumkarbonat. Smeltepunkt: 135 - 136°C. Prepared analogously to example 12a by reacting 3-methyl-5,6-dimethoxy-N-(3-chloropropyl)-phthalimidine with 3,4-dimethoxy-phenylethyl-N-methylamine in chlorobenzene in the presence of potassium carbonate. Melting point: 135 - 136°C.

EKSEMPEL 17 EXAMPLE 17

5,6-dimetoksy-2N-(3-[2- (3,4-dimetoksy)-fenylisopropyl-metylamino]-propyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimidine hydrochloride

a) 4, 5- dimetoksy- 2N- ( 3-[ 2-( 3, 4- dimetoksy)- fenylisopropyl- metylamino]- propyl)- ftalimid a) 4, 5- dimethoxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylisopropyl- methylamino]- propyl)-phthalimide

Fremstilt analogt med eksempel 12a ved omsetning av 4,5-dimetoksy-N-(3-klorpropyl)-ftalimid med 3,4-dimetoksy-fenyl-isopropyl-N-metylamin i klorbenzen i nærvær av kaliumkarbonat. R^-verdi (kloroform/metanol = 9/1): 0,9. Prepared analogously to example 12a by reacting 4,5-dimethoxy-N-(3-chloropropyl)-phthalimide with 3,4-dimethoxy-phenyl-isopropyl-N-methylamine in chlorobenzene in the presence of potassium carbonate. R^ value (chloroform/methanol = 9/1): 0.9.

b) 5, 6- dimetoksy- 2N- ( 3-[ 2-( 3, 4- dimetoksy)- fenyl- isopropyl- metylamino]- propyl)- ftalimidin- hydroklorid b) 5, 6- dimethoxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenyl- isopropyl- methylamino]- propyl)- phthalimidine- hydrochloride

Fremstilt analogt med eksempel 10b ved reduksjon av 4,5-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenylisopropyl-metylamino]-propyl)-ftalimid med sinkstøv i iseddik. Prepared analogously to example 10b by reduction of 4,5-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimide with zinc dust in glacial acetic acid.

Smeltepunkt: 183 - 18 5°C. Melting point: 183 - 185°C.

EKSEMPEL 18 EXAMPLE 18

5,6-metylendioksy-2N-(2-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-etyl)-ftalimidin-hydroklorid 5,6-methylenedioxy-2N-(2-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimidine hydrochloride

a) 4, 5- metylendioksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] - etyl)- ftalimid a) 4, 5- methylenedioxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- ethyl)- phthalimide

Fremstilt analogt med eksempel 10a fra 4,5-metylendioksy-ftalsyreanhydrid og 1-[2-(3,4-dimetoksy-fenyl)-etyl-metylamino]-2-amino-etan. Prepared analogously to example 10a from 4,5-methylenedioxyphthalic anhydride and 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-2-amino-ethane.

R^-verdi (kloroform/metanol = 9:1): 0,55. R^ value (chloroform/methanol = 9:1): 0.55.

b) 5, 6- metylendioksy- 2N-( 2-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino] - etyl)- ftalimidin- hydroklorid b) 5, 6- methylenedioxy- 2N-( 2-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]- ethyl)- phthalimidine- hydrochloride

Fremstilt analogt med eksempel 10b ved reduksjon av 4,5-metylendioksy-2N-(2-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-etyl)-ftalimid med sinkstøv i iseddik. Prepared analogously to example 10b by reduction of 4,5-methylenedioxy-2N-(2-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimide with zinc dust in glacial acetic acid.

R^-verdi (kloroform/metanol = 9:1): 0,4. R^ value (chloroform/methanol = 9:1): 0.4.

EKSEMPEL 19 EXAMPLE 19

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl-phthalimidine hydrochloride

5,3 g (0,02 mol) 5,6-dimetoksy-N-(2-N-metylamino)-propyl-ftalimidin, 4,0 g (0,02 mol) 3,4-dimetoksy-fenyletylklorid og 4,2 g kaliumkarbonat oppvarmes i 5 timer under tilbakeløpskjøl-ing i 100 ml klorbenzen. Efter avkjøling filtrerer man oppløs-ningen og inndamper filtratet i vakuum. Råproduktet renses ved kromatografi på silikagel (kloroform/metanol = 19/1). Man opp-løser de inndampede fraksjoner i aceton og utfeller hydrokloridet ved tilsetning av eterisk saltsyre. 5.3 g (0.02 mol) 5,6-dimethoxy-N-(2-N-methylamino)-propyl-phthalimidine, 4.0 g (0.02 mol) 3,4-dimethoxy-phenylethyl chloride and 4, 2 g of potassium carbonate are heated for 5 hours under reflux in 100 ml of chlorobenzene. After cooling, the solution is filtered and the filtrate evaporated in a vacuum. The crude product is purified by chromatography on silica gel (chloroform/methanol = 19/1). The evaporated fractions are dissolved in acetone and the hydrochloride is precipitated by the addition of ethereal hydrochloric acid.

Smeltepunkt: 170 - 172°C. Melting point: 170 - 172°C.

EKSEMPEL 20 EXAMPLE 20

5,6-dimetoksy-2N- (3-[2 - (3,4-dimetoksy)-fenyletyl-metylamino]-propyl-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl-phthalimidine hydrochloride

I en oppløsning av 3,0 g (15 mmol) 5,6-dimetoksy-ftalimidin i 100 ml dimetylformamid innfører man 0,5 g natriumhydrid og oppvarmer derefter i 30 minutter til 80°C. Derefter tilsetter man dråpevis 8,5 g (30 mmol) 1-[ 2-(3,4-dimetoksy-fenyl)-etyl-metylamino]-3-klor-propan oppløst i 100 ml dimetylformamid, Into a solution of 3.0 g (15 mmol) of 5,6-dimethoxyphthalimidine in 100 ml of dimethylformamide, 0.5 g of sodium hydride is introduced and then heated for 30 minutes to 80°C. 8.5 g (30 mmol) of 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3-chloro-propane dissolved in 100 ml of dimethylformamide are then added dropwise,

og oppvarmer i 7 timer til 140°C. Efter avkjøling tilsettes vann, og utristning foretaes flere ganger med kloroform. De organiske faser tørres og inndampes til tørrhet i vakuum. Råproduktet renses kolonnekromatografisk over silikagel. Ved felling med eterisk saltsyre får man hydrokloridet. and heats for 7 hours to 140°C. After cooling, water is added, and shaking is carried out several times with chloroform. The organic phases are dried and evaporated to dryness in vacuo. The crude product is purified by column chromatography over silica gel. Precipitation with ethereal hydrochloric acid gives the hydrochloride.

Smeltepunkt: 170 - 172°C. Melting point: 170 - 172°C.

EKSEMPEL 21 EXAMPLE 21

1,45 g (5 mmol) 2-brommetyl-4,5-dimetoksy-benzoesyre-metylester, 2,52 g (10 mmol) 1-[2-(3,4-dimetoksy-fenyl)-etyl-metylamino]-3-amino-propan og 3 g kaliumkarbonat oppvarmes i 4 timer under tilbakeløpskjøling i 200 ml metyletylketon. Efter avkjøling frafiltrerer man uoppløselige bestanddeler og inndamper filtratet i vakuum. Råproduktet renses ved kromatografi på silikagel (kloroform/metanol = 19/1). Ved felling med -eterisk saltsyre får man hydrokloridet. 1.45 g (5 mmol) 2-bromomethyl-4,5-dimethoxy-benzoic acid methyl ester, 2.52 g (10 mmol) 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]- 3-amino-propane and 3 g of potassium carbonate are heated for 4 hours under reflux in 200 ml of methyl ethyl ketone. After cooling, insoluble components are filtered off and the filtrate is evaporated in a vacuum. The crude product is purified by chromatography on silica gel (chloroform/methanol = 19/1). Precipitation with -etheric hydrochloric acid gives the hydrochloride.

Smeltepunkt: 170 172°C. Melting point: 170 172°C.

EKSEMPEL 22 EXAMPLE 22

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metyalmino]-propyl)ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)phthalimidine hydrochloride

a) 1-[2-(3,4-dimetoksy-fenyl)-etyl-metylamino]-3,(1-imino-5,6-dimetoksy-ftalimidin- 2-yl)-propan a) 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino]-3,(1-imino-5,6-dimethoxy-phthalimidin-2-yl)-propane

6,4 g (0,02 5 mol) 2-cyano-4,5-dimetoksy-benzylbromid og 6,3 g (0,025 mol) 1-[2-(3,4-dimetoksy-fenyl)-etyl-metylamino]-3-amino-propan oppvarmes i 6 timer under tilbakeløpskjøling i 80 ml etanol. Efter avkjøling avdrives oppløsningsmidlet i vakuum, og råproduktet anvendes videre til reaksjonstrinn b) uten ytterligere rensning. 6.4 g (0.025 mol) 2-cyano-4,5-dimethoxy-benzyl bromide and 6.3 g (0.025 mol) 1-[2-(3,4-dimethoxy-phenyl)-ethyl-methylamino] -3-amino-propane is heated for 6 hours under reflux in 80 ml of ethanol. After cooling, the solvent is driven off in a vacuum, and the crude product is further used for reaction step b) without further purification.

R^-verdi: (kloroform/metanol = 19/1): 0,5. R^ value: (chloroform/methanol = 19/1): 0.5.

b) 5, 6- dimetoksy- 2N-( 3-[ 2-( 3, 4- dimetoksy)- fenyletyl- metylamino]-propyl)- ftalimidin- hydroklorid 5 g 1-[2-(3,4-dimetoksy-fenyl)-etyl-metylamino]-3-(1-imino-5,6-dimetoksy-ftalimidin-2-yl)-propan og llg kaliumkarbonat oppvarmes i 8 timer under tilbakeløpskjøling i en blanding av 5 0 ml etanol og 80 ml vann. Man inndamper i vakuum og renser råproduktet ved kromatografi på silikagel (kloroform/metanol 19/1). Fra dén inndampede fraksjon får man den frie base, som felles som hydrklorid fra aceton med eterisk saltsyre. Smeltepunkt: 170 - 172°C. b) 5, 6- dimethoxy- 2N-( 3-[ 2-( 3, 4- dimethoxy)- phenylethyl- methylamino]-propyl)- phthalimidine- hydrochloride 5 g 1-[2-(3,4-dimethoxy-phenyl) )-ethyl-methylamino]-3-(1-imino-5,6-dimethoxy-phthalimidin-2-yl)-propane and 1.1 g of potassium carbonate are heated for 8 hours under reflux in a mixture of 50 ml of ethanol and 80 ml of water. Evaporate in vacuum and purify the crude product by chromatography on silica gel (chloroform/methanol 19/1). From the evaporated fraction, the free base is obtained, which is separated as hydrochloride from acetone with ethereal hydrochloric acid. Melting point: 170 - 172°C.

EKSEMPEL 2 3 EXAMPLE 2 3

4 5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletylamin]-propyl)-ftalimidin-hydroklorid 4 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethylamine]-propyl)-phthalimidine hydrochloride

I en oppløsning av 2,6 g (10 mmol) l-amino-3-[N-(5,6-dimetoksy-ftalimidin)]-propan og 1,8 g (10 mmol) 2-(3,4-dimetoksy-f enyl)-acetaldehyd i 100 ml etanol innføres hydrogen i 4 timer ved en temperatur på 50°C og 5 atmosærers trykk efter tilsetning av 0,3 g palladium/kull (10%ig). Efter avsluttet hydro-genopptagelse frafiltreres katalysatoren, og oppløseningen inndampes i vakuum. Ved felling med eterisk saltsyre får man hydrokloridet . In a solution of 2.6 g (10 mmol) of 1-amino-3-[N-(5,6-dimethoxy-phthalimidine)]-propane and 1.8 g (10 mmol) of 2-(3,4-dimethoxy -phenyl)-acetaldehyde in 100 ml of ethanol, hydrogen is introduced for 4 hours at a temperature of 50°C and 5 atmospheres of pressure after the addition of 0.3 g of palladium/charcoal (10% strength). After completion of hydrogen absorption, the catalyst is filtered off, and the solution is evaporated in a vacuum. Precipitation with ethereal hydrochloric acid gives the hydrochloride.

Smeltepunkt: 207 - 209°C. Melting point: 207 - 209°C.

EKSEMPEL 24 EXAMPLE 24

I en oppløsning av 3,2 g (10 mmol) 3-[N-(5,6-dimetoksy-ftalimidin]-propionaldehyd-dietylacetal og 1,8 g (10 mmol) 3,4-dimetoksy-fenyl-etylamin i 100 ml etanol innføres hydrogen i 4 timer ved en temperatur på 50°C og 5 atmosfærers trykk efter tilsetning av 0,3 g palladium/kull (10%ig). Efter avsluttet hydro-genopptagelse frafiltreres katalysatoren, og oppløsningen inndampes i vakuum. Ved felling med eterisk saltsyre får man hydrokloridet. In a solution of 3.2 g (10 mmol) 3-[N-(5,6-dimethoxy-phthalimidine]-propionaldehyde-diethyl acetal and 1.8 g (10 mmol) 3,4-dimethoxy-phenyl-ethylamine in 100 ml of ethanol, hydrogen is introduced for 4 hours at a temperature of 50°C and 5 atmospheres of pressure after the addition of 0.3 g of palladium/coal (10% strength). After completion of hydrogen uptake, the catalyst is filtered off, and the solution is evaporated in a vacuum. During precipitation with ethereal hydrochloric acid the hydrochloride is obtained.

Smeltepunkt: 207 - 209°C. Melting point: 207 - 209°C.

Analogt med eksemplene 19 til 24 ble også de følgende forbindelser fremstilt: 2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]propyl)-ftalimidin-hydroklorid Analogous to examples 19 to 24, the following compounds were also prepared: 2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]propyl)-phthalimidine hydrochloride

Smeltepunkt: 14 6 - 148°C. Melting point: 14 6 - 148°C.

Smeltepunkt: 207 - 209°C. Melting point: 207 - 209°C.

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-n-propylamino]-propyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-n-propylamino]-propyl)-phthalimidine hydrochloride

Smeltepunkt: 120 - 122°C (aceton/metanol). Melting point: 120 - 122°C (acetone/methanol).

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-etyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-ethyl)-phthalimidine hydrochloride

Smeltepunkt: 149 - 151°C. Melting point: 149 - 151°C.

R^-verdi (kloroform/metanol = 19/1): 0,4. R^ value (chloroform/methanol = 19/1): 0.4.

3-fenyl-5-klor-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metyl-amino]-propyl)-1,2-benzisothiazolin-l,1-dioksyd-hydroklorid R^-verdi (kloroform/metanol = 19/1): 0,5. 3-phenyl-5-chloro-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methyl-amino]-propyl)-1,2-benzisothiazoline-1,1-dioxide hydrochloride R^- value (chloroform/methanol = 19/1): 0.5.

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-1,2-benzisotiazolin-l,1-dioksyd-hydroklorid Smeltepunkt: 196 - 198°C (aceton). 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide hydrochloride Melting point: 196 - 198°C (acetone).

5,6-metylendioksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-ftalimidin-hydroklorid 5,6-methylenedioxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

Smeltepunkt: 2 37 - 2 39°C. Melting point: 2 37 - 2 39°C.

5,6-etylendioksy-2N-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-ftalimidin-hydroklorid 5,6-ethylenedioxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

Smeltepunkt: 208 - 210°C. Melting point: 208 - 210°C.

Smeltepunkt: 206 - 208°C. Melting point: 206 - 208°C.

5,6-etylendioksy-2N-(3-[2-{3,4-metylendioksy)-fenyletyl-metylamino] -propyl)-ftalimidin-hydroklorid 5,6-ethylenedioxy-2N-(3-[2-{3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

Smeltepunkt: 180 - 182°C. Melting point: 180 - 182°C.

5,6-dimetoksy-2N-(3-[2-(3,4-metylendioksy)-fenyletyl-metylamino] -propyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-methylenedioxy)-phenylethyl-methylamino]-propyl)-phthalimidine hydrochloride

Smeltepunkt: 235 - 237°C. Melting point: 235 - 237°C.

5,6-etylendioksy-2-(3-[2-(3,4-dimetoksy)-fenyletyl-metylamino]-propyl)-1,2-benzisotiazolin-l,1-dioksyd-hydroklorid Rj-verdi (kloroform/metanol = 9/1): 0,6. 5,6-ethylenedioxy-2-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-1,2-benzisothiazoline-1,1-dioxide hydrochloride Rj value (chloroform/methanol = 9/1): 0.6.

Smeltepunkt: 135 - 136°C. Melting point: 135 - 136°C.

5,6-dimetoksy-2N-(3-[2-(3,4-dimetoksy)-fenylisopropyl-metylamino]-propyl)-ftalimidin-hydroklorid 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylisopropyl-methylamino]-propyl)-phthalimidine hydrochloride

Smeltepunkt: 183 - 185°C. Melting point: 183 - 185°C.

Claims

1. Analogous method for the preparation of pharmacologically active arylalkylamines of the general formula I where means a hydrogen atom, a lower alkyl group or a phenyl group, R2 means a hydrogen atom or a methoxy group, -R, means a hydrogen atom or a methoxy group or together with R2 a methylenedioxy or ethylenedioxy group, R^ and Rg, which may be the same or different, each means a hydrogen atom or a 1-3 C alkyl group , Rg means a hydrogen atom or a 1-3 C alkoxy group, R7 means a 1-3 C alkoxy group or together with Rg a methylenedioxy or ethylenedioxy group, X means a carbonyl or sulfonyl group, and n means the number 2 or 3, and their physiologically compatible acid addition salts with inorganic or organic acids, characterized in that a) a compound of the general formula II where R 1 , R 2 , R 8 , X and n are as indicated above, and Z means a leaving group, is reacted with a phenylethylamine of the general formula III where , Rg, Rg and R^ are as indicated above, or b) for the preparation of compounds of the general formula I where R^ means a hydrogen atom and X a carbonyl group, a compound of the general formula IV is reduced where R 2 to R 1 and n are as indicated above, or c) a phthalimidine of the general formula V where R 1 to , X and n are as indicated above, is reacted with an aralkyl compound of the general formula VI where Rc , R^ and R_ are as indicated above, and b b / Z means an outgoing group, or d) a 1H-phthalimidine of the general formula VII where R^, R^, R^ and X are as indicated above, reacted with an alkylamine of the general formula VIII where R4, Rg, Rg, R^ and n are as indicated above, and Z means a leaving group, or e) for the preparation of compounds of the general formula I where X means a carbonyl group, react a benzyl halide of the general formula IX where to R^ is as stated above, and Hal means a chlorine, bromine or iodine atom, with an amine of the general formula X where R^ to R^ and n are as indicated above, and the 1-imino-phthalimidine obtained is hydrolyzed, or f) for the preparation of compounds of the general formula I where X means a carbonyl group, a benzyl halide of the general formula XI is reacted where R^ to R^ are as indicated above, Hal means a chlorine, bromine or iodine atom, and Y means a leaving group, with an amine of the general formula X where to R^ and n are as indicated above, or g) a phthalimidine aldehyde of the general formula XIII where R^, R^, R^, X and n are as indicated above, or its acetal, is reacted with an amine of the general formula III where R 1 to R 7 are as indicated above, in the presence of catalytically activated hydrogen, or h) a carbonyl compound of the general formula XIV wherein Rg to R7 are as indicated above, or its acetal resp. ketal, is reacted with a phthalimidine of the general formula V where R^ to R^, X and n are as above, in the presence of catalytically activated hydrogen, and optionally, if a compound of the general formula I has been prepared by methods a) - h) where R^ denotes a hydrogen atom, this is alkylated, and/or an obtained compound of the general formula I is optionally transferred to a physiologically compatible acid addition salt with an inorganic or organic acid.

2. Process as stated in claim 1 for the production of 5,6-dimethoxy-2N-(3-[2-(3,4-dimethoxy)-phenylethyl-methylamino]-propyl)-phthalimidine, characterized in that starting materials are used where R^ is hydrogen, R2 and R^ are in the 5,6-position (with regard to the completed ring system) and each means a methoxy group, R4 is methyl, Rg is hydrogen, Rg and R^ are in the m- and p-position respectively and each means a methoxy group, X is carbonyl, and n is 3.