NO743023L - - Google Patents

Info

Publication number
NO743023L
NO743023L NO743023A NO743023A NO743023L NO 743023 L NO743023 L NO 743023L NO 743023 A NO743023 A NO 743023A NO 743023 A NO743023 A NO 743023A NO 743023 L NO743023 L NO 743023L
Authority
NO
Norway
Prior art keywords
methyl
formula
compounds
lower alkyl
stands
Prior art date
Application number
NO743023A
Other languages
Norwegian (no)
Inventor
J Pless
E Sandrin
Original Assignee
Sandoz Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from CH1253273A external-priority patent/CH583684A5/en
Application filed by Sandoz Ag filed Critical Sandoz Ag
Publication of NO743023L publication Critical patent/NO743023L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Fremgangsmåte for fremstilling av nye .f enyletylamin-derivater. Process for the production of new .f enylethylamine derivatives.

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

av nye fenyletylamin-derivater med formel I of new phenylethylamine derivatives of formula I

hvori begge betyr lavere alkyl, begge R~betyr hydrogen, lavere alkyl eller hydroksymetyl og ri står for et helt tall mellom 2 og 0, samt salter derav med uorganiske og organiske syrer. in which both mean lower alkyl, both R~ means hydrogen, lower alkyl or hydroxymethyl and ri stands for an integer between 2 and 0, as well as salts thereof with inorganic and organic acids.

Hvis eller R ? betyr lavere alkyl, så inneholder dette 1 til 5, foretrukket 1 til 3 karbonatomer og utgjør spesielt metyl. Hvis n betegner antallet av karbonatomer i en kjede, idet n betyr et helt tall mellom 2 og 10, utgjøres denne kjede foretrukket av 4 til 8, spesielt 6 karbonatomer. If or R ? means lower alkyl, then this contains 1 to 5, preferably 1 to 3 carbon atoms and constitutes especially methyl. If n denotes the number of carbon atoms in a chain, where n means an integer between 2 and 10, this chain preferably consists of 4 to 8, especially 6 carbon atoms.

Det særegne ved fremgangsmåten i henhold til oppfinnelsen for fremstilling av de nye forbindelser med formel I og deres syreaddisjonssalter, er at enten The peculiarity of the method according to the invention for the preparation of the new compounds of formula I and their acid addition salts is that either

a) i forbindelser med formel II a) in compounds of formula II

hvori begge R^betyr lavere alkyl, begge R^betyr hydrogen, in which both R^ means lower alkyl, both R^ means hydrogen,

lavere alkyl eller hydroksymetyl,'n står for et helt tall mellom 2 og 10 og R^ betyr en acidolytisk eller hydrogenolytisk avspaltbar rest, overføres etergruppene i hydroksygrupper, el 1 er lower alkyl or hydroxymethyl,'n stands for an integer between 2 and 10 and R^ means an acidolytically or hydrogenolytically cleavable residue, the ether groups are transferred into hydroxy groups, or 1 is

b) forbindelser med formel III b) compounds of formula III

hvori og R ? har den ovennevnte b±ydning, omsettes med forbindelser med formel IV in which and R ? has the above-mentioned structure, is reacted with compounds of formula IV

hvori n har den ovennevnte betydning og Hal står for klor, brom eller jod. in which n has the above meaning and Hal stands for chlorine, bromine or iodine.

og de således erholdte forbindelser med formel I overføres eventuelt i sine syreaddisjonssalter. and the thus obtained compounds of formula I are optionally transferred in their acid addition salts.

Fremgangsmåten a) i henhold til oppfinnelsen kan gjennomføres ved hjelp av i og for seg kjente metoder for overføring av etergrupper i hydroksygrupper. Method a) according to the invention can be carried out using methods known per se for the transfer of ether groups into hydroxy groups.

Står i forbindelsene med formel II R^for en acidolytisk avspaltbar rest, f.eks. metyl, etyl eller benzyl, gjennomføres eterspaltingen etter vanlige metoder. Således kan f.eks. forbindelser med formel II,. hvori R^står for en acidolytisk avspaltbar rest, i et In the compounds of formula II R^ stands for an acidolytically cleavable residue, e.g. methyl, ethyl or benzyl, the ether cleavage is carried out according to usual methods. Thus, e.g. compounds of formula II,. in which R^ stands for an acidolytically cleavable residue, in et

under reaksjonsbetingelsene inert organisk løsningsmiddel, f.eks. under the reaction conditions inert organic solvent, e.g.

et halogenert hydrokarbon som metylenklorid eller karbonfeetra-klorid eller aromatiske hydrokarboner som toluen eller benzen ved -80 til +70°C bringes til omsetning med Lewis-syrer, f.eks. med bortribromid, eller i løpet av kort tid behandles med sterke .mineralsyrer, som f.eks. bromhydrogensyre eller jodhydrogensyre, eventuelt med forhøyet temperatur fra 20 - 100°C, eller hydroklorider bromider eller jodider av organiske baser som anilin eller pyridin bringes ved forhøyet temperatur til innvirkning på forbindelser med formel II, hvori R^ står for en acidolytisk avspaltbar rest. a halogenated hydrocarbon such as methylene chloride or carbon tetrachloride or aromatic hydrocarbons such as toluene or benzene at -80 to +70°C is reacted with Lewis acids, e.g. with boron tribromide, or within a short time treated with strong mineral acids, such as e.g. hydrobromic acid or hydroiodic acid, possibly with an elevated temperature from 20 - 100°C, or hydrochlorides, bromides or iodides of organic bases such as aniline or pyridine are brought at an elevated temperature to affect compounds of formula II, in which R^ stands for an acidolytically cleavable residue.

Hvis i forbindelsene med formel II R^står for en hydrogenolytisk avspaltbar rest, skjer denne behandling med katalytisk aktivert hydrogen. Som hydrogenolytisk avspaltbar rest kommer en eventuelt substituert benzyl-, benzhydryl-, og trityl-rest på tale. Den katalytiske hydrogenering kan gjennomføres i et under reaksjonsbetingelsene inert løsningsmiddel, £eks etylacetat, dioksan, tetrahydrofuran, dimetylformamid eller i en lavere alkohol som metanol eller etanol. Hydrogeneringen gjennomføres foretrukket ved temperaturer mellom 20 og 100°C ved 1 til 100 atmosfærers hydrogen-trykk. Som katalysator kommer de vanlige edelmetallkatalysatorer■ foretrukket palladium, på tale. Edelmetallkatalysatorene kan f.eks. foreligge som- bærerkatalysatorer, f.eks. i form av palladium på kull. If in the compounds of formula II R^ stands for a hydrogenolytically cleavable residue, this treatment takes place with catalytically activated hydrogen. An optionally substituted benzyl, benzhydryl and trityl residue is used as a hydrogenolytically cleavable residue. The catalytic hydrogenation can be carried out in a solvent inert under the reaction conditions, eg ethyl acetate, dioxane, tetrahydrofuran, dimethylformamide or in a lower alcohol such as methanol or ethanol. The hydrogenation is preferably carried out at temperatures between 20 and 100°C at 1 to 100 atmospheres of hydrogen pressure. As a catalyst, the usual noble metal catalysts, preferably palladium, are used. The precious metal catalysts can e.g. present as carrier catalysts, e.g. in the form of palladium on charcoal.

Fremgangsmåten b) i henhold til oppfinnelsen kan gjennomføres ved at forbindelser med formel III, hvori FL og R„ har den ovennevnte betydning, ved temperaturer på fra 20 til 100°C i nærvær av et under reaksjonsbetingelsene inert løsningsmiddel, f.eks. en lavere alkohol, kondenseres med forbindelser med formel IV, hvori n har den ovennevnte betydning og Hal står for klor, brom eller jod.;. Method b) according to the invention can be carried out by compounds of formula III, in which FL and R„ have the above meaning, at temperatures of from 20 to 100°C in the presence of a solvent inert under the reaction conditions, e.g. a lower alcohol, is condensed with compounds of formula IV, in which n has the above meaning and Hal stands for chlorine, bromine or iodine.;.

Forbindelsene med formel I kan isoleres fra reaksjonsblåndingen, og renses på i og for seg kjent måte, og de fri baser lar seg på The compounds of formula I can be isolated from the reaction mixture and purified in a manner known per se, and the free bases allow

■vanlig måte overføre i sine syreaddisjonssalter og omvendt. ■usual way transfer in their acid addition salts and vice versa.

De som utgangsmaterial anvendte tidligere ukjente forbindelser med formel.' II fremstilles ved at forbindelser med formel V They used previously unknown compounds with formula as starting material.' II is produced by compounds of formula V

hvori R_ betyr hydrogen, lavere alkyl eller hydroksymetyl og R^står for en acidolytisk eller hydrogenolytisk avspaltbar rest, enten omsettes med paraformaldehyd i nærvær av hydrogenhalogenid-gass, behandles deretter med katalytisk aktivert hydrogen, eller omsettes med en forbindelse med formel VI henhv. VI<*> ; hvori R står for en lavere alkylgruppe og X betyr klor eller brom, etter en Friedel-Crafts-metode, idet i tilfellet av formel VI' deretter karbonylgruppen reduseres, deretter behandles med katalytisk aktivert hydrogen, den dannede forbindelse med formel ;VII ; hvori R^betyr lavere alkyl, R^ betyr hydrogen, lavere alkyl eller hydroksymetyl og R^står for en acidolytisk eller hydrogenolytisk avspaltbar rest, behandles med hydrogenhalogenidsyre, den dannede forbindelse med formel VIII ; hvori R^betyr lavere alkyl, R ? betyr hydrogen, lavere alkyl eller hydroksymetyl og R^ står for en acidolytisk eller hydrogenolytisk avspaltbar rest, kondenseres med et dikarboksylsyrederivat med ;.formel IX ; hvori Y. står for halogen og m står for et helt tall mellom 0 og 8, og den dannede forbindelse med formel X ; hvori R betyr lavere alkyl, R2betyr hydrogen, lavere alkyl eller hydroksymetyl, m står for et helt tall mellom 0 og 8 og R^betyr en acidolytisk eller hydrogenolytisk avspaltbar rest, reduseres med et reduksjonsmiddel som selektivt angriper karbonylgruppene. ;De nye fenyletylaminderivater og deres syreaddisjonssalter utmerker seg ved farmakologisk undersøkelse ved kretsløprikkende effekter og kan følgelig anvendes som legemidler. ;Forbindelsene viser en blodtrykkssenkende virkning, påvist i narkotiserte hunder (kloralose-uretan) i doser fra 5^ug/kg i.v.'og i våken hund (Goldblatt) i doser fra 0.1 mg/kg i.v. Denne effekt tilskrives hovedsakelig en dopamin-reseptor-stimulering. Dopamin-reseptor-stimuleringen kunne påvises i narkotisert hund ved nedsettelse av motstanden i mesenterial-karene i doser på 5^ug/kg i.v. i hunder. ;Forbindelsene med formel I og deres fysiologisk tålbare salter ;er på grunn av denne farmakologiske virkning forutsetningsvis egnet for anvendelse raed forhøyet blodtrykk, for sjokkterapi, ved akutt nyresvikt i sammenheng'med forhøyet blodtrykk, for behandling av legemiddel-forgiftninger såvel som gallaktorrhea. ;De doser som anvendes varierer selvfølgelig alt etter tilførsels-måte og den tilstand som skal behandles. Vanlig oppnås dog'tilfredsstillende resultater i forsøksdyr med en dose på'0.1 mg/kg ;til omtrent 1 mg/kg kroppsvekt. ;For større pattedyr ligger den daglige dose på omtrent 15 mg. For oral tilførsel inneholder deldosene omtrent 5 til 50 mg av forbindelsene med formel I ved siden av faste eller flytende bærersubstanser. ;Forbindelsen N, N •-bis-(3,4-dihydroksy-6-metyl-fenyletyl)heksa-metylendiamin har vist seg særlig virksom. ;Som legemiddel kan forbindelsene med formel I henhv. deres fysiologisketålbare syreaddisjonssalter tilføres alene eller i egnet preparatform sammen med farmakologisk indifferente hjelpe-stoffer. ;Hvis fremstillingen av utgangsforbindelsene eikke er beskrevet, er disse kjente eller kan fremstilles på i og for seg kjente måter henhv. analogt med de her beskrevne eller analogt med i og for seg kjente fremgangsmåter. ;Oppfinnelsen illustreres nærmere i de etterfølgende eksempler, hvori alle temperaturangivelser er i grader Celsius. ;Eksempel 1: N, N'- bis-( 3, 4- dihydroksy- 6- metyl- fenyl- etyl)-heksametylendiamin. ;7g N,N'-bis(3,4-dimetoksy-6-metyl-fenyletyl)heksametylendiamin suspenderes i 100 ml metylenklorid og 7.5 ml bortribromid tildryppes under omrøring. Etter en time tildryppes 15 ml metanol og det inndampes deretter flere ganger under vakuum. Etter behandling med eter erholdes den i overskriften nevnte forbindelse i form av dihydrobromidet. ;<C>24H36<N>2°4<+><2>HBr'SmP- 227~228°C ;Det som utgangsmaterial anvendte N,N-(bis-3,4-dimetoksy-6-metyl-fenyletyl)-heksametylendiamin ble fremstilt på følgende måte: ;1. N-acetamido-S^-dim^toks^ ;175 g N-acetylhomoveratrylamin suspenderes i 2.5 1 benzen og det tilsettes 88g paraformaldehyd. Iløpet av 3 timer innledes under svak avkjøling saltsyregass, hvorved det etter hvert dannes et bunnfall i løsningen. Det avsuges på filter og ettervaskes med benzen. Den dannede klormetylforbindelse løses i 2 1 metanol og hydrogeneres katalytisk med 20 g palladium på kull. Etter avsluttet hydrogenopptagelse frafiltreres katalysatoren og løsningen inndampes. Etter behandling med eter erholdes den i overskriften nevnte forbindelse med smp. 108°C. ;■2. ^^-dimetoksy-S-metyl-f enyletylamin(_hydroklorid)__. ;173 g N-acetamido-3,4-dimetoksy-6-metyl-fenyletylamin suspenderes i 2 1 1 N saltsyre og kokes i 16 timer under tilbakeløp. Deretter inndampes i vakuum, det tilsettes en fortynnet natriumhydroksyd-løsning og det frigitte amin ekstraheres med metylenklorid og felles med eterisk saltsyre. Den i ovérskriften nevnte forbindelse med smp. 183°C erholdes. ;3• Adipinsyre-bis^3i4-dimetoksy-6-metyl-fenyletylamid) ;30 g 3,4-dimetoksy-6-metyl-fenyl-etylamin og ,8 ml trietylamin suspenderes i 300 ml metylenklorid, avkjøles til 0°C og det inndryppes i løpet av 15 minutter 10 ml adipinsyrediklorid. ;Etter ytterligere tilsetning av metylenklorid vaskes flere ganger i skilletrakt med fortynnet saltsyre og den organiske fase tøres over natriumsul f at. Etter inndamping og behandling med eter erholdes den i overskriften nevnte forbindelse. Smp. 167°C. 4. ^i^lz^is-^S^-dimetoksy-S-metyl-.f enyLetyl)-heksametylendiamin-(_ hydroklorid)_ 20 g natrlumborhydrid blandes i 1.1 1 diglym og etter dannelse av ;en oppløsning tildryppes en suspensjon av 25 g adipinsyre-di-(3,4-dimetoksy-6-metyl-fenyletylamid) i 300 ml abs. dioksan, idet ;temperaturen holdes på 10°C og nitrogen innføres. Deretter tildryppe 83 'ml bortrifluorideterat i 50 ml diglym. Det omrøres i 6 timer, overskudd av reduksjonsmiddel spaltes deretter ved tilsetning av 30 ml vann og det syres med fortynnet saltsyre. Etter inndamping i vakuum tilsettes metylenklorid og det utfelte produkt frafiltreres og tørres. Den i overskriften nevnte forbindelse erholdes. ;Smp. 249°C. ;Eksempel 2: N, N'- bis-( 3, 4- dihydroksy- 6- metyl- fenyl- etyl)-pentametylendiamin. ;N,N'-bis-(3,4-dimetoksy-6-metyl-fenyletyl)-pentametylendiamin omsettes med bortribromid etter den i eksempel 1 beskrevne fremgangsmåte. ;Eksempel 3: N, N'- bis-( 3, 4- dihydroksy- 6- metyl- fenyl- etyl)-tetrametylendiamin. ;N,N'-bis-(3,4-dimetoksy-6-metyl-fenyletyl)-tetrametylendiamin omsettes med bortribromid etter den i eksempel 1 beskrevne fremgangsmåte. ;Eksempel 4; N, N'- bis-( 3, 4- dihydroksy- 6- metyl- fenyl- etyl)-heftametylendiamin. ;N,N<1->bis-(3,4-dimetoksy-6-metyl-fenyletyl)heptametylendiamin omsettes med bortribromid etter den i eksempel 1 beskrevne fremgangsmåte. ;Eksempel 5: . N, N'- bis-( 3, 4- dihydroksy- 6- metyl- fenyletyl)- octa-me tyl endiamin. ;N,N'-bis-(3,4-dimetoksy-6-metyl-fenyletyl)-octametylendiamin omsettes-med bortribromid etter den i eksempel 1 beskrevne fremgangsmåte. ;<C>26H40N2°42HPr* SmP'220°C. in which R_ means hydrogen, lower alkyl or hydroxymethyl and R^ stands for an acidolytically or hydrogenolytically cleavable residue, either reacted with paraformaldehyde in the presence of hydrogen halide gas, then treated with catalytically activated hydrogen, or reacted with a compound of formula VI or VI<*> ; in which R stands for a lower alkyl group and X means chlorine or bromine, according to a Friedel-Crafts method, in that in the case of formula VI' the carbonyl group is then reduced, then treated with catalytically activated hydrogen, the formed compound of formula ;VII ; in which R^ means lower alkyl, R^ means hydrogen, lower alkyl or hydroxymethyl and R^ stands for an acidolytically or hydrogenolytically cleavable residue, is treated with hydrohalic acid, the formed compound of formula VIII; in which R^means lower alkyl, R ? means hydrogen, lower alkyl or hydroxymethyl and R^ stands for an acidolytically or hydrogenolytically cleavable residue, is condensed with a dicarboxylic acid derivative of formula IX; in which Y. stands for halogen and m stands for an integer between 0 and 8, and the formed compound of formula X; in which R means lower alkyl, R2 means hydrogen, lower alkyl or hydroxymethyl, m stands for an integer between 0 and 8 and R^ means an acidolytically or hydrogenolytically cleavable residue, is reduced with a reducing agent which selectively attacks the carbonyl groups. ;The new phenylethylamine derivatives and their acid addition salts stand out in pharmacological examination for circulatory stimulating effects and can consequently be used as pharmaceuticals. The compounds show a blood pressure-lowering effect, demonstrated in anesthetized dogs (chloralose-urethane) in doses from 5 µg/kg i.v. and in awake dogs (Goldblatt) in doses from 0.1 mg/kg i.v. This effect is mainly attributed to dopamine receptor stimulation. The dopamine receptor stimulation could be demonstrated in anesthetized dogs by a reduction in the resistance in the mesenteric vessels in doses of 5 µg/kg i.v. in dogs. The compounds of formula I and their physiologically tolerable salts are, due to this pharmacological action, presumptively suitable for use in elevated blood pressure, for shock therapy, in acute renal failure in connection with elevated blood pressure, for the treatment of drug poisoning as well as gallactorrhea. The doses used vary, of course, depending on the method of administration and the condition to be treated. Usually, however, satisfactory results are obtained in experimental animals with a dose of 0.1 mg/kg to approximately 1 mg/kg body weight. For larger mammals, the daily dose is approximately 15 mg. For oral administration, the partial doses contain approximately 5 to 50 mg of the compounds of formula I in addition to solid or liquid carrier substances. The compound N,N •-bis-(3,4-dihydroxy-6-methyl-phenylethyl)hexa-methylenediamine has proven particularly effective. As a medicine, the compounds of formula I or their physiologically tolerable acid addition salts are added alone or in suitable preparation form together with pharmacologically indifferent excipients. If the production of the starting compounds is not described, these are known or can be produced in per se known ways or analogously to those described here or analogously to methods known per se. The invention is illustrated in more detail in the following examples, in which all temperature indications are in degrees Celsius. Example 1: N,N'-bis-(3,4-dihydroxy-6-methyl-phenyl-ethyl)-hexamethylenediamine. 7g of N,N'-bis(3,4-dimethoxy-6-methyl-phenylethyl)hexamethylenediamine is suspended in 100 ml of methylene chloride and 7.5 ml of boron tribromide is added dropwise while stirring. After one hour, 15 ml of methanol are added dropwise and it is then evaporated several times under vacuum. After treatment with ether, the compound mentioned in the title is obtained in the form of the dihydrobromide. ;<C>24H36<N>2°4<+><2>HBr'SmP- 227~228°C ;The starting material used N,N-(bis-3,4-dimethoxy-6-methyl-phenylethyl) -hexamethylenediamine was prepared in the following way: ;1. N-acetamido-S^-dim^tox^; 175 g of N-acetylhomoveratrylamine are suspended in 2.5 1 of benzene and 88 g of paraformaldehyde are added. During 3 hours, hydrochloric acid gas is introduced under slight cooling, whereby a precipitate is gradually formed in the solution. It is extracted on a filter and washed with benzene. The chloromethyl compound formed is dissolved in 2 1 methanol and catalytically hydrogenated with 20 g of palladium on charcoal. After completion of hydrogen absorption, the catalyst is filtered off and the solution is evaporated. After treatment with ether, the compound mentioned in the title is obtained with m.p. 108°C. ;■2. ^^-dimethoxy-S-methyl-phenylethylamine(_hydrochloride)__. ; 173 g of N-acetamido-3,4-dimethoxy-6-methyl-phenylethylamine are suspended in 2 1 1 N hydrochloric acid and boiled for 16 hours under reflux. It is then evaporated in vacuo, a dilute sodium hydroxide solution is added and the liberated amine is extracted with methylene chloride and combined with ethereal hydrochloric acid. The connection mentioned in the heading with mp. 183°C is obtained. ;3• Adipic acid-bis^3i4-dimethoxy-6-methyl-phenylethylamide) ;30 g of 3,4-dimethoxy-6-methyl-phenyl-ethylamine and .8 ml of triethylamine are suspended in 300 ml of methylene chloride, cooled to 0°C and the 10 ml of adipic acid dichloride are instilled over the course of 15 minutes. After further addition of methylene chloride, wash several times in a separatory funnel with dilute hydrochloric acid and the organic phase is dried over sodium sulphate. After evaporation and treatment with ether, the compound mentioned in the title is obtained. Temp. 167°C. 4. ^i^lz^is-^S^-dimethoxy-S-methyl-.phenylethyl)-hexamethylenediamine-(_hydrochloride)_ 20 g of sodium borohydride are mixed in 1.1 1 of diglyme and, after forming a solution, a suspension of 25 g adipic acid di-(3,4-dimethoxy-6-methyl-phenylethylamide) in 300 ml abs. dioxane, the temperature being kept at 10°C and nitrogen being introduced. Then add dropwise 83 ml of boron trifluoride etherate in 50 ml of diglyme. It is stirred for 6 hours, excess reducing agent is then split by adding 30 ml of water and it is acidified with dilute hydrochloric acid. After evaporation in a vacuum, methylene chloride is added and the precipitated product is filtered off and dried. The connection mentioned in the heading is obtained. ; 249°C. Example 2: N,N'-bis-(3,4-dihydroxy-6-methyl-phenyl-ethyl)-pentamethylenediamine. N,N'-bis-(3,4-dimethoxy-6-methyl-phenylethyl)-pentamethylenediamine is reacted with boron tribromide according to the method described in example 1. Example 3: N,N'-bis-(3,4-dihydroxy-6-methyl-phenyl-ethyl)-tetramethylenediamine. N,N'-bis-(3,4-dimethoxy-6-methyl-phenylethyl)-tetramethylenediamine is reacted with boron tribromide according to the method described in example 1. ;Example 4; N,N'-bis-(3,4-dihydroxy-6-methyl-phenyl-ethyl)-heptamethylenediamine. ;N,N<1->bis-(3,4-dimethoxy-6-methyl-phenylethyl)heptamethylenediamine is reacted with boron tribromide according to the method described in example 1. ;Example 5: . N,N'-bis-(3,4-dihydroxy-6-methyl-phenylethyl)-octa-methyl diamine. N,N'-bis-(3,4-dimethoxy-6-methyl-phenylethyl)-octamethylenediamine is reacted with boron tribromide according to the method described in example 1. ;<C>26H40N2°42HPr* SmP'220°C.

Eksempel 6: N, N- bis- l-( 3, 4- dihydroksy- 6- metyl- fenyl- propyl- 2)-heksametylendiamin. Example 6: N,N-bis-1-(3,4-dihydroxy-6-methyl-phenyl-propyl-2)-hexamethylenediamine.

13 g 3,4-dihydroksy-6-metyl-a-metyl-fenyletylamin og 4.7 g heksa-metylendibromid kokes under tilbakeløp i 12 timer i 80 ml etanol. Løsningen inndampes i vakuum og resten behandles med isopropanol/ saltsyre. Etter frafiltrering og ettervasking av produktet med isopropanol erholdes den i overskriften nevnte forbindelse._ 13 g of 3,4-dihydroxy-6-methyl-α-methyl-phenylethylamine and 4.7 g of hexamethylene dibromide are refluxed for 12 hours in 80 ml of ethanol. The solution is evaporated in a vacuum and the residue is treated with isopropanol/hydrochloric acid. After filtering off and washing the product with isopropanol, the compound mentioned in the title is obtained._

Smp. 155°C. Temp. 155°C.

Eksempel 7; N, N' - bis- l-( 3 , 4- dihydroksy- 6- metyl- f enyl- propyl- 2-)— Example 7; N,N'-bis-1-(3,4-dihydroxy-6-methyl-phenyl-propyl-2-)—

pentametylendiamin. 3 , 4-dihydroksy-6-metyl-oc-metyl-f enetylamin og pentametylendibromid omsettes etter den i eksempel 6 beskrevne fremgangsmåte. pentamethylenediamine. 3,4-dihydroxy-6-methyl-oc-methyl-phenethylamine and pentamethylene dibromide are reacted according to the method described in example 6.

Eksempel 8: N, N'- bis- l-( 3, 4- dihydroksy- 6- mety1- fenyl- propyl- 2)-tetrametylendiamin. 3 , 4-dihydroksy-5-metyl-oc-metyl-f enyletylamin og tetrametylendibromid omsettes etter den i eksempel 6 beskrevne fremgangsmåte. ' Eksempel 9: N, N'- bis- l-( 3, 4- dihydroksy- 6- mety1- fenyl- propyl- 2)-heptametylendiamin.. 3 , 4-dihydroksy-6-metyl-oc-metyl-f enyletylamin og heptametylendibromid omsettes etter den i eksempel 6 beskrevne fremgangsmåte. Example 8: N,N'-bis-1-(3,4-dihydroxy-6-methyl-1-phenyl-propyl-2)-tetramethylenediamine. 3,4-dihydroxy-5-methyl-oc-methyl-phenylethylamine and tetramethylene dibromide are reacted according to the method described in example 6. Example 9: N,N'-bis-1-(3,4-dihydroxy-6-methyl-1-phenyl-propyl-2)-heptamethylenediamine.. 3,4-dihydroxy-6-methyl-oc-methyl-phenylethylamine and heptamethylene dibromide are reacted according to the method described in example 6.

Eksempel 10; N, N'- bis- l-( 3, 4- dihydroksy- 6- metylfenyl- propyl- 2)-octametylendiamin. 'v' - Example 10; N,N'-bis-1-(3,4-dihydroxy-6-methylphenyl-propyl-2)-octamethylenediamine. 'v' -

3,4-dihydroksy-6-metyl-a-metyl-fenyletylamin og oktametylendibromid omsettes etter den i eksempel 6 beskrevne fremgangsmåte. 3,4-dihydroxy-6-methyl-α-methyl-phenylethylamine and octamethylene dibromide are reacted according to the method described in example 6.

Eksempel 11: N, N'- bis- l-( 3, 4- dihydroksy- 6- metyl- fenyl- 3- hydroksy-pr opy 1- 2-)— hek same tyl endiamin. Example 11: N,N'-bis-1-(3,4-dihydroxy-6-methyl-phenyl-3-hydroxy-propy 1-2-)-hexametylendiamine.

N,N'-bis-l-(3,4-dimetoksy-6-metyl-fenyl-3-hydroksy-propyl-2)-heksametylendiamin omsettes etter den i eksempel 1 beskrevne fremgangsmåte med bortribromid. N,N'-bis-1-(3,4-dimethoxy-6-methyl-phenyl-3-hydroxy-propyl-2)-hexamethylenediamine is reacted according to the method described in example 1 with boron tribromide.

Claims (2)

1. Fremgangsmåte for fremstilling av nye fenyletylaminderivater med formel I1. Process for the production of new phenylethylamine derivatives of formula I og syreaddisjonssalter derav, hvori begge betyr lavere alkyl, begge R^betyr hydrogen, lavere alkyl eller hydroksymetyl og n står for et helt tall mellom 2 og 10,karakterisert vedat enten a) i forbindelse med formel II and acid addition salts thereof, in which both mean lower alkyl, both R^ means hydrogen, lower alkyl or hydroxymethyl and n stands for an integer between 2 and 10, characterized in that either a) in connection with formula II hvori begge betyr lavere alkyl, begge R^betyr hydrogen, lavere alkyl eller hydroksymetyl, n står for et helt tall mellom 2. og 10 og R^betyr en acidolytisk eller hydrogenolytisk avspaltbar rest, overføres etergruppene i hydroksygrupper,, eller b) forbindelser med formel III in which both mean lower alkyl, both R^ means hydrogen, lower alkyl or hydroxymethyl, n stands for an integer between 2 and 10 and R^ means an acidolytically or hydrogenolytically cleavable residue, the ether groups are transferred into hydroxy groups,, or b) compounds with formula III hvori R^og R^har den ovennevnte betydning, omsettes med forbindels.er med formel IV in which R^ and R^ have the above meaning, react with compounds of formula IV hvori n har den ovennevnte betydning og Hal står for klor, brom eller jod, og de således erholdte forbindelser med formel I overføres eventuelt i sine syreaddisjonssalter. where n has the above meaning and Hal stands for chlorine, bromine or iodine, and the thus obtained compounds of formula I are optionally transferred in their acid addition salts. 2. N,N'-bis-(3,4-dihydroksy-6-mety1-fenyletyl)-heksametylendiamin og syreaddisjonssalter derav.2. N,N'-bis-(3,4-dihydroxy-6-methyl-phenylethyl)-hexamethylenediamine and acid addition salts thereof.
NO743023A 1973-08-31 1974-08-22 NO743023L (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH1253273A CH583684A5 (en) 1973-08-31 1973-08-31 Circulatory-active phenylethylamine derivs - from bis-(3,4-dimethoxy-6-methylphenylethyl)-hexamethylenediamine and boronitro-bromide
CH920374 1974-07-04

Publications (1)

Publication Number Publication Date
NO743023L true NO743023L (en) 1975-03-24

Family

ID=25704434

Family Applications (1)

Application Number Title Priority Date Filing Date
NO743023A NO743023L (en) 1973-08-31 1974-08-22

Country Status (13)

Country Link
JP (1) JPS5050332A (en)
AU (1) AU7285874A (en)
DD (1) DD115112A5 (en)
DE (1) DE2440755A1 (en)
DK (1) DK449974A (en)
FI (1) FI248174A (en)
FR (1) FR2242081B1 (en)
GB (1) GB1475375A (en)
IL (1) IL45567A0 (en)
NL (1) NL7411378A (en)
NO (1) NO743023L (en)
PH (1) PH10635A (en)
SE (1) SE7410761L (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA825571B (en) * 1981-08-05 1983-06-29 Fisons Plc Dooamine analogues
DE3263531D1 (en) * 1981-08-05 1985-06-20 Fisons Plc Amine derivatives, processes for their production and pharmaceutical compositions containing them
NZ214823A (en) * 1985-01-15 1989-08-29 Glaxo Group Ltd 2-substituted-3,4-dihydroxyphenethylamino derivatives

Also Published As

Publication number Publication date
DD115112A5 (en) 1975-09-12
IL45567A0 (en) 1974-11-29
FI248174A (en) 1975-03-01
DE2440755A1 (en) 1975-03-13
JPS5050332A (en) 1975-05-06
GB1475375A (en) 1977-06-01
FR2242081B1 (en) 1978-02-03
SE7410761L (en) 1975-03-03
FR2242081A1 (en) 1975-03-28
NL7411378A (en) 1975-03-04
PH10635A (en) 1977-07-21
DK449974A (en) 1975-04-28
AU7285874A (en) 1976-03-04

Similar Documents

Publication Publication Date Title
US3454554A (en) Aminoalkyliminodibenzyl compounds
US2627491A (en) Penicillin salts of substituted alkylene diamines
JP2002525371A (en) Benzimidazolinyl piperidine as CGRP ligand
EP0046666B1 (en) 2(3h)-indolones, process for their preparation and compositions containing them
NO167658B (en) ANALOGY PROCEDURE FOR THE PREPARATION OF NEW THERAPEUTIC-ACTIVE DIPHENYL PROPYLAMINE DERIVATIVES.
EP0416581A1 (en) Substituted N-benzylpiperidine amides
PL119641B1 (en) Process for preparing novel,condensed derivatives of pyrimidine pirimidina
EP0167901B1 (en) Active compounds
NO150605B (en) ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY ACTIVE PYRIDINYL AMINOAL COOLETERS
GB2111478A (en) New 2-(hydroxyphenyl)-indoles and processes for their production
PL150228B1 (en) Method of obtaining novel derivatives of n-4-pyridylamide
NO743023L (en)
US3632587A (en) Piperazino methyl isatinylidine 3 acetates
NO144529B (en) PROCEDURE FOR PREPARING BENZO- (A) -KINOLIZIN DERIVATIVES
US5196454A (en) Method of treating disorders of the dopaminergic systems using 2,5-diaminotetralines
CN112321534A (en) Preparation method of high-purity medicinal roxatidine acetate hydrochloride
EP1075471A1 (en) Indolyl derivatives as serotonergic agents
US3972935A (en) Antiarrhythmic agents
US7601744B2 (en) Benzothiadiazolylphenylalkylamine derivatives and methods of their use
US5053430A (en) Use of 2,7-diamino-1,2,3,4-tetrahydronaphthalenes as medicaments, new 2,7-diamino-1,2,3,4-tetrahydronaphthalenes and processes for their preparation
WO1996036605A1 (en) 4-ARYLCYCLOPENTA[c]PYRROLE ANALGESICS
JPS6360750B2 (en)
US3478039A (en) Certain 2-,4-,5-,6- or 7-azaindolyl-lower-alkylamidoximes,-amidines and -guanidines
NO744465L (en)
US3281468A (en) beta-phenyl-beta-hydroxyethylamines