NO152649B

NO152649B - ANALOGUE PROCEDURE FOR PREPARING PHARMASOYYTIC ACTIVE PHENYLALKYLAMINES

Info

Publication number: NO152649B
Application number: NO814194A
Authority: NO
Inventors: Johannes Keck; Helmut Pieper; Gerd Krueger; Klaus Noll; Juergen Daemmgen; Willi Diederen; Rudolf Kadatz
Original assignee: Thomae Gmbh Dr K
Priority date: 1980-12-10
Filing date: 1981-12-09
Publication date: 1985-07-22
Also published as: PT74112B; CS229924B2; ZA818529B; FR2498596B1; NL8105170A; DD202867A5; GB2088873A; PL234155A1; ES512914A0; FI813934L; NO814194L; PL129385B1; ES507635A0; ES8304537A1; FR2498596A1; AT379378B; IE52007B1; ES8304538A1; KR870000183B1; AU7841481A

Description

Foreliggende oppfinnelse angår nye fenylalkylaminer med den generelle formel The present invention relates to new phenylalkylamines with the general formula

deres diastereomere racemater samt deres syreaddisjonssalter, their diastereomeric racemates as well as their acid addition salts,

spesielt fysiologisk akseptable syreaddisjonssalter med uorganiske eller organiske syrer, legemidler som inneholder disse og fremgangsmåter for fremstilling av sådanne forbindelser. in particular physiologically acceptable acid addition salts with inorganic or organic acids, medicinal products containing these and methods for the preparation of such compounds.

De nye forbindelser oppviser verdifulle farmakologiske The new compounds exhibit valuable pharmacological properties

egenskaper, spésielt hjerte- og kretsløps-virkninger. properties, especially cardiac and circulatory effects.

I den ovenfor angitte generelle formel I betyr In the above general formula I means

R-j en hydroksygruppe, en amihogruppe som eventuelt er sub- R-j a hydroxy group, an amiho group which is optionally sub-

stituert med en alkanoylgruppe med 1-3 karbonatomer eller en alkoksykarbonylgruppe med tilsammen 2-4 karbonatomer, en alkyl- substituted with an alkanoyl group with 1-3 carbon atoms or an alkoxycarbonyl group with a total of 2-4 carbon atoms, an alkyl-

araino- eller dialkylaminogruppe, araino or dialkylamino group,

R2 og , som kan være like eller forskjellige, halogenatomer, trifluormetyl-, cyan- eller nitro-grupper eller en av restene R2 og R., også et hydrogenatom, R2 and , which may be the same or different, halogen atoms, trifluoromethyl, cyano or nitro groups or one of the residues R2 and R., also a hydrogen atom,

R4 et hydrogenatom eller en alkylgruppe med 1-3 karbonatomer, R4 a hydrogen atom or an alkyl group with 1-3 carbon atoms,

Ri- et hydrogenatom, en rettkjedet eller forgrenet alkylgruppe Ri- a hydrogen atom, a straight-chain or branched alkyl group

med 1-4 karbonatomer, en cykloalkyl,gruppe med .3-6 karbonatomer, with 1-4 carbon atoms, a cycloalkyl group with .3-6 carbon atoms,

en alkylengruppe med 2-5 karbonatomer eller en fenylalkylgruppe med 7-10 karbonatomer, an alkylene group with 2-5 carbon atoms or a phenylalkyl group with 7-10 carbon atoms,

A metylen-, etylen- eller hydroksymetylen-gruppen og A the methylene, ethylene or hydroxymethylene group and

B en gruppe med formel B a group with formula

eller hvor or where

Rg er et hydrogen- eller halogen-atom, en hydroksygruppe, alkoksygruppe med 1-3 karbonatomer som eventuelt er substituert med en fenylgruppe, en alkylsulfenyl- eller alkylsulfinyl-gruppe som begge kan ha 1-3 karbonatomer, Rg is a hydrogen or halogen atom, a hydroxy group, alkoxy group with 1-3 carbon atoms which is optionally substituted with a phenyl group, an alkylsulfenyl or alkylsulfinyl group which can both have 1-3 carbon atoms,

R^ er et hydrogenatom, en hydroksygruppe eller en alkoksygruppe med 1-3 karbonatomer eller R^ og R^ tilsammen utgjør metylendioksygruppen, R^ is a hydrogen atom, a hydroxy group or an alkoxy group with 1-3 carbon atoms or R^ and R^ together form the methylenedioxy group,

Rg er et hydrogenatom eller alkylgruppe med 1-3 karbonatomer, D er et oksygen- eller svovelatom, en sulfinyl eller sulfonyl-gruppe, Rg is a hydrogen atom or alkyl group with 1-3 carbon atoms, D is an oxygen or sulfur atom, a sulfinyl or sulfonyl group,

n er tallet 1 eller 2 og n is the number 1 or 2 and

E er en rettkjedet alkylengruppe med 3-5 karbonatomer som eventuelt er substituert med en eller to alkylgrupper som hver har 1-3 karbonatomer. E is a straight-chain alkylene group with 3-5 carbon atoms which is optionally substituted with one or two alkyl groups each having 1-3 carbon atoms.

For restene R^~Rg og E med de foran nevnte betydninger, kommer f.eks. følgende i betraktning: For the residues R^~Rg and E with the aforementioned meanings, e.g. the following in consideration:

iin

for R^: hydroksy-, amino-, metylamino-, etylamino-, propyl-amino-, isopropylamino-, dimetylamino-, dietylamino-, dipropyl-amino-, diisopropylamino-, metyletylamino-, metylpropylamino-, metylisopropylamino-, etylisopropylamino-, formylamino-, acetylamino-, propionylamino-, metoksykarbonylamino-, etoksykarbonylamino-, propoksykarbonylamino-, eller isoprop-oksykarbonylamino-gruppen, for R^: hydroxy-, amino-, methylamino-, ethylamino-, propylamino-, isopropylamino-, dimethylamino-, diethylamino-, dipropylamino-, diisopropylamino-, methylethylamino-, methylpropylamino-, methylisopropylamino-, ethylisopropylamino-, the formylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, or isopropoxycarbonylamino group,

for R2 og , som kan være like eller forskjellige: for R2 and , which may be the same or different:

fluor-, klor-, brom- eller jodatomet, trifluormetyl-, cyan-eller nitrogruppen eller for R2 eller R3 også hydrogenatomet, the fluorine, chlorine, bromine or iodine atom, the trifluoromethyl, cyano or nitro group or for R2 or R3 also the hydrogen atom,

for R4 . og RoQ, som kan være like eller forskjellige: hydrogenatomet, metyl-, etyl-, propyl- eller isopropyl-gruppen, for R4. and RoQ, which may be the same or different: the hydrogen atom, the methyl, ethyl, propyl or isopropyl group,

for R5: hydrogenatomet, metyl-, etyl-, propyl-, isopropy-, butyl-, isobutyl-, tert. butyl-, cyklopropyl-, cyklobutyl-, cyklopentyl-, cykloheksyl-, allyl-, krotylr, pentenyl-, benzyl-, 1- fenyletyl-, 2-fenyletyl-, 3-fenylpropyl- eller 4-fenylbutyl-gruppen, for R5: the hydrogen atom, methyl-, ethyl-, propyl-, isopropyl-, butyl-, isobutyl-, tert. butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, crotyl, pentenyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl or 4-phenylbutyl group,

for R6: hydrogen-, fluor-, klor eller bromatomet, hydroksy-, metoksy-, etoksy-, propoksy-, isopropoksy-, metylsulfenyl-, etylsulfenyl-, metylsulfinyl-, propylsulfinyl-, benzyloksy-, 2- fenyloksy- eller 3-fenylpropoksy-gruppen, for R6: hydrogen, fluorine, chlorine or bromothene, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, methylsulfenyl, ethylsulfenyl, methylsulfinyl, propylsulfinyl, benzyloxy, 2-phenyloxy or 3- the phenylpropoxy group,

for R^: hydrogenatomet, hydroksy-, metoksy-, etoksy-, propoksy-eller isopropoksy-gruppen eller for Rg og R^ tilsammen metylendioksy-gruppen, for R^: the hydrogen atom, the hydroxy, methoxy, ethoxy, propoxy or isopropoxy group or for Rg and R^ together the methylenedioxy group,

for R„: metyl-, etyl-, propyl- eller isopropyl-gruppen, og for R„: the methyl, ethyl, propyl or isopropyl group, and

for E: n-propylen-, n-butylen-, n-pentylen-, 1-metyl-n-propylen-, 1-etyl-n-propylen-, 1-propyl-n-propylen-, 1,1-dimetyl-n-propylen-, 1,1-dietyl-n-propylen-, 1,1-dipropyl-n-propylen-, 1-metyl-1-etyl-n-propylen-, 1-metyl-1-propyl-n-propylen- , 1-etyl-1-propyl-n-propylen-, 1-metyl-n-butylen-eller 1-metyl-n-pentylen-gruppen. for E: n-propylene-, n-butylene-, n-pentylene-, 1-methyl-n-propylene-, 1-ethyl-n-propylene-, 1-propyl-n-propylene-, 1,1-dimethyl -n-propylene-, 1,1-diethyl-n-propylene-, 1,1-dipropyl-n-propylene-, 1-methyl-1-ethyl-n-propylene-, 1-methyl-1-propyl-n -propylene-, 1-ethyl-1-propyl-n-propylene-, 1-methyl-n-butylene- or 1-methyl-n-pentylene group.

Spesielt gunstige egenskaper oppviser forbindelser med Especially favorable properties exhibit connections with

den generelle formel I , hvor the general formula I , where

R^ er en aminogruppe som eventuelt er substituert med R 1 is an amino group which is optionally substituted with

en alkoksykarbonylgruppe med tilsammen 2-4 karbonatomer, an alkoxycarbonyl group with a total of 2-4 carbon atoms,

en alkylamino- eller dialkylaminogruppe hvor hver alkyldel kan inneholde 1-3 karbonatomer, an alkylamino or dialkylamino group where each alkyl part may contain 1-3 carbon atoms,

R2 er et hydrogen-, klor-, brom- eller jodatom, en trifluormetyl-, cyan- eller nitro-gruppe, R2 is a hydrogen, chlorine, bromine or iodine atom, a trifluoromethyl, cyano or nitro group,

R^ er et fluor-, klor- eller brom-atom eller en cyan-gruppe, R^ is a fluorine, chlorine or bromine atom or a cyano group,

R^ er et hydrogenatom eller en metylgruppe, R^ is a hydrogen atom or a methyl group,

R,, er et hydrogenatom, en alkylgruppe med 1-3 karbonatomer som eventuelt er substituert med en fenylgruppe, en allyl- eller cyklopropylgruppe, R,, is a hydrogen atom, an alkyl group with 1-3 carbon atoms which is optionally substituted with a phenyl group, an allyl or cyclopropyl group,

A er metylen-, etylen- eller hydroksymetylen-gruppen og A is the methylene, ethylene or hydroxymethylene group and

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

eller hvor, or where,

Rg, D og n er som tidligere definert, Rg, D and n are as previously defined,

Rg er et hydrogen-, fluor- eller kloratom, en hydroksy-, metoksy-, etoksy-, benzyloksy-, metylsulfenyl- eller metyl-sulf iny1-gruppe, Rg is a hydrogen, fluorine or chlorine atom, a hydroxy, methoxy, ethoxy, benzyloxy, methylsulfenyl or methylsulfinyl group,

R7 er et hydrogenatom eller en metoksygruppe eller Rg og R^ tilsammen utgjør en metylendioksygruppe, og R7 is a hydrogen atom or a methoxy group or Rg and R^ together constitute a methylenedioxy group, and

E er n-propylen-, 1-metyl-n-propylen-, 1,1-dimetyl-n-propylen-eller n-butylengruppen. E is the n-propylene, 1-methyl-n-propylene, 1,1-dimethyl-n-propylene or n-butylene group.

Spesielt foretrukne forbindelser med den ovenfor nevnte generelle formel I er imidlertid de hvor Particularly preferred compounds of the above-mentioned general formula I are, however, those where

R^ er en aminogruppe som eventuelt er substituert med en etoksy-karbonylgruppe, en alkylamino- eller dialkylamino-gruppe, hvor hver alkyldel kan inneholde 1-3 karbonatomer, R^ is an amino group which is optionally substituted with an ethoxycarbonyl group, an alkylamino or dialkylamino group, where each alkyl part may contain 1-3 carbon atoms,

R^ er et hydrogen-, klor- eller brom-atom eller cyangruppen, R^ er et fluor- eller klor-atom eller cyangruppen, R^ is a hydrogen, chlorine or bromine atom or the cyano group, R^ is a fluorine or chlorine atom or the cyano group,

R^ er et hydrogenatom eller metylgruppen, R^ is a hydrogen atom or the methyl group,

Rr er et hydrogenatom, en alkylgruppe med 1-3 karbonatomer som eventuelt er substituert med en fenylgruppe, eller allyl- eller cyklopropylgruppen, Rr is a hydrogen atom, an alkyl group with 1-3 carbon atoms which is optionally substituted with a phenyl group, or the allyl or cyclopropyl group,

A er metylen- eller hydroksymetylen-gruppen og A is the methylene or hydroxymethylene group and

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

hvor where

E er n-propylen-, 1-metyl-,-propylen-, 1,1-dimetyl-n-propylen-, n-butylen-gruppen. E is the n-propylene, 1-methyl-, -propylene, 1,1-dimethyl-n-propylene, n-butylene group.

Rg er et hydrogenatom, eller en hydroksy- eller metoksy-gruppe Rg is a hydrogen atom, or a hydroxy or methoxy group

og and

R^ er et hydrogenatom eller en metoksygruppe. R 1 is a hydrogen atom or a methoxy group.

I norsk patent 126.617 beskrives 4-amino-3-brom-5-klor-0-alkylamino-propiofenoner som har analgetiske, antipyretiske og sedative virkninger. Norwegian patent 126,617 describes 4-amino-3-bromo-5-chloro-0-alkylamino-propiophenones which have analgesic, antipyretic and sedative effects.

I norsk patent 130.155 beskrives basisk substituerte, terti-ære butanoler som har sedative, antiemetiske og sårhemmende virkninger . Norwegian patent 130,155 describes base-substituted, tertiary butanols which have sedative, antiemetic and ulcer-inhibiting effects.

I norsk patent 136.094 beskrives optisk aktive 4-amino-3,5-dihalogen-fenyletanolaminer som på N-atomet er substituert med en alkyl- eller cykloalkylgruppe og har en selektiv virkning på de adrenerge 3-reseptorer. Forbindelsene ifølge disse patenter har en annen kjemisk struktur og som følge derav også andre biologiske egenskaper enn forbindelsene fremstilt ifølge foreliggende oppfinnelse . Norwegian patent 136,094 describes optically active 4-amino-3,5-dihalo-phenylethanolamines which are substituted on the N-atom with an alkyl or cycloalkyl group and have a selective effect on the adrenergic 3-receptors. The compounds according to these patents have a different chemical structure and, as a result, different biological properties than the compounds produced according to the present invention.

I norsk patent 137.782 som i det alt vesentlige svarer til U.S. patent 4.119.710, beskrives aminofenyl-etanolaminer som har 32~mimetiske og/eller Ø^-blokkerende egenskaper. Av den nedenstående forsøksrapport fremgår det (se forbindelsene U til X) at forbindelsene fremstilt ifølge foreliggende oppfinnelse har en overlegen virkning med hensyn til kontraktilitetsparameteren dp/ ^maks un(^er hensyntagen til den i dette tilfelle uønskede 8^-mimetiske virkning. In Norwegian patent 137,782 which essentially corresponds to the U.S. patent 4,119,710, aminophenyl-ethanolamines are described which have 32-mimetic and/or Ø^-blocking properties. From the test report below it appears (see compounds U to X) that the compounds produced according to the present invention have a superior effect with regard to the contractility parameter dp/ ^max un(^ the in this case undesirable 8^-mimetic effect is taken into account.

I norsk patent 139.479 beskrives en ytterligere fremgangs-måte for fremstilling av de 4-amino-halogenfenyl- og 4-amino-dihalogenfenyletanolaminer som er beskrevet i U.S. patent 3.536.712, og dessuten beskrives i U.S. patent 3.536.712 de tilsvarende fenyletanaminer. Disse forbindelser har ved siden av en kretsløpvirkning særlig analgetiske, sedative, antipyretiske, antiflogistiske, hostéstillende og bronkolytiske egenskaper. Norwegian patent 139,479 describes a further process for the production of the 4-amino-halophenyl and 4-amino-dihalophenylethanolamines which are described in the U.S. patent 3,536,712, and also described in U.S. Pat. patent 3,536,712 the corresponding phenylethanamines. In addition to a circulatory effect, these compounds have particularly analgesic, sedative, antipyretic, antiphlogistic, antitussive and broncholytic properties.

Av den nedenstående forsøksrapport fremgår det imidlertid (se forbindelse T) at forbindelsene fremstilt ifølge foreliggende oppfinnelse har en overlegen virkning med hensyn til kontraktilitetsparameteren dp/dt^. However, it appears from the test report below (see compound T) that the compounds produced according to the present invention have a superior effect with regard to the contractility parameter dp/dt^.

I henhold til oppfinnelsen oppnås de nye forbindelser According to the invention, the new compounds are obtained

efter følgende fremgangsmåter: according to the following procedures:

a) reduksjon av en forbindelse med den generelle formel a) reduction of a compound with the general formula

hvor til R, og R^ er som tidligere definert, er en gruppe med formelen gruppe med formelen og X er en B, har de for B innledningsvis angitte betydninger, og X er en gruppe med formelen ■ where to R, and R^ are as previously defined, is a group with the formula group with the formula and X is a B, they have for B the meanings given at the outset, and X is a group with the formula ■

hvor R^, Rg og R^ er som tidligere definert, A"' er en metylen- eller etylengruppe, where R^, Rg and R^ are as previously defined, A"' is a methylene or ethylene group,

k er tallet 1, 2 eller 3, k is the number 1, 2 or 3,

acyl betyr en organisk acylgruppe som acetyl-, propionyl- acyl means an organic acyl group such as acetyl-, propionyl-

eller benzoyl-gruppen, og or the benzoyl group, and

Z betyr en reduktiv avspaltbar gruppe som et brom- eller jod- Z means a reductive leaving group such as a bromine or iodo-

atom eller en karbonsyreester-rest som metoksykarbonyloksy- atom or a carboxylic acid ester residue such as methoxycarbonyloxy-

eller etoksykarbonyloksy-gruppen. or the ethoxycarbonyloxy group.

Reduksjonen foretas avhengig av betydningen av resten som skal reduseres, i et egnet løsningsmiddel som metanol, metanol/vann, etanol, etanol/vann, isopropanol, trifluoreddiksyre, butanol, diety] eter, tetrahydrofuran, tetrahydrofuran/vann, dioksan eller heksametyl-fosforsyretriamid, med et hydrid, med aluminiumisopropylat i nærvær av en primær eller sekundær alkohol, med katalytisk aktivert hydrogen eller med nacerende hydrogen ved temperaturer mellom -2 0°C og kokepunktstemperaturen av reaksjonsblandingen, f. eks. ved temperaturer mellom -20°C og 100°C. The reduction is carried out depending on the importance of the residue to be reduced, in a suitable solvent such as methanol, methanol/water, ethanol, ethanol/water, isopropanol, trifluoroacetic acid, butanol, diethyl ether, tetrahydrofuran, tetrahydrofuran/water, dioxane or hexamethyl phosphoric acid triamide, with a hydride, with aluminum isopropylate in the presence of a primary or secondary alcohol, with catalytically activated hydrogen or with nascent hydrogen at temperatures between -20°C and the boiling point temperature of the reaction mixture, e.g. at temperatures between -20°C and 100°C.

For fremstilling av forbindelser med den generelle formel I, hvor A utgjør hydroksymetylengruppen, foretas reduksjonen hensiktsmessig med f. eks. et komplekst metallhydrid som natriumborhydrid eller litiumaluminiumhydrid i et egnet løsningsmiddel som metanol, metanol/vann, dietyleter eller tetrahydrofuran ved temperaturer mellom -20°C og 50°C, idet reduksjonen med aluminiumisopropylat foretas i isopropanol ved kokepunkts-temperatur og under avdestillering av den dannede aceton, reduksjonen med katalytisk aktivert hydrogen foretas med hydrogen i nærvær av en katalysator som platina, palladium, Raney- For the preparation of compounds with the general formula I, where A constitutes the hydroxymethylene group, the reduction is suitably carried out with e.g. a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, methanol/water, diethyl ether or tetrahydrofuran at temperatures between -20°C and 50°C, the reduction with aluminum isopropylate being carried out in isopropanol at the boiling point temperature and while distilling off the formed acetone, the reduction with catalytically activated hydrogen is carried out with hydrogen in the presence of a catalyst such as platinum, palladium, Raney-

nikkel eller Raney-kobolt ved romtemperatur og med et hydrogentrykk på 1-5 bar, og reduksjonen med nacerende hydrogen foretas f. eks. med aktivert metallisk aluminium og vann eller med sink og saltsyre ved temperaturer opptil kokepunktet for det anvendte løsningsmiddel. nickel or Raney cobalt at room temperature and with a hydrogen pressure of 1-5 bar, and the reduction with nacent hydrogen is carried out e.g. with activated metallic aluminum and water or with zinc and hydrochloric acid at temperatures up to the boiling point of the solvent used.

Dersom X i en av forbindelsene med den generelle formel II står for -CO-CHR^-gruppen foretas omsetningen ved temperaturer på 0-50 C, fortrinnsvis ved romtemperatur, f. eks. med natriumborhydrid i metanol/vann, etanol/vann eller isopropanol eller med litiumaluminiumhydrid i dietyleter eller tetrahydrofuran som If X in one of the compounds with the general formula II stands for the -CO-CHR^ group, the reaction is carried out at temperatures of 0-50 C, preferably at room temperature, e.g. with sodium borohydride in methanol/water, ethanol/water or isopropanol or with lithium aluminum hydride in diethyl ether or tetrahydrofuran as

løsningsmiddel. solvent.

Betyr X Does X mean

foretas omsetningen fortrinns- the sale is carried out preferentially

vis med et hydrid i et egnet løsningsmiddel som eter, tetra-hydrof uran eller dioksan, f. eks. med diboran eller litiumaluminiumhydrid i tetrahydrofuran f. eks. ved temperaturer mellom 0-100°C, fortrinnsvis ved kokepunktstemperaturen for blandingen. show with a hydride in a suitable solvent such as ether, tetrahydrofuran or dioxane, e.g. with diborane or lithium aluminum hydride in tetrahydrofuran, e.g. at temperatures between 0-100°C, preferably at the boiling point temperature of the mixture.

For fremstilling av en forbindelse med den generelle For making a connection with the general

formel I, hvor A utgjør metylen eller etylen-gruppen, foretas reduksjonen med et hydrid som natriumborhydrid, litiumaluminiumhydrid, natriumcyanborhydrid eller pyridin-boran i et egnet løsningsmiddel som etanol, isopropanol, tetrahydrofuran, dioksan, trifluoreddiksyre eller heksametyl-fosforsyretriamid ved 0-100°C. formula I, where A is the methylene or ethylene group, the reduction is carried out with a hydride such as sodium borohydride, lithium aluminum hydride, sodium cyanoborohydride or pyridine-borane in a suitable solvent such as ethanol, isopropanol, tetrahydrofuran, dioxane, trifluoroacetic acid or hexamethylphosphoric acid triamide at 0-100° C.

Dersom X i en forbindelse med den generelle formel II står for -A"'-CO-gruppen eller B-j^ står for If X in a compound of the general formula II represents the -A"'-CO group or B-j^ represents

gruppen, foretas omsetningen fortrinnsvis group, the turnover is preferably carried out

ved høyere temperaturer; f. eks. med litiumaluminiumhydrid i tetrahydrofuran ved kokepunktet for reaksjonsblandingen. at higher temperatures; e.g. with lithium aluminum hydride in tetrahydrofuran at the boiling point of the reaction mixture.

Betyr X hydroksyetyl-gruppen, gjennomføres omsetningen fortrinnsvis med pyridin-boran i trifluoreddiksyre ved 25-100°C, idet reaksjonskomponentene gjerne bringes sammen ved lavere temperaturer, f. eks. ved -10°C. If X is the hydroxyethyl group, the reaction is preferably carried out with pyridine-borane in trifluoroacetic acid at 25-100°C, the reaction components being preferably brought together at lower temperatures, e.g. at -10°C.

Er X en Is X one

foretas omsetningen the transaction is made

fortrinnsvis med natriumborhydrid, natriumcyanborhydrid eller litiumaluminiumhydrid i et egnet løsningsmiddel som isopropanol, heksametyl-fosforsyretriamid, tetrahydrofuran eller dioksan ved 20-100°C. preferably with sodium borohydride, sodium cyanoborohydride or lithium aluminum hydride in a suitable solvent such as isopropanol, hexamethylphosphoric triamide, tetrahydrofuran or dioxane at 20-100°C.

b) Omsetning av en karbonylforbindelse, som eventuelt dannes i reaksjonsblandingen, med den generelle formel b) Reaction of a carbonyl compound, which is possibly formed in the reaction mixture, with the general formula

K - L (III) , K - L (III),

hvor K sammen med et nabohydrogen i alkyldelen av resten L, står for et oksygenatom, where K, together with a neighboring hydrogen in the alkyl part of the residue L, stands for an oxygen atom,

L har de samme betydninger som er definert for B eller, med unntak av hydrogenatomet, står for R,, eller en gruppe med formel L has the same meanings as defined for B or, with the exception of the hydrogen atom, represents R,, or a group of formula

hvor R.j til R^ er som tidligere definert og where R.j to R^ are as previously defined and

A' betyr karbonyl-, metylen- eller etylen-gruppen eller deres aldehydhydrater, med et amin med den generelle formel A' means the carbonyl, methylene or ethylene group or their aldehyde hydrates, with an amine of the general formula

hvor where

M og Q som er forskjellige, har de betydninger som er nevnt for B og R,, eller en av dem utgjør gruppen M and Q which are different have the meanings mentioned for B and R,, or one of them constitutes the group

hvor where

R^ til R^ og A er som tidligere definert, og et reduksjonsmiddel . R^ to R^ and A are as previously defined, and a reducing agent.

Omsetningen foretas fortrinnsvis i et egnet løsnings-middel som metanol, metanol/vann, etanol, etanol/vann, butanol, dietyleter, tetrahydrofuran eller dioksan i nærvær av et reduksjonsmiddel ved temperaturer på mellom -20 og 50°C, dog fortrinnsvis ved temperaturer på mellom 0 og 25°C. Som reduksjonsmiddel kommer herunder komplekse metallhydrider eller katalytisk aktivert hydrogen i betraktning. The reaction is preferably carried out in a suitable solvent such as methanol, methanol/water, ethanol, ethanol/water, butanol, diethyl ether, tetrahydrofuran or dioxane in the presence of a reducing agent at temperatures of between -20 and 50°C, however preferably at temperatures of between 0 and 25°C. As a reducing agent, complex metal hydrides or catalytically activated hydrogen are considered.

Foretas omsetningen med et sekundært amin med den generelle formel IV, blir den imidlertid fortrinnsvis utført i tetrahydrofuran som løsningsmiddel og med natriumcyanborhydrid ved pH <7 If the reaction is carried out with a secondary amine of the general formula IV, it is however preferably carried out in tetrahydrofuran as solvent and with sodium cyanoborohydride at pH <7

f. eks. ved pH 6-6,5 og deretter med natriumborhydrid ved romtemperatur . e.g. at pH 6-6.5 and then with sodium borohydride at room temperature.

Skjer omsetningen med et primært amin med den generelle formel IV, blir de Schiffske baser som dannes i reaksjonsblandingen, fortrinnsvis redusert med et komplekst metallhydrid som natriumborhydrid eller litiumaluminiumhydrid i et egnet løsningsmiddel som metanol, metanol/vann, dietyleter eller tetrahydrofuran ved temperaturer mellom -2 0°C og kokepunktet for det anvendte løsningsmiddel, f. eks. ved temperaturer mellom 0 og 80°C, eller med katalytisk aktivert hydrogen, f. eks. med hydrogen i nærvær av en katalysator som platina, palladium, If the reaction takes place with a primary amine of the general formula IV, the Schiff bases formed in the reaction mixture are preferably reduced with a complex metal hydride such as sodium borohydride or lithium aluminum hydride in a suitable solvent such as methanol, methanol/water, diethyl ether or tetrahydrofuran at temperatures between -2 0°C and the boiling point of the solvent used, e.g. at temperatures between 0 and 80°C, or with catalytically activated hydrogen, e.g. with hydrogen in the presence of a catalyst such as platinum, palladium,

o o

Raney-nikkel eller Raney-kobolt, ved 0-100 C, dog fortrinnsvis ved romtemperatur, og med et hydrogentrykk på 1-5 bar. Raney nickel or Raney cobalt, at 0-100 C, however preferably at room temperature, and with a hydrogen pressure of 1-5 bar.

Metyleringén kan også foretas med formaldehyd og maursyre som reduksjonsmiddel ved høyere temperatur, f. eks. ved reaksjonsblandingens kokepunkt. The methylation can also be carried out with formaldehyde and formic acid as a reducing agent at a higher temperature, e.g. at the boiling point of the reaction mixture.

Foretas omsetningen med en forbindelse med den generelle formel IV, hvor R^ er en amino- eller alkylamino-gruppe med 1-3 karbonatomer, og en karbonylforbindelse med den generelle formel III, hvor L har betydningen Rj-, kan den alkyleres spesielt ved anvendelse av et tilsvarende overskudd. If the reaction is carried out with a compound of the general formula IV, where R^ is an amino or alkylamino group with 1-3 carbon atoms, and a carbonyl compound of the general formula III, where L has the meaning Rj-, it can be alkylated in particular by using of a corresponding surplus.

c) Avspalting av en eller flere beskyttelsesgrupper fra en forbindelse med den generelle formel c) Removal of one or more protecting groups from a compound of the general formula

hvor where

R2, R^ og R^ er som tidligere definert, R2, R^ and R^ are as previously defined,

R1<1> har den tidligere angitte betydning av R^ eller utgjør en beskyttet hydroksy- eller amino-gruppe, R1<1> has the previously indicated meaning of R^ or constitutes a protected hydroxy or amino group,

A'' har den tidligere angitte betydning av A eller utgjør en beskyttet hydroksymetylengruppe, A'' has the previously indicated meaning of A or constitutes a protected hydroxymethylene group,

R,-1 har den tidligere angitte betydning av R^ eller utgjør en beskyttelsesrest1 for en aminogruppe, og B<1> har den ..tidligere. angitte betydning av B eller utgjør en gruppe med formel' R,-1 has the previously indicated meaning of R^ or constitutes a protecting residue1 for an amino group, and B<1> has the ..previously. indicate meaning of B or constitute a group of formula'

eller or

hvor where

Rg, D, E og n er som tidligere definert og Rg, D, E and n are as previously defined and

Ro r ' og R-/,1 , som kan være like eller forskjellige, har de tidligere nevnte betydninger av Rg og R^ eller utgjør beskyttede hydroksygrupper, idet minst en av restene R^ ' , A'<1>, R<- 1 og/eller B' må utgjøre eller inneholde en av de ovenfor nevnte beskyttelsesgrupper. Ro r ' and R-/,1 , which may be the same or different, have the previously mentioned meanings of Rg and R^ or constitute protected hydroxy groups, at least one of the residues R^ ' , A'<1>, R<- 1 and/or B' must constitute or contain one of the above-mentioned protective groups.

Aktuelle beskyttelsesrester er f. eks. acylrester som etoksykarbonyl-, acetyl-, propionyl- eller benzoyl-gruppen eller benzylgruppen og Current protection residues are, for example, acyl residues such as the ethoxycarbonyl, acetyl, propionyl or benzoyl group or the benzyl group and

for A'<1>, acetyl-, metoksykarbonyl- eller etoksykarbonyl-gruppen. for A'<1>, the acetyl, methoxycarbonyl or ethoxycarbonyl group.

Avspaltingen av en av de ovenfor nevnte acyl- og/eller alkoksykarbonyl-rester skjer fortrinnsvis hydrolytisk i et vandig løsningsmiddel, f. eks. i vann, isopropanol/vann, tetra-hydrof uran/vann eller dioksan/vann, i nærvær av en syre som saltsyre eller svovelsyre eller i nærvær av en alkalibase som natriumhydroksyd eller kaliumhydroksyd ved temperaturer på mellom 0 og 100°C, fortrinnsvis ved reaksjonsblandingens kokepunkt . The cleavage of one of the above-mentioned acyl and/or alkoxycarbonyl residues preferably takes place hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at the reaction mixture's boiling point.

Avspaltingen av en benzylrest foretas' fortrinnsvis hydrogenolytisk, f. eks. med hydrogen i nærvær av en katalysator som palladium/karbon, i et løsningsmiddel som metanol, etanol, eddiksyreetylester eller iseddik, eventuelt under tilsetning av en syre som saltsyre, ved temperaturer på mellom 0 og 50°C, dog fortrinnsvis ved romtemperatur, og et hydrogentrykk på The cleavage of a benzyl residue is preferably carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/carbon, in a solvent such as methanol, ethanol, ethyl acetic acid ester or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures of between 0 and 50°C, however preferably at room temperature, and a hydrogen pressure on

1-7 bar, dog fortrinnsvis ved 3-5 bar. 1-7 bar, although preferably at 3-5 bar.

d) For fremstilling av en forbindelse med den generelle formel I, hvor en av restene R^ 0<3 R3 utgjør et hydrogenatom: Dehalogenering av en forbindelse med den generelle formel d) For the preparation of a compound of the general formula I, where one of the residues R^ 0<3 R3 constitutes a hydrogen atom: Dehalogenation of a compound of the general formula

hvor where

, R^ til Rj., A og B er som tidligere definert og Hal utgjør et klor-, brom- eller jod-atom. , R^ to Rj., A and B are as previously defined and Hal constitutes a chlorine, bromine or iodine atom.

Dehalogeneringen skjer fortrinnsvis i et løsningsmiddel, f. eks. med trifenylfosfin i benzen eller toluen, med hydrogen i metanol, etanol, eddikester eller tetrahydrofuran og i nærvær av en hydreringskatalysator eller med et komplekst metallhydrid som litiumaluminiumhydrid eller natrium-dietoksy-aluminiumhydrid i tetrahydrofuran, dioksan eller toluen. Alt etter den anvendte metode, utføres reaksjonen ved romtemperatur eller høyere temperatur, f. eks. 60-150°C, og ved normaltrykk eller et visst overtrykk.Ved anvendelse av Raney-nikkel eller palladium/karbon foretas f. eks. dehalogeneringen ved romtemperatur og normaltrykk. The dehalogenation preferably takes place in a solvent, e.g. with triphenylphosphine in benzene or toluene, with hydrogen in methanol, ethanol, acetate or tetrahydrofuran and in the presence of a hydrogenation catalyst or with a complex metal hydride such as lithium aluminum hydride or sodium diethoxy aluminum hydride in tetrahydrofuran, dioxane or toluene. Depending on the method used, the reaction is carried out at room temperature or a higher temperature, e.g. 60-150°C, and at normal pressure or a certain overpressure. When using Raney nickel or palladium/carbon, e.g. the dehalogenation at room temperature and normal pressure.

e) Alkylering av en forbindelse med den generelle formel e) Alkylation of a compound of the general formula

hvor where

R^ til R4 og A er som tidligere definert, R^ to R4 and A are as previously defined,

R5'' har den tidligere nevnte<?>betydning av R5 eller står for R5'' has the previously mentioned<?>meaning of R5 or stands for

et hydrogenatom og a hydrogen atom and

B'' har den tidligere nevnte betydning av B, idet, dersom Rj-'<1 >ikke utgjør hydrogen, minst en av restene Rg eller R? må utgjøre en hydroksygruppe eller R^ utgjøre en aminogruppe som eventuelt er substituert med en alkylgruppe med 1-3 karbonatomer, hvor alkylgruppen dessuten kan være substituert med en fenylrest. B'' has the previously mentioned meaning of B, in that, if Rj-'<1 >does not constitute hydrogen, at least one of the residues Rg or R? must form a hydroxy group or R^ form an amino group which is optionally substituted with an alkyl group with 1-3 carbon atoms, where the alkyl group can also be substituted with a phenyl residue.

Omsetningen utføres i et løsningsmiddel som vann/metanol, etanol/vann, tetrahydrofuran, dioksan, aceton eller dimetylsulfoksyd med et alkyleringsmiddel som metyljodid, dimetylsulfat, etylbromid, dietylsulfat, benzylbromid, 2-fenyletyl-bromid eller metyl-p-toluensulfonat, eventuelt i nærvær av en base som natronlut eller kaliumkarbonat ved temperaturer mellom -10 og -0°C, dog fortrinnsvis ved temperaturer mellom 0 og 30°C. Omsetningen kan imidlertid også gjennomføres uten løsningsmiddel. The reaction is carried out in a solvent such as water/methanol, ethanol/water, tetrahydrofuran, dioxane, acetone or dimethyl sulfoxide with an alkylating agent such as methyl iodide, dimethyl sulfate, ethyl bromide, diethyl sulfate, benzyl bromide, 2-phenylethyl bromide or methyl p-toluenesulfonate, optionally in the presence of a base such as caustic soda or potassium carbonate at temperatures between -10 and -0°C, however preferably at temperatures between 0 and 30°C. However, the turnover can also be carried out without solvent.

Alkyleringen av nitrogenatomet kan også foretas ved hjelp av formaldehyd/maursyre ved høyere temperaturer, f. eks. ved reaksjonsblandingens kokepunkt, eller med en tilsvarende passende karbonylforbindelse og et komplekst metallhydrid, fortrinnsvis med natriumcyanborhydrid ved pH <7, f. eks. ved pH 6-6,5 i et løsningsmiddel som vann/metanol, etanol, etanol/vann, eller tetrahydrofuran ved temperaturer mellom 0 og 50°C, dog fortrinnsvis ved romtemperatur. The alkylation of the nitrogen atom can also be carried out using formaldehyde/formic acid at higher temperatures, e.g. at the boiling point of the reaction mixture, or with a similarly suitable carbonyl compound and a complex metal hydride, preferably with sodium cyanoborohydride at pH <7, e.g. at pH 6-6.5 in a solvent such as water/methanol, ethanol, ethanol/water, or tetrahydrofuran at temperatures between 0 and 50°C, however preferably at room temperature.

Alkyleringen av en fenolisk hydroksygruppe kan dessuten foretas med et passende diazoalkan i et løsningsmiddel som dietyleter eller tetrahydrofuran ved 0 til 50°C, fortrinnsvis ved romtemperatur. f) For fremstilling av en forbindelse med den generelle formel I, hvor utgjør en aminogruppe som er substituert med en alkanoylgruppe med 1-3 karbonatomer eller en alkoksykarbonylgruppe med tilsammen 2-4 karbonatomer, og R,- ikke er hydrogen: The alkylation of a phenolic hydroxy group can also be carried out with a suitable diazoalkane in a solvent such as diethyl ether or tetrahydrofuran at 0 to 50°C, preferably at room temperature. f) For the preparation of a compound with the general formula I, where an amino group substituted by an alkanoyl group with 1-3 carbon atoms or an alkoxycarbonyl group with a total of 2-4 carbon atoms, and R,- is not hydrogen, constitutes:

Acylering av en forbindelse med den generelle formel Acylation of a compound of the general formula

hvor where

1*2 til R,., A og B er som tidligere definert, med en forbindelse med den generelle formel 1*2 to R,., A and B are as previously defined, with a compound of the general formula

hvor where

R^q utgjør et hydrogenatom, en metyl- eller etylgruppe eller en alkoksygruppe med 1-3 karbonatomer og R^q constitutes a hydrogen atom, a methyl or ethyl group or an alkoxy group with 1-3 carbon atoms and

Y er en nukleofil substituerbar gruppe som halogen, en nitrofenyl-rest, en imidazolylgruppe eller en rest med formelen -0-COR^q. Y is a nucleophilic substitutable group such as halogen, a nitrophenyl residue, an imidazolyl group or a residue of the formula -O-COR^q.

Omsetningen kan f. eks. foretas med acetylklorid, acet-anhydrid, propionsyreanhydrid eller en tilsvarende klormaursyreester, f. eks. klormaursyre-etylester, som samtidig kan tjene som løsningsmiddel, eventuelt i et løsningsmiddel som vann/tetrahydrofuran, dietyleter, tetrahydrofuran eller metylenklorid, eventuelt i nærvær av en base som trietylamin eller pyridin, idet en tertiær organisk base samtidig også kan tjene som løsningsmiddel, ved temperaturer mellom 0 og 100°C, The turnover can e.g. is carried out with acetyl chloride, acetic anhydride, propionic anhydride or a corresponding chloroformic acid ester, e.g. chloroformic acid ethyl ester, which can simultaneously serve as a solvent, optionally in a solvent such as water/tetrahydrofuran, diethyl ether, tetrahydrofuran or methylene chloride, optionally in the presence of a base such as triethylamine or pyridine, as a tertiary organic base can also simultaneously serve as a solvent, by temperatures between 0 and 100°C,

dog fortrinnsvis ved romtemperatur. Omsetningen kan også fore- however, preferably at room temperature. The turnover can also occur

tas uten løsningsmiddel. g) For fremstilling av én forbindelse med den generelle r formel I, hvor D utgjør en sulfinyl- eller sulfonyl-gruppe: taken without solvent. g) For the preparation of one compound of the general formula I, where D is a sulfinyl or sulfonyl group:

Oksydasjon av en forbindelse med den generelle formel Oxidation of a compound with the general formula

hvor where

R. til RD, A og n er som tidligere definert, og m står for tallet 0 eller 1. R. to RD, A and n are as previously defined, and m stands for the number 0 or 1.

Oksydasjonen foretas fortrinnsvis i et løsningsmiddel, The oxidation is preferably carried out in a solvent,

f. eks. i vann, vann/pyridin, etanol, metanol, aceton, iseddik, maursyre, fortynnet svovelsyre eller trifluoreddiksyre, alt etter det anvendte oksydasjonsmiddel ved temperaturer på e.g. in water, water/pyridine, ethanol, methanol, acetone, glacial acetic acid, formic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used at temperatures of

mellom -80 og 100 °C. ; '// between -80 and 100 °C. ; '//

For fremstilling av en sulfinylforbindelse med den generelle formel I foretas oksydasjonen mest hensiktsmessig med en ekvivalent av det anvendte oksydasjonsmiddel, f. eks. med hydrogenperoksyd i iseddik, trifluoreddiksyre eller maursyre ved 0-20°C eller i aceton ved 0-60°C, med en persyre som per-maursyre i iseddik eller trifluoreddiksyre ved 0-50°C eller med m-klorperbenzoesyre i metylenklorid eller kloroform ved -20 til 60°C, med natrium-metaperjodat i vandig metanol eller etanol ved 15-25°C. For the preparation of a sulfinyl compound of the general formula I, the oxidation is most appropriately carried out with an equivalent of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0-20°C or in acetone at 0-60°C, with a peracid such as per-formic acid in glacial acetic acid or trifluoroacetic acid at 0-50°C or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60°C, with sodium metaperiodate in aqueous methanol or ethanol at 15-25°C.

For fremstilling av en sulfonylforbindelse med den generelle formel I foretas oksydasjonen med en, to eller flere ekvivalenter av det anvendte oksydasjonsmiddel, f. eks. med hydrogenperoksyd i iseddik, trifluoreddiksyre eller i maursyre ved 20-100°C eller i aceton ved 0-60°C, med en persyre som per-maursyre eller m-klorperbenzoesyre i iseddik, trifluoreddiksyre, metylenklorid eller kloroform ved temperaturer mellom 0 og 6 0°C eller med kaliumpermanganat i iseddik, vann/svovelsyre eller aceton ved 0-20°c. h) For fremstilling av en forbindelse med den generelle formel I, hvor D utgjør et oksygen- eller svovelatom og R^ ikke står for To prepare a sulfonyl compound of the general formula I, the oxidation is carried out with one, two or more equivalents of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20-100°C or in acetone at 0-60°C, with a peracid such as per-formic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 6 0°C or with potassium permanganate in glacial acetic acid, water/sulfuric acid or acetone at 0-20°c. h) For the preparation of a compound of the general formula I, where D constitutes an oxygen or sulfur atom and R^ does not represent

hydrogen: hydrogen:

Omsetning av en forbindelse med den generelle formel Reaction of a compound with the general formula

hvor where

R1 til R^, Rg og n er som tidligere definert, R1 to R^, Rg and n are as previously defined,

V er en nukleofil utskiftbar gruppe som et halogenatom eller en sulfonsyreester-rest, f. eks. et klor-, brom- eller jod-atom, en p-toluensulfonyloksy- eller metansulfonyloksy-gruppe, og A<11>' er metylen- eller etylen-gruppen, med en forbindelse med den generelle formel V is a nucleophilic replaceable group such as a halogen atom or a sulphonic acid ester residue, e.g. a chlorine, bromine or iodine atom, a p-toluenesulfonyloxy or methanesulfonyloxy group, and A<11>' is the methylene or ethylene group, with a compound of the general formula

hvor where

R,, og R_ er som tidligere angitt og R,, and R_ are as previously indicated and

d 7 d 7

D<1> står for et oksygen- eller svovelatom, eller deres alkali-eller jordalkaliesalter. D<1> stands for an oxygen or sulfur atom, or their alkali or alkaline earth salts.

Det er hensiktsmessig å foreta omsetningen i et løsnings-middel som kloroform, tetrahydrofuran, dioksan eller toluen, dog fortrinnsvis i et vannfritt aprotisk løsningsmiddel som aceton, dimetylformamid. eller dimetylsulfoksyd, eventuelt i nærvær av en alkalibase som natriumkarbonat, kaliumkarbonat, natriumhydroksyd, natriumhydrid eller kalium-tert.butylat ved temperaturer mellom -10°C og kokepunktet for det anvendte løsningsmiddel, f. eks. ved temperaturer mellom -10 og 100°C, fortrinnsvis ved temperaturer mellom 0 og 50°C. Omsetningen kan imidlertid også foretas uten løsningsmiddel. En forbindelse i henhold til oppfinnelsen som har ett, to eller tre optisk aktive karbonatomer, kan deretter skilles etter konvensjonelle metoder i dens opjtisk aktive antipoder, diastereomere racemater og i de optiske antipoder'av disse. It is appropriate to carry out the reaction in a solvent such as chloroform, tetrahydrofuran, dioxane or toluene, although preferably in an anhydrous aprotic solvent such as acetone, dimethylformamide. or dimethylsulfoxide, optionally in the presence of an alkali base such as sodium carbonate, potassium carbonate, sodium hydroxide, sodium hydride or potassium tert.butylate at temperatures between -10°C and the boiling point of the solvent used, e.g. at temperatures between -10 and 100°C, preferably at temperatures between 0 and 50°C. However, the turnover can also be carried out without solvent. A compound according to the invention having one, two or three optically active carbon atoms can then be separated by conventional methods into its optically active antipodes, diastereomeric racemates and into the optical antipodes thereof.

Spaltningen av et racemat av en forbindelse med formel I, skjer fortrinnsvis ved fraksjonert krystallisasjon av en blanding av de diastereomere salter med en optisk aktiv syre, f. eks. D(-)-vinsyre, L(+)-vinsyre, dibenzoyl-D-vinsyre, dibenzoyl-L-vinsyre, (+ )-kamfer-10-sulfonsyre, L (-)-eplesyre, L(+)-mandelsyre, d-a-brom-kamfer-n -sulfonsyre eller 1-kinasyre og påfølgende.frigjøring av den respektive optisk aktive base. Racematspaltningen kan imidlertid også foretas ved søylekromatografi på et optisk aktivt bærermateriale, f. The cleavage of a racemate of a compound of formula I takes place preferably by fractional crystallization of a mixture of the diastereomeric salts with an optically active acid, e.g. D(-)-tartaric acid, L(+)-tartaric acid, dibenzoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, (+ )-camphor-10-sulfonic acid, L (-)-malic acid, L(+)-mandelic acid, d-a-bromo-camphor-n-sulfonic acid or 1-quinic acid and subsequent release of the respective optically active base. However, the racemate separation can also be carried out by column chromatography on an optically active carrier material, e.g.

eks. acetylcellulose. e.g. acetyl cellulose.

Renfremstillingen av'diastereoméré;iacémater skjer f. eks. ved f raks joriért-krystallisering og/e^le.r- /søylekromatograf i på The purification of diastereomers takes place e.g. by f raks joriért crystallization and/e^le.r- /column chromatograph in on

en inert bærer. an inert carrier.

Videre''kan en således,oppnådd ny forbindelse overføres i dens fysiologisk akseptable salter med uorganiske eller organiske syrer. Egnede syrer til formålet er f. eks. saltsyre, hydrogenbromidsyre, svovelsyre, fosforsyre, fumarsyre, ravsyre, melkesyre, citronsyre, vinsyre eller maleinsyre. Furthermore, a new compound thus obtained can be transferred into its physiologically acceptable salts with inorganic or organic acids. Suitable acids for the purpose are e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Utgangsmaterialene med den generelle formel II til XII er tildels nye. Disse oppnås etter i og for seg kjente fremgangsmåter. The starting materials with the general formula II to XII are partly new. These are achieved according to methods known per se.

Således oppnås f. eks. en forbindelse med den generelle formel II, hvor X utgjør en CO-CHR^-gruppe, ved omsetning av et tilsvarende a-halogen-keton med et korresponderende amin og en forbindelse med den generelle formel II, hvor X står for -CH^-CO-gruppen, ved omsetning av det korresponderende fenyl-eddiksyre-derivat med et tilsvarende amin. Thus, e.g. a compound of the general formula II, where X constitutes a CO-CHR^ group, by reacting a corresponding α-halo-ketone with a corresponding amine and a compound of the general formula II, where X stands for -CH^- The CO group, by reaction of the corresponding phenyl-acetic acid derivative with a corresponding amine.

Utgangsmaterialet med formel III, hvor A' utgjør karbonyl-gruppen og R^ et hydrogenatom, oppnås f. eks. ved oksydasjon med selendioksyd av et korresponderende acetofenon henholdsvis en forbindelse med den generelle formel III, hvor A<1> utgjør en metylen- eller etylen-gruppe, ved å overføre en korresponderende hydroksyforbindelse i en tilsvarende halogeriforbindelse, hhv. ved acylering av en korresponderende hydroksyforbindelse med en tilsvarende klormaursyreester og påfølgende reduksjon. The starting material with formula III, where A' constitutes the carbonyl group and R^ a hydrogen atom, is obtained, e.g. by oxidation with selenium dioxide of a corresponding acetophenone or a compound of the general formula III, where A<1> constitutes a methylene or ethylene group, by transferring a corresponding hydroxy compound into a corresponding halogen compound, or by acylation of a corresponding hydroxy compound with a corresponding chloroformate ester and subsequent reduction.

Utgangsmaterialet med formel V oppnås f. eks. ved omsetning av et korresponderende co-fenylalkylhalogenid med et tilsvarende amin. The starting material with formula V is obtained, e.g. by reacting a corresponding co-phenylalkyl halide with a corresponding amine.

Utgangsmaterialene med de generelle formler VI, VII og VIII oppnås f. eks. ved reduksjon av korresponderende karbonsyre-amider eller aminoacetofenoner. The starting materials with the general formulas VI, VII and VIII are obtained, e.g. by reduction of corresponding carboxylic acid amides or aminoacetophenones.

Utgangsmaterialet med den generelle formel X oppnås f. eks. ved alkylering av en korresponderende merkapto-forbindelse og eventuelt påfølgende oksydasjon. The starting material with the general formula X is obtained, e.g. by alkylation of a corresponding mercapto compound and possibly subsequent oxidation.

Utgangsmaterialet med den generelle formel XI oppnås The starting material of the general formula XI is obtained

f. eks. ved alkylering av et korresponderende fenylalkylamin. e.g. by alkylation of a corresponding phenylalkylamine.

Som nevnt innledningsvis, oppviser de nye forbindelser ved siden av lav akutt toksisitet og få bivirkninger, verdifulle farmakologiske egenskaper, nemlig en virkning på hjertet og kretsløpet, særlig på blodtrykket, samt en antiarrytmisk og/eller kardiotonisk virkning. As mentioned at the outset, the new compounds, in addition to low acute toxicity and few side effects, exhibit valuable pharmacological properties, namely an effect on the heart and circulation, particularly on blood pressure, as well as an antiarrhythmic and/or cardiotonic effect.

Forbindelsene The connections

A = 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-amino]-etanol, A = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-amino]-ethanol,

B = 1-(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-methylamino]-etanol, B = 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol,

C = 1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-2-propylamino]-etanol-hydroklorid C = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-2-propylamino]-ethanol hydrochloride

D = 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-metylamino]-etanol, D = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methylamino]-ethanol,

E = 1-(4-amino-3,5-diklor-fenyl)-2-[N-[1,l-dimetyl-3-(4-hydroksy-fenyl)-propyl]-amino]-etanol, E = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-hydroxy-phenyl)-propyl]-amino]-ethanol,

F = 1-(4-amino-3,5-diklor-fenyl)-2-[N-(l-metyl-3-fenylpropyl) -propylamino]-etanol-hydroklorid, F = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenylpropyl)-propylamino]-ethanol hydrochloride,

G = 1-(4-dimetylamino-3,5-diklor-fenyl)-2-[N-(l-metyl-3-fenyl-propyl)-metylamino]-etanol, G = 1-(4-dimethylamino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenyl-propyl)-methylamino]-ethanol,

H = 1-(4-amino-3,5-diklor-fenyl)-2-[N-(l-metyl-3-fenylpropyl) -etylamino]-etanol, H = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenylpropyl)-ethylamino]-ethanol,

I = 1-(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-etylamino]-etanol-hydroklorid, I = 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-ethylamino]-ethanol hydrochloride,

K = 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-allylamino]-etanol, K = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-allylamino]-ethanol,

L = 1-(4-amino-3,5-diklor-fenyl)-2-[N-[1,l-dimetyl-3-(4-metoksy-fenyl)-propyl]-amino]-etanol. L = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-methoxy-phenyl)-propyl]-amino]-ethanol.

N = 1-(4-amino-3-cyan-5-fluorrfenyl)-2t[N- [l-metyl-3-(4-hydroksy-fenyl)-propyl]-amino]-etanol,^ N = 1-(4-amino-3-cyano-5-fluorophenyl)-2[N-[1-methyl-3-(4-hydroxy-phenyl)-propyl]-amino]-ethanol,^

0 = 1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyij-amino]-etanol-hydroklorid, 0 = 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propylij-amino]-ethanol hydrochloride,

P = N-[l-metyl-2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-propyl]-amin-hydroklorid, P = N-[1-methyl-2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]-amine hydrochloride,

Q = N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]-isopropylamin, Q = N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-isopropylamine,

R= N-[3-(4-klor-fenyl)-propyl]-N-[2-(3,5-diklor-4-isopropylamino-fenyl)-etyl]-isopropylamin og R= N-[3-(4-chloro-phenyl)-propyl]-N-[2-(3,5-dichloro-4-isopropylamino-phenyl)-ethyl]-isopropylamine and

S = N-[2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-[4-(4-met-. S = N-[2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[4-(4-meth-.

oksy-fenyl)-butyl]-metylamin oxy-phenyl)-butyl]-methylamine

sammenlignet med compared with

T = 1-(4-amino-3,5-dibrom-fenyl)-2-(N-benzylamino)-etanol-hydroklorid (se eksempel 183 i U.S. patent 3.536.712), T = 1-(4-amino-3,5-dibromo-phenyl)-2-(N-benzylamino)-ethanol hydrochloride (see Example 183 of U.S. Patent 3,536,712),

U = 1-(4-amino-3-klor-5-fluor-fenyl)-2-[N-[l-metyl-2-(3,4-metylendioksy-fenyl)-etyl]-amino]-etanol (se eksempel 18 i U.S. patent 4.119.710), U = 1-(4-amino-3-chloro-5-fluoro-phenyl)-2-[N-[1-methyl-2-(3,4-methylenedioxy-phenyl)-ethyl]-amino]-ethanol ( see Example 18 of U.S. Patent 4,119,710),

V = 1-(4-amino-3-klor-5-trifluormetyl-fenyl)-2-[N-[1-metyl-2-(3,4-metylendioksy-fenyl)-etyl]-amino]-etanol (se eksempel 29 i U.S. patent 4.119.710), V = 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[N-[1-methyl-2-(3,4-methylenedioxy-phenyl)-ethyl]-amino]-ethanol ( see Example 29 of U.S. Patent 4,119,710),

W = 1-(4-amino-3-klor-5-cyan-fenyl)-2-[N-[l-metyl-2-(3,4-metylendioksy-fenyl)-etyl]-amino]-etanol (se eksempel 77 i U.S. patent'4.119.710] og W = 1-(4-amino-3-chloro-5-cyano-phenyl)-2-[N-[1-methyl-2-(3,4-methylenedioxy-phenyl)-ethyl]-amino]-ethanol ( see Example 77 of U.S. Patent' 4,119,710] and

X = 1-(4-amino-3-klor-5-trifluormetyl-fenyl)-2-[N-[1-metyl-2-(4-hydroksy-fenyl)-etyl]-amino]-etanol (se eksempel 108 i U.S. patent 4.119.710). X = 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[N-[1-methyl-2-(4-hydroxy-phenyl)-ethyl]-amino]-ethanol (see example 108 of U.S. Patent 4,119,710).

ble undersøkt med hensyn til sine biologiske egenskaper som følger: 1. Måling av kontraktilitetsparameteren dp/dtmax hhv. hjertefrekvensen på narkotiserte katter. was examined with regard to its biological properties as follows: 1. Measurement of the contractility parameter dp/dtmax respectively. heart rate in anesthetized cats.

Han- og hunkatter med en vekt på ca. 2-4 kg, ble narkotisert med pentobarbital-natrium (40 mg/kg intraperitonealt) og kontinuerlig infundert med pentobarbitalnatrium (8 mg/kg/time) for å opprettholde narkosen. Male and female cats with a weight of approx. 2-4 kg, were anesthetized with pentobarbital sodium (40 mg/kg intraperitoneally) and continuously infused with pentobarbital sodium (8 mg/kg/hour) to maintain anesthesia.

Dyrene pustet spontant. The animals breathed spontaneously.

Kroppstemperaturen ble holdt ved 38°C ved hjelp av en varmepute og en termostat. Body temperature was maintained at 38°C using a heating pad and a thermostat.

Trykket i venstre hjerteventrikkel ble tatt med en trykkføler (Millar PC 350) som var skjøvet inn i venstre hjertekammer via høyre aorta, og trykkstigningshastigheten dp/dt kontinuerlig bestemt ut fra trykksignaler med en differansierer. Hjertefrekvensen ble målt kontinuerlig med en Grass-tachograf (modell 7P4). Som triggersignal ble enten et EKG eller den venstre ventrikulære trykk-kurve benyttet. Parameter-registrer-ingen foregikk på en Grass-polygraf. The pressure in the left ventricle was taken with a pressure sensor (Millar PC 350) which was pushed into the left heart chamber via the right aorta, and the pressure rise rate dp/dt was continuously determined from pressure signals with a differentiator. Heart rate was measured continuously with a Grass tachograph (model 7P4). Either an ECG or the left ventricular pressure curve was used as a trigger signal. Parameter-register-none occurred on a Grass polygraph.

Alle substanser ble injisert som løsninger (vann eller polyetylenglykol 200) i en V. saphena. Doseringen var hver gang 0,3 mg/kg i.v. All substances were injected as solutions (water or polyethylene glycol 200) into a V. saphena. The dosage was each time 0.3 mg/kg i.v.

Maksimalvirkningen og tiden fra administrering til virkningen var sunket til halvparten av maksimaleffekten ble angitt. The maximum effect and time from administration to effect had decreased until half the maximum effect was indicated.

Den g2~mi-metiske virkning ble undersøkt som antagonisme overfor den bronkospasme som ble utløst ved intravenøs administrering av 20 y/kgacetylcholin på narkotiserte marsvin i for-søksanordningen ifølge Konzett-Rossler efter intravenøs administrering. På grunnlag av den prosentvise reduksjonen av bronko-spasmen som ble oppnådd med de forskjellige doser, ble en ED^Q bestemt ved grafisk ekstrapolering. The gamma mimetic effect was investigated as antagonism to the bronchospasm which was triggered by the intravenous administration of 20 µg/kg of acetylcholine to anesthetized guinea pigs in the experimental device according to Konzett-Rossler after intravenous administration. On the basis of the percentage reduction of bronchospasm obtained with the various doses, an ED^Q was determined by graphical extrapolation.

De følgende tabeller inneholder de fundene verdier: The following tables contain the values found:

2. Akutt toksisitet: 2. Acute toxicity:

Han- og hunmus med en vekt på ca. 20 g fikk en tilførsel av den aktuelle prøveforbindelse i en V. saphena (0,1 resp.0,2 ml/10 g kroppsvekt) resp. i maven. Efter en observasjonstid på 14 dager ble LD^q bestemt ved metoden ifølge Lichtfield og Wilcoxon: Male and female mice with a weight of approx. 20 g received a supply of the respective test compound in a V. saphena (0.1 resp. 0.2 ml/10 g body weight) resp. in the stomach. After an observation period of 14 days, LD^q was determined by the method according to Lichtfield and Wilcoxon:

På grunn av deres farmakologiske egenskaper egner forbindelsene i henhold til oppfinnelsen seg til behandling av hjerte- og kretsløpssykdommer. Forbindelser som virker positivt inotropt, egner seg således særlig til behandling av hjerte-insuffisiens, og forbindelsene som senker hjertefrekvensen spesielt til behandling av hjerterytmeforstyrrelser og koronare hjertesykdommer. Due to their pharmacological properties, the compounds according to the invention are suitable for the treatment of heart and circulatory diseases. Compounds that have a positive inotropic effect are thus particularly suitable for the treatment of heart insufficiency, and the compounds that lower the heart rate in particular for the treatment of heart rhythm disorders and coronary heart diseases.

Til slike formål lar de nye forbindelser seg innarbeide, eventuelt i kombinasjon med andre virksomme forbindelser, i de vanlige galeniske sammensetninger som drageer, tabletter, pulvere, suppositorier, suspensjoner, ampuller eller dråper. Enkeltdosen for voksne utgjør herunder 1 til 4 x daglig, 5 til 75 mg, dog fortrinnsvis 10 til 50 mg. For such purposes, the new compounds can be incorporated, possibly in combination with other active compounds, in the usual galenic compositions such as dragees, tablets, powders, suppositories, suspensions, ampoules or drops. The single dose for adults includes 1 to 4 x daily, 5 to 75 mg, however preferably 10 to 50 mg.

Eksempel 1 Example 1

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]- ethanol

Til en løsning av 3,45 g (9 mmol) 4<1->amino-3,5'-diklor-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon i 40 ml metanol og 15 ml vann, ble det porsjonsvis tilsatt 0,5 g (13,5 mmol) natriumborhydrid. Med 2 N saltsyre ble pH holdt mellom 3 og 6. Etter tilsetningen ble løsningen omrørt i ytterligere 30 minutter og deretter inndampet på rotasjonsfordamper. Det oppnådde residuum ble fordelt mellom 100 ml eter og 100 ml 2 n ammoniakkløsning. Den eteriske fase ble vasket med vann, tørket med natriumsulfat og inndampet. Det oljeaktige residuum ble kromatografert på kiselgel (Macherey & Nagel 70 - 230 mesh ASTM) med metylenklorid:metanol = 19:1 som elueringsmiddel. Fraksjoner som inneholdt den ønskede forbindelse, ble samlet, inndampet og den oppnådde olje befridd for løsningsmiddel-rester i vakuum ved 4 0°C. To a solution of 3.45 g (9 mmol) of 4<1->amino-3,5'-dichloro-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone in 40 ml of methanol and 15 ml of water, 0.5 g (13.5 mmol) of sodium borohydride was added in portions. With 2 N hydrochloric acid, the pH was kept between 3 and 6. After the addition, the solution was stirred for a further 30 minutes and then evaporated on a rotary evaporator. The residue obtained was distributed between 100 ml of ether and 100 ml of 2 N ammonia solution. The ethereal phase was washed with water, dried with sodium sulfate and evaporated. The oily residue was chromatographed on silica gel (Macherey & Nagel 70 - 230 mesh ASTM) with methylene chloride: methanol = 19:1 as eluent. Fractions containing the desired compound were collected, evaporated and the resulting oil freed from solvent residues in vacuo at 40°C.

Eksempel 2 Example 2

1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-metylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-methylamino]- ethanol hydrochloride

10 g (0,035 mol) 4'-amino-2-brom-3<1>,5'-diklor-acetofenon, 10 g (0.035 mol) 4'-amino-2-bromo-3<1>,5'-dichloro-acetophenone,

6,7 g (0,036 mol) N-(3-fenyl-propyl)-metylamin-hydroklorid og 10,5 ml (0,075 mol) trietylamin ble tilsatt til 250 ml metylenklorid. Denne blanding ble oppvarmet 6 timer under tilbake-løpskjøling og henstillet natten over ved romtemperatur, vasket med vann, tørket over natriumsulfat og inndampet under vakuum i rotasjonsfordamper. Det oljeaktige residuum som besto av rå 4'-amino-3<1>,5<1->diklor-2-[N-(3-fenyl-propyl)-metylamino]-acetofenon ble løst i 100 ml 90% etanol. Under omrøring og utvendig kjøling med vann, ble det porsjonsvis tilsatt 5 g natriumborhydrid. Blandingen ble stående en time ved romtemperatur hvorpå overskuddet av natriumborhydrid ble fjernet med aceton. Etter fortynning med vann, ble det ekstrahert med metylenklorid. Metylenkloridfasen ble fraskilt, vasket med vann, tørket over natriumsulfat og inndampet under vakuum i rotasjonsfordamper. Det gule oljeaktige residuum ble kromatografert på kiselgel med metylenklorid:eddikester = 4:1. Fraksjoner som inneholdt den ønskede forbindelse, ble inndampet. Det gjenværende oljeaktige residuum ble løst i isopropanol, gjort surt med eterisk saltsyre og tilsatt eter inntil utkrystallisering inntrådte. Herved ble det oppnådd et farveløst krystallinsk produkt. Smeltepunkt: fra 85°C (under sintring). 6.7 g (0.036 mol) of N-(3-phenyl-propyl)-methylamine hydrochloride and 10.5 ml (0.075 mol) of triethylamine were added to 250 ml of methylene chloride. This mixture was heated for 6 hours under reflux and allowed to stand overnight at room temperature, washed with water, dried over sodium sulfate and evaporated under vacuum in a rotary evaporator. The oily residue consisting of crude 4'-amino-3<1>,5<1->dichloro-2-[N-(3-phenyl-propyl)-methylamino]-acetophenone was dissolved in 100 ml of 90% ethanol. During stirring and external cooling with water, 5 g of sodium borohydride were added in portions. The mixture was left for one hour at room temperature, after which the excess of sodium borohydride was removed with acetone. After dilution with water, it was extracted with methylene chloride. The methylene chloride phase was separated, washed with water, dried over sodium sulfate and evaporated under vacuum in a rotary evaporator. The yellow oily residue was chromatographed on silica gel with methylene chloride:acetic ester = 4:1. Fractions containing the desired compound were evaporated. The remaining oily residue was dissolved in isopropanol, acidified with ethereal hydrochloric acid and ether added until crystallization occurred. A colorless crystalline product was thereby obtained. Melting point: from 85°C (during sintering).

Eksempel 3 Example 3

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1-metyl- propyl]- metylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl- propyl]- methylamino]- ethanol

Til en isvann-kjølt løsning av 0,1 mol 4'-amino-3',5'-diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-metyl-amino]-acetofenon i 300 ml tetrahydrofuran og 50 ml vann ble det under omrøring porsjonsvis tilsatt 0,2 mol natriumborhydrid. Reak-sjonsløsningen ble deretter rørt ytterligere 60 minutter ved romtemperatur, og tetrahydrofuranet avdestillert i rotasjonsfordamper etter surgjøring med 2 N saltsyre. Det oppnådde vandig-saltsyre residuum ble, etter tilsetning av 8,5 N ammoniakk til basisk reaksjon, ekstrahert med 2 porsjoner å To an ice-water-cooled solution of 0.1 mol of 4'-amino-3',5'-dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methyl-amino ]-acetophenone in 300 ml of tetrahydrofuran and 50 ml of water, 0.2 mol of sodium borohydride was added in portions while stirring. The reaction solution was then stirred for a further 60 minutes at room temperature, and the tetrahydrofuran distilled off in a rotary evaporator after acidification with 2 N hydrochloric acid. The obtained aqueous-hydrochloric acid residue was, after adding 8.5 N ammonia for a basic reaction, extracted with 2 portions of

250 ml eter. Eterekstraktene ble deretter vasket 2 ganger med 75 ml porsjoner vann og tørket med magnesiumsulfat. Filtratet ble inndampet i rotasjonsfordamper og det oppnådde residuum renset over kiselgel 60 (Macherey & Nagel, 70 - 230 mesh,ASTM). Som elueringsmiddel ble en blanding av metylenklorid:metanol = 30:1 benyttet. Inndampningsresiduet som ble oppnådd etter fraksjonering og inndamping i rotasjonsfordamper, krystalliserte etter poding. Rå-krystallisatet ble omkrystallisert fra metylenklorid og forelå som 1:1-blanding av de diastereomere racemater. 250 ml of ether. The ether extracts were then washed twice with 75 ml portions of water and dried with magnesium sulfate. The filtrate was evaporated in a rotary evaporator and the residue obtained purified over silica gel 60 (Macherey & Nagel, 70 - 230 mesh, ASTM). A mixture of methylene chloride: methanol = 30:1 was used as eluent. The evaporation residue obtained after fractionation and evaporation in a rotary evaporator crystallized after grafting. The crude crystallisate was recrystallized from methylene chloride and was present as a 1:1 mixture of the diastereomeric racemates.

Smeltepunkt: 112-115°C Melting point: 112-115°C

Eksempel 4 Example 4

1- (4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-1 - metyl- propyl]- metylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-1-methyl- propyl]- methylamino]- ethanol

0,02 mol 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-metylamino]-etanol ble løst i 22 ml 1 N natronlut og 10 ml vann. Til denne løsning ble det under omrøring og kjøling med isvann dråpevis tilsatt 0,022 mol dimetylsulfat, hvorpå reaksjonsløsningen etter tilsetning av 50 ml tetrahydrofuran, ble omrørt 20 timer ved romtemperatur. Deretter ble 100 ml eter tilsatt og den organiske fase fraskilt, vasket med 50 ml 0,5 N natronlut, 3 ganger med 75 ml porsjoner vann, og tørket over magnesiumsulfat. Den organiske fase ble inndampet på rotasjonsfordamper og det oppnådde residuum renset over kiselgel 60 (Macherey & Nagel, 70 - 230 mesh, ASTM) med metylenklorid:metanol = 30:1 som eluerings- 0.02 mol of 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methylamino]-ethanol was dissolved in 22 ml 1 N caustic soda and 10 ml water. To this solution, while stirring and cooling with ice water, 0.022 mol of dimethyl sulfate was added dropwise, after which the reaction solution, after the addition of 50 ml of tetrahydrofuran, was stirred for 20 hours at room temperature. Then 100 ml of ether was added and the organic phase separated, washed with 50 ml of 0.5 N caustic soda, 3 times with 75 ml portions of water, and dried over magnesium sulfate. The organic phase was evaporated on a rotary evaporator and the obtained residue purified over silica gel 60 (Macherey & Nagel, 70 - 230 mesh, ASTM) with methylene chloride:methanol = 30:1 as eluent

middel. Det oppnådde oljeaktige inndampings-residuum ble befridd for løsningsmiddelrester i vakuum over svovelsyre. Den oppnådde olje foreligger som 1:1-blanding av de diastereomere racemater. medium. The obtained oily evaporation residue was freed from solvent residues in vacuum over sulfuric acid. The obtained oil exists as a 1:1 mixture of the diastereomeric racemates.

Eksempel 5 Example 5

1-(4-étoksykarbonylamino-3-cyan-5-fluor-fenyl)-2- [N-[ 3-(4-metoksy- fenyl)- propyl]- amino]- etanol 1-(4-ethoxycarbonylamino-3-cyano-5-fluoro-phenyl)-2- [N-[ 3-(4-methoxy- phenyl)- propyl]-amino]- ethanol

Til en løsning av 1,16 g (0,01 mol) selendioksyd i 10 ml dioksan og. 0,7 ml vann ble det under omrøring ved 60°C tilsatt 0,5 Celite og deretter porsjonsvis 2,5 g (0,01 mol) 4'-etoksykarbonylamino-3'-cyan-5'-fluor-acetofenon. Blandingen ble deretter oppvarmet 4 timer til tilbakeløpstemperaturen og deretter befridd for uløst materiale ved filtrering. I den således fremstilte løsning av 4'-etoksy-karbonylamino-31-cyan-51 - fluorfenyl-glyoksal ble det etter avkjøling og utvendig kjøling med is, dråpevis tilsatt en løsning av 2,01 g (0,01 mol) 3-(4-metoksy-fenyl)-propylamin-hydroklorid og 1,01 g (0,01 mol) trietylamin i 12 ml etanol. Løsningen som inneholdt det rå 4'-etoksykarbonylamino-3'-cyan-5'-fluorfenylglyoksyliden-3-(4-metoksy-fenyl)-propylamin, ble under omrøring og kjøling med is, porsjonsvis tilsatt 1,5 g natriumborhydrid og henstillet over natten ved romtemperatur. Overskuddet av natriumborhydrid ble deretter fjernet med aceton, blandingen inndampet under vakuum til et lite volum, tilsatt vann og ekstrahert med metylenklorid. Metylenkloridløsningen ble vasket med vann, tørket med natriumsulfat og inndampet til tørrhet i vakuum. To a solution of 1.16 g (0.01 mol) selenium dioxide in 10 ml dioxane and. 0.5 g of Celite and then 2.5 g (0.01 mol) of 4'-ethoxycarbonylamino-3'-cyano-5'-fluoro-acetophenone were added in portions to 0.7 ml of water while stirring at 60°C. The mixture was then heated for 4 hours to the reflux temperature and then freed of undissolved material by filtration. After cooling and external cooling with ice, a solution of 2.01 g (0.01 mol) 3-( 4-methoxy-phenyl)-propylamine hydrochloride and 1.01 g (0.01 mol) of triethylamine in 12 ml of ethanol. The solution containing the crude 4'-ethoxycarbonylamino-3'-cyano-5'-fluorophenylglyoxylidene-3-(4-methoxy-phenyl)-propylamine was, while stirring and cooling with ice, 1.5 g of sodium borohydride was added portionwise and allowed to stand over overnight at room temperature. The excess sodium borohydride was then removed with acetone, the mixture evaporated under vacuum to a small volume, water added and extracted with methylene chloride. The methylene chloride solution was washed with water, dried with sodium sulfate and evaporated to dryness in vacuo.

Det gjenværende oljeaktige residuum ble kromatografert på The remaining oily residue was chromatographed on

200 kiselgel med metylenklorid:metanol = 20:1 som elueringsmiddel. Fraksjonene som inneholdt den ønskede forbindelse, ble inndampet. Et farveløst krystallinsk produkt ble oppnådd. Smeltepunkt: 111-112°C. 200 silica gel with methylene chloride:methanol = 20:1 as eluent. The fractions containing the desired compound were evaporated. A colorless crystalline product was obtained. Melting point: 111-112°C.

Eksempel 6 Example 6

1-(4-etoksykarbonylamino-3-cyan-5-fluor-fenyl)-2-[N-[3-(4-metoksy- fenyl)- propyl]- metylamino]- etanol 1-(4-ethoxycarbonylamino-3-cyano-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Til en løsning av 6,6 g (0,06 mol) selendioksyd i 60 ml dioksan og 2 ml vann ble det under omrøring ved 60°C porsjonsvis tilsatt 15 g (0,06 mol) 4'-etoksykarbonylamino-3'-cyan-5<1->fluor-acetofenon. Blandingen ble deretter kokt 4 timer under tilbakeløps-kjøling, fortynnet med 100 ml tetrahydrofuran og uløst materiale frafiltrert. Til den således fremstilte løsning av 4'-etoksykarbonylamino-3 ' -cyan-5 1 -f luor-fenylglyoksal ble det etter av-kjøling til romtemperatur tilsatt 10,7 g (0,06 mol) N-[3(4-metoksy-fenyl)-propyl]-metylamin løst i 100 ml tetrahydrofuran. Til denne løsning ble det porsjonsvis tilsatt 8 g (0,13 mol) natriumcyanborhydrid, idet løsningen ved dråpevis tilsetning av 2 N saltsyre ble holdt ved pH 6. Løsningen fikk stå ved romtemperatur til neste dag, ble deretter tilsatt 5 g natriumborhydrid og henstillet ytterligere 5 timer ved romtemperatur. Natriumborhydrid-overskuddet ble deretter fjernet med aceton, hvorpå løsningen ble fortynnet med vann og ekstrahert med metylenklorid. Metylenklorid-løsningen ble vasket med vann, tørket over natriumsulfat og inndampet til tørrhet i vakuum. Det gjenværende oljeaktige residuum ble kromatografert på To a solution of 6.6 g (0.06 mol) of selenium dioxide in 60 ml of dioxane and 2 ml of water, 15 g (0.06 mol) of 4'-ethoxycarbonylamino-3'-cyano were added in portions while stirring at 60°C -5<1->fluoro-acetophenone. The mixture was then boiled for 4 hours under reflux, diluted with 100 ml of tetrahydrofuran and undissolved material filtered off. After cooling to room temperature, 10.7 g (0.06 mol) of N-[3(4-methoxy -phenyl)-propyl]-methylamine dissolved in 100 ml of tetrahydrofuran. To this solution, 8 g (0.13 mol) of sodium cyanoborohydride were added in portions, the solution being maintained at pH 6 by the dropwise addition of 2 N hydrochloric acid. The solution was allowed to stand at room temperature until the next day, then 5 g of sodium borohydride was added and allowed to settle further 5 hours at room temperature. The excess sodium borohydride was then removed with acetone, after which the solution was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining oily residue was chromatographed on

700 g kiselgel med eddikester som elueringsmiddel. Fraksjoner som inneholdt den ønskede forbindelse, ble samlet, inndampet og den oppnådde olje befridd for løsningsmiddelrester i vakuum ved 4 0°C. 700 g silica gel with vinegar as eluent. Fractions containing the desired compound were collected, evaporated and the resulting oil freed from solvent residues in vacuo at 40°C.

Eksempel 7 Example 7

N-[2-(4-amino-3-brom-fenyl)-etyl]-N-t 3-(4-metoksy-fenyl)-propyl]- metylamin- dihydroklorid N-[2-(4-amino-3-bromo-phenyl)-ethyl]-N-t 3-(4-methoxy-phenyl)-propyl]- methylamine- dihydrochloride

2,9 g (0,077 mol) litiumaluminiumhydrid ble suspendert i 100 ml absolutt tetrahydrofuran under nitrogenatomsfære. Til denne ble det under omrøring ved romtemperatur dråpevis tilsatt en løsning av 14,4 g (0,031 mol) 4-amino-3,5-dibrom-N-[3-(4-metoksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid i 100 ml absolutt tetra-hydrof uran. Etter 1 times koking under tilbakeløpskjøling, ble overskuddet av litiumaluminiumhydrid dekomponert med eddikester og vann, hvorpå 10 N natronlut ble tilsatt dråpevis inntil det uorganiske materiale falt ut som granulat. Tetrahydrofuran-fasen over dette ble avdekantert, tørket over natrium-sulf at og inndampet på rotasjonsfordamper. Residuet ble kromato-graf ert på kiselgel (Macherey & Nagel, 70-230 mesh, ASTM) med metylenklorid:metanol = 19:1 som elueringsmiddel. Fraksjoner med ønsket produkt ble samlet og inndampet. Den oppnådde olje ble løst i litt absolutt etanol og det krystallinske dihydroklorid fremstillet med etanolisk saltsyre under tilsetning av eter. Smeltepunkt: 168-171°C (dekomp.). 2.9 g (0.077 mol) of lithium aluminum hydride was suspended in 100 ml of absolute tetrahydrofuran under a nitrogen atmosphere. To this a solution of 14.4 g (0.031 mol) 4-amino-3,5-dibromo-N-[3-(4-methoxy-phenyl)-propyl]-N-methyl was added dropwise while stirring at room temperature -phenylacetic acid amide in 100 ml of absolute tetrahydrofuran. After boiling for 1 hour under reflux, the excess lithium aluminum hydride was decomposed with acetic acid and water, after which 10 N caustic soda was added dropwise until the inorganic material precipitated as granules. The tetrahydrofuran phase above this was decanted off, dried over sodium sulphate and evaporated on a rotary evaporator. The residue was chromatographed on silica gel (Macherey & Nagel, 70-230 mesh, ASTM) with methylene chloride:methanol = 19:1 as eluent. Fractions with the desired product were collected and evaporated. The oil obtained was dissolved in a little absolute ethanol and the crystalline dihydrochloride prepared with ethanolic hydrochloric acid with the addition of ether. Melting point: 168-171°C (decomp.).

Eksempel 8 Example 8

N-[2-(4-amino-3,5-dibrom-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)-butyl]-metylamin N-[2-(4-amino-3,5-dibromo-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-methylamine

2,9 g (0,077 moi), litiumaluminiumhydrid ble suspendert i 100 ml absolutt tetrahydrofuran under nitrogenatmosfære. Til denne ble en løsning av 15,0 g (0,031 mol) 4-amino-3,5-dibrom-N-[4-(4-metoksy-fenyl)-butyl]-N-metyl-fenyleddiksyreamid i 100 ml absolutt tetrahydrofuran dråpevis tilsatt under omrøring ved romtemperatur. Blandingen ble deretter kokt i en time under til- 2.9 g (0.077 moi) of lithium aluminum hydride was suspended in 100 ml of absolute tetrahydrofuran under a nitrogen atmosphere. To this was added a solution of 15.0 g (0.031 mol) of 4-amino-3,5-dibromo-N-[4-(4-methoxy-phenyl)-butyl]-N-methyl-phenylacetic acid amide in 100 ml of absolute tetrahydrofuran added dropwise with stirring at room temperature. The mixture was then boiled for one hour under

bakeløpskjøling. Med eddikester og vann ble det overskytende litiumaluminiumhydrid dekomponert og 10 N natronlut tilsatt dråpevis inntil det uorganiske materialet falt ut som granulat. Den overstående tetrahydrofuran-fase ble avdekantert, tørket over natriumsulfat og inndampet på rotasjonsfordamper. Residuet ble kromatografert på kiselgel (Macherey & Nagel, 70 - 230 mesh ASTM) med metylenklorid:metanol = 19:1 som elueringsmiddel. Fraksjoner med ønsket produkt ble kombinert og inndampet. Den oppnådde olje ble befridd fra løsningsmiddelrester i vakuum ved 40°C. backflow cooling. With vinegar and water, the excess lithium aluminum hydride was decomposed and 10 N caustic soda was added dropwise until the inorganic material fell out as granules. The supernatant tetrahydrofuran phase was decanted off, dried over sodium sulphate and evaporated on a rotary evaporator. The residue was chromatographed on silica gel (Macherey & Nagel, 70 - 230 mesh ASTM) with methylene chloride:methanol = 19:1 as eluent. Fractions with the desired product were combined and evaporated. The obtained oil was freed from solvent residues in vacuum at 40°C.

Eksempel 9 N-[2-(4-amino-3-klor-5-cyan-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-propyl]-metylamin 6,6 g (0,014 mol) 1-(etoksykarbonyloksy)-1-(4-amino-3-klor-5-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etan ble løst i 70 ml isopropanol og omrørt ved romtemperatur natten over med 5,5 g (0,14 mol) natriumborhydrid. Den oppnådde løsning ble inndampet til tørrhet og tatt opp i 100 ml vann. Med 50 ml 2 N saltsyre ble overskuddet av natriumborhydrid dekomponert. Løsningen ble deretter gjort basisk igjen med 100 ml 2 N ammoniakk og ekstrahert to ganger ned 150 ml eddikester. Den organiske fase ble tørket med magnesiumsulfat og inndampet. Den oppnådde olje ble kromatografert på kiselgel (Macherey & Nagel, 70-230 mesh ASTM) med metylenklorid:metanol = 19:1 som elueringsmiddel. Fraksjoner som inneholdt den ønskede forbindelse ble samlet og inndampet, og den oppnådde olje befridd fra løsningsmiddelrester i vakuum ved 40°C. Example 9 N-[2-(4-amino-3-chloro-5-cyano-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]-methylamine 6.6 g (0.014 mol ) 1-(ethoxycarbonyloxy)-1-(4-amino-3-chloro-5-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethane was resolved in 70 ml of isopropanol and stirred at room temperature overnight with 5.5 g (0.14 mol) of sodium borohydride. The solution obtained was evaporated to dryness and taken up in 100 ml of water. With 50 ml of 2 N hydrochloric acid, the excess of sodium borohydride was decomposed. The solution was then made basic again with 100 ml of 2 N ammonia and extracted twice into 150 ml of acetic acid. The organic phase was dried with magnesium sulfate and evaporated. The obtained oil was chromatographed on silica gel (Macherey & Nagel, 70-230 mesh ASTM) with methylene chloride: methanol = 19:1 as eluent. Fractions containing the desired compound were collected and evaporated, and the obtained oil freed from solvent residues in vacuo at 40°C.

Eksempel 10 Example 10

N-[2-(4-amino-3-klor-5-cyan-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)- propyl]- metylamin N-[2-(4-amino-3-chloro-5-cyano-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]- methylamine

1,3 g (0,0027 mol) 1-(4-amino-3-klor-5-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etyljodid ble løst i 30 ml heksametylfosforsyretriamid.Til denne løsning ble det tilsatt 0,25 g (0,004 mol) natriumcyanborhydrid som så ble opp-,varmet til 70°C i 3 timer. Etter avkjøling ble det fortynnet med 100 ml vann og ekstrahert med eter. Den eteriske løsning ble vasket med vann, tørket over natriumsulfat og inndampet til tørrhet i vakuum. Det gjenværende oljeaktige residuum ble. kromatografert på kiselgel med metylenklorid:metanol = 20:1 som elueringsmiddel. Den oppnådde oljeaktige inndampningsrest ble befridd fra løsningsmiddelrester i vakuum. 1.3 g (0.0027 mol) 1-(4-amino-3-chloro-5-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]- ethyl iodide was dissolved in 30 ml of hexamethylphosphoric acid triamide. To this solution was added 0.25 g (0.004 mol) of sodium cyanoborohydride, which was then heated to 70°C for 3 hours. After cooling, it was diluted with 100 ml of water and extracted with ether. The ethereal solution was washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The remaining oily residue remained. chromatographed on silica gel with methylene chloride:methanol = 20:1 as eluent. The obtained oily evaporation residue was freed from solvent residues in vacuo.

Massespektrum: funnet M<+> 357/59 Mass spectrum: found M<+> 357/59

Molvekt: 357,8. Molecular weight: 357.8.

Eksempel 11 Example 11

1 -(4-amino-3-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]- etanol 1 -(4-amino-3-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]- ethanol

En løsning av 3,9 g (0,0095 mol) 1 -(4-amino-3-brom-5-fluor-fenyl) -2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol i 50 ml metanol ble tilsatt 2 g 10% palladium/karbon og hydrert ved romtemperatur i autoklav under et trykk på 3,5 bar. Etter at den teoretisk beregnede mengde hydrogen var tatt opp, ble blandingen filtrert og filtratet inndampet på rotasjonsfordamper. De derved oppnådde 4 g olje ble kromatografert på kiselgel (Macherey & Nagel, 70 - 230 mesh ASTM) med kloroform:metanol = 19:1 som elueringsmiddel. Fraksjoner som inneholdt den ønskede forbindelse, ble samlet og inndampet. Den oppnådde olje ble løst i isopropanol og hydrokloridet utfelt med iso-propanolisk saltsyre og eddikester. Krystallene ble frafiltrert, vasket med litt kald isopropanol og tørket i vakuum. Smeltepunkt: 110°C (dekomp.). A solution of 3.9 g (0.0095 mol) of 1-(4-amino-3-bromo-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]-ethanol in 50 ml of methanol was added to 2 g of 10% palladium/carbon and hydrogenated at room temperature in an autoclave under a pressure of 3.5 bar. After the theoretically calculated amount of hydrogen had been taken up, the mixture was filtered and the filtrate evaporated on a rotary evaporator. The 4 g of oil thus obtained were chromatographed on silica gel (Macherey & Nagel, 70 - 230 mesh ASTM) with chloroform:methanol = 19:1 as eluent. Fractions containing the desired compound were pooled and evaporated. The oil obtained was dissolved in isopropanol and the hydrochloride precipitated with isopropanol hydrochloric acid and acetic acid. The crystals were filtered off, washed with a little cold isopropanol and dried in vacuum. Melting point: 110°C (decomp.).

Eksempel 12 Example 12

1-(4-etoksykarbonylamino-3-brom-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-etanol 1-(4-ethoxycarbonylamino-3-bromo-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethanol

Til en løsning av 5,1 g (0,0125 mol) 1 -(4-amino-3-brom-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-etanol i 40 ml absolutt pyridin ble det ved 0°C under iskjøling tilsatt 1,5 ml (0,015 mol) klormaursyreetylester. Den oppnådde løsning ble opp-bevart natten over ved +4°C i kjøleskap. Pyridinet ble deretter avdestillert på rotasjonsfordamper ved 50°C. Den oppnådde olje ble løst i 100 ml metylenklorid og vasket to ganger med 100 ml vann. Den organiske fase ble tørket over natriumsulfat, filtrert To a solution of 5.1 g (0.0125 mol) 1 -(4-amino-3-bromo-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]- ethanol in 40 ml of absolute pyridine, 1.5 ml (0.015 mol) ethyl chloroformic acid was added at 0°C under ice cooling. The obtained solution was stored overnight at +4°C in a refrigerator. The pyridine was then distilled off on a rotary evaporator at 50°C. The oil obtained was dissolved in 100 ml of methylene chloride and washed twice with 100 ml of water. The organic phase was dried over sodium sulfate, filtered

og inndampet på rotasjonsfordamper. Den oppnådde olje ble kromatografert på kiselgel (Macherey & Nagel. 70 - 230 mesh ASTM) and evaporated on a rotary evaporator. The obtained oil was chromatographed on silica gel (Macherey & Nagel. 70 - 230 mesh ASTM)

med metylenklorid:metanol = 9:1 som elueringsmiddel.Fraksjoner som inneholdt den ønskede substans, ble samlet og inndampet. with methylene chloride:methanol = 9:1 as eluent. Fractions containing the desired substance were collected and evaporated.

Den oppnådde olje ble befridd for løsningsmiddelrester i vakuum ved 4 0°C. The obtained oil was freed from solvent residues in vacuum at 40°C.

Eksempel 13 N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-hydroksy-fenyl)-1- metyl- propyl]- metylamin 0,012 mol N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-amin ble løst i 13 ml 1 N natronlut. Under kjøling med isvann ble løsningen dråpevis tilsatt .0,014 mol dimetylsulfat. Etter kort tid falt et smørig reaksjonsprodukt ut som ble løst ved tilsetning av 150 ml tetra-hydrof uran. Reaksjonsløsningen ble omrørt i 24 timer ved romtemperatur og deretter ekstrahert to ganger med 150 ml prosjoner eter. De organiske ekstrakter ble vasket med vann, tørket over magnesiumsulfat og inndampet i vakuum. Rensingen av den oppnådde inndampningsrest ble foretatt på kiselgel (Polygosil 60-1525; Macherey &Nagel) med metylenklorid:metanol/kons. ammoniakk = 19:1:0,1. Den oljeaktige inndampningsrest ble befridd fra med-følgende løsningsmiddel i vakuum over kaliumhydroksyd. Example 13 N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methylamine 0.012 mol N-[ 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-amine was dissolved in 13 ml of 1 N caustic soda. While cooling with ice water, 0.014 mol of dimethylsulphate was added dropwise to the solution. After a short time, a greasy reaction product precipitated out, which was dissolved by the addition of 150 ml of tetrahydrofuran. The reaction solution was stirred for 24 hours at room temperature and then extracted twice with 150 ml portions of ether. The organic extracts were washed with water, dried over magnesium sulfate and evaporated in vacuo. The purification of the obtained evaporation residue was carried out on silica gel (Polygosil 60-1525; Macherey & Nagel) with methylene chloride:methanol/conc. ammonia = 19:1:0.1. The oily evaporation residue was freed from accompanying solvent in vacuo over potassium hydroxide.

Eksempel 14 Example 14

1-(4-amino-3,5-diklor-fenyl)-2-[N-[2-(4-metoksy-fenyl-sulfinyl)-etyl]-metylamino]-etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[2-(4-methoxy-phenyl-sulfinyl)-ethyl]-methylamino]-ethanol

7,0 g 1-(4-amino-3,5-diklor-fenyl)-2-[N-[2-(4-metoksy-fenyl-sulfenyl)-etyl]-metylamino]-etanol ble løst i 100 ml iseddik og under omrøring ved romtemperatur dråpevis tilsatt 2,0 g 30% hydrogenperoksyd. Røringen ble fortsatt ved samme temperatur over natten, og løsningen deretter inndampet i vakuum. Residuet ble tatt opp i vann og tilsatt kaliumkarbonat til basisk reaksjon. Det ble deretter ekstrahert med diklormetan, hvorpå den 7.0 g of 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[2-(4-methoxy-phenyl-sulfenyl)-ethyl]-methylamino]-ethanol was dissolved in 100 ml glacial acetic acid and, with stirring at room temperature, 2.0 g of 30% hydrogen peroxide added dropwise. Stirring was continued at the same temperature overnight, and the solution was then evaporated in vacuo. The residue was taken up in water and potassium carbonate was added for a basic reaction. It was then extracted with dichloromethane, whereupon the

organiske fase ble vasket med vann, tørket med magnesium-sulf at og inndampet i vakuum. Residuet ble renset kromatografisk (søyle: 40 x 200 mm; kiselgel 60, firma E. Merck, kornstørrelse: 0,06 - 0,2 mm, metylenklorid:metanol = 50:1). Etter inndampning av de ønskede fraksjoner i vakuum, ble tittel-substansen tilbake i form av en olje. organic phase was washed with water, dried with magnesium sulfate and evaporated in vacuo. The residue was purified chromatographically (column: 40 x 200 mm; silica gel 60, company E. Merck, grain size: 0.06 - 0.2 mm, methylene chloride:methanol = 50:1). After evaporation of the desired fractions in vacuo, the title substance remained in the form of an oil.

Eksempel 15 1-(4-amino-3,5-diklor-fenyl)-2-[N-[2-(4-metoksy-fenyl-sulfonyl)-etyl]-metylamino]-etanol 7,0 g 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[2-(4-metoksy-fenyl-sulfenyl)-etyl]-metylamino]-etanol ble som beskrevet i eksempel 14 overført i sulfinyl-derivatet. Residuet (4,7 g) etter inndampning av diklormetan-ekstraktet ble løst i 100 ml dioksan og 30 ml vann og tilsatt 4,0 g magnesiumsulfat. Under.omrøring ble det porsjonsvis tilsatt 2,5 g pulverisert kaliumpermanganat. Etter endt tilsetning ble røringen fortsatt i 2 timer og det uløste frafiltrert over Celite. Dioksanen ble fjernet i vakuum og fordeling mellom diklormetan og vann foretatt. Inn-dampningsresten av den tørkede organiske fase ble renset kromatografisk to ganger (1. søyle: 60 x 300 mm, A^O^ II nøytral, metylenklorid: tetrahydrofuran =. 5:1; 2. søyle: 35 x 300 mm, kiselgel 60, firma E. Merck, kornstørrelse: 0,015-0,025 mm, diklormetan, 8,5 bar). Etter inndampning av de ønskede fraksjoner i vakuum, ble tittelforbindelsen tilbake i form av en olje. Eksempel 16 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-propyl]-metylamino]-etanol 9,2 g 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-benzyloksy-fenyl)-propyl]-metylamino]-etanol ble løst i 150 ml metanol. Løsningen ble tilsatt 1 g 5% palladium/karbon og hydrert ved romtemperatur under et hydrogentrykk på 5 bar. Etter opptak av den beregnede mengde hydrogen, ble katalysatoren frafilt.rert, løsningen inndampet til tørrhet i rotasjonsfordamper og det oljeaktige residuum kromatografert over kiselgel med metylenklorid:metanol = 20:1 som elueringsmiddel. Fraksjonene som inneholdt den ønskede forbindelse, ble samlet, inndampet og den oppnådde olje befridd for løsningsmiddelrester i vakuum ved 4 0°C. Eksempel 17 1 -(4-amino-3-brom-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]- etanol 3 g 1 -(4-acetamino-3-brom-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-etanol ble oppvarmet en time til tilbake-løpstemperatur i 100 ml halvkonsentrert saltsyre. Etter av-kjøling ble det tilsatt 10 N natronlut til alkalisk reaksjon, deretter ekstrahert med metylenklorid, metylenkloridløsningen vasket med vann, tørket over natriumsulfat og inndampet til tørrhet i rotasjonsfordamper. Den gjenværende olje ble kromatografert på kiselgel med metylenklorid:metanol = 20:1 som elueringsmiddel. Fra fraksjoner som inneholdt de ønskede forbindelser, ble disse oppnådd i form av en olje ved inndampning i vakuum ved 4 <0>°C. Example 15 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[2-(4-methoxy-phenyl-sulfonyl)-ethyl]-methylamino]-ethanol 7.0 g 1 -( 4-amino-3,5-dichloro-phenyl)-2-[N-[2-(4-methoxy-phenyl-sulfenyl)-ethyl]-methylamino]-ethanol was, as described in example 14, transferred into the sulfinyl derivative. The residue (4.7 g) after evaporation of the dichloromethane extract was dissolved in 100 ml of dioxane and 30 ml of water and 4.0 g of magnesium sulphate was added. While stirring, 2.5 g of powdered potassium permanganate was added in portions. After the addition was complete, stirring was continued for 2 hours and the undissolved material was filtered off over Celite. The dioxane was removed in vacuo and partitioned between dichloromethane and water carried out. The evaporation residue of the dried organic phase was purified chromatographically twice (1st column: 60 x 300 mm, A^O^ II neutral, methylene chloride: tetrahydrofuran =.5:1; 2nd column: 35 x 300 mm, silica gel 60 , firm E. Merck, grain size: 0.015-0.025 mm, dichloromethane, 8.5 bar). After evaporation of the desired fractions in vacuo, the title compound remained in the form of an oil. Example 16 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-propyl]-methylamino]-ethanol 9.2 g 1 -(4- amino-3,5-dichloro-phenyl)-2-[N-[3-(4-benzyloxy-phenyl)-propyl]-methylamino]-ethanol was dissolved in 150 ml of methanol. The solution was added with 1 g of 5% palladium/carbon and hydrated at room temperature under a hydrogen pressure of 5 bar. After absorption of the calculated amount of hydrogen, the catalyst was filtered off, the solution evaporated to dryness in a rotary evaporator and the oily residue chromatographed over silica gel with methylene chloride:methanol = 20:1 as eluent. The fractions containing the desired compound were collected, evaporated and the resulting oil freed from solvent residues in vacuo at 40°C. Example 17 1 -(4-amino-3-bromo-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethanol 3 g 1 -(4-acetamino-3- bromo-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethanol was heated for one hour to reflux temperature in 100 ml of semi-concentrated hydrochloric acid. After cooling, 10 N caustic soda was added for an alkaline reaction, then extracted with methylene chloride, the methylene chloride solution washed with water, dried over sodium sulfate and evaporated to dryness in a rotary evaporator. The remaining oil was chromatographed on silica gel with methylene chloride: methanol = 20:1 as eluent. From fractions containing the desired compounds, these were obtained in the form of an oil by evaporation in vacuum at 4<0>°C.

Eksempel 18 Example 18

1-(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino]- etanol 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3'-cyan-5'-fluor-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 90% metanol analogt eksempel 1. Prepared from 4'-amino-3'-cyano-5'-fluoro-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 90% methanol analogous to example 1.

Eksempel 19 Example 19

1 -(4-amino-3-brom-5-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino ]- etanol 1 -(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino ]- ethanol

Fremstillet av 4 ' -amino-3 1 --brom-5 ' -cyan-2-[ N- [3- (4-metoksy-fenyl)-propyl ]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1 Prepared from 4'-amino-31-bromo-5'-cyano-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1

Eksempel 20 Example 20

1-(4-amino-3,5-dibrom-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol 1-(4-amino-3,5-dibromo-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 4'-amino-3',5'-dibrom-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3',5'-dibromo-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 21 Example 21

1-(4-amino-3,5-diklor-fenyl)-2-[N-[1,1-dimetyl-3-(4-metoksy-fenyl)- propyl]- amino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-methoxy-phenyl)-propyl]- amino]- ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[1,1-dimetyl-3-(4-hydroksy-fenyl)-propyl]-amino]-etanol, tetrahydrofuran, natronlut og dimetylsulfat analogt eksempel 13. Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-hydroxy-phenyl)-propyl]-amino]-ethanol, tetrahydrofuran, caustic soda and dimethyl sulphate analogously to example 13. Oil.

Eksempel 22 Example 22

1-(4-amino-3,5-diklor-fenyl)-2-[N-[1,1-dimetyl-3-(4-metoksy-f enyl) - propyl ]- metylamino ]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[1,1-dimetyl-3-(4-hydroksy-fenyl)-propyl]-amino]-etanol, tetrahydrofuran, natronlut og dimetylsulfat analogt eksempel 13. Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-hydroxy-phenyl)-propyl]-amino]-ethanol, tetrahydrofuran, caustic soda and dimethyl sulphate analogously to example 13. Oil.

Eksempel 23 Example 23

1 -(4-amino-3-klor-5-trifluormetyl-fenyl)-2-[N-[3-(4-metoksy-fenyl)- propyl]- metylamino]- etanol 1 -(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3<*->klor-5'-trifluormetyl-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3<*->chloro-5'-trifluoromethyl-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous example 1.

Eksempel 24 Example 24

1 - ( 3 , 5-diklor-4-hydroksy-f enyl) -2- [N- [3- (4-metoksy-f enyl).-propyl3- metylamino]- etanol 1 - (3,5-dichloro-4-hydroxy-phenyl)-2-[N-[3-(4-methoxy-phenyl).-propyl3-methylamino]-ethanol

Fremstillet av 3',5'-diklor-4'-hydroksy-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 3',5'-dichloro-4'-hydroxy-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Smeltepunkt: 156-157°C. Melting point: 156-157°C.

Eksempel 25 Example 25

1-(3,5-dibrom-4-hydroksy-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino]- etanol ^ 1-(3,5-dibromo-4-hydroxy-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol ^

Fremstillet av 3',5'-dibrom-4'-hydroksy-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 3',5'-dibromo-4'-hydroxy-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Smeltepunkt for hydrokloridet: 159-162°C. Melting point for the hydrochloride: 159-162°C.

Eksempel 26 Example 26

1-(4-amino-3-brom-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol 1-(4-amino-3-bromo-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 4 '-amino-3 ' -brom-5 1 -f luor-2-[N- [3-(4-metoksy-' fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3'-bromo-51-fluoro-2-[N-[3-(4-methoxy-'phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous example 1.

Smeltepunkt for hydrokloridet (amorft): fra 60°C. Melting point for the hydrochloride (amorphous): from 60°C.

Eksempel 27 Example 27

1 -(4-amino-3-klor-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino]- etanol 1 -(4-amino-3-chloro-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3'-klor-5'-fluor-2-LN-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetof.enon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3'-chloro-5'-fluoro-2-LN-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetoph.enone and sodium borohydride in 80% methanol analogous to example 1 .

Smeltepunkt for hydrokloridet: 103-108°C (dekomp.). Melting point of the hydrochloride: 103-108°C (decomp.).

Eksempel 28 Example 28

1-(4-amino-3-klor-5-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino]- etanol 1-(4-amino-3-chloro-5-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3<1->klor-5'-cyan-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3<1->chloro-5'-cyano-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous example 1.

Eksempel 29 Example 29

1 -(4-amino-3-klor-5-nitro-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino]- etanol 1 -(4-amino-3-chloro-5-nitro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3'-klor-5'-nitro-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3'-chloro-5'-nitro-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 30 Example 30

1-(4-amino-3-klor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol 1-(4-amino-3-chloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 4<1->amino-3'-klor-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4<1->amino-3'-chloro-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 31 Example 31

1-(4-amino-3-brom-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl] - metylamino]- etanol 1-(4-amino-3-bromo-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]- ethanol

Fremstillet av 41-amino-3'-brom-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 41-amino-3'-bromo-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Smeltepunkt for hydrokloridet: 137°C (dekomp.). Melting point of the hydrochloride: 137°C (decomp.).

Eksempel 32 Example 32

1-(4-amino-3,5-dicyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol 1-(4-amino-3,5-dicyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 4<1->amino-3<1>,5<1->dicyan-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4<1->amino-3<1>,5<1->dicyan-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Smeltepunkt for hydrokloridet: 16 7-170°C. Melting point of the hydrochloride: 16 7-170°C.

Eksempel 33 Example 33

1-(4-amino-3-brom-fenyl)—2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]- etanol 1-(4-amino-3-bromo-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]- ethanol

Fremstillet av 4'-amino-3'-brom-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3'-bromo-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 34 Example 34

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]- metylamino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]- methylamino]- ethanol

Fremstillet av 4<1->amino-3'.5<1->diklor-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-acetofenon og natriumborhydrid i . 80% metanol analogt eksempel 1. Prepared from 4<1->amino-3',5<1->dichloro-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-acetophenone and sodium borohydride in . 80% methanol analogous to example 1.

Eksempel 35 Example 35

1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-[ 4-(4-metoksy-fenyl)-butvll-metvlamino]-etanol 1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[ 4-(4-methoxy-phenyl)-butyl-methylamino]-ethanol

Fremstillet av 4'-amino-3'-brom-51-cyan-2-[ N-[ 4-(4-metoksy-fenyl)-butyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3'-bromo-51-cyano-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 36 1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-[2-(4-metoksy-fenyl)-etyl]- metylamino]- etanol -Fremstillet av 4'-amino-3<1->brom-5'-cyan-2-[N-[2-(4-metoksy-fenyl)-etyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Example 36 1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[2-(4-methoxy-phenyl)-ethyl]-methylamino]-ethanol -Prepared from 4'-amino -3<1->bromo-5'-cyano-2-[N-[2-(4-methoxy-phenyl)-ethyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 31 Example 31

1-(4-amino-3-klor-5-cyan-fenyl)-2-[N- [4-(4-metoksy-fenyl)-. butyl ]-metylamino ]-etanol 1-(4-amino-3-chloro-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-. butyl]-methylamino]-ethanol

Fremstillet av 4'-amino-3'-klor-5<1->cyan-2-[N-[4-(4-metoksy-fenyl)-butyl ]-metylamino ]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3'-chloro-5<1->cyano-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous example 1.

Eksempel 38 Example 38

1-(4-amino-3,5-diklor-fenyl)-2-[N-[2-(4-metoksy-fenylsulfenyl)-etyl]- metylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[2-(4-methoxy-phenylsulfenyl)-ethyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3<1>,5'-diklor-2-[N-[2-(4-metoksy-fenyl-sulfenyl)-etyl]-metylamino]-acetofenon og natriumborhydrid i tetrahydrofuran:vann:metanol = 25:5:10 analogt eksempel 1. Olje. Prepared from 4'-amino-3<1>,5'-dichloro-2-[N-[2-(4-methoxy-phenyl-sulfenyl)-ethyl]-methylamino]-acetophenone and sodium borohydride in tetrahydrofuran:water:methanol = 25:5:10 analogous to example 1. Oil.

Eksempel 39 Example 39

1-(4-amino-3,5-diklor-fenyl)-2-[N-[2-(4-metoksy-fenoksy)-etyl]- metylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[2-(4-methoxy-phenoxy)-ethyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3',5<1->diklor-2-[N-[2-(4-metoksy- • fenoksy)-etyl]-metylamino]-acetofenon og natriumborhydrid i tetrahydrofuran:vann:metanol = 15:5:3 analogt eksempel 1. Olje. Prepared from 4'-amino-3',5<1->dichloro-2-[N-[2-(4-methoxy- • phenoxy)-ethyl]-methylamino]-acetophenone and sodium borohydride in tetrahydrofuran:water:methanol = 15:5:3 analogous example 1. Oil.

Eksempel 40 Example 40

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-amino] - propanol- ( 1) 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-amino]-propanol- ( 1 )

Fremstillet av 4'-amino-3',5'-diklor-2-[N-[3-(4-metoksy-fenyl)-propyl]-amino]-propiofenon og natriumborhydrid analogt eksempel 1. Smeltepunkt for hydrokloridet: 201-202°C (dekomp.). Prepared from 4'-amino-3',5'-dichloro-2-[N-[3-(4-methoxy-phenyl)-propyl]-amino]-propiophenone and sodium borohydride analogous to example 1. Melting point of the hydrochloride: 201- 202°C (decomp.).

Eksempel 41 Example 41

1- (4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-2- propylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-2- propylamino]- ethanol

Fremstillet av 4'-amino-3<1>,5<1->diklor-2-[N-[3-(4-metoksy-fenyl)-propyl]-2-propylamino]-acetofenon og natriumborhydrid analogt eksempel 1. Olje. Prepared from 4'-amino-3<1>,5<1->dichloro-2-[N-[3-(4-methoxy-phenyl)-propyl]-2-propylamino]-acetophenone and sodium borohydride analogously to example 1. Oil.

Eksempel ^ 2 Example ^ 2

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-etylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-ethylamino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-2-[ N-[ 3-(4-metoksyfenyl)-propyl]-etylamino]-acetofenon og natriumborhydrid analogt eksempel 1. Prepared from 4'-amino-3',5'-dichloro-2-[ N-[ 3-(4-methoxyphenyl)-propyl]-ethylamino]-acetophenone and sodium borohydride analogous to example 1.

Eksempel 43 Example 43

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- propylamino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- propylamino]- ethanol

Fremstillet av 4<1->amino-3',5<1->diklor-2-[N-[3-(4-metoksy-fenyl)-propyl]-propylamino]-acetofenon og natriumborhydrid analogt eksempel 1. 01je. Prepared from 4<1->amino-3',5<1->dichloro-2-[N-[3-(4-methoxy-phenyl)-propyl]-propylamino]-acetophenone and sodium borohydride analogously to example 1. 01je.

Eksempel 44 Example 44

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- cyklopropylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- cyclopropylamino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-2-[N-[3-(4-metoksy-fenyl)-propyl]-cyklopropylamino]-acetofenon og natriumborhydrid analogt eksempel 1. Olje. Prepared from 4'-amino-3',5'-dichloro-2-[N-[3-(4-methoxy-phenyl)-propyl]-cyclopropylamino]-acetophenone and sodium borohydride analogous to example 1. Oil.

Eksempel 45 Example 45

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl)]-metylamino]-propanol-(1), isomer B 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-propanol-(1), isomer B

Fremstillet av N-[3-(4-metoksy-fenyl)-propyl]-metylamin, 4'-amino-2-brom-3',5■-diklor-propiofenon, trietylamin og natrium-borh<y>drid analogt eksempel 2. Olje. Prepared from N-[3-(4-methoxy-phenyl)-propyl]-methylamine, 4'-amino-2-bromo-3',5■-dichloro-propiophenone, triethylamine and sodium borohydride analogous example 2. Oil.

NMR-spektrum (CDC13/D20: Protonsignal fra karbon 1 i propanoldelen: Dublett ved 4,1 ppm (J = 10 Hz). NMR spectrum (CDC13/D20: Proton signal from carbon 1 in the propanol part: Doublet at 4.1 ppm (J = 10 Hz).

Eksempel 46 Example 46

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]- propanol-( 1), isomer A 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-propanol-(1), isomer A

Fremstillet av N-[3-(4-metoksy-fenyl)-propyl]-metylamin, 4'-amino-3',5<1->diklor-2-brom-propiofenon, trietylamin og natriumborhydrid analogt eksempel 2. Prepared from N-[3-(4-methoxy-phenyl)-propyl]-methylamine, 4'-amino-3',5<1->dichloro-2-bromo-propiophenone, triethylamine and sodium borohydride analogous to example 2.

Smeltepunkt for hydrokloridet: 178-181°C. Melting point for the hydrochloride: 178-181°C.

NMR-spektrum for basen (CDCl^/^O) : Protonsignal fra karbon 1 i propanoldelen: Dublett ved 4,6 ppm (J = 4,5 Hz). NMR spectrum of the base (CDCl^/^O): Proton signal from carbon 1 in the propanol part: Doublet at 4.6 ppm (J = 4.5 Hz).

Eksempel 47 Example 47

1 -(4-amino-3,5-diklor-fenyl)-2-[ N-[ 3-(4-etoksy-fenyl)-propyl] - metylamino ]-etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[ N-[ 3-(4-ethoxy-phenyl)-propyl] - methylamino ]-ethanol

Fremstillet av 4'-amino-3',5'-diklor-2-brom-acetofenon, 1-(4-etoksy-fenyl)-3-metylamino-propan-hydroklorid, trietylamin og natriumborhydrid analogt eksempel 2. Olje. Prepared from 4'-amino-3',5'-dichloro-2-bromo-acetophenone, 1-(4-ethoxy-phenyl)-3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogous to example 2. Oil.

Eksempel 48 Example 48

1 - (4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-benzyloksy-fenyl)-propyl]-metylamino]-etanol 1 - (4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-benzyloxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 4<1->amino-3',5'-diklor-2-brom-acetofenon, 1-(4-benzyloksy-fenyl)-3-metylamino-propan-hydroklorid, trietylamin og natriumborhydrid analogt eksempel 2. Olje. Prepared from 4<1->amino-3',5'-dichloro-2-bromo-acetophenone, 1-(4-benzyloxy-phenyl)-3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogous to example 2. Oil.

Eksempel 49 Example 49

1-(4-amino-3-jod-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino]- etanol 1-(4-amino-3-iodo-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 4<1->amino-3'-jod-5<1->fluor-2-brom-acetofenon, 1 -(4-metoksy-fenyl)-3-metylamino-propan-hydroklorid, trietylamin og natriumborhydrid analogt eksempel 2. Olje. Prepared from 4<1->amino-3'-iodo-5<1->fluoro-2-bromo-acetophenone, 1-(4-methoxy-phenyl)-3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogous example 2. Oil.

Eksempel 50 Example 50

1-(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- 2- propylamino]- etanol 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- 2- propylamino]- ethanol

Fremstillet av 4'-amino-3'-cyan-5'-fluor-2-brom-acetofenon, 1-(4-metoksy-fenyl)-3-(2-propylamino)-propan-hydroklorid og natriumborhydrid analogt eksempel 2. Olje. Prepared from 4'-amino-3'-cyano-5'-fluoro-2-bromo-acetophenone, 1-(4-methoxy-phenyl)-3-(2-propylamino)-propane hydrochloride and sodium borohydride analogous to example 2. Oil.

Eksempel 51 Example 51

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(2-metoksy-fenyl)-propyl]-metylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(2-methoxy-phenyl)-propyl]-methylamino]- ethanol hydrochloride

Fremstillet av 4'-amino-3<1>,5<1->diklor-2-brom-acetofenon, 1-(2-metoksy-fenyl)-3-metylamino-propan-hydroklorid, trietylamin og natriumborhydrid analogt eksempel 2. Prepared from 4'-amino-3<1>,5<1->dichloro-2-bromo-acetophenone, 1-(2-methoxy-phenyl)-3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogous to example 2.

Smeltepunkt fra 75°C (under sintring). Melting point from 75°C (during sintering).

Eksempel 52 Example 52

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(3,4-dimetoksy-fenyl)-propyl]-metylamino]-etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(3,4-dimethoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 4'-amino-3',5'-diklor-2-brom-acetofenon, 1-(3,4-dimetoksy-fenyl)-3-metylamino-propan-hydroklorid, trietylamin og natriumborhydrid analogt eksempel 2. Prepared from 4'-amino-3',5'-dichloro-2-bromo-acetophenone, 1-(3,4-dimethoxy-phenyl)-3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogously to Example 2.

Eksempel 53 Example 53

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-amino ] - etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-amino ] - ethanol hydrochloride

Fremstillet av 4'-amino-3',5'-diklor-2-[N-[3-(4-metoksy-fenyl)-propyl]-amino]-acetofenon og natriumborhydrid i 90% etanol analogt eksempel 1 . Prepared from 4'-amino-3',5'-dichloro-2-[N-[3-(4-methoxy-phenyl)-propyl]-amino]-acetophenone and sodium borohydride in 90% ethanol analogously to example 1.

Smeltepunktet for hydrokloridet: 185-186°C (etanol/eter). Melting point of the hydrochloride: 185-186°C (ethanol/ether).

Eksempel 54 Example 54

1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-2-propyl-amino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-2-propyl-amino]- ethanol hydrochloride

Fremstillet av 4'-amino-3',5'-diklor-2-brom-acetofenon, 1-fenyl-3-(2-propylamino)-propan-hydroklorid, trietylamin og natriumborhydrid analogt eksempel 2. Prepared from 4'-amino-3',5'-dichloro-2-bromo-acetophenone, 1-phenyl-3-(2-propylamino)-propane hydrochloride, triethylamine and sodium borohydride analogous to example 2.

Smeltepunkt: 124-128°C. Melting point: 124-128°C.

Eksempel 55 Example 55

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl)-propyl]-metylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-methylamino]- ethanol hydrochloride

Fremstillet av 4'-amino-3' ,5'-diklor-2-brom-acetofenon, 1-(4-fluor-fenyl)-3-metylamino-propan-hydroklorid, trietylamin og natriumborhydrid analogt eksempel 2. Prepared from 4'-amino-3',5'-dichloro-2-bromo-acetophenone, 1-(4-fluoro-phenyl)-3-methylamino-propane hydrochloride, triethylamine and sodium borohydride analogous to example 2.

Smeltepunkt: 185-188°C (dekomp.). Melting point: 185-188°C (decomp.).

Eksempel 56 Example 56

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1 - metyl- propyl]- amino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-amino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-amino]-acetofenon og natriumborhydrid i vandig tetrahydrofuran analogt eksempel 4. Som elueringsmiddel for den kromatografiske rensing på kiselgel ble det benyttet en blanding av diklormetan/metanol/ammoniakk = 19:1:0,05. Prepared from 4'-amino-3',5'-dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-amino]-acetophenone and sodium borohydride in aqueous tetrahydrofuran analogous to example 4 As eluent for the chromatographic purification on silica gel, a mixture of dichloromethane/methanol/ammonia = 19:1:0.05 was used.

(Olje: 1:1-blanding av de de diastereomere racemater). (Oil: 1:1 mixture of the diastereomeric racemates).

Eksempel 57 Example 57

T-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-1-metyl- propyl]- amino]- etanol T-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-1-methyl- propyl]- amino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-2-[N-[3-(4-metoksy-fenyl)-1-metyl-propyl]-amino]-acetofenon og natriumborhydrid i vandig tetrahydrofuran analogt eksempel 4. Olje. Prepared from 4'-amino-3',5'-dichloro-2-[N-[3-(4-methoxy-phenyl)-1-methyl-propyl]-amino]-acetophenone and sodium borohydride in aqueous tetrahydrofuran analogous to example 4 .Oil.

Forbindelsen foreligger som 1:1-blanding av racematene. The compound exists as a 1:1 mixture of the racemates.

Eksempel 5 8 Example 5 8

1-(4-amino-3-fluor-5-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- amino]- etanol 1-(4-amino-3-fluoro-5-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- amino]- ethanol

Fremstillet av 4'-amino-3'-fluor-5'-cyan-acetofenon, selendioksyd, 3-(4-metoksy-fenyl)-propylamin og natriumborhydrid analogt eksempel 5. Prepared from 4'-amino-3'-fluoro-5'-cyano-acetophenone, selenium dioxide, 3-(4-methoxy-phenyl)-propylamine and sodium borohydride analogously to example 5.

Smeltepunkt: 119-121°C. Melting point: 119-121°C.

Eksempel 59 Example 59

1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-amino]-etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-amino]-ethanol hydrochloride

Fremstillet av 4'-amino-3<1>,5'-diklor-acetofenon, selendioksyd, Prepared from 4'-amino-3<1>,5'-dichloro-acetophenone, selenium dioxide,

3-fenyl-propylamin og natriumborhydrid analogt eksempel 5. Smeltepunkt: 180-181°C (dekomp.). 3-phenyl-propylamine and sodium borohydride analogous to example 5. Melting point: 180-181°C (decomp.).

Eksempel 60 Example 60

1-(4-amino-3-klor-5-fluor-fenyl)-2-[N-(1-metyl-2-fenoksy-etyl)-amino]-etanol-dihydroklorid 1-(4-amino-3-chloro-5-fluoro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-amino]-ethanol dihydrochloride

Fremstillet av 4'-amino-3'-klor-5<1->fluor-acetofenon, selendioksyd, 1-metyl-2-fenoksy-etylamin og natriumborhydrid analogt eksempel 5. Prepared from 4'-amino-3'-chloro-5<1->fluoro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine and sodium borohydride analogously to example 5.

Smeltepunkt: 158-160°C (dekomp.). Melting point: 158-160°C (decomp.).

Eksempel 61 Example 61

1-(4-amino-3-cyan-5-fluor-fenyl)-2-[ N-(1-metyl-2-fenoksy-etyl)-amino]-etanol-hydroklorid 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[ N -(1-methyl-2-phenoxy-ethyl)-amino]-ethanol hydrochloride

Fremstillet av 4'-amino-3'-cyan-5'-fluor-acetofenon, selendioksyd, 1-metyl-2-fenoksy-etylamin og natriumborhydrid analogt eksempel 5. Prepared from 4'-amino-3'-cyano-5'-fluoro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine and sodium borohydride analogously to example 5.

Smeltepunkt: 178-184°C, (dekomp.). Melting point: 178-184°C, (decomp.).

Eksempel 62 Example 62

1- (4-amino-3-brom-5-f luor-fenyl) -2-L'N- (1-metyl-2-fenoksy-etyl)- amino]- etanol- dihydroklorid 1-(4-amino-3-bromo-5-fluoro-phenyl)-2-L'N-(1-methyl-2-phenoxy-ethyl)- amino]- ethanol- dihydrochloride

Fremstillet av 4■-amino-3'-brom-5'-fluor-acetofenon, selendioksyd, 1-metyl-2-fenoksy-etylamin og natriumborhydrid analogt eksempel 5. Prepared from 4■-amino-3'-bromo-5'-fluoro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine and sodium borohydride analogously to example 5.

Smeltepunkt: 156-158°C (dekomp.). Melting point: 156-158°C (decomp.).

Eksempel 63 Example 63

N-[2-(4-amino-3,5-dibrom-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-propyl]- metylamin N-[2-(4-amino-3,5-dibromo-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]- methylamine

Fremstillet av 4-amino-3,5-dibrom-N-[3-(4-metoksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 7. Prepared from 4-amino-3,5-dibromo-N-[3-(4-methoxy-phenyl)-propyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 7.

Smeltepunkt for hydrokloridet: 149-153°C. Melting point for the hydrochloride: 149-153°C.

Eksempel 64 Example 64

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-propyl] - metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]-methylamine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-metoksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 7. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl)-propyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 7.

Smeltepunkt for hydrokloridet: 90-94°C. Melting point for the hydrochloride: 90-94°C.

Eksempel 65 Example 65

N-[2-(4-amino-3,5-diklor-fenyl)-etyl] -N-[ 4-(4-metoksy-fenyl)-butyl] - metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl] -N-[ 4-(4-methoxy-phenyl)-butyl] - methylamine

Fremstillet av 4-amino-3,5-diklor-N-[ 4-(4-metoksy-fenyl)-butyl] -N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Prepared from 4-amino-3,5-dichloro-N-[4-(4-methoxy-phenyl)-butyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 8.

Eksempel 66 Example 66

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-hydroksy-fenyl)-1 - metyl- propyl ] - amin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-amine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-fenyleddiksyreamid og litiumaluminiumhydrid i tetrahydrofuran analogt eksempel 8. Den kromatografiske rensing ble foretatt ved kromatografi på kiselgel (kornstørrelse: 0,01 5-0., 025 mm) under middels trykk med metylenklorid: metanol: kons. ammoniakk = 19:1:0,1 som elueringsmiddel. Skum. Prepared from 4-amino-3,5-dichloro-N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogous to example 8. The chromatographic purification was carried out by chromatography on silica gel (grain size: 0.01 5-0., 025 mm) under medium pressure with methylene chloride: methanol: conc. ammonia = 19:1:0.1 as eluent. Foam.

Eksempel 67 Example 67

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl] -N-[ 3-(4-metoksy-fenyl)-1- metyl- propyl]- amin N-[ 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[ 3-(4-methoxy-phenyl)-1- methyl- propyl]-amine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-metoksy-fenyl)-1 - metyl-propyl]-fenyleddiksyreamid og litiumaluminiumhydrid i tetrahydrofuran analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl)-1-methyl-propyl]-phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogous to example 8. Oil.

Eksempel 68 Example 68

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-benzyloksy-fenyl)-propyl]-metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-benzyloxy-phenyl)-propyl]-methylamine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-benzyloksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-benzyloxy-phenyl)-propyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 69 Example 69

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(3,4-dimetoksy-fenyl)- propyl]- metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(3,4-dimethoxy-phenyl)-propyl]- methylamine

Fremstillet av 4-amino-3,5-diklor-N-[3-(3,4-dimetoksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(3,4-dimethoxy-phenyl)-propyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 70 Example 70

N-t 2-(4-amino-3,5-diklor-fenyl)-etyl] -N-[ 3-(2-metoksy-fenyl)-propyl] -metylamin-hydroklorid N-t 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(2-methoxy-phenyl)-propyl]-methylamine hydrochloride

Fremstillet av 4-amino-3,5-diklor-N-[ 3-(2-metoksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 7. Prepared from 4-amino-3,5-dichloro-N-[3-(2-methoxy-phenyl)-propyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogously to Example 7.

Smeltepunkt: 160-164°C Melting point: 160-164°C

Eksempel 71 Example 71

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-fenyl-propyl)-metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenyl-propyl)-methylamine

Fremstillet av 4-amino-3,5-diklor-N-(3-fenyl-propyl)-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-(3-phenyl-propyl)-N-methyl-phenylacetic acid amide and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 72 Example 72

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-propyl]- amin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]-amine hydrochloride

Fremstillet av 4-ammo-3 , 5-diklor-N-[ 3- (4-metoksy-f enyl) - propyl]-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 7. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl)-propyl]-phenylacetic acid amide and lithium aluminum hydride analogously to example 7.

Smeltepunkt: 203-205°C Melting point: 203-205°C

Eksempel 73 Example 73

N-[ 2- (4-amino-3 , 5-diklor-f enyl) -e'tyl] -N-j) 3- (4-metoksy-fenyl) - propyl]-cyklopropylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-j)3-(4-methoxy-phenyl)-propyl]-cyclopropylamine

Fremstillet av 4-amino-3,5-diklor-N-[ 3-(4-metoksy-fenyl)-propyl]-N^cyklopropy1-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl)-propyl]-N^cyclopropyl-phenylacetic acid amide and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 74 Example 74

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl] -N-[ 3-(4-metoksy-fenyl)-propyl]- propylamin N-[ 2-(4-amino-3,5-dichloro-phenyl)-ethyl] -N-[ 3-(4-methoxy-phenyl)-propyl]- propylamine

Fremstillet av 4-amino-3,5-diklor-N-[ 3-(4-metoksy-fenyl)-propyl]-N-propyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl)-propyl]-N-propyl-phenylacetic acid amide and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 75 Example 75

N- [2-(4-amino-3,5-diklor-fenyl)-etyl ]-N- [3-(4-metoksy-fenyl)- propyl ]- etylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]-ethylamine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-metoksy-fenyl)-propyl ]-N-etyl-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl)-propyl]-N-ethyl-phenylacetic acid amide and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 7 6 Example 7 6

N_ [2-(4-amino-3,5-diklor-fenyl)-etyl ]-N- [3- (4-metoksy-fenyl)-propyl ]-2-propylamin N_ [2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]-2-propylamine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-metoksy-fenyl)-propyl ]-N-(2-propyl)-fenyleddiksyreamid og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl)-propyl]-N-(2-propyl)-phenylacetic acid amide and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 77 Example 77

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-etoksy-fenyl)-propyl3- metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-ethoxy-phenyl)-propyl3-methylamine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-etoksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid. og litiumaluminiumhydrid analogt eksempel 8. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-ethoxy-phenyl)-propyl]-N-methyl-phenylacetic acid amide. and lithium aluminum hydride analogous to example 8. Oil.

Eksempel 78 Example 78

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-1- metyl- propyl]- metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-1- methyl- propyl]- methylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-1-metyl-propyl]-metylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9. Olje. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-1-methyl-propyl]-methylamino]-ethane and sodium borohydride in isopropanol analogous to example 9. Oil.

Eksempel 79 J Example 79 J

N-[2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-[4-metoksy-fenyl) -butyl]-metylamin N-[2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[4-methoxy-phenyl)-butyl]-methylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-etan og natriumborhydrid analogt eksempel 9. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethane and sodium borohydride analogously example 9.

Analyse: Analysis:

Eksempel 80 Example 80

N-[2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-[3-(4-metoksy-feny1)- propyl]- metylamin N-[2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]- methylamine

Fremstillet av 1-etoksykarbonyloksy-1 -(4-amino-3-brom-5-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etan og natriumborhydrid analogt eksempel 9. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethane and sodium borohydride analogously example 9.

Eksempel 81 Example 81

N-[2-(4-amino-3-klor-5-cyan-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)- butyl]- metylamin N-[2-(4-amino-3-chloro-5-cyano-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]- methylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-klor-5-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-etan og natriumborhydrid analogt eksempel 9. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-chloro-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethane and sodium borohydride analogously example 9.

Analyse: Analysis:

Eksempel 82 Example 82

1-(4-amino-3-klor-5-trifluormetyl-fenyl)-2-[N-[4-(4-metoksy-fenyl)- butyl]- metylamino]- etanol 1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]- methylamino]- ethanol

Fremstillet av 4'-amino-3'-klor-5'-trifluormetyl-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-amino-3'-chloro-5'-trifluoromethyl-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 83 Example 83

1-(4-amino-3-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino ] - etanol 1-(4-amino-3-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino ] - ethanol

Fremstillet av 1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol i nærvær av palladium/karbon og hydrogen analogt eksempel 11. Prepared from 1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol in the presence of palladium/carbon and hydrogen analogous to example 11.

Eksempel 84 Example 84

N-[2-(4-aminc—3-klor-fenyl)-etyl]-N-[3-(4-benzyloksy-fenyl)-propyl]-metylamin N-[2-(4-aminoc-3-chloro-phenyl)-ethyl]-N-[3-(4-benzyloxy-phenyl)-propyl]-methylamine

Fremstillet av N-[ 2-(4-amino-3 , 5-diklor-f enyl)-etyl ]-N--[ 3-(4-benzyloksy-fenyl)-propyl]-metylamin og hydrogen analogt eksempel 11. Olje. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-benzyloxy-phenyl)-propyl]-methylamine and hydrogen analogous to example 11. Oil .

Eksempel 85 Example 85

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-hydroksy-fenyl)-propyl]- metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-hydroxy-phenyl)-propyl]- methylamine

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-benzyloksy-fenyl)-propyl]-metylamin og hydrogen analogt eksempel 16. Olje. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-benzyloxy-phenyl)-propyl]-methylamine and hydrogen analogous to example 16. Oil.

Eksempel 86 Example 86

1-(4-amino-3-fluor-fenyl)-2-[N-(1-metyl-2-fenoksy-etyl)-amino]- etanol- tosylat 1-(4-amino-3-fluoro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-amino]- ethanol tosylate

Fremstillet av 1-(4-ace^imino-3-fluor-fenyl)-2-[N-(1-metyl-2-fenoksy)-etyl]-amino-etanol og natriumborhydrid analogt eksempel 17. Prepared from 1-(4-ace^imino-3-fluoro-phenyl)-2-[N-(1-methyl-2-phenoxy)-ethyl]-amino-ethanol and sodium borohydride analogously to example 17.

Smeltepunkt: 124-128°C. Melting point: 124-128°C.

Eksempel 87 Example 87

N-[2 - (4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-metoksy-fenoksy)-propyl ] - metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenoxy)-propyl]-methylamine

1,74 g (0,014 mol) 4-metoksy-fenol løst i 60 ml tørr tetrahydrofuran ble avkjølt til -5°C og under omrøring tilsatt 0,67 g (0,014 mol) av en 50% dispersjon av natriumhydrid i olje. Etter ytterligere 2 timers omrøring ved 0°C ble ved samme temperatur dråpevis tilsatt en løsning av 4,2 g N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-klor-propyl)-metylamin i 50 ml 1.74 g (0.014 mol) of 4-methoxyphenol dissolved in 60 ml of dry tetrahydrofuran was cooled to -5°C and with stirring added 0.67 g (0.014 mol) of a 50% dispersion of sodium hydride in oil. After a further 2 hours of stirring at 0°C, a solution of 4.2 g of N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-chloro) was added dropwise at the same temperature -propyl)-methylamine in 50 ml

tørr tetrahydrofuran. Blandingen ble omrørt 18 timer ved ca. 20°C. Reaksjonsblandingen ble deretter inndampet i vakuum og inndampningsresiduet fordelt mellom eter og vann. Fasene ble adskilt og det vandige skikt ekstrahert ytterligere 3 ganger med eter. De samlede eter-ekstrakter ble vasket med vann, tørket og inndampet i vakuum. Den oljeaktige inndampningsrest ble kromatografisk renset på en kiselgel-søyle (eluent: eter). Etter inndampning av de ønskede fraksjoner, ble tittelforbindelsen oppnådd i form av en olje. dry tetrahydrofuran. The mixture was stirred for 18 hours at approx. 20°C. The reaction mixture was then evaporated in vacuo and the evaporation residue partitioned between ether and water. The phases were separated and the aqueous layer extracted a further 3 times with ether. The combined ether extracts were washed with water, dried and evaporated in vacuo. The oily evaporation residue was chromatographically purified on a silica gel column (eluent: ether). After evaporation of the desired fractions, the title compound was obtained in the form of an oil.

Eksempel 88 1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-etylamino]-etanol-hydroklorid 2 g 1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-amino]-etanol-hydroklorid ble løst i 50 ml etanol. Til denne løsning ble det tilsatt 0,4 ml acetaldehyd og deretter under omrøring ved romtemperatur , 1,2 g natriumcyanborhydrid, under inn-stilling og opprettholdelse av en pH-verdi på 6-6,5 ved tilsetning av 2 N saltsyre. Ved denne pH-verdi ble blandingen om-rørt ytterligere 2 timer. Løsningen ble slått over i vann og gjort sur med 2 N saltsyre for å dekomponere natriumcyanborhydrid-overskuddet. Deretter ble det tilsatt 2 N natronlut til tydelig alkalisk reaksjon, ekstrahert 2 ganger med metylenklorid, og de samlede metylenkloridfaser vasket med vann, tørket over natriumsulfat og inndampet i vakuum til tørrhet. Det prakt-isk talt farveløse oljeaktige residuum ble løst i etanol. Denne etanoliske løsning ble brakt til pH 5 med eterisk saltsyre. Deretter ble løsningsmidlet fjernet i rotasjonsfordamper under vakuum. Den gjenværende oljeaktige rest ble brakt til krystallisasjon ieddikester. Herved ble det oppnådd farveløse krystaller med smeltepunkt 102-105°C. Example 88 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-ethylamino]-ethanol hydrochloride 2 g 1-(4-amino-3,5- dichloro-phenyl)-2-[N-(3-phenyl-propyl)-amino]-ethanol hydrochloride was dissolved in 50 ml of ethanol. To this solution was added 0.4 ml of acetaldehyde and then, with stirring at room temperature, 1.2 g of sodium cyanoborohydride, while setting and maintaining a pH value of 6-6.5 by adding 2 N hydrochloric acid. At this pH value, the mixture was stirred for a further 2 hours. The solution was poured into water and acidified with 2N hydrochloric acid to decompose the excess sodium cyanoborohydride. Then 2 N caustic soda was added to a clearly alkaline reaction, extracted 2 times with methylene chloride, and the combined methylene chloride phases were washed with water, dried over sodium sulfate and evaporated in vacuo to dryness. The practically colorless oily residue was dissolved in ethanol. This ethanolic solution was brought to pH 5 with ethereal hydrochloric acid. The solvent was then removed in a rotary evaporator under vacuum. The remaining oily residue was brought to crystallization in acetic acid. Hereby, colorless crystals with a melting point of 102-105°C were obtained.

Eksempel 89 Example 89

1 -(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl ] -metylamino] -etanol 1 -(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethanol

Fremstillet av 4<1->amino-3'-cyan-5<1->fluor-2-[N-[4-(4-metoksyfenyl)-butyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4<1->amino-3'-cyano-5<1->fluoro-2-[N-[4-(4-methoxyphenyl)-butyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous example 1.

Eksempel 90 1-(4-acetamino-3-brom-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]- etanol Example 90 1-(4-acetamino-3-bromo-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethanol

Fremstillet av 4'-acetamino-3'-brom-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino]-acetofenon og natriumborhydrid i 80% metanol analogt eksempel 1. Prepared from 4'-acetamino-3'-bromo-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-acetophenone and sodium borohydride in 80% methanol analogous to example 1.

Eksempel 91 Example 91

Racemater A og B av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy- fenyl)- 1- metyl- propyl]- metylamino]- etanol 36 g 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-metylamino]-etanol (1:1-blanding av de diastereomere racemater A og B) ble løst i eter og tilsatt 0,5 ekvivalenter 3 N hydrogenklorid i eter. Det oppnådde rå krystallisat av hydrokloridet av racemat A ble omkrystallisert først fra isopropanol og deretter 2 ganger ved løsning i rikelig metanol og etterfølgende inndampning til begynnende krystallisasjon. Racemates A and B of 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1- methyl-propyl]- methylamino]- ethanol 36 g 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methylamino]-ethanol (1:1 mixture of the diastereomeric racemates A and B) were dissolved in ether and 0.5 equivalents of 3 N hydrogen chloride in ether were added. The obtained crude crystallisate of the hydrochloride of racemate A was recrystallized first from isopropanol and then 2 times by solution in abundant methanol and subsequent evaporation until incipient crystallization.

Smeltepunkt for hydrokloridet: 248-249°C (dekomp.). Melting point of the hydrochloride: 248-249°C (decomp.).

1 3 1 3

C-NMR-spektrum av basen (CDC13/CD30D): C-NMR spectrum of the base (CDC13/CD30D):

Den isopropanoliske morlut ble inndampet og fordelt mellom eter og 2 N ammoniakk. Fra inndampingsresiduet av den tørkede organiske fase ble racematet B isolert fra vedheftende racemat A ved HPLC (SiO260; Merck; 0,015-0,025 mm; eter:metanol = 10:1). Det krystallinske inndampings-residuum ble omkrystallisert fra rikelige mengder eter ved konsentrering under oppvarming til kokepunktet. The isopropanolic mother liquor was evaporated and partitioned between ether and 2 N ammonia. From the evaporation residue of the dried organic phase, racemate B was isolated from adhering racemate A by HPLC (SiO260; Merck; 0.015-0.025 mm; ether:methanol = 10:1). The crystalline evaporation residue was recrystallized from copious amounts of ether by concentration while heating to the boiling point.

Smeltepunkt: 128-131°C Melting point: 128-131°C

13C-NMR-spektrum (CDC13/CD30D): 13C-NMR spectrum (CDC13/CD30D):

Eksempel 92 Example 92

1 -(4-amino-3-brom-5-cyan-fenyl)-2- N- 4-(4-metoksy-fenyl)-butyl - benzylamino - etanol- hydroklorid 1 -(4-amino-3-bromo-5-cyano-phenyl)-2- N- 4-(4-methoxy-phenyl)-butyl - benzylamino - ethanol - hydrochloride

Fremstillet av 4<1->amino-3'-brom-5<1->cyan-2-[N-[4-(4-metoksy-fenyl) -butyl]-benzylamino]-acetofenon og natriumborhydrid i . Prepared from 4<1->amino-3'-bromo-5<1->cyano-2-[N-[4-(4-methoxy-phenyl)-butyl]-benzylamino]-acetophenone and sodium borohydride in .

9 0% metanol analogt eksempel 1. 9 0% methanol analogous to example 1.

Smeltepunkt for hydrokloridet: 122-126°C Melting point for the hydrochloride: 122-126°C

Eksempel 93 Example 93

1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]- allylamino]- etanol 1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-allylamino]- ethanol

Fremstillet av 4'-amino-3'-brom-5'-cyan-2-[N-[4-(4-metoksy-fenyl) -butyl]-allylamino]-acetofenon og natriumborhydrid i 90% metanol analogt eksempel 1. Harpiks. Prepared from 4'-amino-3'-bromo-5'-cyano-2-[N-[4-(4-methoxy-phenyl)-butyl]-allylamino]-acetophenone and sodium borohydride in 90% methanol analogous to example 1. Resin.

Eksempel 94 Example 94

1-(4-amino-3-brom-5-cyan-fenyl)-2-{ N-[ 4-(4-metoksy-fenyl)-butyl3- isopropylamino]- etanol- hydroklorid 1-(4-amino-3-bromo-5-cyano-phenyl)-2-{ N-[ 4-(4-methoxy-phenyl)-butyl3- isopropylamino]- ethanol hydrochloride

Fremstillet av 4'-amino-3'-brom-5'-cyan-2-[N-[4-(4-metoksy-fenyl )-butyl]-isopropylamino]-acetofenon og natriumborhydrid i 90% metanol analogt eksempel 1. Prepared from 4'-amino-3'-bromo-5'-cyano-2-[N-[4-(4-methoxy-phenyl)-butyl]-isopropylamino]-acetophenone and sodium borohydride in 90% methanol analogous to example 1.

Smeltepunkt for hydrokloridet: sintring fra 40°C. Melting point of the hydrochloride: sintering from 40°C.

Beregnet: C 55,6 H 6,29 Br 16,2 Cl 2,14 N 8,46 Calculated: C 55.6 H 6.29 Br 16.2 Cl 2.14 N 8.46

Funnet: 55,3 6 ,37 15,4 6 ,84 8,8.3 Found: 55.3 6 .37 15.4 6 .84 8.8.3

Eksempel 95 Example 95

1 -(4-amino-3-brom-5-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]- n- propylamino]- etanol- hydroklorid 1 -(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-n-propylamino]- ethanol hydrochloride

Fremstillet av 4'-amino-3'-brom-5'-cyan-2-[ N-[ 4-(4-metoksy-fenyl)-butyl]-n-propylamino]-acetofenon og natriumborhydrid i 90% metanol analogt eksempel 1. Prepared from 4'-amino-3'-bromo-5'-cyano-2-[ N-[ 4-(4-methoxy-phenyl)-butyl]-n-propylamino]-acetophenone and sodium borohydride in 90% methanol analogous example 1.

Smeltepunkt for hydrokloridet: sintring fra 40°C Melting point of the hydrochloride: sintering from 40°C

Beregnet: C 55,60 H 6,29 N 8,46 Calculated: C 55.60 H 6.29 N 8.46

Funnet: 55,52 6,32 8,39 Found: 55.52 6.32 8.39

Eksempel 9 6 Example 9 6

1- (4-amino-3-brom-5-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl) - butyl]- etylamino]- etanol- hydroklorid 1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-ethylamino]- ethanol hydrochloride

Fremstillet av 4<1->amino-3<1->brom-5'-cyan-2-[N-[4-(4-metoksy-fenyl) -butyl]-etylamino]-acetofenon og natriumborhydrid i 90% metanol analogt eksempel 1. Prepared from 4<1->amino-3<1->bromo-5'-cyano-2-[N-[4-(4-methoxy-phenyl)-butyl]-ethylamino]-acetophenone and sodium borohydride in 90% methanol analogous to example 1.

Smeltepunkt for hydrokloridet: 139-142°C Melting point for the hydrochloride: 139-142°C

Eksempel 97 Example 97

1-(4-amino-3-brom-5-trifluormetyl-fenyl)-2-[N-[3-(4-metoksy-f enyl) - propyl ] - metylamino ] - etanol 1-(4-amino-3-bromo-5-trifluoromethyl-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 4<1->amino-3'-brom-5'-trifluormetyl-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og^ natriumborhydrid i 90% metanol analogt eksempel 1. Olje. Prepared from 4<1->amino-3'-bromo-5'-trifluoromethyl-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and^ sodium borohydride in 90% methanol analogously example 1. Oil.

Eksempel 98 Example 98

1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-(4-fenyl-butyl)-metylamino]- etanol- hydroklorid 1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-(4-phenyl-butyl)-methylamino]- ethanol hydrochloride

Fremstillet av 4'-amino-3<1->brom-5<1->cyan-2-[N-(4-fenyl-butyl)-metylamino]-acetofenon og natriumborhydrid i 90% metanol analogt eksempel 1. Prepared from 4'-amino-3<1->bromo-5<1->cyan-2-[N-(4-phenyl-butyl)-methylamino]-acetophenone and sodium borohydride in 90% methanol analogous to example 1.

Smeltepunkt for hydrokloridet: 153-155°C Melting point for the hydrochloride: 153-155°C

Eksempel 9 9 Example 9 9

1 -(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenylsulfenyl-propyl)-metylamino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenylsulfenyl-propyl)-methylamino]- ethanol

Fremstillet av 4'-amino-2-brom-3',5'-diklor-acetofenon, N-[3-(4-metoksy-fenylsulfenyl)-propyl]-metylamin og natriumborhydrid i 80% metanol analogt eksempel 2. Olje. Prepared from 4'-amino-2-bromo-3',5'-dichloro-acetophenone, N-[3-(4-methoxy-phenylsulfenyl)-propyl]-methylamine and sodium borohydride in 80% methanol analogous to example 2. Oil.

Eksempel i<qq>Example i<qq>

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-propyl]-amino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-propyl]-amino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-2-[N-P-(4-hydroksy-fenyl)-propyl]-amino]-acetofenon og natriumborhydrid i vandig tetra-hydrof uran. analogt eksempel 3. Olje. Prepared from 4'-amino-3',5'-dichloro-2-[N-P-(4-hydroxy-phenyl)-propyl]-amino]-acetophenone and sodium borohydride in aqueous tetrahydrofuran. analogous to example 3. Oil.

Eksempel 101 Example 101

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klorfenyl)-propyl]-amino]-etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chlorophenyl)-propyl]-amino]-ethanol

Fremstillet av 4'-amino-3<1>,5<1->diklor-2-[n-[3-(4-klor-fenyl)-propyl]-amino]-acetofenon og natriumborhydrid i vandig tetra-hydrof uran analogt eksempel 3. Prepared from 4'-amino-3<1>,5<1->dichloro-2-[n-[3-(4-chloro-phenyl)-propyl]-amino]-acetophenone and sodium borohydride in aqueous tetrahydrofuran analogous to example 3.

Smeltepunkt: 103-106°C Melting point: 103-106°C

Eksempel 102 Example 102

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1 - - metyl- propyl]) - isopropylamino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1 - - methyl- propyl])- isopropylamino]- ethanol

Fremstillet av 4<1->amino-3',5'-diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-isopropylamino]-acetofenon og 'natriumborhydrid analogt eksempel 3. Olje. Prepared from 4<1->amino-3',5'-dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-isopropylamino]-acetophenone and 'sodium borohydride analogous to example 3 .Oil.

Eksempel 103 Example 103

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-etylamino]-etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-ethylamino]-ethanol

Fremstillet av 4<1->amino-3',5'-diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-etylamino]-acetofenon og natriumborhydrid analogt eksempel 3. Olje. Prepared from 4<1->amino-3',5'-dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-ethylamino]-acetophenone and sodium borohydride analogously to example 3. Oil.

Eksempel 10<4>Example 10<4>

1 -(4-metylamino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1- metyl- propyl]- metylamino]- etanol 1 -(4-methylamino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1- methyl- propyl]- methylamino]- ethanol

Fremstillet av 4<1->metylamino-3',5'.diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-metylamino]-acetofenon og natriumborhydrid analogt eksempel 3. Olje. Prepared from 4<1->methylamino-3',5'.dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methylamino]-acetophenone and sodium borohydride analogously to example 3. Oil.

Eksempel 1°5 Example 1°5

1-(4-dimetylamino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-feny1)- 1- metyl- propyl]- metylamino]- etanol 1-(4-dimethylamino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)- 1- methyl- propyl]- methylamino]- ethanol

Fremstillet av 4'-dimetylamino-3',5'-diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-metylamino]-acetofenon og natriumborhydrid analogt eksempel 3. Olje. Prepared from 4'-dimethylamino-3',5'-dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methylamino]-acetophenone and sodium borohydride analogous to example 3. Oil.

Beregnet: C 61,31 H 6,86 Cl 17,24 N 6,81 Calculated: C 61.31 H 6.86 Cl 17.24 N 6.81

Funnet: 61,28 6,57 16,80 6,42 Found: 61.28 6.57 16.80 6.42

Eksempel 106 Example 106

1 -(4-acetylamino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1- metyl- propyl]- metylamino]- etanol 1 -(4-acetylamino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1- methyl- propyl]- methylamino]- ethanol

Fremstillet av 4<1->acetylamino-3',5<1->diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]rmetylamino]-acetofenon og natriumborhydrid analogt eksempel 3. Skum. Prepared from 4<1->acetylamino-3',5<1->dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]rmethylamino]-acetophenone and sodium borohydride analogous to example 3 .Foam.

Eksempel 10<7>Example 10<7>

1 - (4-etoksykarbonylami.no-3 , 5-diklor-f enyl) -2- [N- [ 3- (4-hydroksy-fenyl)- 1- metyl- propyl]- metylamino]- etanol 1 - (4-ethoxycarbonylami.no-3 , 5-dichloro-phenyl)-2- [N- [ 3-(4-hydroxy-phenyl)- 1- methyl- propyl]- methylamino]- ethanol

Fremstillet av 4'-etoksykarbonylamino-3',5'-diklor-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-metylamino]-acetofenon og natriumborhydrid analogt eksempel 3. Olje. Prepared from 4'-ethoxycarbonylamino-3',5'-dichloro-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-methylamino]-acetophenone and sodium borohydride analogous to example 3. Oil.

Eksempel 108 Example 108

Racemat A og B av 1 -(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[1-metyl- 3- ( 4- hydroksy- f' enyl) - propyl ]- metylamino3- etanol Fremstillet av 4<1->amino-3'-cyan-5'-fluor-2-[N-[1-metyl-3-(4-hydroksy-fenyl)-propylJ-metylaminoJ-acetofenon og natriumborhydrid analogt eksempel 3. Den oppnådde blanding av de diastereomere racemater ble adskilt vejd hjelp av søylekromatografi (Si02; metylenklorid:metanol:kons.ammoniakk = 50:1:0,1). Racemate A and B of 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[1-methyl-3-(4-hydroxy-phenyl)-propyl]-methylamino3- ethanol Prepared from 4<1->amino-3'-cyano-5'-fluoro-2-[N-[1-methyl-3-(4-hydroxy-phenyl)-propylJ-methylaminoJ-acetophenone and sodium borohydride analogously to example 3 The obtained mixture of the diastereomeric racemates was separated and weighed by means of column chromatography (SiO 2 ; methylene chloride: methanol: conc. ammonia = 50:1:0.1).

RacenuvLjy ^RacenuvLjy ^

Smeltepunkt: l61"1 "^yisulfoksyd) l3c,NMR-spektrum (dg Melting point: 161"1 "(yisulfoxide) 13c, NMR spectrum (dg

Racemat B: Racemate B:

Smeltepunkt: 9 2-98°C Melting point: 9 2-98°C

13 13

C-NMR-spektrum (dg-dimetylsulfoksyd): C-NMR spectrum (dg-dimethylsulfoxide):

Eksempel 109 Example 109

1 -(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[1-metyl-3-(4-metoksy-fenyl)- propyl]- amino]- etanol 1 -(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[1-methyl-3-(4-methoxy-phenyl)-propyl]-amino]- ethanol

Fremstillet av 4'-amino-3'-cyan-5'-fluor-2-[N-[1-metyl-3-(4-metoksy-fenyl)-propyl]-amino]-acetofenon og natriumborhydrid analogt eksempel 3. ■ Prepared from 4'-amino-3'-cyano-5'-fluoro-2-[N-[1-methyl-3-(4-methoxy-phenyl)-propyl]-amino]-acetophenone and sodium borohydride analogously to example 3. ■

Smeltepunkt: 108-110°C Melting point: 108-110°C

Eksempel 110 Example 110

1 -(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[1-metyl-3-(4-hydroksy-fenyl)- propyl]- amino]- etanol 1 -(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[1-methyl-3-(4-hydroxy-phenyl)-propyl]- amino]- ethanol

Fremstillet av 4<1->amino-3'-cyan-5<1->fluor-2-[N-[1-metyl-3-(4-hydroksy-fenyl)-propyl]-amino]-acetofenon og natriumborhydrid analogt eksempel 3. Prepared from 4<1->amino-3'-cyano-5<1->fluoro-2-[N-[1-methyl-3-(4-hydroxy-phenyl)-propyl]-amino]-acetophenone and sodium borohydride analogous to example 3.

Smeltepunkt: 162-164°C Melting point: 162-164°C

Eksempel m Example m

1-(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[1-metyl-3-(4-metoksy-f enyl) - propyl] - metylamino] - etanol 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[1-methyl-3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 1 -(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[1 - metyl-3-(4-hydroksy-fenyl)-propyl]-metylamino]-etanol og dimetylsulfat/1 N natriumhydroksyd i tetrahydrofuran analogt eksempel 4. Olje. Prepared from 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[1-methyl-3-(4-hydroxy-phenyl)-propyl]-methylamino]-ethanol and dimethyl sulfate/ 1 N sodium hydroxide in tetrahydrofuran analogous to example 4. Oil.

Eksempel ^-^ 1 -(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-2-fenoksy-etyl)-amino]-etanol-hydroklorid Example ^-^ 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-amino]-ethanol hydrochloride

Fremstillet av 4<1->amino-3',5<1->diklor-acetofenon, selendioksyd, 1-metyl-2-fenoksy-etylamin og natriumborhydrid analogt eksempel 5. Amorft hydroklorid. Prepared from 4<1->amino-3',5<1->dichloro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine and sodium borohydride analogous to example 5. Amorphous hydrochloride.

Eksempel -^ 3 Example -^ 3

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl)-propyl]-amino]-etanol-hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-amino]-ethanol hydrochloride

Fremstillet av 4'-aminb-3',5'-diklor-acetofenon, selendioksyd, 3-(4-fluor-fenyl)-propylamin og natriumborhydrid analogt eksempel 5. Prepared from 4'-amineb-3',5'-dichloro-acetophenone, selenium dioxide, 3-(4-fluoro-phenyl)-propylamine and sodium borohydride analogous to example 5.

Smeltepunkt for hydrokloridet: 185-187°C (dekomp.). Melting point of the hydrochloride: 185-187°C (decomp.).

Eksempel <114>Example <114>

1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-1-metyl-propyl)-metylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-1-methyl-propyl)-methylamino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-acetofenon, selendioksyd, 3-fenyl-1-metyl-propylamin og natriumborhydrid analogt eksempel 5. Olje. Prepared from 4'-amino-3',5'-dichloro-acetophenone, selenium dioxide, 3-phenyl-1-methyl-propylamine and sodium borohydride analogous to example 5. Oil.

Eksempel Example

1 -(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-2-fenoksy-etyl)-amino] - etanol- hydroklorid 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-amino]-ethanol hydrochloride

Fremstillet av 4'-amino-3',5'-diklor-acetofenon, selendioksyd, 1-metyl-2-fenoksy-etylamin og natriumborhydrid analogt eksempel 5. Prepared from 4'-amino-3',5'-dichloro-acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine and sodium borohydride analogous to example 5.

Smeltepunkt for hydrokloridet: 122-125°C Melting point for the hydrochloride: 122-125°C

Eksempel ^ 6 Example ^ 6

N-[2-(4-amino-3-klor-fenyl)-etyl]-N-(1-metyl-3-fenyl-propyl)-isopropylamin N-[2-(4-amino-3-chloro-phenyl)-ethyl]-N-(1-methyl-3-phenyl-propyl)-isopropylamine

Fremstillet av 4-amino-3,5-diklor-N-isopropyl-N-(1-metyl-3-fenyl-propyl)-fenyleddiksyreamid og litiumaluminiumhydrid i tetrahydrofuran analogt eksempel 7. Olje. Prepared from 4-amino-3,5-dichloro-N-isopropyl-N-(1-methyl-3-phenyl-propyl)-phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogous to example 7. Oil.

IR-spektrum (metylenklorid.) : NH2 3390 + 3490 cm<-1 >UV-spektrum (etanol): /l max. 241 nm (0,15) IR spectrum (methylene chloride.) : NH2 3390 + 3490 cm<-1 >UV spectrum (ethanol): /l max. 241 nm (0.15)

300 nm (0,03) 300 nm (0.03)

Eksempel 11^ Example 11^

N-t 2- (4-amino-3,5-diklor-fenyl)-etyl]-N-(1-metyl-3-fenylpropyl)- isopropylamin N-t 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(1-methyl-3-phenylpropyl)- isopropylamine

IR-spektrum (metylenklorid): NH^ 3390 + 3490 cm<-1 >UV-spektrum (etanol): /Imax. 245 nm (0,15) IR spectrum (methylene chloride): NH^ 3390 + 3490 cm<-1 >UV spectrum (ethanol): /Imax. 245 nm (0.15)

302 nm (0,04) 302 nm (0.04)

Eksempel 118 Example 118

N-[2-(4-amino-3,5-diklor-fenyl)-etyl] -3-(4-fluor-fenyl)-propylamin-hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-3-(4-fluoro-phenyl)-propylamine hydrochloride

Fremstillet av 4-amino-3,5-diklor-N-[ 3-(4-fluor-fenyl)-propyl]-fenyleddiksyreamid og litiumaluminiumhydrid i tetra-hydrof uran analogt eksempel 7. Smeltepunkt for hydrokloridet: 205-206°C Prepared from 4-amino-3,5-dichloro-N-[3-(4-fluoro-phenyl)-propyl]-phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogous to example 7. Melting point for the hydrochloride: 205-206°C

•_. '*' Eksempel H9 •_. '*' Example H9

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(1-metyl-3-fenylpropyl) - metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(1-methyl-3-phenylpropyl)-methylamine

Fremstillet av 4-amind-3,5-diklor-N-(1-metyl-3-fenyl-propyl)-fenyleddiksyreamid og litiumaluminiumhydrid i tetrahydrofuran analogt eksempel 7. Olje. Prepared from 4-amine-3,5-dichloro-N-(1-methyl-3-phenyl-propyl)-phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogous to example 7. Oil.

Eksempel 120 Example 120

N-[2-(4-amino-3,5-dikior-fenyl)-etyl]-N-[3-(4-metoksy-fenyl-sulfenyl)- propyl]- metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl-sulfenyl)-propyl]- methylamine

Fremstillet av 4-amino-3,5-diklor-N-[3-(4-metoksy-fenyl-sulf enyl) -propyl ] -N-metyl-f enyleddiksyreamid og litiumaluminiumhydrid i tetrahydrofuran analogt eksempel 7. Olje. Prepared from 4-amino-3,5-dichloro-N-[3-(4-methoxy-phenyl-sulfenyl)-propyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride in tetrahydrofuran analogous to example 7. Oil.

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Eksempel 121 Example 121

N-[ 2- (4-amino-3-brom-'f enyl) -etyl] -N-[ 4- (4-metoksy-fenyl) - N-[ 2-(4-amino-3-bromo-phenyl)-ethyl]-N-[ 4-(4-methoxy-phenyl)-

butyl] - metylamin butyl] - methylamine

Fremstillet av 4-aminp-3-brom-N-[2-(4-metoksy-fenyl)-butyl]-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid i absolutt tetrahydrofuran analogt eksempel 8. Prepared from 4-aminep-3-bromo-N-[2-(4-methoxy-phenyl)-butyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogous to Example 8.

Eksempel 122 Example 122

N-[2- (4-amino-3-fluor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl) - propyl]- metylamin N-[2-(4-amino-3-fluoro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]-methylamine

Fremstillet av 4-amino-3-fluor-N-[3-(4-metoksy-fenyl)-propyl]-N-metyl-fenyleddiksyreamid og litiumaluminiumhydrid i absolutt tetrahydrofuran analogt eksempel 8. Olje. Prepared from 4-amino-3-fluoro-N-[3-(4-methoxy-phenyl)-propyl]-N-methyl-phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogous to Example 8. Oil.

Eksempel 123 Example 123

N-[2-(4-amino-3-klor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-propyl]- metylamin N-[2-(4-amino-3-chloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]- methylamine

Fremstillet av 4-amino-3-klor-N-metyl-N-[3-(4-metoksy-fenyl)-propyl]-fenyleddiksyreamid og litiumaluminiumhydrid i.absolutt tetrahydrofuran analogt eksempel 8. Harpiks. Prepared from 4-amino-3-chloro-N-methyl-N-[3-(4-methoxy-phenyl)-propyl]-phenylacetic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogous to Example 8. Resin.

Eksempel 12 4 Example 12 4

N-[3-(4-amino-3,5-diklor-fenyl)-propyl]-N-[3-(4-metoksy-fenyl)-propyl]- amin- hydroklorid N-[3-(4-amino-3,5-dichloro-phenyl)-propyl]-N-[3-(4-methoxy-phenyl)-propyl]-amine hydrochloride

Fremstillet av 3-(4-amino-3,5-diklor-fenyl)-N-[3-(4-metoksy-fenyl )-propyl]-propionsyreamid og litiumaluminiumhydrid i absolutt tetrahydrofuran analogt eksempel 8. Prepared from 3-(4-amino-3,5-dichloro-phenyl)-N-[3-(4-methoxy-phenyl)-propyl]-propionic acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogous to Example 8.

Smeltepunkt for hydrokloridet: 138-142°C Melting point for the hydrochloride: 138-142°C

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Eksempel 125 Example 125

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[ 4-(4-metoksy-fenyl)-butyl]- amin- hydroklorid N-[ 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[ 4-(4-methoxy-phenyl)-butyl]-amine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl] -4-(4-metoksy-fenyl)-smørsyreamid og litiumaluminiumhydrid i absolutt tetrahydrofuran analogt eksempel 8. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-4-(4-methoxy-phenyl)-butyric acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogous to Example 8.

Smeltepunkt for hydrokloridet: 186-1.89°C Melting point for the hydrochloride: 186-1.89°C

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Eksempel 126 Example 126

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[ 3-(4-klor-fenyl)-propyl] - amin- hydroklorid N-[ 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[ 3-(4-chloro-phenyl)-propyl]-amine hydrochloride

Fremstillet av 4-amino-3,5-diklor-N-[ 3-(4-klor-fenyl)-propyl] - fenyleddiksyreamid og:litiumaluminiumhydrid i absolutt tetra-hydrof uran analogt eksempel 8. Prepared from 4-amino-3,5-dichloro-N-[3-(4-chloro-phenyl)-propyl]-phenylacetic acid amide and:lithium aluminum hydride in absolute tetrahydrofuran analogous to Example 8.

Smeltepunkt for hydrokloridet: 186-190°C Melting point for the hydrochloride: 186-190°C

Eksempel 127 Example 127

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)-butyl]-isopropylamin , N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-isopropylamine,

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-isopropyl-4-(4-metoksy-fenyl)-smørsyreamid og litiumaluminiumhydrid i absolutt tetrahydrofuran analogt eksempel 8. Olje. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-isopropyl-4-(4-methoxy-phenyl)-butyric acid amide and lithium aluminum hydride in absolute tetrahydrofuran analogous to Example 8. Oil.

j j

Eksempel 128 Example 128

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N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-3-fenyl-propylamin-hydroklorid ; N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-3-phenyl-propylamine hydrochloride;

Fremstillet av 4-amino-3,5-diklor-N-(3-fenyl-propyl)-fenyl-eddiksyreamid og litiumaluminiumhydrid i tetrahydrofuran analogt eksempel 8. i Prepared from 4-amino-3,5-dichloro-N-(3-phenyl-propyl)-phenyl-acetic acid amide and lithium aluminum hydride in tetrahydrofuran analogously to Example 8. i

Smeltepunkt for hydrokloridet: 197-199°C Melting point for the hydrochloride: 197-199°C

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Eksempel 129 Example 129

N-[2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)- butyl]- benzylamin N-[2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-benzylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-brom-b-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-benzylamino]-etan og Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-b-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-benzylamino]-ethane and

Eksempel 130 Example 130

N-[2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-[4-(4-metoksy-fenyl )-butyl ]-allylamin N-[2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-allylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-brom-5-cyan-fenyl)^2- [N-[4-(4-metoksy-fenyl)-butyl]-allylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9. Olje. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-5-cyano-phenyl)^2- [N-[4-(4-methoxy-phenyl)-butyl]-allylamino]-ethane and sodium borohydride in isopropanol analogous to example 9. Oil.

Eksempel 131 Example 131

N-[2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)- butyl]- etylamin N-[2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-ethylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-etylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9. Olje. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-ethylamino]-ethane and sodium borohydride in isopropanol analogous to example 9. Oil.

Eksempel 132 Example 132

N- l~2- (4-amino-3-brom-5-cyan-fenyl) -etyl]-N-[4- (4-metoksy-f enyl) - butyl ] - isopropylamin N-1~2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-isopropylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-brom-5-cyan- Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-5-cyano-

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fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-isopropylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9. Harpiks. phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-isopropylamino]-ethane and sodium borohydride in isopropanol analogous to example 9. Resin.

iEksempel 133 iExample 133

N-[2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)- butyl]- n- propylamin N-[2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-n-propylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-n-propylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9. Olje. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-n-propylamino]-ethane and sodium borohydride in isopropanol analogous to example 9. Oil.

Eksempel 134 Example 134

N-t 2-(4-amino-3-brom-5-cyan-fenyl)-etyl]-N-(4-fenyl-butyl)-metylamin N-t 2-(4-amino-3-bromo-5-cyano-phenyl)-ethyl]-N-(4-phenyl-butyl)-methylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-brom-5-cyan-fenyl)-2-[N-(4-fenyl-butyl)-metylamino]-etan og natriumborhydrid i isopropanol a,nalogt eksempel 9. Olje. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-bromo-5-cyano-phenyl)-2-[N-(4-phenyl-butyl)-methylamino]-ethane and sodium borohydride in isopropanol a, analogous to example 9 .Oil.

Eksempel 135 Example 135

N-t 2-(4-amino-3-cyan-5-fluor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)- propyl]- metylamin- hydroklorid N-t 2-(4-amino-3-cyano-5-fluoro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-propyl]- methylamine hydrochloride

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-cyan-5-fluor-fenyl) -2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9.Hydroklorid i form av harpiks. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethane and sodium borohydride in isopropanol analogous to example 9. Hydrochloride in the form of resin.

Eksempel 136 Example 136

N-[2- (4-amino-3-cyan-5-fluor-fenyl)-etyl] -N-[ 4-(4-metoksy-fenyl) -butyl]-metylamin N-[2-(4-amino-3-cyano-5-fluoro-phenyl)-ethyl]-N-[ 4-(4-methoxy-phenyl)-butyl]-methylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3-cyan-5-fluor-fenyl) -2-[N-[4-(4-metoksy-fenyl)-butyl] -metylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9. Harpiks. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethane and sodium borohydride in isopropanol analogous to example 9. Resin.

Eksempel 137 Example 137

N-[2-(4-amino-3-klor-5rtrifluormetyl-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)-butyl]-metylamin N-[2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-methylamine

Fremstillet av 1-etoksykarbonylbksy-1-(4-amino-3-klor-5-trifluormetyl-fenyl)-2-[N-[4-(4-metoksy-fenyl)-butyl]-metylamino] -etan og natriumborhydrid i isopropanol analogt eksempel 9. Prepared from 1-ethoxycarbonylboxy-1-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-[N-[4-(4-methoxy-phenyl)-butyl]-methylamino]-ethane and sodium borohydride in isopropanol analogous to example 9.

Smeltepunkt: 29°C Melting point: 29°C

Eksempel 138 Example 138

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-fluor-fenyl)-propyl]-metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]-methylamine

Fremstillet av 1-etoksykarbonyloksy-1-(4-amino-3,5-diklor-fenyl)-2- [N- [3-(4-fluor-fenyl)-propyl]-metylamino]-etan og natriumborhydrid i isopropanol analogt eksempel 9. Olje. Prepared from 1-ethoxycarbonyloxy-1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-methylamino]-ethane and sodium borohydride in isopropanol analog example 9. Oil.

Eksempel 139 Example 139

1-(4-amino-3-trifluormetyl-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol 1-(4-amino-3-trifluoromethyl-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 1-(4-amino-3-brom-5-trifluormetyl-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-etanol og hydrogen i nærvær av palladiumoksyd og bariumsulfat i metanol analogt Prepared from 1-(4-amino-3-bromo-5-trifluoromethyl-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-ethanol and hydrogen in the presence of palladium oxide and barium sulfate in methanol analogously

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eksempel 11. Olje. example 11. Oil.

Eksempel 140 Example 140

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1 - • metyl- propyl]- allylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1 - • methyl- propyl]- allylamino]- ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-amino]-etanol med allylbromid/ natriumkarbonat i absolutt etanol analogt eksempel 13. Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-amino]-ethanol with allyl bromide/ sodium carbonate in absolute ethanol analogous to example 13. Oil.

Eksempel 141 Example 141

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-propyl]- isopropylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-propyl]- isopropylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-benzyloksy-fenyl)-propyl]-isopropylamino]-etanol og hydrogen i nærvær av palladium på kull analogt eksempel 16. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-benzyloxy-phenyl)-propyl]-isopropylamino]-ethanol and hydrogen in the presence of palladium on charcoal analogously example 16.

Smeltepunkt for hydrokloridet: 90-110°C Melting point for the hydrochloride: 90-110°C

Eksempel 142 Example 142

1-(4-amino-3-klor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-propyl]-etylamino]- etanol 1-(4-amino-3-chloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-propyl]-ethylamino]- ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-[N-13-(4-benzyloksy-fenyl)-propyl]-etylamino]-etanol og hydrogen i nærvær av palladium på kull analogt eksempel 16. Harpiks. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-13-(4-benzyloxy-phenyl)-propyl]-ethylamino]-ethanol and hydrogen in the presence of palladium on charcoal analogous example 16. Resin.

Eksempel 143 Example 143

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-hydroksy-fenyl)-propyl ] - etylamino ] - etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-hydroxy-phenyl)-propyl]-ethylamino]-ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-benzyloksy-fenyl)-propyl]-etylamino]-etanol og hydrogen i nærvær av palladium på kull analogt eksempel 16. Harpiks. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-benzyloxy-phenyl)-propyl]-ethylamino]-ethanol and hydrogen in the presence of palladium on charcoal analogously example 16. Resin.

Eksempel 144 Example 144

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N-[3-(4-dimetylamino-3,5-diklor-fenyl)^propyl]-N-[3-(4-metoksy-fenyl)-propyl]-metylamin N-[3-(4-dimethylamino-3,5-dichloro-phenyl)^propyl]-N-[3-(4-methoxy-phenyl)-propyl]-methylamine

Fremstillet av N-[3-(4-amino-3,5-diklor-fenyl)-propyl]-N-[3-(4-metoksy-fenyl)-propyl]-amin, paraformaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Olje. Prepared from N-[3-(4-amino-3,5-dichloro-phenyl)-propyl]-N-[3-(4-methoxy-phenyl)-propyl]-amine, paraformaldehyde and sodium cyanoborohydride in ethanol analogous to Example 88 . Oil.

Eksempel 145 Example 145

N-[3-(4-amino-3,5-diklor-fenyl)-propyl]-N-[3-(4-metoksy-fenyl) -propyl]-metylamin N-[3-(4-amino-3,5-dichloro-phenyl)-propyl]-N-[3-(4-methoxy-phenyl)-propyl]-methylamine

Fremstillet av N-[3-(4-amino-3,5-diklor-fenyl)-propyl]-N-[ 3-(4-metoksy-fenyl)-propyl]-amin, paraformaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Olje. Prepared from N-[3-(4-amino-3,5-dichloro-phenyl)-propyl]-N-[3-(4-methoxy-phenyl)-propyl]-amine, paraformaldehyde and sodium cyanoborohydride in ethanol analogous to example 88 . Oil.

Eksempel 146 Example 146

N-[2-(4-dimetylamino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)- propyl]- metylamin N-[2-(4-dimethylamino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]- methylamine

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]amin, paraformaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Olje. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]amine, paraformaldehyde and sodium cyanoborohydride in ethanol analogous to example 88 . Oil.

Eksempel 147 Example 147

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]- 2- fenyletylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]- 2- phenylethylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]-amin, fenylacetaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-amine, phenylacetaldehyde and sodium cyanoborohydride in ethanol analogous to Example 88 .

Smeltepunkt for hydrokloridet: 158-161°C Melting point for the hydrochloride: 158-161°C

Eksempel 148 Example 148

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)-butyl ] - etylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl ]-ethylamine

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[4-(4-metoksy-fenyl)-butyl]-amin, acetaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Olje. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-amine, acetaldehyde and sodium cyanoborohydride in ethanol analogous to example 88 . Oil.

Eksempel 149 Example 149

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]- benzylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]- benzylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]-amin, benzaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-amine, benzaldehyde and sodium cyanoborohydride in ethanol analogous to Example 88 .

Smeltepunkt for hydrokloridet: 164-168°C Melting point of the hydrochloride: 164-168°C

Eksempel 150 Example 150

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]- isopropylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-isopropylamine

Fremstillet av N-[ 2-j( 4-amino-3 ,5-diklor-f enyl)-etyl]-N-[ 3-(4-klor-fenyl)-propyl]-amin, aceton og natriumcyanborhydrid i absolutt metanol analogt eksempel 88 . Olje. Prepared from N-[2-j(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-amine, acetone and sodium cyanoborohydride in absolute methanol analogous example 88 . Oil.

Eksempel 151 Example 151

N-[ 1-metyl-2-(4-amino-3,5-diklor-fenyl)-etyl] -N-[ 3-(4-metoksy-fenyl)-pro py]J-amjjv-h^ N-[ 1-methyl-2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[ 3-(4-methoxy-phenyl)-propyl]J-amjjv-h^

Fremstillet av 1-(4'-amino-3',5<1->diklor-fenyl)-aceton, 3-(4-metoksyfenyl)-propylamin og natriumcyanborhydrid i etanol analogt eksempel 88 . Prepared from 1-(4'-amino-3',5<1->dichloro-phenyl)-acetone, 3-(4-methoxyphenyl)-propylamine and sodium cyanoborohydride in ethanol analogous to example 88 .

Smeltepunkt for hydrokloridet: 193-195°C Melting point for the hydrochloride: 193-195°C

Eksempel 152 Example 152

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl] -N-[ 3-(4-klor-fenyl) - propyl] - n- propylamin N-[ 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[ 3-(4-chloro-phenyl)-propyl]-n-propylamine

Fremstillet av N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl] -N-[ 3-(4-klor-fenyl)-propyl] -amin, propionaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Olje. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-amine, propionaldehyde and sodium cyanoborohydride in ethanol analogously to Example 88 . Oil.

Eksempel 153 Example 153

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl ] - etylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl ]-ethylamine

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]-amin, acetaldehyd og natriumcyanborhydrid i etanol ved pH 6-6,5 analogt eksempel 88. Olje. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-amine, acetaldehyde and sodium cyanoborohydride in ethanol at pH 6 -6.5 analogous example 88. Oil.

Eksempel :154 Example :154

N-[ 1-metyl-2-(4-amiho-3,5-diklor-fenyl)-etyl] -N-[ 3-(4-metoksy-fenyl)- propyl]- metylamin N-[ 1-methyl-2-(4-amiho-3,5-dichloro-phenyl)-ethyl]-N-[ 3-(4-methoxy-phenyl)-propyl]- methylamine

Fremstillet av 1-(4<1->amino-3',5'-diklor-fenyl)-aceton, 3-(4-metoksyfenyl)-N-metyl-propylamin og natriumcyanborhydrid i etanol analogt eksempel 88- Olje. Prepared from 1-(4<1->amino-3',5'-dichloro-phenyl)-acetone, 3-(4-methoxyphenyl)-N-methyl-propylamine and sodium cyanoborohydride in ethanol analogous to example 88- Oil.

Eksempel -*- 55 Example -*- 55

N-12-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-fenylpropyl)-isopropylamin- hydroklorid N-12-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenylpropyl)-isopropylamine hydrochloride

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Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-3-fenyl-propylamin, aceton, molekylarsikt 3 A og natriumcyanborhydrid i absolutt metanol analogt eksempel 88 . Skum. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-3-phenyl-propylamine, acetone, molecular sieve 3 A and sodium cyanoborohydride in absolute methanol analogous to example 88 . Foam.

■ Eksempel 156 ■ Example 156

1-(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-3-fenyl-propyl)-metylamino]-etanol-hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenyl-propyl)-methylamino]-ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[ N-(1-metyl-3-fenyl-propyl)-amino ]-etanol, paraformaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 • Oljeaktig hydroklorid. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[ N -(1-methyl-3-phenyl-propyl)-amino ]-ethanol, paraformaldehyde and sodium cyanoborohydride in ethanol analogous to example 88 • Oily hydrochloride.

Eksempel 15 7 Example 15 7

1 -(4-amino-3,5-diklor-fenyl)-2-[ N-(1-metyl-3-fenyl-propyl) - metylamino]- etanol- hydroklorid 1 -(4-amino-3,5-dichloro-phenyl)-2-[ N -(1-methyl-3-phenyl-propyl)-methylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[ N-(1-metyl-3-fenyl-propyl)-amino ]-etanol, paraformaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[ N -(1-methyl-3-phenyl-propyl)-amino ]-ethanol, paraformaldehyde and sodium cyanoborohydride in absolute ethanol analogous to example 88.

Smeltepunkt for hydrokloridet: 170-173°C Melting point for the hydrochloride: 170-173°C

Eksempel 158 Example 158

1-(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-3-fenyl-propyl)-propylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenyl-propyl)-propylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-(1-mety1-3-fenyl-propyl)-amino]-etanol. propionaldehyd og natriumcyanborhydrid analogt eksempel <88>. oljeaktig hydroklorid. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenyl-propyl)-amino]-ethanol. propionaldehyde and sodium cyanoborohydride analogous example <88>. oily hydrochloride.

Eksempel 159 Example 159

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-fenyl-propyl)-n- propylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenyl-propyl)-n-propylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-3-fenyl-propylamin, propionaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Oljeaktig hydroklorid. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-3-phenyl-propylamine, propionaldehyde and sodium cyanoborohydride in absolute ethanol analogous to Example 88. Oily hydrochloride.

Eksempel 160 Example 160

N- [2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-fenyl-propyl)-etylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenyl-propyl)-ethylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-3-fenyl-propylamin, acetaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Oljeaktig hydroklorid. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-3-phenyl-propylamine, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogous to Example 88. Oily hydrochloride.

Eksempel ^-^ 1 Example ^-^ 1

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(1-metyl-3-fenylpropyl)- etylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(1-methyl-3-phenylpropyl)- ethylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(1 - metyl-3-fenyl-propyl)-amin, acetaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88 . Oljeaktig hydroklorid. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(1-methyl-3-phenyl-propyl)-amine, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogous to example 88 . Oily hydrochloride.

Eksempel 162 1 -(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-2-fenoksy-etyl)-etylamino]-etanol-hydroklorid Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-2-fénoksy-etyl)-amino]-etanol, acetaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Oljeaktig hydroklorid. ;Example 162 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-ethylamino]-ethanol hydrochloride Prepared from 1-(4-amino- 3,5-dichloro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-amino]-ethanol, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogous to example 88. Oily hydrochloride. ;

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Eksempel 163 Example 163

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1-(4-amino-3-brom-5-fluor-fenyl)-2-[N-(1-metyl-2-fenoksy-etyl)- etylamino]- etanol 1-(4-amino-3-bromo-5-fluoro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-ethylamino]- ethanol

Fremstillet av 1-(4-amino-3-brom-5-fluor-fenyl)-2-[N-(1 - metyl-2-fenoksy-etyl)-amino]-etanol, acetaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. olje. Prepared from 1-(4-amino-3-bromo-5-fluoro-phenyl)-2-[N-(1-methyl-2-phenoxy-ethyl)-amino]-ethanol, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogous example 88. oil.

Eksempel 164 Example 164

1-(4-amino-3-cyan-5-fluor-fenyl)-2-fN-[3-(4-metoksy-fenyl)-propyl]- etylamino]- etanol- hydroklorid 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-n-[3-(4-methoxy-phenyl)-propyl]-ethylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3-cyan-5-fluor-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]-amino]-etanol, acetaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 83 . Oljeaktig hydroklorid. Prepared from 1-(4-amino-3-cyano-5-fluoro-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]-amino]-ethanol, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogous example 83 . Oily hydrochloride.

Eksempel 165 Example 165

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-fluor-fenyl)-propyl]- benzylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]- benzylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-fluor-fenyl)-propyl]-amin, benzaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]-amine, benzaldehyde and sodium cyanoborohydride in absolute ethanol analogous example 88.

Smeltepunkt for hydrokloridet: 118-120°C Melting point for the hydrochloride: 118-120°C

Eksempel 166 Example 166

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-fluor-fenyl)-propyl]- n- propylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]- n- propylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-fluor-fenyl)-propyl]-amin,propionaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]-amine, propionaldehyde and sodium cyanoborohydride in absolute ethanol analogous example 88.

Smeltepunkt for hydrok<!>loridet: 130-133°C Melting point for the hydrochloride: 130-133°C

Eksempel 167 Example 167

N-[ 2- (4-amino-3,5-dikl,or-f enyl) -etyl] -N-[ 3- (4-f luor-fenyl) - propyl]- etylamin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]-ethylamine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-fluor-fenyl)-propyl]-amin, acetaldehyd, molekylarsikt 3 Å Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]-amine, acetaldehyde, molecular sieve 3 Å

og natriumcyanborhydrid i absolutt metanol analogt eksempel 88 . Smeltepunkt for hydrokloridet: 182-184°C (dekomp). and sodium cyanoborohydride in absolute methanol analogously to example 88. Melting point of the hydrochloride: 182-184°C (decomp).

Eksempel 168 Example 168

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3- (4-fluor-fenyl)-propyl]- isopropyl- amin- hydroklorid N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]- isopropyl- amine hydrochloride

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-fluor-fenyl)-propyl]-amin, aceton, molekylarsikt 3 Å og natriumcyanborhydrid i absolutt metanol analogt eksempel 88 . Smeltepunkt for hydrokloridet: 182-184°C (dekomp). Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-fluoro-phenyl)-propyl]-amine, acetone, molecular sieve 3 Å and sodium cyanoborohydride in absolute methanol analogous to example 88 . Melting point of the hydrochloride: 182-184°C (decomp).

Eksempel 169 Example 169

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl)-propyl]-2- fenyletylamino]- etanol- hydroklorid 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-2- phenylethylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl )-propyl]-amino]-etanol, fenylacetaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88• Amorft hydroklorid. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl )-propyl]-amino]-ethanol, phenylacetaldehyde and sodium cyanoborohydride in absolute ethanol analogous example 88• Amorphous hydrochloride.

Eksempel 170 Example 170

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl)-propyl]-benzylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-benzylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl) -propyl]-amino]-etanol, benzaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-amino]-ethanol, benzaldehyde and sodium cyanoborohydride in absolute ethanol analogous example 88.

Smeltepunkt for hydrokloridet: 132-134°C (dekomp.). Melting point of the hydrochloride: 132-134°C (decomp.).

Eksempel 171 Example 171

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl)-propyl]-n- propylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-n-propylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl )-propyl]-amino]-etanol, propionaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel Q8• Smeltepunkt for hydrokloridet: 136-138°C (dekomp.). Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl )-propyl]-amino]-ethanol, propionaldehyde and sodium cyanoborohydride in absolute ethanol analogous example Q8• Melting point of the hydrochloride: 136-138°C (decomp.).

Eksempel 172 Example 172

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl)-propyl]-etylamino ]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-ethylamino ]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl) -propyl]-amino]-etanol, acetaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-amino]-ethanol, acetaldehyde and sodium cyanoborohydride in absolute ethanol analogous example 88.

Smeltepunkt for hydrokloridet: 130-134°C Melting point for the hydrochloride: 130-134°C

; Eksempel 17 3' ; Example 17 3'

1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-2-fenyl-etylamino]-etanol-hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-2-phenyl-ethylamino]-ethanol hydrochloride

Fremstillet av 1-(4-amino-3 ,.5-diklor-f enyl)-2-[N-(3-f enyl-propyl)-amino ]-etanol, f enylacetaldehyd og natriumcyanborhydrid ,i absolutt etanol analogt eksempel 88 . Amorft hydroklorid. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-amino]-ethanol, phenylacetaldehyde and sodium cyanoborohydride, in absolute ethanol analogous to example 88 . Amorphous hydrochloride.

i Eksempel 174in Example 174

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl)-propyl]-isopropylamino]- etanolrhydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-isopropylamino]-ethanol hydrochloride

Fremstillet av 1 -(4-amlno-3,5-diklor-fenyl)-2-[N-[3-(4-fluor-fenyl )-propyl]-amino]-etanol, aceton, molekylarsikt 3 Å og natriumcyanborhydrid i absolutt metanol analogt eksempel 88 . Smeltepunkt for hydrokloridet: 80-85°C (dekomp.). Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-fluoro-phenyl)-propyl]-amino]-ethanol, acetone, molecular sieve 3 Å and sodium cyanoborohydride in absolute methanol analogous to example 88 . Melting point of the hydrochloride: 80-85°C (decomp.).

Eksempel 175 Example 175

1-(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-3-fenyl-propyl)-etylamino ]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenyl-propyl)-ethylamino]- ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-[N-(1-metyl-3-fenyl-propyl)-amino]-etanol,acetaldehyd, molekylarsikt 3 Å og natriumcyanborhydrid i absolutt etanol analogt eksempel 88 . Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(1-methyl-3-phenyl-propyl)-amino]-ethanol, acetaldehyde, molecular sieve 3 Å and sodium cyanoborohydride in absolute ethanol analogous example 88 .

Olje. Oil.

IR-spektrum (metylenklorid): NH2 3390 + 3490 cm<-1 >UV-spektrum (etanol):! /Imax. 245 nm (0,13) IR spectrum (methylene chloride): NH2 3390 + 3490 cm<-1 >UV spectrum (ethanol):! /Imax. 245 nm (0.13)

300 nm (0,03) 300 nm (0.03)

I IN

Eksempel 176 Example 176

1 -(4-dimetylamino-3,5-diklor-fenyl)-2-[N-(3-fenyl-1-metyl-propyl) - metylamino ] - etanol 1 -(4-dimethylamino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-1-methyl-propyl)-methylamino]-ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-1-metyl-propyl)-amino]-etanol, formaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88 . Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-1-methyl-propyl)-amino]-ethanol, formaldehyde and sodium cyanoborohydride in absolute ethanol analogous to example 88 . Oil.

Eksempel 177 Example 177

1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenyl-propyl)-benzylamino] -etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenyl-propyl)-benzylamino]-ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-(3-fenylpropyl) -amino]-etanol, benzaldehyd og natriumcyanborhydrid i absolutt etanol analogt eksempel 88 . Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-(3-phenylpropyl)-amino]-ethanol, benzaldehyde and sodium cyanoborohydride in absolute ethanol analogous to example 88 . Oil.

Eksempel 17 8 Example 17 8

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metylsulfinyl-fenyl)-propyl]- amino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methylsulfinyl-phenyl)-propyl]- amino]- ethanol

1,5 g (0,0039 mol) 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metylsulfenylfenyl)-propyl]-amino]-etanol og 639 mg (0,0078 mol) vannfri natriumacetat ble løst i 60 ml 50% eddiksyre. Til løsningen ble det under omrøring ved romtemperatur langsomt dryppet inn en løsning av 622 mg (0,0039 mol) brom i 3 ml 50% eddiksyre. Etter endt tilsetning ble den lysebrune løsning henstillet ved romtemperatur i en time og deretter slått over i vann. Under avkjøling med is, ble pH innstilt på 8,5 med konsentrert ammoniakk og fullstendig ekstrahert med metylenklorid. De samlede metylenklorid-ekstrakter ble tørket over natriumsulfat og inndampet til tørrhet under vakuum. Residuet ble krystallisert fra metanol/eter. Farveløse krystaller. Smeltepunkt : 127-129°C 1.5 g (0.0039 mol) 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methylsulfenylphenyl)-propyl]-amino]-ethanol and 639 mg (0.0078 mol) of anhydrous sodium acetate was dissolved in 60 ml of 50% acetic acid. A solution of 622 mg (0.0039 mol) bromine in 3 ml of 50% acetic acid was slowly added to the solution while stirring at room temperature. After the addition was complete, the light brown solution was allowed to stand at room temperature for one hour and then poured into water. While cooling with ice, the pH was adjusted to 8.5 with concentrated ammonia and fully extracted with methylene chloride. The combined methylene chloride extracts were dried over sodium sulfate and evaporated to dryness under vacuum. The residue was crystallized from methanol/ether. Colorless crystals. Melting point : 127-129°C

Eksempel 179 Example 179

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metylsulfenylfenyl)-propyl]- amino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methylsulfenylphenyl)-propyl]- amino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-acetofenon, selendioksyd, 3-(4-metylsulfenylfenyl)-propylamin og natriumcyanborhydrid analogt eksempel 5. Prepared from 4'-amino-3',5'-dichloro-acetophenone, selenium dioxide, 3-(4-methylsulfenylphenyl)-propylamine and sodium cyanoborohydride analogous to example 5.

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

Eksempel 180 Example 180

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metylsulfinylfenyl)-propyl]-metylamino]-etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methylsulfinylphenyl)-propyl]-methylamino]-ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-metyl-sulf inyl-f enyl) -propyl] -amino] -etanol , paraformaldehyd og natriumcyanborhydrid i metanol analogt eksempel 88 . Skum. Made from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-methyl-sulfinyl-phenyl)-propyl]-amino]-ethanol, paraformaldehyde and sodium cyanoborohydride in methanol analogous to example 88 . Foam.

Eksempel 181 Example 181

1-(4-amino-3,5-diklor-fenyl)-2-[N-[ 3-(4-metylsulfenyl-fenyl)-propyl] -metylamino] -etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[ 3-(4-methylsulfenyl-phenyl)-propyl]-methylamino]-ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[ N-[ 3-(4-metyl-sulf enyl-fenyl)-propyl] -amino] -etanol, paraformaldehyd og natriumcyanborhydrid' i metanol analogt eksempel 88 • Farveløs olje.<i>Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[ N-[ 3-(4-methyl-sulfenyl-phenyl)-propyl]-amino]-ethanol, paraformaldehyde and sodium cyanoborohydride' in methanol analogous example 88 • Colorless oil.<i>

Eksempel 182 Example 182

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl)-propyl]-n- propylåmino] - etanol ' -.'. 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-n-propylamino]-ethanol ' -.'.

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl ) -propyl ] -amino] -etanol , propionaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-amino]-ethanol, propionaldehyde and sodium cyanoborohydride in ethanol analogous to example 88 . Oil.

Eksempel 183 Example 183

- 1-(4-dimetylamino-3,5-diklor-fenyl)-2-metyl-2-[N-[3-(4-metoksy- fenyl)- propyl]- metylamino]- etanol - 1-(4-dimethylamino-3,5-dichloro-phenyl)-2-methyl-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-metyl-2-[N-[3-(4-metoksy-fenyl)-propyl]-amino]-etanol, paraformaldehyd og natriumcyanborhydrid i etanol ved pH 3-7,5 analogt eksempel 88 . Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-methyl-2-[N-[3-(4-methoxy-phenyl)-propyl]-amino]-ethanol, paraformaldehyde and sodium cyanoborohydride in ethanol at pH 3-7.5 analogous to example 88. Oil.

Eksempel 184 Example 184

1-(4-benzylamino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl)-propyl]-amino]-etanol 1-(4-benzylamino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-amino]-ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl)-propyl]-amino]-etanoi, benzaldehyd og natriumcyanborhydrid M etanol:. analogt eksempel 88 . Prepared from 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-amino]-ethane, benzaldehyde and sodium cyanoborohydride M ethanol:. analogous example 88 .

Smeltepunkt base: 85-95°C Melting point base: 85-95°C

Eksempel 185' Example 185'

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl)-propyl]-benzylamino]- etanol- hydroklorid 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-benzylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl) -propyl]-amino]-etanol, benzaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 • Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-amino]-ethanol, benzaldehyde and sodium cyanoborohydride in ethanol analogous to Example 88 •

Smeltepunkt for hydrokloridet: 110-114°C Melting point for the hydrochloride: 110-114°C

Eksempel 186 Example 186

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl)-propyl]-etylamino] - etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-ethylamino] - ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl) -propyl]-amino]-etanol, acetaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 • Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-amino]-ethanol, acetaldehyde and sodium cyanoborohydride in ethanol analogously to Example 88 • Oil.

Eksempel 187 Example 187

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klor-fenyl)-propyl]-metylamin N-[ 2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chloro-phenyl)-propyl]-methylamine

Fremstillet av N-[ 2-'\ 4-amino-3 ,5-diklor-f enyl) -etyl]'-3-(4-klor-fenyl)-propylamin, paraformaldehyd og natriumcyanbor-hydrid i metanol analogt eksempel 88 . Olje. Prepared from N-[2-'\4-amino-3,5-dichloro-phenyl)-ethyl]'-3-(4-chloro-phenyl)-propylamine, paraformaldehyde and sodium cyanoborohydride in methanol analogously to example 88. Oil.

Eksempel 188 Example 188

1 -(4-amino-3,5-diklor-fenyl)-2-[ N-[ 3-(4-klor-fenyl)-propyl]-i 1 -(4-amino-3,5-dichloro-phenyl)-2-[ N -[ 3-(4-chloro-phenyl)-propyl]-i

2- fenyletyl- amino]- etanol- hydroklorid 2- phenylethyl- amino]- ethanol- hydrochloride

Fremstillet av 1-(4Jamino-3,5-diklor-fenyl)-2-[ N-[ 3-(4-klor-fenyl)-propyl] -amino ]-etanol, fenylacetaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Prepared from 1-(4Jamino-3,5-dichloro-phenyl)-2-[ N-[ 3-(4-chloro-phenyl)-propyl]-amino ]-ethanol, phenylacetaldehyde and sodium cyanoborohydride in ethanol analogous to example 88 .

Smeltepunkt for hydrokloridet: 103-109°C (dekomp.). Melting point of the hydrochloride: 103-109°C (decomp.).

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Eksempel 189 Example 189

1 - (4-amino-3 , 5-diklor-f enyl) -2 - L~N- [ 3 - (4-klor-fenyl) -propyl ] - metylamino]- etanol- hydroklorid 1 - (4-amino-3 , 5-dichloro-phenyl)-2 - L~N- [ 3 - (4-chloro-phenyl) -propyl ] - methylamino]- ethanol hydrochloride

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl) -propyl]-amino]-etanol, paraformaldehyd og natriumcyanborhydrid i etanol analogt eksempel 88 . Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-amino]-ethanol, paraformaldehyde and sodium cyanoborohydride in ethanol analogous to Example 88 .

Smeltepunkt for hydrokloridet: 85-100°C (dekomp.). Melting point of the hydrochloride: 85-100°C (decomp.).

Eksempel 190 Example 190

1-(3-klor-4-piperidino-fenyl)-2-[N-[3-(4-metoksy-fenyl)-propyl]- metylamino]- etanol- hydroklorid 1-(3-chloro-4-piperidino-phenyl)-2-[N-[3-(4-methoxy-phenyl)-propyl]- methylamino]- ethanol hydrochloride

Fremstillet av 3'-klor-4<1->piperidino-2-[N-[3-(4-metoksy-fenyl)-propyl]-metylamino]-acetofenon og natriumborhydrid i metanol/ vann analogt eksempel 1. Oljeaktig hydroklorid. Prepared from 3'-chloro-4<1->piperidino-2-[N-[3-(4-methoxy-phenyl)-propyl]-methylamino]-acetophenone and sodium borohydride in methanol/water analogous to example 1. Oily hydrochloride.

Eksempel 191 Example 191

1-(4-amino-3,5-diklor-fenyl)-2-[ N-[ 3-(3-metoksy-fenyl)-propyl]- amino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[ N-[ 3-(3-methoxy-phenyl)-propyl]-amino]- ethanol

Fremstillet av 4'-amino-3',5'-diklor-acetofenon, selendioksyd, 3-(3-metoksy-fenyl)-propylamin og natriumborhydrid analogt eksempel 5. Prepared from 4'-amino-3',5'-dichloro-acetophenone, selenium dioxide, 3-(3-methoxy-phenyl)-propylamine and sodium borohydride analogous to example 5.

Smeltepunkt: 124°C Melting point: 124°C

Eksempel 192 Example 192

1-(4-amino-3,5-diklor-fenyl)- 2-[ N-[ 3-(3-metoksy-fenyl)-propyl] - etylamino] - etanol 1-(4-amino-3,5-dichloro-phenyl)- 2-[ N-[ 3-(3-methoxy-phenyl)-propyl] - ethylamino] - ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[ N-[ 3-(3-metoksy-f enyl)-propyl] -amino]-etanol, acetaldehyd og natriumcyanborhydrid analogt eksempel 88 i metanol. Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[ N-[ 3-(3-methoxy-phenyl)-propyl]-amino]-ethanol, acetaldehyde and sodium cyanoborohydride analogously to Example 88 in methanol. Oil.

Eksempel 193 Example 193

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(3-metoksy-fenyl)-propyl]-metylamino ] - etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(3-methoxy-phenyl)-propyl]-methylamino ] - ethanol

Fremstillet av 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(3-metoksy-f enyl)-propyl]-amino]-etanol, paraformaldehyd og natriumcyanborhydrid i metanol analogt eksempel 88 . Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(3-methoxy-phenyl)-propyl]-amino]-ethanol, paraformaldehyde and sodium cyanoborohydride in methanol analogous example 88 . Oil.

Eksempel 194' Example 194'

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1 -(3,5-diklor-4-isopropylamino-fenyl)-2-[N-[3-(3-metoksy-fenyl)- propyl]- isopropylamino]- etanol 1 -(3,5-dichloro-4-isopropylamino-phenyl)-2-[N-[3-(3-methoxy-phenyl)-propyl]- isopropylamino]- ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(3-metoksy-fenyl)-propyl]-amino]-etanol, aceton og natriumcyanborhydrid i metanol analogt eksempel 88 . Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(3-methoxy-phenyl)-propyl]-amino]-ethanol, acetone and sodium cyanoborohydride in methanol analogous to example 88 . Oil.

Eksempel 195 Example 195

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klorfenyl)-propyl]-isopropylamino] - etanol! 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chlorophenyl)-propyl]-isopropylamino] - ethanol!

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor- Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-

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fenyl)-propyl]-amino]-etanol, aceton og natriumcyanborhydrid i etanol analogt eksempel 88 . Olje. phenyl)-propyl]-amino]-ethanol, acetone and sodium cyanoborohydride in ethanol analogous to example 88 . Oil.

Eksempel 196 Example 196

1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klorfenyl)-propyj]-allylamino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chlorophenyl)-propyl]-allylamino]- ethanol

Fremstillet av 1-(4-amino-3,5-diklor-fenyl)-2-[N-[3-(4-klor-fenyl) -propyl] -amino] -etanol, allylbromid og trietylamin analogt eksempel 13. Olje. Prepared from 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[3-(4-chloro-phenyl)-propyl]-amino]-ethanol, allyl bromide and triethylamine analogous to example 13. Oil .

Eksempel 197 Example 197

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-klorfenyl)-propyl] - allylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-chlorophenyl)-propyl]-allylamine

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-3-(4-klor-fenyl) -propylamin, allylbromid og trietylamin analogt eksempel 13. Olje." "■', Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-3-(4-chloro-phenyl)-propylamine, allyl bromide and triethylamine analogous to example 13. Oil." "■',

Eksempel 198 Example 198

N-[2-(4-amino-3,5-diklpr-fenyl)-1-metyl-etyl]-N-[4-(4-metoksy-fenyl ) - butyl ] - metylamin N-[2-(4-amino-3,5-dichlorophenyl)-1-methyl-ethyl]-N-[4-(4-methoxy-phenyl)-butyl]-methylamine

Fremstillet av 4<1->amino-3<1>,5<1->diklor-propiofenon, N-[4-(4-metoksy-fenyl)-butyl]-metylamin og natriumcyanborhydrid analogt eksempel 88 . joije. Prepared from 4<1->amino-3<1>,5<1->dichloro-propiophenone, N-[4-(4-methoxy-phenyl)-butyl]-methylamine and sodium cyanoborohydride analogous to example 88 . joey.

Eksempel 199 Example 199

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-metoksy-fenyl)-, 1- metyl- propyl]- etylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-methoxy-phenyl)-, 1- methyl-propyl]-ethylamine

Fremstillet av N- [ 2 - (/l-amino-3 , 5-diklor-f enyl) -etyl] -N- [ 3-(4-hydroksy-fenyl)-1-metyl-propyl)]-etylamin i tetrahydrofuran med natronlut og dimétylsulfat analogt eksempel 13. Prepared from N-[2-([l-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-hydroxy-phenyl)-1-methyl-propyl)]-ethylamine in tetrahydrofuran with caustic soda and dimethyl sulphate analogously to example 13.

i in

Rensingen ble foretatt over aluminiumoksyd (nøytral, aktivitetstrinn I) og med elueringsmiddelblandingen eter:petroleter = 1:1,5. Olje. The purification was carried out over aluminum oxide (neutral, activity level I) and with the eluent mixture ether:petroleum ether = 1:1.5. Oil.

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Eksempel 200 Example 200

N-[ 2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[1,1-dimetyl-3-(4-hydroksy- fenyl)- propyl]- metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[1,1-dimethyl-3-(4-hydroxy-phenyl)-propyl]- methylamine

Til en løsning av 3 g (0 ,0075 mol) 1 -(4-amino-3,5-diklor-fenyl)-2-[N-[ 1,1-dimetyl-3-(4-hydroksy-fenyl)-propyl] -metylamino]-etanol i 12 ml trifluoreddiksyre ble det under om-røring ved -10°C dråpevis tilsatt 1,8 ml(0,018 mol) pyridin-boran. Etter fjerning av kjølemediet antok reaksjonsløsningen romtemperatur i løpet av 30 minutter, hvorpå den ble oppvarmet på dampbad under omrøring i 6 0 minutter. Etter for-damping av trifluoréddiksyren i rotasjonsfordamper ved 50°C under vakuum, ble inndampingsresiduet tilsatt 40 ml 2 N natronlut og holdt i 30 minutter ved 120°C under omrøring. Reaksjonsblandingen ble etter avkjøling forsiktig surgjort med konsentrert saltsyre og deretter tilsatt konsentrert ammoniakk til basisk reaksjon og ekstrahert 2 x med 75 ml porsjoner eter. De oppnådde eter-ekstrakter ble vasket 2 ganger med 50 ml porsjoner vann, samlet og tørket med magnesiumsulfat og inndampet til tørrhet i vakuum på rotasjonsfordamper. Inndampingsresiduet ble underkastet en foreløpig rensing på kiselgel 60 (Macherey & Nagel 70-230 mesh, ASTM) med elueringsmidlet metylenklorid/metanol =2:1. Sluttrensingen ble foretatt på aluminiumoksyd (nøytral, aktivitetstrinn III). Som elueringsmiddel ble eter/n-heksan = 2:1 benyttet. Den oppnådde oljeaktige inndampingsrest krystalliserte etter kort tid. To a solution of 3 g (0.0075 mol) 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[ 1,1-dimethyl-3-(4-hydroxy-phenyl)- propyl]-methylamino]-ethanol in 12 ml of trifluoroacetic acid, 1.8 ml (0.018 mol) of pyridine-borane was added dropwise while stirring at -10°C. After removal of the coolant, the reaction solution assumed room temperature within 30 minutes, after which it was heated on a steam bath with stirring for 60 minutes. After evaporation of the trifluoroacetic acid in a rotary evaporator at 50°C under vacuum, the evaporation residue was added to 40 ml of 2 N caustic soda and kept for 30 minutes at 120°C with stirring. After cooling, the reaction mixture was carefully acidified with concentrated hydrochloric acid and then concentrated ammonia was added for a basic reaction and extracted twice with 75 ml portions of ether. The ether extracts obtained were washed twice with 50 ml portions of water, collected and dried with magnesium sulfate and evaporated to dryness in vacuo on a rotary evaporator. The evaporation residue was subjected to a preliminary purification on silica gel 60 (Macherey & Nagel 70-230 mesh, ASTM) with the eluent methylene chloride/methanol =2:1. The final cleaning was carried out on aluminum oxide (neutral, activity level III). Ether/n-hexane = 2:1 was used as eluent. The obtained oily evaporation residue crystallized after a short time.

Smeltepunkt : 122-124°C Melting point: 122-124°C

Eksempel 201 Example 201

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-[3-(4-hydroksy-fenyl)- 1- metyl- propyl]- etylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-[3-(4-hydroxy-phenyl)-1- methyl-propyl]-ethylamine

Fremstillet av 4'-amino-2-brom-3',5'-diklor-acetofenon,N-[3-(4-hydroksy-fenyl)-1-metyl-propyl]-etylamin, natriumkarbonat i vandig tetrahydrofuran og påfølgende reaksjon av det oppnådde reaksjonsprodukt med pyridin-boran i trifluoreddiksyre analogt eksempel ~200 Rensingen ble foretatt på aluminiumoksyd (nøytral, aktivitetstrinn III). Som eluent ble'benyttet eter/petroleter = 2:1. Olje. Prepared from 4'-amino-2-bromo-3',5'-dichloro-acetophenone, N-[3-(4-hydroxy-phenyl)-1-methyl-propyl]-ethylamine, sodium carbonate in aqueous tetrahydrofuran and subsequent reaction of the obtained reaction product with pyridine-borane in trifluoroacetic acid analogous to example ~200 The purification was carried out on aluminum oxide (neutral, activity level III). Ether/petroleum ether = 2:1 was used as eluent. Oil.

Eksempel 202 Example 202

1 -(4-amino-3,5-diklor-fenyl)-2-[N-[1, 1-dimetyl-3-(4-hydroksy-fenyl)- propyl]- metylamino]- etanol 1 -(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-hydroxy-phenyl)-propyl]- methylamino]- ethanol

Fremstillet av 4 '-ami'no-2-brom-3 1 , 5 '-diklor-acetof enon ,N-[ 1 ,1 - dimetyl-3-(4-hydroksy-fenyl)-propyl]-metylamin, natriumkarbonat og påfølgende reduksjon med natriumborhydrid i vandig tetra- Prepared from 4 '-amino-2-bromo-3 1 , 5 '-dichloro-acetophenone , N-[ 1 ,1-dimethyl-3-(4-hydroxy-phenyl)-propyl]-methylamine, sodium carbonate and subsequent reduction with sodium borohydride in aqueous tetra-

i in

hydrofuran analogt eksempel 3. De to rensetrinn ble foretatt på kiselgel 60 (Macherey & Nagel, 70-230 mesh, ASTM). Som elueringsmiddel ble éter/tetrahydrofuran = 3:1 og metylenklorid/metanol/kons.ammoniakk = 30:1:03 benyttet. hydrofuran analogous to example 3. The two purification steps were carried out on silica gel 60 (Macherey & Nagel, 70-230 mesh, ASTM). Ether/tetrahydrofuran = 3:1 and methylene chloride/methanol/concentrated ammonia = 30:1:03 were used as eluents.

Smeltepunkt : 155-158°C Melting point: 155-158°C

Eksempel 203 Example 203

1-(4-amino-3,5-diklor-fenyl)-2-[N-[1,1-dimetyl-3-(4-hydroksy-fenyl)- propyl]- amino]- etanol 1-(4-amino-3,5-dichloro-phenyl)-2-[N-[1,1-dimethyl-3-(4-hydroxy-phenyl)-propyl]- amino]- ethanol

Fremstillet av 4'-amino-2-brom-3',5'-diklor-acetofenon, 1,1-dimetyl-3-(4-hydroksy-fenyl)-propylamin, natriumkarbonat og reduksjon med natriumborhydrid i vandig tetrahydrofuran analogt eksempel 3. Rensingen ble foretatt på kiselgel 60 (Macherey & Nagel, 70-230 mesh, ASTM). Som elueringsmiddel ble en blanding av metylenklorid/metanol/kons. ammoniakk = 25:1:0,2 Prepared from 4'-amino-2-bromo-3',5'-dichloro-acetophenone, 1,1-dimethyl-3-(4-hydroxy-phenyl)-propylamine, sodium carbonate and reduction with sodium borohydride in aqueous tetrahydrofuran analogous to example 3 The purification was carried out on silica gel 60 (Macherey & Nagel, 70-230 mesh, ASTM). As eluent, a mixture of methylene chloride/methanol/conc. ammonia = 25:1:0.2

benyttet. used.

Smeltepunkt: 142-144°c' Melting point: 142-144°c'

Eksempel204 Example 204

N-[3-(4-klorfenyl)-propyl]-N-[2-(3,5-diklor-4-isopropylamino-fenyl)-etylJ-isopropylamin N-[3-(4-chlorophenyl)-propyl]-N-[2-(3,5-dichloro-4-isopropylamino-phenyl)-ethyl J-isopropylamine

Fremstillet av N-[2-(4-amino-3,5-diklorfenyl)-etyl]-[3-(4-klor-fenyl )-propyl] amin, aceton og natriumcyanborhydrid analogt eksempel 88 . Olje. i Prepared from N-[2-(4-amino-3,5-dichlorophenyl)-ethyl]-[3-(4-chloro-phenyl)-propyl] amine, acetone and sodium cyanoborohydride analogous to example 88 . Oil. in

Eksempel 205 Example 205

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-fenyl-1-metyl-propyl)- metylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenyl-1-methyl-propyl)- methylamine

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-fenyl-1-metyl-propyl)-amin, paraformaldehyd og natriumcyanborhydrid analogt eksempel 88. Oljeaktig hydroklorid. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenyl-1-methyl-propyl)-amine, paraformaldehyde and sodium cyanoborohydride analogous to Example 88. Oily hydrochloride.

Eksempel 206 Example 206

N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N-(3-fenyl-1-metyl-propyl)- n- propylamin N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenyl-1-methyl-propyl)-n-propylamine

Fremstillet av N-[2-(4-amino-3,5-diklor-fenyl)-etyl]-N- (3-fenyl-1-metyl-propyl)-amin, propionaldehyd og natriumcyanborhydrid analogt eksempel qq . Oljeaktig hydroklorid. Prepared from N-[2-(4-amino-3,5-dichloro-phenyl)-ethyl]-N-(3-phenyl-1-methyl-propyl)-amine, propionaldehyde and sodium cyanoborohydride analogous to example qq . Oily hydrochloride.

Claims

Analogifremgangsmåte for fremstilling av farmasøytisk aktiveAnalogy method for the production of pharmaceutical actives

fenylalkylaminer med; den generelle formelphenylalkylamines with; the general formula

hvorwhere

er en hydroksygruppe, en aminogruppe som eventuelt er substituis a hydroxy group, an amino group which is optionally substituted

ert med en alkanoylgfuppe med 1-3 karbonatomer eller en alkoksypea with an alkanoyl group of 1-3 carbon atoms or an alkoxy

karbonylgruppe med tilsammen 2-4 karbonatomer, en alkylamino- ellecarbonyl group with a total of 2-4 carbon atoms, an alkylamino group

dialkylaminogruppe,dialkylamino group,

R2 og R^, som kan være like eller forskjellige, er halogenatomer,R 2 and R 3 , which may be the same or different, are halogen atoms,

trifluormetyl-, cyanf eller nitro-grupper eller en av restene R2 trifluoromethyl, cyano or nitro groups or one of the radicals R2

og R, også utgjør et;hydrogenatom, R^ er et hydrogenatom eller en alkylgruppe med 1-3 karbonatomer,and R, also constitutes a hydrogen atom, R^ is a hydrogen atom or an alkyl group with 1-3 carbon atoms,

Rr er et hydrogenatom, en rettkjedet eller forgrenet alkylgruppeRr is a hydrogen atom, a straight-chain or branched alkyl group

med 1-4 karbonatomer, en cykloalkylgruppe med 3-6 karbonatomer,with 1-4 carbon atoms, a cycloalkyl group with 3-6 carbon atoms,

en alkylengruppe med 2-5 karbonatomer eller en fenylalkylgruppean alkylene group with 2-5 carbon atoms or a phenylalkyl group

med 7-10 karbonatomer,with 7-10 carbon atoms,

A er metylen-, etylen- eller hydroksymetylen-gruppen ogA is the methylene, ethylene or hydroxymethylene group and

B er en gruppe med formelB is a group with formula

eller or

hvor i 6 er et hydrogen- el■ler halogen-atom, en hydroksygruppe, where in 6 is a hydrogen or halogen atom, a hydroxy group,

alkoksygruppe med 1-3 karbonatomer som eventuelt er substituert med en fenylgruppe, en alkylsulfenyl- eller alkylsulfinyl-gruppe som begge kan ha 1-3 karbonatomer,alkoxy group with 1-3 carbon atoms which is optionally substituted with a phenyl group, an alkylsulfenyl or alkylsulfinyl group which can both have 1-3 carbon atoms,

R7 er et hydrogenatom, en hydroksygruppe eller en alkoksygruppe med 1-3 karbonatomer eller Rg og' R^ tilsammen utgjør metylendioksygruppen,R7 is a hydrogen atom, a hydroxy group or an alkoxy group with 1-3 carbon atoms or Rg and' R^ together make up the methylenedioxy group,

Rg er et hydrogenatom eller alkylgruppe med 1-3 karbonatomer,Rg is a hydrogen atom or alkyl group with 1-3 carbon atoms,

D er et oksygen- eller svovelatom, en sulfinyl- eller sulfonyl-gruppe,D is an oxygen or sulfur atom, a sulfinyl or sulfonyl group,

n er tallet 1 eller 2 ogn is the number 1 or 2 and

E er en rettkjedet alkylengruppe med 3-5 karbonatomer som eventuelt er substituert med en eller to alkylgrupper som hver har 1-3 karbonatomer, og deres diastereomere racemater samt deres syreaddisjonssalter, karakterisert ved at a) en forbindelse med den generelle formelE is a straight-chain alkylene group with 3-5 carbon atoms which is optionally substituted with one or two alkyl groups each having 1-3 carbon atoms, and their diastereomeric racemates as well as their acid addition salts, characterized in that a) a compound with the general formula

hvor R^ til R^ og R,- er som tidligere definert,where R^ to R^ and R,- are as previously defined,

B, er en gruppe med formelenB, is a group with the formula

X(CH2)k-<^^J ogX(CH2)k-<^^J and

X er en gruppe med formelenX is a group with the formula

eller B. har de for B innledningsvis angitte betydninger, ogor B. have the meanings given for B at the beginning, and

X er en gruppe med formelen -A"'-CO-,X is a group of the formula -A"'-CO-,

hvor R4, Rg og R^ er som tidligere definert, A"' er en metylen- eller etylengruppe,where R4, Rg and R^ are as previously defined, A"' is a methylene or ethylene group,

k er tallet 1, 2 eller 3,k is the number 1, 2 or 3,

acyl betyr en organisk acylgruppe, og Z betyr en reduktivt avspaltbar gruppe, . Iacyl means an organic acyl group, and Z means a reductively cleavable group, . IN

reduseres eller j b) en karbonylforbindelse, som eventuelt dannes i reaksjonsblandingen, med den generelle formelis reduced or j b) a carbonyl compound, which is optionally formed in the reaction mixture, with the general formula

hvor K sammen med et nabohydrogen i alkyldelen av resten L, står for et oksygenatom,where K, together with a neighboring hydrogen in the alkyl part of the residue L, stands for an oxygen atom,

L har de samme betydninger som er definert for B eller, med unntak av hydrogenatomet, står for R,- eller en gruppe med formelL has the same meanings as defined for B or, with the exception of the hydrogen atom, represents R,- or a group of formula

hvor R^ til R4 er som tidligere definert og A' betyr karbonyl-, metylen- eller etylen-gruppen eller deres aldehydhydrater, omsettes med et amin med den generelle formelwhere R^ to R4 are as previously defined and A' means the carbonyl, methylene or ethylene group or their aldehyde hydrates, is reacted with an amine of the general formula

hvorwhere

M og Q som er forskjellige, har de betydninger som er nevnt for B og R^ eller en av dem utgjør gruppenM and Q which are different have the meanings mentioned for B and R^ or one of them constitutes the group

iin

hvor R^ til R^ og A er som■tidligere definert, og et reduksjonsmiddel, eller c) en eller flere beskyttelsesgrupper fra en forbindelse med den generelle formelwhere R^ to R^ and A are as previously defined, and a reducing agent, or c) one or more protecting groups from a compound of the general formula

hvorwhere

R2, R^ og R^ er som tidligere definert,R2, R^ and R^ are as previously defined,

R1<1> har den tidligere angitte betydning av R1 eller utgjør en beskyttet hydroksy- eller amino-gruppe,R1<1> has the previously stated meaning of R1 or constitutes a protected hydroxy or amino group,

A" har den tidligere angitte betydning av A eller utgjør en beskyttet hydroksymetylengruppe,A" has the previously stated meaning of A or constitutes a protected hydroxymethylene group,

R5' har den tidligere angitte betydning av R,- eller utgjør en beskyttelsesrest for en aminogruppe, og B' har den tidligere angitte betydning av B eller utgjør en gruppe med formel R5' has the previously indicated meaning of R,- or constitutes a protective residue for an amino group, and B' has the previously indicated meaning of B or constitutes a group of formula

elleror

hvorwhere

Ro0, D, E og n er som tidligere definert ogRo0, D, E and n are as previously defined and

R ' og R_', som kan være like eller forskjellige, har de tidligere nevnte betydninger av Rfi og R7 eller utgjør beskyttede hydroksygrupper, idet minst en av restene R1', A", R5<1> og/eller B' må utgjøre eller inneholde en av de ovenfor nevnte beskyttelsesgrupperavspaltes; eller d) en forbindelse med den generelle formelR' and R_', which may be the same or different, have the previously mentioned meanings of Rfi and R7 or constitute protected hydroxy groups, whereby at least one of the residues R1', A", R5<1> and/or B' must constitute or contain one of the above-mentioned protecting groups, or d) a compound of the general formula

iin

hvorwhere

, R^ til R,-, A og B er som tidligere definert og Hal utgjør et klor-, brom- eller jod-atom, dehalogeneres; eller e) en forbindelse med den generelle formel, R^ to R,-, A and B are as previously defined and Hal constitutes a chlorine, bromine or iodine atom, is dehalogenated; or e) a compound of the general formula

]]

hvor R^ til R^ og A er som.tidligere definert,where R^ to R^ and A are as previously defined,

R,-" har den tidligere nevnte betydning av R,, eller står for et hydrogenatom ogR,-" has the previously mentioned meaning of R,, or stands for a hydrogen atom and

B" har den tidligere nevnte betydning av B, idet, dersom R^" ikke utgjør hydrogen, minst en av restene R, eller R_, må ut-gjøre en hydroksygruppe eller R^ utgjøre en aminogruppe som eventuelt er substituert med en alkylgruppe med 1-3 karbonatomer, hvor alkylgruppen dessuten kan være substituert med en fenylrest, alkyleres; eller f) for fremstilling av en forbindelse med den generelle formel I hvor R^ utgjør en aminogruppe som er substituert med en alkanoylgruppe med 1-3| karbonatomer eller en alkoksykarbonylgruppe med tilsammen 2-4 karbonatomer og R^ ikke er hydrogen, ved at en forbindelse med den generelle formelB" has the previously mentioned meaning of B, in that, if R" does not constitute hydrogen, at least one of the residues R, or R_, must constitute a hydroxy group or R^ must constitute an amino group which is optionally substituted with an alkyl group with 1 -3 carbon atoms, where the alkyl group may also be substituted with a phenyl residue, are alkylated; or f) for the preparation of a compound of the general formula I where R 1 constitutes an amino group which is substituted by an alkanoyl group of 1-3| carbon atoms or an alkoxycarbonyl group with a total of 2-4 carbon atoms and R^ is not hydrogen, in that a compound with the general formula

iin

hvorwhere

R2 til R^, A og B er som tidligere definert, acyleres med en forbindelse med den generelle formelR 2 to R 1 , A and B are, as previously defined, acylated with a compound of the general formula

hvor R^ q utgjør et hydrogenatom, en metyl- eller etyl-gruppe eller en alkoksygruppe med 1-3 karbonatomer ogwhere R^ q constitutes a hydrogen atom, a methyl or ethyl group or an alkoxy group with 1-3 carbon atoms and

Y er en nukleofil substituerbar gruppe, eller g) for fremstilling av en forbindelse med den generelle formel I hvor D utgjør en sulfinyl- eller sulfonyl-gruppe ved at en forbindelse med den generelle formelY is a nucleophilic substitutable group, or g) for the preparation of a compound of the general formula I where D constitutes a sulfinyl or sulfonyl group in that a compound of the general formula

nvor R. I til Ro0, A og n er som tidligere definert og m står for tallet 0 eller 1, oksyderes, eller h) for fremstilling av en forbindelse med den generelle formel I, hvor D utgjør et oksygen- eller svovel-atom og R^ ikke står for hydrogen, ved at en forbindelse med den generelle formel hvorwhen R. I to Ro0, A and n are as previously defined and m stands for the number 0 or 1, is oxidized, or h) for the preparation of a compound of the general formula I, where D constitutes an oxygen or sulfur atom and R^ does not stand for hydrogen, in that a compound with the general formula where

til R^, Rg og n er som tidligere definert, V er en nukleofil utskiftbar gruppe og A "' er metylen- eller etylen-gruppen, omsettes med en forbindelse med den generelle formelto R^, Rg and n are as previously defined, V is a nucleophilic replaceable group and A"' is the methylene or ethylene group, is reacted with a compound of the general formula

hvorwhere

Rg og <R>^ er som tidligere angitt og D' er et oksygen- eller svovel-atom, eller deres alkali- eller jordalkaliesalter,Rg and <R>^ are as previously indicated and D' is an oxygen or sulfur atom, or their alkali or alkaline earth salts,

og den oppnådde forbindelse med den generelle formel I, som inneholder ett, to eller tre optisk aktive karbonatomer, spaltes eventuelt i* sine diastereomere racemater og/eller den oppnådde forbindelse med den generelle formel I overføres i sine fysiologisk akseptable syreaddisjons-salter med uorganiske eller organiske syrer.and the obtained compound of the general formula I, which contains one, two or three optically active carbon atoms, is optionally cleaved into* its diastereomeric racemates and/or the obtained compound of the general formula I is transferred into its physiologically acceptable acid addition salts with inorganic or organic acids.