DK156718B - Analogifremgangsmaade til fremstilling af substituerede 2-phenyl-2-(pyridyloxy, pyridylamino eller pyridylthio)-ethylaminer eller syreadditionssalte deraf - Google Patents

Analogifremgangsmaade til fremstilling af substituerede 2-phenyl-2-(pyridyloxy, pyridylamino eller pyridylthio)-ethylaminer eller syreadditionssalte deraf Download PDF

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DK156718B
DK156718B DK428582A DK428582A DK156718B DK 156718 B DK156718 B DK 156718B DK 428582 A DK428582 A DK 428582A DK 428582 A DK428582 A DK 428582A DK 156718 B DK156718 B DK 156718B
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pyridyl
ethylamine
dimethyl
acid
bromophenyl
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DK428582A
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DK156718C (da
DK428582A (da
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Claus Schneider
Gerhard Walther
Karl-Heinz Weber
Wolf Dietrich Bechtel
Karin Boeke-Kuhn
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Boehringer Ingelheim Kg
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

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Description

DK 156718 B
Opfindelsen angâr en analogifremgangsmàde til fremstilling af hidtil ukendte substituerede
2-phenyl-2-(pyridyloxy, pyridylamino eller pyridylthio)-ethylaminer med den almene formel I
5 10 /
R2 ? R
r t /r4 ch - ch, - ir 15 hvor R-j og R2, der kan være ens eller forskellige, er hydro-gen, et halogenatom, methyl, methoxy, amino eller nitro, R3 er hydrogen, halogen eller methyl, 20 R4 og Rg, der kan være ens eller forskellige, er hydrogen eller en alkylgruppe med 1-2 C-atomer, eller de danner sammen med nitrogenatomet en pyrrolidin- eller morpholinring, og X er 0, NH eller S, 25 eller fysiologisk acceptable syreadditionssalte deraf, hvilken fremgangsmâde er ejendommelig ved, at
a) en phenylethylamin med den almene formel II
R2 Y R
-£h - CH, - 4 30 Rl-PJ \R5 (II) hvor R^, R2, R4 og R^ har ovennævnte betydninger, og Y er et halogenatom eller en hydroxygruppe, eller et syre-22 additionssalt deraf, omsættes med et pyridinderi-
vat med den almene formel III
2
DK 156 718 B
0' R3 5 hvor har ovennævnte betydning, og Z er en hydroxy-, amino- eller mercaptogruppe f eller b) til fremstilling af en forbindelse med formlen I, hvor R^ og/eller R,- er en alkylgruppe med 1-2 C-atom-er, en forbindelse med den almene formel la 10 R, pr 15 ^2 ? R ' ^a)
- CH0 - N
«.-Çr hvor 20 R^, R^, R^ og X har de for formel I angivne betydninger, og R^' og Rg' hver er hydrogen eller en alkylgruppe med 1- 2 C-atomer med den betingelse, at mindst den ene af grupperne er hydrogen, 25 alkyleres pâ i og for sig kendt mâde, og at en dannet forbindelse med formlen I, om onsket, overfores i et fysiologisk acceptabelt syreadditionssalt.
Med udgangsforbindelser med den almene formel IX, hvor Y er en hydroxygruppe, foregâr kondensationen med en forbindelse med den almene formel III i surt medium ved forh0jet temperatur. Til denne omsætning kommer stær- ke uorganiske eller organiske syrer, f.eks. koncentrere- de mineralsyrer, sâsom saltsyre, hydrogenbromidsyre, svovlsyre, polyphosphorsyre, endvidere eddikesyreanhy-35 drid, phosphorpentoxid eller trifluoreddikesyre i be-tragtning.
DK 156718B
3
Phenylethylaminer med den almene formel II, hvor Y er et halogenatom, bliver fortrinsvis omsat med pyridin-derivatet med den almene formel III under anvendelse af et basisk stof og fortrinsvis under faseomlejrings-betin-gelser (dvs. under tilsætning af én eller flere langkæde-5 de tertiære aminer, sâsom et benzyltributylammoniumhalo-genid eller et tetrabutylammoniumhalogenid eller under tilsætning af benzyltriphenylphosphoniumchlorid).
Som basiske stoffer kommer uorganiske baser, sâsom alkalimetal- eller jordalkalimetalhydroxider eller -car-10 bonater, organiske baser, sâsom pyridin, piperidin, tertiaire aminer eller ogsâ alkalimetalalkoholater, i be-tragtning.
Ved fremgangsmâden b) kan alkyleringen for eksem-pel foregâ ved oms&tning med et dialkylsulfat eller et 15 alkylhalogenid.
Ved ovennævnte fremgangsmâde kan for eksempel f0l-gende slutprodukter vindes, eventuelt i form af deres syreadditionssalte: 2-Phenyl-2-(pyridyl-(3)-oxy)-N,N-dimethyl-ethylamin, 20 2-phenyl-2-(pyridyl-(2)-oxy)-N,N-dimethyl-ethylamin, 2- (p-bromphenyl) -2- (pyridyl- (2) -oxy) -N,N-dimethyl-ethyl- amin, 25 2-(p-bromphenyl)-2-(pyridyl-(3)-oxy)-N,N-dimethyl-ethyl-amin 2-(p-bromphenyl)-2-(2-chlor-pyridyl-(3)-oxy)-N,N-di-30 methyl-ethylamin, 2-(p-bromphenyl)^2-(5-chlor-pyridyl-(2)-oxy)-N,N-di-methyl-ethylamin, 35 2-(p-bromphenyl)-2-(6-chlor-pyridyl-(2)-oxy)-N,N-di- methyl-ethylamin,
DK 156718 B
4 2- (p-brompheny 11 -2- (pyridyl-(4)-oxy) -N,N-dimethyl-ethyl-amin, 2·=· ( p-chlorphenyl ) -2- (pyridyl- (3)-oxy) -N, N-dimethyl-ethy 1- amin, 5 2-(m,p-dichlorphenyl)-2-(pyridyl-(3)-oxy)-N,N-dimethyl-ethylamin, ^ 2-phenyl-2-(pyridyl-(2)-amino)-N,N-dimethy1-ethylamin, 2-phenyl-2-(pyridyl-(3)-amino)-N,N-dimethy1-ethylamin, 2- (p-bromphenyl) -2- (pyridyl- (2) -amino) -N-methyl-ethyl-15 amin, 2-(p-bromphenyl)-2-(pyridyl-(2)-amino)-Ν,Ν-dimethyl-ethylamin, 2-(p-bromphenyl)-2-(pyridyl-(3)-amino)-N,N-dimethyl-20 ethylamin, 2-phenyl-2-(4-methyl-pyridyl-(2)-amino)-N,N-dimethy1-ethylamin, 25 2-(p-bromphenyl)-2-(5-methyl-pyridyl-(2)-amino)-N,N- dimethyl-ethylamin, 2-(p-bromphenyl)-2-(6-methyl-pyridyl-(2)-amino)-N,N-dimethyl-ethylamin, 30 2-(4-p-bromphenyl)-2-(5-chlor-pyridyl-(2)-amino)-N,N-dimethy1-ethylamin, 2-(4-p-bromphenyl)-2-(pyridyl-(2)-thio)-N,N-dimethyl- 4 35 ethylamin,
DK 156718 B
5 2-(p-bromphenyl)-2-(pyridyl-(3)-oxy)-morpholino-ethyl-amin, 2- (p-bromphenyl) -2- (pyridyl- (3) -oxy) -pyrrolidino-ethyl-^ amin, 2- (p-bromphenyl) -2- (pyridyl-(2) -amino) -morpholino-ethyl-amin, 1q 2-(p-bromphenyl)-2-(pyridyl-(2)-amino)-pyrrolidino-ethylamin, 2-(p-methoxyphenyl)-2-(pyridyl-(3)-oxy)-N,N-dimethy1-ethylamin, 15 2- (p-tolyl) -2- (pyridyl- (3).-oxy) -N,N-diethyl-ethylamin, 2-(p-nitrophenyl)-2-(pyridyl-(2)-oxy)-N,N-dimethy1-ethylamin, 20 2-(4-aminophenyl)-2-(pyridyl-(2)-oxy)-NfN-dimethyl- ethylamin, 2- (m,p-dichlorphenyl) -2- (pyridyl- (3) -amino) -N,N-dimethyl·· ethylamin, 25 2-(m,p-dimethoxyphenyl)-2-(pyridyl-(3)-oxy)-N,N-dimethy 1-ethylamin.
Udgangsforbindelserne (II) og (III) er gængse 50 kemikalier, der er i handelen eller kan fremstilles ved aiment kendte fremgangsmâder.
Fremstillede forbindelser med den almene formel I kan, om onsket, ved sædvanlige metoder overfores i deres fysiologisk acceptable syreadditionssalte.
6
DK 156 718 B
Som syrer egner sig hertil bâde uorganiske syrer, sâsom hydrogenhalogenidsyrer, svovlsyre, phosphorsyre og aminosulfonsyre, og organiske syrer, sâsom myresyre, ed-dikesyre, propionsyre, mælkesyre, glycolsyre, gluconsyre, maleinsyre, ravsyre, vinsyre, benzoesyre, salicylsyre, 5 citronsyre, ascorbinsyre, p-toluensulfonsyre eller oxy-ethansulfonsyre.
De hidtil ukendte forbindelser med den almene formel I og deres syreadditionssalte er værdifulde farma-ceutica. De er godt virksomme ved de for antidepressiva 1Q specifikke biokemiske og farmakologiske f or s 0g sanordnin- ger. De har sâledes evnen til at hæmme den pâ mus med tetrabenaz in inducerede ptosis. ED^q er ned til storrelses-ordenen 1 mg/kg. Denne pr0ve tjener som standardpr0ve for antidepressive egenskaber (International Journal of 15 Neuropharmacology 8^, 73 (1969)).
Ogsâ ved pr0ven for reserpinantagonisme, en ophæ-velse af den af reserpin forârsagede hypotermiske effekt med et antidepressivt virksomt stof, har de omhandlede forbindelser vist overordentlig gunstig virkning. Det er 20 endvidere konstateret, at forbindelserne haeramer genop-tagelsen af serotonin og adrenalin i neuronerne.
I nedenstâende tabel er samlet en række farmakologiske undersogelsesresultater vedrorende de oven-nævnte aktiviteter. IC50-værdierne ved henholdsvis sero-25 tonin- og noradrenalin-hæmning angiver den mol-mængde af testforbindelsen, der er tilstrækkelig til at sænke optagelsen af nævnte biogene aminer med 50%.
30 35
DK 156718B
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DK 156718 B
De hidtil ukendte forbindelser er særligt værdi-fulde som f0lge af en fra de hidtil kendte antidepressi-va afvigende struktur. Med hensyn til virkning er de jævnbyrdige med eller bedre end kendte handelsprodukter, samtidigt med at toxiciteten er mindre.
5 Der skal navnlig fremhæves sâdanne forbindelser med den almene formel I, hvor er et bromatom i p-stil-ling, X er et oxygenatom eller en aminogruppe, R2 er hy-drogen, og og er methylgrupper. Særligt skal fremhæves f0lgende forbindelser: 30 2- (p-Bromphenyl) -2- (pyridyl- (3) -oxy) -N,N-dimetlhyl-ethyl- amin, 2-(p-bromphenyl-2-(pyridyl-(2)-amino)-N,N-dimethyl-ethylamin/ 2- (p-’-bromphenyl) -2-'(pyridyl·^- (3) -amino) -N,N-dimethyl-35 .ethylamin.
Fremgangsmâden'‘ifolge opfindelsen beskrives nærmere gennem folgende eksempler:
Eksempel 1 20 2^p-Bromphenyl'-2f '(3-pyridyloxy) -N,N^dimethyl^ethylamin-dihydrochlorid » 29,9 g 2^Chl'Dr-2^-p^bromphenyl’-N,N-dimethyl-ethyl-amin^hydrochlorid (0,1 mol), og 14,3 g 3-hydroxypyridin (0,15 mol) blev i 150 ml 25%'s natriumhydroxid©pl0sning 25 og 150 ml toluen sammen med 0,5 g benzyltriphenylphos-phoniumchlorid opvarmet 16 timer til kogning under til-bagesvaling. Efter afdestination af opl0sningsmidlet fra den organiske fase vandtes en inddampningsrest, der blev opl0st i alkohol. Med saltsyre dannedes dihydrochlo-30 ridet af titelforîbindelsen. Til rensning blev titelfor-bindelsen i cycloîaexan behandlet med aktivt kul og kisel-gur. Udbyttet af dihydrochlorid var 20 g (44% af det teor.), smp. 128-129°C (éthanol).
35
DK 156718 B
10
Eksempel 2 2-p-Bromphenyl-2-(2-pyridylamino)-N,N-dimethyl-ethyl-amin-dioxalat.
24/5 g 2-p-Bromphenyl-N/N-dimethylethanolamin (0,1 5 mol) og 11 g 2-aminopyridin (0,11 mol) blev i 50 ml me-thansulfonsyre opvarmet 30 minutter ved 60°C. Den endnu varme reaktionsblanding blev hældt pâ is, gjort alkalisk med ammoniak og ekstraheret med ethylacetat. Rensningen foregik s0jlechromatografisk over silicagel/methylenchlo-10 rid-ethylacetat-methanol. Ved tilsætning af alkoholisk oxalsyre dannedes det krystallinske dioxalat af titel-forbindelsen.
Udbyttet var 21 g (42% af det teor.), smp. 170- 171°C.
15 Ved den ovenfor beskrevne fremgangsmâde blev der fremstillet f01gende forbindelser med den almene formel I: __ pyri-
Nfp.elSl R2 «3 r4 r5 X&£: s»p.°C
20 * * ding 3 4-Br H H H CK^ NH 2 181 - 182 4 E H H CH3 CH3 0 2 161 - 162 5 H H H CH3 CH3 0 3 151 - 152 25 6 . H H H CH3 CH3 NH 2 129 - 130 7 H H H CH3 CH3 NH 3 123 - 125 8 4-Br H 2-Cl CH3 CH3 0 3 135 - 136 9 4-Br H 5-C1 CH3 CH3 0 2 234 - 235 10 4-Br H 6-Cl CH3 CH3 0 2 193 - 194 30 11 H H 4-CH3 CH3 CH3 NH 2 139 - 140 12 4-Br H 5-C1 CH3 CH3 NH 2 134 - 136 13 4-Br H 5-CH3 ' CH3 CH3 NH 2 103 - 104 14 4-Br H 6-CH3 CH3 CH3 NH 2 135 - 136 15 4-Br H H CH3 CH3 NH 3 144 - 145 35 16 4-Br * H H CHj ’ CHj 0 2 162 - 163 17 4-Br -HH CH3 CH3 S 2 190 - 191 (fortsættesi
DK 156718 B
11 empel Rx R2 R3 R, R5 X fJr_ Smp. °c nr,: bin- _ dinq __ 5 18 4-Br H H Morpholin 0 3 95 - 97 19 4-Br H H Morpholin NH 2 194 - 195 20 4-Br H H Fyrrolidin 0 3 152 - 153 21 4-Br H H Pyrrolidin NH 2 117 - 119 22 4-Br H H CH, CH, 0 4 112 (dek.) .
5 0 η ρβ - 129 10 23 4-C1 H H CH3 CH3 0 3 (dek-.) 24 3-Cl 4-Cl H CK3 CH3 O 3 175 - 176 25 4-0CH3 H H CH3 CH3 0 3 103 - 105 26 3-C1 4-Cl H CH3 CHj NH 3 152 - 153 27 3-0CH3 H H H H 0 3 222 - 223 15 28 4-CH3 H H CH3 CH3 0 3 ISO - 181 29 4-Br H 4-CH, CH, CH, NH 2 219 - 220 3 0 0
Kompos i tions éks empler 20 a) Dragéer: 1 Dragëekerne indeholdt:
Aktivt stof fremstillet ifolge opfindelsen 25,0 mg Mælkesukker 50,0 mg
Majsstivelse 22,0 mg 25 Gélatine 2,0 mg
Magnesiumstearat 1,0 mg 100,0 mg
Fremstilling:
Blandingen af det aktive stof med mælkesukker 30 og majsstivelse blev sammen med en 10%'s vandig gelatine-opl0sning granuleret gennem en sigte med en maskevidde pâ 1 mm, t0rret ved 40°C og igen drevet gennem en sigte.
Det herved vundne granulat blev blandet med magnesiumstearat og presset. De herved vundne kerner blev pâ sæd-35 vanlig mâde overtrukket med en kappe, der pâf0rtes ved hjælp af en vandig suspension af sukker, titandioxid, talkum 'og gummi arabicum. De færdige dragée blev poleret med bivoks, Dragêe^slutvægt: 200 mg.
DK 156718 B
12 b) Tabletter:
Aktivt stof fremstillet if0lge opfindelsen 10,0 mg Mælkesukker 40,0 mg
Majsstivelse 44,0 mg 5 Opl0selig stivelse 5,0 mg
Magnesiumstearat 1,0 mg 100,0 mg
Fremstilling:
Aktivt stof og magnesiumstearat blev granuleret 10 med en vandig opl0sning af den opl0selige stivelse, gra-nulatet blev t0rret og blandet grundigt med mælkesukker og majsstivelse. Blandingen blev derefter presset til tabletter med en vægt pâ 100 mg, og som hver indeholdt 10 mg aktivt : stof.
15 c) Suppositorier: 1 Suppositorie indeholdt:
Aktivt stof fremstillet ifolge opfindelsen 10,0 mg
Suppositoriemasse 1.690,0 mg 20 Fremstilling:
Det finpulveriserede stof blev ved hjælp af en ned-dypnings-homogenisator indr0rt i den smeltede og til 40°C afk0lede suppositoriemasse. Massen blev ved 35°C hældt i let forafk01ede forme.
25 d) . Ampuller (injektionsopl0sningeri ;
Sammensætning:
Aktivt stof fremstillet ifolge opfindelsen 5,0 vægtdele
Natriumpyrosulfit 1,0 vægtdele 30 Dinatriumsalt af ethylendiamin- tetraeddikesyre Q,5 vægtdele
Natriumchlorid 8,5 vægtdele
Dobbelt destillèret vand til 1000,0 vægtdele
Fremstilling: 35 Det aktive stof og hjælpestofferne blev opl0st i en tilstrækkelig mængde vand og ved hjælp af den n0d-vendige vandmængde bragt til den 0nskede koncentration.

Claims (1)

  1. 20 H-ÇT hvor R.], R2r R3 og X har de for formel I angivne betydninger, og 25 R4' og Rj.1 hver er hydrogen eller en alkylgruppe med 1-2 C-atomer med den betingelse, at mindst den ene af grupperne er hydrogen, alkyleres pâ i og for sig kendt mâde, og at en dannet forbindelse med formlen I, om onsket, 30 overfores 1 et fysiologisk acceptabelt syreadditionssalt. 35
DK428582A 1981-09-28 1982-09-27 Analogifremgangsmaade til fremstilling af substituerede 2-phenyl-2-(pyridyloxy, pyridylamino eller pyridylthio)-ethylaminer eller syreadditionssalte deraf DK156718C (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19813138550 DE3138550A1 (de) 1981-09-28 1981-09-28 Substituierte 2-phenyl-2-(pyridyloxy)-ethylamine und isostere verbindungen, verfahren zu ihrer herstellung und verwendung
DE3138550 1981-09-28

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GB8320699D0 (en) * 1983-08-01 1983-09-01 Wellcome Found Ethylenediamines
GB0004153D0 (en) * 2000-02-23 2000-04-12 Astrazeneca Uk Ltd Novel use
GB0004152D0 (en) 2000-02-23 2000-04-12 Astrazeneca Uk Ltd Novel compounds
GB0004151D0 (en) * 2000-02-23 2000-04-12 Astrazeneca Uk Ltd Novel use
AR035700A1 (es) * 2001-05-08 2004-06-23 Astrazeneca Ab Derivados de arilheteroalquilamina, composicion farmaceutica, usos de estos derivados para la fabricacion de medicamentos, metodos de tratamiento, y proceso para la preparacion de estos derivados
SE0102641D0 (sv) * 2001-07-31 2001-07-31 Astrazeneca Ab Novel compounds
SE0102639D0 (sv) * 2001-07-31 2001-07-31 Astrazeneca Ab Novel compounds
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US6800652B2 (en) 2002-08-16 2004-10-05 Pfizer Inc. Diaryl compounds
GB0219154D0 (en) * 2002-08-16 2002-09-25 Pfizer Ltd Diaryl compounds
SE0203304D0 (sv) * 2002-11-07 2002-11-07 Astrazeneca Ab Novel Coumpounds
CN1886398A (zh) * 2003-10-09 2006-12-27 米伦纽姆医药公司 作为Xa因子抑制剂的经硫醚取代的苯甲酰胺

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GR77657B (da) 1984-09-25
IL66870A0 (en) 1982-12-31
DK156718C (da) 1990-03-05
ES515972A0 (es) 1983-09-16
CA1171086A (en) 1984-07-17
FI78074C (fi) 1989-06-12
NZ202015A (en) 1985-11-08
FI78074B (fi) 1989-02-28
AU8873882A (en) 1983-04-14
AR231534A1 (es) 1984-12-28
DE3269839D1 (en) 1986-04-17
EP0075752A2 (de) 1983-04-06
PT75611B (de) 1985-12-09
EP0075752A3 (en) 1984-03-21
ES8308543A1 (es) 1983-09-16
AU550614B2 (en) 1986-03-27
NO159999B (no) 1988-11-21
GB2106902B (en) 1985-08-07
US4666910A (en) 1987-05-19
ZA827055B (en) 1984-05-30
IE822330L (en) 1983-03-28
NO823253L (no) 1983-03-29
JPS5869865A (ja) 1983-04-26
FI823246L (fi) 1983-03-29
KR840001555A (ko) 1984-05-07
FI823246A0 (fi) 1982-09-22
NO159999C (no) 1989-03-01
PT75611A (de) 1982-10-01
DK428582A (da) 1983-03-29
KR880002705B1 (ko) 1988-12-26
EP0075752B1 (de) 1986-03-12
IE53959B1 (en) 1989-04-26
PH23219A (en) 1989-06-06
GB2106902A (en) 1983-04-20
IL66870A (en) 1986-02-28
ATE18551T1 (de) 1986-03-15
JPH0316952B2 (da) 1991-03-06

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