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 PDFInfo
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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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- 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
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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
- C07D213/64—One oxygen atom attached in position 2 or 6
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- 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
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- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
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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
- C07D213/65—One oxygen atom attached in position 3 or 5
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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
- 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
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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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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
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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.
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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
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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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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
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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)
- 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
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 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK428582A DK428582A (da) | 1983-03-29 |
| DK156718B true DK156718B (da) | 1989-09-25 |
| DK156718C DK156718C (da) | 1990-03-05 |
Family
ID=6142812
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK428582A DK156718C (da) | 1981-09-28 | 1982-09-27 | Analogifremgangsmaade til fremstilling af substituerede 2-phenyl-2-(pyridyloxy, pyridylamino eller pyridylthio)-ethylaminer eller syreadditionssalte deraf |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US4666910A (da) |
| EP (1) | EP0075752B1 (da) |
| JP (1) | JPS5869865A (da) |
| KR (1) | KR880002705B1 (da) |
| AR (1) | AR231534A1 (da) |
| AT (1) | ATE18551T1 (da) |
| AU (1) | AU550614B2 (da) |
| CA (1) | CA1171086A (da) |
| DE (2) | DE3138550A1 (da) |
| DK (1) | DK156718C (da) |
| ES (1) | ES515972A0 (da) |
| FI (1) | FI78074C (da) |
| GB (1) | GB2106902B (da) |
| GR (1) | GR77657B (da) |
| IE (1) | IE53959B1 (da) |
| IL (1) | IL66870A (da) |
| NO (1) | NO159999C (da) |
| NZ (1) | NZ202015A (da) |
| PH (1) | PH23219A (da) |
| PT (1) | PT75611B (da) |
| ZA (1) | ZA827055B (da) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8320699D0 (en) * | 1983-08-01 | 1983-09-01 | Wellcome Found | Ethylenediamines |
| GB0004151D0 (en) * | 2000-02-23 | 2000-04-12 | Astrazeneca Uk Ltd | Novel use |
| 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 |
| 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 |
| SE0102639D0 (sv) * | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
| SE0102640D0 (sv) | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
| SE0102641D0 (sv) * | 2001-07-31 | 2001-07-31 | Astrazeneca Ab | Novel compounds |
| 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 |
| ES2338881T3 (es) * | 2003-10-09 | 2010-05-13 | Millennium Pharmaceuticals, Inc. | Benzamidas sustituidas con tioeter como inhibidores del factor xa. |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2734845A (en) * | 1956-02-14 | Aqueous suspension of procaine penicil- | ||
| US2734846A (en) * | 1956-02-14 | Aqueous suspension of procaine penicil- | ||
| FR1511398A (fr) * | 1966-02-16 | 1968-01-26 | Takeda Chemical Industries Ltd | Procédé de préparation de nouveaux dérivés de picoline |
| BE790592A (da) * | 1971-10-28 | 1973-04-26 | Oreal | |
| US4011324A (en) * | 1976-01-20 | 1977-03-08 | Pfizer Inc. | Esters and amides of pyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylic acids as antiulcer agents |
| JPS53141271A (en) * | 1977-05-13 | 1978-12-08 | Yamanouchi Pharmaceut Co Ltd | Heterocyclic compounds and process for their preparation |
-
1981
- 1981-09-28 DE DE19813138550 patent/DE3138550A1/de not_active Withdrawn
-
1982
- 1982-09-06 EP EP82108196A patent/EP0075752B1/de not_active Expired
- 1982-09-06 AT AT82108196T patent/ATE18551T1/de not_active IP Right Cessation
- 1982-09-06 DE DE8282108196T patent/DE3269839D1/de not_active Expired
- 1982-09-22 FI FI823246A patent/FI78074C/fi not_active IP Right Cessation
- 1982-09-24 IL IL66870A patent/IL66870A/xx unknown
- 1982-09-24 AR AR290759A patent/AR231534A1/es active
- 1982-09-27 ZA ZA827055A patent/ZA827055B/xx unknown
- 1982-09-27 PT PT75611A patent/PT75611B/pt not_active IP Right Cessation
- 1982-09-27 GB GB08227449A patent/GB2106902B/en not_active Expired
- 1982-09-27 CA CA000412268A patent/CA1171086A/en not_active Expired
- 1982-09-27 ES ES515972A patent/ES515972A0/es active Granted
- 1982-09-27 IE IE2330/82A patent/IE53959B1/en not_active IP Right Cessation
- 1982-09-27 NZ NZ202015A patent/NZ202015A/en unknown
- 1982-09-27 JP JP57168221A patent/JPS5869865A/ja active Granted
- 1982-09-27 DK DK428582A patent/DK156718C/da not_active IP Right Cessation
- 1982-09-27 AU AU88738/82A patent/AU550614B2/en not_active Ceased
- 1982-09-27 KR KR8204342A patent/KR880002705B1/ko active
- 1982-09-27 NO NO823253A patent/NO159999C/no unknown
- 1982-09-28 GR GR69383A patent/GR77657B/el unknown
-
1984
- 1984-08-28 US US06/645,007 patent/US4666910A/en not_active Expired - Fee Related
-
1985
- 1985-03-07 PH PH31952A patent/PH23219A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |