DK164699B - Analogifremgangsmaade til fremstilling af terapeutisk aktive aminopropanolderivater og fysiologisk acceptable syreadditionssalte heraf - Google Patents

Analogifremgangsmaade til fremstilling af terapeutisk aktive aminopropanolderivater og fysiologisk acceptable syreadditionssalte heraf Download PDF

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DK164699B
DK164699B DK416082A DK416082A DK164699B DK 164699 B DK164699 B DK 164699B DK 416082 A DK416082 A DK 416082A DK 416082 A DK416082 A DK 416082A DK 164699 B DK164699 B DK 164699B
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hydroxy
propoxy
phenyl
propiophenone
atoms
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DK416082A (da
DK164699C (da
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Albrecht Franke
Josef Mueller
Helmut Lietz
Walter-Wielant Wiersdorff
Hans-Guenther Hege
Claus D Mueller
Josef Gries
Dieter Lenke
Gerda Von Philipsborn
Manfred Raschack
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Basf Ag
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
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    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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    • C07C45/73—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with hydrogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/72—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups
    • C07C45/74—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction of compounds containing >C = O groups with the same or other compounds containing >C = O groups combined with dehydration
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
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    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
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    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/835—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups having unsaturation outside an aromatic ring
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
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    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
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    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

DK 164699B
i
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte terapeutisk aktive aminopropanolderivater og fysiologisk acceptable salte heraf med den i kravets indledning angivne formel I.
5 Analogifremgangsmåden er ejendommelig ved det i kravets kendetegnende del angivne. De fremstillede forbindelser kan anvendes som antiarrhytmika.
I DE-OS 20 01 431 er beskrevet, at n-propylamino-, n-bu-10 tylamino-, see.-butylamino- og tert.-butylaminopropanol-derivater af 2-hydroxy-0-phenyl-propiophenon er anti-arrhytmisk virksomme. Dette gælder specielt for 2-(2'-hydroxy-3 ' -n-propylamino-propoxy) - /5 -phenyl-propiophenonhy-drochloridet, der også kendes under betegnelsen Propafe-15 non som antiarrhytmikum. Den foreliggende opfindelse har til hensigt at tilvejebringe en fremgangsmåde til fremstilling af forbedrede antiarrhytmika.
Som eksempler på sådanne forbindelser udover de i eksemp-20 lerne angivne forbindelser kan f.eks. nævnes; 2-C 2'-Hydroxy-3'-(2-hydroxyethylamino)-propoxy]-S-phenyl--propiophenon, 2-[2'-Hydroxy-3’-(2-ethoxyethylamino)-propoxy]-S-phenyl-25 -propiophenon, 2-[2'-Hydroxy-3’-(2-n-propoxy-l-methyl-ethylamino)-propoxy1--β-phenyl-propiophenon, 2-(2'-Hydroxy-3’-propargylamino-propoxy)-S-phenyl-propio-pnenon, 30 2-i2’-Hydroxy-3'-(4-hydroxybutylamino)-propoxy]-S-phenyl- propiephenon, 2-(2'-Hydroxy-3 1 -di-n-propylamino-propoxy)-3-phenyl-propio-phenon, 2—C 21-Hydroxy-31-(N-methyl-N-propylamino)-propoxyj-S-phenyl-propiophenon,
DK 164699 B
2 2-(2' -Hydroxy-3’ -pyrrolidino-propoxy)-S-phenyl-propiophenon, 2-(2’-Hydroxy-3’-cyclobutylamino-propoxy)-S-phenyl-propio-phenon, 2-(2 ’-Hydroxy-3 '-eyclopentylaniino-propoxy)-S-phenyl-pro-5 piophenon, 2-[2’-Hydroxy-3’-(l-methyl-2-phenyl-ethylamino)-propoxy]-- S- pheny 1-p ro p io phenon, 2-[2 ’-Hydroxy-3 '-(2-diethylaminoethylainino)-propoxy ]-S-phenyl--propiophenon, 2—Γ2 ’ -Hydroxy-3 ’-(3-diefchylaininopropyla:niriO)-propoxy]-5--phenyl-propiophenon, 2-C2’-Hydroxy-3’-(2-piperidinoethylamino)-propoxy]-S-phsnyI--propiophenon, 15 2-[2 ’ -Hydroxy-3 ’ - (2-morpholinoethylamino)-propoxy]-fe-phenyl- -propiophenon, 2-[ 2 ’ -Hydroxy-3 ’ - (4-ethyl-l-piperazino )-propoxy]-S-phenyl--propiophenon, 2-[2’-Hydroxy-3’-(2-raethylaminoethylamino)-propoxy]-β-phenyl-20 -propiophenon, 2-[2’-Hydroxy-3’-(3-hydroxy-piperidino)-propoxy]-B-phenyl-propiophenon, 2-[2’-Hydroxy-3’-(4-phenyl-piperidino)-propoxy]-S-phenyl-propiophenon, 25 2-[2 *-Hydroxy-3’-(^-hydroxy-4-p-chlorphenyl-piperidino)- -propoxy]-fi-phenyl-propiophenon, 2-(21-Hydroxy-3 *-n-propyiamino-propoxy)-5-methyl-£-phenyl--propiophenon, 2-(2 ’ -Hydroxy-3-’ -n-but ylamino-propoxy)-5-methyl-S-phenyl-30 -propiophenon, 2-(2’-Hydroxy-3’-isopropylamino-propoxy)-5-mefchyl-5-phenyl--propiophenon, 2-(2’-Hydroxy-3’-tert.-butylamino-propoxy)-5-methyl-fi-phenyl--propiophenon, 35 2—C2' -Hydroxy-3 ’-(2-methoxyethylamino)-propoxy]-5-methyl- -β-phenyl-propiophenon,
DK 164699 B
3 2-[ 2 ’ -Hydroxy-3 ' - (4-hydroxybut-2-ylamino)-propoxy]-5-niethyl--S-phenyl-propiophenon, 2-Γ 2'-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--5-niethyl-3-phenyl~propiophenon 5 2-(2'-Hydroxy-3 ’-piperidino-propoxy)-5-Risthyl-S-phenyl-pro- piophenon, 2-(2 ' -Hydroxy-3 ’ -n-propylamino-propoxy) -4-methyl-3-phenyl--propiophenon, 2-(2’-Hydroxy-3’-n-butylamino-propoxy)-4-methyl-3-phenyl-10 -propiophenon, 2-(2 * -Hydroxy-3 ’-isopropylamino-propoxy)-4-methyi-S-phenyl--propiophenon, 2-(2 *-Hydroxy-3’-tert.-butylamlno-propoxy)-4-raethyl-få-phenyl-15 -propiophenon, 2—[2'-Hydroxy-3'-(2-methoxyethylamino)-propoxy]-4-methyl--S-phenyl-propiophenon, 2-[2'-Hydroxy-3'-(4-hydroxybut-2-ylamino)-propoxy]-4-methyl--β-phenyl-propiophenon, 2q 2-[2’-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--4-niethyl-6-phenyl-propiophenon, 2-(2’-Hydroxy-3'-pipe ridino-propoxy)-4-methyl-få-phenyl-pro-piophenon, 2-{2'-Hydroxy-3’-n-propylamino-propoxy)-p-methoxy-fi-phenyl-25 -propiophenon, 2-(21-Hydroxy-3'-n-butylamino-propoxy)-5-nethoxy-S-phenyl--propiophenon, 2-(2 ' -Hydroxy-3 '-isopropylamino-propoxy)-5-niethoxy-S-phe-nyl-propiophenon, 30 2-(2 '-Hydroxy-3 '-tert.-butylamino-propoxy)-5-methoxy-E- -phenyl-propiophenon, 2-[2'-Hydroxy-3’-(2-methoxyethylamino)-propoxy]-5-methoxy--β-phenyl-propiophenon, 2-[2'-Hydroxy-3’-(4-hydroxybut-2-ylamino)-propoxy]-5-meth-35 oxy-B-phenyl-propiophenon, 2-C 2'-Hydroxy-3’- C 4-hydroxy-4-phenyl-piperidino)-propoxy]--5-Riethoxy-S-phenyl-propiophenon,
DK 164699 B
4 2-(2 ’ -Hydroxy-3 '-piperidino-propoxy)-5-methoxy-S-phenyl--propiophenon, 2-(2' -Hydroxy-3 r-n-propylamino-propoxy)-5-fluor-!3-phenyl--propiophenon, 5 2- (2' -Hydroxy-3’-n-butylamino-propoxy)-o-fluor-S-phenyl- -propiephenon, 2- (2 ’-Kydroxy-3 ’-iso-propylaitiino-propoxy)-5-fluor-S-phenyl--p ro p io phenon, 2- (2'-Hydroxy-3'-terfc.-butylamino-propoxy)-5--luor-B-phsnyl--propiophenon, 2-[2'-Kydroxy-31- (2-methoxyethylamino) -propoxy ]-5-fluor--S-phsnyl-propiophenon, 2—C 2'-Hydroxy-3 f-(4-hydroxybut-2-ylamino)-propoxy]-5-fluor- -S-phenyl-propiophenon, 15 2-Γ 2 ’ -Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--5-fluo r-S-phsnyl-propiophenon, 2-(2' -Hydroxy-3’-piperidino-propoxy)-5-fluor-3-phenyl--propiophenon, 2-(2 ’-Hydroxy-3’-n-propylamino-propoxy)-4-fluor-3-phenyl- 20 -propiophenon, 2-(2’-Hydroxy-3 *-n-butylamino-propoxy)-4-fluor-£-phenyl--propiophenon, 2-(2 *-Hydroxy-3’-isopropylamino-propoxy)-4-fluor-B-phenyl-25 -propiophenon, 2-(2'-Hydroxy-3 r-tert.-butylamino-propoxy)-4-fluor-£-phenyl--propiophenon, 2-Γ 2 *-Kydroxy-3 *-(2-methoxyethylamino)-propoxy]-4-fluor--£-phenyl-propiophenon, 30 2-C 2 ’ -Hydroxy-3’-(4-hydroxybut-2-ylamino)-propoxy]-4-fluor- -S-phenyl-propiophenon, 2-[2’-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--4-fluor-£-phenyl-propiophenon, 2-(2’-Hydroxy-3T-piperidino-propoxy)-4-fluor-B-phenyl-pro-35 piophenon, 2-(2' -Hydroxy-3’-n-propylamino-propoxy)-4-chlor-S-phenyl--propiophenon,
DK 164699 B
5 2-(2’-Hydroxy-3'-n-butylamino-propoxyJ^-chlor-S-phenyl--propiophenon, 2-(2’ -Kydroxy-3 '-isopropylaaiino-propoxy)-4-chlor-3-phenyl~ -propiophenon, 5 2-(2 ' -Hydroxy-3 ' -tert .-butylainino-propoxy)-4-ehlor-S-phenyl--propiophenon, 2—[2'-Hydroxy-3’-(2-methoxyethylamino)-propoxy]-4-chlor--3-phenyl-propiophencn, 2-[2f-Hydroxy-3'-(4-hydroxybut-2-ylami.no)-propoxy]-4-chlor--S-phenyl-propiophenon, 2-[2'-Hydroxy-3 ' -(4-hydroxy-4-phenyl-piperidino)-propoxy]--4-chlor-S-phenyl-proplophenon, 2-(2'-Hydroxy-3 T-piperidino-propoxy)-4-chlor-B-phenyl-pro-15 piophenon, 2—(21-Hydroxy-3’-n-propylamino-propoxy)-5-n-propoxy-fi--phenyl-propiophenon, 2-(2‘-Hydroxy-31-n-butylaraino-propoxy)-5-n-propoxy-B-phsnyl--propiophenon, 20 2-(2'-Hydroxy-3'-isopropylamino-propoxy)-5-n-propoxy-S- -phenyl-propiophenon, 2- (2 ’ -Hydroxy-3 ' -tert. -butylaniino)-propoxy) -5-n-propoxy-S--phenyl-propiophenon, 2-C 2 ’ -Hydroxy-3 ’ - (2-me t’noxye thylamino) -propoxy-5-n-propoxy-25 -B-phenyl-propiophenon, 2-[21-Hydroxy-3’-(4-hydroxybut-2-ylami.no)-propoxy]-5-n-pro-oxy-B-phenyl-propiophenon, 2-[2'-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--5-n-propoxy-S-phenyl-propiophenon, 30 2-(21-Hydroxy-3’-piperidino-propoxy)-5-n-propoxy-fi-phenyl- -propiophenon, 2-(21-Hydroxy-3'-n-propylamino-propoxy)-5-n-propyl-B-phenyl--proplophenon, 2-(2'-Hydroxy-3'-n-butylamino-propoxy)-5-n-propyl-6-phenyl-35 -propiophenon, 2-(2'-Hydroxy-3’-isopropylamino-propoxy)-5-n-propyl-S--phenyl-propiophenon,
DK 164699 B
6 2-(2 ' -Hydroxy-3 '-tert.-butylamino-propoxy)-5-n-propyl-3--pheny1-propiophenon , 2-[21-Hydroxy-3’-(2-methoxyethylamino)-propoxy]-5-n-propyl--B-pheny1-propiophenon, 5 2-[2,-Hydroxy-3'-(4-hydroxybut-2-ylamino)-propoxy]-5-n- -propyl-3-phenyl-propiophenon, 2-[2’-Hydroxy-3 * -(4-hydroxy-4-phenyl-piperidino)-propoxy]--5~n-propyl-B-phenyl-propiophenon, 2- (2 ’-Hydroxy-3'-piperidino^propoxy)-5-n-propyl-B-phenyl--propiophenon, 2-(21-Hydroxy-2 *-n-propylamino-propoxy)-4-n-but yl-β-pheny1--propiophenon, 2-(2’-Hydroxy-3’-n-butylamino-propoxy)-4-n-butyl-S-phenyl-,_ -propiophenon, 15 2-(2'-Hydroxy-3 *-isopropylamino-propoxy)-4-n-butyl-S--phenyl-propiophenon, 2-(2'-Kydroxy-3’-tert.-butylamino-propoxy)-4-n-butyl-S--phenyl-p rop iophenon, ao 2-Ca* -Hydroxy-31-(2-methoxyethylamino)-propoxy]-4-n-butyl--β-pheny1-pro p iophenon, 2-[2'-Hydroxy-3’-(4-hydroxybut-2-ylamino)-propoxy]-4-n--buty.l-β-pheny 1-p ro pio phenon, 2-[2’-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]-25 -4-n-butyl-S-phenyl-propiophenon, 2-(2'-Hydroxy-3’-piperidino-propoxy)-4-n-butyl-B-phenyl--propiophenon, 2-(2'-Hydroxy-3’-n-butylamino-propoxy)-4-hydroxy-S-phenyl--propiophenon, 30 2-(2’-Hydroxy-3’-isopropylamino-propoxy)-4-hydroxy-S- -pheny1-propiophenon, 2— C 21-Hydroxy-3'-tert.-butylamino-propoxy)-4-hydroxy-S--phenyl-propiophenon, 2-C 2’-Hydroxy-3'-(2-methoxyethylamino)-propoxy]-4-hydroxy-35 -β-pheny1-propiophenon,
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7 2-[2'-Hydroxy-3'-(ii-hydroxybut~2-ylamino)-propoxy]-i}- -hydroxy-B-phenyl-propiophenon, 2-[2'-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--^-hydroxy-3-phenyl-propiophenon, ^ 2-(21-Hydroxy-3'-ρiperidino-propoxy)-4-hydroxy-a-phenyl- 2- ( 2 ' -Hydroxy-3 *-n-butylamino~propoxy)-5-hydroxy-B-phenyl--propiophenon, 2-(2'-Hydroxy-31-isopropylamino-propoxy)-5-hydroxy-B--phenyl-propiophenon, 10 2-(2'-Hydroxy-2'-tert.-butylamino-propoxy)-5-hydroxy-B--plienyl-prO'piophenon, . .
2-[2'-Hydroxy-3 '-(2-methoxyethylamino)-propoxy]5-hydroxy--β-phenyl-propiophenon, 2-C 2'-Hydroxy-3'-(4-hydroxybut-2-ylamino)-propoxy]-5-hy-15 droxy-B-phenyl-propiophenon, 2-[2'-Hydroxy-31-(4-hydroxy-4-phenyl-piperidino)-propoxy]--5-hydroxy-B-phenyl-propiophenon, 2-[2’-Hydroxy-3'-piperidino-propoxy)-5-hydroxy-S-phenyl--propiophenon, 2- (2'-Hydroxy-3f-n-propylamino-propoxy)-β-(2-methyl-phenyl)--propiophenon, 2-(2'-Hydroxy-3,-n-butylamino-propoxy)-fi-(2-methyl-phenyl)--propiophenon, 25 2-(2'-Hydroxy-3’-isopropylamino-propoxy)-S-(2-methyl-phe- nyl)-propiophenon, 2-(2 *-Hydroxy-3'-tert.-butylamino-propoxy)-β-(2-raethyl--phenyl)-propiophenon, 2-[2’-Hydroxy-3'-(2-methoxyethylamino)~propoxy]-B-(2-30 -methylphenyl)-propiophenon, 2-C 2’-Hydroxy-3'-(4-hydroxy-but-2-ylamino)-propoxy]-β--(2-methylphenyl)-propiophenon, 2-C2'-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--β-(2-methylphenyl)-propiophenon, 35 2-(2'-Hydroxy-3'-piperidino-propoxy)-B-(2-methylphenyl)- -propiophenon,
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8 2- (2' -Hydroxy-3 ' -n-propylamino-propoxy)-β-(3-methoxyphenyl)--p ro p io phenon, 2- (2' -Hydroxy-3' -n-but ylaraino-propoxy) -3- (3-methoxyphenyl) - -propiophenon, 5 2-(2’-Hydroxy-3 '-isopropylamino-propoxy)-fi-(3-methoxy-phenyl)-propiophenon, 2-(21-Hydroxy-3'-tert.-butylamino-propoxy)-fi-(3-methoxy-pheny1)-propiophenon, 10 2-Γ 2’-Hydroxy-3 '-(2-methoxyethylamino)-propoxy]-3-(3-meth oxyphenyl) -propiophenon, 2-[2'-Hydroxy-3’-(4-hydroxybut-2-ylåmino)-propoxy]-β -(3-methoxyphenyl)-propiophenon, 2-[2'-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]-15 -β-(3-methoxyphenyl)-propiophenon, 2—(2T-Hydroxy-3 *-piperidino-propoxy)-β-(3-methoxyphenyl)--propiophenon, 2-(2T-Hydroxy-3'-n-propylamino-propoxy)-β-(3,4-methylen-d iox ypheny1)-p rop io phenon, 20 2-(2'-Hydroxy-3 *-n-butylamino-propoxy)-β-(3,4-methylertdioxy- phenyl)-propiophenon, 2- (2'-Hydroxy-3'-isopropylamino-propoxy)-β-(3,4-methylen-dioxyphenyl)-propiophenon, 2-(2’-Hydroxy-3’-tert.-butylamino-propoxy)-S-(3,4-methylen-25 dioxyphenyD-propiophenon, 2-C2'-Hydroxy-31 -(2-methoxyethylamino)-propoxy]-β-(3,4--me thylendioxypheny1)-p rop iophenon, 2-C 21-Hydroxy-3’-(4-hydroxybut-2-ylamino)-propoxy]-β--(3,4-methylendioxyphenyl)-propiophenon, 30 2-C2’-Hydroxy-3,-(4-hydroxy-4-phenyl-piperidino)-propoxy]- -S-(3,4-methylendioxyphenyl)-propiophenon, 2-(2'-Hydroxy-3 *-piperidino-propoxy)-fi-(3,4-methylendioxyphenyl )-propiophenon, 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-B-(3,4-dichlor-35 phenyl)-propiophenon,
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9 2-(2'-Hydroxy-3'-n-butylamino-propoxy)-β-(3,4-dichlorphenyl)--propiophenon, 2-(2'-Hydroxy-3'-isopropylamino-propcxy)-S-(3 j 4-dichlor- ohenyD-orooiophenon, 5 2-(2'-Hydroxy-3'-tert.-butylamino-propoxy)-B-(3,4-dichlor-phenyl)-propiophenon, 2-[2'-Hydroxy-3,-(2-methoxyethylamIno)-propoxy]-S-(3, -dichlorphenyD-propiophenon, 10 2-[2'-Hydroxy-3'-(4-hydroxybut-2-ylamino)-propoxy]-B- -(3i^-dichlorphenyl)-propiophenon, 2-[2'-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-propoxy]--β-(3,4-dichlorphenyl)-propiophenon, 2-(2'-Hydroxy-3'-piperidino-propoxy)-S-(3,4-dichlorphenyl)-15 -propiophenon, 2-(2'-Hydroxy-3'-n-propylaraino-propoxy)-fi-(3-hydroxyphe-nyl)-propiophenon, 2-(2'-Hydroxy-3'-n-butylamino-propoxy)-β-(3-hydroxyphenyl)--propiophenon, 20 2-(2'-Hydroxy-3 f-isopropylamino-propoxy)-S-(3-hydroxyphe- nyl)-propiophenon, 2-(2'-Hydroxy-3 '-tert.-butylamino-propoxy)-β-(3-hydroxy-phenyl)-propiophenon, 2-[ 2' -Hydroxy-3 1 - (2-me thoxye thylamino) -propoxy] -β- (3-hy-droxyphenyl)-propiophenon, 2-C2'-Hydroxy-3'-(4-hydroxy-but-2-ylamino)-propoxy]-S--(3-hydroxyphenyl)-propiophenon, 2-[2'-Hydroxy-31-(4-hydroxy-4-phenyl-pipe ridino)-propoxy]- -β-(3-hydroxyphenyl)-propiophenon, 30 2-(2'-Hydroxy-3'-piperidino-propoxy)-S-(3-hydroxyphenyl)--propiophenon, 2-(2'-Hydroxy-3 ?-n-propylaraino-propoxy)-fi-(4-hydroxyphe-nyl)-propiophenon, 2-(2'-Hydroxy-3'-n-butylamino-propoxy)-β-(4-hydroxyphenyl)-35 -propiophenon,
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10 2-(2'-Hydroxy-31-isopropylamino-propoxy)-S-(4-hydroxyphe-nyl)-propiophenon, 2-(2' -Hydroxy-3’-tert.-butylamino-propoxy)-S-(4-hydroxy- phenyl)-propiophenon, 5 2-[2’-Hydroxy-3’-(2-methoxyethylamino)-propoxy]-S-(4-hy-droxyphenyl)-propiophenon, 2-[2? -Hydroxy-3 f-( 4-hydroxybut-2-ylamino) -propoxy]-β--(4-hydroxyphenyl)-propiophenon, 10 2 -C.21 -Hydroxy-3? - (4-hydroxy-4-phenyl-piperidino) -propoxy] - -S-(4-hydroxyphenyl)-propiophenon*, .2-(21-Hydroxy-3’-plperidino-propoxy)-S-(4-hydroxyphenyl)--propiophenon, 2-(2’-Hydroxy-3 *-n-propylamino-propoxy)-β-(2-dimethyl-^5 aminophenyl)-propiophenon, 2- (2 ’ -Hydroxy-3 ' -piperidino-propoxy) -β- (2-dimethylamino-phenyT) -propiophenon, 2— (2f -Hydroxy-3' -n-propylamino-propoxy) -S- (3-dime thylamino phenyl)-p ropiophenon, 20 2-[ 2 '-Hydroxy-3 ’-(Ν,Ν-diisopropylamino)-propoxy]-S-(3- -d ie thylam ino phenyl)-p ropiophenon, 2-(2f-Hydroxy-3 '-mo rpholino-propoxy)-B-(2-piperidino-phenyl)-propiophenon, 2- (2T -Hydroxy-3 * -n-propylamino-propoxy) -S- (4-pipe ridino-25 phenyl)-propiophenon, 2-(21 -Hydroxy-3 ' -n-propylamino-propoxy) -S- (4-diisopropyl- aminophenyl)-propiophenon, 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-S-(4-piperidino-phenyl)-propiophenon, 30 2-(2’-Kydroxy-3’-n-propylamino-propoxy)-5-hydroxy-fl-(4- -dimethylaminophenyl)-propiophenon, 2-(2r-Hydroxy-3 ' -n-propylamino-propoxy) -5-methoxy-S- (4--diethylaminophenyl)-propiophenon, 2-(2 *-Hydroxy-3'-piperidino-propoxy)-5-methoxy-S-(4-pipe-35 ridinophenyl)-propiophenon.
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11
De omhandlede forbindelser kan fremstilles ved, at man a) omsætter en forbindelse med formel II 5 0 11 (r4> 11 10 2 hvori A betegner grupperne 15
O eller OH
/ \ i -CH - CH2 -CH-CH2-B, hvor B betegner en nukleofugal fraspaltningsgruppe, og 20 r3, og n har den i krav 1 angivne betydning, med en
amin med formel III
IINR^2 Ill 25 hvori R1 og R2 har de i krav 1 angivne betydninger, eller
b) katalytisk hydrerer en forbindelse med formel IV
30 ^ R3 _^r “ -CH - CH-[gf 1 Π
CH2-NRV
12 3 4 hvori R , R , R , R og n har ovenfor angivne betydnin- 35
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12 ger, hvorpå man eventuelt overfører de fremstillede forbindelser til syreadditionssaltene af fysiologisk acceptable syrer.
5 Når det drejer sig om fremgangsmåde a) betegner fraspalt-ningsgruppen B fortrinsvis et halogenatom, specielt et chlor-, brom- eller iodatom. Yderligere kommer som nu-kleofugale fraspaltningsgrupper aromatiske eller alifatiske sulfonsyregrupper i betragtning som f.eks. p-tolu-10 ensulfonsyre- eller methansulfonsyregruppen.
Omsætningen gennemføres ved stuetemperatur eller ved højere temperaturer, hensigtsmæssigt ved temperaturer fra 50 til 120 °C. Omsætningen kan gennemføres under atmosfæ-15 retryk eller i et lukket udstyr under forhøjet tryk, eventuelt under opvarmning inden for det angivne temperaturområde.
Udgangsforbindelserne kan omsættes direkte, dvs. uden 20 tilsætning af fortyndings- eller opløsningsmiddel. Hen sigtsmæssigt gennemføres omsætningen dog i nærværelse af et inert fortyndings- eller opløsningsmiddel f.eks. en lavere alkohol med 1-4 C-atomer som methanol, ethanol eller propanol, fortrinsvis isopropanol eller ethanol, en 25 lavere mættet dialkylether, dialkylglycolether eller cyc-lisk ether som f.eks. diethylether, 1,2-dimethoxyethan, tetrahydrofuran eller dioxan, benzen eller en alkylbenzen som toluen eller xylen, eller en alifatisk carbonhydrid som hexan, heptan eller octan, en lavere alifatisk keton 30 som acetone, methylethylketon eller methylisobutylketon, et dialkylformamid som dimethyl- eller diethylformamid, dimethylsulfoxid eller i nærværelse af vand eller i blandinger af nævnte opløsningsmidler. Eventuelt kan den i 1 2 overskud anvendte amin med den almene formel HNR R an-35 vendes som fortyndings- eller opløsningsmiddel.
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13
Foretrukne opløsningsmidler ved omsætningen af forbindelserne II (R = dicH2) med en amin HNR^R^ er lavere alkoholer, specielt ethanol eller isopropanol, idet omsætning fortrinsvis gennemføres ved temperaturer fra 50 til 120 5 °C og ved normaltryk.
Den fuldstændige omsætning afhænger af reaktionsterapera-turen og er sædvanligvis løbet til ende i løbet af fra 2 til 15 timer. Reaktionsproduktet kan fås på sædvanlig må-10 de f.eks. ved filtrering eller afdestillation af fortyndings- eller opløsningsmidlet fra reaktionsblandingen. En oprensning af den opnåede forbindelse sker på sædvanlig måde, f.eks. ved omkrystallisation med et opløsningsmiddel, overførsel til en syreadditionsforbindelse eller ved 15 søjlechromatografi.
Udgangsforbindelserne med den almene formel II er delvis kendt eller kan fremstilles på følgende måde: 20 En passende substitueret acetophenon kondenseres med et benzaldehyd til den a,t-umættede keton således som beskrevet i litteraturen, f.eks. i Org. Reactions, bd. 16, s. 1., John Wiley, New York, 1968, i Houben-Weyl, Methoden der organischen Chemie, bd. 7/2b, s. 14576.
25 Thieme Verlag, Stuttgart, 1976 eller i Chem. Ber. 94, 26 (1961). Disse ketoner hydreres katalytisk til de tilsvarende 2-hydroxy-0-phenylpropiophenoner, hvilke metoder også er beskrevet i litteraturen f.eks. i R.N. Rylander, "Catalytic Hydrogenation over Pt-Metals", s.282, Academic 30 Press 1967.
Overførslen af disse 2-hydroxy-5-phenylpropiophenoner til propiophenonerne med formel II sker ved alkylering med en epihalogenhydrin eller en l,3-dihalogen-2-propanol på i 35 og for sig kendt måde.
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14
Som epihalogenhydriner kan anvendes epichlorhydrin, epi-bromhydrin og epiiodhydrin og som 1,3-dihalogen-2-propa-noler kan specielt anvendes 1,3-dichlor-2-propanol og 1,3-dibrom-2-propanol.
5
Omsætningen af 2-hydroxy-0-phenylpropiophenoner til fremstilling af forbindelser med formel II foretages ved temperaturer fra 50 til 80 °C og ved normaltryk eller ved forhøjet tryk i et inert fortyndings- eller opløsnings-10 middel som f.eks. acetone, methanol eller dimethylformamid i nærværelse af en base som kaliumcarbonat, der virker som syrebindende middel.
2-Hydroxy-β-phenylpropiophenonerne og udgangsforbindel-15 serne II kan tildels direkte uden forudgående oprensning anvendes i de efterfølgende reaktionstrin.
Fremgangsmåde b) gennemføres udmærket i alkoholisk opløsning. Som katalysatorer er specielt ædelmetalkatalysato-20 rer velegnede, som palladium-på-carbon.
De omhandlede forbindelser med formel I er ved carbonatom 2 i den alifatiske sidekæde i besiddelse af et chirali-tetscenter og kan fås som racemater, der på velkendte 25 måder f.eks. ved dannelse af diastereomere salte med optisk aktive hjælpesyrer som dibenzoylvinsyre, kamfer-10-sulfonsyre, ditoluylvinsyre eller 3-bromkamfer-8-sulfonsyre kan adskilles i de optisk aktive antipoder.
30 Eventuelt overføres de fremstillede omhandlede forbindelser til syreadditionssaltene af en fysiologisk acceptabel syre. Som almindelige fysiologisk acceptable organiske eller uorganiske syrer kan f.eks. anvendes saltsyre, hy-drogenbromidsyre, phosphorsyre eller svovlsyre og som or-35 ganiske syrer f.eks. oxalsyre, maleinsyre, fumarsyre, mælkesyre, vinsyre, æblesyre, citronsyre, salicylsyre, adipinsyre eller benzoesyre eller kan fremstilles således
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15 som beskrevet i Fortschitte der Arzneimittelforschung bind 10, side 224-225, Birkhåuser Ver lag, Basel og Stuttgart, 1966.
5 Syreadditionssaltene fås som regel på i og for sig kendt måde ved blanding af de frie baser eller opløsninger deraf med de tilsvarende syrer eller opløsninger heraf i et organisk opløsningsmiddel som f.eks. lavere alkoholer som methanol, ethanol eller propanol, eller i lavere ketoner 10 som acetone, methylethylketon eller methyl i sobu tylketon eller i ethere som diethyl ether, tetrahydrofuran eller dioxan. For at forbedre krystaludskillelsen kan blandinger af de nævnte opløsningsmidler anvendes. Herudover kan farmaceutisk acceptable vandige opløsninger af syreaddi-15 tionsforbindelserne af aminopropanolderivaterne med formel I fås ved opløsning af de frie baser i en vandig syreopløsning.
De omhandlede forbindelser og deres fysiologisk acceptab-20 le syreadditionssalte er specielt velegnede til farmako-terapi af hjerterytmeforstyrrelser på grund af deres an-tiarrhytmiske, Ø-symphatolytiske og Ca-antagonistiske egenskaber og er egnede til profylaxe af pludselige hjertestop samt ved behandling af coronare hjertesygdomme.
25
Den antiarr hytmi ske virkning af de omhandlede forbindelser undersøgtes på isolerede venstre forkamre af hanmarsvin (stamme: Pirbright white, vægt 350-450 g).
30 I et organbad (rumfang 125 ml) med carbogenmættet Tyrode-opløsning (pH 7,4, temperatur 32 °C) blev ophængte forkamre belastet med 1,0 g og enerveret ved hjælp af ret-vinkelimpulser på 1 Hz grundrytme og dobbelte irritationstærskelværdier (rheobase: 0,2-1,4 V, chronaxi: 0,3-35 0,5 msec.)
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16
Som kriterium for antiarrhytmisk virkning bestemtes gennem automatisk kontinuert frekvensforhøjelse den frekvens (Hz), som efter hvert irritiament blev efterfulgt af en kontraktion (maximal følgefrekvens, MFF). Ud fra den li-5 neære sammenhæng mellem log koncentration (mg/liter) og den relative formindskelse af den maximale følgefrekvens (δ%) beregnedes den koncentration, der bevirker en formindskelse af den maximale følgefrekvens med 50% (EC
50%).
10
Herudover blev de omhandlede forbindelser administreret peroralt eller intravenøst til bestemmelse af den antiar-rhytmiske virkning på hanrotter (stamme: Spraque Dawley, vægt 200-230 g). 45 minutter senere narkotiseredes dyrene 15 med natriumthiobutabarbital (100 mg/kg intraperitonealt).
Som arrhytmogen forbindelse tjente aconitin, der infunderedes intravenøst 60 minutter efter indgift af forbindelsen (doseringshastighed: 0,005 mg/kg x min). Hos ubehandlede dyr (n = 52) indtraf arrhytmier på EKG efter 2,74 + 20 0,07 min, hvis opståen kunne forsinkes dosisafhængigt med antiarrhytmika.
Ud fra den lineære sammenhæng mellem log dosis (mg/kg) af forsøgsforbindelsen og den relative forlængelse af aconi-25 tininfusionsvarigheden (δ%) bestemtes den dosis, der forlængede infusionsvarigheden med 50% (ED 50%). Som sammenligningsforbindelsen anvendtes det kendte antiarrhytmikum Propaf enon [2- (2-hydroxy-3-propylaminopropoxy) -3-phenyl-propiophenon-hydrochlorid].
30 På isolerede marsvineforkamre (tabel 1) bevirker de omhandlede forbindelser en nedgang i MFF, der overgår aktiviteten af Propaf enon med 3 fold. Også i forsøget med· aconitinantiarrhytmi hos rotter viser der sig i forhold 35 til Propaf enon en stærk antiarrhytmisk virkning (tabel 2). De omhandlede forbindelser tåles udemærket i dette forsøg. Herudover viser der sig en stor afstand mellem
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17 den antiarrhytmisk virksomme dosis og den toxiske dosis.
5 10 15 20 25 30 35
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18 TABEL 1
Antiarrhytmisk virkning på isolerede marsvineforkamre 5
Maksimal følgefrekvens
Forbindelse fra eksempel nr. EC 50% mg/1 ’ 1 1,90 2 0,874 3 1,51 10 6 1'71 10 7 1,66 9 0,757 10 1,13 12 1,25 14 2,17 15 0,728 18 1,30 15 22 1,21 23 1,64 24 2,65 25 1,01 29 1,71 33 2,05 34 1,72 on 35 1,65 20 46 0,778 47 1,45 48 0,923 49 1,82 55 0,854 57 2,04 58 1,92 25 60 1,82 54 1,36 67 0,658
Propafenon 2,02 30 ^ Koncentration (mg/1), der bevirker en nedgang på 50% af den maksimale følgefrekvens 35 TABEL 2
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19
Antiarrhytmisk virkning på aconltinarrhytmi hos rotter (indgift pr. os).
5
Forbindelse fra eksempel nr. EC 50% mg/kg ^ 1 15 2 46,4 3 38,2 10 4 46'4 1U 8 21 9 27 10 46,4 16 29 23 31,6 24 25,4 25 11,2 15 33 24,5 34 21,5 35 1,99 36 6,92 37 46,4 38 21,5 40 46,4 20 49 31'6 55 5,70 56 3,40 57 1,78 58 2,33 59 · 21,5 60 3,25 61 1,90 25 62 21,5 63 3,03 66 21,5 67 2,15 68 46,4 69 31,6 71 0,510 Δ)
Propafenon 58,7 30 0,724 Z)
Dosis (mg/kg), der bevirker en forøgelse på 50% i aconitinfusionsvarigheden 35 2) ' Indgift intravenøst
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20
De omhandlede forbindelser kan indgives peroralt eller intravenøst på sædvanlig måde. Dosis afhænger af patientens alder, tilstand og vægt samt af indgiftsmåden. Som regel andrager den daglige dosis af aktiv forbindelse 5 mellem ca. 5 og 75 mg/kg legemsvægt ved peroral indgift og mellem 1 og 10 mg/kg legemsvægt ved parenteral indgift.
De omhandlede forbindelser kan anvendes i fast eller fly-10 dende form i almindeligt anvendte galeniske former og fremstilles f.eks. som tabletter, filmtabletter, kapsler, pulvere, granulater, dragéer, suppositorier eller opløsninger. Den aktive forbindelse kan til dette formål blandes med almindelige galeniske hjælpemidler som tabletbin-15 demidler, fyldstoffer, konserveringsmidler, tablethenfaldsmidler, viskositetsregulerende midler, blødgørere, befugtningsmidler, dispergeringsmidler, emulgatorer, opløsningsmidler, retarderingsmidler og/eller antioxidanter (se H. Sucker et al., Pharmazeutische Technologie, 20 Thieme-Verlag, Stuttgart, 1978). Den således fremstillede applikationsform indeholder sædvanligvis den aktive forbindelse i en mængde på fra 1 til 99 vægt-%.
Følgende eksempler belyser opfindelsen nærmere.
25 Δ) Fremstilling af udgangsforbindelserne.
EKSEMPEL I
30 3-0xo-l-phenyl-3-( 2 * -hydroxy-51 -chlorphenyl) -propen
Til en blanding af 180 ml H20 og 37 g 50% natronlud sættes ved stuetemperatur 34,1 g 5-chlor-2-hydroxyacetophe~ non og 22 g benzaldehyd. Reaktionsblandingen opvarmes til 35 55-60 °C under kraftig omrøring ca. 1 time ved denne tem peratur. Under kraftig afkøling syrnes herefter svagt med 25% HL^SO^ (ca. 100 ml); bundfaldet frasuges, vaskes grun-
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21 digt med KLjO og omkrystalliseres med methanol/acetone (9:1). Der opnås 38,7 g 3-oxo-l-phenyl-3-(2'-hydroxy-5'-chlorphenyl)-propen med smeltepunktet 88-90 °C.
5 Analogt hermed fremstilledes følgende forbindelser: 3-oxo-l-(4'-methoxyphenyl )-3-(2'-hydroxyphenyl)-propen, smp. 91-92 °C, 10 3-oxo-l-(2',4'-dichlorphenyl)-3-(2·-hydroxyphenyl)- propen, smp. 169-172 °C, 3-oxo-l-(2'-methoxyphenyl)-3-(2'-hydroxyphenyl)-propen, smp. 110-112 °C, 15 3-oxo-(3',4'-dimethoxyphenyl)-3-(2'-hydroxyphenyl)-pro-pen, smp. 110-116 °C, 3-oxo-(3’,4’,51 -trimethoxyphényl)-3-(21-hydroxyphenyl)-20 propen, smp. 152-153 °C, 3-oxo-l-(4'-dimethylaminophenyl)-3-(2'-hydroxyphenyl)-propen, smp. 174-176 °C, 25 3-oxo-l-(4'-chlorphenyl)-3-(2'-hydroxyphenyl)-propen, smp. 149-150 °C, 3-oxo-l-(4'-methylphenyl)-3-(2'-hydroxyphenyl)-propen, smp. 118-120 °C, 30 3-oxo-l-(4'- fluorphenyl )-3-(2'-hydroxyphenyl)-propen, smp. 115-119 °C, 3-oxo-l-(3',4'-dimethoxyphenyl)-3-(2'-hydroxy-5'-methyl-35 phenyl)-propen, smp. 142-145 °C, 22
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3-oxo-l-(4,-chlorphenyl)-3-(2'-hydroxy-5'-methylphenyl)- propen, smp. 151-156 °C, 3-oxo-l-(4'-methoxyphenyl)-3-(2'-hydroxy-5,-chlorphenyl)-5 propen, smp. 108-111 °C, 3-oxo-l-(4'-fluorphenyl)-3-(2'-hydroxy-5'-chlorphenyl)-propen, smp. 183-185 °C, 10 3-oxo-l-(4'-diethylaminophenyl)-3-(2'-hydroxyphenyl)- propen, 117-119 °C, 3-oxo-l-(41-dimethylaminophenyl)-3-(2'-hydroxy-5'-chlor-phenyl)-propen, smp. 159-162 °C, 15 3-oxo-l-(4*-dimethylaminophenyl)-3-(2'-hydroxy-5'-methyl-phenyl ) -propen , smp. 125-129 °C.
EKSEMPEL II
20 a) 2-Hydroxy-5-chlor-0-phenyl-propiophenon 25 g 3-oxo-l-phenyl-3-(2'-hydroxy-5'-chlorphenyl)-propen (0,097 mol) opløstes i 200 ml tetrahydrofuran og hydrere-25 des i nærværelse af 1,5 g katalysator (0,5% Pd på Al2Og) ved normaltryk og ved en temperatur på 40-50 °C. Efter 2 til 3 timers forløb var hydrogenoptagelsen afsluttet (2100 ml). Herefter frafiltreredes katalysatoren, og opløsningsmidlet fjernedes fra filtratet ved destillation 30 under formindsket tryk. Den tilbageblevne remanens omkrystalliseredes med methanol. Udbytte 19,9 g med smeltepunkt 56-57 °C.
Analogt hermed fremstilledes følgende forbindelser: 2-hydroxy-p-(4-methoxyphenyl)-propiophenon, smp. 51-54 °C, 35 23
DK 164699 B
2-hydroxy-|3-(2,4-dichlorphenyl)-propiophenon, smp. 106 °C, 5 2-hydroxy-P-(4-dimethylaminophenyl)-propiophenon, smp. 69-71 °C,
2-hydroxy-p-(3,4-dimethoxyphenyl)-propiophenon, smp. 84-87 0C
10
2-hydroxy-P-(4-dimethylaminophenyl)-propiophenon, smp. 62 °C
2-hydroxy-P-(4-diethylaminophenyl)-propiophenon,
15 smp. 49-51 °C
2-Hydroxy-5-methyl-p-(4-dimethylaminophenyl)-propiophenon, smp. 90-92 °C
20 2-hydroxy-5-chlor-P-(4-dimethylaminophenyl)-propiophenon,
smp. 99 °C
2-Hydroxy-P-(4-chlorphenyl)-propiophenon, ^15^13^^^2 (260,72); som olie 25
Beregnet: C 69,10 H 5,03 Cl 13,60
Fundet: C 69,5 H 5,4 Cl 13,2 2-Hydroxy-p-(2-methoxyphenyl)-propiophenon 30 ^16^16^3 (256,30); som olie
Beregnet: C 74,98 H 6,29
Fundet: C 74,7 H 6,4
De øvrige propiophenoner anvendtes uden yderligere rensning.
35
EKSEMPEL III
24
DK 164699 B
2-Hydroxy-4-methoxy- £ -phenyl-pr op iophenon 5 16,6 g (100 nunol) 2-hydroxy-4-methoxyacetophenon og 10,6 g (100 nunol) benzaldehyd opløstes i 300 ml methanol og tildryppedes 8 g (200 nunol) natriumhydroxid, der var opløst i 30 ml H2O. Opløsningen farvedes gul. Reaktionsproduktet omrørtes 72 timer ved stuetemperatur. Herefter 10 fortyndedes med 200 ml methanol, og der tilsattes ca. 2 g Pd/C (5%). Den gule opløsning hydreredes. Hydrogenoptagelsen androg 1800 ml. Suspensionen frafiltreredes, og moderluden indstilledes til pH 5 med ca. 10 ml koncentreret eddikesyre. De udfældede krystaller frasugedes. Ud-15 bytte 18 g (= 70,2%) med smeltepunkt 100 °C.
EKSEMPEL IV
2-(2',31-Epoxypropoxy)-5-chlor-Ø-phenyl-propiophenon 20 69 g (0,265 mol) 2-hydroxy-5-chlor-£-phenylpropiophenon omrørtes med 125,4 g (0,915 mol) epibromhydrin, 70 ml dimethylformamid og 48,7 g (0,353 mol) vandfrit K2C03 ved 60 °C i 5 timer. Efter afkøling tilsattes 250 ml 1^0, og 25 overskud af epibromhydrin fjernedes fra den organiske fase ved destillation under formindsket tryk. Den tilbageblevne remanens omkrystalliseredes med cyclohexan/me-thyl-tert.-butylether. Udbytte 67 g (= 79%) med smeltepunkt 46-47 °C.
30
Analogt hermed fremstilledes: 2- (2',3'-epoxypropoxy)-5-chlor-£- (4-dimethylaminophenyl)-propiophenon med smeltepunkt 93-95 °C.
Analogt hermed fremstilledes alle andre udgangsmaterialer, der dog anvendtes uden yderligere oprensning.
35
EKSEMPEL V
25
DK 164699 B
3- 0xo-l-phenyl-3-[(21-hydroxy-3’-n-propylamino-propoxy)- 4- benzyloxy-phenyl]-propen 5 a) 2-Hydroxy-4-benzyloxy-acetophenon 15,2 g (100 mmol) 2,4-dihydroxyacetophenon, 17,1 g (100 mmol) benzylbromid og 13,8 g (100 mmol) kaliumcarbonat 10 opvarmedes 8 timer under omrøring i 150 ml acetone med tilbagesvaling (farveændring fra violet til rødbrun). Efter afkøling afdestilleredes opløsningsmidlet. Remanensen optoges i 100 ml eddikesyreethylester og udrystedes med 100 ml 1 N natronlud. Faserne adskiltes. Den organis-15 ke fase syrnedes med 110 ml 1 N HC1 og fraskiltes atter.
Den organiske fase tørredes med natriumsulfat. Tørremidlet frafiltreredes, og opløsningsmidlet afdestilleredes (råudbytte 20,5 g). Råproduktet omkrystalliseredes med 180 ml ethanol. Udbyttet 17,5 g med smeltepunkt 108-109 20 °C.
b) 3-0xo-l-phenyl-3-(2'-hydroxy-4-benzyloxyphenyl)-propen 17,63 g (72,6 mmol) 2-hydroxy-4-benzyloxyacetophenon, 25 17,60 g (165,8 mmol) benzaldehyd og 35,20 g 50% natronlud omrørtes 3 dage i 200 ml ethanol. Under reaktionen udfældede krystaller. Krystalgrøden syrnedes med 100 ml 5 N saltsyre og omrørtes herefter 10 minutter. Krystallerne frasugedes (40,0 g fugtige krystaller). Råproduktet om-30 krystalliseredes med 800 ml ethanol. Udbytte 13,6 g med smeltepunkt 116-118 °C.
c) 3-0xo-l-phenyl-3- [2^(2^31 - epoxypr opoxy) -4 * -benzyl-oxy-phenyl]-propen 13,55 g (41,0 mmol) 3-oxo-l-phenyl-3-(2’-hydroxy-4-benz-yloxyphenyl)-propen opvarmedes med 1,64 g (41,0 mmol) na- 35
DK 164699 B
26 triumchlorid med tilbagesvaling i 4 timer i 200 ml epi-chlorhydrin. Det under reaktionen dannede reaktionsvand fraskiltes under opvarmningen. Herefter afkøledes reaktionsproduktet, og det dannede natriumchlorid frasugedes.
5 Filtratet inddampedes i vacuum. Remanensen anvendtes uden rensning ned næste trin.
d) 3-Oxo-l-phenyl-3-[ (21 -hydroxy-3 * -n-propylamino-pro-poxy) -4-benzyloxy-phenyl] -propen 10 16,3 g (42,2 mmol) 3-oxo-l-phenyl-3-[2,-(2',3,-epoxyprop-oxy)-4'-benzyloxyphenyl]propen opvarmedes i 200 ml n-pro-pylamin med tilbagesvaling i 4 timer. Herefter afdestilleredes overskud af amin. Det fremstillede råprodukt an-15 vendtes direkte uden yderligere oprensning til fremstilling af de omhandlede slutprodukter.
Analogt hermed fremstilledes: 20 3-oxo-l-phenyl-3- [ (2' -hydroxy-3' -n-propylamino-propoxy) - 5-benzyloxy-phenyl]-propen B) Fremstilling af de omhandlede forbindelser: 25 EKSEMPEL 1 2- [21 -Hydroxy-3' - (4-hydroxybut-2-yl-amino) -propoxy] -0-phenyl-propiophenon-hydrochlorid 30 5 g 2-(2' ,3'-epoxypropoxy)-0-phenylpropiophenon og 1,55 g 4-hydroxy-but-2-yl-amin opløstes i 100 ml isopropanol og opvarmedes 8 timer med tilbagesvaling på dampbad. Herefter afdestilleredes opløsningsmidlet under reduceret tryk; der opnåedes 5,5 g olieagtig remanens. Råproduktet 35 rensedes over en kiselgelsøjle (elueringsmiddel: tolu- en/methanol 70:30), og de rensede fraktioner overførtes til hydrochloridet. Udbytte 2,9 g (40,5%) med smeltepunkt 27
DK 164699 B
88,5 °C (acetone/ether).
EKSEMPEL 2 5 2- [21 -Hydroxy-31 - (3-methoxyprop-2-ylamino) -propoxy] -£>- phenyl-propiophenon-hydrochlorid 10 g 2-(2’,3'-epoxypropoxy)-i-phenyl-proplophenon (0,035 mol) og 16 g 3-methoxyprop-2-yl-amin (0,18 mol) opløstes 10 i 150 ml isopropanol, og blandingen opvarmedes med tilbagesvaling i 6 timer på vandbad. Herefter afdestilleredes opløsningsmidlet under formindsket tryk. Den olieag-tige remanens (12,85 g) omdannedes ved hjælp af etherhol-dig saltsyre til hydrochloridet og omkrystalliseredes med 15 acetone/ether. Udbytte 9,8 g (68%) med smeltepunkt 119 °C.
Analogt hermed fremstilledes: 20 3. 2-(2 ' --Hydroxy-3 '-cyclopropylamino-propoxy )-|3-phenyl-
propiophenon-hydrochlorid, smp. 153 °C
4. 2-(2'-Hydroxy-3'-cyclohexylamino-propoxy)-P-phenyl- propiophenon-hydrochlorid, smp. 162 °C 25 5. 2-(2'-Hydroxy-3'-allylamino-propoxy)-p-phenyl-pro-
piophenon-hydrochlorid, smp. 153 °C
6. 2-[2'-Hydroxy-3'-(l-butin-3-ylamino)propoxy]-p-
30 phenyl-propiophenon-hydrochlorid, smp. 133 °C
7. 2-[2 '-Hydroxy-3 ' -(3-methyl-l-butin-3-ylami.no)-propoxy]-P-phenyl-propiophenon-hydrochlorid, smp. 131-132 °C
35
DK 164699 B
28
8. 2-[2'-Hydroxy-3'-(3-hydroxy-3-methyl-butylamino)-propoxy]-8-phenyl-propiophenon-hydrochlorid, smp. 145-146 °C
5 9. 2-[2'-Hydroxy-3'-(2-methoxyethylamino)-propoxy]-β-
phenyl-propiophenon-hydrochlorid, smp. 112-113 °C
10. 2—[2'-Hydroxy-3'-(3-thiomethoxyprop-2-ylamino)-propoxy]-p-phenyl-propiophenon-hydrochlorid, smp. 119 °C
10
11. 2-[2'-Hydroxy-3'-(2-phenylethylamino)-propoxy]-P-phenyl-propiophenon-hydrochlorid, smp. 157-158 °C
12. 2-[2'-Hydroxy-3'-(2-phenylpropylamino)-propoxy]-P-
15 phenyl-propiophenon-hydrochlorid, smp. 152 °C
13. 2 — C2'-Hydroxy-3'-(l-methylbenzylamino)-propoxyl-p-phenyl-propiophenon-hydrochlorid, smp. 119-120 °C
20 14. 2 — C21-Hydroxy-3(2-(3,4-dimethoxyphenyl)-ethylamino)-
propoxyl-p-phenyl-propiophenon-hydrochlorid, smp. 129 °C
15. 2-[2'-Hydroxy-3'-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethylamino)l-propoxy-Ø-phenyl-propiophenon-hydrochlo-
25 rid, smp. 121 °C
16. 2-[2,-Hydroxy-3,-(2-dimethylaminoethylamino)-propoxy]~ P-phenyl-propiophenon-bis-hydrochlorid, smp. 136- 137 °C 30 17. 2-[21-Hydroxy-3(3-dimethylaminopropylamino)-propoxy]-P-phenyl-propiophenon-bis-hydrochlorid, smp. 150- 151 C° 35 18. 2-[2'-Hydroxy-3(N,N-dimethylamino)-propoxy]-P-phenyl-
propiophenon-hydrochlorid, smp. 154 °C
DK 164699 B
29
19. 2-(2'-Hydroxy-3'-(N,N-di-isopropylamino)-propoxy]-P-phenyl-propiophenon-hydrochlorid, smp. 131 °C
20. 2-(2'-Hydroxy-3'-piperidino-propoxy)-3-phenyl-propio-
5 phenon-hydrochlorid, smp. 155-156 °C
21. 2-(2'-Hydroxy-3'-morpholino-propoxy)-P-phenyl-propio-phenon-hydrochlorid, smp. 153 °C
10 22. 2-[2'-Hydroxy-3'-(3-phenyl-pyrrolidino)-propoxy]-β-
phenyl-propiophenon-hydrochlorid, smp. 128-130 °C
23. 2-[2'-Hydroxy-3'-(4-hydroxypiperidino)~propoxy]-p-phenyl-propiophenon-hydrochlorid, smp. 150-152 °C
15
24. 2 — [21-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-prop-oxyl-p-pheny1-propiophenon-hydrochlorid, smp. 107-108 °C
25. 2-[2'-Hydroxy-3'-(4-methyl-l-piperazinyl)-propoxy]-P-
20 phenyl-propiophenon-bis-hydrochlorid, smp. 152-153 °C
26. 2-{2'-Hydroxy-3'— C4-(4— f1uorphenyl)-l-piperazinyl]-propoxy)-β-pheny1-propiophenon, smp. 119-120 °C
25 27. 2-(2'-Hydroxy-3'-[4-(4-fluorphenyl)-1-plperazinyl]-
propoxy]-β-phenyl-propiophenon, smp. 93 °C
28. 2-[2'-Hydroxy-3'-[2-(2-methylphenyl)-propylamino]~ propoxy}-P-phenyl-propiophenon-hydrochlorld,
30 smp. 140-141 °C
29. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-P-(2-methoxy-phenyl)-propiophenon-hydrochlorid, smp. 123 C° 35 30. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-P-(4-methoxy-
phenyl)-propiophenon-hydrochlorid, smp. 159 °C
DK 164699 B
30
31. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-p-(4-chlor-phenyl)-propiophenon-hydrochlorid, smp. 157 °C
32. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-p-(2,4-di- 5 chlorphenyl)-propiophenon-hydrochlorid, ·smp. 119-
123 °C
33. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-P-(4-fluor-phenyl)-propiophenon-hydrochlorid, smp. 144 °C
10
34. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-p-(4-methyl-phenyl)-propiophenon-hydrochlorid, smp. 148-149 °C
35. 2 —(2'-Hydroxy-3'-n-propylamino-propoxy)-P-(4-dimethyl-
15 aminophenyl)-propiophenon-hydrochlorid, smp. 165-166 °C
36. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-β-(3,4-dimeth-oxyphenyl)-propiophenon-hydrochlorid, smp. 185-186 °C
20 37. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-5-chlor-p-
phenyl-propiophenon-hydrochlorid, smp. 163-164 °C
38. 2-[2'-Hydroxy-3'-(3-methoxy-prop-2-yl-amino)-propoxy]- 5-chlor-P-phenyl-propiophenon-hydrochlorid, smp. 105-
25 106 °C
39. 2-(2'-Hydroxy-3'-cyclopropylamino-propoxy)-5-chlor-P-phenyl-propiophenon-hydrochlorid, smp. 152 °C
30 40. 2-(21-Hydroxy-3'-piperidino-propoxy)-5-chlor-p-phenyl-
propiophenon, smp. 91-92 °C
41. 2 — [2'-Hydroxy-3'-(2-(3,4-dimethoxyphenyl)-ethylamino)-propoxy]-5-chlor-8-phenyl-propiophenon-hydrochlorid,
35 smp. 137-141 °C
DK 164699 B
31
42. 2-(2'-Hydroxy-3'-[N-methyl-N-2-(3,4-dimethoxyphenyl)-ethylamino)]-propoxy}-5-chlor-P-phenyl-propiophenon-hydrochlorid, smp. 135 °C
5 43. 2-[2'-Hydroxy-3'-(4-hydroxy-4-phenyl-piperidino)-prop-
oxy]-5-chlor-0-phenyl-propiophenon-hydrochlorid, smp. 214-216 °C
44. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-5-chlor-0-(4- 10 methoxy-phenyl)-propiophenon-hydrochlorid, smp. 165-
167 °C
45. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-5-methyl-p-(4-chlorphenyl)-propiophenon-hydrochlorid, smp. 134- 15 135 °c 46. 2-(2'-Hydroxy-3,-di-n-propylamino-propoxy)-5-methyl-p-(4-chlorphenyl)-propiophenon-hydrochlorid, smp. 119-
123 °C
20
47. 2-(2'-Hydroxy-3'-di-n-propylamino-propoxy)-5-chlor-p-(p-fluorphenyl)-propiophenon-hydrochlorid, smp. 139-144 °C
25 48. 2-(2'-Hydroxy-31-n-propylamino-propoxy)-5-methyl-P-
(3,4-dimethoxyphenyl)-propiophenon-hydrochlorid, smp. 132-133 °C
49. 2-(2'-Hydroxy-3'-n-propylaminopropoxy)-P-(3,4,5-tri-
30 methoxyphenyl)-propiophenon, smp. 197-198 °C
50. 2-[2'-Hydroxy-3l-(2-hydroxyethylamino)-propoxy]-5-chlor-Ø-phenyl-propiophenon, smp. 99-103 °C
35 51. 2-(2'-Hydroxy-31-aminopropoxy)-P-pheny1-propiophenon-
oxalat, smp. 149-151 °C
DK 164699 B
32
52. 2-(2'-Hydroxy-3'-methylaminopropoxy)-P-phenyl-propio-phenon-hydrochlorid, smp. 141-143 °C
53. 2-(21-Hydroxy-3'-ethylaminopropoxy)-p-phenyl-propio-
5 phenon-hydrochlorid, smp. 162-164 °C
54. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-4-methoxy-p-pheny1-propiophenon-hydrochlorid, smp. 174-177 °C
10 EKSEMPEL 55 2-(21-Hydroxy-31-piperidino-propoxy)- g - (4-dimethylamino-phenyl)-propiophenon 15 8 g 2-(2*,3’-epoxypropoxyJ-Ø-H-dimethylaminophenylJ-pro- piophenon (0,025 mol) og 20 ml piperidin opløstes i 100 ml isopropanol, og blandingen opvarmedes 6 timer på vandbad. Herefter afdestilleredes opløsningsmidlet og overskud af amin under formindsket tryk. De tilbageblevne 9 g 20 olieagtig remanens udkrystalliseredes med lidt ethanol under tilsætning af aktivt kul. Udbytte 3,15 g (31%) med smeltepunkt 113-115 °C.
EKSEMPEL 56 25 2-(21-Hydroxy-31-isopropylamino-propoxy)-0-(4-dimethyl-aminophenyl) -propiophenon-hydrochlorid 1 g 2-(2’,3'-epoxypropoxy)-0-(4-dimethylamino-phenyl)-30 propiophenon og 13 ml isopropylamin omsattes i isopropanol som beskrevet i eksempel 55. Den tilbageblevne remanens opløstes efter sædvanlig oparbejdning i 150 ml acetone og tilsattes 4,6 ml etherholdig HC1 (ca. 5 N). Krystallerne frasugedes og omkrystalliseredes atter med ace-35 tone. Udbytte 3,8 g (36,5%) med smeltepunkt 149 °C.
DK 164699 B
33
Analogt hermed fremstilledes: 57. 2-(2'-Hydroxy-3'-cyclopropylamino-propoxy)-P-(4-di-methylaminophenyl)-propiophenon-hydrochlorid, smp.
5 128-133 °C
58. 2-(2'-Hydroxy-3'-n-butylamino-propoxy)-p-(4-dimethyl-aminophenyl)-propiophenon-hydrochlorid, smp. 161-163 °C
10 59. 2-[21-Hydroxy-3'-(2-hydroxyethylamino)-propoxy]-p~
(dorne thylaminophenyl)-propiophenon-hydrogenoxalat, smp. 138 °C
60. 2-[2'-Hydroxy-3'-(3-methoxy-prop-2-ylamino)-propoxy]- 15 P-(4-dimethylaminophenyl)-propiophenon-hydrochlorid, smp. 134-135 C°
61. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-p-(4-diethyl-aminophenyl)-propiophenon-hydrochlorid, smp. 154-155 °C
20
62. 2-(21-Hydroxy-3'-n-propylamino-propoxy)-5-chlor-p-(4-dimethylaminophenyl)-propiophenon-hydrochlorid, smp. 166-167 °C
25 63. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-5-methyl-p-
(4-dimethylaminopheny1)-propiophenon-hydrochlorid, smp. 161-162 °C
64. 2 — [2 *-Hydroxy-3'-(Ν,Ν-diisopropylamino)-propoxy]-P- 30 (4-dimethylaminophenyl)-propiophenon-hydrochlorid,
smp. 143-144 °C
65. 2-[2'-Hydroxy-3'-(N,N-diisopropylamino)-propoxy]-5-methyl-p-(4-dimethylaminophenyl)-propiophenon-hydro-
35 chlorid, smp. 143-145 °C
DK 164699 B
34
66. 2-[2'-Hydroxy-3'-(N,N-diisopropylamino)-propoxy]-5-chlor-β-(4-dimethylaminophenyl)-propiophenon-hydro-chlorid, smp. 148-150 °C
5 67. 2-[2'-Hydroxy-3'-(4-methyl-l-piperazinyl)-propoxy]-0-
(4-dimethylaminophenyl)-propiophenon-hydrochlorid, smp. 129 °C
68. 2-[2'-Hydroxy-3'-(4-methyl-l-piperazinyl)-propoxy]- 10 5-methyl-Ø-(4-dimethylaminophenyl)-propiophenon-
hydrochlorid, smp. 169-170 °C
69. 2-[2'-Hydroxy-3'-(3-methoxy-prop-2-ylamino)-propoxy]- 5-methyl-Ø-(4-dimethylaminophenyl)-propiophenon-
15 hydrochlorid, smp. 121-124 °C
EKSEMPEL 70 2-(21-Hydroxy-3*-n-propylamino-propoxy)-4-hydroxy-g-phe-20 nyl-propiophenon-hydrochlorid
Forbindelsen fremstillet som beskrevet i eksempel V tilsattes 1 g Pd/C (5%) og opløstes i 150 ml methanol. Herefter hydreredes (hydrogenoptagelse 1830 ml). Efter af-25 slutning af hydrogenoptagelsen frafiltreredes katalysato ren, og opløsningsmidlet afdestilieredes. Der opnåedes 5,8 g af en rød sej olie, der opvarmedes 1 time med 100 ml 1 N saltsyre med tilbagesvaling. Olien, der ikke opløstes, fraskiltes. Efter afkøling frasugedes de dannede 30 krystaller, og der omkrystalliseredes med 150 ml etha-nol/acetone (1:2) ialt to gange. Udbytte 2,7 g med smeltepunkt 145-148 °C.
Analogt hermed fremstilledes: 71. 2-(2'-Hydroxy-3'-n-propylamino-propoxy)-5-hydroxy-0- phenyl-propiophenon-hydrochlorid, smp. 220-221 °C.
35

Claims (3)

  1. 2 I 2 OH 1 2 hvori R og R er ens eller forskellig og betegner hydro-15 genatomer, alkyl-, cycloalkyl-, alkenyl-, alkynyl- eller hydroxyalkylgrupper med hver især indtil 6 C-atomer, alkoxyalkyl-, alkylthioalkyl- eller dialkylaminoalkyl-grupper med hver især indtil 9 C-atomer, eller phenyl-alkylgrupper med indtil 6 C-atomer i alkylgruppen, og 20 hvor phenylgruppen eventuelt er substitueret med alkyl eller alkoxy med hver især indtil 3 C-atomer, eller 1 2 R og R sammen med det nitrogenatom, der forbinder dem, danner pyrrolidin eller piperidin, der eventuelt kan være 25 substitueret med 1 eller 2 phenyl- og/eller hydroxygrup-per eller kan danne morpholln eller piperazin, idet det yderligere nitrogenatom kan være substitueret med en alkylgruppe med 1 til 3 C-atomer eller en phenylgruppe eventuelt monosubstitueret med halogen eller med en 30 alkoxygruppe med 1 til 3 C-atomer, 3 R betegner et hydrogenatom, en alkylgruppe med 1 til 3 C-atomer, et fluor-, chlor- eller bromatom, en hydroxy-gruppe eller en alkoxygruppe med indtil 6 C-atomer, 35 4 R betegner et hydrogenatom, en alkylgruppe med indtil 3 C-atomer, et fluor-, chlor- eller bromatom, en alkoxy- DK 164699B 36 5 6 5 gruppe med indtil 3 C-atomer eller gruppen NR R , hvor R g og R er ens eller forskellige og betegner alkylgrupper 13 4 med indtil 6 C-atomer, idet grupperne R , R og R ikke 2 samtidig kan være hydrogenatomer, dersom R betegner en 5 alkylgruppe med 3 til 5 C-atomer, og n er tallet 1, 2 eller 3, og fysiologisk acceptable syreadditionssalte heraf, 10 kendetegnet ved, at a) en forbindelse med formel II 0 15 _ . _ /(R4)n 11 v 0-CH2-A^/ hvor A betegner gruppen 20 0 eller OH / \ I -CH - CH2 -CH-CH2-B, hvor B betegner en nukleofugal fraspaltningsgruppe, og 25 3 4 R , R og n har ovenfor angivne betydning, omsættes med en amin med formel III HNR1R^ III ^ hvor R^ og R^ har ovennævnte betydninger, eller b) en forbindelse med formel IV 35 37 DK 164699 B /ν(*4)η IV - CH = “'[g]
  2. 2 I 12 CH«-NR R
  3. 5 L 12 3 4 hvori R , R , R , R og n har ovennævnte betydning, katalytisk hydreres, hvorpå de fremstillede forbindelser eventuelt overføres til deres syreadditionssalte af fysiologisk acceptable syrer. 10 15 20 25 30 35
DK416082A 1981-09-18 1982-09-17 Analogifremgangsmaade til fremstilling af terapeutisk aktive aminopropanolderivater og fysiologisk acceptable syreadditionssalte heraf DK164699C (da)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE3137178 1981-09-18
DE3137178 1981-09-18
DE19823226863 DE3226863A1 (de) 1981-09-18 1982-07-17 Aminopropanolderivate von 2-hydroxy-ss-phenyl-propiophenonen, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel
DE3226863 1982-07-17

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DK416082A DK416082A (da) 1983-03-19
DK164699B true DK164699B (da) 1992-08-03
DK164699C DK164699C (da) 1992-12-21

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US (1) US4571409A (da)
EP (1) EP0075207B1 (da)
CA (1) CA1175831A (da)
CS (1) CS236489B2 (da)
DE (2) DE3226863A1 (da)
DK (1) DK164699C (da)
ES (1) ES8305684A1 (da)
FI (1) FI77224C (da)
HU (1) HU186576B (da)
IL (1) IL66783A0 (da)
NO (1) NO155771C (da)

Families Citing this family (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3309595A1 (de) * 1983-03-17 1984-09-20 Basf Ag, 6700 Ludwigshafen Neue aminopropanolderivate von 1-(2-hydroxy-phenyl)-3-phenyl-propanolen, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel
DE3348170C2 (da) * 1983-07-21 1993-03-11 Helopharm W. Petrik Gmbh & Co Kg, 1000 Berlin, De
DE3343671A1 (de) * 1983-12-02 1985-06-20 Basf Ag, 6700 Ludwigshafen Aminopropanolderivate von substituierten 2-hydroxy-propiophenonen, verfahren zu ihrer herstellung und diese enthaltende therapeutische mittel
DE3424685A1 (de) * 1984-07-05 1986-02-06 Beiersdorf Ag, 2000 Hamburg Neue substituierte phenylpiperazinyl-propanole, verfahren zu ihrer herstellung und ihre verwendung sowie diese verbindungen enthaltende zubereitungen
DE3429667A1 (de) * 1984-08-11 1986-02-20 Knoll Ag, 6700 Ludwigshafen Verfahren zur herstellung von substituierten aryl-alkylketonen
EP0283540B1 (de) * 1987-03-26 1991-09-18 Helopharm W. Petrik GmbH & Co.KG. Verfahren zur Herstellung von 5-Hydroxydiprafenon und seiner Salze mit Säuren
ATE72562T1 (de) * 1987-06-23 1992-02-15 Helopharm Petrik Co Kg Aminopropanolderivate von 3-(2-hydroxyphenyl)-1- propanon-verbindungen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel.
EP0296264A1 (de) * 1987-06-23 1988-12-28 Helopharm W. Petrik GmbH & Co.KG. Aminopropanolderivate von 3-(2-Hydroxyphenyl)-1-propanonderivaten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
EP0296265A1 (de) * 1987-06-23 1988-12-28 Helopharm W. Petrik GmbH & Co.KG. Aminopropanolderivate von 3-(3-Hydroxyphenyl)-1-propanon-derivaten, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel
DE3725273A1 (de) * 1987-07-30 1989-02-09 Basf Ag Verfahren zur synthese von enantiomeren des propafenons sowie diese enthaltende therapeutische mittel
DE3834132A1 (de) * 1988-10-07 1990-04-12 Knoll Ag Hydroxypropafenonglyceride
DE4000213A1 (de) * 1990-01-05 1991-07-11 Helopharm Petrik Co Kg O-hydroxy-ss-(1-naphthyl)-propiophenonderivate, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
JPH08508270A (ja) * 1993-03-29 1996-09-03 ビーエーエスエフ アクチエンゲゼルシャフト マルチ・ドラッグ耐性のモジュレーターとしての１−アミノ−３−フェノキシ−プロパン誘導体
AT401726B (de) * 1993-05-17 1996-11-25 Gerhard Dr Ecker O-acylaryloxypropanolamine mit tertiärem oder quartärem stickstoff als reversionsmodulatoren für p-glykoprotein mediierte multidrug-resistenz
CN104262178A (zh) * 2014-09-28 2015-01-07 常州瑞明药业有限公司 盐酸普罗帕酮的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3812129A (en) * 1966-06-24 1974-05-21 Hoffmann La Roche Piperazinyl substituted alkoxy benzophenones
DE2001431C3 (de) 1970-01-06 1974-12-12 Helopharm W. Petrik & Co Kg, 1000 Berlin 2-(2'-Hydroxy-3'-alkylaminopropoxy)-Omega-phenyl-propiophenone und Verfahren zur Herstellung derselben
DE3133814C2 (de) * 1981-08-25 1983-12-22 Helopharm W. Petrik & Co Kg, 1000 Berlin 2-[2'-Hydroxy-3'-(1,1-dimethylpropylamino)-propoxy]-β-phenylpropiophenon, seine Säureadditionssalze und Arzneimittel

Also Published As

Publication number Publication date
NO155771C (no) 1987-05-27
DE3226863A1 (de) 1983-04-07
EP0075207A3 (en) 1984-05-16
EP0075207B1 (de) 1986-02-05
ES515788A0 (es) 1983-05-01
FI823217L (fi) 1983-03-19
FI823217A0 (fi) 1982-09-17
DK416082A (da) 1983-03-19
CA1175831A (en) 1984-10-09
CS236489B2 (en) 1985-05-15
NO823161L (no) 1983-03-21
US4571409A (en) 1986-02-18
FI77224B (fi) 1988-10-31
DE3268963D1 (en) 1986-03-20
ES8305684A1 (es) 1983-05-01
EP0075207A2 (de) 1983-03-30
HU186576B (en) 1985-08-28
DK164699C (da) 1992-12-21
FI77224C (fi) 1989-02-10
NO155771B (no) 1987-02-16
IL66783A0 (en) 1982-12-31

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