CH632246A5 - Process for preparing novel 3-aminopropoxyindoles - Google Patents
Process for preparing novel 3-aminopropoxyindoles Download PDFInfo
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- CH632246A5 CH632246A5 CH907777A CH907777A CH632246A5 CH 632246 A5 CH632246 A5 CH 632246A5 CH 907777 A CH907777 A CH 907777A CH 907777 A CH907777 A CH 907777A CH 632246 A5 CH632246 A5 CH 632246A5
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- 238000004519 manufacturing process Methods 0.000 title claims description 5
- VONDEAICGOZHRO-UHFFFAOYSA-N 3-(1h-indol-2-yloxy)propan-1-amine Chemical class C1=CC=C2NC(OCCCN)=CC2=C1 VONDEAICGOZHRO-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 32
- 238000005576 amination reaction Methods 0.000 claims abstract description 3
- 150000003839 salts Chemical class 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- IMLAIXAZMVDRGA-UHFFFAOYSA-N 2-phenoxyethanamine Chemical compound NCCOC1=CC=CC=C1 IMLAIXAZMVDRGA-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- -1 cyano, carbamoyl Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Natural products OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N isopropyl alcohol Natural products CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- KTODVGFADXOWDU-UHFFFAOYSA-N 1-[(3-chloro-2-methyl-1h-indol-4-yl)oxy]-3-(2-phenoxyethylamino)propan-2-ol Chemical compound C=12C(Cl)=C(C)NC2=CC=CC=1OCC(O)CNCCOC1=CC=CC=C1 KTODVGFADXOWDU-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- PGANIVKNTNPEIF-UHFFFAOYSA-N 3-chloro-2-methyl-4-(oxiran-2-ylmethoxy)-1h-indole Chemical compound C=12C(Cl)=C(C)NC2=CC=CC=1OCC1CO1 PGANIVKNTNPEIF-UHFFFAOYSA-N 0.000 claims description 2
- QISOBCMNUJQOJU-UHFFFAOYSA-N 4-bromo-1h-pyrazole-5-carboxylic acid Chemical compound OC(=O)C=1NN=CC=1Br QISOBCMNUJQOJU-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 230000008020 evaporation Effects 0.000 claims description 2
- 235000013312 flour Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-M malonate(1-) Chemical compound OC(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-M 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 230000003285 pharmacodynamic effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 229910052717 sulfur Chemical group 0.000 claims description 2
- 239000011593 sulfur Chemical group 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 2
- 230000000903 blocking effect Effects 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 230000003042 antagnostic effect Effects 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 1
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 206010021333 Ileus paralytic Diseases 0.000 description 1
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 206010047139 Vasoconstriction Diseases 0.000 description 1
- 230000001800 adrenalinergic effect Effects 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000001834 epinephrinelike Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000002837 heart atrium Anatomy 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000297 inotrophic effect Effects 0.000 description 1
- 230000008991 intestinal motility Effects 0.000 description 1
- 229960001317 isoprenaline Drugs 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 201000007620 paralytic ileus Diseases 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The compounds of the formula I, <IMAGE> in which the substituents possess the meaning given in Patent Claim 1, are novel. They exhibit alpha - and beta -adrenoceptor-blocking and antihypertensive effects and can therefore be used as drugs. They are obtained by amination.
Description
**WARNUNG** Anfang DESC Feld konnte Ende CLMS uberlappen **.
PATENTANSPRÜCHE 1. Verfahren zur Herstellung der neuen Verbindungen der For mehl,
EMI1.1
worin
A Alkylen mit 2 bis 5 Kohlenstoffatomen bedeutet,
X für Sauerstoff oder Schwefel steht,
R3 Wasserstoff, Hydroxy, Alkoxy mit 1 bis 4 Kohlenstoffatomen, Halogen mit einer Ordnungszahl von 9 bis 35, Cyano, Carbamoyl oder Acetamido bedeutet, und R4Wasserstoff bedeutet und, falls R3 Alkoxy mit 1 bis 4 Kohlenstoffatomen bedeutet, zudem auch für Alkoxy mit 1 bis 4 Kohlenstoffatomen oder, falls R3 Halogen mit einer Ordnungszahl von 9 bis 35 bedeutet, zudem auch für Halogen mit einer Ordnungszahl von 9 bis 35 stehen kann, entweder R1 Methyl und R2 Halogen mit einer Ordnungszahl von 17 oder 35, oder Rl Halogen mit einer Ordnungszahl von 17 oder 35 und R2 Wasserstoffoder Methyl bedeuten,
mit der Massgabe, dass
X durch mindestens 2 Kohlenstoffatome vom Stickstoffatom der 3-Amino-2-hydroxypropoxykette entfernt ist, und ihrer Salze, dadurch gekennzeichnet, dass man Verbindungen der Formel II,
EMI1.2
worin Rl und R2 obige Bedeutung besitzen und Rx für einen Rest steht, der bei der Umsetzung mit einem Amin eine 2-Amino-lhydroxyethylgruppe ergibt, mit entsprechenden Verbindungen der Formel III,
EMI1.3
worin A, X, R3 und R4 obige Bedeutung besitzen, umsetzt, und die so erhaltenen Verbindungen der Formel I in freier Form oder in Salzform gewinnt.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass man Verbindungen der Formel II, in denen Rl Chlor und R2 Methyl bedeuten und Rx die in Anspruch 1 angegebene Bedeutung besitzt, mit 2-Phenoxyethylamin umsetzt und das so erhaltene 1-(3-Chlor-2 methylindol-4-yloxy)-3-(2-phenoxyethylamino)-2-propanol in freier Form oder in Salzform gewinnt.
Die Erfindung betrifft den in den Ansprüchen definierten Gegenstand.
Strukturell ähnliche Verbindungen sind z.B. aus ICI DOS Nr. 1493853, ICI DOS Nr. 1593901 oder Cigy DOS Nr.2520910 be- kannt.
R2 bedeutet vorzugsweise Wasserstoff oder Methyl. R3 steht vorzugsweise für Wasserstoff, Hydroxy, Alkoxy, Cyano oder Carbamoyl. X steht vorzugsweise für Sauerstoff.
Alkyl und Alkoxy enthalten vorzugsweise 1 oder 2, insbesondere 1 Kohlenstoffatom(e). Halogen bedeutet insbesondere Chlor.
A steht vorzugsweise für verzweigtes, insbesondere in a-Stellung zum Stickstoffatom der Seitenkette verzweigtes Alkylen, z.B. 2-Butylen, 2-Methyl-2-butylen oder 2-Methyl-2-propylen, oder für Ethylen.
Ist der Phenylring der Seitenkette mono- bzw. disubstituiert, so stehen die Substituenten vorzugsweise in 4- bzw. 3,4-Stellung.
Die Verbindungen der Formel I können in freier Form oder in Salzform vorliegen. Aus den Verbindungen der Formel I in freier Form lassen sich in bekannter Weise Salze gewinnen und umgekehrt.
So bilden die Verbindungen der Formel I, z.B. mit anorganischen Säuren wie Chlorwasserstoff- oder Bromwasserstoffsäure, oder mit organischen Säuren wie Fumar- oder Maleinsäure, Säureadditionssalze.
Die erfindungsgemässe Umsetzung ist eine Aminierung durch ein primäres Amin. Sie kann unter Verwendung von für die Herstellung bekannter 3-Amino-2-hydroxypropoxyarylverbindungen bekannten Bedingungen erfolgen. Als Gruppe Rx verwendet man beispielsweise die Gruppe
EMI1.4
oder ein reaktionsfähiges Derivat dieser Gruppe, beispielsweise eine Gruppe der Formel
EMI1.5
worin Y für Halogen, vorzugsweise Chlor oder Brom, oder eine Gruppe R,-SO,-O- steht, worin Ry Phenyl, Tolyl oder niederes Alkyl bedeutet. Y steht insbesondere für Chlor.
Aus dem Reaktionsgemisch können die Verbindungen der Formel I nach bekannten Methoden isoliert und gereinigt werden.
In den Verbindungen der Formel list das Kohlenstoffatom der Seitenkette, das die Hydroxygruppe trägt, asymmetrisch; sie können daher in Form der entsprechenden Enantiomeren auftreten. Die Enantiomeren der Verbindungen der Formeln können auf an sich bekannte Weise erhalten werden, z.B. durch Ausführung der erfindungsgemässen Umsetzung ausgehend von entsprechenden, optisch aktiven Ausgangsprodukten.
Soweit die Herstellung der benötigten Ausgangsmaterialien nicht beschrieben wird, sind diese bekannt oder können nach bekannten Verfahren bzw. analog zu an sich bekannten Verfahren hergestellt werden.
Im nachfolgenden Beispiel erfolgen alle Temperaturangaben in Celsiusgraden und sind unkorrigiert.
Beispiel: I- (3-Chlor-2-methylindol-4-yloxy) -3- (2-phenoxyetl?ylamino) -
2-propanol
5 g 3-Chlor-4-(2,3-epoxypropoxy)-2-methylindol, 4,3 g 2phenoxyethylamin und 75 ml Dioxan werden 15 h in einem Autoklaven auf 130 erhitzt. Nach Abkühlen wird das Dioxan am Wasserstrahlvakuum und der Überschuss an 2-Phenoxyethylamin am Hochvakuum bei 80 abdestilliert. Den Rückstand schüttelt man zwischen Weinsäurelösung und Methylenchlorid aus, stellt die saure Phase mit konz. Ammoniak alkalisch und extrahiert mit Methylenchlorid. Nach Abdampfen des Lösungsmittels kristallisiert der Rückstand mit 0,5 mol Malonsäure aus Methanol (Smp. der Hydrogenmalonats 135 bis 137"; Smp. des Bis[base]fumarats 187 bis l90).
Die Verbindungen der Formel I in freier Form oder in Form ihrer physiologisch verträglichen Salze, zeichnen sich durch interessante pharmakodynamische Eigenschaften aus. Sie können als Heilmittel verwendet werden.
Sie zeigen an isolierten Spiralstreifen der Venafemoralis und Ar
teria coronaria von Hunden nach Noradrenalin- bzw. Isoprenalinzusatz [E. Müller-Schweinitzer und E. Stürmer, Br. J. Pharmac. (1974) 51, 441-446; T.J. Bücher et al., Naunyn-Schmiedberg's Arch.
Pharmacol. 280 (1973) 153-160] eine Blockade von x-bzw. p-Adre- nozeptoren, wobei diese antagonistische Wirkung bei Badkonzentrationen von ca. 10-9 bis 10 -6 M auftritt. Am spontanschlagenden, isolierten Meerschweinchenvorhof [K. Saameli, Helv. Physiol.
Acta 25(1967) CR 219-CR 221) zeigen sie eine Hemmung der positivinotropen Adrenalinwirkung, wobei diese antagonistische Wirkung bei Badkonzentrationen von ca. 0,005 bis 2,5 mg/l auftritt.
Sie können daher als x- und -Rezeptorenblocker u.a. zur Prophylaxe und Therapie von Krankheitszuständen, die mit einer adrenergischen Vasokonstriktion verbunden sind, sowie von Koronarerkrankungen, insbesondere zur Behandlung von Anginapectoris, Verwendung finden. Ausserdem eignen sie sich zur Behandlung von Krankheitszuständen, die mit einer Lähmung der Darmmotilität einhergehen, z.B. vom paralytischen Ileus. Aufgrund ihrer antiarrhythmischen Wirkung können sie zudem zur Behandlung von Herzrhythmusstörungen eingesetzt werden.
Für obige Anwendungen variieren die zu verwendenden Dosen naturgemäss je nach Art der verwendeten Substanz, der Verabreichung und des zu behandelnden Zustandes. Im allgemeinen werden jedoch befriedigende Resultate mit einer Tagesdosis von etwa 1 bis 100 mg erreicht. Diese Dosis kann nötigenfalls in 2 bis 4 Anteilen oder auch als Retardform verabreicht werden. Für orale Applikationen enthalten die Teildosen etwa 0,25 bis 50 mg der neuen Verbindungen neben festen oder flüssigen Trägersubstanzen.
Sie besitzen ausserdem antihypertensive Eigenschaften, wie sich bei Tierversuchen an der hypertonen Grollman-Ratte [Methode nach A. Grollman, Proc. Soc. Exptl. Biol. and Med. 57(1944)102] bei Dosen von ungefähr 0,1 bis 10 mg/kg s.c. und ungefähr 10 bis 100 mg/kg p.o. und an der normotonen narkotisierten Ratte [Methode nach D. Chu, A. Hofmann und E. Stürmer, Naunyn Schmiedberg's Arch. Pharmacol. (1975), Suppl. 287, R 18] bei Dosen von ungefähr 0,01 bis 5 mg/kg i.v. zeigt.
Aufgrund ihrer blutdrucksenkenden Wirkung können sie als Antihypertensiva z.B. in der Hochdrucktherapie Anwendung finden.
Die zu verwendenden Dosen variieren naturgemäss je nach Art der Substanz, der Verabreichung und des zu behandelnden Zustandes.
Im allgemeinen werden jedoch befriedigende Resultate mit einer täglichen Dosis von ca. 0,1 bis 100 mg erhalten; diese Dosis kann nötigenfalls in 2 bis 4 Anteilen oder auch als Retardform verabreicht werden. So enthalten z.B. für orale Applikationen die Teildosen etwa 0,025 bis 50 mg der Verbindungen der Formel I neben festen oder flüssigen Trägersubstanzen.
Von den Verbindungen der Formel I in optisch aktiver Form sind diejenigen Verbindungen, in denen das Kohlenstoffatom in 2-Stellung der Seitenkette die (S)-Konfiguration aufweist, p-blockierend und antihypertensiv aktiver als die entsprechenden (R)-Enantiomeren.
Die Verbindungen der Formel I in freier Form oder in Form ihrer physiologisch verträglichen Salze können allein oder in geeigneter Dosierungsform verabreicht werden. Die Arzneiformen, z.B. eine Tablette, können analog zu bekannten Methoden hergestellt werden.
** WARNING ** beginning of DESC field could overlap end of CLMS **.
PATENT CLAIMS 1. Process for the production of new compounds of flour,
EMI1.1
wherein
A denotes alkylene with 2 to 5 carbon atoms,
X represents oxygen or sulfur,
R3 is hydrogen, hydroxy, alkoxy with 1 to 4 carbon atoms, halogen with an atomic number of 9 to 35, cyano, carbamoyl or acetamido, and R4 is hydrogen and, if R3 is alkoxy with 1 to 4 carbon atoms, also for alkoxy with 1 to 4 carbon atoms or, if R3 is halogen with an atomic number from 9 to 35, can also stand for halogen with an atomic number from 9 to 35, either R1 methyl and R2 halogen with an atomic number of 17 or 35, or Rl halogen with an atomic number of 17 or 35 and R2 are hydrogen or methyl,
with the proviso that
X is removed from the nitrogen atom of the 3-amino-2-hydroxypropoxy chain and its salts by at least 2 carbon atoms, characterized in that compounds of the formula II,
EMI1.2
wherein Rl and R2 have the above meaning and Rx is a radical which, when reacted with an amine, gives a 2-amino-lhydroxyethyl group, with corresponding compounds of the formula III,
EMI1.3
wherein A, X, R3 and R4 have the meaning given above, and the compounds of the formula I thus obtained are obtained in free form or in salt form.
2. The method according to claim 1, characterized in that compounds of the formula II in which Rl is chlorine and R2 are methyl and Rx has the meaning given in claim 1, are reacted with 2-phenoxyethylamine and the 1- (3-chloro -2 methylindol-4-yloxy) -3- (2-phenoxyethylamino) -2-propanol in free form or in salt form.
The invention relates to the subject-matter defined in the claims.
Structurally similar connections are e.g. known from ICI DOS No. 1493853, ICI DOS No. 1593901 or Cigy DOS No. 2520910.
R2 is preferably hydrogen or methyl. R3 preferably represents hydrogen, hydroxy, alkoxy, cyano or carbamoyl. X preferably represents oxygen.
Alkyl and alkoxy preferably contain 1 or 2, in particular 1 carbon atom (s). Halogen in particular means chlorine.
A is preferably branched, especially branched alkylene to the nitrogen atom of the side chain, e.g. 2-butylene, 2-methyl-2-butylene or 2-methyl-2-propylene, or for ethylene.
If the phenyl ring of the side chain is mono- or disubstituted, the substituents are preferably in the 4- or 3,4-position.
The compounds of formula I can be in free form or in salt form. Salts can be obtained in a known manner from the compounds of formula I in free form and vice versa.
Thus the compounds of formula I, e.g. with inorganic acids such as hydrochloric or hydrobromic acid, or with organic acids such as fumaric or maleic acid, acid addition salts.
The reaction according to the invention is an amination by a primary amine. It can be carried out using conditions known for the preparation of known 3-amino-2-hydroxypropoxyaryl compounds. For example, the group Rx is used as the group
EMI1.4
or a reactive derivative of this group, for example a group of the formula
EMI1.5
wherein Y is halogen, preferably chlorine or bromine, or a group R, -SO, -O-, where Ry is phenyl, tolyl or lower alkyl. Y stands in particular for chlorine.
The compounds of the formula I can be isolated and purified from the reaction mixture by known methods.
In the compounds of the formula the carbon atom of the side chain which carries the hydroxyl group is asymmetrical; they can therefore occur in the form of the corresponding enantiomers. The enantiomers of the compounds of the formulas can be obtained in a manner known per se, e.g. by carrying out the implementation according to the invention on the basis of corresponding, optically active starting products.
Insofar as the production of the required starting materials is not described, they are known or can be produced by known processes or analogously to processes known per se.
In the following example, all temperatures are in degrees Celsius and are uncorrected.
Example: I- (3-chloro-2-methylindol-4-yloxy) -3- (2-phenoxyetl? Ylamino) -
2-propanol
5 g of 3-chloro-4- (2,3-epoxypropoxy) -2-methylindole, 4.3 g of 2phenoxyethylamine and 75 ml of dioxane are heated to 130 in an autoclave for 15 h. After cooling, the dioxane is distilled off in a water jet vacuum and the excess of 2-phenoxyethylamine in a high vacuum at 80. The residue is shaken out between tartaric acid solution and methylene chloride, the acid phase is made up with conc. Ammonia alkaline and extracted with methylene chloride. After evaporation of the solvent, the residue crystallizes with 0.5 mol of malonic acid from methanol (mp. Of the hydrogen malonate 135 to 137 "; mp. Of the bis [base] fumarate 187 to 190).
The compounds of the formula I in free form or in the form of their physiologically tolerable salts are distinguished by interesting pharmacodynamic properties. They can be used as a remedy.
They show isolated spiral strips of the Venafemoralis and Ar
teria coronaria of dogs after noradrenaline or isoprenaline addition [E. Müller-Schweinitzer and E. Stürmer, Br. J. Pharmac. (1974) 51, 441-446; T.J. Buech et al., Naunyn-Schmiedberg's Arch.
Pharmacol. 280 (1973) 153-160] a blockage of x or. p-adrenoceptors, whereby this antagonistic effect occurs at bath concentrations of approx. 10-9 to 10 -6 M. In the spontaneously striking, isolated guinea pig atrium [K. Saameli, Helv. Physiol.
Acta 25 (1967) CR 219-CR 221) show an inhibition of the positively inotropic adrenaline effect, this antagonistic effect occurring at bath concentrations of approximately 0.005 to 2.5 mg / l.
Therefore, as x and receptor blockers, you can for the prophylaxis and therapy of disease states associated with an adrenergic vasoconstriction, as well as coronary diseases, in particular for the treatment of angina pectoris. They are also suitable for the treatment of conditions associated with paralysis of the intestinal motility, e.g. from the paralytic ileus. Due to their antiarrhythmic effects, they can also be used to treat cardiac arrhythmias.
For the above applications, the doses to be used naturally vary depending on the type of substance used, the administration and the condition to be treated. In general, however, satisfactory results are achieved with a daily dose of approximately 1 to 100 mg. If necessary, this dose can be administered in 2 to 4 portions or as a slow-release form. For oral applications, the partial doses contain about 0.25 to 50 mg of the new compounds in addition to solid or liquid carriers.
They also have antihypertensive properties, as can be seen in animal experiments on the hypertonic Grollman rat [method according to A. Grollman, Proc. Soc. Exptl. Biol. And Med. 57 (1944) 102] at doses of approximately 0.1 to 10 mg / kg s.c. and about 10 to 100 mg / kg p.o. and on the normotonic anesthetized rat [method according to D. Chu, A. Hofmann and E. Stürmer, Naunyn Schmiedberg's Arch. Pharmacol. (1975), Suppl. 287, R 18] at doses of approximately 0.01 to 5 mg / kg IV. shows.
Due to their hypotensive effects, they can be used as antihypertensives e.g. find application in high pressure therapy.
The doses to be used naturally vary depending on the type of substance, the administration and the condition to be treated.
In general, however, satisfactory results are obtained with a daily dose of approximately 0.1 to 100 mg; if necessary, this dose can be administered in 2 to 4 portions or as a slow-release form. For example, for oral applications, the partial doses of about 0.025 to 50 mg of the compounds of the formula I in addition to solid or liquid carriers.
Of the compounds of formula I in optically active form, those compounds in which the carbon atom in the 2-position of the side chain has the (S) configuration are p-blocking and antihypertensively more active than the corresponding (R) -enantiomers.
The compounds of the formula I in free form or in the form of their physiologically tolerable salts can be administered alone or in a suitable dosage form. The dosage forms, e.g. a tablet, can be prepared analogously to known methods.
Claims (2)
Priority Applications (22)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH907777A CH632246A5 (en) | 1977-07-21 | 1977-07-21 | Process for preparing novel 3-aminopropoxyindoles |
| CH141082A CH634050A5 (en) | 1977-07-21 | 1978-01-01 | 3-Aminopropoxyindoles |
| DE19782830211 DE2830211A1 (en) | 1977-07-21 | 1978-07-10 | SUBSTITUTED INDOL DERIVATIVES, THEIR PRODUCTION AND USE |
| SE7807753A SE435374B (en) | 1977-07-21 | 1978-07-12 | THERAPEUTICALLY ACTIVE DERIVATIVES OF 4- (2-HYDROXY-3-AMINO-PROPOXY) INDOLES, THEIR PREPARATION AND USE. |
| FI782229A FI782229A7 (en) | 1977-07-21 | 1978-07-12 | ORGANISKA FOERENINGAR DERAS FRAMSTAELLNING OCH ANVAENDNING |
| DK312878A DK312878A (en) | 1977-07-21 | 1978-07-12 | PROCEDURE FOR THE PREPARATION OF CONTENT DERIVATIVES |
| IT50299/78A IT1105092B (en) | 1977-07-21 | 1978-07-14 | INDOLATION DERIVATIVES THEIR PREPARATION AND THEIR APPLICATION AS MEDICATIONS |
| US05/925,196 US4235919A (en) | 1977-07-21 | 1978-07-17 | 1-(Indol-4-yloxy)-3-(2-substituted amino)-2-propanols and pharmaceutical use thereof |
| NL7807626A NL7807626A (en) | 1977-07-21 | 1978-07-17 | NEW ORGANIC COMPOUNDS, AND METHOD FOR PREPARING THEM, AND THERAPEUTIC PREPARATIONS CONTAINING THESE COMPOUNDS. |
| AU38182/78A AU523105B2 (en) | 1977-07-21 | 1978-07-19 | l-(INDOL-4-YLOXY)-3-AMINO-2-PROPANOI COMPOUNDS |
| BE189392A BE869133A (en) | 1977-07-21 | 1978-07-19 | NEW DERIVATIVES OF INDOLE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
| GB7830345A GB2001971B (en) | 1977-07-21 | 1978-07-19 | Organic compounds |
| ES471863A ES471863A1 (en) | 1977-07-21 | 1978-07-19 | PROCEDURE TO PREPARE INDOLIC DERIVATIVES |
| IE1448/78A IE47131B1 (en) | 1977-07-21 | 1978-07-19 | Indoles |
| NZ187909A NZ187909A (en) | 1977-07-21 | 1978-07-19 | 3-(indol-4-yloxy)-1-substitutedaminopropan-2-ols and pharmaceutical compositions |
| SU782639449A SU843740A3 (en) | 1977-07-21 | 1978-07-19 | Method of preparing indole derivatives or their salts |
| IL55170A IL55170A (en) | 1977-07-21 | 1978-07-19 | Indole derivatives,their production and pharmaceutical compositions containing them |
| PT68317A PT68317A (en) | 1977-07-21 | 1978-07-19 | PROCESS FOR THE PREPARATION OF NEW ORGANIC COMPOUNDS PHARMACEUTICAL EFFECT |
| AT525878A AT371111B (en) | 1977-07-21 | 1978-07-20 | METHOD FOR PRODUCING NEW INDOLES AND THEIR SALTS |
| CA307,768A CA1098909A (en) | 1977-07-21 | 1978-07-20 | Indolyloxy-aminopropanol derivatives |
| JP8781878A JPS5422364A (en) | 1977-07-21 | 1978-07-20 | Improvement of organic compound |
| FR7821679A FR2398058A1 (en) | 1977-07-21 | 1978-07-21 | NEW DERIVATIVES OF INDOLE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH907777A CH632246A5 (en) | 1977-07-21 | 1977-07-21 | Process for preparing novel 3-aminopropoxyindoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH632246A5 true CH632246A5 (en) | 1982-09-30 |
Family
ID=4348101
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH907777A CH632246A5 (en) | 1977-07-21 | 1977-07-21 | Process for preparing novel 3-aminopropoxyindoles |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH632246A5 (en) |
-
1977
- 1977-07-21 CH CH907777A patent/CH632246A5/en not_active IP Right Cessation
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