DD237657A1 - PROCESS FOR PREPARING 3-CYAN-6-METHYL-2- (OXAALKYLAMINO) -5- (PYRID-4-YL) -PYRIDINES - Google Patents
PROCESS FOR PREPARING 3-CYAN-6-METHYL-2- (OXAALKYLAMINO) -5- (PYRID-4-YL) -PYRIDINES Download PDFInfo
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- DD237657A1 DD237657A1 DD27664185A DD27664185A DD237657A1 DD 237657 A1 DD237657 A1 DD 237657A1 DD 27664185 A DD27664185 A DD 27664185A DD 27664185 A DD27664185 A DD 27664185A DD 237657 A1 DD237657 A1 DD 237657A1
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- 238000004519 manufacturing process Methods 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims abstract description 4
- 125000005191 hydroxyalkylamino group Chemical group 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 2
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract 2
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- 150000003839 salts Chemical class 0.000 claims description 3
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- 230000003177 cardiotonic effect Effects 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 4
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- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 229940124549 vasodilator Drugs 0.000 abstract 1
- 239000003071 vasodilator agent Substances 0.000 abstract 1
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- 239000002244 precipitate Substances 0.000 description 5
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- MUEMRZQRGPTWBY-UHFFFAOYSA-N 6-methyl-2-morpholin-4-yl-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound N#CC=1C=C(C=2C=CN=CC=2)C(C)=NC=1N1CCOCC1 MUEMRZQRGPTWBY-UHFFFAOYSA-N 0.000 description 3
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- 210000002837 heart atrium Anatomy 0.000 description 3
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- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
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- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000011835 investigation Methods 0.000 description 2
- CKFGINPQOCXMAZ-UHFFFAOYSA-N methanediol Chemical compound OCO CKFGINPQOCXMAZ-UHFFFAOYSA-N 0.000 description 2
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- 238000010992 reflux Methods 0.000 description 2
- KWFNMKXFFILFEL-WLHGVMLRSA-N (E)-but-2-enedioic acid 6-methyl-2-morpholin-4-yl-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound OC(=O)\C=C\C(O)=O.N#CC=1C=C(C=2C=CN=CC=2)C(C)=NC=1N1CCOCC1 KWFNMKXFFILFEL-WLHGVMLRSA-N 0.000 description 1
- HXKKHQJGJAFBHI-UHFFFAOYSA-N 1-aminopropan-2-ol Chemical compound CC(O)CN HXKKHQJGJAFBHI-UHFFFAOYSA-N 0.000 description 1
- AMSBCMMFDIWJJF-UHFFFAOYSA-N 2-(2-hydroxyethylamino)-6-methyl-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound CC1=NC(NCCO)=C(C#N)C=C1C1=CC=NC=C1 AMSBCMMFDIWJJF-UHFFFAOYSA-N 0.000 description 1
- RVIMXLUBAUPIDN-UHFFFAOYSA-N 2-(2-hydroxypropylamino)-6-methyl-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(NCC(O)C)=NC(C)=C1C1=CC=NC=C1 RVIMXLUBAUPIDN-UHFFFAOYSA-N 0.000 description 1
- WCPPYYZHEYLCAG-UHFFFAOYSA-N 2-(3-hydroxypropylamino)-6-methyl-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound CC1=NC(NCCCO)=C(C#N)C=C1C1=CC=NC=C1 WCPPYYZHEYLCAG-UHFFFAOYSA-N 0.000 description 1
- YJEJMRKEAZEQLG-UHFFFAOYSA-N 2-[bis(2-hydroxyethyl)amino]-6-methyl-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound CC1=NC(N(CCO)CCO)=C(C#N)C=C1C1=CC=NC=C1 YJEJMRKEAZEQLG-UHFFFAOYSA-N 0.000 description 1
- MKAWYORPNLOIRQ-UHFFFAOYSA-N 5-pyridin-4-ylpyridine-3-carbonitrile Chemical class N#CC1=CN=CC(C=2C=CN=CC=2)=C1 MKAWYORPNLOIRQ-UHFFFAOYSA-N 0.000 description 1
- MMVKROVBZFILBY-UHFFFAOYSA-N 6-methyl-5-pyridin-4-ylpyridine-3-carbonitrile Chemical class CC1=NC=C(C#N)C=C1C1=CC=NC=C1 MMVKROVBZFILBY-UHFFFAOYSA-N 0.000 description 1
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- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
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- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229960005195 morphine hydrochloride Drugs 0.000 description 1
- XELXKCKNPPSFNN-BJWPBXOKSA-N morphine hydrochloride trihydrate Chemical compound O.O.O.Cl.O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O XELXKCKNPPSFNN-BJWPBXOKSA-N 0.000 description 1
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- RLZZZVKAURTHCP-UHFFFAOYSA-N phenanthrene-3,4-diol Chemical compound C1=CC=C2C3=C(O)C(O)=CC=C3C=CC2=C1 RLZZZVKAURTHCP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
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- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
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Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung von 3-Cyan-6-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridinen, wobei als Oxaalkylaminosubstituenten Hydroxyalkylamino, Bis-(hydroxyalkyl)-amino, Alkoxyalkylamino oder Morpholino in Frage kommen. Ziel der Erfindung ist es, biologisch aktive 3-Cyan-6-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridine herzustellen. Diese Aufgabe wird in der Weise geloest, dass 3-Cyan-2-halogen-6-methyl-5-(pyrid-4-yl)-pyridine mit durch OH- bzw.- Alkoxygruppen substituierten primaeren und sekundaeren Alkylaminen in organischen Loesungsmitteln umgesetzt werden. Die Verbindungen sind moegliche Kardiotonika und Vasodilatatoren. Anwendungsgebiet der Erfindung ist die pharmazeutische Industrie.The invention relates to a process for the preparation of 3-cyano-6-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines, wherein as Oxaalkylaminosubstituenten hydroxyalkylamino, bis (hydroxyalkyl) amino, alkoxyalkylamino or morpholino come into question. The aim of the invention is to produce biologically active 3-cyano-6-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines. This object is achieved by reacting 3-cyano-2-halo-6-methyl-5- (pyrid-4-yl) -pyridines with primary and secondary alkylamines substituted by OH or alkoxy groups in organic solvents , The compounds are possible cardiotonics and vasodilators. Field of application of the invention is the pharmaceutical industry.
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von 3-Cyan-6-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridinen der Formel IThe invention relates to a process for preparing 3-cyano-6-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines of the formula I.
in der X Hydroxyalkylamino, Bis-(hydroxyalkyl)-amino, Alkoxyalkylamino oder Morpholino bedeutet.in which X is hydroxyalkylamino, bis (hydroxyalkyl) amino, alkoxyalkylamino or morpholino.
Die Verbindungen zeigen kardiotonische und vasodilatatorische Wirkungen. Die Erfindung ist in der pharmazeutischen Industrie anwendbar.The compounds show cardiotonic and vasodilatory effects. The invention is applicable in the pharmaceutical industry.
Einige 6-unsubstituierte und 6-alkylsubstituierte 2-Alkyl-amino-3-cyan-5-(pyrid-4-yl)-pyridine sind bekannt (G. Y. Lesher, Ch.J.Opalka, D.F.Page US-PS 4362734).Some 6-unsubstituted and 6-alkyl-substituted 2-alkyl-amino-3-cyano-5- (pyrid-4-yl) -pyridines are known (G.Y. Lesher, Ch.J.Opalka, D.F.Page U.S. Patent 4,362,734).
Beschrieben worden sind auch 6-unsubstituierte 3-Amino-(bzw. 3-Nitro- bzw. 3-Carbamido-)2-oxaalkylamino-5-(phyrid-4-yl)-pyridine(G.Y.Lesher, Ch.J.Opalka, D.F.Page, US-PS 4297360 und US-PS 4374141). Namentlich genannt, aber nicht charakterisiert, werden analoge 6-methyl-substituierte Pyridinderivate (G.A.Lesher, Ch.J.Opalka, D.F.Page, US-PS 4297360 und US-PS 4374141).Also described are 6-unsubstituted 3-amino (or 3-nitro or 3-carbamido) 2-oxaalkylamino-5- (phyrid-4-yl) pyridines (GY Lesher, Ch.J.Opalka, DFPage, US Pat. No. 4,297,360 and US Pat. No. 4,374,141). Mentioned by name, but not characterized, are analogous 6-methyl-substituted pyridine derivatives (G.A. Lesher, Ch.J.Opalka, D.F.Page, U.S. Patent 4,291,760 and U.S. Patent 4,374,141).
Die Darstellung erfolgt in der Regel durch Umsetzung entsprechender 2-Halogen-5-(pyrid-4-yl)-pyridine mit Aminen. Die kardiotonische Wirkung der aufgeführten Stoffe ist bekannt.The preparation is generally carried out by reacting corresponding 2-halo-5- (pyrid-4-yl) -pyridines with amines. The cardiotonic effect of the listed substances is known.
3-Cyan-6-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridine sind bisher nicht beschrieben worden.3-cyano-6-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines have not previously been described.
Die erfindungsgemäß hergestellten 3-Cyan-6-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridine weisen gute kardiotonische und zusätzlich vasodilatatorische Eigenschaften auf, bei relativ geringer Beeinflussung der Herzfrequenz.The 3-cyano-6-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines prepared according to the invention have good cardiotonic and additionally vasodilatory properties, with relatively little influence on the heart rate.
Die Erfindung stellt sich das Ziel, neue biologisch aktive 3-Cyan-6-methyl-5-(pyrid-4-yl)-pyridine herzustellen.The invention aims to produce novel biologically active 3-cyano-6-methyl-5- (pyrid-4-yl) -pyridines.
Darlegung des Wesens der ErfindungExplanation of the essence of the invention
Der Erfindung liegt die Aufgabe zugrunde, ein Verfahren zur Herstellung neuer 3-Cyan-5-(pyrid-4-yl)-pyridine zu entwickeln. Die Aufgabe wurde dadurch gelöst, daß 3-Cyan-6-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridine hergestellt werden. Erfindungsgemäß werden Verbindungen der Formel I hergestellt, indem man 3-Cyan-2-halogen-6-methyl-5-(pyrid-4-yl)-pyridine in organischen Lösungsmitteln unter Erwärmen mit Hydroxyalkylaminen, Bis-(hydroxyalkyl)-aminen, Alkoxyalkylaminen bzw. Morphol'rh umsetzt. Als organische Lösungsmittel können Alkohole, tertiäre Amine, Pyridin, Methylglykol, Dimethylformamid, Dimethylsulfoxid, Acetonitril oder auch entsprechende Lösungsmittelgemische eingesetzt werden.The invention has for its object to develop a process for the preparation of new 3-cyano-5- (pyrid-4-yl) -pyridines. The object has been achieved by preparing 3-cyano-6-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines. According to the invention, compounds of the formula I are prepared by reacting 3-cyano-2-halo-6-methyl-5- (pyrid-4-yl) -pyridines in organic solvents with heating with hydroxyalkylamines, bis (hydroxyalkyl) -amines, alkoxyalkylamines or Morphol'rh. As organic solvents it is possible to use alcohols, tertiary amines, pyridine, methyl glycol, dimethylformamide, dimethyl sulfoxide, acetonitrile or else corresponding solvent mixtures.
Die 3-Cyan-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridine lassen sich mit organischen und anorganischen Säuren in Wasser oder organischen Lösungsmitteln in die entsprechenden Salze überführen. Die freien Basen und ihre Salze sind biologisch aktiv. Insbesondere wurden kardiotonische und vasodilatatorische Wirkungen gefunden. ' 'The 3-cyano-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines can be converted into the corresponding salts with organic and inorganic acids in water or organic solvents. The free bases and their salts are biologically active. In particular, cardiotonic and vasodilatory effects were found. ''
Beispielsweise zeigen die 3-Cyan-2-(hydroxy-alkylamino)-6-methyl-5-(pyrid-4-yl)-pyridine am isolierten spontanaktiven Vorhof des Meerschweinchens eine ausgeprägte und dosisabhängige positiv inotrope Wirkung. Gute positiv inotrope Wirkungen sowie eine Abnahme des peripheren Gesamtwiderstandes wurden auch nach i.v. Injektion am narkotisierten Hund gefunden. Die Erfindung soll anhand von Ausführungsbeispielen näher erläutert werden.For example, the 3-cyano-2- (hydroxyalkylamino) -6-methyl-5- (pyrid-4-yl) -pyridines on isolated guinea pig spontaneously active atria show a pronounced and dose-dependent positive inotropic effect. Good positive inotropic effects as well as a decrease in total peripheral resistance were also reported after i.v. Injection found on anesthetized dog. The invention will be explained in more detail with reference to embodiments.
Beispiel 1 2-Chlor-3-cyan-6-methyl-5-(pyrid-4-yl)-pyridinExample 1 2-Chloro-3-cyano-6-methyl-5- (pyrid-4-yl) -pyridine
4g 3-Cyan-6-methyl-5-(pyrid-4-yl)-1,2-dihydro-pyrid-2-on werden mit 24ml POCL3 und 0,5ml Dimethylformamid 6 Stunden am Rückfluß gekocht. Nach Abkühlen auf Raumtemperatur wird die Reaktionslösung vorsichtig in 100 ml Eiswassergegossen, mit 6 N NH4OH neutralisiert, der ausfallende Feststoff abgesaugt und mit Wasser gewaschen. Der Niederschlag wird wieder in verdünnter HCL gelöst, die Lösung in der Wärme mit Aktivkohle versetzt, filtriert, mit NH4OH neutralisiert, der ausfallende Niederschlag abgesaugt, mit Wasser gewaschen und getrocknet4 g of 3-cyano-6-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one are refluxed with 24 ml of POCL 3 and 0.5 ml of dimethylformamide for 6 hours. After cooling to room temperature, the reaction solution is carefully poured into 100 ml of ice water, neutralized with 6 N NH 4 OH, the precipitated solid is filtered off with suction and washed with water. The precipitate is redissolved in dilute HCL, the solution is mixed with activated charcoal in the heat, filtered, neutralized with NH 4 OH, the resulting precipitate is filtered off with suction, washed with water and dried
Ausbeute: 3,8g (87,5% der Theorie). Schmp.: 155-7°C. Yield: 3.8 g (87.5% of theory). Mp .: 155-7 ° C.
Beispiel 2 3-Cyan-6-methyl-2-morpholino-5-(pyrid-4-yl)-pyridinExample 2 3-Cyano-6-methyl-2-morpholino-5- (pyrid-4-yl) -pyridine
1 g 2-Chlor-3-cyan-6-methyl-5-(pyrid-4-yl)-pyridin werden mit 2 ml Morpholin und 1 ml Pyridin in 25ml Acetonitril 5 Stunden unter Rückfluß gekocht. Nach Einengen des Absatzes auf die Hälfte und Stehen in der Kälte wird abgesaugt, das Produkt in verdünnter HCL gelöst, die Lösung mit Aktivkohle versetzt, filtriert und mit NH4OH neutralisiert. Der ausfallende Niederschlag wird abgesaugt und aus Ethanol/Wasser umkristallisiert1 g of 2-chloro-3-cyano-6-methyl-5- (pyrid-4-yl) -pyridine are refluxed with 2 ml of morpholine and 1 ml of pyridine in 25 ml of acetonitrile for 5 hours. After concentration of the paragraph to half and standing in the cold, the product is filtered off with suction, the product is dissolved in dilute HCL, the solution is mixed with activated charcoal, filtered and neutralized with NH 4 OH. The precipitate is filtered off and recrystallized from ethanol / water
Ausbeute: 0,7g (57,2% der Theorie). Schmp.: 169-710C.Yield: 0.7 g (57.2% of theory). M.p .: 169-71 0 C.
Beispiel 3 3-Cyan-2-(2-hydroxy-ethylamino)-6-methyl-5-(pyrid-4-yl)-pyridinExample 3 3-Cyano-2- (2-hydroxy-ethylamino) -6-methyl-5- (pyrid-4-yl) -pyridine
1g 2-Chlor-3-cyan-6-methyl-5-(pyrid-4-yl)-pyridin werden mit 2ml 1-Amino-ethanol-(2) in 25ml Ethanol 5 Stunden am Rückfluß erhitzt. Es wird in der Wärme mit Aktivkohle versetzt, heiß filtriert, etwas eingeengt und in der Kälte stehengelassen. Der ausfallende Niederschlag wird abgesaugt1 g of 2-chloro-3-cyano-6-methyl-5- (pyrid-4-yl) -pyridine are refluxed with 2 ml of 1-amino-ethanol- (2) in 25 ml of ethanol for 5 hours. Activated charcoal is added to the heat, filtered while hot, concentrated slightly and allowed to stand in the cold. The precipitate is sucked off
Ausbeute: 0,7g (62,9% der Theorie). Schmp.: 192-4°C. Yield: 0.7 g (62.9% of theory). Mp .: 192-4 ° C.
Beispiel 4 3-Cyan-2-(3-hydroxy-propylamino)-6-methyl-5-(pyrid-4-yl)-pyridinExample 4 3-Cyano-2- (3-hydroxy-propylamino) -6-methyl-5- (pyrid-4-yl) -pyridine
1g2-Chlor-3-cyan-6-methyl-5-(pyrid-4-yl)-pyridin werden mit 2ml 1-Amino-propanol-(3) und 1 ml Pyridin in 25ml Ethanol1g2-Chloro-3-cyano-6-methyl-5- (pyrid-4-yl) -pyridine are mixed with 2 ml of 1-amino-propanol- (3) and 1 ml of pyridine in 25 ml of ethanol
5 Stunden am Rückfluß gekocht. Der Absatz wird im Vakuum eingeengt, der Rückstand in HCL gelöst, mit Aktivkohle versetzt, filtriert und mit NH4OH gefällt. Anschließend wird aus Ethanol/Wasser umkristallisiert und das Produkt bei 1100C getrocknet. Ausbeute: 0,65g (55,4%derTheorie). Schmp:: 122-4°C.Cooked for 5 hours at reflux. The heel is concentrated in vacuo, the residue dissolved in HCL, treated with activated charcoal, filtered and precipitated with NH 4 OH. / Water is then recrystallized from ethanol and the product dried at 110 0 C. Yield: 0.65 g (55.4% of theory). Mp: 122-4 ° C.
Beispiel 5 3-Cyan-2-(2-hydroxy-propylamino)-6-methyl-5-(pyrid-4-yl)-pyridinExample 5 3-Cyano-2- (2-hydroxy-propylamino) -6-methyl-5- (pyrid-4-yl) -pyridine
1 g 2-Chlor-3-cyan-6-methyl-5-(pyrid-4-yl)-pyridin werden mit 2ml 1-Amino-propanol-(2) und 1ml Pyridin in 25ml Methylglykol1 g of 2-chloro-3-cyano-6-methyl-5- (pyrid-4-yl) -pyridine are mixed with 2 ml of 1-amino-propanol- (2) and 1 ml of pyridine in 25 ml of methylene glycol
6 Stunden am Rückfluß gekocht. Es wird im Vakuum etwas eingeengt, mit Wasser versetzt und in der Kälte stehengelassen. Der ausfallende Niederschlag wird abgesaugt und aus iso-Propanol umkristallisiert.Cooked for 6 hours at reflux. It is slightly concentrated in vacuo, mixed with water and allowed to stand in the cold. The precipitate is filtered off with suction and recrystallized from isopropanol.
Ausbeute: 0,8g (68,2% der Theorie). Schmp.: 178-810C.Yield: 0.8 g (68.2% of theory). M.p .: 178-81 0 C.
Beispiel 6 2-[Bis-(2-hydroxyethyl)-amino]-3-cyan-6-methyi-5-(pyrid-4-yl)-pyridinExample 6 2- [Bis (2-hydroxyethyl) amino] -3-cyano-6-methyl-5- (pyrid-4-yl) pyridine
1 g 2-Chlor-3-cyan-6-methyl-5-(pyrid-4-yl)-pyridin werden mit 2ml Diethanolamin und 1 ml Pyridin in 25 ml iso-Propanol 5 Stunden am Rückfluß gekocht. Das iso-Propanol wird im Vakuum abrotiert, der Rückstand in 1 N HCL gelöst, mit Aktivkohle versetzt, filtriert und mit NH4OH gefällt. Anschließend wird aus Ethanol/Wasser umkristallisiert und bei 120°C getrocknet. Ausbeute: 0,85g (65,2% der Theorie). Schmp.: 133-6°C.1 g of 2-chloro-3-cyano-6-methyl-5- (pyrid-4-yl) -pyridine are refluxed with 2 ml of diethanolamine and 1 ml of pyridine in 25 ml of isopropanol for 5 hours. The isopropanol is evaporated in vacuo, the residue dissolved in 1 N HCL, mixed with activated charcoal, filtered and precipitated with NH 4 OH. It is then recrystallized from ethanol / water and dried at 120 ° C. Yield: 0.85 g (65.2% of theory). Mp .: 133-6 ° C.
Beispiel 7 3-Cyan-6-methyl-2-morphoIino-5-(pyrid-4-yl)-pyridin-fumaratExample 7 3-Cyano-6-methyl-2-morpholino-5- (pyrid-4-yl) -pyridine fumarate
280 mg 3-Cyan-6-methyl-2-morpholino-5-(pyrid-4-yl)-pyridin werden in der Wärme in 20 ml Ethanol gelöst und mit 116mg Fumarsäure in 10ml Ethanol versetzt. Nach Stehen über Nacht bei 6-100C wird abgesaugt. Ausbeute: 260mg (77% der Theorie). Schmp.: 179-8O0C.280 mg of 3-cyano-6-methyl-2-morpholino-5- (pyrid-4-yl) -pyridine are dissolved in 20 ml of ethanol while warm and treated with 116 mg of fumaric acid in 10 ml of ethanol. After standing overnight at 6-10 0 C is filtered with suction. Yield: 260 mg (77% of theory). Mp .: 179-8O 0 C.
Für die Versuche wurden männliche Meerschweinchen mit einer Körpermasse von 400-50Og verwendet.For the experiments male guinea pigs with a body mass of 400-50Og were used.
Am isolierten, spontanaktiven Vorhof erfolgte nach einer 60 Min. währenden Adaptationszeit der Organpräparate in 30°C temperiertercarbogendurchperlterTyrodelösung (nach A.A.AIousi, A.E. Farah,G.Y. Lesher, C.J.Opalka: Circ. Res. 45,666 (1979)) die Untersuchung der Beeinflussung von Inotropie und Frequenz unter Einwirkung der 3-Cyan-6-methyl-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridine. Die Verbindungen zeigten eine deutliche und konzentrationsabhängige positiv inotrope Wirkung.The isolated, spontaneously active atrium was examined after 60 min of adaptation of the organ preparations in 30 ° C tempered percolates of tyrodolysis (according to AA Aousousi, AE Farah, GY Lesher, CJOpalka: Circ.Res.45,666 (1979)) the investigation of the influence of inotropy and Frequency under the action of 3-cyano-6-methyl-2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridine. The compounds showed a marked and concentration-dependent positive inotropic effect.
Beispielsweise zeigen die Verbindungen von Beispiel 3,4 und 5 30 % Steigerung der Inotropie bei Konzentrationen von 5,8 · 10~s, 9,1 10~5, bzw. 1,6-10~4mol/l.For example, the compounds of Example 3,4, and 5 30% increase in inotropy at concentrations of 5.8 x 10 ~ s, ~ 9.1 10 5, or 1.6 to 10 ~ 4 mol / l.
Beispiel 9 Narkotisierter Hund i. v.Example 9 Anesthetized dog i. v.
Die Untersuchungen wurden an Bastardhunden in Chloralose-Urethan-Narkose bei Prämedikation mit Morphinhydrochforid unter spontaner Atmung durchgeführt.Investigations were performed on bastard dogs in chloralose urethane anesthesia when premedicated with morphine hydrochloride under spontaneous respiration.
Der linksventrikuläre Druck wurde mittels Tipmanometer und der arterielle Druck wurde über Herzkatheter via A. brachialis gemessen (vgl. K. Femmer et al. ,Pharmazie 30,642(1975)). Unter dem Einfluß der 3-Cyan-6-methyl-2-oxaalkylamino-5-(pyrid-4-yl)-pyridine wurde eine dosisabhängige deutliche Steigerung der Kontraktionskraft des Herzens sowie eine signifikante Senkung des pheripheren Gesamtwiderstandes beobachtet.The left ventricular pressure was measured by means of a tip manometer and the arterial pressure was measured via cardiac catheter via the brachial artery (compare K. Femmer et al., Pharmacia 30, 642 (1975)). Under the influence of 3-cyano-6-methyl-2-oxaalkylamino-5- (pyrid-4-yl) -pyridines, a dose-dependent marked increase in the contraction force of the heart as well as a significant reduction of the peripheral total resistance was observed.
So zeigt beispielsweise 3-Cyan-6-methyl-2-morpholino-5-(pyrid-4-yl)-pyridin bei einer Dosis von 6,1 · 10~6mol/kg eine 50%ige Steigerung des Kontraktilitätsparameters dp/dtmax sowie bei 2,1 · 10~6mol/kg eine 10%ige Senkung desdiastolischen Blutdruckes als relevantes Maß der Abnahme des peripheren Gesamtwiderstandes.For example, FIG 3-cyano-6-methyl-2-morpholino-5- (pyrid-4-yl) -pyridine at a dose of 6.1 x 10 -6 mol / kg, a 50% increase in Kontraktilitätsparameters dp / dt max as well as 2.1 x 10 -6 mol / kg, a 10% reduction in blood pressure desdiastolischen as a relevant measure of the decrease in total peripheral resistance.
Claims (3)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD27664185A DD237657A1 (en) | 1985-05-23 | 1985-05-23 | PROCESS FOR PREPARING 3-CYAN-6-METHYL-2- (OXAALKYLAMINO) -5- (PYRID-4-YL) -PYRIDINES |
| EP86104594A EP0200024B1 (en) | 1985-04-30 | 1986-04-04 | 3-cyano-pyridines, process for their preparation and their pharmaceutical use |
| DE8686104594T DE3685840D1 (en) | 1985-04-30 | 1986-04-04 | 3-CYAN-PYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR PHARMACEUTICAL USE. |
| AT86104594T ATE77817T1 (en) | 1985-04-30 | 1986-04-04 | 3-CYAN-PYRIDINE, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL USE. |
| HU861790A HU196059B (en) | 1985-04-30 | 1986-04-29 | Process for producing 3-cyano-pyridine derivatives and pharmaceutical compositions containing them as active components |
| JP61100804A JPS61254563A (en) | 1985-04-30 | 1986-04-30 | Novel 3-cyan-pyridine, manufacture and pharmacological use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD27664185A DD237657A1 (en) | 1985-05-23 | 1985-05-23 | PROCESS FOR PREPARING 3-CYAN-6-METHYL-2- (OXAALKYLAMINO) -5- (PYRID-4-YL) -PYRIDINES |
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| Publication Number | Publication Date |
|---|---|
| DD237657A1 true DD237657A1 (en) | 1986-07-23 |
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| Application Number | Title | Priority Date | Filing Date |
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| DD27664185A DD237657A1 (en) | 1985-04-30 | 1985-05-23 | PROCESS FOR PREPARING 3-CYAN-6-METHYL-2- (OXAALKYLAMINO) -5- (PYRID-4-YL) -PYRIDINES |
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| DD (1) | DD237657A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0445553A1 (en) * | 1990-03-09 | 1991-09-11 | ARZNEIMITTELWERK DRESDEN GmbH | Compact crystalline 3-cyano-2-morpholino-5-(pyridyl-4)-pyridine with high bulk density and process for preparation |
-
1985
- 1985-05-23 DD DD27664185A patent/DD237657A1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0445553A1 (en) * | 1990-03-09 | 1991-09-11 | ARZNEIMITTELWERK DRESDEN GmbH | Compact crystalline 3-cyano-2-morpholino-5-(pyridyl-4)-pyridine with high bulk density and process for preparation |
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