DD237656A1 - PROCESS FOR THE PREPARATION OF 2-ACYLOXYALKYLAMINO- BZW. 2-acyloxyalkoxy-3-cyano-5 (pyrid-4-yl) -pyridines - Google Patents
PROCESS FOR THE PREPARATION OF 2-ACYLOXYALKYLAMINO- BZW. 2-acyloxyalkoxy-3-cyano-5 (pyrid-4-yl) -pyridines Download PDFInfo
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- DD237656A1 DD237656A1 DD27664085A DD27664085A DD237656A1 DD 237656 A1 DD237656 A1 DD 237656A1 DD 27664085 A DD27664085 A DD 27664085A DD 27664085 A DD27664085 A DD 27664085A DD 237656 A1 DD237656 A1 DD 237656A1
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- cyano
- pyrid
- pyridine
- pyridines
- acyloxyalkoxy
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- 238000000034 method Methods 0.000 title claims abstract description 6
- 238000002360 preparation method Methods 0.000 title abstract description 6
- RMHQDKYZXJVCME-UHFFFAOYSA-N 2-pyridin-4-ylpyridine Chemical class N1=CC=CC=C1C1=CC=NC=C1 RMHQDKYZXJVCME-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 4
- 150000004820 halides Chemical class 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 36
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 17
- 125000000217 alkyl group Chemical group 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
- -1 hydrogen halides Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 150000001412 amines Chemical class 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 150000001242 acetic acid derivatives Chemical class 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 150000003893 lactate salts Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000005528 methosulfate group Chemical group 0.000 claims 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 claims 1
- 150000003892 tartrate salts Chemical class 0.000 claims 1
- 230000003177 cardiotonic effect Effects 0.000 abstract description 5
- 229940124549 vasodilator Drugs 0.000 abstract description 2
- 239000003071 vasodilator agent Substances 0.000 abstract description 2
- 125000002252 acyl group Chemical group 0.000 abstract 1
- 125000003435 aroyl group Chemical group 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 239000000496 cardiotonic agent Substances 0.000 abstract 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
- IGONFPONKAUKLD-UHFFFAOYSA-N 2-(2-hydroxyethylamino)-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(NCCO)=NC=C1C1=CC=NC=C1 IGONFPONKAUKLD-UHFFFAOYSA-N 0.000 description 5
- YJLXVWCBWNRUMT-UHFFFAOYSA-N 2-(3-hydroxypropoxy)-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(OCCCO)=NC=C1C1=CC=NC=C1 YJLXVWCBWNRUMT-UHFFFAOYSA-N 0.000 description 4
- SBCUSYDATNLIBA-UHFFFAOYSA-N 2-(3-hydroxypropylamino)-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(NCCCO)=NC=C1C1=CC=NC=C1 SBCUSYDATNLIBA-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 3
- 231100000673 dose–response relationship Toxicity 0.000 description 3
- 229960003512 nicotinic acid Drugs 0.000 description 3
- 235000001968 nicotinic acid Nutrition 0.000 description 3
- 239000011664 nicotinic acid Substances 0.000 description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 230000000304 vasodilatating effect Effects 0.000 description 3
- GPVDHNVGGIAOQT-UHFFFAOYSA-N 2,4-dimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1 GPVDHNVGGIAOQT-UHFFFAOYSA-N 0.000 description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 2
- 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 2
- 241000700199 Cavia porcellus Species 0.000 description 2
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- 230000009090 positive inotropic effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- HETVWNJEAWTHHK-UHFFFAOYSA-N 2,4-dinitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C([N+]([O-])=O)=C1 HETVWNJEAWTHHK-UHFFFAOYSA-N 0.000 description 1
- OTGWBCPBQUKBIQ-UHFFFAOYSA-N 2-(2-hydroxyethoxy)-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(OCCO)=NC=C1C1=CC=NC=C1 OTGWBCPBQUKBIQ-UHFFFAOYSA-N 0.000 description 1
- KQYLRNMZLCARAZ-UHFFFAOYSA-N 2-(3-cyano-5-pyridin-4-ylpyridin-2-yl)oxyethyl acetate Chemical compound C1=C(C#N)C(OCCOC(=O)C)=NC=C1C1=CC=NC=C1 KQYLRNMZLCARAZ-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- GFYOLZOHEWUDBJ-UHFFFAOYSA-N 2-[(3-cyano-5-pyridin-4-ylpyridin-2-yl)amino]ethyl acetate Chemical compound C1=C(C#N)C(NCCOC(=O)C)=NC=C1C1=CC=NC=C1 GFYOLZOHEWUDBJ-UHFFFAOYSA-N 0.000 description 1
- KKAVIENLSFYGOI-UHFFFAOYSA-N 2-[(3-cyano-5-pyridin-4-ylpyridin-2-yl)amino]ethyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCNC(C(=C1)C#N)=NC=C1C1=CC=NC=C1 KKAVIENLSFYGOI-UHFFFAOYSA-N 0.000 description 1
- OMTXVPVNIDAYKD-UHFFFAOYSA-N 2-[(3-cyano-5-pyridin-4-ylpyridin-2-yl)amino]ethyl propanoate Chemical compound C1=C(C#N)C(NCCOC(=O)CC)=NC=C1C1=CC=NC=C1 OMTXVPVNIDAYKD-UHFFFAOYSA-N 0.000 description 1
- TYHPEZCKIXJZDZ-UHFFFAOYSA-N 2-[(3-cyano-5-pyridin-4-ylpyridin-2-yl)amino]ethyl pyridine-3-carboxylate Chemical compound C=1C=CN=CC=1C(=O)OCCNC(C(=C1)C#N)=NC=C1C1=CC=NC=C1 TYHPEZCKIXJZDZ-UHFFFAOYSA-N 0.000 description 1
- GQOJAXOTQYEZOS-UHFFFAOYSA-N 2-ethoxy-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(OCC)=NC=C1C1=CC=NC=C1 GQOJAXOTQYEZOS-UHFFFAOYSA-N 0.000 description 1
- SEQOYYYZFNJQSV-UHFFFAOYSA-N 2-oxo-5-pyridin-4-yl-1h-pyridine-3-carbonitrile Chemical compound C1=C(C#N)C(=O)NC=C1C1=CC=NC=C1 SEQOYYYZFNJQSV-UHFFFAOYSA-N 0.000 description 1
- RBIGCGZSGZUIPA-UHFFFAOYSA-N 3-(3-cyano-5-pyridin-4-ylpyridin-2-yl)oxypropyl acetate Chemical compound C1=C(C#N)C(OCCCOC(=O)C)=NC=C1C1=CC=NC=C1 RBIGCGZSGZUIPA-UHFFFAOYSA-N 0.000 description 1
- GAWJPDQHHWPWFG-UHFFFAOYSA-N 3-(3-cyano-5-pyridin-4-ylpyridin-2-yl)oxypropyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCCOC(C(=C1)C#N)=NC=C1C1=CC=NC=C1 GAWJPDQHHWPWFG-UHFFFAOYSA-N 0.000 description 1
- GKMNTBISTSVOGO-UHFFFAOYSA-N 3-(3-cyano-5-pyridin-4-ylpyridin-2-yl)oxypropyl propanoate Chemical compound C1=C(C#N)C(OCCCOC(=O)CC)=NC=C1C1=CC=NC=C1 GKMNTBISTSVOGO-UHFFFAOYSA-N 0.000 description 1
- SWOVITIVRHVQRN-UHFFFAOYSA-N 3-[(3-cyano-5-pyridin-4-ylpyridin-2-yl)amino]propyl acetate Chemical compound C1=C(C#N)C(NCCCOC(=O)C)=NC=C1C1=CC=NC=C1 SWOVITIVRHVQRN-UHFFFAOYSA-N 0.000 description 1
- GBSUZXCQSXHBDN-UHFFFAOYSA-N 3-[(3-cyano-5-pyridin-4-ylpyridin-2-yl)amino]propyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCCNC(C(=C1)C#N)=NC=C1C1=CC=NC=C1 GBSUZXCQSXHBDN-UHFFFAOYSA-N 0.000 description 1
- FAZPZUHICMEOEZ-UHFFFAOYSA-N 3-[(3-cyano-5-pyridin-4-ylpyridin-2-yl)amino]propyl propanoate Chemical compound C1=C(C#N)C(NCCCOC(=O)CC)=NC=C1C1=CC=NC=C1 FAZPZUHICMEOEZ-UHFFFAOYSA-N 0.000 description 1
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- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 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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- 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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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung von 2-Acyloxyalkylamino- bzw. 2-Acyloxyalkoxy-3-cyan-5-(pyrid-4-yl)-pyridinen, wobei als Acylgruppen Alkanoyl, Aroyl und Hetaroyl in Frage kommen. Das Ziel der Erfindung ist es, biologisch aktive 2-Acyl-oxyalkylamino- bzw. 2-Acyloxyalkoxy-3-cyan-5-(pyrid-4-yl)-pyridine herzustellen. Diese Aufgabe wird in der Weise geloest, dass 3-Cyan-2-hydroxyalkylamino- und 3-Cyan-2-hydroxalkoxy-5-(pyrid-4-yl)-pyridine mit Saeureanhydriden bzw. Saeurehalogeniden 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 2-acyloxyalkylamino or 2-acyloxyalkoxy-3-cyano-5- (pyrid-4-yl) -pyridines, alkanoyl, aroyl and hetaroyl being considered as acyl groups. The object of the invention is to produce biologically active 2-acyl-oxyalkylamino or 2-acyloxyalkoxy-3-cyano-5- (pyrid-4-yl) -pyridines. This object is achieved by reacting 3-cyano-2-hydroxyalkylamino and 3-cyano-2-hydroxyalkoxy-5- (pyrid-4-yl) -pyridines with acid anhydrides or acid halides, respectively. 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 2-Acyloxyalkylamino- bzw. 2-Acyloxyalkoxy-3-cyan-5-(pyrid-4-yl)-pyridinen der Formel IThe invention relates to a process for the preparation of 2-acyloxyalkylamino or 2-acyloxyalkoxy-3-cyano-5- (pyrid-4-yl) -pyridines of the formula I
CNCN
X-QCq--У IX-QCq - У I
in der X Z(CH2)nCHR, Y Alkyl, Phenyl, subst. Phenyl oder Hetaryl, Z O, NH oder N(CH2I2OCOY, R H, Alkyl oder OCOY und η 1 oder 2 bedeuten.in the XZ (CH 2 ) n CHR, Y is alkyl, phenyl, subst. Phenyl or hetaryl, ZO, NH or N (CH 2 I 2 OCOY, RH, alkyl or OCOY and η 1 or 2.
Die Verbindungen zeigen kardiotonische und vasodilatatorische Wirkung. Die Erfindung ist in der pharmazeutischen Industrie anwendbar.The compounds show cardiotonic and vasodilator effect. The invention is applicable in the pharmaceutical industry.
Einige 2-Alkylamino-3-cyan-5-(pyrid-4-yl!-pyridine sowie 2-Methoxy- und 2-Ethoxy-3-cyan-5-(pyrid-4-yl)-pyridin sind beschrieben (G.Y. Lesher, Ch. J. Opalka, D. F. Page; US-PS 4362734; P. Nantke-Namirski, LKaczmarek: Pol. J. Pharmacol. Pharm.Some 2-alkylamino-3-cyano-5- (pyrid-4-yl! -Pyridines as well as 2-methoxy- and 2-ethoxy-3-cyano-5- (pyrid-4-yl) -pyridine are described (GY Lesher Ch. J. Opalka, DF Page; U.S. Patent 4,362,734; P. Nantke-Namirski, LKaczmarek: Pol. J. Pharmacol. Pharm.
30,707 (1978); G.Y. Lesher, Ch.J.Opalka, B.Singh: US-PS 4463008).30,707 (1978); G.Y. Lesher, Ch.J.Opalka, B. Singh: U.S. Patent 4,463,008).
Bekannt sind auch 3-Amino-(bzw. 3-Nitro-, bzw. 3-Carbamido-)-2-(oxaalkylamino)-5-(pyrid-4-yl)-pyridine (G. Y. Lesher, Ch. J. Opalka, D. F. Page, US-PS 4297360 und US-PS 4374141) sowie 3-Cyan-5-(pyrid-4-yl)-1,2-dihydro-pyrid-2-on (s.z. B. G. Y. Lesher, Ch. J. Opalka, US-PS 4004012, US-PS 4199586 und US-PS 4264609). Die kardiotonische Wirkung der aufgeführten Stoffe ist beschrieben.Also known are 3-amino (or 3-nitro or 3-carbamido) -2- (oxaalkylamino) -5- (pyrid-4-yl) -pyridines (GY Lesher, Ch. J. Opalka, DF Page, US Pat. No. 4,297,360 and US Pat. No. 4,374,141) and also 3-cyano-5- (pyrid-4-yl) -1,2-dihydro-pyrid-2-one (see BGY Lesher, Ch. J. Opalka, U.S. Patent 4,004,012, U.S. Patent 4,195,586 and U.S. Patent 4,264,609). The cardiotonic effect of the listed substances is described.
Nicht bekannt sind bisher 2-Acyloxyalkylamino- bzw. 2-Acyloxyalkoxy-3-cyan-5-(pyrid-4-yl)-pyridine.2-Acyloxyalkylamino- or 2-acyloxyalkoxy-3-cyano-5- (pyrid-4-yl) -pyridines are not previously known.
Die erfindungsgemäß hergestellten 2-Acyloxyalkylamino- bzw. 2-Acyloxyalkoxy-3-cyan-5-(pyrid-4-yl)-pyridine weisen überraschend gute kardiotonische und vasodilatorische Wirkungen auf.The 2-acyloxyalkylamino- or 2-acyloxyalkoxy-3-cyano-5- (pyrid-4-yl) -pyridines prepared according to the invention have surprisingly good cardiotonic and vasodilatory effects.
Die Erfindung stellt sich das Ziel, neue biologisch aktive 3-Cyan-5-(pyrid-4-yl)-pyridine herzustellen.The invention aims to produce novel biologically active 3-cyano-5- (pyrid-4-yl) -pyridines.
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 2-Acyloxyalkoxy- bzw. 2-Acyloxyalkylamino-3-cyan-5-(pyrid-4-yl)-pyridine hergestellt 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 producing 2-acyloxyalkoxy or 2-acyloxyalkylamino-3-cyano-5- (pyrid-4-yl) -pyridines.
Erfindungsgemäß werden Verbindungen der Formel I hergestellt, indem man З-Суап-2-hydroxyalkylamino- bzw. 3-Cyan-2-hydroxyalkoxy-5-(pyrid-4-yl)-pyidine mit Säureanhydriden oder Säurehalogeniden umsetzt. Die Reaktion wird vorteilhaft in tert.According to the invention, compounds of the formula I are prepared by reacting З-С-Суап-2-hydroxyalkylamino- or 3-cyano-2-hydroxyalkoxy-5- (pyrid-4-yl) -pyidine with acid anhydrides or acid halides. The reaction is advantageously in tert.
Aminen, wie Pyridin oder Trialkylaminen als Lösungsmittel durchgeführt. Die З-Суап-2-acyloxyalkyl-amino- bzw. 3-Cyan-2-acyloxyalkoxy-5-(pyrid-4-yl)-pyridine lassen sich mit anorganischen oder organischen Säuren in die entsprechenden SalzeAmines, such as pyridine or trialkylamines carried out as a solvent. The З-Суап-2-acyloxyalkylamino or 3-cyano-2-acyloxyalkoxy-5- (pyrid-4-yl) -pyridines can be converted into the corresponding salts with inorganic or organic acids
überführen. Sowohl die freien Basen als auch ihre Salze sind biologisch aktiv. Insbesondere wurden kardiotonische und vasodilatatorische Wirkungen gefunden.convict. Both the free bases and their salts are biologically active. In particular, cardiotonic and vasodilatory effects were found.
So zeigen beispielsweise die 2-(Alkanoylalkylamino)- und die 2-(Alkanoylalkoxy)-3-cyan-5-(pyrid-4-yl)-pyridine sowohl am isolierten Vorhofpräparat des Meerschweinchens als auch nach i. v. Injektion am narkotisierten Hund ausgeprägt und dosisabhängige positiv inotrope Wirkungen. Zusätzlich konnte am narkotisierten Hund nach i.v. Injektion eine periphere vasodilatatorische Wirkung durch die gefundene Senkung des diastolischen Blutdruckes nachgewiesen werden.Thus, for example, the 2- (alkanoylalkylamino) - and the 2- (alkanoylalkoxy) -3-cyano-5- (pyrid-4-yl) -pyridine both on the isolated atrial preparation of the guinea pig and after i. v. Injection on anesthetized dog pronounced and dose-dependent positive inotropic effects. In addition, the anesthetized dog after i.v. Injecting a peripheral vasodilatory effect can be detected by the found reduction in diastolic blood pressure.
Die Erfindung soll anhand von Ausführungsbeispielen näher erläutert werden.The invention will be explained in more detail with reference to embodiments.
Beispiel 1 2-(2-Acetoxy-ethylamino)-3-cyan-5-(pyrid-4-yl)-pyridin 4,8g 3-Cyan-2-(2-hydroxy-ethylamino)-5-(pyrid-4-yl)-pyridin werden in 40 ml Pyridin mit 3ml Acetanhydrid 0,5Std. unter Feuchtigkeitsausschluß unter Rückfluß gekocht. Es wird eingeengt, mit Wasser versetzt und stehengelassen. Der ausfallende Feststoff wird abgesaugt, getrocknet und anschließend aus Ethanol unter Zusatz von Aktivkohle umkristallisiert. Ausbeute: 4,57g (80,1 % der Theorie). Schmp.:,141-2°C.Example 1 2- (2-Acetoxy-ethylamino) -3-cyano-5- (pyrid-4-yl) -pyridine 4.8g 3-cyano-2- (2-hydroxy-ethylamino) -5- (pyridine-4 -yl) -pyridine are dissolved in 40 ml of pyridine with 3 ml of acetic anhydride 0.5 h. boiled under reflux with exclusion of moisture. It is concentrated, mixed with water and allowed to stand. The precipitated solid is filtered off, dried and then recrystallized from ethanol with addition of activated carbon. Yield: 4.57 g (80.1% of theory). Schmp.:,141-2°C.
Beispiel 2 2-(3-Acetoxy-propylamino)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 1 aus 2,54g 3-Cyan-2-(3-hydroxy-propyl-amino)-5-(pyrid-4-yl)-pyridin und 1,5ml Acetanhydrid in 20ml Pyridin.Example 2 2- (3-Acetoxy-propylamino) -3-cyano-5- (pyrid-4-yl) pyridine Analogously to Example 1 from 2.54 g of 3-cyano-2- (3-hydroxy-propyl-amino) - 5- (pyrid-4-yl) -pyridine and 1.5 ml of acetic anhydride in 20 ml of pyridine.
Ausbeute: 2,47g (79,7% der Theorie). Schmp.: 137-8°C.Yield: 2.47 g (79.7% of theory). M.p .: 137-8 ° C.
Beispiel 3 2-(2-Acetoxy-ethoxy)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 1 aus 4,8g 3-Cyan-2-(2-hydroxy-ethoxy)-5-(pyrid-4-yl)-pyridin und 3ml Acetanhydrid in 40ml Pyridin. Ausbeute: 4,6g (81,1% der Theorie). Schmp.: 111-2°C.Example 3 2- (2-Acetoxy-ethoxy) -3-cyano-5- (pyrid-4-yl) -pyridine Analogous to Example 1 from 4.8 g of 3-cyano-2- (2-hydroxyethoxy) -5- (pyrid-4-yl) -pyridine and 3ml of acetic anhydride in 40ml of pyridine. Yield: 4.6 g (81.1% of theory). Mp .: 111-2 ° C.
Beispiel 4 2-(3-Acetoxy-propoxy)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 1 aus 1,28g 3-Cyan-2-(3-hydroxy-propoxy)-5-(pyrid-4-yl)-pyridin und 1 ml Acetanhydrid in 10ml Pyridin. Ausbeute: 0,7g (44,3% der Theorie). Schmp.: 94-60C.Example 4 2- (3-Acetoxy-propoxy) -3-cyano-5- (pyrid-4-yl) -pyridine Analogously to Example 1 from 1.28 g of 3-cyano-2- (3-hydroxy-propoxy) -5- (pyrid-4-yl) -pyridine and 1 ml of acetic anhydride in 10 ml of pyridine. Yield: 0.7 g (44.3% of theory). M.p .: 94-6 0 C.
Beispiel 5 2-(2-Propionyloxy-ethylamino)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 1 durch 1,5Std. Kochen von 3,6g 3-Cyan-2-(2-hydroxy-ethylamino)-5-(pyrid-4-yl)-pyridin mit 3ml Propionsäureanhydrid in 30ml Pyridin.Example 5 2- (2-Propionyloxyethylamino) -3-cyano-5- (pyrid-4-yl) -pyridine Analogously to Example 1, 1.5 h. Boil 3.6 g of 3-cyano-2- (2-hydroxyethylamino) -5- (pyrid-4-yl) -pyridine with 3 ml of propionic anhydride in 30 ml of pyridine.
Ausbeute: 4,18g (94,1 %derTheorie). Schmp.: 137-9°C.Yield: 4.18g (94.1% of theory). M.p .: 137-9 ° C.
Beispiel 6 2-(3-Propionyloxy-propylamino)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 1 durch 0,5Std. Kochen von 1,64g 3-Cyan-2-(3-hydroxy-propylamino)-5-(pyrid-4-yl)-pyridin mit 1,5ml Propionsäureanhydrid in 12ml Pyridin.Example 6 2- (3-Propionyloxypropylamino) -3-cyano-5- (pyrid-4-yl) -pyridine Analogously to Example 1, by 0.5 h. Boil 1.64 g of 3-cyano-2- (3-hydroxy-propylamino) -5- (pyrid-4-yl) -pyridine with 1.5 ml of propionic anhydride in 12 ml of pyridine.
Ausbeute: 1,59g (79,5%derTheorie). Schmp.: 126-7°C.Yield: 1.59 g (79.5% of theory). M.p .: 126-7 ° C.
Beispiel 7 2-(3-Propionyloxy-propoxy)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 1 aus 0,241 g 3-Cyan-2-(3-hydroxy-propoxy)-5-(pyrid-4-yl)-pyridin und 0,5ml Propionsäureanhydrid in 2ml Pyridin.Example 7 2- (3-Propionyloxy-propoxy) -3-cyano-5- (pyrid-4-yl) -pyridine Analogously to Example 1, 0.241 g of 3-cyano-2- (3-hydroxy-propoxy) -5- ( pyrid-4-yl) -pyridine and 0.5 ml of propionic anhydride in 2 ml of pyridine.
Ausbeute: 0,110g (35,4% der Theorie). Schmp.: 59-61 °C.Yield: 0.110 g (35.4% of theory). M .: 59-61 ° C.
Beispiel 8 2-(2-Benzoyloxy-ethylamino)-3-cyan-5-(pyrid-4-yl)-pyridin 1,2g 3-Cyan-2-(2-hydroxy-ethylamino)-5-(pyrid-4-yl)-pyridin werden in 10 ml Pyridin unter Rühren mit 2ml Benzoylchlorid versetzt. Es wird unter leichtem Erwärmen 10 Min. nachgerührt und mit 20 ml Wasser versetzt. Der ausfallende Feststoff wird abgesaugt und mit Wasser, Ethanol und Ether gewaschen. Ausbeute: 1,5g (87,2% der Theorie). Schmp.: 169-71°C.Example 8 2- (2-Benzoyloxyethylamino) -3-cyano-5- (pyrid-4-yl) pyridine 1.2g 3-Cyano-2- (2-hydroxy-ethylamino) -5- (pyrid-4 -yl) -pyridine are added in 10 ml of pyridine while stirring with 2ml of benzoyl chloride. The mixture is stirred with gentle warming for 10 min. And mixed with 20 ml of water. The precipitated solid is filtered off with suction and washed with water, ethanol and ether. Yield: 1.5 g (87.2% of theory). Mp .: 169-71 ° C.
Beispiel 9 2-(3-Benzoyloxy-propylamino)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 8 durch 10Min. Rühren von 1,11 g 3-Cyan-2-(3-hydroxy-propylamino)-5-(pyrid-4-yl)-pyridin mit 1 ml Benzoylchlorid in 10ml Pyridin.Example 9 2- (3-Benzoyloxy-propylamino) -3-cyano-5- (pyrid-4-yl) -pyridine Analogously to Example 8, by 10 min. Stir 1.11 g of 3-cyano-2- (3-hydroxy-propylamino) -5- (pyrid-4-yl) -pyridine with 1 ml of benzoyl chloride in 10 ml of pyridine.
Ausbeute: 1,45g (92,9% der Theorie). Schmp.: 152,5-3,5°C.Yield: 1.45 g (92.9% of theory). M .: 152.5-3.5 ° C.
Beispiel 10 2-(3-Benzoyloxy-propoxy)-3-cyan-5-(pyrid-4-yl)-pyridin Analog Beispiel 8 durch 10Min. Rühren von 0,48g 3-Cyan-2-(3-hydroxy-propoxy)-5-(pyrid-4-yl)-pyridin mit 1 ml Benzoylchlorid in 5ml Pyridin.Example 10 2- (3-Benzoyloxy-propoxy) -3-cyano-5- (pyrid-4-yl) -pyridine Analogously to Example 8, by 10 min. Stir 0.48 g of 3-cyano-2- (3-hydroxy-propoxy) -5- (pyrid-4-yl) -pyridine with 1 ml of benzoyl chloride in 5 ml of pyridine.
Ausbeute: 0,28g (38,9% der Theorie). Schmp.: 112-4°C.Yield: 0.28 g (38.9% of theory). Mp .: 112-4 ° C.
Beispiel 11 2-[2-(2,4-Dimethoxy-benzoyloxy)-ethylamino]-3-cyan-5-(pyrid-4-yl)-pyridin Durch Versetzen einer Lösung von 0,911 g 2,4-Dimethoxy-benzoesäure in 5ml Pyridin mit 0,6ml SOCI2, 5Min. Stehenlassen und Hinzufügen von 1,2g 3-Cyan-2-(2-hydroxy-ethylamino)-5-(pyrid-4-yl)-pyridin. Nach 15МІП. wird mit 20ml Wasser und 1 ml 5N NH3 versetzt. Der ausfallende Feststoff wird abgesaugt und aus Ethanol unter Zusatz von Aktivkohle umkristallisiert. Ausbeute: 0,87g (43,0% der Theorie). Schmp.: 155-8°C (Gelbfärbung).Example 11 2- [2- (2,4-Dimethoxybenzoyloxy) ethylamino] -3-cyano-5- (pyrid-4-yl) pyridine By treating a solution of 0.911 g of 2,4-dimethoxy-benzoic acid in 5ml pyridine with 0.6ml SOCl 2 , 5min. Leaving and adding 1.2 g of 3-cyano-2- (2-hydroxy-ethylamino) -5- (pyrid-4-yl) -pyridine. After 15МІП. 20 ml of water and 1 ml of 5N NH 3 are added. The precipitated solid is filtered off and recrystallized from ethanol with addition of activated carbon. Yield: 0.87 g (43.0% of theory). Mp .: 155-8 ° C (yellowing).
Beispiel 12 3-Cyan-2-[3-(2,4-dinitro-benzoyloxy)-propylamino]-5-(pyrid-4-yl)-pyridin Durch Versetzen von 1,27g 3-Cyan-2-(3-hydroxy-propylamino)-5-(pyrid-4-yl)-pyridin in 10ml Pyridin mit 1,2g 2,4-Dinitrobenzoylchlorid, 5 Min. Erwärmen, Stehenlassen bei Raumtemperatur, Versetzen mit Wasser, Absaugen und Waschen mit Wasser, Ethanol und Ether. Ausbeute: 1,45g (64,7% der Theorie). Schmp.: 204-70C (Zers.).Example 12 3-Cyano-2- [3- (2,4-dinitro-benzoyloxy) -propylamino] -5- (pyrid-4-yl) -pyridine By treating 1.27 g of 3-cyano-2- (3 Hydroxy-propylamino) -5- (pyrid-4-yl) -pyridine in 10 ml of pyridine with 1.2 g of 2,4-dinitrobenzoyl chloride, 5 min. Heating, leaving at room temperature, water, suction and washing with water, ethanol and ether. Yield: 1.45 g (64.7% of theory). M.p .: 204-7 0 C (Zers.).
Beispiel 13 3-Cyan-2-(2-nicotinoyloxy-ethylamino)-5-(pyrid-4-yl)-pyridin 3,5g Nicotinsäure in 20 ml Pyridin werden mit 3,3ml SOCI2 versetzt. Es wird 5 Min. auf 1000C erwärmt, abgekühlt, mit 4,8g 3-Cyan-2-(2-hydrox-ethylamino)-5-(pyrid-4-yl)-pyridin versetzt, 10 Min. unter Erwärmen auf 500C gerührt, abgekühlt und mit ca. 50 ml Wasser versetzt. Der ausfallende Feststoff wi rd abgesaugt, mitWasser, Ethanol und Ether gewaschen und aus Methylglykol/Ethanol unter Zusatz von Aktivkohle umkristallisiert. Ausbeute: 1,7g (24,6% der Theorie). Schmp.: 174-5°C.Example 13 3-Cyano-2- (2-nicotinoyloxyethylamino) -5- (pyrid-4-yl) -pyridine 3.5 g of nicotinic acid in 20 ml of pyridine are mixed with 3.3 ml of SOCl 2 . It is heated for 5 min. At 100 0 C, cooled, with 4.8 g of 3-cyano-2- (2-hydroxy-ethylamino) -5- (pyrid-4-yl) pyridine, 10 min. With warming to 50 0 C stirred, cooled and treated with about 50 ml of water. The precipitated solid was filtered off with suction, washed with water, ethanol and ether and recrystallized from methylglycol / ethanol with the addition of activated carbon. Yield: 1.7 g (24.6% of theory). M.p .: 174-5 ° C.
Beispiel 14 S-Cyan^-fS-nicotinoyloxy-propylaminol-S-lpyrid^-yO-pyridin Analog Beispiel 13 aus 0,369g Nicotinsäure, 0,33ml SOCI2, 2ml Pyridin und 0,509g S-Cyan^-O-hydroxy-propylaminol-S-lpyrid-4-yl)-pyridin.Example 14 Scyanyl-5-S-nicotinoyloxy-propylaminol-S-1-pyridyl-o-pyridine Analogously to Example 13, 0.369 g of nicotinic acid, 0.33 ml of SOCl 2 , 2 ml of pyridine and 0.509 g of S-cyano-O-hydroxy-propylaminol -S-lpyrid-4-yl) -pyridine.
Ausbeute: 0,155g (21,6% der Theorie). Schmp.: 192-5°C.Yield: 0.155 g (21.6% of theory). Mp .: 192-5 ° C.
Beispiel 15 З-Суап-г-ІЗ-пісоііпоуІоху-ргорохуЬБ-ІРУгісі^-уІІ-ругіаіп Analog Beispiel 13 aus 0,369g Nicotinsäure, 0,33 ml SOCI2,2 ml Pyridin und 0,481 g 3-Cyan-2-(3-hydroxy-propoxy)-5-(pyrid-4-yl)-pyridin.Example 15 З-Суап-г-ІЗ-пісоііпоуІоху-ргорохуЬБ-ІрУгісі ^ -уІІ-ругіаіp Analogously to Example 13 from 0.369 g of nicotinic acid, 0.33 ml of SOCl 2 , 2 ml of pyridine and 0.481 g of 3-cyano-2- (3 hydroxy-propoxy) -5- (pyrid-4-yl) -pyridine.
Ausbeute: 0,210g (29,2% derTheorie). Schmp.: 160-50C (Zers.).Yield: 0.210g (29.2% of theory). M .: 160-5 0 C (Zers.).
Beispiel 16 Narkotisierter Hund i.v.Example 16 Anesthetized dog i.v.
Die Untersuchungen wurden an Bastardhunden in Chloralose-Urethan-Narkose bei Prämediakation mit Morphinhydrochlorid unter spontaner Atmung durchgeführt.The studies were conducted on bastard dogs in chloralose-urethane anesthesia on premedication 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)].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 [cf. K. Femmer et al., Pharmacy 30, 642 (1975)].
Unter dem Einfluß der 2-Acyloxyalkylamino- und der 2-Acyloxyalkoxy-3-cyan-5-(pyrid-4-yl)-pyridine wurde eine dosisabhängige beträchtliche Steigerung der Kontraktionskraft des Herzens sowie teilweise eine signifikante Senkung des peripheren Gesamtwiderstandes beobachtet.Under the influence of 2-acyloxyalkylamino and 2-acyloxyalkoxy-3-cyano-5- (pyrid-4-yl) -pyridines, a dose-dependent significant increase in the contraction force of the heart and, in part, a significant reduction in total peripheral resistance were observed.
Beispielsweise zeigen die Verbindungen von Beispiel 1, 3 und 5 eine 50%ige Steigerung des Kontraktilitätsparameters dp/dtmax bei einer Dosis von 1,4 · 10"6,2,5 · 10~6bzw. 2,0 · 10~6mol/kg sowie eine 10%ige Senkung desdiastolischen Blutdruckes als relevantes Maß einer Abnahme des peripheren Gesamtwiderstandes bei einer Dosis von 1,6 · 10~6,1,6 · 10~6 bzw. 1,2- 10"6mol/kg.For example, the compounds of Examples 1, 3 and 5 show a 50% increase in Kontraktilitätsparameters dp / dt max at a dose of 1.4 x 10 "6 2.5 x 10 -6 and 2.0 x 10 ~ 6 mol / kg and a 10% reduction in blood pressure as desdiastolischen relevant measure a decrease in total peripheral resistance at a dose of 1.6 x 10 ~ 6, ~ 1.6 x 10 6 and 1.2 10 "6 mol / kg ,
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, spontan aktiven Vorhof erfolgte nach einer 60Min. währenden Adaptationszeit der Organpräparate in 320C temperierter carbogen-durchperlterTyrodelösung [nach A.A.AIousi, A. E.Farah, G. Y. Lesher, C. J.Opalka: Circ. Res. 45, (1979)] die Untersuchung der Beeinflussung von Inotropie und Frequenz unter Einwirkung der2-(Acyloxy-alkylamino)- und 2-Acyloxyalkoxy-3-cyan-5-(pyrid-4-yl)-pyridine.The isolated, spontaneously active atrium occurred after a 60 min. ending adaptation time of organ preparations tempered in 32 0 C carbogen-durchperlterTyrodelösung [according AAAIousi, AEFarah, GY Lesher, CJOpalka: Circ. Res. 45, (1979)] investigating the influence of inotropy and frequency under the action of 2- (acyloxyalkylamino) and 2-acyloxyalkoxy-3-cyano-5- (pyrid-4-yl) -pyridines.
Die Verbindungen zeigten eine teilweise starke und dosisabhängige positiv inotrope Wirkung.The compounds showed a partially strong and dose-dependent positive inotropic effect.
Beispielsweise zeigen die Verbindungen von Beispiel 1 und 3 eine 30%ige Steigerung der Inotropie bei Konzentrationen von 3,5 10~5 bzw. 5,4 · 10~5mol/l.For example, the compounds of Example 1 and 3 show a 30% increase in inotropy at concentrations of 3.5 10 -5 and 5.4 x 10 -5 mol / l.
Claims (3)
Priority Applications (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD27664085A DD237656A1 (en) | 1985-05-23 | 1985-05-23 | PROCESS FOR THE PREPARATION OF 2-ACYLOXYALKYLAMINO- BZW. 2-acyloxyalkoxy-3-cyano-5 (pyrid-4-yl) -pyridines |
| AT86104594T ATE77817T1 (en) | 1985-04-30 | 1986-04-04 | 3-CYAN-PYRIDINE, PROCESS FOR THEIR PRODUCTION AND PHARMACEUTICAL USE. |
| 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. |
| 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 |
|---|---|---|---|
| DD27664085A DD237656A1 (en) | 1985-05-23 | 1985-05-23 | PROCESS FOR THE PREPARATION OF 2-ACYLOXYALKYLAMINO- BZW. 2-acyloxyalkoxy-3-cyano-5 (pyrid-4-yl) -pyridines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DD237656A1 true DD237656A1 (en) | 1986-07-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DD27664085A DD237656A1 (en) | 1985-04-30 | 1985-05-23 | PROCESS FOR THE PREPARATION OF 2-ACYLOXYALKYLAMINO- BZW. 2-acyloxyalkoxy-3-cyano-5 (pyrid-4-yl) -pyridines |
Country Status (1)
| Country | Link |
|---|---|
| DD (1) | DD237656A1 (en) |
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1985
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