DD263759A1 - PROCESS FOR PREPARING 1-SUBSTITUTED 2-IMINO-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRIDINE-3-CARBOXYLIC ACID DERIVATIVES - Google Patents
PROCESS FOR PREPARING 1-SUBSTITUTED 2-IMINO-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRIDINE-3-CARBOXYLIC ACID DERIVATIVES Download PDFInfo
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- DD263759A1 DD263759A1 DD28857986A DD28857986A DD263759A1 DD 263759 A1 DD263759 A1 DD 263759A1 DD 28857986 A DD28857986 A DD 28857986A DD 28857986 A DD28857986 A DD 28857986A DD 263759 A1 DD263759 A1 DD 263759A1
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- German Democratic Republic
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- pyrid
- pyridine
- diene
- dihydro
- dimethylamino
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- -1 1-SUBSTITUTED 2-IMINO-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRIDINE-3-CARBOXYLIC ACID Chemical class 0.000 title claims abstract description 29
- 238000004519 manufacturing process Methods 0.000 title 1
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims abstract description 8
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 18
- MMLMEECXZDRMKF-UHFFFAOYSA-N 2-[3-(dimethylamino)-2-pyridin-4-ylprop-2-enylidene]propanedinitrile Chemical compound N#CC(C#N)=CC(=CN(C)C)C1=CC=NC=C1 MMLMEECXZDRMKF-UHFFFAOYSA-N 0.000 claims description 9
- LZUPMCSGVZIFGY-UHFFFAOYSA-N 3-pyridin-4-ylpenta-1,3-diene-1,1,5,5-tetracarbonitrile Chemical compound N#CC(C#N)C=C(C=C(C#N)C#N)C1=CC=NC=C1 LZUPMCSGVZIFGY-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- CHCQMZSLUCAICN-UHFFFAOYSA-M [(z)-3-(dimethylamino)-2-pyridin-4-ylprop-2-enylidene]-dimethylazanium;hydron;dichloride Chemical compound Cl.[Cl-].CN(C)\C=C(\C=[N+](C)C)C1=CC=NC=C1 CHCQMZSLUCAICN-UHFFFAOYSA-M 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 claims description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 125000005270 trialkylamine group Chemical group 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims 1
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical class OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 230000007935 neutral effect Effects 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 238000011084 recovery Methods 0.000 claims 1
- 150000003141 primary amines Chemical class 0.000 abstract description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 abstract 1
- 235000019270 ammonium chloride Nutrition 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- SJSWRKNSCWKNIR-UHFFFAOYSA-N azane;dihydrochloride Chemical compound N.Cl.Cl SJSWRKNSCWKNIR-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 210000002837 heart atrium Anatomy 0.000 description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- LLQIOINUINTIRY-UHFFFAOYSA-N 1-amino-2-imino-5-pyridin-4-ylpyridine-3-carbonitrile Chemical compound C1=C(C#N)C(=N)N(N)C=C1C1=CC=NC=C1 LLQIOINUINTIRY-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- 241000700199 Cavia porcellus Species 0.000 description 2
- 150000003973 alkyl amines Chemical class 0.000 description 2
- 238000005576 amination reaction Methods 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- QOHMWDJIBGVPIF-UHFFFAOYSA-N n',n'-diethylpropane-1,3-diamine Chemical compound CCN(CC)CCCN QOHMWDJIBGVPIF-UHFFFAOYSA-N 0.000 description 2
- 230000009090 positive inotropic effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- PIUXLKSAXJSXII-UHFFFAOYSA-N 1-[3-(diethylamino)propyl]-2-imino-5-pyridin-4-ylpyridine-3-carboxamide Chemical compound C1=C(C(N)=O)C(=N)N(CCCN(CC)CC)C=C1C1=CC=NC=C1 PIUXLKSAXJSXII-UHFFFAOYSA-N 0.000 description 1
- ODFNIQQRJXTWFD-UHFFFAOYSA-N 1-amino-2-imino-5-pyridin-4-ylpyridine-3-carboxamide Chemical compound NN1C(=N)C(C(=O)N)=CC(C=2C=CN=CC=2)=C1 ODFNIQQRJXTWFD-UHFFFAOYSA-N 0.000 description 1
- KPIVDNYJNOPGBE-UHFFFAOYSA-N 2-aminonicotinic acid Chemical class NC1=NC=CC=C1C(O)=O KPIVDNYJNOPGBE-UHFFFAOYSA-N 0.000 description 1
- PYADPEUGUMOZIC-UHFFFAOYSA-N 2-imino-1-(2-methoxyethyl)-5-pyridin-4-ylpyridine-3-carboxamide Chemical compound C1=C(C(N)=O)C(=N)N(CCOC)C=C1C1=CC=NC=C1 PYADPEUGUMOZIC-UHFFFAOYSA-N 0.000 description 1
- CTVDPRQKVHCUBZ-UHFFFAOYSA-N 2-iminopyridin-1-amine Chemical compound NN1C=CC=CC1=N CTVDPRQKVHCUBZ-UHFFFAOYSA-N 0.000 description 1
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 1
- MRBBILGEGDTQSU-UHFFFAOYSA-N 4-(1,2-dihydropyridin-5-yl)pyridine Chemical class N1CC=CC(=C1)C1=CC=NC=C1 MRBBILGEGDTQSU-UHFFFAOYSA-N 0.000 description 1
- KUJGPWCHTNKMII-UHFFFAOYSA-N 5-pyridin-4-ylpyridin-2-amine Chemical class C1=NC(N)=CC=C1C1=CC=NC=C1 KUJGPWCHTNKMII-UHFFFAOYSA-N 0.000 description 1
- FDCZBYDNEANTDK-UHFFFAOYSA-N C(#N)C(=CC(=CN(C)C)C1=CC=NC=C1)C(=O)O Chemical class C(#N)C(=CC(=CN(C)C)C1=CC=NC=C1)C(=O)O FDCZBYDNEANTDK-UHFFFAOYSA-N 0.000 description 1
- ICXKAWHEUJAZBX-UHFFFAOYSA-N C1=C(C#N)C(=N)N(CCN)C=C1C1=CC=NC=C1 Chemical compound C1=C(C#N)C(=N)N(CCN)C=C1C1=CC=NC=C1 ICXKAWHEUJAZBX-UHFFFAOYSA-N 0.000 description 1
- FGCMNZPTVXVFRT-UHFFFAOYSA-N CN(C(=C(C=CC#N)C1=CC=NC=C1)C#N)C Chemical compound CN(C(=C(C=CC#N)C1=CC=NC=C1)C#N)C FGCMNZPTVXVFRT-UHFFFAOYSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- CHKQALUEEULCPZ-UHFFFAOYSA-N amino 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S(=O)(=O)ON)C(C)=C1 CHKQALUEEULCPZ-UHFFFAOYSA-N 0.000 description 1
- IMUDHTPIFIBORV-UHFFFAOYSA-N aminoethylpiperazine Chemical compound NCCN1CCNCC1 IMUDHTPIFIBORV-UHFFFAOYSA-N 0.000 description 1
- 150000003974 aralkylamines Chemical class 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- QDXJJOSPIHZHMZ-UHFFFAOYSA-N penta-1,3-diene-1,1,5,5-tetracarbonitrile Chemical compound N#CC(C#N)C=CC=C(C#N)C#N QDXJJOSPIHZHMZ-UHFFFAOYSA-N 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- LTEKQAPRXFBRNN-UHFFFAOYSA-N piperidin-4-ylmethanamine Chemical compound NCC1CCNCC1 LTEKQAPRXFBRNN-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridine hydrochloride Substances [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
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- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung von 1-substituierten 2-Imino-5-(pyrid-4-yl)-1,2-dihydro-pyridin-3-carbonsaeure-Derivaten der Formel I durch Umsetzung von N,N-Dimethylamino-N-&3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyliden!-ammoniumchloriden mit Malodinitril bzw. Cyanacetamid und nachfolgende Reaktion mit primaeren Aminen oder Hydrazin. Das Anwendungsgebiet der Erfindung ist die pharmazeutische Industrie.The invention relates to a process for the preparation of 1-substituted 2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives of the formula I by reacting N, N-dimethylamino N- & 3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene! Ammonium chlorides with malononitrile or cyanoacetamide and subsequent reaction with primary amines or hydrazine. The field of application of the invention is the pharmaceutical industry.
Description
Die Erfindung betrifft ein Verfahren zur Herstellung von 1 -substituierten 2-lmino-5-(pyrid-4-yl)-1,2-dihydro-pyridin-3-carbonsäurederivaten der Formel IThe invention relates to a process for the preparation of 1-substituted 2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives of the formula I.
in der X Cyan oder Carbamoyl und R Alkyl, Hydroxyalkyl, Aminoalkyl, Aralkyl oder Amino bedeuten.in which X is cyano or carbamoyl and R is alkyl, hydroxyalkyl, aminoalkyl, aralkyl or amino.
Die Verbindungen sind Zwischenprodukte für die Darstellung von biologisch aktiven Stoffen, insbesondere von Pharmska und Pflanzenschutzmitteln.The compounds are intermediates for the preparation of biologically active substances, especially pharmaceuticals and pesticides.
Die Erfindung ist in dei pharmazeutischen Industrie anwendbar.The invention is applicable to the pharmaceutical industry.
Es ist bekannt, daß unsubstituierte, alkylsubstituierte und ary.3ubstjtuierte 1 -Cyan^-dialkylamino-buta- 1,3-dien-1 -carbonsäure-Derivate mit NH3 zu 2-Amino-pyridin-3-carbonsäure-Derivaten cyciisiert werden können (s. z. B. G. Ege, H. O. Frey, E. Schuck, Synthesis 1979, 336; R.-D. Acker, G. Hamprecht EP-PS 57827; H.Kurihara, H.Mishima, J.Heterocycl. Chem. 14,1077(1977]; J. Liebscher, H.Hartmann, J. prakt. Chem. 318,705 [1976); N.I.Smetskaya, N.A.Muchina, W.G.Granik, Khim. Geterosikl. SoecJin. 1984,799, J. L. Miesel US-PS 440555?, 1JS-PS 4508722 und EP-PS 60071). Beschrieben worden sind auch 1-Alky!-6-aryl-2-imino-1,2-dihydro-pyndin-3-carbonsäure-Derivate (J. Liebscher, H. Hartmann, J. prakt. Chem. 318,705 [1976]. Ihre Darstellung erfolgteIt is known that unsubstituted, alkyl-substituted and aryl-substituted 1-cyano-dialkylamino-1,3-diene-1-carboxylic acid derivatives can be cyciisiert with NH 3 to 2-amino-pyridine-3-carboxylic acid derivatives (See BG Ege, HO Frey, E. Schuck, Synthesis 1979, 336, R.-D. Acker, G. Hamprecht EP-PS 57827, H.Kurihara, H.Mishima, J. Heterocycl, Chem. Chem. 318,705 [1976]; NISmetskaya, NAMuchina, WG Granik, Khim. Geterosikl Soec Jin 1984, 799, JL Miesel US Patent 4,405,555, 1 JS-PS 4508722 and EP-PS 60071). 1-Alky! -6-aryl-2-imino-1,2-dihydro-pyndin-3-carboxylic acid derivatives have also been described (J. Liebscher, H. Hartmann, J. prakt. Chem. 318,705 [1976]. Your presentation took place
durch Umsetzung von 4-Aryl-4-chlor-1-cyan-buta-1,3-dien-1-carbonsäure-Derivaten mit Alkylaminen zu 4-Alkylamino-4-aryl-1-cyan-buta-I.S-dien-i-carbonsäure-Derivaten und anschließende Cyclisierung. Als Syntheseverfahren für 1-Amino-2-imino-1,2-dihydro-pyridin ist die Aminierung von 2-Amino-pyridin mit O-Mesitylensulfonylhydroxylamin beschrieben (vgl. Y.Tamura. J. Minamikawa, M. Ikeda, Synthesis 1977,1).by reacting 4-aryl-4-chloro-1-cyano-buta-1,3-diene-1-carboxylic acid derivatives with alkylamines to give 4-alkylamino-4-aryl-1-cyano-buta-IS-diene-i carboxylic acid derivatives and subsequent cyclization. As a synthetic method for 1-amino-2-imino-1,2-dihydro-pyridine, the amination of 2-amino-pyridine with O-mesitylenesulfonylhydroxylamine is described (see Y. Tamura, J. Minamikawa, M. Ikeda, Synthesis 1977, 1).
4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril, 3-(Py rid-4-yl)-penta-1,3-dien-1,1,5,5-tetracarbonitril sowie 1-substituierte 2-lmino-5-(pyrid-4-yl)-1,2-dihydro-pyridin-carbonsäure-Derivate sind bisher nicht bekannt.4-Dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile, 3- (Pyrid-4-yl) -penta-1,3-diene-1,1 , 5,5-Tetracarbonitril and 1-substituted 2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine-carboxylic acid derivatives are not known.
Die Erfindung stellt sich das Ziel, neue, als Zwischenprodukte für die Synthese biologisch aktiver Verbindungen nutzbare 3-(Pyrid-4-yl)-1,2-dihydro-pyridin-3-carbonsäure-Derivate, herzustellen.The invention seeks to produce novel, useful as intermediates for the synthesis of biologically active compounds 3- (pyrid-4-yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives.
Der Erfindung liegt die Aufgabe zugrunde, ein Verfahren zur Herste'lung neuer 5-(Pyrid-4-yl)-1,2-dihydro-pyridine zu entwickeln. Die Aufgabe wurde dadurch gelöst, daß 1 -substituierte 2-lmino-b-(pyrid-4-yl)-1 ^-dihydro-pyridin-S-carbonsäure-Derivate hergestellt werden.The object of the invention is to develop a process for the preparation of novel 5- (pyrid-4-yl) -1,2-dihydro-pyridines. The object has been achieved by preparing 1-substituted 2-imino-b- (pyrid-4-yl) -1-dihydro-pyridine-S-carboxylic acid derivatives.
Erfindungsgemäß werden Verbindungen der Formel I, in der X Cyan oder Carbamoyl und R Alkyl, Hydroxyalkyl, Aminoalkyl oder Amino bedeuten, hergestellt, indem N.N-Dimethy.'-N-IS-dimethylamino^-lpyrid^-yD-prop^-enylidenl-ammoniumchloridhydrochlorid mit Malodinitril oder Cyanacetamid in geeigneten Lösungsmitteln, wie Alkoholen, Wasser, Pyridin, tertiären Aminen, Dimethylformamid oder Gemischen dieser Lösungsmittel in Gegenwart von Basen, beispielsweise Alkalialkoliolaten, Alkalicarbonate!!, Pyridin oder Trialkylaminen zu 1-Cyan-4-dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1-carbonsäure-Derivaten umgesetzt werden und diese dann durch Reaktion mit primären Alkylaminen, Aralkylamine^ Hydroxyalkylaminen, Aminoalkylaminen oder Hydrazin in 1-substituierte 2-lmino-5-(pyrid-4-yl)-1,2-dihydro-pyridin-3-carbonsäure-Derivate überführt werden.According to the invention, compounds of the formula I in which X is cyano or carbamoyl and R is alkyl, hydroxyalkyl, aminoalkyl or amino are prepared by reacting N, N-dimethyl-N-is-dimethylamino-1-pyridyl, -N-propyl-enylidenyl ammonium chloride hydrochloride with malononitrile or cyanoacetamide in suitable solvents, such as alcohols, water, pyridine, tertiary amines, dimethylformamide or mixtures of these solvents in the presence of bases, for example alkali metal glycolates, alkali metal carbonates, pyridine or trialkylamines to give 1-cyano-4-dimethylamino-3-ol (pyrid-4-yl) -buta-1,3-diene-1-carboxylic acid derivatives are then reacted and this by reaction with primary alkylamines, Aralkylamine ^ hydroxyalkylamines, aminoalkylamines or hydrazine in 1-substituted 2-imino-5- ( pyrid-4-yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives.
Erfindungsgemäß kann hierbei 4-Dimethy!amino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril als Zwischenprodukt isoliert werden und in vorteilhafter Weise gesondert in der 2. Stufe mit primären Aminen oder Hydrazin zur Reaktion gebracht werden. Die 1-substituierten 2-lmino-5-(pyrid-4-yl)-1,2-dihydro-pyridin 3-carbonitrile fallen hierbei in besonders reiner Form und hohen Ausbeuten an. Besonders vorteilhaft sind auch die milden Reaktionsbedingungen und kurzen Reaktionszeiten. Bei der Umsetzung von N,N-Dimethyl-N-[3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyliden)-ammoniumchlorid-hydrochlorid mit Malodinitril kann auch 3-(Pyrid-4-yl)-penta-1,3-dien-1,1,5,5-tetracarbonitril entstehen, das durch Ansäuern der Reaktionslösung gefällt werden kann und gleichfalls mit Aminen oder Hydrazin 1-substituierte 2-lmino-b(pyrid-4-yl)-1,2-dihydro-pyridin-3-carbonitrile ergibt.According to the invention, in this case 4-dimethyl-amino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile can be isolated as an intermediate and advantageously in the second stage separately with primary amines or separately Hydrazine be reacted. The 1-substituted 2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine 3-carbonitriles are obtained in a particularly pure form and in high yields. Also particularly advantageous are the mild reaction conditions and short reaction times. In the reaction of N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene] ammonium chloride hydrochloride with malononitrile, 3- (pyrid-4-yl) may also be used. penta-1,3-diene-1,1,5,5-tetracarbonitrile which can be precipitated by acidification of the reaction solution and also with amines or hydrazine 1-substituted 2-imino-b (pyrid-4-yl) - 1,2-dihydro-pyridine-3-carbonitrile gives.
Besonders überraschend ist die glatte Reaktion der 1-Cyan-4-dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1-carbonsäure-Derivate mit Hydrazin, die zu den wertvollen, durch Aminierung entsprechender 2-Amino-5-(pyrid-4-yl)-pyridine nicht zugänglichen, 1-Amino-2-imino-5-(pyrid-4-yl)-1,2-diliydro-pyridin-3-carbonsäure-Derivaten führt, zumal die Reaktion von 4-Aryl-4-chlor-1-cyanbutadien-1-carbonsäure-Derivaten mit Hydrazin Azin-Derivate ergibt (J. prakt. Chemie 318,705 [197GJ). Die erfindungsgemäß hergestellten neuen 1-substituierten 2-lmino-5-(pyrid-4-yl)-1,2-dihydro-pyridin-3-carbonsäure-Derivate und ihre Salze sind wertvolle Zwischenprodukte für die Herstellung biologisch aktiver pyridylsubstituierter Heterocyclen, z. B. solcher mit kaidiotoner, vasodilatatorischer und bronchodilatatorischer Wirkung. Einige der erfindungsgemäß hergestellten neuen 1-substituierten 2-lmino-5-(pyrid-4 yl)-1,2-dihydro-pyridin-3-carbonsäure-Derivate und ihre Salze sind selbst biologisch wirksam. Insbesondere besitzen sie kardiotone und vasodilatatorische Wirkungen. So zeigt beispielsweise 1-Benzyl-3-cyan-2-imino-5-(pyrid-4-yl)-1,2-dihydro-pyridin am isolierten, spontanschlagenden Vorhof des Meerschweinchens eine ausgeprägte positiv inotrope Wirkung. Besonders vorteilhaft ist, daß hierbei die Herzfrequenz nicht oder im Sinne einer Senkung beeinflußt wirdParticularly surprising is the smooth reaction of 1-cyano-4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1-carboxylic acid derivatives with hydrazine, which is the valuable, by amination corresponding 2 Amino-5- (pyrid-4-yl) -pyridines inaccessible, 1-amino-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives, especially since the reaction of 4-aryl-4-chloro-1-cyano butadiene-1-carboxylic acid derivatives with hydrazine azine derivatives results (J. prakt. Chemistry 318,705 [197GJ]. The inventively prepared new 1-substituted-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives and their salts are valuable intermediates for the preparation of biologically active pyridylsubstituierter heterocycles, eg. B. those with kaidiotoner, vasodilatatorischer and bronchodilator effect. Some of the novel 1-substituted-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives prepared by this invention and their salts are themselves biologically active. In particular, they have cardiotonic and vasodilatory effects. For example, 1-benzyl-3-cyano-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine exhibits marked positive inotropic activity on the isolated, spontaneously-disrupting guinea pig atria. It is particularly advantageous that in this case the heart rate is not affected or in the sense of a reduction
Die Erfindung wird im folgenden anhand von Ausführungsbeispielen näher erläutert. The invention will be explained in more detail below with reference to exemplary embodiments.
Ausführungsbeispieleembodiments
4-Oimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril und3-iPyrid-4-yl)-penta-1,3-dien-1,1,5,5-tetracatbonitril Zu 3,78g (1OmMoI) N,N-Dimethyl-N-|3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyiiden)-ammoniumchlorid-hydrochlorid (73%ig.4-Oimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile and 3-iPyrid-4-yl) -penta-1,3-diene-1,1,5, 5-tetracatonitrile To 3.78g (10mMoI) N, N-dimethyl-N- | 3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene) ammonium chloride hydrochloride (73%).
Rohprodukt) in 10ml Methanol werden unter Rühren 14mMol Natriummethylat in 7ml Methanoi und 0,60g (1OmMoI) Malodinitril in 5ml Methanol gegeben. Es wird 1 Std. bei Raumtemperatur gerührt, mit 10ml Wasser versetzt, mit 3 N HCI angesäuert und der ausfallende orangerote Niederschlag von 3-(Pyrid-4-yl)-penta-1,3-dien-1,1,5,5-tetracarbonitril abgesaugt.Crude product) in 10 ml of methanol are added with stirring 14 mmol of sodium methylate in 7 ml of methanol and 0.60 g (1OmMoI) of malononitrile in 5 ml of methanol. It is stirred for 1 hr. At room temperature, mixed with 10 ml of water, acidified with 3 N HCl and the precipitated orange-red precipitate of 3- (pyrid-4-yl) -penta-1,3-diene-1,1,5,5 -tetracarbonitrile aspirated.
Aus der Lösung wird durch Versetzen mit vsrdünnter NaOH bis zur schwach alkalischen Reaktion und Stehenlassen das 4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-dicarbonitril gewonnen, 'Jas durch Auflösen ·η 1 N HCI, Versetzen mit Aktivkohle und erneutes Fällen mit 1 N NaOH gereinigt wird.From the solution, the 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-dicarbonitrile is obtained by treatment with dilute NaOH to a slightly alkaline reaction and standing, 'Jas by dissolving .eta. 1 N HCI, with charcoal and re-precipitation with 1 N NaOH is purified.
3-(Pyrid-4-yl)-penta-1,3-dien-1,1,5,5-tetracarbonitril: C4H7N5 ber. C 68,56 H 2,88 N 28,563- (pyrid-4-yl) -penta-1,3-diene-1,1,5,5-tetracarbonitrile: C 4 H 7 N 5 calc. C 68.56 H 2.88 N 28.56
gef. C 68,31 H 3,00 N 28.27gef. C 68.31 H 3.00 N 28.27
Ausbeute: 0,44g (18% d. Th.). Schmp.: 263-27O0C (Zers.).Yield: 0.44 g (18% of theory). M .: 263-27O 0 C (Zers.).
4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril: C13H12N4 ber. C 69,62 H 5,39 N 24,984-Dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile: C 13 H 12 N 4 calc. C 69.62 H 5.39 N 24.98
gef. C 69,52 H 5,36 N 24,73gef. C 69.52 H 5.36 N 24.73
Ausbeute: 1,17g (52,2% d. Th.). Schmp.: 222-2240C.Yield: 1.17 g (52.2% of theory). Mp .: 222-224 0 C.
^Dimethylamino-a-lpyrid^-yO-bufa-i.a-dien-i.i-dicarbonitrilunda-IPyrid-i-ylJ-penta-i.a-dien-I.I.B.B-tetracarbonitril 4,Og(IOmMoI) N,N-Dimethyl-N-[3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyliden]-ammoniumchlorid-hydrochlorid(69%ig Rohprodukt) in 10ml Methanol werden unter Rühren portionsweise mit 0,848g (8mMol) Na2COa und anschließend mit 0,66g (1OmMoI) Malodinitril in 5 ml Methanol versetzt. Es wird 1 Std. bei Raumtemperatur gerührt und analog Beispiel 1 aufgearbeitet.^ Dimethylamino-a-1-pyridine ^ -yO-bufa-ia-diene-ii-dicarbonitrilunda-IPyrid-i-ylJ-penta-ia-diene-IIBB-tetracarbonitrile 4, Og (10mMoI) N, N-dimethyl-N- [ 3-Dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene] -ammonium chloride hydrochloride (69% crude) in 10 ml of methanol are added in portions with 0.848g (8 mmol) Na 2 COa and then with 0 , 66g (1OmMoI) malodinitrile in 5 ml of methanol. It is stirred for 1 hr. At room temperature and worked up analogously to Example 1.
3-(Pyrid-4-yl)-penta-1,3-dien-1,1,5,5-tetracarbonitril Ausbeute: 0,41g (16,7% d. Th.).3- (pyrid-4-yl) -penta-1,3-diene-1,1,5,5-tetracarbonitrile Yield: 0.41 g (16.7% of theory).
4-Dimethylamino-3-(pyrid-4-yl)-penta-1,3-dien-1,1-dicarbonitril Ausbeute: 1,05g (46,8% d. Th.).4-Dimethylamino-3- (pyrid-4-yl) -penta-1,3-diene-1,1-dicarbonitrile Yield: 1.05 g (46.8% of theory).
Beispiel 3 3-Cyan-2-imino-1-methyl-5-(pyrid-4-yl)-1,2dihydro-pyridinExample 3 3-Cyano-2-imino-1-methyl-5- (pyrid-4-yl) -1,2dihydro-pyridine
37,8g (10OmMoI) N,N-Dimethyl-N-[3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyliden|-ammoniumchlorid-hydrochlorid(73%ig. Rohprodukt) in 100ml Pyridin werden auf -10 bis -5°C gekühlt, unter Rühren mil 20OmMoI Natriummethylat in 100 ml Methanol und C,6g (10OmMoI) Malodinitril in 50ml Ethanol versetzt und 0,5 Std. bei etwa 0°C gerührt. Danach werden 30ml 30%ig. wäßrige Methylamin-Lsg. hinzugefügt und es wird 2,5 Std. bei Raumtemperatur gerührt. Das ausfallende gelbe Produkt wird abgesaugt, mit Wasser, wenig Ethanol und Ether gewaschen und aus i-Propanol unter Zusatz von Aktivkohle umkristallisiert.37.8 g (10 μmol) of N, N-dimethyl-N- [3-dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene-ammonium chloride hydrochloride (73% crude product) in 100 ml of pyridine cooled to -10 to -5 ° C, added with stirring 20 20mMoI sodium methylate in 100 ml of methanol and C, 6g (10OmMoI) of malononitrile in 50 ml of ethanol and 0.5 hrs. At about 0 ° C stirred. Then 30ml are 30%. aqueous methylamine solution. is added and it is stirred for 2.5 hrs. At room temperature. The precipitated yellow product is filtered off, washed with water, a little ethanol and ether and recrystallized from i-propanol with addition of activated carbon.
C12H10N4 ber. C 68,55 H 4,79C 12 H 10 N 4 calc. C 68.55 H 4.79
gef. C 68,30 H 4,72gef. C 68.30 H 4.72
Ausbeute: 9,5g (45,2%d. Th.). Schmp.: 268-2700C.Yield: 9.5 g (45.2% of theory). M.p .: 268-270 0 C.
3-Cyan-2-imino-1-methyl-5-(pyrid-4-yl)-1,2-dihydro-pyridin3-cyano-2-imino-1-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyridine
224mg (1 mMol) 4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril werden mit 1 ml 30%ig. wäßrige Methylamin-Lösung 10 Min. bei Raumtemperatur verrührt. Es wird mit 5 ml Wasser versetzt, abgesaugt und mit Wasser, wenig Ethanol und Ether gewaschen224 mg (1 mmol) of 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile are mixed with 1 ml of 30% strength. aqueous methylamine solution stirred for 10 min. At room temperature. It is mixed with 5 ml of water, filtered off with suction and washed with water, a little ethanol and ether
Ausbeute: 0,2g (95,1 % d. Th.). Schmp.: 268-27O0C.Yield: 0.2 g (95.1% of theory). M.p .: 268-27O 0 C.
3-Cyan-2-imino-1-methyl-5-(pyrid-4-yl)-1,2-dihydro-pyridin3-cyano-2-imino-1-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyridine
490mg (2mMol) 3-(pyrid-4-yl)-penta-1,3-dien-1,1,5,5-tetracarbonitril werden mit 2ml 30%ig. wäßrige Methylamin-Lösung 10 Min. unter leichtem Erwärmen gerührt. Es wird mit etwas Wasser versetzt, abgesaugt und mit Wasser, wenig Ethanol und Ether gewaschen.490 mg (2 mmol) of 3- (pyrid-4-yl) -penta-1,3-diene-1,1,5,5-tetracarbonitrile are mixed with 2 ml of 30% pure. aqueous methylamine solution for 10 min. With gentle heating. It is mixed with a little water, filtered off with suction and washed with water, a little ethanol and ether.
Ausbeute: 0,38mg (9ü,4% d. Th.). Schmp. 268-270X.Yield: 0.38 mg (9μ, 4% of theory). Schmp. 268-270X.
3-Cyan-1-(2-hydroxy-ethyl)-2-imino-5-(pyrid-4-yl)-1,2-dihydro-pyridin3-cyano-1- (2-hydroxy-ethyl) -2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine
2,24g (1OmMoI) 4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril werden in 20ml Pyridin mit 2 ml Ethanolamin 0,5 Std. bei Raumtemperatur gerührt. Es wird mit etwas Ether versetzt, der sich bildende gelbe Feststoff abgesaugt und mit Ether gewaschen.2.24 g (10 μmol) of 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile are stirred in 20 ml of pyridine with 2 ml of ethanolamine for 0.5 hour at room temperature. It is mixed with a little ether, the resulting yellow solid is filtered off with suction and washed with ether.
Ci3H12N4O, ber. C 64,99 H 5,03 N 23,32Ci 3 H 12 N 4 O, calc. C 64.99 H 5.03 N 23.32
gef. C 64,76 H 5,09 N 22,57gef. C 64.76 H 5.09 N 22.57
Ausbeute: 2,33g (97% d. Th.). Schmp. 188-190°C.Yield: 2.33 g (97% of theory). M.p. 188-190 ° C.
224mg (1 mMol) 4-Oimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitiil werden mit 0,2ml 3-Diethylamino-propylamin in 1,5ml Pyridin 1 Std. bei Raumtemperatur gerührt. Es wird mit etwas Ether versetzt und dann durch Hinzufügen von Pentan gefällt. Der gelbe Niederschlag wird abgesaugt und mit Pentan/Ether gewaschen.224 mg (1 mmol) of 4-oimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarboxylic acid are treated with 0.2 ml of 3-diethylamino-propylamine in 1.5 ml of pyridine for 1 h. stirred at room temperature. It is mixed with a little ether and then precipitated by adding pentane. The yellow precipitate is filtered off with suction and washed with pentane / ether.
C18H23N6 ber. C 69,87 H 7,49 N 22,63C 18 H 23 N 6 calc. C 69.87 H 7.49 N 22.63
gef. C 69,64 H 7,49 N 22,39gef. C 69.64 H 7.49 N 22.39
Ausbeute: 0,21 g (67,9% d. Th.). Schmp.: 100-101CC.Yield: 0.21 g (67.9% of theory). Mp .: 100-101 C. C
Beispiel 8 3-Cyan-2-imino-1-isopropyl-5-(pyrid-4-yl)-1,2-dihydro-pyridinExample 8 3-cyano-2-imino-1-isopropyl-5- (pyrid-4-yl) -1,2-dihydro-pyridine
Analog Beispiel 7 aus 224mg (1 mMol) 4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril und 0,2ml Isopropylamin und Umkristallisation aus Wasser unter Zusatz von Aktivkohle.Analogously to Example 7 from 224 mg (1 mmol) of 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile and 0.2 ml of isopropylamine and recrystallization from water with the addition of activated carbon.
C14H14N4 ber. C 70,56 H 5,92 N 23,51C 14 H 14 N 4 calc. C 70.56 H 5.92 N 23.51
gef. C 70,48 H 5,89 N 23,36gef. C 70.48 H 5.89 N 23.36
Ausbeute: 0,18g (75,9% d. Th.). Schmp.: 162-163°C.Yield: 0.18 g (75.9% of theory). Mp .: 162-163 ° C.
Beispiel 9 1-Amino-3-cyan-2-imino-5-(pyrid-4-yl)-1,2-dihydro-pyridinExample 9 1-Amino-3-cyano-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine
224mg (1 mMol)4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril werden mit 2ml 25%ig. Hydrazinhydrat einige Minuten verrührt. Es wird abgesaugt und mit Wasser gewaschen.224 mg (1 mmol) of 4-dimethylamino-3- (pyrid-4-yl) -buta-1,3-diene-1,1-dicarbonitrile are mixed with 2 ml of 25% pure. Hydrazine hydrate stirred for a few minutes. It is filtered off with suction and washed with water.
CnH9N5 ber. C62.55 H4.29 N33.16C n H 9 N 5 calc. C62.55 H4.29 N33.16
gef. C 62,61 H 4,53 N 32,55gef. C 62.61 H 4.53 N 32.55
Ausbeute: 0,21 g (99,4% d. Th.). Schmp.: >360°C (Zers.).Yield: 0.21 g (99.4% of theory). M .:> 360 ° C (Zers.).
1-Amino-3cyan-2-imino-5-(pyrid-4 yl)-1,2-dihydro-pyridin 245mg (1 mMol) 3-(Pyrid-4-yl)-penta-1,3-dien-1,1,5,5-tetracarbonitril werden mit 0,6ml 70%ig. Hydrazinhydrat versetzt und einige Min. auf ca. 5O0C erwärmt. Nach dem Abkühlen wird abgesaug'. und mit Wasser gewaschen.1-Amino-3-cyano-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine 245 mg (1 mmol) of 3- (pyrid-4-yl) -penta-1,3-diene-1 , 1,5,5-tetracarbonitrile be with 0.6ml 70%. Hydrazine hydrate added and heated to about 5O 0 C for a few min. After cooling, it is removed by suction. and washed with water.
Ausbeute: 0,125g (59,2% d. Th.). Schmp.: >360°C (Zers.).Yield: 0.125 g (59.2% of theory). M .:> 360 ° C (Zers.).
1-Amino-3-carbamoyl-2-imino-5-(pyrid-4-yl)-1,2-dihydro-pyridin 6,3g (16,7 mMol) N,N-Dimethyl-N-[3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyliden]-ammoniumchlorid-hydrochlorid(73%ig.1-Amino-3-carbamoyl-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine 6.3g (16.7mmol) N, N-dimethyl-N- [3-dimethylamino -2- (pyrid-4-yl) prop-2-enylidene] ammonium chloride hydrochloride (73% pure.
Rohprodukt) in 100ml Pyridin werden auf 0 bis -5°C gekühlt und unter Rühren mit 20OmMoI Natriummethylatin iOOml Methanol und 1,4g (16,7 mMol) Cyanacetamid versetzt. Es wird 1 Stunde bei 0 bis 100C gerührt, mit 8ml 70%ig. Hydrazinhydrat versetzt, 1 Std. bei Raumtemperatur gerührt, abgesaugt und mit Wasser, Ethanol und Ether gewaschen.Crude product) in 100 ml of pyridine are cooled to 0 to -5 ° C and treated with 20OmMoI Natriummethylatin iOOml of methanol and 1.4 g (16.7 mmol) of cyanoacetamide with stirring. It is stirred for 1 hour at 0 to 10 0 C, with 8ml 70%. Hydrazine hydrate added, stirred for 1 hr. At room temperature, filtered off with suction and washed with water, ethanol and ether.
C11HnN5O, ber. C57.54 H4.83 N30.66C 11 H n N 5 O, calc. C57.54 H4.83 N30.66
gef. C 57,58 H 4,94 N 29,98gef. C 57.58 H 4.94 N 29.98
Ausbeute: 1,6g (41,8% d. Th.). Schmp.: 235-2380C (Zers.).Yield: 1.6 g (41.8% of theory). M .: 235-238 0 C (Zers.).
1-(3-Amino-propyl)-3-cyan-2-imino-5-(pyrid-4-yl)-1,2-dihydro-pyridin 224mg (1 mMol) 4-Diinethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril in 2ml Pyridin werden unter Rühren mit 0,2ml 1,3-Diamino-nropan versetzt. Es wird 20 Min. bei Raumtemperatur gerührt, der ausgefallene Niederschlag abgesaugt und mit Pyridin und Ether gewaschen.1- (3-Amino-propyl) -3-cyano-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine 224 mg (1 mmol) 4-di-ethylamino-3- (pyrid-4 -yl) -buta-1,3-diene-1,1-dicarbonitrile in 2 ml of pyridine are added with stirring with 0.2 ml of 1,3-diamino-nropane. It is stirred for 20 min. At room temperature, the precipitate was filtered off with suction and washed with pyridine and ether.
C14H15N5 ber. C 66,38 H 5,97C 14 H 15 N 5 calc. C 66.38 H 5.97
gef. C 65,90 H 6,04gef. C 65.90 H 6.04
Ausbeute: 230mg (90,8% d. Th.). Schmp.: 175-1770C.Yield: 230 mg (90.8% of theory). Mp .: 175-177 0 C.
3-Cyhn-2-lmino-1-(4-methyl-benzyl)-5-(pyrid-4-yl)-1,2-dihydro-pyridin 224mg (1 mMol) 4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril in 2ml Pyridin werden unter Rühren mit 0,2ml 4-Metliyl-benzylamin versetzt. Es wird 50 Min. bei Raumtemperatur gerührt, der ausgefallene Niederschlag abgesaugt und mit wenig Pyridin und Ether gewaschen.3-Cyhn-2-imino-1- (4-methyl-benzyl) -5- (pyrid-4-yl) -1,2-dihydro-pyridine 224 mg (1 mmol) 4-dimethylamino-3- (pyridine-4 -yl) -buta-1,3-diene-1,1-dicarbonitrile in 2 ml of pyridine are added with stirring with 0.2 ml of 4-methyl-benzylamine. It is stirred for 50 min. At room temperature, the precipitate was filtered off with suction and washed with a little pyridine and ether.
C19H16N4 ber. C7F98 H 5,37 N 18,65C 19 H 16 N 4 calc. C7F98 H 5.37 N 18.65
gef. C 75,86 H 5,44 N 18,10gef. C, 75.86, H, 5.44, N, 18.10
Ausbeute: 290mg (96,7% d. Th.). Schmp.: 191-193,50C.Yield: 290 mg (96.7% of theory). M.p .: 191-193.5 0 C.
3-Cyan-2-imino-1-benzyl-5-(pyrid-4-yl)-1,2-dihydro-pyridin 224mg (1 mMol) 4-Dimethylamino-3-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril in 2ml Pyridin werden unter Rühren mit 0.2ml Benzylarnin versetzt. Es wird 5 Min. bei Raumtemperatur gerührt, abgesaugt und aus Pyridin/Ether umgefällt.3-cyano-2-imino-1-benzyl-5- (pyrid-4-yl) -1,2-dihydro-pyridine 224 mg (1 mmol) 4-dimethylamino-3- (pyrid-4-yl) -buta 0.2 ml of benzylamine is added to 1.3-diene-1,1-dicarbonitrile in 2 ml of pyridine with stirring. It is stirred for 5 min. At room temperature, filtered off and reprecipitated from pyridine / ether.
C18H14N4 ber. C75.50 H4,93 N 19,57C 18 H 14 N 4 calc. C75.50 H4,93 N 19.57
gef. C 75,35 H 5,02 N 19,44gef. C 75.35 H 5.02 N 19.44
Ausbeute: 210mg (73,4% d. Th.). Schmp.: 231-2320C.Yield: 210 mg (73.4% of theory). M.p .: 231-232 0 C.
1-(2-Amino-ethyl)-3-cyan-2-imino-5-(pyrid-4-yl)-1,2-dihydro-pyridin 22,4g (1OmMoI) 4-Dimethylamino-5-(pyrid-4-yl)-buta-1,3-dien-1,1-dicarbonitril in 25ml Pyridin werden 0,5 Std. mit 3ml Ethylendiamin verrührt. Es wird abgesaugt und mit Pyridin gewaschen.1- (2-aminoethyl) -3-cyano-2-imino-5- (pyrid-4-yl) -1,2-dihydro-pyridine 22.4g (10mMoI) 4-dimethylamino-5-pyridine 4-yl) -buta-1,3-diene-1,1-dicarbonitrile in 25 ml of pyridine are stirred for 0.5 h with 3 ml of ethylenediamine. It is filtered off with suction and washed with pyridine.
C13H13N6 ber. C 65,25 H 5,48 N 29,27C 13 H 13 N 6 calc. C 65.25 H 5.48 N 29.27
gef. C 65,12 H 5,50 N 28,95gef. C 65.12 H 5.50 N 28.95
Ausbeute: 1,95g (81,6% d. Th.). Schmp.: 167,5-169,5 0C.Yield: 1.95 g (81.6% of theory). M.p .: 167.5-169.5 0 C.
3-Cyan-2-imino-1-(2-piperazino-ethyl)-5-(pyrid-4-yl)-1,2-dihydro-pyridin 224mg (1 mMol) 4-Dimethylamino-5-(pyrid-4-yl)-buta-1,3-tJien-1,1-dicarbonitril in 2ml Pyridin werden unter Rühren mit 0,3ml 1-(2-Amino-ethyl)-piperazin versetzt. Es wird 0,5 Std. gerührt, mit etwas Ether versetzt und abgesaugt.3-cyano-2-imino-1- (2-piperazino-ethyl) -5- (pyrid-4-yl) -1,2-dihydro-pyridine 224 mg (1 mmol) 4-dimethylamino-5- (pyrid-4 -yl) -buta-1,3-tien-1,1-dicarbonitrile in 2 ml of pyridine are added with stirring 0.3 ml of 1- (2-amino-ethyl) piperazine. It is stirred for 0.5 h, mixed with a little ether and filtered with suction.
C17H20N6 ber. C 66,20 H 6,54 N 27,26C 17 H 20 N 6 calc. C 66.20 H 6.54 N 27.26
gef. C 65,74 H 6,57 N 26,70gef. C 65.74 H 6.57 N 26.70
Ausbeute: 220mg (71,3% d. Th.). Schmp.: 190-195°C(Zeis.).Yield: 220 mg (71.3% of theory). M.p .: 190-195 ° C (Zeis.).
3Xyan-2-!mino-1-(piperidin-4-yl-mothyl-)-5-(pyr!d-4-yl)-1,2-dihydro-pyridin 224mg (1 mMolM-Dimethylamino-ö-lpyrid^-yD-buta-I.S-dien-i.i-dicarbonitril in 2 ml Pyridin werden unter Rühren mit 0,3ml 4-Aminomethyl-piperidin versetzt. Es wird 1 Std. gerührt, mit etwas Ether und Pentan versetzt und abgesaugt.3-Xyan-2-mino-1- (piperidin-4-yl-mothyl-5- (pyr! D-4-yl) -1,2-dihydro-pyridine 224 mg (1 mmol M-dimethylamino-6-pyrrole) 0.3 ml of 4-aminomethylpiperidine are added with stirring to 2-yl-butadiene-1,2-dicarbonitrile in 2 ml of pyridine, the mixture is stirred for 1 h, treated with ether and pentane and filtered with suction.
C17H19N5 ber. C 69,60 H 6,53 N 23,87C 17 H 19 N 5 calc. C 69.60 H 6.53 N 23.87
gef. C 69,17 H 6,95 N 23,34gef. C 69.17 H 6.95 N 23.34
Ausbeute: 60mg (20,5% d. Th.). Schmp.: 153-1580C.Yield: 60 mg (20.5% of theory). M.p .: 153-158 0 C.
3-Carbamoyl-1 -imino-1 -methy l-5-(pyrid-4-yl)-1,2-dihydro-pyridin 20,0g (5OmMoI) N,N-Dimethyl-N-[3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyliden)-ammoniumchlorid-hydrochloric'(69%ig Rohprodukt) werden in 35ml Wasser gelöst und mit 4,2 g (5OmMoI) Cyanacetamid und 20ml 32%ig wäßrige Methylamin-Lösung versetzt. Es wird 2 Sid. bei Raumtemperatur gerührt, eingeengt und abgesaugt. Das Rohprodukt wird in etwas 2 N HCI gelöst, mit 2 N NaOH gefällt, abgesaugt und aus Acetonitril umkristallisiert.3-Carbamoyl-1-imino-1-methyl-5- (pyrid-4-yl) -1,2-dihydro-pyridine 20.0g (50mMoI) N, N-dimethyl-N- [3-dimethylamino-2 - (pyrid-4-yl) -prop-2-enylidene) -ammoniumchlorid-hydrochloric '(69% crude product) are dissolved in 35 ml of water and with 4.2 g (5OmMoI) cyanacetamide and 20ml of 32% aqueous methylamine solution added. It will be 2 sid. stirred at room temperature, concentrated and filtered with suction. The crude product is dissolved in a little 2N HCl, precipitated with 2N NaOH, filtered off with suction and recrystallized from acetonitrile.
C12H12N4O, ber. C 63,14 H 5,32 N 24,55C 12 H 12 N 4 O, calc. C 63.14 H 5.32 N 24.55
gef. C 63,10 H 5,36 N 24,44gef. C 63.10 H 5.36 N 24.44
Ausbeuts: 9,2g (80,7%d. Th.). Schmp.: 220-2240C.Yield: 9.2 g (80.7% of theory). Mp .: 220-224 0 C.
a-Carbamoyl-i-U-hydroxy-ethyll^-imino-B-lpyrid-A-yll-i^-dihydro-pyridin-hydrochlorid 20g (5OmMoI) N,N-Dimethyl-N-[3-dimethylamino-2-(pyrid-4-yl)-prop-2-enyliden|-ammoniumchlorid-hydrochlorid(69%ig Rohprodukt) werden in 35ml Wasser gelöst und mit 4,2g (5OmMoI) Cyanacetamid und danach mit 10ml Ethanolamin versetzt.a-Carbamoyl-iU-hydroxy-ethyl-1-amino-B-1-pyrrole-A-yl-i-dihydro-pyridine hydrochloride 20g (50mMoI) N, N-dimethyl-N- [3-dimethylamino-2- (pyrid -4-yl) -prop-2-enylidene | ammonium chloride hydrochloride (69% crude product) are dissolved in 35 ml of water and admixed with 4.2 g (5OmMoI) cyanacetamide and then with 10 ml of ethanolamine.
Es wird 1 Std. bei Raumtemperatur gerührt, eingeengt und abgesaugt.It is stirred for 1 hr. At room temperature, concentrated and filtered with suction.
C13H15N4O2CI ber. C52.97 H5,13 N 19,01 CI12,02C 13 H 15 N 4 O 2 Cl calc. C52.97 H5,13 N 19.01 CI12,02
gef. C 53,29 H 4,94 N 19,17 Cl 12,02gef. C 53.29 H 4.94 N 19.17 Cl 12.02
Ausbeute: 9,7g (65,8%d. Th.). Schmp.: 260-265°C (Zers.).Yield: 9.7 g (65.8% of theory). M .: 260-265 ° C (Zers.).
Beispiel 20 S-Carbamoyl-i-^-hydroxy-ethyO^-imino-S-lpyrid^-ylM^-dihydro-pyridin-hydrat Durch Auflösen von 9,7g vorstehender Verbindung in 100ml Wasser und Fällen mit 1 N NaOHExample 20 S-Carbamoyl-i-hydroxy-ethyl-O-imino-S-pyridyl-Y-methyl-dihydro-pyridine hydrate By dissolving 9.7 g of the above compound in 100 mL of water and precipitating with 1 N NaOH
C13H16N4O3 ber. C 56,51 H 5,83 N 20,28C 13 H 16 N 4 O 3 calc. C 56.51 H 5.83 N 20.28
gef. C 56,44 H 5,81 N 19,93gef. C 56.44 H 5.81 N 19.93
Ausbeute: 6,2g (68,1 %d. Th.) Schmp.: 168-1710C.Yield: 6.2 g (68.1% of theory..), M.p .: 168-171 0 C.
3-Carbamoyl-2-imino-1-(2-methoxy-ethyl)-5-(pyrid-4-yl)-1,2-dihydro-pyridin 4,0g (1OmMoI) N,N-Dimethyl-N-|3-dimethylamino-2-(pyrid-4-yl)-prop-2-enylidcnl-ammoniumchlorid-hydrochlorid(69%ig Rohprodukt) werden in 7 ml Wasser gelöst und mit 840mg (1OmMoI) Cyanacetamid und 2,5ml 2-Methoxy-ethylamin versetzt. Es wird 2 Std. bei Raumtemperatur gerührt, eingeengt, abgekühlt und mit etwas 1 N NaOH versetzt. Der gelbe Niederschlag wird abgesaugt, mit wenig Wasser, EtOH und Ether gewaschen und aus Acetonitril umkristallisiert.3-Carbamoyl-2-imino-1- (2-methoxy-ethyl) -5- (pyrid-4-yl) -1,2-dihydro-pyridine 4.0g (10mMoI) N, N-dimethyl-N- | 3-Dimethylamino-2- (pyrid-4-yl) -prop-2-enylidene-ammonium chloride hydrochloride (69% crude) is dissolved in 7 ml of water and treated with 840 mg (10 mM) cyanacetamide and 2.5 ml of 2-methoxy ethylamine. It is stirred for 2 hrs. At room temperature, concentrated, cooled and treated with a little 1 N NaOH. The yellow precipitate is filtered off, washed with a little water, EtOH and ether and recrystallized from acetonitrile.
C14H16N4O2 ber. C 61,75 H 5,92 N 20,58C 14 H 16 N 4 O 2 calc. C 61.75 H 5.92 N 20.58
gef. C 61,70 H5.7C N 20,19gef. C 61.70 H5.7C N 20.19
Ausbeute: 1,88g (69,1% d. Th.). Schmp.: 187-188,5°CYield: 1.88 g (69.1% of theory). M .: 187-188.5 ° C
Beispiel 22 3-Carbamoyl-1-(3-diethylamino-propyl)-2-imino-5-(pyrid-4-yl)-1,2-dihydropyridin 4,0g (1OmMoI) N,N-Dimethyl-N-[3-dimsthyiamino-2-(pyrid-4-yl)-prop-2-enylidenl-ammoniumchlorid-hydrochlorid (69%ig Rohprodukt) werden in 10 ml Wasser gelöst und mit 840 mg (1OmMoI) Cyanacetamid sowie 1,5 ml 3-Diethylamino-propylamin versetzt. Es wird 3 Std. bei Raumtemperatur gerührt, zur Trockne eingeengt, das gebildete Hydrochlorid in Wasser gelöst, mit 2 N NaOH versetzt und 3-4mal mit CH2CI2 ausgeschüttelt. Nach Trocknen über Na2SO4 wird filtriert, eingeengt, mit etwas Ether versetzt und abgesaugt.Example 22 3-Carbamoyl-1- (3-diethylamino-propyl) -2-imino-5- (pyrid-4-yl) -1,2-dihydropyridine 4.0g (10mMoI) N, N-dimethyl-N- [ 3-Dimethyiamino-2- (pyrid-4-yl) -prop-2-enylidene-1-ammonium chloride hydrochloride (69% crude product) are dissolved in 10 ml of water and treated with 840 mg (10 μmol) of cyanoacetamide and 1.5 ml of 3- Diethylamino-propylamine added. The mixture is stirred for 3 hrs. At room temperature, concentrated to dryness, the hydrochloride formed dissolved in water, treated with 2 N NaOH and extracted 3-4 times with CH 2 Cl 2 . After drying over Na 2 SO 4 is filtered, concentrated, mixed with a little ether and filtered with suction.
C18H26N5Oi ber. C66.03 H7.70 M21.39C 18 H 26 N 5 Oi over. C66.03 H7.70 M21.39
gef. C 65,66 H 7,88 N 20,65gef. C 65.66 H 7.88 N 20.65
Ausbeute: 0,6g (18,3% d. Th.). Schmp.: 123-129°C.Yield: 0.6 g (18.3% of theory). M .: 123-129 ° C.
Isolierter, spontanaktiver Vorhof des Meerschweinchens Für die Versuche wurden männliche Meerschweinchen mit einer Köi permasse von 400-50Og verwendet.Isolated, spontaneously active guinea pig atrium For the experiments, male guinea pigs with a permeability of 400-50Og were used.
Am isolierten., spontanaktiven Vorhof erfolgte nach einer 60 Min. währenden Adaptionszeit der Organpräparate in 32°C temperierter carbogen-durchperlter Tyrodelösung die Untersuchung der Beeinflussung von Inotropie und Frequenz unter Einwirkung der 1-substituierten 2-lmino-5-(pyrid-4-yl)-1,2-dihydro-pyridin-3-carbonsäure-Derivate der Formel I. Die Verbindungen zeigten teilweise beträchtliche und dosisabhängige positiv inotrope Wirkungen. Die Frequenz blieb dabei unbeeinflußt bzw. wurde dosisabhängig gesenkt.At the isolated, spontaneously active atrium after a 60-min. Adaptation time of the organ preparations in 32 ° C tempered carbogen-perforated Tyrodelösung the investigation of the influence of inotropy and frequency under the action of 1-substituted 2-lmino-5- (pyrid-4 yl) -1,2-dihydro-pyridine-3-carboxylic acid derivatives of the formula I. The compounds showed, in part, considerable and dose-dependent positive inotropic effects. The frequency was unaffected or lowered in a dose-dependent manner.
Bei Verwendung einer Tyrodelösung nach A. A. Alousi et al. (Circ. Res. 45,666 [1979]) zeigte beispielsweise die Verbindung von Beispiel 14 bei einer Konzentration von 3,9 10~6mo!/l eine 30%ige Steigerung der Inotropie, bei gleichzeitiger Senkung der Frequenz um 5%.When using a Tyrodel solution according to AA Alousi et al. (Circ. Res. 45.666 [1979]), for example, the compound of Example 14 at a concentration of 3.9 10 -6 mo! / L, a 30% increase in inotropy, while reducing the frequency by 5%.
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD28857986A DD263759A1 (en) | 1986-04-01 | 1986-04-01 | PROCESS FOR PREPARING 1-SUBSTITUTED 2-IMINO-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRIDINE-3-CARBOXYLIC ACID DERIVATIVES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD28857986A DD263759A1 (en) | 1986-04-01 | 1986-04-01 | PROCESS FOR PREPARING 1-SUBSTITUTED 2-IMINO-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRIDINE-3-CARBOXYLIC ACID DERIVATIVES |
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| DD28857986A DD263759A1 (en) | 1986-04-01 | 1986-04-01 | PROCESS FOR PREPARING 1-SUBSTITUTED 2-IMINO-5- (PYRID-4-YL) -1,2-DIHYDRO-PYRIDINE-3-CARBOXYLIC ACID DERIVATIVES |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008050732A1 (en) | 2006-10-23 | 2008-05-02 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| WO2009131135A1 (en) | 2008-04-23 | 2009-10-29 | 武田薬品工業株式会社 | Iminopyridine derivative and use thereof |
| US7982044B2 (en) | 2008-04-23 | 2011-07-19 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and use thereof |
-
1986
- 1986-04-01 DD DD28857986A patent/DD263759A1/en not_active IP Right Cessation
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008050732A1 (en) | 2006-10-23 | 2008-05-02 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| EP2077262A4 (en) * | 2006-10-23 | 2011-12-28 | Takeda Pharmaceutical | Iminopyridine derivative and use thereof |
| EP2535330A2 (en) | 2006-10-23 | 2012-12-19 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| US8470859B2 (en) | 2006-10-23 | 2013-06-25 | Takeda Pharmaceutical Company Limited | Iminopyridine derivative and use thereof |
| WO2009131135A1 (en) | 2008-04-23 | 2009-10-29 | 武田薬品工業株式会社 | Iminopyridine derivative and use thereof |
| US7982044B2 (en) | 2008-04-23 | 2011-07-19 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and use thereof |
| US7985862B2 (en) | 2008-04-23 | 2011-07-26 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and use thereof |
| US7985863B2 (en) | 2008-04-23 | 2011-07-26 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and uses thereof |
| US8481569B2 (en) | 2008-04-23 | 2013-07-09 | Takeda Pharmaceutical Company Limited | Iminopyridine derivatives and use thereof |
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