DE2204064A1 - 2-Oxo-l (2H) -pyridincarbonitrile, process for their preparation and medicinal preparations containing these compounds - Google Patents
2-Oxo-l (2H) -pyridincarbonitrile, process for their preparation and medicinal preparations containing these compoundsInfo
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- DE2204064A1 DE2204064A1 DE19722204064 DE2204064A DE2204064A1 DE 2204064 A1 DE2204064 A1 DE 2204064A1 DE 19722204064 DE19722204064 DE 19722204064 DE 2204064 A DE2204064 A DE 2204064A DE 2204064 A1 DE2204064 A1 DE 2204064A1
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- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Description
" 2~0xo-1(2H)-pyridincarbonitrile, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneipräparate ""2 ~ 0xo-1 (2H) -pyridine carbonitrile, process for their preparation and medicinal preparations containing these compounds "
Priorität:Priority:
29. Januar 1971, V.St.A., Nr. 111 125 und 28. Mai 1971, V.St.A., Nr. 148 037January 29, 1971, V.St.A., No. 111 125 and May 28, 1971, V.St.A., No. 148 037
Die Erfindung betrifft 2-0xo-1(2H)-pyridincarbonitrile der allgemeinen Formel IThe invention relates to 2-0xo-1 (2H) -pyridine carbonitriles of the general type Formula I.
(D(D
C=NC = N
in der die Reste R gleich oder verschieden sind und ein Wasserstoff atom, einen nieder-Alkyl-, nieder-Alkenyl- oder nieder-Alkoxyrest mit bis 12 Kohlenstoffatomen, eine Hydroxyl-, Nitro-, Cyan-, Carboxy-, Amido- oder Mercaptogruppe, ein Halogenatom, einen aliphatischen oder aromatischen Acylrest mit bis 20 Kohlenstoffatomen, eine unsubstituierte oder mit einem der vorgenannten Substituenten substituierte Phenylgruppe oder einen Aryloxyrest mit bis 10 Kohlenstoffatomen bedeuten oder zwei benachbarte Reste R zusammen eine unsubstituierte oder substitu-in which the radicals R are identical or different and one is hydrogen atom, a lower-alkyl, lower-alkenyl or lower-alkoxy radical with up to 12 carbon atoms, a hydroxyl, nitro, cyano, carboxy, amido or mercapto group, a halogen atom, an aliphatic or aromatic acyl radical with up to 20 carbon atoms, an unsubstituted one or one of the aforementioned Substituents-substituted phenyl group or an aryloxy radical with up to 10 carbon atoms or two adjacent Radicals R together an unsubstituted or substituted
209834/1213209834/1213
ierte Phenylgruppe bilden.form ated phenyl group.
Die Erfindung betrifft ferner ein Verfahren zur Herstellung der erfindungsgemäßen Verbindungen, das im nachstehenden Reaktionsschema dargestellt ist:The invention also relates to a process for the preparation of the compounds according to the invention, which is shown in the reaction scheme below is shown:
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tx."tx. "
■- 3 -■ - 3 -
^.c^ .c
CH.CH.
Nitritsalz ---Nitrite salt ---
(ill)(ill)
1) . Baae1) . Baae
2) Halogencyan2) cyanogen halide
QMQM
(IT) QCN (V)(IT) QCN (V)
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Zur Herstellung der erfindungsgemäßen Verbindungen der allgemeinen Formel I wird ein Acetoacetamidopyridin der allgemeinen Formel II, in der die Reste R die vorstehend angegebene Bedeutung haben, mit einem Nitritsalz in einem sauren Medium umgesetzt. Als Nitritsalz wird ein wasserlösliches Alkaliraetallnitrit, wie LiNO2, NaNO2 oder KNO2, oder ein wasserlösliches Erdalkalimetallnitrit, wie Ca(NO2)2,eingesetzt. Die Umsetzung wird in einem wäßrigen Medium bei niedrigen Temperaturen, vorzugsweise bei Temperaturen unter etwa 100C und insbesondere bei etwa O0C, durchgeführt. Die entstandenen Verbindungen der allgemeinen Formel I werden aus dem wäßrigen Medium mittels eines mit Wasser nicht mischbaren organischen Lösungsmittels extrahiert. Solche Lösungsmittel sind z.B. Ester, wie Essigsäureäthylester, Äther, wie Diäthyläther, halogenierte Alkane, wie Chloroform, oder aromatische Kohlenwasserstoffe, wie Benzol, Toluol oder Xylol.To prepare the compounds of general formula I according to the invention, an acetoacetamidopyridine of general formula II, in which the radicals R have the meaning given above, is reacted with a nitrite salt in an acidic medium. A water-soluble alkali metal nitrite, such as LiNO 2 , NaNO 2 or KNO 2 , or a water-soluble alkaline earth metal nitrite, such as Ca (NO 2 ) 2 , is used as the nitrite salt. The reaction is carried out in an aqueous medium at low temperatures, preferably at temperatures below about 10 ° C. and in particular at about 0 ° C. The resulting compounds of general formula I are extracted from the aqueous medium using an organic solvent which is immiscible with water. Such solvents are, for example, esters such as ethyl acetate, ethers such as diethyl ether, halogenated alkanes such as chloroform, or aromatic hydrocarbons such as benzene, toluene or xylene.
Die Verbindungen der allgemeinen Formel I können auch durch Umsetzen eines Alkalimetallsalzes eines 2-Pyridons der allgemeinen Formel III, in der die Reste R die vorstehend angegebene Bedeutung haben, mit einer Halogencyanverbindung hergestellt werden. Die Umsetzung wird in einem polaren Lösungsmittel bei niedrigen Temperaturen durchgeführt. Geeignete Lösungsmittel sind Amide, wie Dimethylformamid oder Dimethylacetamid, oder Äther, wie Bis-(2-methoxyäthyl)-äther. Die Umsetzung wird vorzugsweise bei Temperaturen von etwa -10 bis etwa 100C und insbesondere bei etwa 0°C durchgeführt.The compounds of the general formula I can also be prepared by reacting an alkali metal salt of a 2-pyridone of the general formula III, in which the radicals R have the meaning given above, with a cyanogen halide compound. The reaction is carried out in a polar solvent at low temperatures. Suitable solvents are amides, such as dimethylformamide or dimethylacetamide, or ethers, such as bis (2-methoxyethyl) ether. The reaction is preferably carried out at temperatures of about -10 to about 10 0 C and especially at about 0 ° C.
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Das als Ausgangsverbindung eingesetzte Alkalimetallsalz eines 2-Pyridons der allgemeinen Formel III kann durch Umsetzen eines 2-Pyridons der allgemeinen Formel III mit einem Alkalimetallhydroxid, -wie LiOH, NaOH oder KOH, einem Alkalimetallhydrid, wie LiH, NaH oder KH, einem Alkalimetallamid, wie LiNH2, NaNH2 oder KNH2, oder einem Alkalimetallalkyl, wie Lithiumbutyl, Natriumbutyl oder Kaliumbutyl, hergestellt werden.The alkali metal salt of a 2-pyridone of the general formula III used as the starting compound can be prepared by reacting a 2-pyridone of the general formula III with an alkali metal hydroxide, such as LiOH, NaOH or KOH, an alkali metal hydride such as LiH, NaH or KH, an alkali metal amide such as LiNH 2 , NaNH 2 or KNH 2 , or an alkali metal alkyl such as lithium butyl, sodium butyl or potassium butyl.
Als Halogencyanverbindung wird erfindungsgemäß vorzugsweise Bromcyan oder Chlorcyan eingesetzt.According to the invention, cyanogen bromide or cyanogen chloride is preferably used as the cyanogen halide compound.
Die Erfindung betrifft ferner ein Verfahren zur Herstellung von 2-Pyridonen der allgemeinen Formel IVThe invention also relates to a process for the preparation of 2-pyridones of the general formula IV
in der die Reste R die vorstehend angegebene Bedeutung haben und M mit der Ausnahme, daß Q in der allgemeinen Formel V ein Alkyl- oder Arylrest ist, ein Wasserstoffatom bedeutet oder ein Alkalimetall, ein Erdalkalimetall,Thalliumt zweiwertiges Cadmium oder ein Rest der Formel MgBr, MgQ oder. CaQ ist, und von Cyanverbindungen der allgemeinen Formel Vin which the radicals R have the meaning given above and M with the exception that Q in the general formula V is an alkyl or aryl radical, a hydrogen atom or an alkali metal, an alkaline earth metal, thallium t divalent cadmium or a radical of the formula MgBr , MgQ or. CaQ, and of cyano compounds of the general formula V
QCN (V)QCN (V)
in der Q einen Alkyl-, Alkoxy-, Thioalkyl-, Aryl-, Aryloxy-, Arylthio-, Monoalkylamino-, Dialky!amino-, Monoarylamino oder Diarylaminorest, der Rest der Formel /CH(COOC2Hk)27 "" » die Aminogruppe oder einen basischen stickstoffhaltigen Rest bedeutet, der an M über das Stickstoffatom gebunden ist. Zur Her-in which Q is an alkyl, alkoxy, thioalkyl, aryl, aryloxy, arylthio, monoalkylamino, dialky, amino, monoarylamino or diarylamino radical, the remainder of the formula / CH (COOC 2 Hk) 2 7 "" » denotes the amino group or a basic nitrogen-containing radical which is bonded to M via the nitrogen atom. To the her-
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stellung der 2-Pyridone der allgemeinen Formel IV wird eine Verbindung der allgemeinen Formel I mit einer nucleophilen Verbindung der allgemeinen FormelPosition of the 2-pyridones of the general formula IV is a compound of the general formula I with a nucleophilic compound the general formula
QMQM
in der Q und M die vorstehend angegebene Bedeutung haben, umgesetzt. Als nucleophile Verbindung kann erfindungsgemäß jede Verbindung eingesetzt werden, aus der ein Anion freigesetzt werden kann. Dies erfolgt gewöhnlich mittels einer starken Base. Spezielle Beispiele solcher nucleophiler Verbindungen sind Alkohole, Thiole, Amine, Ammoniak, Phenole, Thiophenole, Grignard-Reagentien und Malonester. Wenn als nucleophile Verbindung Ammoniak eingesetzt wird, wird als Cyanverbindung Cyanamid erhalten.in which Q and M have the meanings given above, implemented. According to the invention, any compound from which an anion is released can be used as the nucleophilic compound can be. This is usually done using a strong base. Specific examples of such nucleophilic compounds are Alcohols, thiols, amines, ammonia, phenols, thiophenols, Grignard reagents and malonic esters. When as a nucleophilic compound Ammonia is used, the cyano compound is cyanamide obtain.
Spezielle Beispiele erfindungsgemäß einsetzbarer nucleophiler Verbindungen sind: ■Specific examples of nucleophilic compounds which can be used according to the invention are: ■
I. Alkohole mit 1 bis 20 Kohlenstoffatomen;1 I. alcohols having 1 to 20 carbon atoms; 1
A. Primäre Alkohole, z.B. Alkanole, Cycloalkanole und arylsubstituierte Alkanole, wie Methanol, Äthanol, n-Propanol, n-Butanol, n-Pentanol, n-Hexanol, n-Heptanol, n-Octanol, n-Nonanol, n-Decanol, n-Dodecanol, n-Tetradecanol, n-Hexadecanol, n-Octadecanol, 2-Methyl-1-propanol, Isoamylalkohol, 2-Methyl~1-buta~ nol, Benzylalkohol, Cyclohexylcarbinol, Äthylenglycol und Trimethylenglycol; A. Primary alcohols, e.g., alkanols, cycloalkanols, and aryl substituted Alkanols, such as methanol, ethanol, n-propanol, n-butanol, n-pentanol, n-hexanol, n-heptanol, n-octanol, n-nonanol, n-decanol, n-dodecanol, n-tetradecanol, n-hexadecanol, n-octadecanol, 2-methyl-1-propanol, isoamyl alcohol, 2-methyl-1-butanol, benzyl alcohol, cyclohexyl carbinol, ethylene glycol and trimethylene glycol;
B. Sekundäre Alkohole, z.B. Alkanole, Cycloalkanole und arylsubstituierte Alkanole, wie 2-Propanol, 2-Methyl-2-propanol, 3-Methyl-2-butanol, 2-Pentanol, 3-Pentanol, 3-Hexanol, Benzhydrol, Cyclohexanol und Dicyclohexylcarbinol;B. Secondary alcohols, e.g., alkanols, cycloalkanols and aryl substituted Alkanols, such as 2-propanol, 2-methyl-2-propanol, 3-methyl-2-butanol, 2-pentanol, 3-pentanol, 3-hexanol, benzhydrol, Cyclohexanol and dicyclohexylcarbinol;
2-1-3-2-1-3-
C. Tertiäre Alkohole, z.B. Alkanole, Cycloalkanole und arylsubstituierte Alkanole, wie tert.-Butanol, tert.-Amylalkohol, 2,3-Dimethyl-2-butanol, TriphenylcarMnol und Tricyclohexylcarbinol; C. Tertiary alcohols, e.g., alkanols, cycloalkanols, and aryl substituted Alkanols, such as tert-butanol, tert-amyl alcohol, 2,3-dimethyl-2-butanol, triphenylcarbinol and tricyclohexylcarbinol;
D. Alkohole, die sowohl primäre als auch sekundäre Alkoholgruppen enthalten, wie Propylenglycol, Glycerin, ß-Methylglycerin, Glucose, Fructose, Apiöse, Mannose, Mannit, Galactose und AcrosejD. Alcohols that contain both primary and secondary alcohol groups, such as propylene glycol, glycerin, ß-methylglycerin, Glucose, fructose, apiose, mannose, mannitol, galactose and acrosej
II. Thiole mit 1 bis 20 Kohlenstoffatomen, .die den vorstehend genannten Alkoholen entsprechen. Die Thiole werden üblicherweise durch Erhitzen von Alkylhalogeniden mit Natriumhydrogensulfid hergestellt.II. Thiols having 1 to 20 carbon atoms, .the above correspond to the alcohols mentioned. The thiols are usually made by heating alkyl halides with sodium hydrogen sulfide manufactured.
III. Ammoniak und organische Amine mit 1 bis 20 Kohlenstoffatomen und deren Alkali- und Erdalkalimetallderivate;III. Ammonia and organic amines having 1 to 20 carbon atoms and their alkali and alkaline earth metal derivatives;
A. Primäre Alkylamine, Cycloalkylamine, arylsubstituierte Alkylamine und aromatische Amine, wie Methylamin, Äthylamin, n-Propylamin, Isopropylamin, n-Butylamin, Isobutylamin, tert.-Butylamin, n-Amylamin, n-Hexylamin, n-Octylamin, 2-Aminooctan, 2-Äthyl-1-aminohexan, n-Decylamin, Laurylamin, Cyclohexylamin, Benzylamin, cc-Phenyläthylamin, ß-Phenyläthylamin, Anilin und AminopyridineA. Primary alkyl amines, cycloalkyl amines, aryl substituted alkyl amines and aromatic amines, such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, tert-butylamine, n-Amylamine, n-Hexylamine, n-Octylamine, 2-Aminooctane, 2-ethyl-1-aminohexane, n-decylamine, laurylamine, cyclohexylamine, benzylamine, cc-phenylethylamine, ß-phenylethylamine, aniline and Aminopyridines
B. Sekundäre Amine, wie Dialkylamine, arylsubstituierte Alkylamine, Dicyclohexylamine, Diarylamine und stickstoffhaltige heterocyclische Amine, wie Dimethylamin, Diäthylamin, Di-npropylamin, Diisopropylamin, Äthyl-sek.-butylamin, Diphenylamin, Benzylanilin, N-Methylanilin, N-Äthylanilin, N-Phenylbenzyl-B. Secondary amines, such as dialkylamines, aryl-substituted alkylamines, Dicyclohexylamines, diarylamines and nitrogen-containing heterocyclic amines, such as dimethylamine, diethylamine, di-npropylamine, Diisopropylamine, ethyl sec-butylamine, diphenylamine, Benzylaniline, N-methylaniline, N-ethylaniline, N-phenylbenzyl-
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amin, N-Methylbenzylarain, Diphenylamin, Dicyclohexylarain, Morpholin, Piperidin, Pyrrolidin, Pyrrol, Pyrazol, Imidazol, Benzopyrrol, Skatol, 2-Methylindol, 2-Phenylindol, 1,2,3,4-Tetrahydrochinolin, Decahydrochinolin und CarbazolJamine, N-methylbenzylarain, diphenylamine, dicyclohexylarain, Morpholine, piperidine, pyrrolidine, pyrrole, pyrazole, imidazole, benzopyrrole, skatole, 2-methylindole, 2-phenylindole, 1,2,3,4-tetrahydroquinoline, Decahydroquinoline and carbazole J.
IV. Phenole, z.B. Phenol und substituierte Phenole mit 6 bisIV. Phenols, e.g. phenol and substituted phenols with 6 to
12 Kohlenstoffatomen, wie o-Kresol, m-Kresol, p-Kresol, o-Chlorphenol, m-Chlorphenol, p-Chlorphenpl, p-Bromphenol, 2,4,6-Trichlorphenol, 2,4,6-Trifluorphenol, o-Nitrophenol, m-Nitrophenol, p-Nitrophenol, 2,4-Dinitrophenol, Guajacol, Saligenin, Carvacrol, Thymol, ο-Hydroxy diphenyl, p-Hydro.-r^diphenyl, o-Cyclohexylphenol, p-Cyclohexy!phenol, Brenzcatechin, Resorcin, Hydrochinon, Pyrogallol und Phloroglucin;12 carbon atoms, such as o-cresol, m-cresol, p-cresol, o-chlorophenol, m-chlorophenol, p-chlorophenol, p-bromophenol, 2,4,6-trichlorophenol, 2,4,6-trifluorophenol, o-nitrophenol, m-nitrophenol, p-nitrophenol, 2,4-dinitrophenol, guaiacol, saligenin, Carvacrol, Thymol, ο-Hydroxy diphenyl, p-Hydro.-r ^ diphenyl, o-Cyclohexylphenol, p-Cyclohexylphenol, pyrocatechol, resorcinol, Hydroquinone, pyrogallol and phloroglucinol;
V. Thiophenole, wie Thiophenol und substituierte Thiophenole mit 6 bis 12 Kohlenstoffatomen, die den vorstehend aufgeführten Phenolen entsprechen;V. Thiophenols such as thiophenol and substituted thiophenols having 6 to 12 carbon atoms similar to the phenols listed above correspond;
VI. Grignard-Reagentien der Formel RMgX, in der R der Rest einer organischen Verbindung ist, die ein Grignard-Reagenz bildet, und X ein Halogenatom bedeutet; R kann z.B. ein unsubstituierter oder substituierter Alkylrest, ein unsubstituierter oder substituierter Cycloalkylrest oder ein unsubstituierter oder substituierter. Arylrest sein-»VI. Grignard reagents of the formula RMgX, in which R is the remainder of a is an organic compound which forms a Grignard reagent and X is a halogen atom; For example, R can be an unsubstituted or substituted alkyl radical, an unsubstituted or substituted cycloalkyl radical or an unsubstituted or substituted. Be aryl radical- »
VII. Malonester, wie Na+^cH(00002%)2?~f VII. Malonic esters, such as Na + ^ cH (00002%) 2? ~ F
VIII. Metallorganische Verbindungen, in denen der organische Rest ein Alkyl- oder Arylrest und das Metall ein Alkalimetall, ein Erdalkalimetall oder zweiwertiges Cadmium ist, wie Lithiumbutyl, Lithiumphenyl, Natriumäthyl, Natriumamyl, Natriumoctyl,VIII. Organometallic compounds in which the organic radical is an alkyl or aryl radical and the metal is an alkali metal, is an alkaline earth metal or bivalent cadmium, such as lithium butyl, lithium phenyl, sodium ethyl, sodium amyl, sodium octyl,
209834/1213'209834/1213 '
220406A220406A
Magnesiumdiphenyl, Magnesiumdiäthyl, Calciumdiäthyl und Cadmiumdioctyl. Magnesium diphenyl, magnesium diethyl, calcium diet and cadmium dioctyl.
Die Umsetzung einer Verbindung der allgemeinen Formel I mit einer nucleophilen Verbindung der allgemeinen Formel QM wird in einem leicht verdampf baren inerten Lösungsmittel., d.h., in einem Lösungsmittel, dessen Siedepunkt bei einem Druck von 1 at nicht über etwa 1000C liegt, durchgeführt. Die Wahl des Lösungsmittels hängt im wesentlichen von den Löslichkeiten der Reaktionspartner ab. Die Umsetzung kann bei Temperaturen im Bereich von etwa 0 bis etwa dem Siedepunkt des Lösungsmittels, vorzugsweise bei etwa Raumtemperatur, durchgeführt werden. Spezielle Beispiele solcher Lösungsmittel sind Äther, wie Diäthyläther oder Dioxan, aromatische Kohlenwasserstoffe, wie ; Benzol, Toluol oder Xylol, haiogenierte Kohlenwasserstoffe, wie Chloroform und Methylenchlorid, Ketone, wie Aceton und Methyläthylketon, und aliphatische Kohlenwasserstoffe, wie- Hexan und Heptan, und Gemische der vorgenannten Lösungsmittel. Das 2-Pyridon der allgemeinen Formel IV und die Cyanverbindung der allgemeinen Formel V werden aus dem Reaktionsgemisch in üblicher Weise, z.B. durch Destillation, Kristallisation oder Dünnschichtchromatographie, isoliert.The reaction of a compound of general formula I with a nucleophilic compound of the general formula QM is in a readily vaporized cash inert solvent., Ie, in a solvent whose boiling point at a pressure of 1 is not higher than about 100 0 C is performed. The choice of solvent depends essentially on the solubilities of the reactants. The reaction can be carried out at temperatures ranging from about 0 to about the boiling point of the solvent, preferably at about room temperature. Specific examples of such solvents are ethers, such as diethyl ether or dioxane, aromatic hydrocarbons, such as; Benzene, toluene or xylene, halogenated hydrocarbons such as chloroform and methylene chloride, ketones such as acetone and methyl ethyl ketone, and aliphatic hydrocarbons such as hexane and heptane, and mixtures of the aforementioned solvents. The 2-pyridone of the general formula IV and the cyano compound of the general formula V are isolated from the reaction mixture in a customary manner, for example by distillation, crystallization or thin layer chromatography.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel I sind wertvolle Arzneimittel. Sie zeichnen sich durch ihre Wirkung gegen Hefen der Gattung Candida aus. Diese Wirkung wird durch den Filterrondellen-Agardiffusionstest nachgewiesen. Hefen der Gattung Candida sind für zahlreiche pathogene Zustände bei Menschen verantwortlich. Candida albicans ruft z.B. Mund-The compounds of the general formula I according to the invention are valuable medicines. They are distinguished by their action against yeasts of the Candida genus. This effect will detected by the filter disc agar diffusion test. Yeasts of the genus Candida are responsible for numerous pathogenic conditions in humans. Candida albicans causes e.g. oral
209834/1213 .209834/1213.
schwamm und andere Arten von Moniliasis hervor.swam and other types of moniliasis.
Die 2-Pyridone der allgemeinen Formel IV sind wertvolle Zwischenprodukte zur Herstellung zahlreicher Verbindungen, z.B« von 2-Chlorpyridinen.The 2-pyridones of the general formula IV are valuable intermediates for the production of numerous compounds, e.g. 2-chloropyridines.
Verschiedene Cyanamide sind wertvolle Herbizide und wertvolle Zwischenprodukte zur Herstellung von Carbamaten und Guanidinen.Various cyanamides are valuable herbicides and valuable intermediates for the production of carbamates and guanidines.
Die Beispiele erläutern die Erfindung.The examples illustrate the invention.
2 g Natriumnitrit und 1 g 2-Aceto-amidopyridin werden mit 200 ml Wasser vermischt. Das Gemisch wird darin mit Essigsäure auf 3,0 eingestellt und in einem Eisbad gekühlt. Nach 2 Stunden2 g of sodium nitrite and 1 g of 2-aceto-amidopyridine are mixed with 200 ml Water mixed. The mixture is then adjusted to 3.0 with acetic acid and cooled in an ice bath. After 2 hours
bei O0C wird die Lösung mit Essigsäureäthylester extrahiert. Der Extrakt wird über Natriumsulfat getrocknet und unter vermindertem Druck konzentriert. Das Reaktionsprodukt wird durch Chromatographie auf Kieselgel unter Verwendung von Chloroform-Methanol (49 : 1) isoliert. Nach der Sublimation bei 900C und 0,02 Torr und anschließender Umkristallisation aus Benzol-Cyclohexan (4 ι 1) werden 20 mg 2-0xo-1(2H)-pyridincarbonitril vom Fp. 100,5 bis 101,5°C erhalten. Das IR-Spektrum in Chloroform ist in der Zeichnung dargestellt. Es werden die nachstehend aufgeführten Absorptionsbanden in cm beobachtet.at 0 ° C. the solution is extracted with ethyl acetate. The extract is dried over sodium sulfate and concentrated under reduced pressure. The reaction product is isolated by chromatography on silica gel using chloroform-methanol (49: 1). After sublimation at 90 0 C and 0.02 Torr, followed by recrystallization from benzene-cyclohexane (4 ι 1) are obtained 20 mg 2-0xo-1 (2H) -pyridincarbonitril mp. 100.5 to 101.5 ° C . The IR spectrum in chloroform is shown in the drawing. The absorption bands in cm listed below are observed.
2259 1539 11352259 1539 1135
1713 1384 11151713 1384 1115
1701 1266 8691701 1266 869
1619 1180 8391619 1180 839
Das UV-Spektrum in Cyclohexan weist Maxima oder Schultern (sh) bei folgenden Wellenlängen (mia) auf.The UV spectrum in cyclohexane shows maxima or shoulders (sh) at the following wavelengths (mia).
209834/1213209834/1213
>•
>
9 •
9
Die Verbindung ist leicht löslich in Chloroform und in Essigsäureäthylester, mäßig löslich in Benzol und schwach löslich in Tetrachlorkohlenstoff und in Hexan.The compound is easily soluble in chloroform and in ethyl acetate, moderately soluble in benzene and slightly soluble in carbon tetrachloride and in hexane.
Das Kernresonanzspektrum in Deuterochloroform zeigt außer zwei komplexen Multipletts bei 6,0 bis 6,8 ppm (2 Protonen) und bei 7,2 bis 7,7 ppm (2 Protonen) keine weiteren Absorptionen. Die Aktivität gegen Candida älbicans SC5314 und Candida tropicalis ATCC 13803 wird mittels des Filterrondellen-Agardiffusionstests nachgewiesen.The nuclear magnetic resonance spectrum in deuterochloroform shows two exceptions complex multiplets at 6.0 to 6.8 ppm (2 protons) and no further absorptions at 7.2 to 7.7 ppm (2 protons). Activity against Candida älbicans SC5314 and Candida tropicalis ATCC 13803 is determined using the Filter Disc Agar Diffusion Test proven.
• ■ £ • ■ £
Beispie- 1 2Example 1 2
Eine Lösung von 2(1H)-Pyridon in 1 Äquivalent 2 η Natronlauge wird unter vermindertem Druck zur Trockene eingedampft. Der Rückstand wird aus 95prozentigem Äthanol umkristallisiert, wobei perlmuttartig schimmernde Plättchen des hydratisierten Natriumsalzes von 2(1H)-Pyridon erhalten werden. Eine Lösung von 10,8 g dieses Salzes in 260 ml Dimethylformamid wird unter Rühren während 90 Minuten bei 0 C zu einer Lösung von 13,0 g Bromcyan in 10 ml Dimethylformamid gegeben. Das Gemisch wird weitere 10 Minuten bei 00C gerührt. Anschließend wird das Dimethyl-A solution of 2 (1H) -pyridone in 1 equivalent of 2 η sodium hydroxide solution is evaporated to dryness under reduced pressure. The residue is recrystallized from 95 percent ethanol, giving pearlescent platelets of the hydrated sodium salt of 2 (1H) -pyridone. A solution of 10.8 g of this salt in 260 ml of dimethylformamide is added to a solution of 13.0 g of cyanogen bromide in 10 ml of dimethylformamide over 90 minutes at 0 ° C. while stirring. The mixture is stirred at 0 ° C. for a further 10 minutes. Then the dimethyl
209834/1213209834/1213
formamid unter vermindertem Druck abgedampft. Der dunkelbraune Rückstand wird soweit wie möglich in Chloroform gelöst, die Lösung wird filtriertjund das Filtrat wird unter vermindertem Druck zur Trockene eingedampft. Der so erhaltene Rückstand wird in Essigsäureäthylester gelöst. Diese Lösung wird zur Entfernung des Großteils der gefärbten Verunreinigungen über eine mit 300 g Kieselgel gefüllte Säule gegeben. Nach dem Verdampfen des Lösungsmittels werden 7165 g Feststoff erhalten, der anschließend bei 90 bis 1100C und 0,02 Torr sublimiert wird. Nach dem Umkristallisieren des Sublimats (5,67 g) aus Benzol-Cyclohexan-(4:1) werden 4,24 g reines 2-0xo-1(2H)-pyridincarbonitril vom Fp. 100,5 bis 101,5°C erhalten. Die Aktivität dieser Verbindung gegen Candida-Arten wird wie in Beispiel 1 nachgewiesen.formamide evaporated under reduced pressure. The dark brown residue is dissolved in chloroform as much as possible, the solution is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue obtained in this way is dissolved in ethyl acetate. To remove most of the colored impurities, this solution is passed through a column filled with 300 g of silica gel. After evaporation of the solvent 7 1 65 g of solid are obtained, which is then sublimed at 90 to 110 0 C and 0.02 Torr. After recrystallization of the sublimate (5.67 g) from benzene-cyclohexane (4: 1), 4.24 g of pure 2-oxo-1 (2H) -pyridine carbonitrile with a melting point of 100.5 to 101.5 ° C. are obtained . The activity of this compound against Candida species is demonstrated as in Example 1.
Eine Lösung von 6 g 2-0xo-1(2H)-pyridincarbonitril in 60 ml Chloroform wird unter Rühren bei Raumtemperatur mit 4,0 g Diäthylamin versetzt. Die so erhaltene Lösung wird 30 Minuten bei Raumtemperatur weiter gerührt. Nach Abdestillieren des Lösungsmittels wird Diäthylcyanamid durch Destillation bei 10 Torr isoliert. Aus dem Rückstand wird 2-Pyridon kristallisiert. A solution of 6 g of 2-0xo-1 (2H) -pyridine carbonitrile in 60 ml of chloroform is stirred at room temperature with 4.0 g of diethylamine offset. The resulting solution is 30 minutes at Room temperature further stirred. After the solvent has been distilled off, diethyl cyanamide is added by distillation 10 torr isolated. 2-pyridone is crystallized from the residue.
Beispiele 4 bis 35Examples 4 to 35
Das Verfahren wird gemäß Beispiel 2 durchgeführt, mit der Ausnahme, daß 2(1H)-Pyridon durch die in der nachstehenden Tabelle " I aufgeführten substituierten 2-Pyridone ersetzt wird. Hierbei werden die nachstehend aufgeführten, entsprechend substituierten 2-0x0-1(2H)-pyridincarbonitrile erhalten. Die SubstituentenThe procedure is carried out according to Example 2, with the exception that 2 (1H) -pyridone is replaced by the substituted 2-pyridones listed in Table "I" below the appropriately substituted 2-0x0-1 (2H) -pyridine carbonitriles listed below are obtained. The substituents
209834/1213209834/1213
-13~ 220A06A- 13 ~ 220A06A
R^, Rp, R^ und Ri der jeweiligen Ausgangsverbindungen und der Reaktionsprodukte sind in Tabelle I zusammengestellt.R ^, Rp, R ^ and Ri of the respective starting compounds and the Reaction products are listed in Table I.
H C=NH C = N
2098 3-4/12132098 3-4 / 1213
20 21 22 23 24 2520 21 22 23 24 25
2626th
28 2928 29
3030th
3131
3232
3333
3434
3535
- 14 -- 14 -
Tabelle I - FortsetzungTable I - continued
R.R.
Il
CH3C-0
Il
CH 3 C-
H CH3°H CH 3 °
h.H.
H H. H NO,H H. H NO,
OCH3 0CH3OCH 3 0CH 3
ClCl
ΝΟ.ΝΟ.
ClCl
ClCl
R/R /
CH-CH-
CH-CH-
ClCl
209834/1213209834/1213
Beispiele 36 bis 43Examples 36 to 43
Das Verfahren wird gemäß Beispiel 2 durchgeführt mit der Ausnahme, daß 2(1H)-Pyridon durch die in der nachstehenden Tabelle II aufgeführten 2-Pyridone ersetzt wird. Hierbei werden die nachstehenden, entsprechend substituierten 2-0xo-1(2H)-pyridincarbonitrile erhalten. In den nachfolgenden Beispielen bilden die in den Beispielen 4 bis 35 als FU und R^ bezeichneten Substituenten zusammen eine gegebenenfalls mit den SubstituentenThe procedure is carried out according to Example 2 with the exception that 2 (1H) -pyridone is replaced by the 2-pyridones listed in Table II below. Here are the the following, correspondingly substituted 2-0xo-1 (2H) -pyridine carbonitrile obtain. In the examples below, the substituents identified as FU and R ^ in Examples 4 to 35 form together optionally with the substituents
und Rq substituierte Phenylgruppe. Die Substituenten Rg, Ry und RQ in den jeweiligen Äusgangsverbindungenand Rq substituted phenyl group. The substituents Rg, Ry and R Q in the respective starting compounds
und den Reaktionsprodukten sind in Tabelle II zusammengestellt.and the reaction products are summarized in Table II.
Rc R,R c R,
8 H8 H.
Il0
Il
/■■ ■■ ^ H
/ ■■ ■■ ^
CH3C- Il
CH 3 C-
IlO
Il
CH3C Il
CH 3 C
H H H HH H H H
R6 H Cl HR 6 H Cl H
H H HH H H
209834/ 1213209834/1213
Beispiele 44 Ms 58Examples 44 Ms 58
Das Verfahren wird gemäß Beispiel 2 durchgeführt, mit der Ausnahme, daß 2(1H)-Pyridon durch die in der nachstehenden Tabelle III aufgeführten 2-Pyridone ersetzt wird. Hierbei v/erden die nachstehend -aufgeführten, entsprechend substituierten 2-Oxo-i(2H)-pyridincarbonitrile erhalten. In den nachstehenden Beispielen bilden die in den Beispielen 4 bis 35 als R1 und Rp bezeichneten Substituenten zusammen eine gegebenenfalls mit den Resten R^, R10, R11 und R12 substituierte Phenylgruppe. Die Substituenten R-2, R^, Rq, R1Qf R11 und R12 in den jeweiligen Ausgangsverbindungen und den Reaktionsprodukten sind in Tabelle III zusammengestellt.The process is carried out as in Example 2, with the exception that 2 (1H) -pyridone is replaced by the 2-pyridones listed in Table III below. This gives the correspondingly substituted 2-oxo-i (2H) -pyridine carbonitriles listed below. In the examples below, the substituents designated as R 1 and Rp in Examples 4 to 35 together form a phenyl group which is optionally substituted by the radicals R 1, R 10 , R 11 and R 12. The substituents R-2, R ^, Rq, R 1, Qf, R 11 and R 12 in the respective starting compounds and the reaction products are listed in Table III.
Il0
Il
C-II
C-
-C-Il
-C-
R H HR H H
H HH H
H HH H
1111
R12 H R 12 H
NO2 NO 2
H HH H
209834/ 1213209834/1213
55 t{ ^^— Ά Η55 t { ^^ - Ά Η
,56 H <ι »- H H H H, 56 H <ι »- H H H H
57 HH HH no_ H57 HH HH no_ H
58 H H H H58 H H H H
Beispiele 59 "bis- 61Examples 59 "to -61
Das Verfahren wird gemäß Beispiel 2 durchgeführt, mit der Ausnahme, daß 2(1H)-Pyridon durch die in der nachstehenden Tabelle IV aufgeführten substituierten 2-Pyridone ersetzt wird. Hierbei werden die entsprechend substituierten 2-0xo-1(2H)-pyridincarbonitrile erhalten. In den nachstehenden Beispielen bilden die in den Beispielen 4 bis 35 mit R2 und IU bezeichneten Substituenten zusammen eine gegebenenfalls mit den Resten R1,, R*/,» R^c und R^g substituierte Phenylgruppe. Die Reste R^, R^, R13, R^, R^ und Ry,r in den jeweiligen Ausgangsverbindungen und den Reaktionsprodukten sind in Tabelle IV zusammengestellt.The process is carried out according to Example 2 with the exception that 2 (1H) -pyridone is replaced by the substituted 2-pyridones listed in Table IV below. The correspondingly substituted 2-0xo-1 (2H) -pyridine carbonitriles are obtained here. In the examples below, the substituents denoted by R 2 and IU in Examples 4 to 35 together form a phenyl group which is optionally substituted by the radicals R 1 , R * /, R ^ c and R ^ g. The radicals R ^, R ^, R 13 , R ^, R ^ and Ry, r in the respective starting compounds and the reaction products are listed in Table IV.
■ 20983 4/1213■ 20983 4/1213
- 18 -- 18 -
BrBr
R13 R] R 13 R ]
1515th
Beispiele 62 bis 80Examples 62 to 80
Das Verfahren wird gemäß Beispiel 3 durchgeführt, mit der Ausnahme,
daß Diäthylamin durch eine äquivalente Menge der in der nachstehenden Tabelle V unter Spalte .1 aufgeführten nucleophilen
Verbindungen ersetzt wird. Hierbei werden die in Spalte
2 aufgeführten Cyanverbindungen erhalten.The process is carried out according to Example 3, with the exception that diethylamine is replaced by an equivalent amount of the nucleophilic compounds listed in Table V below under column .1. The in column
2 listed cyano compounds obtained.
2098 3 4/12132098 3 4/1213
65 6665 66
6767
68 6968 69
7070
71 7271 72
7373
Natriumphenylat AnilinSodium phenylate aniline
n-Rentylaminn-rentylamine
Phenylmagne s iumbromid ÄthylmagnesiumbromidPhenylmagne s iumbromid Ethylmagnesiumbromid
Kalium-tert.-butylatPotassium tert-butoxide
Ammoniak MethylmercaptanAmmonia methyl mercaptan
DiphenylaminDiphenylamine
Spalte 2Column 2
N-CNN-CN
-CN-CN
S-CNS-CN
-CN H-CN H
N-CNN-CN
CNCN
C3H5-CN CH-C 3 H 5 -CN CH-
I 3 I 3
H-C-C-O-CNH-C-C-O-CN
II.
H2N-CN CH3S-CNH 2 N-CN CH 3 S-CN
:n-cn: n-cn
Morpholin N-CNMorpholine N-CN
2 0 9 G 3 4 / 1 2 1 32 0 9 G 3 4/1 2 1 3
Tabelle V - Fortsetzung Table V - continued
5J 5 y
2 0 9 8 3 Λ / 1 2 1 32 0 9 8 3 Λ / 1 2 1 3
Claims (8)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US11112571A | 1971-01-29 | 1971-01-29 | |
US14803771A | 1971-05-28 | 1971-05-28 |
Publications (1)
Publication Number | Publication Date |
---|---|
DE2204064A1 true DE2204064A1 (en) | 1972-08-17 |
Family
ID=26808656
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DE19722204064 Pending DE2204064A1 (en) | 1971-01-29 | 1972-01-28 | 2-Oxo-l (2H) -pyridincarbonitrile, process for their preparation and medicinal preparations containing these compounds |
Country Status (6)
Country | Link |
---|---|
CA (1) | CA978965A (en) |
CH (1) | CH540254A (en) |
DE (1) | DE2204064A1 (en) |
FR (1) | FR2123525B1 (en) |
GB (1) | GB1381168A (en) |
HU (1) | HU163950B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4931452A (en) * | 1987-11-10 | 1990-06-05 | The Dow Chemical Company | N-cyanomethyl-2-pyridinone insecticides |
-
1972
- 1972-01-26 GB GB376872A patent/GB1381168A/en not_active Expired
- 1972-01-28 CH CH125472A patent/CH540254A/en not_active IP Right Cessation
- 1972-01-28 FR FR7202949A patent/FR2123525B1/fr not_active Expired
- 1972-01-28 DE DE19722204064 patent/DE2204064A1/en active Pending
- 1972-01-28 CA CA133,391A patent/CA978965A/en not_active Expired
- 1972-01-29 HU HUSU000715 patent/HU163950B/hu unknown
Also Published As
Publication number | Publication date |
---|---|
HU163950B (en) | 1973-11-28 |
FR2123525B1 (en) | 1975-10-10 |
CA978965A (en) | 1975-12-02 |
CH540254A (en) | 1973-08-15 |
GB1381168A (en) | 1975-01-22 |
FR2123525A1 (en) | 1972-09-08 |
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