DD232275A5 - METHOD FOR PRODUCING ACYL-GAMMA-BUTYROLACTONES - Google Patents
METHOD FOR PRODUCING ACYL-GAMMA-BUTYROLACTONES Download PDFInfo
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- DD232275A5 DD232275A5 DD85278102A DD27810285A DD232275A5 DD 232275 A5 DD232275 A5 DD 232275A5 DD 85278102 A DD85278102 A DD 85278102A DD 27810285 A DD27810285 A DD 27810285A DD 232275 A5 DD232275 A5 DD 232275A5
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Abstract
Die Erfindung betrifft die Herstellung neuer Acyl-g-butyrolactone, die wertvolle Zwischenprodukte fuer die Herstellung pharmakologisch wirksamer Tetrahydropyridazinonderivate darstellen. Erfindungsaufgabe ist die Bereitstellung eines Herstellungsverfahrens fuer die neuen Verbindungen. Erfindungsgemaess stellt man die Verbindungen der Formel IIdurch Umsetzung von in 4-Stellung substituierter 4-Ketobuttersaeure mit Formaldehyd unter Katalysatorzugabe und anschliessendem Ansaeuern bei erhoehter Temperatur her. Die mit den neuen Zwischenprodukten herstellbaren Tetrahydropyridazinonderivate sind in der Medizin insbesondere als Herz- und Kreislaufmittel einsetzbar.The invention relates to the preparation of novel acyl-g-butyrolactones, which are valuable intermediates for the preparation of pharmacologically active Tetrahydropyridazinonderivate. Invention task is the provision of a manufacturing process for the new compounds. According to the invention, the compounds of the formula II are prepared by reacting 4-substituted-4-keto-butyric acid with formaldehyde with addition of catalyst and subsequent acidification at elevated temperature. The tetrahydropyridazinone derivatives which can be prepared with the new intermediates can be used in medicine, in particular, as cardiovascular agents.
Description
Berlin, den 24. 4. 1935 ~ 1 — AP C 07 D/264 247/6Berlin, April 24, 1935 ~ 1 - AP C 07 D / 264 247/6
65 336/1265 336/12
Verfahren zur Herstellung von Acyl-^ -butyrolactonenProcess for the preparation of acyl-butyrolactones
Die Erfindung betrifft die Herstellung neuer Acyl-ν butyrolactone, die Zwischenprodukte für die Herstellung antithrombotisch, cardioton und antianginös wirkender Tetrahydropyridazinonderivate darstellen. Die Erfindung ist somit in der Pharma-Industrie verwertbar.The invention relates to the production of new acyl ν butyrolactone which are intermediates for the preparation of an antithrombotic, represent cardioton and antianginal Tetrahydropyridazinonderivate. The invention is thus utilizable in the pharmaceutical industry.
Es sind keine Angaben über strukturell vergleichbare Verbindungen bekannt· Die Herstellung der neuen Verbindungen erfolgt über chemisch analoge Verfahren.There are no data on structurally comparable compounds known · The preparation of the new compounds via chemically analogous processes.
Es ist Ziel der Erfindung, pharmakologisch wertvolle Produkte über die neuen Zwischenprodukte besonders günstig herzustellen.It is an object of the invention to produce pharmacologically valuable products on the new intermediates particularly favorable.
Der Erfindung liegt die Aufgabe zugrunde, ein Verfahren zur Herstellung neuer Acyl-y- butyrolactone zu entwickeln. Erfindungsgemäß hergestellt werden Acyl-γ -butyrolactone der Formel II, worin R einen der Reste der FormelnThe invention has for its object to develop a process for the preparation of new acyl-y-butyrolactone. Acyl-γ-butyrolactones of the formula II in which R is one of the radicals of the formulas
-VJliü985*2ü43s0-VJliü985 * 2ü43s0
3 4 5 R1R und R unabhängig voneinander öod. Alkyl rait 3 bis 5 C-Atomen, -OH; Alkoxy mit 2 bis 5 C-Atomen; Alkanoyloxy mit 1 bis 5 C-Atomen; Benzoyloxy; Alkylmercapto mit 1 bis 5 C-Atomen; -NH2; Monoalkylamino mit 1 bis 5 C-Atomen; Dialkylamino mit insgesamt 2 bis 5 C-Atomen; Alkanoylamino mit 1 bis 4 C-Atomen; und R und R zusätzlich auch Wasser-3 4 5 R 1 R and R independently of one another öod. Alkyl has 3 to 5 C atoms, -OH; Alkoxy having 2 to 5 C atoms; Alkanoyloxy of 1 to 5 C atoms; benzoyloxy; Alkylmercapto having 1 to 5 C atoms; -NH 2 ; Monoalkylamino having 1 to 5 C atoms; Dialkylamino having a total of 2 to 5 carbon atoms; Alkanoylamino having 1 to 4 C atoms; and R and R additionally include water
3 4 5 stoff; einer der Reste R , R oder R o- oder m-Methoxyf o- oder m-Methyl oder -Ethyl, ο- oder m-Brom, o-Fluor und o-Chlor, die beiden anderen Wasserstoff; zwei der Reste R3, R4 oder R5 2,3-, 2,4-, 2,5- 2,6-, 3,5-Diraethoxy, -Dichlor oder -Difluor oder 3,4-Difluor und der dritte Wasserstoff, oder alle drei der Reste R3, R4 und R5 2,3,4-; 2,3,5-; 2,3,6-; 2,4,5- oder 2,4,6-Trimethoxy; und R und R außerdem Nitro; Cyan ; Alkylmercapto, Alkylsulfoxy und Alkylsulfonyl mit jeweils3 4 5 fabric; one of the radicals R, R or R o- or m-methoxy f o- or m-methyl or ethyl, ο- or m-bromo, o-fluoro and o-chloro, the other two hydrogen; two of the radicals R 3 , R 4 or R 5 are 2,3-, 2,4-, 2,5- 2,6-, 3,5-diraethoxy, dichloro or difluoro or 3,4-difluoro and the third Hydrogen, or all three of the radicals R 3 , R 4 and R 5 2,3,4-; 2,3,5; 2,3,6; 2,4,5- or 2,4,6-trimethoxy; and R and R also nitro; Cyan; Alkylmercapto, alkylsulfoxy and alkylsulfonyl each with
1 bis 5 C-Atomen, A^yI-(C1 -C-)-oxycarbonyl, eine Gruppe1 to 5 C atoms, A ^ yI (C 1 -C -) - oxycarbonyl, a group
IO 11 3 4IO 11 3 4
der Formel -NR R , wobei für R und R stehendes Alkyl,of the formula -NR R, where R and R are alkyl,
Alkoxy, Alkylamino, Dialkylainino, Alkylmercapto, Alkylsulfoxy und Alkylsulfonyl in dem Alkylteil noch durch Hydroxy, Alkoxy mit 1 bis 5, vorzugsweise 1 oder 2» C-Atomen, Carboxyl, Alkoxycarbonyl mit insgesamt 2 bis 7 C-Atomen, Aminocarbonyl der Formel ,15Alkoxy, alkylamino, dialkylamino, alkylmercapto, alkylsulfoxy and alkylsulfonyl in the alkyl moiety by hydroxy, alkoxy having 1 to 5, preferably 1 or 2 C atoms, carboxyl, alkoxycarbonyl having a total of 2 to 7 carbon atoms, aminocarbonyl of the formula, 15
N-CO-,N-CO-,
wobei R und R unabhängig voneinander Wasserstoff, Alkyl mit 1 bis 5 C-Atomen, das seinerseits durch Alkoxy mit 1 bis 4 C-Atomen, Halogen, insbesondere Chlor und Brom, -NH2, Mono- und Dialkylamino mit 1 bis 4 C-Atomen in den Alkylgruppen substituiert sein kann, bedeuten oder wobei R und R zusammen mit dem N-Atom, an das sie gebunden sind, den Rest eines 5- oder 6-gliedrigen, gegebenenfalls ein weiteres Heteroatom aufweisenden Heterocyclus, wie z. B. Pyrrolidin, Piperidin, Piperazin, Alkylpiperazin, Morpholin, Thiomorpholin bilden, Amino, Monoalkylamino mit 1 bis 5, vorzugsweise 1 oder 2, C-Atomen, Dialkylamino mit insgesamt 2 bis 6 C-Atomen oder durch einen 5- oder 6-gliedrigen Heterocyclus mit 1 bis 3 Heteroatomen substituiert sein kann;where R and R independently of one another are hydrogen, alkyl having 1 to 5 C atoms, which in turn is substituted by alkoxy having 1 to 4 C atoms, halogen, in particular chlorine and bromine, -NH 2 , mono- and dialkylamino having 1 to 4 C atoms Let R and R together with the N-atom to which they are bonded, the radical of a 5- or 6-membered, optionally another heteroatom-containing heterocycle, such as. As pyrrolidine, piperidine, piperazine, alkylpiperazine, morpholine, thiomorpholine, amino, monoalkylamino having 1 to 5, preferably 1 or 2, carbon atoms, dialkylamino having a total of 2 to 6 carbon atoms or by a 5- or 6-membered Heterocycle may be substituted by 1 to 3 heteroatoms;
4 5 R und R zusätzlich auch Wasserstoff; R und R unabhängig voneinander Wasserstoff; Halogen; insbesondere Chlor und Brom; Amino, Monoalkylamino mit 1 bis 5 C-Atomen, Dialkylamino mit insgesamt 2 bis 6 C-Atomen, Hydroxy, Alkoxy mit 1 bis 5 C-Atomen oder Alkyl mit 1 bis 5 C-Atomen;4 5 R and R additionally also hydrogen; R and R are independently hydrogen; Halogen; especially chlorine and bromine; Amino, monoalkylamino having 1 to 5 C atoms, dialkylamino having a total of 2 to 6 C atoms, hydroxy, alkoxy having 1 to 5 C atoms or alkyl having 1 to 5 C atoms;
R a und R unabhängig voneinander Halogen, insbesondere Chlor und Brom; Amino Monoalkylamino rait I bis 5 C-Atomen, Dialkylamino mit insgesamt 2-6 C-Atomen» Hydroxy,R a and R independently of one another are halogen, in particular chlorine and bromine; Amino monoalkylamino raises I to 5 C atoms, dialkylamino having a total of 2-6 C atoms »hydroxy,
Alkoxy rait Ibis 5 C-Atomen oder Alkyl mit 1 bis 5 C-Atomen; und, sofern Pyridyl in 2- oder 4-Position und Thienyl in 3-Position gebunden sind, zusätzlich Wasserstoff,Alkoxy rait Ibis 5 C atoms or alkyl having 1 to 5 carbon atoms; and, if pyridyl is attached in the 2- or 4-position and thienyl in the 3-position, additionally hydrogen,
R Wasserstoff, Alkyl mit 1 bis 5 C-Atomen, Alkanoyl mit 1 bis 5 C-Atomen oder ein Rest der FormelR is hydrogen, alkyl having 1 to 5 C atoms, alkanoyl having 1 to 5 C atoms or a radical of the formula
1414
R Alkyl mit 1 bis 5 C-Atomen, gegebenenfalls substituiert durch einen gegebenenfalls substituierten Phenoxyrest,R is alkyl having 1 to 5 C atoms, optionally substituted by an optionally substituted phenoxy radical,
eine Gruppe der Formel >3a group of formula> 3
oder Pyridyl;or pyridyl;
10 R Alkanoyl mit 1 bis 5 C-Atomen, das gegebenenfalls durch -OH, -NH^, Halogen, insbesondere Chlor oder Brom, Alkoxy mit 1 bis 5 C-Atomen oder Phenoxy der Formel10 R alkanoyl having 1 to 5 carbon atoms, optionally substituted by -OH, -NH ^, halogen, in particular chlorine or bromine, alkoxy having 1 to 5 carbon atoms or phenoxy of the formula
substituiert sein kann; Benzoyl der Formelmay be substituted; Benzoyl of the formula
R12 R 12
R14 Heteroaryl der FormelR 14 heteroaryl of the formula
^CH-CO^ CH-CO
worin η « 2; 3 oder 4,wherein η «2; 3 or 4,
m = 0; 1 oder 2 ist, wobei vorzugsweise n+m = 3 oder 4m = 0; Is 1 or 2, preferably n + m = 3 or 4
X für Sauerstoff, Schwefel oder eine Gruppe der FormelX is oxygen, sulfur or a group of the formula
=N-R steht, wobei der heterocyclische Kern noch durch Alkyl mit 1 bis 5, vorzugsweise 1 oder 2, C-Atomen, Chlor, Brom oder doppeltgebundenen Sauerstoff (=0) substituiert sein kann,= NR, wherein the heterocyclic core may be substituted by alkyl having 1 to 5, preferably 1 or 2, C atoms, chlorine, bromine or double bonded oxygen (= 0),
R Wasserstoff, Alkyl mit 1 bis 5 C-Atomen, AlkanoylR is hydrogen, alkyl of 1 to 5 C atoms, alkanoyl
mit 1 bis 5 C-Atomen bedeutenwith 1 to 5 carbon atoms
10 11 oder R und R gemeinsam mit dem Stickstoffatom, an das sie gebunden sind, einen Pyrrolidin-, Piperidin-, Piperazin-, Morpholin- oder Thiomorpholinring oder einen Ring der Formeln10 11 or R and R together with the nitrogen atom to which they are attached, a pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine ring or a ring of the formulas
0 .110 .11
(CH2)p (CH 2 ) p
-N-N
(CH2)q (CH 2 ) q
Il οIl ο
Il οIl ο
worin ρ = 3, 4 oder 5; q = 2 oder 3 ist;wherein ρ = 3, 4 or 5; q = 2 or 3;
R8-NR 8 -N
R8-NR 8 -N
worin r = 1 oder 2 ist,wherein r = 1 or 2,
Ζ"; ΝΖ "; Ν
oderor
wobei u = 0, 1 oder 2 und t = 0, 1 oder 2 ist, der gegebenenfalls noch durch Alkyl mit 1 bis 5, vorzugsweise 1 bis 2, C-Atomen substituiert sein kann, bilden, und R12 bis R14 Wasserstoff, Alkyl mit 1 bis 5 C-Atomen, Alkoxy mit 1 bis 5 C-Atomen, Nitro, Cyan, Halogen, insbesondere Chlor oder Brom, Amino, Monoalkylamino mit 1 bis 5 C-Atomen, Dialkylamino mit insgesamt 2 bis 6 C-Atomen, Alkanoylamino mit 1 bis 5 C-Atomen oder Benzoylamino bedeuten. Diese Verbindungen sind bisher nicht beschrieben worden·where u = 0, 1 or 2 and t = 0, 1 or 2, which may optionally be substituted by alkyl having 1 to 5, preferably 1 to 2, carbon atoms, form, and R 12 to R 14 is hydrogen, Alkyl having 1 to 5 C atoms, alkoxy having 1 to 5 C atoms, nitro, cyano, halogen, in particular chlorine or bromine, amino, monoalkylamino having 1 to 5 C atoms, dialkylamino having a total of 2 to 6 C atoms, Alkanoylamino having 1 to 5 carbon atoms or benzoylamino mean. These compounds have not been described so far.
Acyl-γ -butyrolactone der Formel .11 lassen sich aus in 4-Stellung substituierten 4-Ketobuttersäuren der Formel VI durch Umsetzung mit Formaldehyd herstellen:Acyl-γ-butyrolactones of the formula .11 can be prepared from 4-substituted-4-keto-butanoic acids of the formula VI by reaction with formaldehyde:
O Il R-C-CH2-CH2-COOH + HCHO-O II RC-CH 2 -CH 2 -COOH + HCHO-
(VI)(VI)
0 Il0 Il
R-C-CH-CH0-COOH 2 RC-CH-CH 0 -COOH 2
[ CH2OH[CH 2 OH
-H9O-H 9 O
(II)(II)
Die Bedeutungen von R sind in den Formeln II und VI gleich. Oxymethylierungen von CH-Acidverbindungen durch Umsetzung mit Formaldehyd sind ebenfalls bereits Stand der Technik (vgl. hierzu 3. Org. Chem. 24, S. 586-89 (1959); Synthesis (1980) S. 825-828.The meanings of R are the same in formulas II and VI. Oxymethylations of CH-Acidverbindungen by reaction with formaldehyde are also already state of the art (see also 3. Org Chem 24, p 586-89 (1959) Synthesis (1980) p 825-828.
Die Reaktion kann mit oder ohne Lösungsmittel und unter Verwendung von wäßrigem Formaldehyd, Paraformaldehyd, oder eines in einem organischen Lösungsmittel gelösten Formaldehyds durchgeführt werden. Die Umsetzung erfolgt in der Regel in Gegenwart eines schwach basischen Katalysators« wie z. B. Ammonacetat- oder Piperidinacetat. Beim Arbeiten im wäßrigen Medium werden als basische Katalysatoren zweckmäßigerweise Hydroxyde oder basisch reagierende Salze von Alkali- oder Erdalkalimetallen eingesetzt. Die Hydroxymethylierung verläuft in der Regel bereits bei Zimmertemperatur mit beachtlicher Geschwindigkeit. Die Reaktion kann daher bei Temperaturen zwischen 20 und 100 0C ausgeführt werden. Nach erfolgter Hydroxymethylierung wird das Reaktionsgeraisch angesäuert und einige Stunden bei Temperaturen zwischen 20 und 120 0C vorzugsweise bei Zimmertemperatur, nachgerührt. Hierbei tritt Ringschluß der gebildeten Hydroxymethyl-ν -Ketobuttersäure zu dem Butyrolactonderivat der Formel II ein.The reaction may be carried out with or without solvent and using aqueous formaldehyde, paraformaldehyde, or a formaldehyde dissolved in an organic solvent. The reaction is usually carried out in the presence of a weakly basic catalyst «such. B. Ammonacetat- or piperidine acetate. When working in an aqueous medium, suitable basic catalysts are hydroxides or basic salts of alkali or alkaline earth metals. The hydroxymethylation usually proceeds at room temperature at considerable speed. The reaction can therefore be carried out at temperatures between 20 and 100 0 C. After Hydroxymethylierung the Reaktionsgeraisch is acidified and a few hours at temperatures between 20 and 120 0 C, preferably at room temperature, stirred. In this case, ring closure of the hydroxymethyl-ν-keto-butyric acid formed occurs to the butyrolactone derivative of the formula II.
Prinzipiell ist es auch möglich, nach dem Ansäuern die Hydroxymethyl-v^ketobuttersäure in freier, nichtringgeschlossener Form zu isolieren und mit Hydrazin oder einemIn principle, it is also possible to isolate the hydroxymethyl-v ^ ketobutyric acid in free, non-ring-closed form after acidification and with hydrazine or a
Hydrazinderivat R-NH-NH2 zu den erfindungsgemäßen Tetrahydropyridazinonderivaten umzusetzen. (Vgl. E. Fischer, Liebigs Annalen der Chemie).Hydrazine derivative R-NH-NH 2 to implement the Tetrahydropyridazinonderivaten invention. (See E. Fischer, Liebig's Annalen der Chemie).
^-Ketobuttersäurederivate der Formel VI, die zur Herstellung der Acyl-^-butyrolactone der Formel II verwendet werden, können auf verschiedenen bekannten Wegen erhalten werden. Unabhängig von der Natur des Restes R führt die Addition von Aldehyden der Formel R-CHO an Acrylsäure oder Acry!säurederivate, insbesondere Acrylsäureester in guten Ausbeuten zu den gewünschten • -Keto-buttersäuren, bzw« -buttersäurederivaten. Diese Additionsreaktion ist 1976 von H. Stetter in "Angewandte Chemie", Heft 21, Seite 695ff., beschrieben worden. Die Reaktion wird durch die gleichen Katalysatoren katalysiert, die für die bekannte Benzoin-Kondensation geeignet sind. Insbesondere kommen hierfür Cyanid-Ionen und quartäre Thiazaliumsalze in Betracht. Als Lösungsmittel für die Durchführung dieser Additionsreaktionen eignen sich polare Lösungsmittel, wobei sich niedere Alkanole wie Methanol oder Ethanol und Dimethylformamid besonders bewährt haben. Bereits bei Zimmertemperatur erreicht die Additionsreaktion eine beachtliche Geschwindigkeit, die durch Erwärmen noch gesteigert werden kann. Zweckmäßigerweise arbeitet man zwischen Raumtemperatur und 60 0C* vorzugsweise zwischen 30 und 50 0C. Beispiele für Aldehyde, die in der angegebenen Weise mit Acrylsäure oder Acrylsäurederivaten, insbesondere Acrylsäureestern, umgesetzt werden können, sind Benzaldehyd, 2-, 3- oder 4-Chlorbenzal- dehyd ; 2,4- oderKeto-butyric acid derivatives of the formula VI which are used to prepare the acyl-butyrolactones of the formula II can be obtained in various known ways. Regardless of the nature of the radical R, the addition of aldehydes of the formula R-CHO to acrylic acid or acrylic acid derivatives, in particular acrylic acid esters, leads to the desired -K-keto-butanoic acids or--butanoic acid derivatives in good yields. This addition reaction was described in 1976 by H. Stetter in "Angewandte Chemie", Issue 21, page 695ff.,. The reaction is catalyzed by the same catalysts that are suitable for the known benzoin condensation. In particular, cyanide ions and quaternary thiazalium salts are suitable for this purpose. Suitable solvents for carrying out these addition reactions are polar solvents, with lower alkanols such as methanol or ethanol and dimethylformamide having proven particularly suitable. Even at room temperature, the addition reaction reaches a considerable speed, which can be further increased by heating. It is expedient to work between room temperature and 60 ° C. *, preferably between 30 and 50 ° C. Examples of aldehydes which can be reacted in the manner indicated with acrylic acid or acrylic acid derivatives, in particular acrylic acid esters, are benzaldehyde, 2-, 3- or 4- Chlorobenzaldehyde; 2,4- or
3,4-Dichlorbenzaldehyd; 4-Brombenzaldehyd, 2-, 3- oder 4-Methyl- oder -Ethylbenzaldehyd; 4-Isopropyl-benzaldehyd, 2-, 3- oder 4-Hydroxybenzaldehyd, 2,4-Dihydroxybenzaldehyd, 2-, 3- oder 4-Methoxy- oder -Ethoxybenzaldehyd, 2,4-, 3*4- oder 3,5-Dimethoxybenzaldehyd, 3,4,5-Triraethoxybenzaldehyd, p-Acetoxybenzaldehydf p-Benzyioxybenzaldehyd, 2-, 3- oder 4-Methylmerkaptobenzaldehyd, 2-,3,4-dichlorobenzaldehyde; 4-bromobenzaldehyde, 2-, 3- or 4-methyl- or -ethylbenzaldehyde; 4-isopropylbenzaldehyde, 2-, 3- or 4-hydroxybenzaldehyde, 2,4-dihydroxybenzaldehyde, 2-, 3- or 4-methoxy- or -ethoxybenzaldehyde, 2,4-, 3 * 4- or 3,5- Dimethoxybenzaldehyde, 3,4,5-trirethoxybenzaldehyde, p-acetoxybenzaldehyde f p-benzyioxybenzaldehyde, 2-, 3- or 4-methylmercaptobenzaldehyde, 2-,
3- oder 4-Araino-f -Monoinethylamino- oder -Dimethylaminobenzaldehyd, 2-, 3- oder 4-Nitrobenzaldehyd, 3-Methyl-, 3-Ethyl- oder 3-Butylpyridin-2-aldehyd, 4-", 5- oder 6-Methylpyridin-2-aldehyd , 4-Chlorpyridin-2-aldehyd, 5-Nitropyridin-2-aldehyd, 4-Chlor-6-methylpyridin-2-aldehyd, 4t6-Dichlorpyridin-2-aldehyd, 4,6-Diraethylpyridin-2-aldehyd, 6-Methyl-4-nitropyridin-2-aldehydt 5-Brom- oder S-Chlor-pyridin-S-aldehyd, 2- oder S-Methylpyridin-S-aldehyd, Sje-Dichlorpyridin-S-aldehyd, 2-Methylpyridin-4- -aldehyd, 3-Ethylpyridin-4-aldehyd, 2-Methyl-5-ethylpyridin-4-aldehyd, 2,6-Dichiorpyridin-4-aldehydt 2,6-Dimethylpyridin-4-aldehyd, 3-Nitropyridin-4-aldehyd, 5-Chlor- oder 5-Brom-thiphen-2-aldehyd, 3- oder 4-Bromthiophen-2-aldehyd, 4,5-Dichlor- oder 4#5-Dibromthiophen-2-aldehyd, 3- or 4-f Araino- -Monoinethylamino- or -Dimethylaminobenzaldehyd, 2-, 3- or 4-nitrobenzaldehyde, 3-methyl-, 3-ethyl- or 3-butylpyridine-2-aldehyde, 4- ", 5- or 6-methylpyridine-2-aldehyde, 4-chloropyridine-2-aldehyde, 5-nitropyridine-2-aldehyde, 4-chloro-6-methylpyridine-2-aldehyde, 4- t 6-dichloropyridine-2-aldehyde, 4,6- Diraethylpyridine-2-aldehyde, 6-methyl-4-nitropyridine-2-aldehyde t 5-bromo or S-chloro-pyridine-S-aldehyde, 2- or S-methylpyridine-S-aldehyde, Sje-dichloropyridine-S aldehyde, 2-methylpyridine-4-aldehyde, 3-ethylpyridine-4-aldehyde, 2-methyl-5-ethylpyridine-4-aldehyde, 2,6-dichloropyridine-4-aldehyde t, 2,6-dimethylpyridine-4-aldehyde , 3-nitropyridine-4-aldehyde, 5-chloro- or 5-bromo-thiophene-2-aldehyde, 3- or 4-bromothiophene-2-aldehyde, 4,5-dichloro or 4 # 5-dibromothiophene-2 aldehyde ,
4- oder 5-Nitrothiophen-2-aldehyd, 3-Brom-4-Nitrothiophen-2-aldehyd, 5-Methyl-, -ethyl-, -butyl- oder-isobutyl-thiophen-2-aldehyd, 3-Methyl-5-Nitrothiophen-2-aldehyd, 2-Chlor-, 2-Brom- oder 2-Nitrothiophen-3-aldehyd, 2,5-Dichlorthiophen-3-aldehyd, 2,5-Diraethyl- oder 2,5-Diethylthiophen-3-aldehyd, 2-Butyl-5-methylthiophen-3-aldehyd, 5-tert. Butyl-2-raethylthlophen-3-aldehyd·4- or 5-nitrothiophene-2-aldehyde, 3-bromo-4-nitrothiophene-2-aldehyde, 5-methyl, -ethyl, -butyl or -isobutyl-thiophene-2-aldehyde, 3-methyl-5 -Nitrothiophene-2-aldehyde, 2-chloro, 2-bromo or 2-nitrothiophene-3-aldehyde, 2,5-dichlorothiophene-3-aldehyde, 2,5-diraethyl- or 2,5-diethylthiophene-3 aldehyde, 2-butyl-5-methylthiophene-3-aldehyde, 5-tert. Butyl-2-raethylthlophen-3-aldehyde ·
1st R ein substituierter Phenyl- oder Heteroarylrest, so können die γ -Ketobuttersäurederivate der Formel VI auch dadurch erhalten werden, daß man entsprechend substitu-If R 1 is a substituted phenyl or heteroaryl radical, the γ- ketobutyric acid derivatives of the formula VI can also be obtained by reacting appropriately with
-liierte Benzolderivate oder Heterocyclen unter Friedel-Crafts-Bedingungen mit Bernsteinsäureanhydrid oder Bernsteinsäure-ester-chlorid acyliert. Friedel-Crafts-Reaktionen mit Bernsteinsäureanhydrid sind ebenfalls seit langem Stand der Technik und in zahlreichen Publikationen, beispielsweise in D. Am. Chem. Soc. 70, S. 3197 (1948); Liebigs Annalen d. Chemie, 462, S. 148 (1928); US Patent Mo. 2,447,998, detailliert dargestellt worden.-liierte benzene derivatives or heterocycles under Friedel-Crafts conditions acylated with succinic anhydride or succinic acid ester chloride. Friedel-Crafts reactions with succinic anhydride have also long been known in the art and in numerous publications, for example in D. Am. Chem. Soc. 70, p. 3197 (1948); Liebig's Annals d. Chemistry, 462 , p. 148 (1928); U.S. Patent No. 2,447,998, in detail.
Bei Acylierung nach Friedel-Crafts werden die Reaktanten in einem inerten Lösungsmittel, vorzugsweise einem inerten aromatischen Kohlenwasserstoff, oder auch in Schwefelkohlenstoff in Gegenwart eines Friedel-Crafts-Katalysators bei Temperaturen zwischen Raumtemperatur und dem Siedepunkt des Lösungsmittels miteinander umgesetzt. Verwendet man Schwefelkohlenstoff als Lösungsmittel, so muß für ausreichende Kühlung Sorge getragen werden, damit das Lösungsmittel nicht verdampft* Beim Einsatz von Nitrobenzol, einem sehr gut geeigneten Lösungsmittel für die Durchführung von Friedel-Crafts-Reaktionen, sollte bekanntlich nicht oberhalb 50 C gearbeitet werden, da es sonst zu heftigen Reaktionen kommen kann· Sollen Y -Ketobuttersäuren der Formel VI hergestellt werden, in denen R beispielsweise Chlorphenyl, Alkylphenyl oder Dialkylphenyl ist, so kann man in einfacher Weise Bernsteinsäureanhydrid mit einem Friedel-Crafts-Katalysator in dem entsprechend substituierten Benzolderivat, welches in größerem Überschuß eingesetzt wird und damit gleichzeitig als Lösungsmittel wirkt, umsetzen. Als Friedel-Crafts-Katalysator werden bekanntlich in der Regel Lewissäuren, wie AlCl.,, SbCl1-, BF,, ZnCl-, oder Protonensäuren, wie z. 3, HF1 H3SO4, H3PO4 beziehungsweise P2 0S*In acylation according to Friedel-Crafts, the reactants are reacted in an inert solvent, preferably an inert aromatic hydrocarbon, or else in carbon disulfide in the presence of a Friedel-Crafts catalyst at temperatures between room temperature and the boiling point of the solvent. If carbon disulfide is used as the solvent, sufficient cooling must be ensured so that the solvent does not evaporate. * When using nitrobenzene, a very suitable solvent for carrying out Friedel-Crafts reactions, it is well known not to work above 50 C, otherwise it can lead to violent reactions. If Y-ketobutyric acids of the formula VI are to be prepared in which R is, for example, chlorophenyl, alkylphenyl or dialkylphenyl, succinic anhydride can be prepared in a simple manner using a Friedel-Crafts catalyst in the correspondingly substituted benzene derivative, which is used in greater excess and thus acts as a solvent, implement. As a Friedel-Crafts catalyst are known, as a rule, Lewis acids, such as AlCl. ,, SbCl 1 -, BF ,, ZnCl-, or protic acids, such as. 3, HF 1 H 3 SO 4 , H 3 PO 4 or P 2 0 S *
eingesetzt. Vorzugsweise arbeitet man mit Aluminiurachlorid als Friedel-Crafts-Katalysator.used. Preferably, one works with aluminum chloride as Friedel-Crafts catalyst.
Die neuen Verbindungen stellen Zwischenprodukte zur Herstellung von Tetrahydropyridazinonderivaten nach folgendemThe new compounds are intermediates for the preparation of tetrahydropyridazinone derivatives according to the following
2 Schema dar2 Scheme
R-C-R-C-
+ H2N-NHR'+ H 2 N-NHR '
(II)(II)
(la)(La)
wobei diese Umsetzung auch in zwei Sdiritten durchgeführt werden kann durch Umsetzung von (II) mit Hydrazin und anschließender Alkylierung in 2-Stellung des entstandenen heterozyklischen Sechs ringes·this reaction can also be carried out in two groups by reacting (II) with hydrazine and subsequent alkylation in the 2-position of the resulting heterocyclic six-membered ring ·
Die 5-ständige Hydroxymethylgruppe kann weiterhin noch verethert oder verestert werden, wodurch sich Verbindungen der Formel (I) ergebenThe 5-membered hydroxymethyl group can furthermore be etherified or esterified, resulting in compounds of the formula (I)
R2 R 2
N —NN -N
Die Tetrahydropyridazinonderivate der Formel I1 worin R ein gemäß obiger Definition substituierter Phenylrest oder ein unsubstituierter oder substituierter hetero-The tetrahydropyridazinone derivatives of the formula I 1 in which R is a phenyl radical which is substituted as defined above or an unsubstituted or substituted heteroaryl radical
cyclischer Rest ist, sowie auch Tetrahydropyridazinone der Formel I, in denen R ein unsubstituierter Phenylrest istf und ihre physiologisch verträglichen Salze zeigen ausgeprägte antithrombotische, thrombozytenaggregationshemmende, antianginöse, kardiotone und blutdrucksenkende Wirkungen. Sie sind den bisher bekannten Verbindungen gleicher Wirkungsrichtung überraschenderweise erheblich überlegen und eignen sich daher vorzüglich zur Behandlung von Erkrankungen des Herzens und des Kreislaufsystems. Sie zeigen eine ausgezeichnete Wirksamkeit in verschiedenartigen Tests, wie z. B. Thrombozytenaggregation nach Born, Nature 194, S. 927, (1961); Arachidonsäureletalität am Kaninchen, Science 193, S. 1085, (1974); arterielle und venöse Thromboseverhinderung beim Kaninchen, günstiges hämodynamisches Profil nach per os-Applikation am wachen Hund. Die Prüfung in den genannten und einer Reihe weiterer Tests ergibt, daß die erfindungsgemäß herstellbaren Verbindungen bei geringer Toxizität überraschenderweise ein besonders günstiges, bei bekannten Präparaten in dieser Form nicht vorliegendes Wirkungsprofil aufweisen.is cyclic radical, as well as Tetrahydropyridazinone of formula I, in which R is an unsubstituted phenyl radical f and their physiologically acceptable salts show pronounced antithrombotic, platelet aggregation-inhibiting, antianginal, cardiotonic and hypotensive effects. They are surprisingly considerably superior to the previously known compounds of the same mode of action and are therefore excellently suitable for the treatment of diseases of the heart and of the circulatory system. They show excellent effectiveness in various tests, such. B. platelet aggregation according to Born, Nature 194 , p. 927, (1961); Rabbit arachidonic acid etiology, Science 193 , p. 1085, (1974); Rabbit arterial and venous thrombosis prevention, favorable haemodynamic profile after per os application on awake dog. The test in the cited and a number of other tests shows that the compounds which can be prepared according to the invention surprisingly have, with low toxicity, a particularly favorable profile of action, which is not present in this form in the case of known preparations.
Die Erfindung wird nachstehend durch Beispiele näher erläutert.The invention will be explained in more detail by examples.
4-(3-Indolyl)-carbonyl- 4- (3-indolyl) -carbonyl SS -butyrolactonbutyrolactone
Diese Verbindung wird wie folgt hergestellt:This compound is made as follows:
21,7 g (0,1 mol) 4-(3-Indolyl)-4-oxo-buttersäure, 8 ml 39 %ige Formaldehydlösung und 130 ml 3,5 %±ge Natronlauge werden 24 Stunden bei 50 C im Autoklaven gerührt. Nach Zugabe von 10 ml konz. Salzsäure wird 12 Stunden bei Raumtemperatur weitergerührt, mit Methylenchlorid extrahiert, mit Natriumhydrogencarbonatlösung gewaschen, eingeengt und aus Toluol umkristallisiert.21.7 g (0.1 mol) of 4- (3-indolyl) -4-oxo-butyric acid, 8 ml of 39% formaldehyde solution and 130 ml of 3.5 % ± sodium hydroxide solution are stirred for 24 hours at 50 C in an autoclave. After addition of 10 ml of conc. Hydrochloric acid is further stirred for 12 hours at room temperature, extracted with methylene chloride, washed with sodium bicarbonate solution, concentrated and recrystallized from toluene.
Ausbeute: 10,4 g (45 % d. Theorie) Schmelzpunkt: 188 - 191 0C Elementaranalyse: εΐ3ΗιιΝ03 (229,24) berechnet: C 68,1 H 4,8 N 6,1 O 20,9 gefunden: C 67,7 H 4,9 N 6,3 O 20,8Yield: 10.4 g (45% of theory). Melting point: 188-191 0 C. Elemental analysis: ε ΐ3 Η ιι Ν0 3 (229.24) calculated: C 68.1 H 4.8 N 6.1 O 20, 9 found: C 67.7 H 4.9 N 6.3 O 20.8
In analoger Weise lassen sich weitere 4-Aryl-carbonyl-)fbutyrolactone herstellen, beispielsweise:In an analogous manner, further 4-aryl-carbonyl) fbutyrolactone can be prepared, for example:
4-(3~Nitrophenyl)-carbonyl- Y-butyrolacton 4-(l-Acetyl-2-pyrrolidinyl)-carbonyl- y-butyrolacton 4-(l-Formyl-2-pyrrolidinyl)-carbonyl-γ -butyrolacton 4-(-2-Pyrrolidinyl)-carbonyl- Y-butyrolacton 4-(2-Pyrrolyl)-carbonyl- y-butyrolacton 4-(2-Furyl)-carbonyl- y-butyrolacton 4-(4-Cyanophenyl)-carbonyl-γ-butyrolacton 4-(4-Methoxycarbonylphenyl)-carbonyl- y-butyrolacton 4-(4-Nitrophenyl)-carbonyl-γ-butyrolacton 4-(4-Aminocarbonylaminophenyl)-carbonyl-γ-butyrolacton 4-(4-(2-(l-Imidazolyl)-ethoxy)-phenyl)-carbonyl-γ-butyrolacton4- (3-Nitrophenyl) carbonyl-Y-butyrolactone 4- (1-Acetyl-2-pyrrolidinyl) carbonyl- γ -butyrolactone 4- (1-Formyl-2-pyrrolidinyl) carbonyl- γ- butyrolactone 4- ( -2-pyrrolidinyl) carbonyl-Y-butyrolactone 4- (2-Pyrrolyl) -carbonyl-γ-butyrolactone 4- (2-Furyl) -carbonyl-γ-butyrolactone 4- (4-Cyanophenyl) -carbonyl-γ-butyrolactone 4- (4-Methoxycarbonylphenyl) carbonyl-γ-butyrolactone 4- (4-Nitrophenyl) carbonyl-γ-butyrolactone 4- (4-aminocarbonylaminophenyl) carbonyl-γ-butyrolactone 4- (4- (2- imidazolyl) ethoxy) phenyl) carbonyl-γ-butyrolactone
4-(4-(2-Oxo-l,3-oxazolidin-5-yl)-methoxyphenyl)-carbonyl-J-butyrolacton4- (4- (2-oxo-l, 3-oxazolidin-5-yl) methoxyphenyl) carbonyl-J-butyrolactone
4-(4-(l,4-Dioxobutylenimino)-phenyl)-carbonyl-^-butyrolacton.4- (4- (l, 4-Dioxobutylenimino) phenyl) carbonyl - ^ - butyrolactone.
2,3,4,5-Tetrahydro-5-hydroxymethyl-6-(3-indolyl)-pyridazin-3-on 2,3,4,5-tetrahydro-5-hydroxymethyl-6- (3-indolyl) pyridine zin-3-one
3t3 g (0,014 mol) 4-(3-Indolyl)-carbonyl- ]f -butyrolacton nach Beispiel 1 und 0,85 ml (0,018 mol) Hydrazinhydrat werden in 50 ml Ethylenglykolmonomethylether und 1 ml Essigsäure 13 Stunden bei 80 0C gerührt· Nach Zugabe von 10 ml Petrolether zum Reaktionsgemisch kristallisiert das Produkt in guter Reinheit aus.3 t 3 g (0.014 mol) of 4- (3-indolyl) -carbonyl] f-butyrolactone according to Example 1 and 0.85 ml (0.018 mol) of hydrazine hydrate in 50 ml of ethylene glycol monomethyl ether and 1 ml of acetic acid for 13 hours at 80 0 C. stirred · After addition of 10 ml of petroleum ether to the reaction mixture, the product crystallized in good purity.
Ausbeute: 1,2 g (35 % d. Theorie) Schmelzpunkt: 235 - 237 0CYield: 1.2 g (35% theory d.) Melting point: 235-237 0 C.
Elementaranalyse: c±z^iz^3°2 C243*27) berechnet: C 64,2 H 5,4 N 17,3 0 13,2 gefunden: C 63,8 H 5,3 N 17,1 0 13,5Elemental analysis: c ± z ^ iz ^ 3 ° 2 C 243 * 27 ) Calculated: C 64.2 H 5.4 N 17.3 O 13.2 Found: C 63.8 H 5.3 N, 17.1 O 13 , 5
Claims (1)
=N-R steht, wobei der heterocyclische Kern noch durch Alkyl mit 1 bis 5, vorzugsweise 1 oder 2, C-Atomen, Chlor, Brom oder doppeltgebundenen Sauerstoff (=0) substituiert sein kann,8th
= NR, wherein the heterocyclic core may be substituted by alkyl having 1 to 5, preferably 1 or 2, C atoms, chlorine, bromine or double bonded oxygen (= 0),
R Wasserstoff, Alkyl mit 1 bis 5 C-Atomen, Alkanoyl mit 1 bis 5 C-Atomen bedeuten11
R is hydrogen, alkyl having 1 to 5 carbon atoms, alkanoyl having 1 to 5 carbon atoms
Ii
R-C - CH2CH2 - COGH (VI)O
ii
RC - CH 2 CH 2 - COGH (VI)
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