DE2845220A1 - 6-Indolyl or quinolyl substd. pyridazinone derivs. - useful as antithrombotic and antihypertensive agents - Google Patents
6-Indolyl or quinolyl substd. pyridazinone derivs. - useful as antithrombotic and antihypertensive agentsInfo
- Publication number
- DE2845220A1 DE2845220A1 DE19782845220 DE2845220A DE2845220A1 DE 2845220 A1 DE2845220 A1 DE 2845220A1 DE 19782845220 DE19782845220 DE 19782845220 DE 2845220 A DE2845220 A DE 2845220A DE 2845220 A1 DE2845220 A1 DE 2845220A1
- Authority
- DE
- Germany
- Prior art keywords
- oxo
- lower alkyl
- tetrahydropyridazin
- methyl
- hydrogen atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—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
- C07D215/04—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—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 only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Description
Pyridazinon-Derivate, ihre Salze mit Säuren, Verfahren zu Pyridazinone derivatives, their salts with acids, method too
ihrer Herstellung und ihre Verwendung bei der Behandlung von Thrombosen und Hypertonie Die Erfindung betrifft den in den Patentansprüchen gekennzeichneten Gegenstand. their manufacture and their use in the treatment of thrombosis and hypertension The invention relates to that characterized in the claims Object.
Spezielle Beispiele für niedere Alkylreste, durch die die Äthylen- oder Vinylengruppe A substituiert sein kann, sind Reste mit 1 bis 4 Kohlenstoffatomen, wie die Methyl-, Äthyl-, Propyl- oder Butylgruppe. Spezielle Beispiele fürniedere Alkylreste R1 sind die Methyl-, Äthyl-, Propyl- und Butylgruppe. Spezielle Beispiele für den Alkanoylrest R1 sind die Acetyl-, Propionyl- und Butyrylgruppe. Spezielle Beispiele für Alkylsulfonylreste sind die Methansulfonyl-und Äthansulfonylgruppe. Als Substituenten für den Benzolkern der Benzoylgruppe kommen z.B. in Frage Halogenatome, wie Fluor-, Chlor- oder Bromatome, niedere Alkylreste, wie die Methyl-, Äthyl-, Propyl- oder Butylgruppe, oder niedere Alkoxyreste, wie die Methoxy- oder Äthoxygruppe. Spezielle Beispiele für den Alkylrest R2 sind die Methyl-, Äthyl-, Propyl-, Butyl-, Pentyl-, Hexyl-, Heptyl-, Octyl-, Nonyl-, Decyl-, Pentadecyl-, Hexadecyl-, Heptadecyl-, Octadecyl-, Nonadecyl-, Eicosyl-, Heneicosyl- oder Docosylgruppe.Specific examples of lower alkyl radicals through which the ethylene or vinylene group A can be substituted, are radicals with 1 to 4 carbon atoms, such as the methyl, ethyl, propyl or butyl group. Specific examples of lower Alkyl radicals R1 are the methyl, ethyl, propyl and butyl groups. Specific examples for the alkanoyl radical R1 are the acetyl, propionyl and butyryl groups. Specific Examples of alkylsulfonyl radicals are the methanesulfonyl and ethanesulfonyl groups. Possible substituents for the benzene nucleus of the benzoyl group are, for example, halogen atoms, such as fluorine, chlorine or bromine atoms, lower alkyl radicals such as methyl, ethyl, Propyl or butyl group, or lower alkoxy radicals, such as the methoxy or ethoxy group. Specific examples of the alkyl radical R2 are the methyl, ethyl, propyl, butyl, Pentyl, hexyl, heptyl, octyl, nonyl, decyl, pentadecyl, hexadecyl, heptadecyl, Octadecyl, nonadecyl, eicosyl, heneicosyl or docosyl group.
Spezielle Beispiele für niedere Hydroxyalkylreste RL sind die Hydroxymethyl-, 2-Hydroxyäthyl- und 3-Hydroxypropylgruppe. Spezielle Beispiele für Carbamoylalkylreste sind Reste mit 6 bis 11 Kohlenstoffatomen im Alkylrest, wie die Carbamoylhexyl-, Carbamoyloctyl-, Carbamoyldecyl- und Carbamoylundecylgruppe. Spezielle Beispiele für den Napthyloxyalkylrest R2 sind die Naphthyloxymethyl-und 2-Naphthyloxyäthylgruppe. Spezielle Beispiele für Oxoalkylreste R2 sind Reste mit 3 bis 6 Kohlenstoffatomen, wie die 3-Oxobutyl- und 4-Oxopentylgruppe. Spezielle Beispiele für niedere Alkylreste R6 und R7 sind die Methyl-, Äthyl-, Propyl- und Butylgruppe.Specific examples of lower hydroxyalkyl radicals RL are the hydroxymethyl, 2-hydroxyethyl and 3-hydroxypropyl groups. Specific examples of carbamoylalkyl groups are radicals with 6 to 11 carbon atoms in the alkyl radical, such as the carbamoylhexyl, Carbamoyloctyl, carbamoyldecyl and carbamoylundecyl groups. Specific examples for the napthyloxyalkyl radical R2 are the naphthyloxymethyl and 2-naphthyloxyethyl groups. Specific examples of oxoalkyl radicals R2 are radicals with 3 to 6 carbon atoms, such as the 3-oxobutyl and 4-oxopentyl groups. Specific examples of lower alkyl groups R6 and R7 are the methyl, ethyl, propyl and butyl groups.
Spezielle Beispiele für den heterocyclischen ing R6R7N-sind der Pyrrolidin-, Piperidin-, Morpholin-, Piperazin-und N-Methylpiperazinring. Spezielle Beispiele für niedere 4 Alkylreste R sind die Methyl-, Äthyl-, Propyl- und Butylgruppe. Spezielle Beispiele für niedere Alkanoyloxymethylreste R4 sind die Acetoxymethyl-, propionyloxymethyl-und Butyryloxymethylgruppe. Spezielle Beispiele für nieder Alkylreste R5 sind die Methyl-, Äthyl-, Propyl- und Butylgruppe.Specific examples of the heterocyclic ing R6R7N- are the pyrrolidine, Piperidine, morpholine, piperazine and N-methylpiperazine ring. Specific examples for lower 4 alkyl radicals R are the methyl, ethyl, propyl and butyl groups. Specific Examples of lower alkanoyloxymethyl radicals R4 are acetoxymethyl, propionyloxymethyl and Butyryloxymethyl group. Specific examples of lower alkyl radicals R5 are the methyl, Ethyl, propyl and butyl groups.
Bevorzugt sind Verbindungen der allgemeinen Formel I, in der A eine gegebenenfalls durch einen niederen Alkylrest substituierte Äthylen- oder Vinylengruppe, B ein Carbonylsauerstoffatom, R1 ein Wasserstoffatom oder einen niederen Alkylrest, R2 ein Wasserstoffatom, einen Alkylrest oder eine Gruppe der allgemeinen Formel R6R7N-(CH2) bedeutet, wobei R6 und R7 Wasserstoffatome oder niedere Alkylreste darstellen oder R6 und R7 zusammen mit dem Stickstoffatom einen heterocyclischen Ring bilden und n den Wert 2 oder 3 hat, R3 ein Wasserstoffatom, R4 ein Wasserstoffatom, einen niederen Alkylrest, eine Hydroxymethylgruppe oder einen niederen Alkanoyloxymethylrest un; R5 ein Wasserstoffatom oder einen niederen Alkylrest darstellt.Compounds of the general formula I are preferred in which A is a ethylene or vinylene group optionally substituted by a lower alkyl radical, B is a carbonyl oxygen atom, R1 is a hydrogen atom or a lower alkyl radical, R2 is a hydrogen atom, an alkyl radical or a group of the general formula R6R7N- (CH2), where R6 and R7 represent hydrogen atoms or lower alkyl radicals or R6 and R7 together with the nitrogen atom form a heterocyclic ring and n is 2 or 3, R3 is a hydrogen atom, R4 is a hydrogen atom, a lower alkyl, hydroxymethyl or lower alkanoyloxymethyl U.N; R5 represents a hydrogen atom or a lower alkyl radical.
Speziell bevorzugt sind Verbindungen der allgemeinen Formel I, in der A eine gegebenenfalls durch einen niederen Alkylrest substituierte Äthylengruppe, B ein Carbonylsauerstoffatom, R1 ein Wasserstoffatom oder einen niederen Alkylrest, R ein Wasserstoffatom, einen niederen Alkylrest oder eine Gruppe der allgemeinen Formel R6R7N(CH2)n bedeutet, wobei R6 und R7 Wasserstoffatome oder niedere Alkylreste darstellen oder R6 und R7 zusammen mit dem Stickstoffatom einen heterocyclischen Ring bilden und n den Wert 2 oder 3 hat, R3 ein Wasser-4 stoffatom, R ein Wasserstoffatom, einen niederen Alkylrest, eine Hydroxymethylgruppe oder einen niederen Alkanoyloxymethylrest und R5 ein Wasserstoffatom bedeutet.Particularly preferred are compounds of the general formula I, in the A is an ethylene group optionally substituted by a lower alkyl radical, B is a carbonyl oxygen atom, R1 is a hydrogen atom or a lower alkyl radical, R is a hydrogen atom, a lower alkyl radical or a group of the general Formula R6R7N (CH2) n denotes, where R6 and R7 are hydrogen atoms or lower alkyl radicals represent or R6 and R7 together with the nitrogen atom form a heterocyclic one Form a ring and n has the value 2 or 3, R3 is a hydrogen atom, R is a hydrogen atom, a lower alkyl group, a hydroxymethyl group or a lower alkanoyloxymethyl group and R5 represents a hydrogen atom.
Die Verbindungen der allgemeinen Formel I können hergestellt werden entweder a) aus einer Verbindung der allgemeinen Formel II oder deren funktionellem Derivat, beispielsweise einem Ester oder Säureanhydrid, oder b) einem Y-Butyrolacton der allgemeinen Formel III in der die Reste A, B, R , R3, R4 und R5 die vorstehende Bedeutung haben, mit einer Hydrazinverhindung der allgemeinen Formel IV R2-NH-NH2 (IV) in der R2 die vorstehende Bedeutung hat, oder dessen Hydrat. Danach wird das erhaltene Produkt gegebenenfalls verestert, alkyliert, acyliert, sulfoniert, dehydriert oder in ein Salz einer Säure überführt.The compounds of the general formula I can be prepared either a) from a compound of the general formula II or their functional derivative, for example an ester or acid anhydride, or b) a Y-butyrolactone of the general formula III in which the radicals A, B, R, R3, R4 and R5 have the above meaning, with a hydrazine compound of the general formula IV R2-NH-NH2 (IV) in which R2 has the above meaning, or its hydrate. The product obtained is then optionally esterified, alkylated, acylated, sulfonated, dehydrated or converted into a salt of an acid.
Die Umsetzung der Verbindungen der allgemeinen Formel II mit der Hydrazinverbindung der allgemeinen Formel IV wird gewöhnlich entweder ohne ein Lösungsmittel oder in einem inerten Lösungsmittel, wie Wasser, Methanol, Äthanol, Propanol, Isopropanol, Tetrahydrofuran, Dioxan, Benzol, Toluol, Chloroform, Dimethylformamid oder deren Gemisch bei Raumtemperatur oder unter Erwärmen durchgeführt.The reaction of the compounds of general formula II with the hydrazine compound of the general formula IV is usually either without a solvent or in an inert solvent such as water, methanol, ethanol, propanol, isopropanol, Tetrahydrofuran, dioxane, benzene, toluene, chloroform, dimethylformamide or their Mixture carried out at room temperature or with heating.
Die Umsetzung der Verbindung der allgemeinen Formel III mit der Hydrazinverbindung der allgemeinen Formel IV wird vorzugsweise durch 1- bis 20-stündiges Erhitzen unter Rückfluß in einem Lösungsmittel,wie Methanol, Äthanol oder Isopropanol, durchgeführt.The reaction of the compound of general formula III with the hydrazine compound of the general formula IV is preferably obtained by heating for 1 to 20 hours Reflux is carried out in a solvent such as methanol, ethanol or isopropanol.
Die Verbindungen der allgemeinen Formel I, in der R4 einen niederen Alkanoyloxymethylrest bedeutet, können durch Veresterung der Verbindungen der allgemeinen Formel I herge-4 stellt werden, in der R eine Hydroxymethylgruppe darstellt.The compounds of general formula I in which R4 is lower Alkanoyloxymethylrest means, can by esterification of the compounds of the general Formula I are produced, in which R represents a hydroxymethyl group.
Die Umsetzung wird vorzugsweise durch 1- bis 10-stündiges Erhitzen unter Rückfluß in Gegenwart einer Base, wie Triäthylamin oder Pyridin, in einem inerten Lösungsmittel, wie Chloroform, Dimethylformamid oder Tetrahydrofuran, durchgeführt.The reaction is preferably carried out by heating for 1 to 10 hours under reflux in the presence of a base such as triethylamine or pyridine in one inert solvents such as chloroform, dimethylformamide or tetrahydrofuran carried out.
Beispiele für verwendbare Veresterungsmittel sind Essigsäure, Propionsäure, Buttersäure oder deren funktionelle Derivate, wie die Säureanhydride oder Säurehalogenide.Examples of esterifying agents that can be used are acetic acid, propionic acid, Butyric acid or its functional derivatives, such as the acid anhydrides or acid halides.
Die Verbindungen der allgemeinen Formel I, in der R2 kein Wasserstoffatom darstellt, können durch Alkylierung der Verbindungen der allgemeinen Formel I hergestellt werden, in der R2 ein Wasserstoffatom bedeutet. Die Umsetzung wird vorzugsweise bei Temperaturen von 0 bis 100"C während 1 bis 10 Stunden in Gegenwart einer starken Base, wie Natriumhydrid, Natriummethoxid oder Natriumamid, in einem Lösungsmittel, wie Dimethylformamid, Dimethylsulfoxid, Dimethylacetamid, N-Methylpyrrolidon oder Tetrahydrofuran, durchgeführt. Beispiele für verwendbare Alkylierungsmittel sind Alkylhalogenide, wie Methyljodid, Äthylbromid, Butylbromid, Octylbromid oder Docosylbromid, niedere Hydroxyalkylhalogenide, wie 2-Fydroxyäthylbromid oder 3-Hydroxypropylbromid, Carbamoylalkylhalogenide, wie 10-Carbamoyldecylbromid, Naphthyloxyalkylhalogenide, wie 2-(2-Naphthyloxy)-äthylbromid, Oxoalkylhalogenide, wie 4-Oxopentylbromid, Halogenide der allgemeinen Formel A ,v7N-(cH2)n-Ealt wobei R6, R7 und n die vorstehende Bedeutung haben und Hal ein Halogenatom darstellt, wie 2-Dimethylaminoäthylbromid, 3-Dimethylaminopropylbromid, 2-Morpholinoäthylbromid oder 3-Piperidinopropylbromid, oder mit einem entsprechenden organischen Sulfonsäureester, wie Methansulfonsäuremethylester oder p-Toluolsulfonsäuremethylester, oder Sulfate, wie Dimethylsulfat.The compounds of general formula I in which R2 is not a hydrogen atom represents, can be prepared by alkylation of the compounds of general formula I. in which R2 is a hydrogen atom. Implementation is preferred at temperatures from 0 to 100 "C for 1 to 10 hours in presence a strong base such as sodium hydride, sodium methoxide or sodium amide in one Solvents such as dimethylformamide, dimethyl sulfoxide, dimethylacetamide, N-methylpyrrolidone or tetrahydrofuran. Examples of usable alkylating agents are alkyl halides, such as methyl iodide, ethyl bromide, butyl bromide, octyl bromide or Docosyl bromide, lower hydroxyalkyl halides, such as 2-hydroxyethyl bromide or 3-hydroxypropyl bromide, Carbamoylalkyl halides, such as 10-carbamoyldecyl bromide, naphthyloxyalkyl halides, such as 2- (2-naphthyloxy) ethyl bromide, oxoalkyl halides such as 4-oxopentyl bromide, halides of the general formula A, v7N- (cH2) n-Ealt where R6, R7 and n have the above meaning and Hal represents a halogen atom, such as 2-dimethylaminoethyl bromide, 3-dimethylaminopropyl bromide, 2-Morpholinoäthylbromid or 3-Piperidinopropylbromid, or with a corresponding one organic sulfonic acid esters, such as methyl methanesulfonate or methyl p-toluenesulfonate, or sulfates such as dimethyl sulfate.
Die Verbindungen der allgemeinen Formel I, in der B zwei Wasserstoffatome darstellt und R1 einen Alkanoylrest, einen Alkylsulfonylrest oder eine gegebenenfalls im Benzolkern durch mindestens ein Halogenatom, einen niederen Alkyl- - oder Alkoxyrest substituierte Benzoylgruppe darstellt, können durch Umsetzung einer Verbindung der allgemeinen Formel I, in der B zwei Wasserstoffatome und R1 ein Wasserstoffatom bedeutt, mit einem Acylierungsmittel, wie einem Säureanhydrid oder einem Säurehalogenid oder einem Alkylsulfonylhalogenid, wie Methansulfonylchlorid, hergestellt werden.The compounds of general formula I in which B has two hydrogen atoms and R1 represents an alkanoyl radical, an alkylsulfonyl radical or an optionally in the benzene nucleus by at least one halogen atom, a lower alkyl or alkoxy radical Substituted benzoyl group can be obtained by reacting a compound of general formula I, in which B two hydrogen atoms and R1 one hydrogen atom means with an acylating agent such as an acid anhydride or an acid halide or an alkyl sulfonyl halide such as methanesulfonyl chloride.
Vorzugsweise wird die Umsetzung in einem geeigneten Lösungsmittel, wie Benzol, Toluol, Chloroform oder Dioxan, und gegebenenfalls in Gegenwart eines Säureacceptors, wie Natriumcarbonat, Kaliumcarbonat, Pyridin oder Triäthylamin,4durchgeführt. Pyridin kann auch als Lösungsmittel dienen.The reaction is preferably carried out in a suitable solvent, such as benzene, toluene, chloroform or dioxane, and optionally in the presence of one Acid acceptors, such as sodium carbonate, potassium carbonate, pyridine or triethylamine, are carried out. Pyridine can also serve as a solvent.
Die Verbindungen der allgemeinen Formel I, in der B zwei Wasserstoffatome und R1 ein Wasserstoffatom bedeutet, können durch Hydrolyse einer Verbindung der allgemeinen Formel I hergestellt werden, in der B zwei Wasserstoffatome und R1 einen Alkanoylrest, einen Alkylsulfonylrest oder eine gegebenenfalls durch eine im Benzolkern durch mindestens ein Halogenatom, einen niederen Alkyl- oder Alkoxyrest substituierte Benzoylgruppe bedeutet. Die Hydrolyse wird vorzugsweise durch Erhitzen unter Rückfluß in Gegenwart von Natriumhydroxid in einem Alkohol durchgeführt.The compounds of general formula I in which B has two hydrogen atoms and R1 is a hydrogen atom, can be obtained by hydrolysis of a compound of general formula I are prepared in which B has two hydrogen atoms and R1 one Alkanoyl radical, an alkylsulfonyl radical or optionally one in the benzene nucleus substituted by at least one halogen atom, a lower alkyl or alkoxy radical Means benzoyl group. The hydrolysis is preferably carried out by refluxing carried out in the presence of sodium hydroxide in an alcohol.
Die Verbindungen der allgemeinen Formel I, in der R3 und einer der Reste R4 und R5 zusammen eine Einfachbindung bilden, können durch Dehydrierung einer Verbindung der allgemeinen Formel I hergestellt werden, in der R3 ein Wasser-4 stoffatom, R ein Wasserstoffatom, einen niederen Alkylrest, eine Hydroxymethylgruppe oder einen niederen Alkanoyloxymethylrest und R5 ein Wasserstoffatom oder einen niederen Alkylrest bedeutet. Die Umsetzung wird vorzugsweise bei Temperaturen von 0 bis 100°C bis zu mehreren Stunden in Gegenwart eines Dehydrierungsmittels, wie Brom oder Chlor und gegebenenfalls in Gegenwart eines inerten Lösungsmittels, wie Chloroform, Dichloräthan, Benzol, Toluol oder Essigsäure, durchgeführt; Die Verbindungen der allgemeinen Formel I, in der A eine gegebenenfalls durch einen niederen Alkylrest substituierte Vinylengruppe bedeutet, können durch Dehydrierung einer Verbindung der allgemeinen Formel I hergestellt werden, in der A eine gegebenenfalls durch einen niederen Alkylrest substituierte Äthylengruppe darstellt. Die Umsetzung wird vorzugsweise bei Raumtemperatur oder unter Rückflußkochen und bis zu mehreren Stunden in Gegenwart eines Dehydrierungsmitals, wie 2,3-Dichlor-5,6-dicyano-1,4-benzochinon, 2,3,5,6-Tetrachlor-l,4-benzochinon oder Palladium-auf-Kohlenstoff, in einem inerten Lösungsmittel, wie Methanol, Benzol, Toluol, Xylol oder Dioxan, durchgeführt.The compounds of general formula I in which R3 and one of the Residues R4 and R5 together form a single bond, can by dehydrating a Compound of the general formula I are prepared in which R3 is a hydrogen atom, R represents a hydrogen atom, a lower alkyl radical, a hydroxymethyl group or a lower alkanoyloxymethyl radical and R5 is a hydrogen atom or a lower alkyl radical means. The reaction is preferably carried out at temperatures from 0 to 100 ° C up to several hours in the presence of a dehydrating agent such as bromine or chlorine and optionally in the presence of an inert solvent such as chloroform, dichloroethane, Benzene, toluene or acetic acid; The compounds of the general formula I, in which A is a vinylene group optionally substituted by a lower alkyl radical means can be prepared by dehydrogenating a compound of general formula I in which A is optionally substituted by a lower alkyl radical Represents ethylene group. The reaction is preferably carried out at room temperature or under reflux and for up to several hours in the presence of a dehydrating agent, such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 2,3,5,6-tetrachloro-1,4-benzoquinone or palladium-on-carbon, in an inert solvent such as methanol, benzene, Toluene, xylene or dioxane.
Die Verbindungen der Erfindung können in üblicher Weise durch Umsetzung mit anorganischen oder organischen Säuren in die entsprechenden Salze überführt werden. Spezielle Beispiele für die zur Salzbildung verwendbaren Säuren sind Salzsäure, Bromwasserstoffsäure, Schwefelsäure, Äpfelsäure, Maleinsäure, Fumarsäure, Oxalsäure und Citronensäure.The compounds of the invention can be reacted in a customary manner converted into the corresponding salts with inorganic or organic acids will. Specific examples of the acids that can be used for salt formation are hydrochloric acid, Hydrobromic acid, sulfuric acid, malic acid, maleic acid, fumaric acid, oxalic acid and citric acid.
Die im erfindungsgemäßen Verfahren eingesetzten Verbindungen der allgemeinen Formel II und III lassen sich nach üblichen Verfahren gemäß folgendem Reaktionsschema herstellen: Spezielle Beispiele für verfahrensgemäß eingesetzte Verbindungen sind nachstehend aufgeführt: (1) 4-Oxo-4-(1-methyl-2-oxoindolin-5-yl)-3-methylbutansäure, F. 180 - 1820C; (2) 4-Oxo-4-(1-methyl-2-oxoindolin-5-yl)-butansäure, F. 236 - 2400C; (3) 4-Oxo-4-(indolin-5-yl)-3-methylbutansäure, F 193 - 195 OC; (4) 4-Oxo-4-(1,2,3,4-tetrahydrochinolin-6-yl)-3-methylbutansäure; (5) 4-oxo-4-(1,4,4-trimethyl-2-oxo-1,2,3,4-tetrhydrochinolin-6yl)-3-methylbutansäure, F. 133 - 135 OC; (6) 4-Oxo-4-(4-methyl-2-oxo-1,2,3,4-tetrahydrochinolin-6-yl)-3-methylbutansäure, F. 172 - 174°C; (7) 4-oxo-4-(1,4,5-trimethyl-2-oxo-1,2,3,4-tetrahydrochinoli-6-yl)-butansäure, F. 194 - 1970C (8) 4-(1-Athyl-2-oxo-1,2,3,4-tetrahydrochinolin-6-yl)-carbonyl-g-butyrolacton, F. 135 - 1380C und (9) 4-(1-Methyl-2-oxo-1,2,3,4-tetrahydrochinolin-6-yl]-carbonyl-<-butyrolacton, F. 142 - 144°C.The compounds of the general formulas II and III used in the process according to the invention can be prepared by customary processes according to the following reaction scheme: Specific examples of compounds used according to the process are listed below: (1) 4-Oxo-4- (1-methyl-2-oxoindolin-5-yl) -3-methylbutanoic acid, mp 180-1820C; (2) 4-Oxo-4- (1-methyl-2-oxoindolin-5-yl) -butanoic acid, m.p. 236-2400C; (3) 4-oxo-4- (indolin-5-yl) -3-methylbutanoic acid, F 193-195 OC; (4) 4-oxo-4- (1,2,3,4-tetrahydroquinolin-6-yl) -3-methylbutanoic acid; (5) 4-oxo-4- (1,4,4-trimethyl-2-oxo-1,2,3,4-tetrhydroquinoline-6yl) -3-methylbutanoic acid, mp 133-135 ° C; (6) 4-Oxo-4- (4-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -3-methylbutanoic acid, mp 172-174 ° C; (7) 4-oxo-4- (1,4,5-trimethyl-2-oxo-1,2,3,4-tetrahydroquinoli-6-yl) butanoic acid, m.p. 194-1970C (8) 4- ( 1-Ethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) carbonyl-g-butyrolactone, m.p. 135-1380C and (9) 4- (1-methyl-2-oxo-1 , 2,3,4-tetrahydroquinolin-6-yl] carbonyl - <- butyrolactone, mp 142-144 ° C.
Die Verbindungen der allgemeinen Formel I und ihre Salze mit Säuren hemmen die Aggregation der Thrombocyten und senken den Blutdruck. Dies geht aus folgenden Versuchen hervor: I. Hemmung der Thrombocytenaggregation bei Ratten und Kaninchen Für die Versuche werden Gruppen von 4 bis 6 Ratten (Körpergewicht 250 bis 300 g) oder 3 Kaninchen (Körpergewicht 3 bis Zwei Stunden 3,5 kg) verwendet./nach oraler Behandlung mit der zu untersuchenden Verbindung wird Blut entnommen und mit Citrat versetzt. Die Thrombocytenaggregation von thrombocytenreichem Plasma wird durch Zusatz von 1,5 x 10 5 Mol Adenosindiphosphat (Endkonzentration) induziert und mit einem Aggregometer nach Born (G.V.R. Born, J. Physiol., Bd. 162 (1962), S. 67) be- stimmt. Die Ergebnisse sind in Tabelle I als prozentuale Hemmung der Aggregation im Vergleich zur Kontrollgruppe angegeben.The compounds of general formula I and their salts with acids inhibit platelet aggregation and lower blood pressure. This goes out the following experiments: I. Inhibition of platelet aggregation in rats and Rabbits Groups of 4 to 6 rats (body weight 250 up to 300 g) or 3 rabbits (body weight 3 to two hours 3.5 kg) used./after Oral treatment with the compound to be investigated, blood is taken and with Citrate added. The platelet aggregation of platelet-rich plasma is induced by the addition of 1.5 × 10 5 mol of adenosine diphosphate (final concentration) and with an aggregometer according to Born (G.V.R. Born, J. Physiol., Vol. 162 (1962), P. 67) it's correct. The results are shown in Table I as percentages Inhibition of aggregation indicated in comparison to the control group.
II. Blutdrucksenkende Wirkung bei Ratten mit spontanem Hochdruck.II. Hypotensive effect in rats with spontaneous hypertension.
Für die Versuche werden Gruppen von 5 Ratten mit einem Körpergewicht von 300 bis 350 g und spontanem Hochdruck verwendet.Groups of 5 rats with a body weight are used for the experiments from 300 to 350 g and spontaneous high pressure is used.
Der Blutdruck in der Schwanzvene wird ohne Anästhesie mittels eines Manometers unmittelbar vor und 5 Stunden nach oraler Gabe der zu untersuchenden Verbindung bestimmt. Die Ratte wird 10 Minuten auf 40"C erwärmt. Der Puls in der Schwanzvecwird mit einem Pulsmesser bestimmt. Der arterielle Blutstrom wird durch Anwendung von Druck mittels einer pneumatischen Klammer unterbrochen. Der Blutstrom tritt wieder auf, wenn der Druck mit der Klammer vermindert wird. Der Wert ist etwa gleich dem maximalen Blutdruck. Die Ergebnisse sind in Tabelle I in mm Hg Abnahme des maximalen Blutdrucks 5 Stunden nach der Behandlung angegeben.The blood pressure in the tail vein is measured without anesthesia by means of a Manometers immediately before and 5 hours after oral administration of the substance to be examined Connection determined. The rat is heated to 40 ° C. for 10 minutes. The pulse in the Tailvec is determined with a heart rate monitor. The arterial blood flow is through Application of pressure interrupted by means of a pneumatic clamp. The bloodstream occurs again when the pressure is released with the clamp. The value is about equal to the maximum blood pressure. The results are in Table I in mm Hg decrease the maximum blood pressure indicated 5 hours after the treatment.
Für die Versuche wurden folgende Verbindungen verwendet: Verbindung
A: 6- (5-Methyl-3-oxo-2 3,4, 5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung B: 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung C: 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung D: 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung E: 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung
F: 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung G: 6-(5-Äthyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-äthyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung H: 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-äthyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung I: 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-äthyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung J: 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-äthyl-1,2,3,4-tetrahydrochinolin-2-on
Verbindung K: 6-[5-Methyl-2-(2-morpholinoäthyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-1-methyl-1,2,3,4-tetrahydrochinolin-2-on-hydrochloridhemihydrat
Tabelle
I
Die Verbindungen der allgemeinen Formel I und ihre Salze können entweder allein oder in Form von Arzneimitteln mit üblichen Trägerstoffen und/oder Verdünnungsmitteln und/oder Hilfsstoffen oral gegeben werden. Als Arzneimittel kommen Tabletten, Granulate, Pulver oder Kapseln zur oralen Gabe oder Injektionspräparate zur subkutanen oder intramuskulären Gabe in Frage.The compounds of general formula I and their salts can either alone or in the form of medicaments with customary carriers and / or diluents and / or excipients are given orally. Tablets, granules, Powder or capsules for oral administration or injection preparations for subcutaneous or intramuscular administration in question.
Die Beispiele erläutern die Erfindung.The examples illustrate the invention.
Beispiel 1 Eine Lösung von 7 g 4-Oxo-4-(1-methyl-2-ozoindolin-5-yl)-butansäure und 3 ml Hydrazinhydrat in 70 ml Dimethylformamid wird 4 Stunden auf einem Wasserbad erhitzt. Sodann werden die entstandenen Kristalle abfiltriert und aus Dimethylformamid umkristallisiert. Es werden 4,0 g 5-(3-Oxo-2,3,4, 5-tetra,hydropyridazin-6-yl) -1 -methylindolin-2-on in hellgelben Prismen vom F. 261 bis 2640C erhalten. Example 1 A solution of 7 g of 4-oxo-4- (1-methyl-2-ozoindolin-5-yl) butanoic acid and 3 ml of hydrazine hydrate in 70 ml of dimethylformamide is placed on a water bath for 4 hours heated. The crystals formed are then filtered off and removed from dimethylformamide recrystallized. There are 4.0 g of 5- (3-oxo-2,3,4, 5-tetra, hydropyridazin-6-yl) -1 -methylindolin-2-one obtained in light yellow prisms from F. 261 to 2640C.
Beispiel 2 Eine Lösung von 27 g 4-Oxo-4-(indolin-5-yl)-3-methylbutansäure-hydrochlorid und 15 ml Hydrazinhydrat in 200 ml Äthanol wird 2 Stunden auf einem Wasserbad unter Rückfluß erhitzt. Example 2 A solution of 27 g of 4-oxo-4- (indolin-5-yl) -3-methylbutanoic acid hydrochloride and 15 ml of hydrazine hydrate in 200 ml of ethanol is taken on a water bath for 2 hours Heated to reflux.
Sodann wird das Reaktionsgemisch unter vermindertem Druck eingedampft und der Rückstand mit Wasser versetzt. Die entstandenen Kristalle werden abfiltriert, mit Wasser gewaschen und aus Äthanol umkristallisiert. Es werden 20 g 5-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-indolin in weißen Kristallen vom F. 187 bis 189"C erhalten.The reaction mixture is then evaporated under reduced pressure and water is added to the residue. The resulting crystals are filtered off, washed with water and recrystallized from ethanol. There are 20 g of 5- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) indoline obtained in white crystals from m.p. 187 to 189 "C.
Beispiel 3 Eine Lösung von 5- (5-Methyl-3-oxo-2' 3,4, 5-tetrahydropyridazin-6-yl)-indolin in 100 ml Chloroform wird unter Rühren mit 5 ml Triäthylamin versetzt. Sodann wird das Gemisch tropfenweise mit 3 ml Essigsäureanhydrid versetzt. Nach 1stündigem Stehen bei Raumtemperatur wird das Reaktionsgemisch unter vermindertem Druck eingedampft. Der erhaltene kristalline Rückstand wird abfiltriert' mit Wasser gewaschen und aus Äthanol umkristallisiert. Es werden 4,3 g 5-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1 -acetylindolin in weißen Kristallen vom F. 258 bis 2610C erhalten. Example 3 A solution of 5- (5-methyl-3-oxo-2 '3,4,5-tetrahydropyridazin-6-yl) indoline in 100 ml of chloroform, 5 ml of triethylamine are added with stirring. Then will 3 ml of acetic anhydride were added dropwise to the mixture. After standing for 1 hour at room temperature the reaction mixture is evaporated under reduced pressure. The crystalline residue obtained is filtered off, washed with water and removed Recrystallized ethanol. 4.3 g of 5- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-acetylindoline obtained in white crystals with a temperature of 258 to 2610C.
In analoger Weise können nach den vorstehenden Beispielen folgende Verbindungen hergestellt werden: 5-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)-indolin-2-on, F. 340°C, Zers. In an analogous manner, the following can be used according to the preceding examples Compounds are made: 5- (3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl) -indolin-2-one, Mp 340 ° C, dec.
5-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-indolin-2-on, F. 2760C; 5-15-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methylindolin-2-on, F. 213 - 214"C; 5-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methansulfonylindolin, F. 230 - 2320C; 6-(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-acetyl-1,2,3,4-tetrahydrochinolin, F. 210°C; 6-(3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,2,3,4-tetrahydrochinolin, F. 166 - 1680C; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-(4-fluorbenzOyl)-1,2,3,4-tetrahydrochinolin, 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-(3,4-dichlorbenzoyl)-1,2,3,4-tetrahydrochinolin; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-(4-methOxybenzoyl)-1,2,3,4-tetrahydrochinolin, 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,2,3,4-tetrahydrochinolin, F. 154 - 157"C; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-acetyl-1,2,3,4-tetrahydrochinolin, F. 175 - 178°C; 6-(3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-(4-methylbenzoyl)-1,2,3,4-tetrahydrochinolin; 5-(5-Butyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-indolin; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 166 - 168"C; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,2,3,4-tetrahydrochinolin-2-on, F. 300 - 3050C Zers.; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-(4-chlorbenzoyl)-1 ,2,3,4-tetrahydrochinolin, F. 236 - 2380C; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin, F. 164 - 165"C. 5- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) indolin-2-one, M.p. 2760C; 5-15-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methylindolin-2-one, F. 213-214 "C; 5- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methanesulfonylindoline, M.p. 230-2320C; 6- (3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-acetyl-1,2,3,4-tetrahydroquinoline, Mp 210 ° C; 6- (3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,2,3,4-tetrahydroquinoline, M.p. 166-1680C; 6- (3-Oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1- (4-fluorobenzOyl) -1,2,3,4-tetrahydroquinoline, 6- (3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1- (3,4-dichlorobenzoyl) -1,2,3,4-tetrahydroquinoline; 6- (3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1- (4-methoxybenzoyl) -1,2,3,4-tetrahydroquinoline, 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,2,3,4-tetrahydroquinoline, M.p. 154-157 "C; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-acetyl-1,2,3,4-tetrahydroquinoline, Mp 175-178 ° C; 6- (3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1- (4-methylbenzoyl) -1,2,3,4-tetrahydroquinoline; 5- (5-butyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) indoline; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, F. 166-168 "C; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,2,3,4-tetrahydroquinolin-2-one, M.p. 300-3050C dec .; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1- (4-chlorobenzoyl) -1 , 2,3,4-tetrahydroquinoline, m.p. 236-2380C; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinoline, F. 164-165 "C.
Beispiel 4 Eine Lösung von 2,72 g 4-Oxo-4-(1-methyl-2-oxo-1,2,3,4-tetrahydrochinolin-6-yl) -3-methylbutansäure und 1,5 g 2-Hydrazinoäthanol in 30 ml Äthanol wird 2 Stunden auf einem Wasserbad unter Rückfluß erhitzt. Danach wird das Reaktionsgemisch unter vermindertem Druck eingedampft und der Rückstand mit Wasser versetzt. Die entstandenen Kristalle werden abfiltriert und aus Isopropanol umkristallisiert. Es werden 2,5 g 6-g2-(2-Hydroxyäthyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylg-1-methyl-1t2,3,4-tetrahydrochinolin-2-on in farblosen Kristallen vom F. 171 bis 1730C erhalten. Example 4 A solution of 2.72 g of 4-oxo-4- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -3-methylbutanoic acid and 1.5 g of 2-hydrazinoethanol in 30 ml of ethanol is 2 hours refluxed on a water bath. Thereafter, the reaction mixture is under evaporated under reduced pressure and water is added to the residue. The resulting Crystals are filtered off and recrystallized from isopropanol. It will be 2.5 g of 6-g2- (2-hydroxyethyl) -5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylg-1-methyl-1t2,3,4-tetrahydroquinolin-2-one Preserved in colorless crystals from 171 to 1730C.
Beispiel 5 Eine Lösung von 5,4 g 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on in 50 ml Dimethylformamid wird mit 1,1 g 50prozentigem Natriumhydrid versetzt. Nach 30minütigem Rühren werden 2,4 g Äthylbromid eingetragen, und das Gemisch wird 1 Stunde bei 400C gerührt. Danach wird das Reaktionsgemisch in 200 ml Wasser gegossen und mit 100 ml ÄthylaceLat extrahiert. Der Äthylacetatextrakt wird über Magnesiumsulfat getrocknet und unter vermindertem Druck eingedampft. Der Rückstand wird aus Äthanol umkristallisiert. Es werden 3,7 g 6-(2-Äthyl-5-methyl-3-oXo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl- 1,2,3,4-tetrahydrochinolin-2-on in farblosen Kristallen vom F. 170 bis 1720C erhalten. Example 5 A solution of 5.4 g of 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinoline-2 -on 1.1 g of 50 percent sodium hydride are added to 50 ml of dimethylformamide. To Stirring for 30 minutes, 2.4 g of ethyl bromide are added and the mixture becomes 1 Stirred at 400C for an hour. The reaction mixture is then poured into 200 ml of water and extracted with 100 ml of ethyl acetate. The ethyl acetate extract is made over magnesium sulfate dried and evaporated under reduced pressure. The residue is made from ethanol recrystallized. 3.7 g of 6- (2-ethyl-5-methyl-3-oXo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl- 1,2,3,4-tetrahydroquinolin-2-one obtained in colorless crystals from 170 to 1720C.
Nach den vorstehenden Beispielen können folgende Verbindungen in analoger Weise hergestellt werden: 6-g2-(2-Naphthyloxy)-äthyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyrldazin-6-yl7-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 127 - 1290C; 5-[2-(2-Hydroxyäthyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylJ-indolin, F. 117 - 1200C; 6-(2-Butyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F 109 - 1 100C; 6-(5-Methyl-2-octadecyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 66 -700C; 6-(2-Docosyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-metehyl-1,2,3,4-tetrahydrochinolin-2-on, F. 65 - 670C; 6-(5-Methyl-2-pentadecyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 68,5 -70,5°C; 6-g2-(4-Oxopentyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl7-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 80 - 830C; 6-g2-(10-Carbamoyldecyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl7-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 77 - 81°C; 6-(2-Heptadecyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 76-78°C-6-(2-Hexadecyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 70 - 710C; 5-(2-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methylindolin-2-on, F. 200 - 203°C.According to the above examples, the following compounds can be used in analogous manner Ways to be prepared: 6-g2- (2-naphthyloxy) -ethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyrldazin-6-yl7-1-methyl-1,2,3,4- tetrahydroquinolin-2-one, M.p. 127-1290C; 5- [2- (2-hydroxyethyl) -5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylI-indoline, M.p. 117-1200C; 6- (2-butyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, F 109-1100C; 6- (5-methyl-2-octadecyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 66-700C; 6- (2-docosyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 65-670C; 6- (5-methyl-2-pentadecyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, 68.5-70.5 ° C; 6-g2- (4-oxopentyl) -5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl7-1-methyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 80-830C; 6-g2- (10-carbamoyldecyl) -5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl7-1-methyl-1,2,3,4-tetrahydroquinolin-2-one, 77-81 ° C; 6- (2-heptadecyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 76-78 ° C-6- (2-hexadecyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4- tetrahydroquinolin-2-one, M.p. 70-710C; 5- (2-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methylindolin-2-one, Mp 200-203 ° C.
Beispiel 6 Eine Lösung von 3 g 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on in 30 ml Dimethylformamid wird mit 0,9 g 50prozentigem Natriumhydrid versetzt. Nach 30minütigem Rühren werden 1,7 g 2-Morpholinoäthylchlorid eingetragen, und das Gemisch wird 1 Stunde bei 500C gerührt. Danach wird das Reaktionsgemisch in 200 ml Eiswasser eingegossen und mit 150 ml Chloroform extrahiert. Der Chloroformextrakt wird über Kaliumcarbonat getrocknet und unter vermindertem Druck eingedampft. Der Rückstand wird mit einer Lösung von Chlorwasserstoff in Äthanol versetzt, und die entstandenen Kristalle werden abfiltriert. Nach Umkristallisation aus Isopropanol werden 2,5 g 6-l%-Methyl-2-(2-morpholinoäthyl)-3-oxo-2,3,4,5-tetrahydropyriaazin-6-yl/-1,4 ,4-trimethyl-1,2 , 3, 4-tetrahydrochinolin-2-onhydrochlorid vom F. 243 bis 2460C erhalten. Example 6 A solution of 3 g of 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline -2-on in 30 ml of dimethylformamide with 0.9 g of 50 percent Sodium hydride offset. After stirring for 30 minutes, 1.7 g of 2-morpholinoethyl chloride are added, and the mixture is stirred at 50 ° C. for 1 hour. Thereafter, the reaction mixture Poured into 200 ml of ice water and extracted with 150 ml of chloroform. The chloroform extract is dried over potassium carbonate and evaporated under reduced pressure. Of the A solution of hydrogen chloride in ethanol is added to the residue, and the Crystals formed are filtered off. After recrystallization from isopropanol 2.5 g of 6-1% methyl 2- (2-morpholinoethyl) -3-oxo-2,3,4,5-tetrahydropyriaazin-6-yl / 1,4 , 4-trimethyl-1,2, 3, 4-tetrahydroquinolin-2-one hydrochloride of m.p. 243 to 2460C obtain.
Auf die vorstehend beschriebene Weise können folgende Verbindungen hergestellt werden: 6-lS-Methyl-2-(2-morpholinoäthyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yll-1-methyl-1,2,3,4-tetrahydrochinolin-2-on-hyerochlorid-hemihydrat, F. 221 - 2290C; 5-[5-Methyl-2-(3-piperidinopropyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl7-1-methyl-1,2,3,4-tetrahyerochinolin-2-onhydrochlorid, F. 232 - 2330C; 6-[5-Methyl-2-(3-(4-methylpiperazin-1-yl)propyl)-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-1-methyl-1,2,3,4-tetrahydrochinolin-2-on-dihydrochlorid, F. 257 - 259'0C1 Zers.; 6-[2-(2-Dimethylaminoäthyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl2-1-methyl-1,2,3,4-tetrahydrochinolin-2-onhydrochlorid, F. 237 - 239°C Zers.; 6-2-(3-Dimethylaminopropyl)-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl]-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on-hydrochlorid-hydrat, F. 220 - 2240C.In the manner described above, the following compounds are prepared: 6-IS-methyl-2- (2-morpholinoethyl) -3-oxo-2,3,4,5-tetrahydropyridazin-6-yll-1-methyl-1,2,3,4-tetrahydroquinoline-2 -on-hyerochloride-hemihydrate, F. 221-2290C; 5- [5-methyl-2- (3-piperidinopropyl) -3-oxo-2,3,4,5-tetrahydropyridazin-6-yl7-1-methyl-1,2,3,4-tetrahyeroquinolin-2-one hydrochloride , F. 232-2330C; 6- [5-methyl-2- (3- (4-methylpiperazin-1-yl) propyl) -3-oxo-2,3,4,5-tetrahydropyridazin-6-yl] -1-methyl-1,2 , 3,4-tetrahydroquinolin-2-one dihydrochloride, F. 257-259.0C1 dec .; 6- [2- (2-dimethylaminoethyl) -5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl2-1-methyl-1,2,3,4-tetrahydroquinolin-2-one hydrochloride , Mp 237-239 ° C dec .; 6-2- (3-dimethylaminopropyl) -5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl] -1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline -2-one hydrochloride hydrate, F. 220-2240C.
Beispiel 7 Ein Gemisch von 20 g 4-Oxo-4-(1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydrochinolin-6-yl) -3-methylbutansäure, 10 g Hydrazinhydrat und 200 ml Äthanol wird 1 Stunde unter Rückfluß erhitzt. Nach dem Abkühlen werden die entstandenen Kristalle abfiltriert und aus Äthanol umkristallisiert. Es werden 15,1 g 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on vom F. 238 -2410C erhalten. Example 7 A mixture of 20 g of 4-oxo-4- (1,4,4-trimethyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) -3-methylbutanoic acid, 10 g of hydrazine hydrate and 200 ml of ethanol is taken for 1 hour Heated to reflux. After cooling, the resulting crystals are filtered off and recrystallized from ethanol. It will 15.1 g 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline-2- on obtained from F. 238-2410C.
Beispiel 8 Ein Gemisch von 6 g 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on und 60 ml Dimethylformamid wird mit 1,8 g Natriumhydrid versetzt. Nach 30 Minuten werden 4,6 g Butylbromid eingetragen, und das Gemisch wird 1 Stunde gerührt. Nach beendeter Umsetzung wird das Reaktionsgemisch in Eiswasser gegossen. Die entstandenen Kristalle werden abfiltriert und aus einem Gemisch von Äthanol und Wasser umkristallisiert. Example 8 A mixture of 6 g of 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline -2-on and 1.8 g of sodium hydride are added to 60 ml of dimethylformamide. After 30 minutes 4.6 g of butyl bromide are added and the mixture is stirred for 1 hour. To When the reaction has ended, the reaction mixture is poured into ice water. The resulting Crystals are filtered off and recrystallized from a mixture of ethanol and water.
Es werden 5,2 g 6-(2-Butyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on vom F. 137 bis 1390C erhalten.5.2 g of 6- (2-butyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1,2,3, 4-tetrahydroquinolin-2-one obtained from F. 137 to 1390C.
Beispiel 9 Ein Gemisch von 12 g 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-4-methyl-1,2,3,4-tetrahydrochinolin-2-on und 200 ml Essigsäure wird tropfenweise mit 8,4 g Brom versetzt. Sodann wird das Gemisch 3 Stunden auf 60 bis 700C erhitzt und gerührt. Hierauf wird das Lösungsmittel unter vermindertem Druck abdestilliert. Der Rückstand wird mit Wasser versetzt und die entstandenen Kristalle werden abfiltriert. Nach Umkristallisation aus Essigsäure werden 6,5 g 6-(5-Methyl-3-oxo-2,3-dihydropyridazin-6-yl)-4-methyli,2,3, 4-tetrahydrochinolin-2-on vom F. >3000C erhalten. Example 9 A mixture of 12 g of 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -4-methyl-1,2,3,4-tetrahydroquinolin-2-one and 8.4 g of bromine are added dropwise to 200 ml of acetic acid. Then it will The mixture was heated to 60 ° to 70 ° C. for 3 hours and stirred. Then the solvent distilled off under reduced pressure. The residue is mixed with water and the resulting crystals are filtered off. After recrystallization from acetic acid 6.5 g of 6- (5-methyl-3-oxo-2,3-dihydropyridazin-6-yl) -4-methyli, 2,3,4-tetrahydroquinolin-2-one received from F.> 3000C.
B e i 5 p i e 1 10 Ein Gemisch von 5,4 g 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, 5,5 g 2,3-Dichlor-5,6-dicyano-1,4-benzochinon und 500 ml Benzol wird 48 Stunden unter Rückfluß erhitzt. Nach dem Abkühlen werden die entstandenen Kristalle abfiltriert. Das Filtrat wird mit loprozentiger Natronlauge gewaschen und über Natriumsulfat getrocknet. Hierauf wird das Lösungsmittel unter vermindertem Druck abdestilliert. Der Rückstand und die Kristalle werden vereinigt und säulenchromatographisch gereinigt. Sodann werden die erhaltenen Kristalle aus Methanol umkristallisiert. Es werden 1,5 g 6-(5-Methyl-3-oxo-2,3,4, 5-tetrahydropyridazin-6-yl)-1-methyl-1,2-dihydrochinolin-2-on vom F. 248 bis 251"C erhalten. B ei 5 pie 1 10 A mixture of 5.4 g of 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4 -tetrahydroquinolin-2-one, 5.5 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 500 ml of benzene is 48 hours heated to reflux. After cooling, the resulting crystals are filtered off. The filtrate is washed with 10 percent sodium hydroxide solution and above Dried sodium sulfate. The solvent is then reduced under reduced pressure distilled off. The residue and the crystals are combined and column chromatographically cleaned. The crystals obtained are then recrystallized from methanol. 1.5 g of 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2-dihydroquinolin-2-one are obtained obtained from F. 248 to 251 "C.
Nach den vorstehenden Beispielen können folgende Verbindungen hergestellt werden: 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2,3,4-tetrahydrochinolin-2-on, F. 223 - 2250C; 6-(5-Methyl-3-oXo-2,3,4,5-tetrahydropyridazin-6-yl)-4-methyl-1 ,2,3,4-tetrahydrochinolin-2-on, F. 275 - 2780C; 6-(3-Oxo-2t3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1 ,2,3,4-tetrahydrochinolin-2-on, F. 233 - 235"C; 6-(2,5-Dimethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on, F. 165 - 1 6 9 OC ; 6-(5-Methyl-3-oxo-2,3-dihydropyridazin-6-yl)-1,4,4-trimethyl-1;2,3,4-tetrahydrochinolin-2-on, F. 270 - 2740C; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2-dihydrochinolin-2-on; 6-(5-Methyl-3-oxo-2,3-dihydropyridazin-6-yl)-1-methyl-1,2-dihydrochinolin-2-on; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-äthyl-4-methyl-1,2,3,4-tetrahydrochinolin-2-on; 6-(5-Äthyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on; 6-(2-Athyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4,4-trimethyl-1,2,3,4-tetrahydrochinolin-2-on; 6-(5-Athyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2-dihydrochinolin-2-on; 6-(5-Methyl-2-propyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2-dihydrochinolin-2-on; 6-(2,5-Dimethyl-3-oxo-2,3-dihydropyridazin-6-yl)-1,4-dimethyl-1,2-dihydrochinolin-2-on; 6-(5-Methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-butyl-4,4-dimethyl-1,2,3,4-tetrahydrochinolin-2-on.The following compounds can be prepared according to the above examples are: 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one, F. 223-2250C; 6- (5-methyl-3-oXo-2,3,4,5-tetrahydropyridazin-6-yl) -4-methyl-1, 2,3,4-tetrahydroquinolin-2-one, M.p. 275-2780C; 6- (3-Oxo-2t3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1, 2,3,4-tetrahydroquinolin-2-one, F. 233-235 "C; 6- (2,5-dimethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1,2,3, 4-tetrahydroquinolin-2-one, M.p. 165-1 6 9 OC; 6- (5-methyl-3-oxo-2,3-dihydropyridazin-6-yl) -1,4,4-trimethyl-1; 2,3,4-tetrahydroquinolin-2-one, M.p. 270-2740C; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4-dimethyl-1,2-dihydroquinolin-2-one; 6- (5-methyl-3-oxo-2,3-dihydropyridazin-6-yl) -1-methyl-1,2-dihydroquinolin-2-one; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-ethyl-4-methyl-1,2,3,4-tetrahydroquinolin-2-one; 6- (5-ethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-2-one; 6- (2-ethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4,4-trimethyl-1,2,3,4-tetrahydroquinoline-2- on; 6- (5-ethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4-dimethyl-1,2-dihydroquinolin-2-one; 6- (5-methyl-2-propyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4-dimethyl-1,2-dihydroquinolin-2-one; 6- (2,5-dimethyl-3-oxo-2,3-dihydropyridazin-6-yl) -1,4-dimethyl-1,2-dihydroquinolin-2-one; 6- (5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-butyl-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one.
B e i s p i e 1 11 Eine Lösung von 4,9 g 4-(1-Methyl-2-oxo-1,2,3,4-tetrahydrochinolin-6-yl)-carbonyl-r-butyrolacton und 3,0 ml 85prozentigem Hydrazinhydrat in 50 ml Äthanol wird etwa 15 Stunden unter Rückfluß erhitzt. Danach wird das Reaktionsgemisch unter vermindertem Druck eingedampft und der Rückstand mit Eiswasser versetzt. Hierauf wird das Gemisch stehengelassen. EXAMPLE 11 A solution of 4.9 g of 4- (1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl) carbonyl-r-butyrolactone and 3.0 ml of 85 percent hydrazine hydrate in 50 ml of ethanol is taken for about 15 hours Heated to reflux. The reaction mixture is then evaporated under reduced pressure and ice water is added to the residue. The mixture is then left to stand.
Die entstandenen Kristalle werden abfiltriert und aus Wasser umkristallisiert. Es werden 2,5 g 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on in farblosen Prismen vom F. 201 bis 2040C erhalten.The resulting crystals are filtered off and recrystallized from water. 2.5 g of 6- (5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one are obtained obtained in colorless prisms from F. 201 to 2040C.
B e i s p i e 1 12 Eine Lösung von 13,6 g 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylj-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, 5,8 g Essigsäureanhydrid und 10 ml Triäthylamin in 300 ml Chloroform wird 3 Stunden auf einem Wasserbad unter Rückfluß erhitzt. Danach wird das Reaktionsgemisch mit Wasser gewaschen, über Kaliumcarbonat getrocknet und unter vermindertem Druck eingedampft. Der Rückstand wird in einer geringen Menge Äthylacetat gelöst und zur Kristallisation stehengelassen. Die entstandenen Kristalle werden abfiltriert und aus Isopropanol umkristallisiert. Es werden 7,3 g 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on als Nadeln vom F. 149 bis 1530C erhalten. Nach den vorstehenden Beispielen können folgende Verbindungen hergestellt werden: 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,2,3,4-tetrahydrochinolin-2-on, F. 325 - 3300C; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1, 4,4-trimethyl-1 ,2,3,4-tetrahydrochinolin-2-on' F. 241 -2430C; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-äthyl-1,2,3,4-tetrahydrochinolin-2-on, F. 198 - 2000C; 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-äthyl-1,2,3,4-tetrahydrochinolin-2-on, F. 157 - 1590C; 6-(5-Hydroxymethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on; F. 218 - 2190C; 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 230 - 2320C; 6-(5-ButyrylOxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, F. 93 - 980C; 6-(5-HydroMymethyl-2-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2-dihydrochinolin-2-on; 6-(5-Hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2,3,4-tetrahydrochinolin-2-on, F. 222 - 2230C; 6-(2-Butyl-5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1-methyl-1,2,3,4-tetrahydrochinolin-2-on, 6-(5-Acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl)-1,4-dimethyl-1,2,3,4-tetrahydrochinolin-2-on. Example 1 12 A solution of 13.6 g of 6- (5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-ylj-1-methyl-1,2,3,4-tetrahydroquinoline 2-on, 5.8 g of acetic anhydride and 10 ml of triethylamine in 300 ml of chloroform is 3 hours refluxed on a water bath. Thereafter, the reaction mixture is with Washed water, dried over potassium carbonate and evaporated under reduced pressure. The residue is dissolved in a small amount of ethyl acetate and allowed to crystallize ditched. The resulting crystals are filtered off and extracted from isopropanol recrystallized. 7.3 g of 6- (5-acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one are obtained obtained as needles from F. 149 to 1530C. Following the examples above, you can the following compounds are produced: 6- (5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,2,3,4-tetrahydroquinolin-2-one, M.p. 325-3300C; 6- (5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1, 4,4-trimethyl-1 , 2,3,4-tetrahydroquinolin-2-one 'm.p. 241-2430C; 6- (5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-ethyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 198-2000C; 6- (5-acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-ethyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 157-1590C; 6- (5-hydroxymethyl-5-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one; F. 218-2190C; 6- (5-acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 230-2320C; 6- (5-butyryl-oxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, F. 93-980C; 6- (5-HydroMymethyl-2-methyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one; 6- (5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4-dimethyl-1,2-dihydroquinolin-2-one; 6- (5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one, M.p. 222-2230C; 6- (2-butyl-5-hydroxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1-methyl-1,2,3,4-tetrahydroquinolin-2-one, 6- (5-acetoxymethyl-3-oxo-2,3,4,5-tetrahydropyridazin-6-yl) -1,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-one.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782845220 DE2845220A1 (en) | 1978-10-17 | 1978-10-17 | 6-Indolyl or quinolyl substd. pyridazinone derivs. - useful as antithrombotic and antihypertensive agents |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19782845220 DE2845220A1 (en) | 1978-10-17 | 1978-10-17 | 6-Indolyl or quinolyl substd. pyridazinone derivs. - useful as antithrombotic and antihypertensive agents |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2845220A1 true DE2845220A1 (en) | 1980-04-30 |
Family
ID=6052410
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19782845220 Withdrawn DE2845220A1 (en) | 1978-10-17 | 1978-10-17 | 6-Indolyl or quinolyl substd. pyridazinone derivs. - useful as antithrombotic and antihypertensive agents |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE2845220A1 (en) |
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0068310A1 (en) * | 1981-06-24 | 1983-01-05 | BASF Aktiengesellschaft | 2-Aryl-3,4-diaza-bicyclo(4.n.0)alken-(2)-ones-(5), process for their preparation, and medicines containing these compounds |
| EP0071102A1 (en) * | 1981-07-25 | 1983-02-09 | Dr. Karl Thomae GmbH | Benzotriazoles, their preparation and use as medicines |
| EP0219737A1 (en) * | 1985-10-09 | 1987-04-29 | BASF Aktiengesellschaft | Preparation on the basis of a mixture |
| EP0223937A1 (en) * | 1985-09-05 | 1987-06-03 | Roche Diagnostics GmbH | Indoles substituted with heterocycles, intermediates, process for their preparation and medicaments |
| US4925845A (en) * | 1987-02-27 | 1990-05-15 | Boehringer Mannheim Gmbh | 2 heteroaryl 3,3 dialkyl-5-(3 oxo-2,3,4,5 tetrahydro-6 pyridazinyl)-3H-indoles |
| EP2088154A1 (en) | 2004-03-09 | 2009-08-12 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| WO2012118972A2 (en) | 2011-03-01 | 2012-09-07 | Synegy Pharmaceuticals Inc. | Process of preparing guanylate cyclase c agonists |
| WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
| WO2014131024A2 (en) | 2013-02-25 | 2014-08-28 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| WO2015021358A2 (en) | 2013-08-09 | 2015-02-12 | Dominique Charmot | Compounds and methods for inhibiting phosphate transport |
| EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| WO2020237096A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Combination for lowering serum phosphate in a patient |
-
1978
- 1978-10-17 DE DE19782845220 patent/DE2845220A1/en not_active Withdrawn
Cited By (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0068310A1 (en) * | 1981-06-24 | 1983-01-05 | BASF Aktiengesellschaft | 2-Aryl-3,4-diaza-bicyclo(4.n.0)alken-(2)-ones-(5), process for their preparation, and medicines containing these compounds |
| EP0071102A1 (en) * | 1981-07-25 | 1983-02-09 | Dr. Karl Thomae GmbH | Benzotriazoles, their preparation and use as medicines |
| EP0223937A1 (en) * | 1985-09-05 | 1987-06-03 | Roche Diagnostics GmbH | Indoles substituted with heterocycles, intermediates, process for their preparation and medicaments |
| US4851406A (en) * | 1985-09-05 | 1989-07-25 | Boehringer Mannheim Gmbh | Heterocyclic-substituted indoles and pharmaceutical compositions containing them |
| EP0219737A1 (en) * | 1985-10-09 | 1987-04-29 | BASF Aktiengesellschaft | Preparation on the basis of a mixture |
| US4925845A (en) * | 1987-02-27 | 1990-05-15 | Boehringer Mannheim Gmbh | 2 heteroaryl 3,3 dialkyl-5-(3 oxo-2,3,4,5 tetrahydro-6 pyridazinyl)-3H-indoles |
| EP2088154A1 (en) | 2004-03-09 | 2009-08-12 | Ironwood Pharmaceuticals, Inc. | Methods and compositions for the treatment of gastrointestinal disorders |
| EP2998314A1 (en) | 2007-06-04 | 2016-03-23 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| EP2810951A2 (en) | 2008-06-04 | 2014-12-10 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| EP3241839A1 (en) | 2008-07-16 | 2017-11-08 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| EP2923706A1 (en) | 2009-12-03 | 2015-09-30 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia |
| WO2011069038A2 (en) | 2009-12-03 | 2011-06-09 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| WO2012118972A2 (en) | 2011-03-01 | 2012-09-07 | Synegy Pharmaceuticals Inc. | Process of preparing guanylate cyclase c agonists |
| WO2013138352A1 (en) | 2012-03-15 | 2013-09-19 | Synergy Pharmaceuticals Inc. | Formulations of guanylate cyclase c agonists and methods of use |
| EP3708179A1 (en) | 2012-03-15 | 2020-09-16 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
| EP4309673A2 (en) | 2012-03-15 | 2024-01-24 | Bausch Health Ireland Limited | Formulations of guanylate cyclase c agonists and methods of use |
| WO2014131024A2 (en) | 2013-02-25 | 2014-08-28 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| EP3718557A2 (en) | 2013-02-25 | 2020-10-07 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonist sp-333 for use in colonic cleansing |
| WO2014151200A2 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Compositions useful for the treatment of gastrointestinal disorders |
| WO2014151206A1 (en) | 2013-03-15 | 2014-09-25 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| WO2014197720A2 (en) | 2013-06-05 | 2014-12-11 | Synergy Pharmaceuticals, Inc. | Ultra-pure agonists of guanylate cyclase c, method of making and using same |
| WO2015021358A2 (en) | 2013-08-09 | 2015-02-12 | Dominique Charmot | Compounds and methods for inhibiting phosphate transport |
| EP3492106A1 (en) | 2013-08-09 | 2019-06-05 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| EP3884935A1 (en) | 2013-08-09 | 2021-09-29 | Ardelyx, Inc. | Compounds and methods for inhibiting phosphate transport |
| WO2020237096A1 (en) | 2019-05-21 | 2020-11-26 | Ardelyx, Inc. | Combination for lowering serum phosphate in a patient |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2845220A1 (en) | 6-Indolyl or quinolyl substd. pyridazinone derivs. - useful as antithrombotic and antihypertensive agents | |
| US5391556A (en) | Benzimidazolyl derivatives, pharmaceutical compositions containing these compounds and processes for preparing them | |
| DE69929689T2 (en) | Heterocyclic compounds and methods for the treatment of heart failure and other diseases | |
| US4258185A (en) | Pyridazinone compounds | |
| DE4221583A1 (en) | SUBSTITUTED BIPHENYLPYRIDONE | |
| EP0569795B1 (en) | Sulphonylbenzyl substituted benzo- and pyridopyridones | |
| CH620438A5 (en) | ||
| DE4206045A1 (en) | SULFONYLBENZYL SUBSTITUTED PYRIDONE | |
| EP0779279A1 (en) | Bicyclic heterocycles | |
| EP0764647A1 (en) | Substituted xanthins | |
| EP0047923B1 (en) | Isoquinoline derivatives, processes for their preparation and pharmaceutical compositions containing them | |
| EP0185964B1 (en) | Dihydropyridine-carboxylic acid amides, process for their preparation and their use in medicaments | |
| DD223151A5 (en) | PROCESS FOR THE PREPARATION OF 1,6-NAPHTHYRIDINONE DERIVATIVES | |
| EP0610698B1 (en) | Substituted imidazo(4,5-b)pyridines and benzimidazoles as angiotensin II antagonistes | |
| EP0535465A1 (en) | Cyclic substituted imidazolylpropen acid derivatives as angiotensin II antagonists | |
| EP0569794A1 (en) | Biphenylmethyl-substituted pyridones useful as angiotensin II receptor antagonists. | |
| WO2003011858A1 (en) | Substituted isoindoles and e use thereof | |
| EP0608709A1 (en) | 2-Oxo-quinolin-1-yl-methyl-phenylacetic acid derivatives as angiotensin II Antagonists | |
| EP0617035B1 (en) | Heterotricyclic substituted phenylcyclohexanecarboxylic acid derivatives | |
| EP0630896A1 (en) | Substituted mono- and bipyridylmethyl derivatives as angiotensin II antagonist | |
| DD202563A5 (en) | PROCESS FOR PREPARING 1,5-DIPHENYLPYRAZOLIN-3-ON COMPOUNDS | |
| HU188475B (en) | Process for producing benzothiopyrano-pyridinones | |
| EP0362632A2 (en) | Basic 4-aryl-DHP amides, process for their preparation and their pharmaceutical use | |
| EP0622358A1 (en) | Phenylglycinamides of 4-imidazolylmethyl-phenyl-acetic acids and their use against hypertension and atherosclerosis | |
| EP0362635A1 (en) | Use of nitro-phenyl-dihydropyridine amides as medicaments, compounds and processes for their preparation using intermediates |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8139 | Disposal/non-payment of the annual fee |