WO1996002540A1 - Heterocyclyl-1-phenyl substituted quinolone carboxylic acids as antiviral agents - Google Patents

Heterocyclyl-1-phenyl substituted quinolone carboxylic acids as antiviral agents Download PDF

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Publication number
WO1996002540A1
WO1996002540A1 PCT/EP1995/002642 EP9502642W WO9602540A1 WO 1996002540 A1 WO1996002540 A1 WO 1996002540A1 EP 9502642 W EP9502642 W EP 9502642W WO 9602540 A1 WO9602540 A1 WO 9602540A1
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Prior art keywords
compounds
phenyl
general formula
optionally
acid
Prior art date
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PCT/EP1995/002642
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German (de)
French (fr)
Inventor
Wolfgang Bender
Wolfgang RÖBEN
Arnold Paessens
Stephan Bartel
Original Assignee
Bayer Aktiengesellschaft
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Priority to AU30762/95A priority Critical patent/AU3076295A/en
Publication of WO1996002540A1 publication Critical patent/WO1996002540A1/en

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    • 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to heterocyclyl-1-phenyl substituted quinolone carboxylic acids, processes for their preparation and their use as medicaments, in particular as antiviral agents.
  • the present invention now relates to heterocyclyl-1-phenyl substituted quinolonecarboxylic acids of the general formula (I),
  • A represents hydrogen or methyl
  • X represents a nitrogen atom or a group of the formula -CH, C-F or
  • T stands for an oxygen or sulfur atom or for the -CH -, - group
  • R represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which may be up to 3 times the same or different by nitro, trifluoromethyl.
  • Halogen, cyano, hydroxy or by straight-chain or branched alkyl, acyl, Alkoxy or alkylthio are each substituted with up to 8 carbon atoms,
  • R 2 represents hydrogen or fluorine
  • Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids are particularly preferred.
  • Physiologically acceptable salts can also be alkali, alkaline earth, silver and guanidinium salts of the compounds according to the invention.
  • A represents hydrogen or methyl
  • X represents a nitrogen atom or a group of the formula -CH, C-F or C-Cl,
  • T represents an oxygen atom
  • R 1 represents phenyl, pyridyl, py ⁇ midyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio with each up to 6 carbon atoms are substituted,
  • R 2 represents hydrogen or fluorine
  • A represents hydrogen or methyl
  • X represents a nitrogen atom or a group of the formula -CH, C-F or C-Cl,
  • T represents an oxygen atom
  • R 1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio with each up to 4 carbon atoms are substituted,
  • R 2 , X and T have the meaning given above and
  • R J represents halogen, preferably fluorine or chlorine
  • a and R 1 have the meaning given above,
  • Suitable solvents for all process steps are the customary inert solvents which do not change under the reaction conditions.
  • These preferably include organic solvents such as ethers, for example diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride,
  • the usual basic compounds are suitable as bases for individual reaction steps. These include, for example, alkali or alkaline earth metal hydroxides, pyridine, triethylamine, diisopropylethylamine or N-methylpiperidine. or bicyclic amidines such as diazabicyclo [2,2,3] octane, 1,5-diazabicyclo [3,4,0] -nonene-5 (DBN) or 1,5-diazabicyclo [3,4,0] undecene- 5 (DBU). Diisopropylethylamine is preferred.
  • the bases are generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the corresponding carboxylic acid.
  • the process is generally carried out in a temperature range from 0 ° C. to -60 ° C., preferably from 0 ° C. to + 140 ° C.
  • normal pressure In general, normal pressure is used. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).
  • R 4 represents C r C 4 alkyl
  • R 5 represents C j -C 4 alkoxy or C j -C 4 dialkylamino
  • D represents halogen, preferably chlorine or fluorine
  • the process is generally carried out in a temperature range from 0 ° C. to -150 ° C., preferably from 0 ° C. to + 120 ° C.
  • the saponification is generally carried out in a mixture of glacial acetic acid / water and in the presence of an inorganic acid, preferably sulfuric acid or hydrochloric acid, in a temperature range from 50 to 100 ° C., preferably at 100 ° C.
  • an inorganic acid preferably sulfuric acid or hydrochloric acid
  • the compounds according to the invention showed activity in cell cultures infected with lentivirus. This could be shown using the example of the HIV virus.
  • the HIV test was carried out with minor modifications using the method of Pauwels et al. [see. Journal of Virological Methods 20, (1988), 309-321].
  • PBL Normal human blood lymphocytes
  • RPMI 1640 20% fetal calf serum with phythema agglutinin (90 ⁇ g / ml) and interleukin-2 (40U / ml).
  • phythema agglutinin 90 ⁇ g / ml
  • interleukin-2 40U / ml
  • PBLs were pelleted and the cell pellet was then suspended in 1 ml of HIV virus adsorption solution and incubated at 37 ° C. for 1 hour.
  • the virus adsorption solution was centrifuged and the infected cell pellet in
  • the remaining wells contained the compounds according to the invention in different combinations.
  • test batches were incubated at 37 ° C. until the untreated virus control showed the syncytia formation typical of HIN (between days 3 and 6 after infection), which was then evaluated microscopically.
  • the untreated virus control resulted in about 20 syncytia under these test conditions, while the untreated cell control showed no syncytia.
  • the IC 50 values were determined as the concentration of the treated and infected cells at which 50% (approx. 10 syncytia) of the virus-induced syncytia were suppressed by the treatment with the compound according to the invention.
  • the compounds according to the invention are valuable active substances for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine.
  • Areas of indication in human medicine include: 1) The treatment and prophylaxis of human retrovirus infections
  • HIV I virus of human
  • AIDS AIDS related complex
  • LAS lymphadenopathy syndrome
  • Points 2, 3 and 4 above are preferred from the area of indications in human medicine
  • the present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more
  • the active compounds of the formula (I) should be present in the pharmaceutical preparations listed above, preferably in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95% by weight of the total mixture
  • the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients
  • the pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
  • the active compound (s) according to the invention in total amounts of from about 0.5 to about 500, preferably from 1 to 100 mg / kg of body weight per 24 hours , if necessary in the form of several single doses, to achieve the desired results.
  • a single dose contains the
  • Active ingredients preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place.
  • the retention indices relate to a series of homologous 2-alkanones
  • Example II The title compound is obtained analogously to Example III from the acrylic acid ester of Example IIIc and 3-morpholinoaniline (Example II).
  • DC system VI: R f 0.49
  • Example XI The title compound is prepared analogously to Example X by acidic saponification of the ester from Example XI.
  • Example XIII The title compound is prepared analogously to Example X by acidic saponification of the ester from Example XIII.
  • Example II The title compound is prepared analogously to Example XV from 2- (2,4-difluorobenzoyl) acrylic acid ethyl ester and 3-Mo ⁇ holinoanilin (Example II).
  • HPLC system I Rt 6.087 min.
  • Example II The title compound is prepared analogously to Example XV from 2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester and 2-morpholinoaniline (Example II).
  • DC system I: R f 0.68
  • Example XV The title compound is prepared analogously to Example XV from 2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid ethyl ester and 4-Mo ⁇ holinoanilin (Janssen Chimica).
  • Example XV The title compound is prepared analogously to Example XV from 2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid ethyl ester and 2-Mo ⁇ holinoanilin (Lancaster).
  • Example II The title compound is prepared analogously to Example XV from 2- (3-chloro-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester and 3-Mo ⁇ holinoanilin (Example II)
  • Example 1 The examples listed in Tables 1a and 1b below are prepared analogously to Example 1 by reacting the compound from Example IV and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl):
  • Example 2a and 2b are prepared analogously to Example 1 by reacting the compound from Example ⁇ T and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example VTH 7-chloro-1,4-dihydro-4-oxo-1 - [(4-moopholino) phenyl] -1, 8-naphthyridine-3- carboxylic acid hydrochloride
  • Example VTH 7-chloro-1,4-dihydro-4-oxo-1 - [(4-moopholino) phenyl] -1, 8-naphthyridine-3- carboxylic acid hydrochloride
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 4a and 4b are prepared analogously to Example 2 by reacting the compound from Example XII and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized using known methods (Houben-Weyl).
  • Example 2 The examples listed in Tables 5a and 5b below are prepared analogously to Example 2 by reacting the compound from Example X and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 6a and 6b are prepared analogously to Example 2 by reacting the compound from Example XIV and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 7a and 7b are prepared analogously to Example 3 by reacting the compound from Example XV and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 8a and 8b are prepared analogously to Example 4 by reacting the compound from Example XX and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl) .
  • Example 9a and 9b are prepared analogously to Example 4 by reacting the compound from Example XTX and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 10a and 10b are prepared analogously to Example 4 by reacting the compound from Example X ⁇ TII and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 11a and 11b are prepared analogously to Example 5 by reacting the compound from Example XXI and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 12a and 12b are prepared analogously to Example 6 by reacting the compound from Example XXVI and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 13a and 13b are prepared analogously to Example 6 by reacting the compound from Example XXV and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 14a and 14b are prepared analogously to Example 6 by reacting the compound from Example XXIV and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
  • Example 15a and 15b are prepared analogously to Example 4 by reacting the compound from Example X ⁇ T and the corresponding piperazine derivatives.
  • the latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention concerns heterocyclyl-1-phenyl substituted quinolone carboxylic acids of general formula (I), (I), in which the substitutents have the meanings given in the description. The invention further concerns a process for their preparation and their use as drugs, in particular as antiviral agents.

Description

HETER0CYCLYL-1-PHENYL SUBSTITUIERTE CHINOLOCARBONSAUREN ALS ANTIVIRALE MITTELHETER0CYCLYL-1-PHENYL SUBSTITUTED CHINOLOCARBONIC ACIDS AS AN ANTIVIRAL AGENT
Die vorliegende Erfindung betrifft Heterocyclyl-1-phenyl substituierte Chinolon- carbonsäuren, Verfahren zu ihrer Herstellung, sowie ihre Verwendung als Arz¬ neimittel, insbesondere als antivirale Mittel.The present invention relates to heterocyclyl-1-phenyl substituted quinolone carboxylic acids, processes for their preparation and their use as medicaments, in particular as antiviral agents.
5 Die erfindungsgemäßen Verbindungen der allgemeinen Formel (I) werden von dem Bedeutungsumfang der Publikation EP 422 4885 umfaßt.5 The compounds of the general formula (I) according to the invention are included in the scope of the publication EP 422 4885.
Die vorliegende Erfindung betrifft jetzt Heterocyclyl-1-phenyl substituierte Chinoloncarbonsäuren der allgemeinen Formel (I),The present invention now relates to heterocyclyl-1-phenyl substituted quinolonecarboxylic acids of the general formula (I),
Figure imgf000003_0001
Figure imgf000003_0001
10 in welcher10 in which
A für Wasserstoff oder Methyl steht,A represents hydrogen or methyl,
X für ein Stickstoffatom oder für eine Gruppe der Formel -CH, C-F oderX represents a nitrogen atom or a group of the formula -CH, C-F or
C-Cl steht,C-Cl stands,
T für ein Sauerstoff- oder Schwefelatom oder für die -CH-,-Gruppe steht,T stands for an oxygen or sulfur atom or for the -CH -, - group,
15 R für Phenyl, Pyridyl, Pyrimidyl oder Pyrazinyl steht, die gegebenenfalls bis zu 3-fach gleich oder verschieden durch Nitro, Trifluormethyl. Halogen, Cyano, Hydroxy oder durch geradkettiges oder verzweigtes Alkyl, Acyl, Alkoxy oder Alkylthio mit jeweils bis zu 8 Kohlenstoffatomen substituiert sind,15 R represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which may be up to 3 times the same or different by nitro, trifluoromethyl. Halogen, cyano, hydroxy or by straight-chain or branched alkyl, acyl, Alkoxy or alkylthio are each substituted with up to 8 carbon atoms,
R2 für Wasserstoff oder Fluor stehtR 2 represents hydrogen or fluorine
und deren Hydrate und Salze, gegebenenfalls in einer isomeren Form.and their hydrates and salts, optionally in an isomeric form.
Physiologisch unbedenkliche Salze der erfindungsgemäßen Verbindungen könnenPhysiologically acceptable salts of the compounds according to the invention can
Salze der erfindungsgemäßen Stoffe mit Mineral säuren, Carbonsauren oder Sulfon- sauren sein. Besonders bevorzugt sind z.B. Salze mit Chlorwasserstoffsaure, Brom¬ wasserstoffsäure, Schwefelsäure, Phosphorsaure, Methansulfonsaure, Ethansulfon- saure, Toluolsulfonsaure, Benzolsulfonsaure, Naphthalindisulfonsaure, Essigsaure, Propionsaure, Milchsaure, Weinsaure, Zitronensaure, Fumarsaure, Maleinsäure oder Benzoesaure.Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. For example, particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, maleic acid or fumaric acid, malic acid, fumaric acid.
Physiologisch unbedenkliche Salze können ebenso Alkali-, Erdalkali, Silber- und Guanidiniumsalze der erfindungsgemäßen Verbindungen sein.Physiologically acceptable salts can also be alkali, alkaline earth, silver and guanidinium salts of the compounds according to the invention.
Bevorzugt sind Verbindungen der allgemeinen Formel (I),Compounds of the general formula (I) are preferred
in welcherin which
A für Wasserstoff oder Methyl steht,A represents hydrogen or methyl,
X für ein Stickstoffatom oder für eine Gruppe der Formel -CH, C-F oder C-Cl steht,X represents a nitrogen atom or a group of the formula -CH, C-F or C-Cl,
T für ein Sauerstoffatom steht,T represents an oxygen atom,
R1 für Phenyl, Pyridyl, Pyπmidyl oder Pyrazinyl steht, die gegebenenfalls bis zu 3-fach gleich oder verschieden durch Nitro, Trifluormethyl, Fluor, Chlor, Brom, Cyano, Hydroxy oder durch geradkettiges oder verzweigtes Alkyl, Acyl, Alkoxy oder Alkylthio mit jeweils bis zu 6 Kohlenstoffatomen substituiert sind,R 1 represents phenyl, pyridyl, pyπmidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio with each up to 6 carbon atoms are substituted,
R2 für Wasserstoff oder Fluor stehtR 2 represents hydrogen or fluorine
und deren Hydrate und Salze, gegebenenfalls in einer isomeren Form Besonders bevorzugt sind Verbindungen der allgemeinen Formel (I),and their hydrates and salts, optionally in an isomeric form Compounds of the general formula (I) are particularly preferred
in welcherin which
A für Wasserstoff oder Methyl steht,A represents hydrogen or methyl,
X für ein Stickstoffatom oder für eine Gruppe der Formel -CH, C-F oder C-Cl steht,X represents a nitrogen atom or a group of the formula -CH, C-F or C-Cl,
T für ein Sauerstoffatom steht,T represents an oxygen atom,
R1 für Phenyl, Pyridyl, Pyrimidyl oder Pyrazinyl steht, die gegebenenfalls bis zu 3-fach gleich oder verschieden durch Nitro, Trifluormethyl, Fluor, Chlor, Brom, Cyano, Hydroxy oder durch geradkettiges oder verzweigtes Alkyl, Acyl, Alkoxy oder Alkylthio mit jeweils bis zu 4 Kohlenstoffatomen substituiert sind,R 1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio with each up to 4 carbon atoms are substituted,
für Wasserstoff oder Fluor stehtrepresents hydrogen or fluorine
und deren Hydrate und Salze, gegebenenfalls in einer isomeren Form.and their hydrates and salts, optionally in an isomeric form.
Außerdem wurde ein Verfahren zur Herstellung der erfindungsgemäßen Verbin¬ dungen der allgemeinen Formel (I) gefunden, dadurch gekennzeichnet, daß manIn addition, a process for the preparation of the compounds of the general formula (I) according to the invention was found, characterized in that
Verbindungen der allgemeinen Formel (II)Compounds of the general formula (II)
Figure imgf000005_0001
Figure imgf000005_0001
in welcherin which
R2, X und T die oben angegebene Bedeutung haben undR 2 , X and T have the meaning given above and
RJ für Halogen, vorzugsweise für Fluor oder Chlor steht,R J represents halogen, preferably fluorine or chlorine,
mit Verbindungen der allgemeinen Formel (III)with compounds of the general formula (III)
R1-N N - H (mR 1 -NN - H (m
in welcherin which
A und R1 die oben angegebene Bedeutung haben,A and R 1 have the meaning given above,
in inerten Lösemitteln, gegebenenfalls in Anwesenheit von Säurefängern umsetzt.in inert solvents, optionally in the presence of acid scavengers.
Das erfindungsgemäße Verfahren kann durch folgendes Formelschema beispielhaft erläutert werden:The process according to the invention can be illustrated by the following formula scheme:
Figure imgf000006_0001
Figure imgf000006_0001
Figure imgf000006_0002
Als Lösemittel eignen sich für alle Verfahrensschritte die üblichen inerten Löse¬ mittel, die sich unter den Reaktionsbedingungen nicht verändern. Hierzu gehören bevorzugt organische Lösemittel wie Ether z.B. Diethylether, Dioxan oder Tetrahydrofuran, oder Kohlenwasserstoffe wie Benzol, Toluol, Xylol, Cyclohexan oder Erdöl fr aktionen oder Halogenkohlenwasserstoffe wie Methylenchlorid,
Figure imgf000006_0002
Suitable solvents for all process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride,
Chloroform, Tetrachlorkohlenstoff, oder Dimethylsulfoxid, N,N-Dimethylform- amid, Hexamethylphosphorsäuretriamid, Sulfolan, Essigester, Pyridin, Acetonitril, Triethylamin, N-Methylpyrrolidon, Anisol oder Picolin. Ebenso ist es möglich, Gemische der genannten Lösemittel zu verwenden. Bevorzugt sind Dimethylsulf- oxid und Acetonitril.Chloroform, carbon tetrachloride, or dimethyl sulfoxide, N, N-dimethylformamide, hexamethylphosphoric triamide, sulfolane, ethyl acetate, pyridine, acetonitrile, triethylamine, N-methylpyrrolidone, anisole or picoline. It is also possible to use mixtures of the solvents mentioned. Dimethyl sulfoxide and acetonitrile are preferred.
Als Basen für einzelne Reaktionsschritte eignen sich die üblichen basischen Verbindungen. Hierzu gehören beispielsweise Alkali- oder Erdalkalihydroxide, Pyridin, Triethylamin, Diisopropylethylamin oder N-Methylpiperidin. oder bi- cyclische Amidine wie Diazabicyclo[2,2,3]octan, l,5-Diazabicyclo[3,4,0]-nonene-5 (DBN) oder l,5-Diazabicyclo[3,4,0]undecene-5 (DBU). Bevorzugt ist Diisopropyl¬ ethylamin.The usual basic compounds are suitable as bases for individual reaction steps. These include, for example, alkali or alkaline earth metal hydroxides, pyridine, triethylamine, diisopropylethylamine or N-methylpiperidine. or bicyclic amidines such as diazabicyclo [2,2,3] octane, 1,5-diazabicyclo [3,4,0] -nonene-5 (DBN) or 1,5-diazabicyclo [3,4,0] undecene- 5 (DBU). Diisopropylethylamine is preferred.
Die Basen werden im allgemeinen in einer Menge von 1 bis 3mol, bevorzugt von 1 bis l,5mol, bezogen auf lmol der entsprechenden Carbonsäure, eingesetzt.The bases are generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the corresponding carboxylic acid.
Das Verfahren wird im allgemeinen in einem Temperaturbereich von 0°C bis -rl60°C, bevorzugt von 0°C bis +140°C, durchgeführt.The process is generally carried out in a temperature range from 0 ° C. to -60 ° C., preferably from 0 ° C. to + 140 ° C.
Im allgemeinen wird bei Normaldruck gearbeitet. Es ist aber auch möglich, das Verfahren bei Unterdruck oder bei Überdruck durchzuführen (z.B. in einem Bereich von 0,5 bis 5bar).In general, normal pressure is used. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).
Die Verbindungen der allgemeinen Formel (II) sind teilweise bekannt oder neu und können hergestellt werden, indem man zunächst Verbindungen der allge¬ meinen Formel (IV)Some of the compounds of the general formula (II) are known or new and can be prepared by first preparing compounds of the general formula (IV)
Figure imgf000007_0001
in welcher R >2 , K D3 und X die oben angegebene Bedeutung haben,
Figure imgf000007_0001
in which R> 2, K D 3 and X have the meaning given above,
R4 für CrC4-Alkyl steht,R 4 represents C r C 4 alkyl,
R5 für Cj-C4-Alkoxy oder Cj-C4-Dialkylamino steht,R 5 represents C j -C 4 alkoxy or C j -C 4 dialkylamino,
undand
D für Halogen, vorzugsweise für Chlor oder Fluor steht,D represents halogen, preferably chlorine or fluorine,
durch Umsetzung mit Aminen der allgemeinen Formel (V)by reaction with amines of the general formula (V)
Figure imgf000008_0001
Figure imgf000008_0001
in welcherin which
T die oben angegebene Bedeutung hat,T has the meaning given above,
in einem der oben aufgeführten Lösemittel, vorzugsweise Ethanol,in one of the solvents listed above, preferably ethanol,
in die Verbindungen der allgemeinen Formel (VI)into the compounds of the general formula (VI)
Figure imgf000008_0002
Figure imgf000008_0002
in welcherin which
R >2", D R3 , n R4 , D, T und X die oben angegebene Bedeutung haben,R> 2 ", D R3, n R4, D, T and X have the meaning given above,
überfuhrt, und in einem letzten Schritt in einem der oben aufgeführten Losemittel und einer dort genannten Base, vorzugsweise DMF und K2CO3 cyclisieπ. und die Ester verseift.transferred, and in a last step in one of the solvents listed above and a base mentioned there, preferably DMF and K 2 CO 3 cyclisieπ. and saponified the esters.
Das Verfahren wird im allgemeinen in einem Temperaturbereich von 0°C bis -150°C, bevorzugt von 0°C bis +120°C, durchgeführt.The process is generally carried out in a temperature range from 0 ° C. to -150 ° C., preferably from 0 ° C. to + 120 ° C.
Im allgemeinen wird bei Normaldruck gearbeitet. Es ist aber auch möglich, das Verfahren bei Unterdruck oder bei Überdruck durchzuführen (z.B. in einemIn general, normal pressure is used. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in one
Bereich von 0,5 bis 5 bar).Range from 0.5 to 5 bar).
Die Verseifung erfolgt im allgemeinen in einem Gemisch Eisessig / Wasser und in Anwesenheit einer anorganischen Säure, vorzugsweise Schwefelsäure oder Salz¬ säure, in einem Temperaturbereich von 50 - 100°C, vorzugsweise bei 100°C.The saponification is generally carried out in a mixture of glacial acetic acid / water and in the presence of an inorganic acid, preferably sulfuric acid or hydrochloric acid, in a temperature range from 50 to 100 ° C., preferably at 100 ° C.
Die Verbindungen der allgemeinen Formel (IV) und (V) sind an sich bekannt oder können nach publizierten Methoden hergestellt werden.The compounds of the general formulas (IV) and (V) are known per se or can be prepared by published methods.
Die Verbindungen der allgemeinen Formel (VI) sind neu und können dann bei¬ spielsweise wie oben beschrieben hergestellt werden.The compounds of the general formula (VI) are new and can then be prepared, for example, as described above.
Überraschenderweise zeigten die erfindungsgemäßen Verbindungen Wirkung in Lentivirus infizierten Zellkulturen. Dies konnte am Beispiel des HIV-Virus gezeigt werden.Surprisingly, the compounds according to the invention showed activity in cell cultures infected with lentivirus. This could be shown using the example of the HIV virus.
HIV-Infektion in ZellkulturHIV infection in cell culture
Der HIV- Test wurde mit geringen Modifikationen nach der Methode von Pauwels et al. [vgl. Journal of Virological Methods 20, (1988), 309-321] durchgeführt.The HIV test was carried out with minor modifications using the method of Pauwels et al. [see. Journal of Virological Methods 20, (1988), 309-321].
Normale menschliche Blutlymphozyten (PBL's) wurden über Ficoll-Hypaque ange¬ reichert und im RPMI 1640, 20% fötales Kälberserum mit Phythaemagglutinin (90μg/ml) und Interleukin-2 (40U/ml) stimuliert. Zur Infektion mit dem infektiösen HIV wurden PBL's pelletiert und das Zellpellet wurde anschließend in 1ml HIV- Virusadsorptionslösung suspendiert und 1 Stunde bei 37°C inkubiert.Normal human blood lymphocytes (PBL's) were enriched via Ficoll-Hypaque and stimulated in the RPMI 1640, 20% fetal calf serum with phythema agglutinin (90μg / ml) and interleukin-2 (40U / ml). For infection with the infectious HIV, PBLs were pelleted and the cell pellet was then suspended in 1 ml of HIV virus adsorption solution and incubated at 37 ° C. for 1 hour.
Die Virusadsorptionslösung wurde zentrifugiert und das infizierte Zellpellet inThe virus adsorption solution was centrifuged and the infected cell pellet in
Wachstumsmedium aufgenommen, so daß 1 x 105 Zellen pro ml eingestellt waren. Die derart infizierten Zellen wurden zu 1 x 104 Zellen/Napf in die Näpfe von 96er Mikrotiterplatten pipettiert. Die erste vertikale Reihe der Mikrotiterplatte enthielt nur Wachstumsmedium und Zellen, die nicht infiziert, aber ansonsten genauso wie oben beschrieben, behandelt worden waren (Zellkontrolle). Die zweite vertikale Reihe der Mikrotiterplatte erhielt nur HlV-infizierte Zellen (Viruskontrolle) in Wachstumsmedium. Die übri- gen Näpfe enthielten die erfindungsgemäßen Verbindungen in unterschiedlichenGrowth medium was added so that 1 x 10 5 cells per ml were set. The cells infected in this way were pipetted into the wells of 96-well microtiter plates at 1 × 10 4 cells / well. The first vertical row of the microtiter plate contained only growth medium and cells that were not infected but were otherwise treated exactly as described above (cell control). The second vertical row of the microtiter plate only received HIV-infected cells (virus control) in growth medium. The remaining wells contained the compounds according to the invention in different
Konzentrationen, ausgehend von den Näpfen der 3. vertikalen Reihe der Mikro¬ titerplatte, von der die Prüf Substanzen in 2er Schritten 210fach verdünnt wurden.Concentrations, starting from the wells of the 3rd vertical row of the microtiter plate, from which the test substances were diluted 2 to 10 times in steps of 2.
Die Testansätze wurden so lange bei 37°C inkubiert, bis in der unbehandelten Viruskontrolle die für das HIN typische Syncytienbildung auftrat (zwischen Tag 3 und 6 nach Infektion), die dann mikroskopisch ausgewertet wurde. In der unbehandelten Niruskontrolle resultierten unter diesen Testbedingungen etwa 20 Syncytien, während die unbehandelte Zellkontrolle keine Syncytien aufwies.The test batches were incubated at 37 ° C. until the untreated virus control showed the syncytia formation typical of HIN (between days 3 and 6 after infection), which was then evaluated microscopically. The untreated virus control resulted in about 20 syncytia under these test conditions, while the untreated cell control showed no syncytia.
Die IC50-Werte wurden als die Konzentration der behandelten und infizierten Zellen ermittelt, bei der 50% (ca. 10 Syncytien) der virusinduzierten Syncytien durch die Behandlung mit der erfindungsgemäßen Verbindung unterdrückt waren.The IC 50 values were determined as the concentration of the treated and infected cells at which 50% (approx. 10 syncytia) of the virus-induced syncytia were suppressed by the treatment with the compound according to the invention.
Es wurde nun gefunden, daß die erfindungsgemäßen Verbindungen HJN infizierte Zellen vor der virusinduzierten Zellzerstörung schützen. It has now been found that the compounds according to the invention protect HJN-infected cells from virus-induced cell destruction.
Figure imgf000011_0001
Figure imgf000011_0001
Die erfindungsgemäßen Verbindungen stellen wertvolle Wirkstoffe zur Behandlung und Prophylaxe von Erkrankungen, hervorgerufen durch Retroviren, in der Human-und Tiermedizin dar.The compounds according to the invention are valuable active substances for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine.
Als Indikationsgebiete in der Humanmedizin können beispielsweise genannt werden: 1 ) Die Behandlung und Prophylaxe von menschlichen RetrovirusinfektionenAreas of indication in human medicine include: 1) The treatment and prophylaxis of human retrovirus infections
) Für die Behandlung oder Prophylaxe von HIV I (Virus der humanen) For the treatment or prophylaxis of HIV I (virus of human
Immundefizienz, früher HTLV III/LAN genannt) und HIV II verursachtenImmunodeficiency, formerly called HTLV III / LAN) and HIV II
Erkrankungen (AIDS) und den damit assoziierten Stadien wie ARC (AIDS related complex) und LAS (Lymphadenopathie-Syndrom) sowie der durch dieses Virus verursachten Immunschwache und EncephalopathieDiseases (AIDS) and the associated stages such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome) as well as the immune deficiency and encephalopathy caused by this virus
3 ) Für die Behandlung oder die Prophylaxe einer HTLV-I oder HTLN-II3) For the treatment or prophylaxis of an HTLV-I or HTLN-II
Infektioninfection
4 ) Für die Behandlung oder die Prophylaxe des ALDS-carrier Zustandes ( AID S-Ubertrager-Zustand)4) For the treatment or prophylaxis of the ALDS carrier state (AID S transmitter state)
Als Indikationen in der Tiermedizin können beispielsweise angeführt werden'Indications in veterinary medicine can be given, for example '
Infektionen mit a) Maedivisna (bei Schafen und Ziegen) b) progressivem Pneumonievirus (PPN) (bei Schafen und Ziegen) c) caprine arthritis encephaliüs Virus (bei Schafen und Ziegen) d) Zwoegerziekte Virus (bei Schafen) e) infektiösem Virus der Anämie (des Pferdes) f) Infektionen verursacht durch das Katzenleukamievirus g) Infektionen verursacht durch das Virus der Katzen-Immundefizienz (FIV) h) Infektionen verursacht durch das Virus der Affen-Immundefizienz (SIN)Infections with a) Maedivisna (in sheep and goats) b) Progressive Pneumonia Virus (PPN) (in sheep and goats) c) caprine arthritis encephaliüs virus (in sheep and goats) d) Zwoegerziezie virus (in sheep) e) infectious virus of anemia (of the horse) f) infections caused by the feline leukemia virus g) infections caused by the virus of the cat immunodeficiency (FIV) h) infections caused by the virus of the monkey immunodeficiency (SIN)
Bevorzugt werden aus dem Indikaüonsgebiet in der Humanmedizin die oben aufgeführten Punkte 2, 3 und 4Points 2, 3 and 4 above are preferred from the area of indications in human medicine
Zur vorliegenden Erfindung gehören pharmazeutische Zubereitungen, die neben nicht-toxischen, inerten pharmazeutisch geeigneten Tragerstoffen eine oder mehrere Verbindungen der Formel (I) enthalten oder die aus einem oder mehrerenThe present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more
Wirkstoffen der Formel (I) bestehen, sowie Verfahren zur Herstellung dieser ZubereitungenActive ingredients of formula (I) exist, as well as processes for the preparation of these preparations
Die Wirkstoffe der Formel (I) sollen in den oben aufgeführten pharmazeutischen Zubereitungen, vorzugsweise in einer Konzentration von etwa 0,1 bis 99,5, vor- zugsweise von etwa 0,5 bis 95Gew -% der Gesamtmischung vorhanden sein Die oben aufgeführten pharmazeutischen Zubereitungen können außer den Verbin¬ dungen der Formel (I) auch weitere pharmazeutische Wirkstoffe enthaltenThe active compounds of the formula (I) should be present in the pharmaceutical preparations listed above, preferably in a concentration of approximately 0.1 to 99.5, preferably approximately 0.5 to 95% by weight of the total mixture In addition to the compounds of the formula (I), the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients
Die Herstellung der oben aufgeführten pharmazeutischen Zubereitungen erfolgt in üblicher Weise nach bekannten Methoden, z.B. durch Mischen des oder der Wirk- Stoffe mit dem oder den Trägerstoffen.The pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.
Im allgemeinen hat es sich sowohl in der Human- als auch in der Veterinärmedi¬ zin als vorteilhaft erwiesen, den oder die erfindungsgemäßen Wirkstoffe in Gesamt¬ mengen von etwa 0,5 bis etwa 500, vorzugsweise 1 bis 100 mg/kg Körpergewicht je 24 Stunden, gegebenenfalls in Form mehrerer Einzelgaben, zur Erzielung der gewünschten Ergebnisse zu verabreichen. Eine Einzelgabe enthält den oder dieIn general, both in human and in veterinary medicine, it has proven to be advantageous to use the active compound (s) according to the invention in total amounts of from about 0.5 to about 500, preferably from 1 to 100 mg / kg of body weight per 24 hours , if necessary in the form of several single doses, to achieve the desired results. A single dose contains the
Wirkstoffe vorzugsweise in Mengen von etwa 1 bis etwa 80, insbesondere 1 bis 30 mg/kg Körpergewicht. Es kann jedoch erforderlich sein, von den genannten Dosierungen abzuweichen, und zwar in Abhängigkeit von der Art und dem Kör¬ pergewicht des zu behandelnden Objekts, der Art und der Schwere der Erkrankung, der Art der Zubereitung und der Applikation des Arzneimittels sowie dem Zeitraum bzw. Intervall, innerhalb welchem die Verabreichung erfolgt. Active ingredients preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or Interval within which the administration takes place.
Erläuterungen zum experimentellen Teil:Explanation of the experimental part:
DC-SvstemeDC systems
Stationäre PhaseStationary phase
Merck DC-Fertigplatten Kieselgel 60 F-254, 5 x 10 cm, Schichtdicke 0.25 mm, Art-Nr. 5719.Merck DC pre-assembled silica gel 60 F-254 plates, 5 x 10 cm, layer thickness 0.25 mm, Art-No. 5719.
Mobile Phasen: (im Test als "DC-System")Mobile phases: (in the test as "DC system")
I CH2C12 / MeOH 9:1 π CH2C12 / MeOH 95:5I CH 2 C1 2 / MeOH 9: 1 π CH 2 C1 2 / MeOH 95: 5
UJ: NH3 / CH2C12 / MeOH 0,2:9: 1 IN Essigsäure / CH2C12 / MeOH 0,2:9: 1UJ: NH 3 / CH 2 C1 2 / MeOH 0.2: 9: 1 IN acetic acid / CH 2 C1 2 / MeOH 0.2: 9: 1
V CH2C12 / MeOH 10: 1V CH 2 C1 2 / MeOH 10: 1
VT. Toluol / Ethanol 5: 1VT. Toluene / ethanol 5: 1
VTI: Petrolether / Essigester 6: 1VTI: petroleum ether / ethyl acetate 6: 1
Vm: ΝH3 / CH2C12 / MeOH 2:80:20 LX: Essigsaure / CH2C12 / MeOH 0, 1 : 10: 1Vm: ΝH 3 / CH 2 C1 2 / MeOH 2:80:20 LX: acetic acid / CH 2 C1 2 / MeOH 0, 1: 10: 1
X. Toluol / Aceton 2:1X. toluene / acetone 2: 1
XI: CH2C12 / MeOH / NH3 95:5:0,2XI: CH 2 C1 2 / MeOH / NH 3 95: 5: 0.2
HPLC-Svstem IHPLC system I
Säule Nucleosil 120-5 C 18, 5 μm, 125 x 4 mm Eluens; A = 0,01 M H3PO4, B = AcetonitrilColumn Nucleosil 120-5 C 18.5 µm, 125 x 4 mm eluent; A = 0.01 MH 3 PO 4 , B = acetonitrile
EluentenprogramnrEluent program no
0-1 min: 10% B0-1 min: 10% B
1 -9 min Gradient mit 10% B/min1 -9 min gradient with 10% B / min
9-13 min: 90% B Fluß: 2 ml/min, Raumtemperatur9-13 min: 90% B flow: 2 ml / min, room temperature
5 μl, Probenmenge ca 1 mg/ml5 μl, sample amount approx. 1 mg / ml
Detektion UV-Di odenarray bei 210 nmDetection UV diode array at 210 nm
Die Retentionsindices beziehen sich auf eine Reihe homologer 2-AlkanoneThe retention indices relate to a series of homologous 2-alkanones
( Methyl-n-alkylketone). C3 = 300, C4 = 400, C16 = 1600 Ausgangsverbindungen(Methyl-n-alkyl ketones). C3 = 300, C4 = 400, C16 = 1600 Output connections
Beispiel IExample I
(3-Mo holino)-nitrobenzol(3-Mo holino) nitrobenzene
Figure imgf000015_0001
Figure imgf000015_0001
29 g (107 mmol) 3-Nitrophenyl-trifluormethansulfonat (Synthesis, 12 (1990) pp.29 g (107 mmol) 3-nitrophenyl trifluoromethanesulfonate (Synthesis, 12 (1990) pp.
1145 ff.) werden in 150 ml (1,72 mol) Morpholin unter Argon 16 h im 130°C-Bad gerührt. Der Morpholin-Uberschuß wird im Hochvakuum am Rotavapor entfernt und das resultierende Öl an Kieselgel mit Petrolether / Essigester 3:1 Chromato¬ graphien. Ausbeute: 14,5 g Öl (= 65% d.Th.)1145 ff.) Are stirred in 150 ml (1.72 mol) morpholine under argon for 16 h in a 130 ° C bath. The excess morpholine is removed in a high vacuum on a Rotavapor and the resulting oil on silica gel with petroleum ether / ethyl acetate 3: 1 chromatography. Yield: 14.5 g of oil (= 65% of theory)
Beispiel IIExample II
(3 -Morpholino)anilin(3-morpholino) aniline
Figure imgf000015_0002
Figure imgf000015_0002
25 g (120,2 mmol) der Verbindung aus Beispiel I werden in 700 ml Essigester gelöst und an 2 g Pd-Katalysator (10% Pd auf Aktivkohle) 4 Stunden lang bei 3,2 bar hydriert. Der Katalysator wird abgetrennt, das Filtrat eingedampft und der25 g (120.2 mmol) of the compound from Example I are dissolved in 700 ml of ethyl acetate and hydrogenated over 2 g of Pd catalyst (10% Pd on activated carbon) at 3.2 bar for 4 hours. The catalyst is separated off, the filtrate is evaporated and the
Rückstand in wenig Essigester gelöst. Das Produkt wird mit Petrolether gefällt und aus Essigester umkristallisiert.Residue dissolved in a little ethyl acetate. The product is precipitated with petroleum ether and recrystallized from ethyl acetate.
Ausbeute: 17,74 g (41% d.Th.) DC-System VI: Rf = 0,37 Beispiel HIYield: 17.74 g (41% of theory) TLC system VI: R f = 0.37 Example HI
7-Chlor-l ,4-dihydro-4-oxo-l-[(2-morpholino)phenyl]-l,8-napthyridin-3-carbon- saureethylester7-chloro-l, 4-dihydro-4-oxo-l - [(2-morpholino) phenyl] -l, 8-napthyridine-3-carbonic acid ethyl ester
Figure imgf000016_0001
Figure imgf000016_0001
a) (2,6-Dichlornicoünoyl)malonsaurediethylestera) (2,6-Dichlornicoünoyl) malonic acid diethyl ester
iVIan legt 7,21 g (0,075 mol) Magnesiumchlorid bei 0°C in 75 ml absolutem Acetonitril vor und tropft unter Eisbadkühlung 12,12 g (0,075 mol) Malon- saurediethylester zu. Anschließend werden 15,34 g (0,150 mol) Triethylamin bei 0°C zugetropft, nach 60 minuügem Nachruhren werden bei 0°C 17,0 g (0,075 mol) 2,6-Dichlornicotinsaurechlorid (Helvitia Chimica Acta 59, 222 (1976)) zugetropft und unter Erwärmung auf Raumtemperatur über Nacht nachgeruhrt Es wird mit 80 ml 18%iger Salzsaure versetzt und mit Methyl-tert.butylether extra¬ hiert, über Natriumsuflat getrocknet und im Vakuum eingeengtiVIan places 7.21 g (0.075 mol) of magnesium chloride at 0 ° C in 75 ml of absolute acetonitrile and drops in 12.12 g (0.075 mol) of diethyl malonate while cooling with an ice bath. 15.34 g (0.150 mol) of triethylamine are then added dropwise at 0 ° C., after 60 minutes of stirring, 17.0 g (0.075 mol) of 2,6-dichloronicicotinic acid chloride (Helvitia Chimica Acta 59, 222 (1976)) added dropwise and stirred overnight with heating to room temperature. 80 ml of 18% hydrochloric acid are added and the mixture is extracted with methyl tert-butyl ether, dried over sodium sulfate and concentrated in vacuo
b) (2,6-Dichlornιcotιnoyl)essigsaureethylesterb) (2,6-Dichlornιcotιnoyl) ethyl acetate
Der rohe (2,6-Dichlornicotinoyl)-malonsaurediethylester wird in 45 ml Wasser mitThe crude (2,6-dichloronicotinoyl) malonic acid diethyl ester is dissolved in 45 ml of water
90 mg p-Toluolsulfonsaure 2 Stunden zum Rückfluß erhitzt Es wird mit Methylenchlorid extrahiert, mit Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum eingeengt Das Rohprodukt wird an Kieselgel (Laufmittel Dichlormethan) gereinigt Ausbeute 14,2 g (72% d Th über zwei Schritte) c) 2-(2,6-Dιchlornicotinoyl)-3-ethoxy-acrylsaurethylester90 mg of p-toluenesulfonic acid heated to reflux for 2 hours. It is extracted with methylene chloride, washed with water, dried over sodium sulfate and concentrated in vacuo. The crude product is purified on silica gel (mobile phase dichloromethane). Yield 14.2 g (72% of theory over two steps ) c) 2- (2,6-dichloronicotinoyl) -3-ethoxy-acrylate
10 g (38,15 mmol) des unter ITJb erhaltenen (2,6-Dichlor-nιcotinoyl)-essιgsaure- ethylesters werden in 1 15 ml Essigsaureanhydrid und 86 ml Triethylorthoformiat 10 Stunden am Ruckfluß gerührt Man dampft im Hochvakuum am Rotavapor ein und azeotropiert das erhaltene Rohprodukt zur Entfernung der Restspuren von10 g (38.15 mmol) of the (2,6-dichloro-nicotinoyl) ethyl acetate obtained under ITJb are stirred in 1 15 ml of acetic anhydride and 86 ml of triethyl orthoformate for 10 hours under reflux obtained crude product for removing the traces of
Essigsaureanhydrids mehrmals mit Toluol am Hochvakuum Das olige Rohprodukt wird direkt in der nächsten Stufe (IT d) umgesetztAcetic anhydrides several times with toluene in a high vacuum. The oily crude product is reacted directly in the next stage (IT d)
d) 2-(2,5-Dichlornicotinoyl)-3-[(2-morpholino)-phenylamino]-acrylsaureethyl- esterd) 2- (2,5-dichloronicotinoyl) -3 - [(2-morpholino) phenylamino] ethyl acrylate
Das unter HIc erhaltene Rohprodukt wird in Ethanol bei -5°C mit 6,79 g (38,15 mmol) o-(l-Morpholino)-anihn (Lancaster, gelost in Ethanol) versetzt DC-Kon- trolle) Zur Aufarbeitung wird im Vakuum eingedampft und der durchkristallisierte Ruckstand über Kieselgel 60 mit Toluol Aceton = 15 1 Chromatographien Ausbeute 9,65 g (62,5% d Th )The crude product obtained under HIc is mixed with 6.79 g (38.15 mmol) of o- (l-morpholino) -anihn (Lancaster, dissolved in ethanol) in ethanol at -5 ° C. DC control) evaporated in vacuo and the crystallized residue on silica gel 60 with toluene acetone = 15 1 chromatographies yield 9.65 g (62.5% of theory)
5,65 g (12,55 mmol) der unter ITJd erhaltenen Verbindung werden in 50 ml 1,2-5.65 g (12.55 mmol) of the compound obtained under ITJd are dissolved in 50 ml of 1,2-
Dimethoxyethan mit 15 g (108,5 mmol) Kaliumcarbonat (Pulver) 3 Tage bei Raumtemperatur unter Argon gerührt Man saugt vom Ungelöstem ab, dampft ein und verteilt den Ruckstand zwischen Wasser und Dichlormethan Die organische Phase wird vereinigt, über Natnumsulfat getrocknet und am Vakuum eingeengt Ausbeute 4,66 g (90% d Th ) DC-System VI Rf = 0,59 (+)FAB-MS m/z 414 (M+H)Dimethoxyethane with 15 g (108.5 mmol) potassium carbonate (powder) stirred for 3 days at room temperature under argon. The undissolved material is filtered off with suction, evaporated and the residue is partitioned between water and dichloromethane. The organic phase is combined, dried over sodium sulfate and concentrated in vacuo Yield 4.66 g (90% of theory) DC system VI R f = 0.59 (+) FAB-MS m / z 414 (M + H)
Beispiel INExample IN
7-Chlor-l ,4-dιhydro-4-oxo-l-[(2-morphohno)phenyl]-l,8-naphthyπdιn-3-carbon- saure
Figure imgf000018_0001
7-chloro-l, 4-dιhydro-4-oxo-l - [(2-morphohno) phenyl] -l, 8-naphthyπdιn-3-carboxylic acid
Figure imgf000018_0001
167,6 mg (0,4 mmol) des Esters aus dem Beispiel III werden mit 5 ml Säuregemisch (Essigsäure: Wasser: Schwefelsäure = 12:8: 1) 4 h im 100°C-Bad gerührt. Das Produkt wird mit Eiswasser gefällt, abgesaugt und getrocknet. Ausbeute: 125,2 mg (80% d.Th.) DC-System IX: Rf = 0,55 (+)FAB-MS: m/z = 386 (M+H)167.6 mg (0.4 mmol) of the ester from Example III are stirred with 5 ml of acid mixture (acetic acid: water: sulfuric acid = 12: 8: 1) in a 100 ° C. bath for 4 h. The product is precipitated with ice water, suction filtered and dried. Yield: 125.2 mg (80% of theory) DC system IX: R f = 0.55 (+) FAB-MS: m / z = 386 (M + H)
Beispiel VExample V
7-Chlor-l,4-dihydro-4-oxo-l-[(3-morpholino)phenyl]-l,8-naphthyridin-3-carbon- säureethylester7-chloro-l, 4-dihydro-4-oxo-l - [(3-morpholino) phenyl] -l, 8-naphthyridine-3-carboxylic acid, ethyl ester
Figure imgf000018_0002
Figure imgf000018_0002
Die Titelverbindung wird analog Beispiel III aus dem Acrylsäureester des Beispiels IIIc und 3-Morpholinoanilin (Beispiel II) erhalten. DC-System VI: Rf = 0,49The title compound is obtained analogously to Example III from the acrylic acid ester of Example IIIc and 3-morpholinoaniline (Example II). DC system VI: R f = 0.49
(-^FAB-MS: m/z 414 = (M+H) Beispiel VI(- ^ FAB-MS: m / z 414 = (M + H) Example VI
7-Chlor- 1 ,4-dihydro-4-oxo- 1 [(3-moφholino)phenyl]- 1 ,8-naphthyridin-3-carbonsäure7-chloro-1,4-dihydro-4-oxo-1 [(3-moφholino) phenyl] -1,8-naphthyridine-3-carboxylic acid
Figure imgf000019_0001
Figure imgf000019_0001
Die Titelverbindung wird analog Beispiel IV durch saure Verseifung des Esters aus dem Beispiel V erhalten. DC-System V: Rf = 0,53 (+)FAB-MS: m/z = 386 (M+H)The title compound is obtained analogously to Example IV by acidic hydrolysis of the ester from Example V. DC system V: R f = 0.53 (+) FAB-MS: m / z = 386 (M + H)
Beispiel NuExample Nu
7-Chlor-l,4-dihydro-4-oxo-[(4-moφholino)phenyl]-l,8-naphthyridin-3-carbonsäure- ethvlester7-chloro-1,4-dihydro-4-oxo - [(4-moφholino) phenyl] -1, 8-naphthyridine-3-carboxylic acid, ethyl ester
Figure imgf000019_0002
Die Titelverbindung wird analog Beispiel III aus dem Acrylsäureester des Bei¬ spiels IIIc und 4-Morpholinoanilin (Janssen Chimica) erhalten. DC-System VI: Rf = 0,51 (+)FAB-MS: m/z = 414 (M+H)
Figure imgf000019_0002
The title compound is obtained analogously to Example III from the acrylic acid ester of Example IIIc and 4-morpholinoaniline (Janssen Chimica). DC system VI: R f = 0.51 (+) FAB-MS: m / z = 414 (M + H)
Beispiel VTUExample VTU
7-Chlor- 1 ,4-dihydro-4-oxo- 1 -[(4-morpholino)phenyl]- 1 ,8-naphthyridin-3-carbon- säure7-chloro-1,4-dihydro-4-oxo-1 - [(4-morpholino) phenyl] -1,8-naphthyridine-3-carboxylic acid
Figure imgf000020_0001
Figure imgf000020_0001
Die Titelverbindung wird analog Beispiel IN durch saure Verseifüng des Esters aus dem Beispiel VII erhalten.The title compound is obtained analogously to Example IN by acidic saponification of the ester from Example VII.
DC-System V: Rf = 0,52 (+)FAB-MS: m/z = 386 (M+H)DC system V: R f = 0.52 (+) FAB-MS: m / z = 386 (M + H)
Beispiel IXExample IX
7-Chlor-6-fluor-l,4-dihydro-4-oxo-l-[(3-morpholino)phenyl]-l,8-naphthyridin-3- carbonsäureethylester
Figure imgf000021_0001
7-Chloro-6-fluoro-l, 4-dihydro-4-oxo-l - [(3-morpholino) phenyl] -l, 8-naphthyridine-3-carboxylic acid ethyl ester
Figure imgf000021_0001
a) 2-(2,6-Dichlor-5-fluor-nicotinoyl)-3-ethoxyacrylsäureethylestera) Ethyl 2- (2,6-dichloro-5-fluoro-nicotinoyl) -3-ethoxyacrylic acid
7 g (25 mmol) 2,6-Dichlor-5-fluor-nicotinoylessigsäureethylester werden in 110 ml Essigsäureanhydrid mit 80 ml Triethylorthoformiat 16 Smnden im 140°C-Bad unter Argon gerührt. Es wird im Hochvakuum am Rotavapor eingedampft und zur7 g (25 mmol) of ethyl 2,6-dichloro-5-fluoro-nicotinoylacetate are stirred in 110 ml of acetic anhydride with 80 ml of triethyl orthoformate in a 140 ° C bath under argon in 140 ° C. It is evaporated in a high vacuum on the Rotavapor and used for
Entfernung allen Essigsaureanhydrids mehrmals mit Toluol azeotropiert. Die Ver¬ bindung wird als Rohprodukt direkt zu IXb weiter umgesetzt.Removal of all acetic anhydride azeotroped several times with toluene. The compound is directly converted to IXb as a crude product.
b) 2-(2,6-Dichlor-5-fluor-nicoünoyl-3-[(3-moφholin)-phenylamino]-acrylsäure- ethylesterb) 2- (2,6-dichloro-5-fluoro-nicoünoyl-3 - [(3-moφholin) phenylamino] acrylic acid ethyl ester
Das unter IXa erhaltene Rohprodukt (25 mmol) wird in 90 ml Ethanol bei 0°C unter Argon mit der Suspension von 4,7 g N-(3-Aminophenyl)-moφholin (Verbin¬ dung aus Beispiel II) in 45 ml Ethanol versetzt. Dann wird bei -40°C abgesaugt, der Rückstand mit kaltem Ethanol (-40°C) gewaschen und im Hochvakuum ge¬ trocknet. Ausbeute: 7,26 g (74% d.Th.)The crude product obtained under IXa (25 mmol) in 90 ml of ethanol at 0 ° C. under argon is mixed with the suspension of 4.7 g of N- (3-aminophenyl) -moφholin (compound from Example II) in 45 ml of ethanol . It is then suctioned off at -40 ° C., the residue is washed with cold ethanol (-40 ° C.) and dried in a high vacuum. Yield: 7.26 g (74% of theory)
1,2 g (2,56 mmol) der unter IXb erhaltenen En-anilino- Verbindung werden in 30 ml 1 ,2-Dimethoxyethan mit 5 g Kaliumcarbonat (Pulver) 2 Tage bei Raumtempe¬ ratur gerührt. Man fügt 200 ml Wasser hinzu, rührt 1 Stunde, saugt ab und trocknet im Hochvakuum. Ausbeute: 0,9 g (82% d.Th.) DC-System VI: Rf = 0,53 (+)FAB-MS: m/z 432 (M+H) Beispiel X1.2 g (2.56 mmol) of the en-anilino compound obtained under IXb are stirred in 30 ml of 1, 2-dimethoxyethane with 5 g of potassium carbonate (powder) for 2 days at room temperature. 200 ml of water are added, the mixture is stirred for 1 hour, suction filtered and dried under high vacuum. Yield: 0.9 g (82% of theory) DC system VI: R f = 0.53 (+) FAB-MS: m / z 432 (M + H) Example X
7-Chlor-6-fluor-l,4-dihydro-4-oxo-l-[(3-morpholino)phenyl]-l ,8-naphthyridin-3- carbonsäure7-chloro-6-fluoro-l, 4-dihydro-4-oxo-l - [(3-morpholino) phenyl] -l, 8-naphthyridine-3-carboxylic acid
Figure imgf000022_0001
Figure imgf000022_0001
1,9 g (4,4 mmol) Ester werden mit 20 ml Säuregemisch (Essigsäure Wasser : Schwefelsäure = 12:8:1) 5 Stunden im 100°-Bad gerührt. Bei Raumtemperatur wird mit Wasser gefällt, dann abgesaugt und im Hochvakuum getrocknet Ausbeute: 1,6 g (90% d.Th.) DC-System IX: Rf = 0,39 (+)FAB-MS: m/z 404(M+H)1.9 g (4.4 mmol) of ester are stirred with 20 ml of acid mixture (acetic acid water: sulfuric acid = 12: 8: 1) in a 100 ° bath for 5 hours. It is precipitated with water at room temperature, then suction filtered and dried under high vacuum. Yield: 1.6 g (90% of theory) DC system IX: R f = 0.39 (+) FAB-MS: m / z 404 ( M + H)
Beispiel XIExample XI
7-Chlor-6-fluor-l ,4-dihydro-4-oxo-l-[(2-morpholino)phenyl]-l,8-naphthyridin-3- carbonsaureethylester7-Chloro-6-fluoro-l, 4-dihydro-4-oxo-l - [(2-morpholino) phenyl] -l, 8-naphthyridine-3-carboxylic acid ethyl ester
Figure imgf000022_0002
Die Titelverbindung wird analog Beispiel IX aus 2,6-Dichlor-5-fluor-nicotinsäure- ethylester und 2-Moφholinoanilin (Lancaster) hergestellt. DC-System X: Rf = 0,43 (+)FAB-MS: m/z = 432 (M+H)
Figure imgf000022_0002
The title compound is prepared analogously to Example IX from 2,6-dichloro-5-fluoro-nicotinic acid ethyl ester and 2-Moφholinoanilin (Lancaster). DC system X: R f = 0.43 (+) FAB-MS: m / z = 432 (M + H)
Beispiel XDExample XD
7-Chlor-6-fluor-l,4-dihydro-4-oxo-l-[(2-morpholino)phenyl]-l,8-naphthyridin-3- carbonsäure7-chloro-6-fluoro-l, 4-dihydro-4-oxo-l - [(2-morpholino) phenyl] -l, 8-naphthyridine-3-carboxylic acid
Figure imgf000023_0001
Figure imgf000023_0001
Die Titelverbindung wird analog Beispiel X durch saure Verseifung des Esters aus dem Beispiel XI hergestellt.The title compound is prepared analogously to Example X by acidic saponification of the ester from Example XI.
DC-System IX: Rf = 0,45 (+)FAB-MS: m/z = 404 (M+H)DC system IX: R f = 0.45 (+) FAB-MS: m / z = 404 (M + H)
Beispiel XH1Example XH1
7-Chlor-6-fluor-l,4-dihydro-4-oxo-l-[(4-morpholino)phenyl]-l,8-naphthyridin-3- carbonsäureethylester7-Chloro-6-fluoro-l, 4-dihydro-4-oxo-l - [(4-morpholino) phenyl] -l, 8-naphthyridine-3-carboxylic acid ethyl ester
Figure imgf000023_0002
Die Titelverbindung wird analog Beispiel IX aus 2,6-Dichlor-5-fluor-nicotinoyi- essigsäureethylester und 4-Moφholinoanilin (Janssen Chimica) hergestellt. DC-System VI: Rf = 0,55 (+)FAB-MS: m/z = 432 (M+H)
Figure imgf000023_0002
The title compound is prepared analogously to Example IX from 2,6-dichloro-5-fluoro-nicotinoyi-acetic acid ethyl ester and 4-Moφholinoanilin (Janssen Chimica). DC system VI: R f = 0.55 (+) FAB-MS: m / z = 432 (M + H)
Beispiel XIVExample XIV
7-Chlor-6-fluor-l,4-dihydro-4-oxo-l-[(4-morpholino)phenyl]-l,8-naphthyridin-3- carbonsäure7-chloro-6-fluoro-l, 4-dihydro-4-oxo-l - [(4-morpholino) phenyl] -l, 8-naphthyridine-3-carboxylic acid
Figure imgf000024_0001
Figure imgf000024_0001
Die Titelverbindurig wird analog Beispiel X durch saure Verseifung des Esters aus dem Beispiel XIII hergestellt.The title compound is prepared analogously to Example X by acidic saponification of the ester from Example XIII.
DC-System IX: Rf = 0,39 (+)FAB-MS: m/z = 404 (M+H)DC system IX: R f = 0.39 (+) FAB-MS: m / z = 404 (M + H)
Beispiel XVExample XV
7-Fluor-l,4-dihydro-4-oxo-l-[(4-morpholino)phenyl]-3-chinolincarbonsäure Hydrochlorid
Figure imgf000025_0001
a) 2-(2,4-Difluorbenzoyl)-3-[(4-moφholino)phenylamino]-acrylsäureethylester7-Fluoro-1,4-dihydro-4-oxo-l - [(4-morpholino) phenyl] -3-quinolinecarboxylic acid hydrochloride
Figure imgf000025_0001
a) Ethyl 2- (2,4-difluorobenzoyl) -3 - [(4-moφholino) phenylamino] acrylic acid
15 g (0,053 mol) 3-Ethoxy-2-(2,4-difluorbenzoyl)-acrylsäureethylester werden in 65 ml Ethanol p.a. gelöst und portionsweise mit insgesamt 9,49 g (O,053mol) 4- Moφholinoanilin (Janssen Chimica) versetzt. Nach Zugabe von 30 ml Ethanol rührt man den Ansatz 3 Stunden bei Raumtemperatur. Der Produktniederschlag wird abgesaugt, mit wenig Ethanol und dann mit n-Pentan nachgewaschen. Das Produkt wird im Vakuum über Calciumchlorid getrocknet. Ausbeute: 18,8 g (85,6% d.Th.) DC-System II: Rf = 0,6115 g (0.053 mol) of 3-ethoxy-2- (2,4-difluorobenzoyl) acrylic acid ethyl ester are dissolved in 65 ml of ethanol pa and a total of 9.49 g (0.05 mol) of 4-Moφholinoaniline (Janssen Chimica) are added in portions. After adding 30 ml of ethanol, the mixture is stirred for 3 hours at room temperature. The product precipitate is suctioned off, washed with a little ethanol and then with n-pentane. The product is dried over calcium chloride in vacuo. Yield: 18.8 g (85.6% of theory) TLC system II: R f = 0.61
b) 7-Fluor-l,4-dihydro-4-oxo-l-[(4-moφholino)phenyl]-3-chinolincarbonsäure- ethylesterb) 7-Fluoro-l, 4-dihydro-4-oxo-l - [(4-moφholino) phenyl] -3-quinolinecarboxylic acid, ethyl ester
18 g (0,043 mol) der unter a) erhaltenen Verbindung werden mit 24 g (4,02 eq, 0,172 mol) Kaliumcarbonat in 120 ml Dichlormethan und 50 ml Dimethylform- amid zwanzig Stunden bei Raumtemperatur gerührt. Man saugt ab und wascht den18 g (0.043 mol) of the compound obtained under a) are stirred for 20 hours at room temperature with 24 g (4.02 eq, 0.172 mol) of potassium carbonate in 120 ml of dichloromethane and 50 ml of dimethylformamide. You vacuum and wash it
Rückstand mit Dichlormethan und Dimethylformamid nach. Die vereinigten Fil- trate werden am Hochvakuum zur Trockene eingeengt. Der Rückstand (17,1 g) wird mit 60 ml Diethylether versetzt, gerührt und schließlich abgesaugt. Das Produkt wird mit Diethylether nachgewaschen und im Vakuum getrocknet Ausbeute: 16,9 g (98,7% d.Th.)Residue with dichloromethane and dimethylformamide. The combined filtrates are evaporated to dryness in a high vacuum. The residue (17.1 g) is mixed with 60 ml of diethyl ether, stirred and finally suction filtered. The product is washed with diethyl ether and dried in vacuo. Yield: 16.9 g (98.7% of theory)
DC-System II Rf = 0,35 HPLC-System I Rt = 6,261 min.DC system II R f = 0.35 HPLC system I Rt = 6.261 min.
16,89 g (42,6 mmol) des unter b) erhaltenen Esters werden mit 60 ml 4 N wäßrige Salzsaure und 120 ml Wasser versetzt und 20 Stunden am Ruckfluß gekocht. Man läßt auf Raumtemperatur kommen und saugt ab. Der Rückstand wird dreimal mit je 200 ml Wasser verrührt und abfiltriert. Das Produkt wird in16.89 g (42.6 mmol) of the ester obtained under b) are mixed with 60 ml of 4 N aqueous hydrochloric acid and 120 ml of water and refluxed for 20 hours cooked. The mixture is allowed to come to room temperature and suction filtered. The residue is stirred three times with 200 ml of water and filtered off. The product is in
100 ml Diethylether suspendiert, bei Raumtemperamr gerührt, abgesaugt und bei100 ml of diethyl ether suspended, stirred at room temperature, suction filtered and at
30°C im Vakuum über Kaliumhydroxid getrocknet.30 ° C in a vacuum over potassium hydroxide.
Ausbeute: 15,0 g (87,1% d.Th.)Yield: 15.0 g (87.1% of theory)
DC-System III: Rf = 0,19DC system III: R f = 0.19
HPLC-System I: Rt = 5,992 minHPLC system I: Rt = 5.992 min
(+)FAB-MS: m/z = 369 (M+H)(+) FAB-MS: m / z = 369 (M + H)
]H-NMR (DCOOD): δ = 4,12 (m, 2H); 4,38 (m, 2H); 7,08 (dd, 1H); 7,57 (m, ] H NMR (DCOOD): δ = 4.12 (m, 2H); 4.38 (m. 2H); 7.08 (dd, 1H); 7.57 (m,
1H); 8,06 (m, 2H); 8,22 (m, 2H); 8,66 (dd, 1H); 9,16 (s, 1H); [10,79 (s,1H); 8.06 (m, 2H); 8.22 (m, 2H); 8.66 (dd, 1H); 9.16 (s. 1H); [10.79 (s,
DCOOD)].DCOOD)].
Beispiel XVIExample XVI
7-Fluor-l,4-dihydro-4-oxo-l-[(3-moφholino)-phenyl]-3-chinolincarbonsäure Hvdrochlorid7-Fluoro-l, 4-dihydro-4-oxo-l - [(3-moφholino) phenyl] -3-quinoline carboxylic acid hydrochloride
Figure imgf000026_0001
Figure imgf000026_0001
Die Titelverbindung wird analog Beispiel XV aus 2-(2,4-Difluorbenzoyl)-acryl- saureethylester und 3-Moφholinoanilin (Beispiel II) hergestellt. DC-System Vπi: P^ = 0,61 HPLC-System I: Rt 6,087 min. (-)FAB-MS: m/z = 369 (M+H)The title compound is prepared analogously to Example XV from 2- (2,4-difluorobenzoyl) acrylic acid ethyl ester and 3-Moφholinoanilin (Example II). DC system Vπi: P ^ = 0.61 HPLC system I: Rt 6.087 min. (-) FAB-MS: m / z = 369 (M + H)
Beispiel XVIIExample XVII
7-Fluor-l,4-dihydro-4-oxo- l-[(2-morpholino)phenyl]-3-chinolincarbonsaure Hvdrochlorid 7-Fluoro-1,4-dihydro-4-oxo - [(2-morpholino) phenyl] -3-quinoline carboxylic acid hydrochloride
Figure imgf000027_0001
Figure imgf000027_0001
Die Titelverbindung wird analog Beispiel XV aus 2-(2,4-Difluorbenzoyl)-acryl- säureethylester und 2-Mθφholinoanilin (Lancaster) hergestellt. (+)FAB-MS: m z = 369 (M+H) The title compound is prepared analogously to Example XV from 2- (2,4-difluorobenzoyl) acrylic acid ethyl ester and 2-Mθφholinoanilin (Lancaster). (+) FAB-MS: mz = 369 (M + H)
Beispiel XNmExample XNm
6,7-Difluor-l,4-dihydro-4-oxo-l-[(4-morpholino)phenyl]-3-chinolincarbonsäure Hydrochlorid6,7-difluoro-1,4-dihydro-4-oxo-l - [(4-morpholino) phenyl] -3-quinolinecarboxylic acid hydrochloride
Figure imgf000028_0001
Figure imgf000028_0001
Die Titelverbindung wird analog Beispiel XV aus 2-(2,4,5-Trifluorbenzoyl)acryl- säureethylester und 4-Moφholinoanilin (Janssen Chimica) hergestellt. DC-System VTII: Rf = 0,55 DC-System IV: Rf = 0,67 DC-System I: Rf = 0,70 (+)FAB-MS: m/z = 387 (M+H)The title compound is prepared analogously to Example XV from 2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester and 4-Moφholinoanilin (Janssen Chimica). DC system VTII: R f = 0.55 DC system IV: R f = 0.67 DC system I: R f = 0.70 (+) FAB-MS: m / z = 387 (M + H)
Beispiel XIXExample XIX
6,7-Difluor- l ,4-dihydro-4-oxo-l-[(3-morpholino)phenyl]-3-chinolincarbonsaure Hydrochlorid6,7-difluoro-l, 4-dihydro-4-oxo-l - [(3-morpholino) phenyl] -3-quinolinecarboxylic acid hydrochloride
Figure imgf000028_0002
Die Titelverbindung wird analog Beispiel XV aus 2-(2,4,5-Trifluorbenzoyl)acryl- säureethylester und 2-Morpholinoanilin (Beispiel II) hergestellt. DC-System I: Rf = 0,68
Figure imgf000028_0002
The title compound is prepared analogously to Example XV from 2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester and 2-morpholinoaniline (Example II). DC system I: R f = 0.68
DC-System IV: Rf = 0,68 (+)FAB-MS: m/z = 387 (M+H)DC system IV: R f = 0.68 (+) FAB-MS: m / z = 387 (M + H)
Beispiel XXExample XX
6,7-Difluor-l,4-dihydro-4-oxo-l-[(2-morpholino)phenyl]-3-chinolincarbonsäure Hydrochlorid6,7-difluoro-1,4-dihydro-4-oxo-l - [(2-morpholino) phenyl] -3-quinolinecarboxylic acid hydrochloride
Figure imgf000029_0001
Figure imgf000029_0001
Die Titelverbindung wird analog Beispiel XV aus 2-(2,4,5-Trifluorbenzoyl)acryl- säureethylester und 3-Mθφholinoanilin (Lancaster) hergestellt. DC-System I: Rf = 0,71 DC-System IV: Rf = 0,73 (+)FAB-MS: m/z = 387 (M+H)The title compound is prepared analogously to Example XV from 2- (2,4,5-trifluorobenzoyl) acrylic acid ethyl ester and 3-Mθφholinoanilin (Lancaster). DC system I: R f = 0.71 DC system IV: R f = 0.73 (+) FAB-MS: m / z = 387 (M + H)
Beispiel XXIExample XXI
6,7,8-Trifluor-l,4-dihydro-4-oxo-l-[(4-morpholino)phenyl]-3-chinolincarbonsäure Hydrochlorid
Figure imgf000030_0001
6,7,8-trifluoro-l, 4-dihydro-4-oxo-l - [(4-morpholino) phenyl] -3-quinolinecarboxylic acid hydrochloride
Figure imgf000030_0001
Die Titelverbindung wird analog Beispiel XV aus 2-(2,3,4,5-Tetrafluorbenzoyl)- acrylsäureethylester und 4-Moφholinoanilin (Janssen Chimica) hergestellt.The title compound is prepared analogously to Example XV from 2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid ethyl ester and 4-Moφholinoanilin (Janssen Chimica).
DC-System I: Rf = 0,62DC system I: R f = 0.62
(-)FAB-MS: m z = 404/405 (M+H)(-) FAB-MS: m z = 404/405 (M + H)
1H-NMR (CF3COOD): δ = 4,12 (s, 4H); 4,51 (s, 4H); 8,02 - 8,23 (m, 4H); 8,39 -1H NMR (CF 3 COOD): δ = 4.12 (s, 4H); 4.51 (s, 4H); 8.02 - 8.23 (m, 4H); 8.39 -
8,53 (m, 1H); 9,31 (s, 1H) [11,7 s, CF3COOD]8.53 (m, 1H); 9.31 (s, 1H) [11.7 s, CF 3 COOD]
Beispiel XXIIExample XXII
6,7,8-Trifluor- 1 ,4-dihydro-4-oxo- 1 -[(3-moφholino)phenyl]-3-chinolin-carbonsäure Hvdrochlorid6,7,8-trifluoro-1,4-dihydro-4-oxo-1 - [(3-moφholino) phenyl] -3-quinoline-carboxylic acid hydrochloride
Figure imgf000030_0002
Figure imgf000030_0002
Die Titelverbindung wird analog Beispiel XV aus 2-(2,3,4,5-Tetrafluorbenzoyl)- acrylsäureethylester und 3-Moφholinoanilin (Beispiel II) hergestellt. (-)FAB-MS: m/z = 401/405 (M+H)The title compound is prepared analogously to Example XV from 2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid ethyl ester and 3-Moφholinoanilin (Example II). (-) FAB-MS: m / z = 401/405 (M + H)
Beispiel XXIII 6,7,8-Trifluor-l,4-dihydro-4-oxo-l-[(2-moφholino)phenyl]-3-chinolincarbonsäure HvdrochloridExample XXIII 6,7,8-trifluoro-l, 4-dihydro-4-oxo-l - [(2-moφholino) phenyl] -3-quinolinecarboxylic acid hydrochloride
Figure imgf000031_0001
Figure imgf000031_0001
Die Titelverbindung wird analog Beispiel XV aus 2-(2,3,4,5-Tetrafluorbenzoyl)- acrylsäureethylester und 2-Moφholinoanilin (Lancaster) hergestellt.The title compound is prepared analogously to Example XV from 2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid ethyl ester and 2-Moφholinoanilin (Lancaster).
(+)FAB-MS: m/z = 404/405 (M+H)(+) FAB-MS: m / z = 404/405 (M + H)
Beispiel XXIVExample XXIV
8-Chlor-6,7-difluor-l,4-dihydro-4-oxo-l-[(4-moφholino)phenyl]-3-chinolincarbon- säure Hydrochlorid8-chloro-6,7-difluoro-l, 4-dihydro-4-oxo-l - [(4-moφholino) phenyl] -3-quinoline carbonic acid hydrochloride
Figure imgf000031_0002
Figure imgf000031_0002
Die Titelverbindung wird analog Beispiel XV aus 2-(3-Chlor-2,4,5-trifluorbenzoyl)- acrylsäureethylester und 4-Morpholinoanilin (Janssen Chimica) hergestellt. DC-System I: Rf = 0,68 DC-System IV: Rf = 0,66 HPLC-System I: Rt = 6,771 min. (+)FAB-MS: m/z = 421 (M+H)The title compound is prepared analogously to Example XV from 2- (3-chloro-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester and 4-morpholinoaniline (Janssen Chimica). DC system I: R f = 0.68 DC system IV: R f = 0.66 HPLC system I: Rt = 6.771 min. (+) FAB-MS: m / z = 421 (M + H)
Beispiel XXV 8-Chlor-6,7-difluor-l,4-dihydro-4-oxo-l-[(3-moφholino)phenyl]-3-chinolincarbon- saure HydrochloridExample XXV 8-chloro-6,7-difluoro-l, 4-dihydro-4-oxo-l - [(3-moφholino) phenyl] -3-quinolinecarboxylic acid hydrochloride
Figure imgf000032_0001
Figure imgf000032_0001
Die Titelverbindung wird analog Beispiel XV aus 2-(3-Chlor-2,4,5-trifluorben- zoyl)-acrylsäureethylester und 3-Moφholinoanilin (Beispiel II) hergestelltThe title compound is prepared analogously to Example XV from 2- (3-chloro-2,4,5-trifluorobenzoyl) acrylic acid ethyl ester and 3-Moφholinoanilin (Example II)
DC-System I: Rf = 0,69 DC-System IV: Rf = 0,63 (+)FAB-MS: m/z = 421 (M+H)DC system I: R f = 0.69 DC system IV: R f = 0.63 (+) FAB-MS: m / z = 421 (M + H)
Beispiel XXVIExample XXVI
8-Chlor-6,7-difluor- 1 ,4-dihydro-4-oxo-l -[(2-moφholino)phenyl]-3-chinolincarbon- saure Hydrochlorid8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-l - [(2-moφholino) phenyl] -3-quinoline carboxylic acid hydrochloride
Figure imgf000032_0002
Figure imgf000032_0002
Die Titelverbindung wird analog Beispiel XV aus 2-(3-Chlor-2,4,5-tnfluorben- zoyl)-acrylsäureethylester und 2-Morpholinoanilin (Lancaster) hergestellt DC-System I Rf = 0,74The title compound is prepared analogously to Example XV from 2- (3-chloro-2,4,5-tnfluorobenzoyl) acrylic acid ethyl ester and 2-morpholinoaniline (Lancaster) DC system IR f = 0.74
DC-System IV Rf = 0,69 (+)FAB-MS m/z = 421 (M+H) HerstellungsbeispieleDC system IV R f = 0.69 (+) FAB-MS m / z = 421 (M + H) Manufacturing examples
Beispiel 1example 1
l,4-Dihydro-4-oxo-7-(4-phenylpiperazin-l-yl)-l-(2-morpholino)phenyl]-1.8-naph- thyridin-3-carbonsäure1,4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1- (2-morpholino) phenyl] -1.8-naphthyridine-3-carboxylic acid
Figure imgf000033_0001
Figure imgf000033_0001
193 mg (0,5 mmol) der Verbindung aus Beispiel IV werden mit 162 mg (1 mmol) N-Phenylpiperazin und 0,26 ml (1,5 mmol) N,N-Diisopropylethylamin in 2 ml Dimethylsulfoxid 1,5 Stunden bei 100°C gerührt. Man läßt auf Raumtemperatur kommen und saugt ab. Der Niederschlag wird zuerst mit Dimethylsulfoxid, dann mit Wasser gewaschen und im Vakuum getrocknet. Ausbeute: 194,6 mg (76% d.Th.) DC-System IX: Rf = 0,62 (+)FAB-MS: m/z = 512 (M+H)193 mg (0.5 mmol) of the compound from Example IV are mixed with 162 mg (1 mmol) of N-phenylpiperazine and 0.26 ml (1.5 mmol) of N, N-diisopropylethylamine in 2 ml of dimethyl sulfoxide at 100 for 1.5 hours ° C stirred. The mixture is allowed to come to room temperature and suction filtered. The precipitate is washed first with dimethyl sulfoxide, then with water and dried in vacuo. Yield: 194.6 mg (76% of theory) DC system IX: R f = 0.62 (+) FAB-MS: m / z = 512 (M + H)
Beispiel 2Example 2
6-Fluor- 1 ,4-dihydro-4-oxo-7-[4-(2-chlorphenyl)piperazin- 1 -yl]- 1 -(3 -moφholino)- pheny 1 ] - 1 , 8-naphthyridin-3 -carbonsäure6-fluoro-1,4-dihydro-4-oxo-7- [4- (2-chlorophenyl) piperazin-1-yl] -1 - (3-moopholino) -pheny 1] - 1,8-naphthyridine-3 -carboxylic acid
Figure imgf000033_0002
200 mg (496 μmol) der Verbindung aus Beispiel X werden mit 194 mg l-(2- Chlorphenyl)piperazin (992 μmol) und 259 μl (1,5 mmol) N,N-Diisopropylethyl- amin in 3 ml Dimethylsulfoxid 3 Smnden bei 100°C gerührt. Man läßt auf Raum¬ temperamr kommen und tropft unter Rühren 12 ml Wasser hinzu. Der Nieder¬ schlag wird abgesaugt, mit Wasser und Diethylether gewaschen und im Vakuum getrocknet.
Figure imgf000033_0002
200 mg (496 μmol) of the compound from Example X are combined with 194 mg of 1- (2-chlorophenyl) piperazine (992 μmol) and 259 μl (1.5 mmol) of N, N-diisopropylethylamine in 3 ml of dimethyl sulfoxide 100 ° C stirred. The mixture is allowed to come to room temperature and 12 ml of water are added dropwise with stirring. The precipitate is filtered off, washed with water and diethyl ether and dried in vacuo.
Ausbeute: 199 mg (71% d.Th.) DC-System IX: Rf = 0,63 (+)FAB-MS: m/z = 564 (M+H)Yield: 199 mg (71% of theory) DC system IX: R f = 0.63 (+) FAB-MS: m / z = 564 (M + H)
Beispiel 3Example 3
1.4-Dihydro-4-oxo-7-[4-(2-methoxyphenyl)piperazin- 1 -y 1 J - 1 -[(4-morpholino)phe- nyl]-3-chinolin-carbonsäure1,4-Dihydro-4-oxo-7- [4- (2-methoxyphenyl) piperazin-1-y 1 J - 1 - [(4-morpholino) phenyl] -3-quinoline-carboxylic acid
Figure imgf000034_0001
Figure imgf000034_0001
808 mg (2 mmol) der Verbindung aus Beispiel XV werden mit 461 mg (2,4 mmol) l-(2-Methoxy)phenyl-piperazin und 3,4 ml (20 mmol) N,N-Diisopropyl- ethylamin in 5 ml Dimethylsulfoxid 2,5 Smnden bei 120°C gerührt. Man läßt auf Raumtemperamr kommen und verdünnt den Ansatz mit 20 ml Wasser. Der Niederschlag wird abgesaugt, zuerst mit viel Wasser, dann mit Diethylether nach¬ gewaschen und schließlich im Vakuum bei 30°C getrocknet. Ausbeute: 1,0 g (92,6% d.Th.)808 mg (2 mmol) of the compound from Example XV are mixed with 461 mg (2.4 mmol) of l- (2-methoxy) phenylpiperazine and 3.4 ml (20 mmol) of N, N-diisopropylethylamine in 5 ml Dimethyl sulfoxide 2.5 mouths stirred at 120 ° C. The mixture is allowed to come to room temperature and the batch is diluted with 20 ml of water. The precipitate is filtered off, washed first with plenty of water, then with diethyl ether and finally dried in vacuo at 30 ° C. Yield: 1.0 g (92.6% of theory)
DC-System III: Rf = 0,26 HPLC-System I: Rt = 6,957 min ι-)FAB-MS: m/z = 541 (M+H)DC system III: R f = 0.26 HPLC system I: Rt = 6.957 min ι-) FAB-MS: m / z = 541 (M + H)
Beispiel 4 6-Fluor-7-[4-(4-fluorphenyl)piperazin-l-yl]- l,4-dihydro-4-oxo-l-[3-(morpholino)- phenyl]-3-chinolincarbonsäureExample 4 6-Fluoro-7- [4- (4-fluorophenyl) piperazin-l-yl] -1,4-dihydro-4-oxo-l- [3- (morpholino) phenyl] -3-quinolinecarboxylic acid
Figure imgf000035_0001
Figure imgf000035_0001
1,1 g (2,6 mmol) der Verbindung aus Beispiel XIX werden mit 790 mg (4,2 mol) l-(4-Fluoφhenyl)-piperazin und 5 ml (28,5 mmol) N,N-Diisopropylethylamin in 10 ml Acetonitril und 5 ml Dimethylformamid 8 Smnden bei 100°C gerührt. Man läßt auf Raumtemperamr kommen und saugt ab. Der Niederschlag wird mit 40 ml Diethylether / Ethanol 3:1 verrührt und abfiltriert. Man wäscht mit Diethylether nach und trocknet den Rückstand bei 30°C im Vakuum. Ausbeute: 1,37 g (89,3% d.Th.) DC-System II: Rf = 0,75 (+)FAB-MS: m/z = 547 (M+H) 1.1 g (2.6 mmol) of the compound from Example XIX are mixed with 790 mg (4.2 mol) of l- (4-fluorophenyl) piperazine and 5 ml (28.5 mmol) of N, N-diisopropylethylamine in 10 ml of acetonitrile and 5 ml of dimethylformamide 8 mouths were stirred at 100 ° C. It is allowed to come to room temperature and is suctioned off. The precipitate is stirred with 40 ml of diethyl ether / ethanol 3: 1 and filtered off. It is washed with diethyl ether and the residue is dried at 30 ° C. in vacuo. Yield: 1.37 g (89.3% of theory) DC system II: R f = 0.75 (+) FAB-MS: m / z = 547 (M + H)
Beispiel 5Example 5
6,8-Difluor-l,4-dihydro-4-oxo-7-[4-(3-methylphenyl)piperazin-l-yl]-l-[4-(moφho- lino)phenyl]-3-chinolin-carbonsäure6,8-difluoro-l, 4-dihydro-4-oxo-7- [4- (3-methylphenyl) piperazin-l-yl] -l- [4- (moφholino) phenyl] -3-quinoline- carboxylic acid
Figure imgf000036_0001
620 mg (1,4 mmol) der Verbindung aus Beispiel XXI werden mit 296 mg (1,68 mmol) l-(3-Methylphenyl)piperazin und 2,4 ml N,N-Diisopropylethylamin in 5 ml Dimethylsulfoxid 3 Smnden bei 120°C gerührt. Man läßt auf Raumtemperatur kommen und versetzt den Ansatz mit 5 ml Diethylether und 5 ml Wasser. Nach 10 minütigem Verrühren der Mischung wird der gebildete Niederschlag abgesaugt, nacheinander gründlich mit Wasser und Diethylether nachgewaschen und schlie߬ lich bei 30°C im Hochvakuum getrocknet. Ausbeute: 510 mg (65% d Th.) DC-System I: Rf = 0,66 HPLC-System I: Rt = 8,217 min. (+)FAB-MS: m/z = 561 (M+H)
Figure imgf000036_0001
620 mg (1.4 mmol) of the compound from Example XXI are mixed with 296 mg (1.68 mmol) of l- (3-methylphenyl) piperazine and 2.4 ml of N, N-diisopropylethylamine in 5 ml of dimethyl sulfoxide at 120 ° C stirred. The mixture is allowed to come to room temperature and 5 ml of diethyl ether and 5 ml of water are added to the mixture. After the mixture has been stirred for 10 minutes, the precipitate formed is filtered off with suction, washed successively thoroughly with water and diethyl ether and finally dried at 30 ° C. in a high vacuum. Yield: 510 mg (65% of theory) DC system I: R f = 0.66 HPLC system I: Rt = 8.217 min. (+) FAB-MS: m / z = 561 (M + H)
Beispiel 6Example 6
8-Chlor-6-fluor- 1 ,4-dihydro-4-oxo-7-[4-(4-methoxyphenyl)piperazin- 1 -yl]- 1 -[2- (morpholino)phenyI]-3-chinolin-carbonsaure
Figure imgf000037_0001
8-chloro-6-fluoro-1,4-dihydro-4-oxo-7- [4- (4-methoxyphenyl) piperazin-1-yl] -1 - [2- (morpholino) phenyl] -3-quinoline- carboxylic acid
Figure imgf000037_0001
480 mg (0,95 mmol) der Verbindung aus Beispiel XXV werden mit 329 mg (1,71 mmol) 1 -(4-Methoxyphenyl)piperazin und 2 ml N,N-Diisopropylemylamm in 2 ml Acetonitril und 1 ml Dimethylformamid 9 Smnden bei 100°C gerührt. .Alle flüch¬ tigen Komponenten werden im Hochvakuum entfernt und der Rückstand mit 20 ml Diethylether / Ethanol 3:1 verrührt. Man saugt ab, wäscht den Feststoff mit Was¬ ser und Diethylether nach und trocknet bei 30°C im Hochvakuum. Ausbeute: 504 mg (89,5% d.Th.) DC-System IV: Rf = 0,78 (+)FAB-MS: m/z = 593 (M+H); m/z = 699 (M+Ag)480 mg (0.95 mmol) of the compound from Example XXV are mixed with 329 mg (1.71 mmol) of 1 - (4-methoxyphenyl) piperazine and 2 ml of N, N-diisopropylemylamm in 2 ml of acetonitrile and 1 ml of dimethylformamide 100 ° C stirred. .All volatile components are removed in a high vacuum and the residue is stirred with 20 ml of diethyl ether / ethanol 3: 1. It is suctioned off, the solid is washed with water and diethyl ether and dried at 30 ° C. in a high vacuum. Yield: 504 mg (89.5% of theory) DC system IV: Rf = 0.78 (+) FAB-MS: m / z = 593 (M + H); m / z = 699 (M + Ag)
Die in den nachstehenden Tabellen la und lb aufgeführten Beispiele werden analog Beispiel 1 durch Umsetzen der Verbindung aus Beispiel IV und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden: The examples listed in Tables 1a and 1b below are prepared analogously to Example 1 by reacting the compound from Example IV and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl):
Tabelle la:Table la:
Figure imgf000038_0001
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0002
Figure imgf000039_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000042_0001
Figure imgf000042_0001
O O
Tabelle 1b:Table 1b:
Figure imgf000043_0001
Figure imgf000043_0001
II.
.c-.c-
Figure imgf000043_0002
Figure imgf000043_0002
Die in den nachstehenden Tabellen 2a und 2b aufgeführten Beispiele werden analog Beispiel 1 durch Umsetzen der Verbindung aus Beispiel \T und den entspechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 2a and 2b below are prepared analogously to Example 1 by reacting the compound from Example \ T and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 2aTable 2a
Figure imgf000045_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000048_0001
Figure imgf000049_0002
Figure imgf000049_0002
Figure imgf000049_0001
Figure imgf000049_0001
Tabelle 2b:Table 2b:
Figure imgf000050_0001
Figure imgf000050_0001
Figure imgf000050_0002
Figure imgf000050_0002
Die in den nachstehenden Tabellen 3a und 3b aufgeführten Beispiele werden analog Beispiel 1 durch Umsetzen von 7-Chlor-l ,4-dihydro-4-oxo-l -[(4- moφholino)phenyl]-l,8-naphthyridin-3-carbonsäure Hydrochlorid (Beispiel VTH) und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 3a and 3b below are prepared analogously to Example 1 by reacting 7-chloro-1,4-dihydro-4-oxo-1 - [(4-moopholino) phenyl] -1, 8-naphthyridine-3- carboxylic acid hydrochloride (example VTH) and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 3aTable 3a
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000054_0001
Figure imgf000054_0002
Figure imgf000055_0002
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000056_0001
Tabelle 3b:Table 3b:
Figure imgf000057_0001
Figure imgf000057_0001
Ui UiUi Ui
Figure imgf000057_0002
Figure imgf000057_0002
Die in den nachstehenden Tabellen 4a und 4b aufgeführten Beispiele werden analog Beispiel 2 durch Umsetzen von der Verbindung aus Beispiel XII und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) svnthetisiert werden. The examples listed in Tables 4a and 4b below are prepared analogously to Example 2 by reacting the compound from Example XII and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized using known methods (Houben-Weyl).
Tabelle 4a:Table 4a:
Figure imgf000059_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000061_0001
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000062_0001
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000063_0001
Figure imgf000063_0004
Figure imgf000063_0004
II.
Figure imgf000063_0002
Figure imgf000063_0002
Figure imgf000063_0003
Figure imgf000063_0003
Tabelle 4b:Table 4b:
Figure imgf000064_0001
Figure imgf000064_0001
Figure imgf000064_0003
Figure imgf000064_0002
Figure imgf000064_0003
Figure imgf000064_0002
Die in den nachstehenden Tabellen 5a und 5b aufgeführten Beispiele werden analog Beispiel 2 durch Umsetzen von der Verbindung aus Beispiel X und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 5a and 5b below are prepared analogously to Example 2 by reacting the compound from Example X and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 5a:Table 5a:
Figure imgf000066_0001
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000066_0002
Figure imgf000067_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000068_0001
Figure imgf000069_0002
Figure imgf000069_0001
Figure imgf000069_0002
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000070_0001
oo oo
Tabelle 5b:Table 5b:
Figure imgf000071_0001
Figure imgf000071_0001
soso
Figure imgf000071_0002
Figure imgf000071_0002
Die in den nachstehenden Tabellen 6a und 6b aufgeführten Beispiele werden analog Beispiel 2 durch Umsetzen von der Verbindung aus Beispiel XIV und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 6a and 6b below are prepared analogously to Example 2 by reacting the compound from Example XIV and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 6a:Table 6a:
Figure imgf000073_0001
Figure imgf000073_0001
II.
Figure imgf000073_0003
Figure imgf000073_0002
Figure imgf000073_0003
Figure imgf000073_0002
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000074_0001
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000076_0001
UlUl
Figure imgf000077_0001
Figure imgf000077_0002
Figure imgf000077_0001
Figure imgf000077_0002
Tabelle 6b:Table 6b:
Figure imgf000078_0001
Figure imgf000078_0001
Figure imgf000078_0002
Figure imgf000078_0002
Die in den nachstehenden Tabellen 7a und 7b aufgeführten Beispiele werden analog Beispiel 3 durch Umsetzen von der Verbindung aus Beispiel XV und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 7a and 7b below are prepared analogously to Example 3 by reacting the compound from Example XV and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 7a:Table 7a:
Figure imgf000080_0001
Figure imgf000080_0001
oooo
Figure imgf000080_0002
Figure imgf000080_0003
Figure imgf000080_0004
Figure imgf000080_0002
Figure imgf000080_0003
Figure imgf000080_0004
Figure imgf000081_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000083_0001
I oo I oo
Tabelle 7b:Table 7b:
Figure imgf000084_0001
Figure imgf000084_0001
o to t
Figure imgf000084_0003
Figure imgf000084_0003
Figure imgf000084_0002
Figure imgf000084_0002
Figure imgf000085_0001
Figure imgf000085_0001
Figure imgf000085_0003
Figure imgf000085_0003
0000
Figure imgf000085_0002
Figure imgf000085_0002
Die in den nachstehenden Tabellen 8a und 8b aufgeführten Beispiele werden analog Beispiel 4 durch Umsetzen von der Verbindung aus Beispiel XX und den entsprechenden Piperazinderivaten hergestellt Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 8a and 8b below are prepared analogously to Example 4 by reacting the compound from Example XX and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl) .
Tabelle 8a:Table 8a:
Figure imgf000087_0001
Figure imgf000087_0001
co mco m
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000087_0002
Figure imgf000087_0003
Figure imgf000088_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000089_0001
oo oo
Tabelle 8b:Table 8b:
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000091_0001
Die in den nachstehenden Tabellen 9a und 9b aufgeführten Beispiele werden analog Beispiel 4 durch Umsetzen von der Verbindung aus Beispiel XTX und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 9a and 9b below are prepared analogously to Example 4 by reacting the compound from Example XTX and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 9a:Table 9a:
Figure imgf000093_0001
Figure imgf000093_0001
II.
SS
Figure imgf000093_0002
Figure imgf000093_0002
Figure imgf000094_0001
Figure imgf000094_0001
Figure imgf000095_0001
so
Figure imgf000095_0001
so
Figure imgf000095_0002
Figure imgf000095_0002
Tabelle 9b:Table 9b:
Figure imgf000096_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000097_0001
Figure imgf000097_0003
Figure imgf000097_0003
Figure imgf000097_0002
Figure imgf000097_0002
Die in den nachstehenden Tabellen 10a und 10b aufgeführten Beispiele werden analog Beispiel 4 durch Umsetzen von der Verbindung aus Beispiel XΛTII und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 10a and 10b below are prepared analogously to Example 4 by reacting the compound from Example XΛTII and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 10a:Table 10a:
Figure imgf000099_0001
Figure imgf000099_0001
soso
Figure imgf000099_0003
Figure imgf000099_0003
Figure imgf000099_0002
Figure imgf000099_0002
Figure imgf000100_0002
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000102_0001
Figure imgf000102_0002
Figure imgf000103_0001
Figure imgf000103_0001
Tabelle 10b:Table 10b:
Figure imgf000104_0001
Figure imgf000104_0001
oO
Figure imgf000104_0002
Figure imgf000104_0003
Figure imgf000104_0002
Figure imgf000104_0003
Die in den nachstehenden Tabellen 11a und 1 1b aufgeführten Beispiele werden analog Beispiel 5 durch Umsetzen von der Verbindung aus Beispiel XXI und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 11a and 11b below are prepared analogously to Example 5 by reacting the compound from Example XXI and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 11a:Table 11a:
Figure imgf000106_0001
Figure imgf000106_0001
Figure imgf000106_0002
Figure imgf000106_0002
Figure imgf000107_0001
Figure imgf000107_0001
Figure imgf000107_0002
Figure imgf000107_0002
Figure imgf000108_0002
Figure imgf000108_0002
Figure imgf000108_0001
Figure imgf000108_0001
Tabelle 11b:Table 11b:
Figure imgf000109_0001
Figure imgf000109_0001
Figure imgf000109_0003
Figure imgf000109_0003
Figure imgf000109_0002
Figure imgf000109_0002
Die in den nachstehenden Tabellen 12a und 12b aufgeführten Beispiele werden analog Beispiel 6 durch Umsetzen von der Verbindung aus Beispiel XXVI und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 12a and 12b below are prepared analogously to Example 6 by reacting the compound from Example XXVI and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 12a:Table 12a:
Figure imgf000111_0001
Figure imgf000111_0001
Figure imgf000111_0002
Figure imgf000111_0002
Figure imgf000111_0003
Figure imgf000111_0003
Figure imgf000112_0001
Figure imgf000112_0002
Figure imgf000112_0001
Figure imgf000112_0002
Figure imgf000113_0001
Figure imgf000113_0001
Tabelle 12b:Table 12b:
Figure imgf000114_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000115_0001
II.
Figure imgf000115_0002
Figure imgf000115_0002
Die in den nachstehenden Tabellen 13a und 13b aufgeführten Beispiele werden analog Beispiel 6 durch Umsetzen von der Verbindung aus Beispiel XXV und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 13a and 13b below are prepared analogously to Example 6 by reacting the compound from Example XXV and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 13a:Table 13a:
Figure imgf000117_0001
Figure imgf000117_0001
Figure imgf000117_0002
Figure imgf000117_0003
Figure imgf000117_0002
Figure imgf000117_0003
Figure imgf000118_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000119_0001
Figure imgf000119_0002
Figure imgf000119_0002
Figure imgf000120_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000121_0001
so I so I
Tabelle 13b:Table 13b:
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0001
Figure imgf000122_0002
Die in den nachstehenden Tabellen 14a und 14b aufgeführten Beispiele werden analog Beispiel 6 durch Umsetzen von der Verbindung aus Beispiel XXIV und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 14a and 14b below are prepared analogously to Example 6 by reacting the compound from Example XXIV and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 14a:Table 14a:
Figure imgf000124_0001
Figure imgf000124_0001
Figure imgf000124_0002
Figure imgf000124_0002
Figure imgf000125_0001
Figure imgf000125_0001
Figure imgf000126_0002
Figure imgf000126_0001
Figure imgf000126_0002
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000127_0001
Figure imgf000127_0002
Figure imgf000127_0002
Tabelle 14b:Table 14b:
Figure imgf000128_0001
Figure imgf000128_0003
Figure imgf000128_0002
Figure imgf000128_0001
Figure imgf000128_0003
Figure imgf000128_0002
Die in den nachstehenden Tabellen 15a und 15b aufgeführten Beispiele werden analog Beispiel 4 durch Umsetzen der Verbindung aus dem Beispiel XΛT und den entsprechenden Piperazinderivaten hergestellt. Letztere sind kommerziell erhältlich (Aldrich, Janssen, Emka) oder können nach bekannten Methoden (Houben-Weyl) synthetisiert werden. The examples listed in Tables 15a and 15b below are prepared analogously to Example 4 by reacting the compound from Example XΛT and the corresponding piperazine derivatives. The latter are commercially available (Aldrich, Janssen, Emka) or can be synthesized by known methods (Houben-Weyl).
Tabelle 15a:Table 15a:
Figure imgf000130_0001
Figure imgf000130_0001
00
Figure imgf000130_0002
Figure imgf000130_0002
Figure imgf000131_0001
Figure imgf000131_0001
Figure imgf000132_0002
Figure imgf000132_0001
Figure imgf000132_0002
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000133_0001
Figure imgf000133_0003
Figure imgf000133_0003
Figure imgf000133_0002
Figure imgf000133_0002
Tabelle 15b:Table 15b:
Figure imgf000134_0001
Figure imgf000134_0001
Figure imgf000134_0002
Figure imgf000134_0002
10
Figure imgf000135_0001
wäscht mit Diethylether nach und trocknet im Hochvakuum über Kaliumhydroxid. Ausbeute: 9 mg (97% d.Th.) (+)FAB-MS: m/z = 558 (M+H) 10
Figure imgf000135_0001
rinses with diethyl ether and dries over potassium hydroxide in a high vacuum. Yield: 9 mg (97% of theory) (+) FAB-MS: m / z = 558 (M + H)
Beispiel 262Example 262
in]- 1 -[(4-morpho- l onatin] - 1 - [(4-morphol onate
Figure imgf000136_0003
Figure imgf000136_0003
lphenyl)-3- ure (Beispie olaren Losu
Figure imgf000136_0002
pension wird zum n Bestandteile amlphenyl) -3- ure (example olaren Losu
Figure imgf000136_0002
pension becomes n components on
10 nd viermal mit lether suspendiert, getrocknet
Figure imgf000136_0001
Figure imgf000136_0004
Suspended 10 times four times with ether, dried
Figure imgf000136_0001
Figure imgf000136_0004
Tabelle 16Table 16
Figure imgf000137_0001
Figure imgf000137_0001
Figure imgf000137_0002
Figure imgf000137_0002
Figure imgf000137_0003
Figure imgf000137_0003
Figure imgf000138_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000139_0001
Tabelle 17:Table 17:
Figure imgf000140_0001
Figure imgf000140_0001
Figure imgf000140_0003
Figure imgf000140_0003
Figure imgf000140_0002
Figure imgf000140_0002
) SD) SD
Figure imgf000141_0001
Figure imgf000141_0001
Figure imgf000142_0003
Figure imgf000142_0003
4-. o4-. O
Figure imgf000142_0001
Figure imgf000142_0001
Figure imgf000142_0002
Figure imgf000142_0002
Tabelle 18:Table 18:
Figure imgf000143_0001
Figure imgf000143_0001
Figure imgf000143_0003
Figure imgf000143_0003
Figure imgf000143_0002
Figure imgf000143_0002
Figure imgf000144_0001
Figure imgf000144_0001
(-0(-0
Figure imgf000145_0002
Figure imgf000145_0002
Figure imgf000145_0001
Figure imgf000145_0001
Tabelle 19a:Table 19a:
Figure imgf000146_0001
Figure imgf000146_0001
4-> 4-.4-> 4-.
Figure imgf000146_0002
Figure imgf000146_0002
Figure imgf000147_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000149_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000150_0001
4-. 00 4-. 00
Tabelle 19b:Table 19b:
Figure imgf000151_0002
Figure imgf000151_0001
Figure imgf000151_0003
Figure imgf000151_0002
Figure imgf000151_0001
Figure imgf000151_0003
Tabelle 20Table 20
Figure imgf000152_0001
Figure imgf000152_0001
Figure imgf000152_0002
Figure imgf000152_0002
Figure imgf000153_0001
Figure imgf000153_0001
11
UlUl
I I
Tabelle 21Table 21
Figure imgf000154_0001
Figure imgf000154_0001
Figure imgf000154_0002
Figure imgf000154_0002
Figure imgf000155_0002
Figure imgf000155_0001
Figure imgf000155_0002
Figure imgf000155_0001
Tabelle 22a:Table 22a:
Figure imgf000156_0001
Figure imgf000156_0001
UU
4-4-
Figure imgf000156_0002
Figure imgf000156_0002
Figure imgf000157_0001
Figure imgf000157_0001
Figure imgf000157_0002
Figure imgf000157_0002
Figure imgf000158_0001
Figure imgf000158_0002
Figure imgf000158_0003
Figure imgf000158_0001
Figure imgf000158_0002
Figure imgf000158_0003
Figure imgf000159_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000160_0001
Tabelle 22b:Table 22b:
Figure imgf000161_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000163_0002
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000163_0002
Figure imgf000163_0003
Figure imgf000163_0003
Tabelle 23b:Table 23b:
Figure imgf000164_0001
Figure imgf000164_0001
as.as.
Figure imgf000164_0002
Figure imgf000164_0002
Tabelle 24:Table 24:
Figure imgf000165_0001
Figure imgf000165_0001
σsσs
Figure imgf000165_0002
Figure imgf000165_0002
Figure imgf000166_0001
Figure imgf000166_0001
4k 4k
Tabelle 25a:Table 25a:
Figure imgf000167_0001
Figure imgf000167_0001
UiUi
Figure imgf000167_0002
Figure imgf000167_0003
Figure imgf000167_0002
Figure imgf000167_0003
Figure imgf000168_0001
Figure imgf000168_0001
σsσs
Figure imgf000168_0002
Figure imgf000168_0002
Figure imgf000169_0003
Figure imgf000169_0003
Figure imgf000169_0001
Figure imgf000169_0001
Figure imgf000169_0002
Figure imgf000169_0002
Tabelle 25b:Table 25b:
Figure imgf000170_0001
Figure imgf000170_0002
Figure imgf000170_0001
Figure imgf000170_0002
Figure imgf000171_0003
Figure imgf000171_0003
cn socn so
Figure imgf000171_0001
Figure imgf000171_0001
Figure imgf000171_0002
Figure imgf000171_0002
Tabelle 26a:Table 26a:
Figure imgf000172_0001
Figure imgf000172_0001
oO
Figure imgf000172_0003
Figure imgf000172_0002
Figure imgf000172_0003
Figure imgf000172_0002
Figure imgf000173_0002
Figure imgf000173_0002
Figure imgf000173_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000174_0001
Tabelle 26b:Table 26b:
Figure imgf000175_0002
Figure imgf000175_0002
Figure imgf000175_0001
Figure imgf000175_0001
Tabelle 27aTable 27a
Figure imgf000176_0001
Figure imgf000176_0001
Figure imgf000176_0002
Figure imgf000176_0002
Figure imgf000177_0002
Figure imgf000177_0002
UU
Figure imgf000177_0001
Figure imgf000177_0001
Tabelle 27bTable 27b
Figure imgf000178_0001
Figure imgf000178_0001
-J-J
OSOS
Figure imgf000178_0003
Figure imgf000178_0003
Figure imgf000178_0002
Figure imgf000178_0002

Claims

PatentansprücheClaims
Heterocyclyl-1 -phenyl substimierte Chinoloncarbonsäuren der allgemeinen Formel (I),Heterocyclyl-1-phenyl-substituted quinolonecarboxylic acids of the general formula (I),
Figure imgf000179_0001
Figure imgf000179_0001
in welcherin which
A für Wasserstoff oder Methyl steht,A represents hydrogen or methyl,
X für ein Stickstoffatom oder für eine Gruppe der Formel -CH, C-F oder C-Cl steht,X represents a nitrogen atom or a group of the formula -CH, C-F or C-Cl,
für ein Sauerstoff- oder Schwefelatom oder für die -CH,-Gruppe steht,stands for an oxygen or sulfur atom or for the -CH, group,
R für Phenyl, Pyridyl, Pyrimidyl oder Pyrazinyl steht, die gegebenen¬ falls bis zu 3-fach gleich oder verschieden durch Nitro, Trifluor- methyl, Halogen, Cyano, Hydroxy oder durch geradkettiges oder verzweigtes Alkyl, Acyl, Alkoxy oder Alkylthio mit jeweils bis zu 8 Kohlenstoffatomen substituiert sind.R represents phenyl, pyridyl, pyrimidyl or pyrazinyl, optionally up to 3 times the same or different by nitro, trifluoromethyl, halogen, cyano, hydroxyl or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each with up to are substituted to 8 carbon atoms.
R^ für Wasserstoff oder Fluor stehtR ^ represents hydrogen or fluorine
und deren Hydrate und Salze, gegebenenfalls in einer isomeren Form.and their hydrates and salts, optionally in an isomeric form.
Verbindungen der allgemeinen Formel (I) gemäß Anspruch 1,Compounds of the general formula (I) according to Claim 1,
in welcherin which
A für Wasserstoff oder Methyl steht, X für ein Stickstoffatom oder für eine Gruppe der Formel -CH, C-F oder C-Cl steht,A represents hydrogen or methyl, X represents a nitrogen atom or a group of the formula -CH, CF or C-Cl,
T für ein Sauerstoff atom steht,T stands for an oxygen atom,
R1 für Phenyl, Pyridyl, Pyrimidyl oder Pyrazinyl steht, die gegebenen- falls bis zu 3-fach gleich oder verschieden durch Nitro. Trifluor- methyl, Fluor, Chlor, Brom, Cyano, Hydroxy oder durch gerad¬ kettiges oder verzweigtes Alkyl, Acyl, Alkoxy oder Alkylthio mit jeweils bis zu 6 Kohlenstoffatomen substituiert sind,R 1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, optionally up to 3 times the same or different by nitro. Trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or substituted by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each having up to 6 carbon atoms,
R2 für Wasserstoff oder Fluor stehtR 2 represents hydrogen or fluorine
und deren Hydrate und Salze, gegebenenfalls in einer isomeren Formand their hydrates and salts, optionally in an isomeric form
Verbindungen der allgemeinen Formel (I) gemäß Anspruch 1,Compounds of the general formula (I) according to Claim 1,
in welcherin which
A für Wasserstoff oder Methyl steht,A represents hydrogen or methyl,
X für ein Stickstoff atom oder für eine Gruppe der Formel -CH, C-F oder C-Cl steht,X represents a nitrogen atom or a group of the formula -CH, C-F or C-Cl,
T für ein Sauerstoff atom steht,T stands for an oxygen atom,
R1 für Phenyl, Pyπdyl, Pyrimidyl oder Pyrazinyl steht, die gegebenen¬ falls bis zu 3-fach gleich oder verschieden durch Nitro, Trifluorme- thyl, Fluor, Chlor, Brom, Cyano, Hydroxy oder durch geradkettiges oder verzweigtes Alkyl, Acyl, Alkoxy oder Alkylthio mit jeweils bis zu 4 Kohlenstoffatomen substituiert sind,R 1 represents phenyl, pyπdyl, pyrimidyl or pyrazinyl, optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio each having up to 4 carbon atoms,
R" für Wasserstoff oder Fluor stehtR "represents hydrogen or fluorine
und deren Hydrate und Salze, gegebenenfalls in einer isomeren Formand their hydrates and salts, optionally in an isomeric form
Verfahren zur Herstellung der Verbindungen der allgemeinen Formel (I) gemäß Anspruch 1. dadurch gekennzeichnet, daß man Verbindungen der allgemeinen Formel (II)A process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that Compounds of the general formula (II)
Figure imgf000181_0001
Figure imgf000181_0001
in welcherin which
R2, X und T die im Anspruch 1 angegebene Bedeutung habenR 2 , X and T have the meaning given in claim 1
undand
für Halogen, vorzugsweise für Fluor oder Chlor steht,represents halogen, preferably fluorine or chlorine,
mit Verbindungen der allgemeinen Formel (III)with compounds of the general formula (III)
Figure imgf000181_0002
in welcher
Figure imgf000181_0002
in which
A und R1 die im Anspruch 1 angegebene Bedeutung haben,A and R 1 have the meaning given in claim 1,
in inerten Lösemitteln, gegebenenfalls in Anwesenheit von Säurefängern umsetzt.in inert solvents, optionally in the presence of acid scavengers.
Arzneimittel, enthaltend eine oder mehrere Verbindungen aus den Ansprüchen 1 bis 3.Medicaments containing one or more compounds from claims 1 to 3.
Verwendung der Verbindungen aus den Ansprüchen 1 bis 3 zur Herstellung von antiviral wirksamen Arzneimitteln. Use of the compounds from claims 1 to 3 for the production of antivirally active drugs.
PCT/EP1995/002642 1994-07-20 1995-07-07 Heterocyclyl-1-phenyl substituted quinolone carboxylic acids as antiviral agents WO1996002540A1 (en)

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Publication number Priority date Publication date Assignee Title
WO1997011068A1 (en) * 1995-09-22 1997-03-27 Wakunaga Pharmaceutical Co., Ltd. Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient
EP1927589A1 (en) 2006-11-30 2008-06-04 Cadila Healthcare Ltd. Quinoline derivatives

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0927164A1 (en) 1996-09-10 1999-07-07 PHARMACIA & UPJOHN COMPANY 8-hydroxy-7-substituted quinolines as anti-viral agents
WO1998018795A1 (en) * 1996-10-30 1998-05-07 Bayer Aktiengesellschaft Method or producing naphthyridine compounds and novel intermediate products

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EP0422485A2 (en) * 1989-10-12 1991-04-17 Bayer Ag Quinolone carboxylic acid derivatives, process for their preparation and their use
EP0572259A1 (en) * 1992-05-27 1993-12-01 Ube Industries, Ltd. Aminoquinolone derivatives as anti-HIV agents
DE4303657A1 (en) * 1993-02-09 1994-08-11 Bayer Ag New quinolone and naphthyridonecarboxylic acid derivatives

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Publication number Priority date Publication date Assignee Title
EP0422485A2 (en) * 1989-10-12 1991-04-17 Bayer Ag Quinolone carboxylic acid derivatives, process for their preparation and their use
EP0572259A1 (en) * 1992-05-27 1993-12-01 Ube Industries, Ltd. Aminoquinolone derivatives as anti-HIV agents
DE4303657A1 (en) * 1993-02-09 1994-08-11 Bayer Ag New quinolone and naphthyridonecarboxylic acid derivatives

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997011068A1 (en) * 1995-09-22 1997-03-27 Wakunaga Pharmaceutical Co., Ltd. Novel pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient
US5998436A (en) * 1995-09-22 1999-12-07 Wakunaga Pharmaceuticals Co., Ltd. Pyridonecarboxylic acid derivatives or their salts and antibacterial agent comprising the same as the active ingredient
US6133284A (en) * 1995-09-22 2000-10-17 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
US6156903A (en) * 1995-09-22 2000-12-05 Wakunaga Pharmaceutical Co., Ltd. Pyridonecarboxylic acid derivatives or their salts, and antibacterial agents containing the same as their effective components
EP1927589A1 (en) 2006-11-30 2008-06-04 Cadila Healthcare Ltd. Quinoline derivatives

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