NZ250823A

NZ250823A - Quinolone and naphthyridone carboxylic acid derivatives, medicaments, preparation and pharmaceutical compositions thereof

Info

Publication number: NZ250823A
Application number: NZ250823A
Authority: NZ
Inventors: Stephan Bartel; Gerd Kleefeld; Thomas-J Schulze; Arnold Paessens; Rainer Neumann; Jurgen Reefschlager; Gert Streissle
Original assignee: Bayer Ag
Priority date: 1993-02-09
Filing date: 1994-02-04
Publication date: 1995-04-27
Also published as: GR3024686T3; JPH06271570A; HUT70044A; ZA94841B; EP0612731B1; CA2115021A1; TW248559B; DE59403757D1; IL108571A0; AU5314894A; AU670470B2; KR940019702A; DK0612731T3; HU9400352D0; DE4303657A1; EP0612731A1; ES2105362T3; ATE157088T1

Abstract

The invention relates to novel quinolone- and naphthyridone-carboxylic acid derivatives of the general formula (I) <IMAGE> where the substituents have the meaning indicated in the description, processes for their preparation, and their use as medicaments, in particular as anti-viral agents.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £50823 Patents Form 5 Priority Date(s): 9. A-.'/'. 3 Complete Specification Fi* 3d: J~h. £ • Class: £Q;/Q^?.*.W.i.V, 3>l19,' .C<? lQ^?fi,<Or J5??f .$£C Publication Date: .... 2.7. .!???.... P.O. Journal. No: . .^.\ NO C^ViNGS., NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION NOVEL DERIVATIVES OF OUINOLONECARBOXYLIC ACID AND NAPHTHYRIDONECARBOXYLIC ACID We, Bayer Aktiengesellschaft, a company registered under the laws of Germany, of FeJe^l j D-51368 Leverkusen^Germany, do hereby declare the invention, for which we pray that a patent may be granted to us. and the method by which it is to be performed, to be particularly described in and by the following statement:- - 1 - (Followed by 1A & IB) : h n q o * v-' v / ,y ) BAYER AKTIENGESELLSCHAFT 51368 Leverkusen Konzernverwaltung RP Patente Konzern Novel derivatives of ouinolonecarboxylic acid and naphthvridonecarboxvlic acid CD DIP guiiluii muiiLii - ]A - 250823 The present invention relates to novel derivatives of quinolonecarboxylic acid and napthvridonecarboxylic acid, processes for their preparation and their use as medicaments/ in particular as antiviral agents. 5 The antibacterial effect of certain quinolonecarboxylic acids has been known for a relatively long time. Little is known about the antiviral efficacy of such substances [cf. JP 022 64 724 A2, US 4 959 363; EP 431 991 Al]. Quinolones for the treatment of AIDS-infected cells are 10 described in: AIDS 4(12), 1283 (1990); Cell Struc. funct. 15(5), 295 (1990); EP 394 553 A2; WO 90 135 42 Al; in these cases, a protective effect is evident for certain cell lines without the virus being destroyed. The described substances also have an antibacterial effect. 15 The present invention now relates to novel derivatives of quinolonecarboxylic acid and napthyridonecarboxylic acid of the general formula (I) R1 o R2 CO-R* R3 A N D (I) -R4 R5 which represents hydrogen, hydroxyl, mercapto, halogen, straight-chain or branched alkyl having up to 3 carbon atoms, perfluoroalkyl having up to 3 carbon atoms, straight-chain or branched alkoxy or alkyl-thio having in each case up to 6 carbon atoms, arylthio having 6 to 10 carbon atoms, or the group of the formula -NR7R8, in which R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, represents hydrogen, nitro or halogen, R9 - if \j — represents a residue of the formula R 10 in which R9 and R10 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, or a residue of the formula 25 .'i r R" R'2 R13 w N7/ ^ or in which R11, R12 and R13 are identical or different and denote hydrogen, halogen, nitro, hydroxyl, cyano, mercapto, arylthio having 6 to 10 carbon atoms, straight-chain or branched alkyl, alkoxy, acyl or alkyl-thio having in each case up to 6 carbon atoms, or perfluoroalkyl having up to 4 carbon atoms, A represents a nitrogen atom or represents the group of the formula -CR14, in which denotes hydrogen, halogen, methyl, hydroxyl, methoxy, vinyl or alkinyl, R15 / R4 represents a residue of the formula -(CHj).,—N ^R16 0 P vi O in which a denotes a number 1, 2, 3 or 4, and R1S and R1S, together with the nitrogen atom, form an imidazolyl, pyrrolyl, 1,2,3-triazol-l-yl, l/2,3-triazol-2-yl/ 1,2,4-triazol-l-yl, 1,2,4-triazol-4-yl or tetrazolyl ring, R5 represents hydrogen, hydroxyl, halogen, or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, Rs represents hydroxyl, benzyloxy, morpholino, straight-chain or branched alkoxy having up to 6 carbon atoms, which can be substituted identically or differently up to 3 times by halogen, hydroxyl, or a heterocyclic residue of the formula / -0, ch3 X , or ■0 CH, represents a group of the formula -NR17R18, in which R17 and R18 are identical or different and denote 7 •• 250823 or hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted identically or differently up to 3 times by hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, / \ represents a residue of the formula —N N —R19, in which R1S denotes hydrogen or straight-chain or branched 10 alkyl having up to 4 carbon atoms,and D represents hydrogen, amino, phenyl, cyano, or hydroxyl,. or represents straight-chain or branched alkenyl, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, or 15 represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, and hydrates and salts thereof, optionally in sin isomeric 20 form. Physiologically harmless salts of the compounds according 0 f). y o to the invention can be salts of the compounds according to the invention with mineral acids, carboxylic acids or sulphonic acids. Those which are particularly preferred are, for example, salts with hydrochloric acid, 5 hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluene-sulphonic acid, benzenesulphonic acid, naphthalene-disulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic 10 acid or benzoic acid. Physiologically harmless salts can also be alkali metal, alkaline earth metal, silver and guanidinium salts of the compounds according to the invention. Compounds of the general formula (I) are preferred 15 in which R1 represents hydrogen, hydroxyl, mercapto, fluorine, chlorine, bromine, straight-chain or branched alkyl having up to 3 carbon atoms, trifluoromethyl, straight-chain or branched alkoxy or alkylthio 20 having in each case up to 4 carbon atoms, phenyl- thio, or represents the group of the formula -NR7R8, in which R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl 25 082 having up to 4 carbon atoms, R: represents hydrogen, nitro, fluorine, chlorine or bromine, R3 represents a residue of the formula R9 -N N — R to in which Rs and R10 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or denote a residue of the formula Ru R12 R13 ,£> . O-.O 10 ■N // \\ : N or in which R11 and R12 and R13 are identical or different and denote hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, cyano, phenyl-thio, straight-chain or branched alkyl, alkoxy, acyl or alkylthio having in each case up to 4 carbon atoms, or trifluoro-methyl, represents a nitrogen atom or represents the group of the formula -CR14, in which R14 denotes hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, vinyl or alkinyl, R15 / represents a residue of the formula -(CH2)a—n \ie in which a denotes a number 1, 2 or 3, R15 and R16, together with the nitrogen atom, form an imidazolyl , pyrrolyl, 1,2,3-triazol-l-yl, l,2,3-triazol-2-yl, 1,2,4-triazol-l-yl, 1,2,4-triazol-4-yl or tetrazolyl ring, represents hydrogen, hydroxyl, fluorine, chlorine, bromine, or represents straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, represents hydroxyl, benzyloxy, morpholino, or straight-chain or branched alkoxy having up to 5 carbon atoms, where the latter can be substituted identically or differently up to 2 times by halogen, hydroxyl, or by a heterocyclic residue of the represents a group of the formula -NR17R18, in which R17 and R18 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted identically or differently up to 2 times by hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms, |-° CH formula or iD 0 or 25 o r represents a residue of the formula —n n - R19 , in which R13 denotes hydrogen or straight-chain or branched 5 alkyl having up to 4 carbon atoms, and D represents methyl, vinyl, phenyl or hydrogen, and hydrates and salts thereof, optionally in an isomeric form. 10 Compounds of the general formula (I) are particularly preferred in which R1 represents hydrogen, fluorine, chlorine, bromine or methyl, 15 RJ represents hydrogen, fluorine or chlorine, r r '■ g 9 R9 -N N — R3 represents a residue of the formula H7 Rl° in which R5 and R10 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or denote a residue of the formula in which Ru, R1J and R13 are identical or different and denote hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, cyano, phenylthio, straight-chain or branched alkyl, alkoxy, acyl or alkylthio having in each case up to 3 carbon atoms, or trifluoromethyl, or Ijl ft DO Sfrft 11 15 A represents a nitrogen atom or represents the group of the formula -CR14, in which R14 denotes hydrogen, fluorine or chlorine, R4 represents a residue of the formula -CHZ / -N \ 315 -16 in which R15 and R1S, together with the nitrogen atom, form an imidazolyl, pyrrolyl, 1, 2,3-triazol-l-yl, 1.2.3-triazol-2-yl, 1,2,4-triazol-l-yl or 1.2.4-triazol-4-yl ring, R5 represents hydrogen, Rs represents hydroxyl, benzyloxy, morpholino or, straight-chain or branched alkoxy having up to 4 carbon atoms, where the latter can optionally be substituted by fluorine, chlorine, bromine, liu ft B9 Gfrft - 12 - #• 25 10 or hydroxyl, or by a residue of the formula / r°v ch3 v 3 -o ch3- or represents a group of the formula -NR17R18, in which R17 and R18 are identical or different and denote hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted identically or differently up to 2 times by hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms, Rs represents a residue of the formula —N in which R1S denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, 15 and D represents hydrogen, and hydrates ana salts thereof, optionally in an isomeric form. In addition, a process for preparing the compounds of the general formula (I) according to the invention has been 5 found which is characterized in that compounds of the general formula (II) R' 0 r2- ^ .CO-R6 in which R1, R2, R4, R5, R6, A and D have the abovementioned meaning and 10 E represents halogen, preferably chlorine and fluorine, are reacted with compounds of the general formula (III) R3-H (III) in which !■ * 1 I R3 has the abovementioned meaning, in inert solvents, optionally in the presence of acid-capturing agents, and, in the case of the acids, the esters are hydrolyzed, and, in the case of the esters, the acids are reacted with the corresponding alcohols according to customary methods, and, in the case of the amides, the acids are amidated, optionally after prior activation and in the presence of a base and/or auxiliary substance. The process according to the invention may be clarified, by way of example, by the following formula scheme: o N-H - 91 - oio eg v "i EH0-Z(ZH0)-NZH (2 ■< — W0)N / VOO^jo (l EH0-2(SH0)HN-0 Tf d II o o V o The customary inert solvents, which are not altered under the reaction conditions, are suitable for use as solvents for all the process steps. These solvents preferably include organic solvents, such as etherB, for example diethyl ether, dioxane or tetrahydrofuran, or hydrocarbons, such as benzene, toluene, xylene, cyclohexane, or petroleum fractions, or halogeno hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, or dimethyl sulphoxide, N,N-dimethylformamide, hexamethyl-phosphoric triamide, sulpholane, ethyl acetate, pyridine, eras * l i C; • V Q C triethylamine, N-methylpyrrolidone, anisole or picoline. It is also possible to use mixtures of the said solvents. Dimethyl sulphoxide, N,N-dimethylformamide and N-methylpyrrolidone are preferred. 5 The customary basic compounds are suitable for use as bases for individual reaction steps. These compounds include, for example, alkali metal or alkaline earth metal hydroxides, pyridine, triethylamine, diisopropyl-ethylamine or N-methylpiperidine, or bicyclic amidines, 10 such as 1,4-diazabicyclo [2.2.2] octane (DABCO) , 1,5- diazabicyclo[4.3.0]non-5-ene (DBN) or 1,5-diazabicyclo-[5 .4 .0] undec-5-ene (DBU) . Diisopropylethylamine and DABCO are preferred. The bases are in general employed in a quantity of 1 to 15 3 mol, preferably of 1 to 1.5 mol, based on 1 mol of the corresponding carboxvlic acid. The process is generally carried out in a temperature range of +0°C to +160°C, preferably of +0°C to +140°C. In general, atmospheric pressure is employed. However, it 20 is also possible to carry out the process under negative pressure or under excess pressure (e.g. in a range from 0.5 to 5 bar) . Suitable solvents to use for the hydrolysis are water or water in combination with a customary organic solvent. 25 The latter preferably include alcohols, such as methanol, liu li E9 - 18 - O r:1 ethanol, propanol, isopropanol or butanol, or ethers, such as tetrahydrofuran or dioxane, or dimethylf ormcimide or dimethyl sulphoxide. The use of alcohols, such as methanol, ethanol, propanol or isopropanol, is parti -5 cularly preferred. The hydrolysis is effected using bases, for example alkali metal or alkaline earth metal hydroxides, preferably lithium hydroxide or sodium hydroxide, in one of the above listed solvents, preferably dimethylf ormcimide, 10 tetrahydrofuran or ethanol in combination with water. The hydrolysis can also be effected using acids, such as, for example, acetic acid, hydrochloric acid, hydrobromic acid, methanesulphonic acid, sulphuric acid or perchloric acid. 15 The hydrolysis is generally carried out in a temperature range of 0°C to +130°C, preferably of +20°C to +110°C. In general, the hydrolysis is carried out under atmospheric pressure. However, it is also possible to carry it out under negative pressure or under excess pressure 20 (e.g. from 0.5 to 5 bar). In carrying out the hydrolysis, the acid is generally employed in a quantity of 1 to 3 mol, preferably of 1 to 1.5 mol, based on 1 mol of the ester. The use of molar quantities of the reactants is particularly preferred. A BO DIP - 19 - 25 2P-* ■■■■J \s ^ " \jr Vi/ The hydrolysis of tert-butyl esters is generally effected using acids, such as, for example, hydrochloric acid or trif luoroacetic acid, in the presence of one of the abovementioned solvents and/or water or their mixtures, preferably using dioxane or tetrahydrofuran. The esterification of the acids is effected a) according to a customary method by reacting the acids with the corresponding alcohols optionally in one of the above listed solvents in the presence of a catalyst. In this case it is preferred that the corresponding alcohol is also employed as the solvent. b) Alternatively, the acid is activated by methods of organic chemistry which are also well known and converted, for example using C1-C02C2HS, into the mixed anhydride, which is converted into the ester in accordance with a) . Inorganic acids, such as, for example, sulphuric acid, or inorganic acid chlorides, such as, for example, thionyl chloride, may be employed as catalyst for a) . In the case of b) , one of the above listed bases, which is inert under the reaction conditions, such as, for example, triethylamine, pyridine or bicyclic ami dines, can optionally be added. In general, 0.01 to 1, preferably 0.05 to 0.5, mol of catalyst are employed in the case of a), and 0.5 - 2, preferably 1 - 1,5, mol of catalyst in the case of b), in Li. A BP - 20 - 2?™ n "'S '• \ ■ : each case based on 1 mol of reaction partner. The amidation is in general effected in inert solvents and optionally" in the presence of one of the above listed bases and of a dehydrating agent. In this context, inert organic solvents which are not altered under the reaction conditions are suitable for use as solvents. These include halogeno hydrocarbons, such as dichloromethane, trichloromethane, tetrachloro-methane, 1,2-dichloroethane, trichloroethane, tetra-chloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylf ormamide, aceto-nitrile or hexamethylphosphoric triamide. It is also possible to employ mixtures of the solvents. Dichloro-methane is particularly preferred. The amidation is in general carried out in a temperature range from 0°C to 150°C, preferably at 25°C to 40°C. The amidation is in general carried out under atmospheric pressure. However, it is also possible to carry out the process under negative pressure or under excess pressure (e.g. in a range from 0.5 to 5 bar) . In carrying out the amidation, the base is in general employed in a quantity of 1 to 3 mol, preferably of 1 to 1.5 mol, based on 1 mol of the carboxylic acid. 508 The compounds of the general formula (II) are novel ana can be prepared by first converting compounds of the general formula (IV) R1 0 I II R2^ ^C02- R6 (IV) in which R1, R2, A and E have the abovementionea meaning, L represents halogen, preferably chlorine or fluorine, Rs' represents C^-C^-alkyl, and R represents C^-C^-alkoxy or Ci-C^dialkylamino, 10 by reaction with amines of the general formula (V) NH2 R5 (V) in which R4 R4 and R5 have the abovementioned meaning, in one of the above listed solvents, preferably ethanol, ■\ o /. A //*- ■tiu a o sio 22 - into the compounds of the general formula (VI) R1 0 R2 CO-R*' (VI) in which R1, R2, R4, R5, A, E, L and R6' have the abovementioned meaning, and, in a final step, cyclizing the latter compounds in one of the above listed solvents and one of the above listed bases, preferably DMF and KjC03/KF, and, in the case where D * H, varying these substituents according to customary methods. The process is in general carried out in a temperature range from +0°C to +150°C, preferably of +0°C to +120°C. In general, atmospheric pressure is employed. However, it is also possible to carry out the process under negative pressure or under excess pressure (e.g. in a range from 0.5 to 5 bar). The compounds of the general formulae (IV) and (V) are f l"' * ! &VXt< c • *: «. known per se or can be prepared in accordance with published methods. The compounds of the general formula (VI) are novel and can, for example, be prepared as described above. 5 Surprisingly, the compounds according to the invention were found to have an effect in lentivirus-infected cell cultures. It was possible to demonstrate this using HIV virus as an example. HIV infection in cell culture 10 The HIV test was carried out according to the method of Pauwels et al [cf. Journal of Virological Methods 20, (1988), 309-321] with minor modifications. Normal human blood lymphocytes (PBL's) were enriched on Ficoll-Hypaque and stimulated with phytohaemagglutinin 15 (90 ng/ml) and interleukin-2 (40 U/ml) in RPMI 1640 containing 20% foetal calf serum. For the infection with infectious HIV, the PBL's were pelleted and the cell pellet was subsequently suspended in 1 ml of HIV virus adsorption solution and the suspension was incubated at 2 0 37°C for 1 hour. The virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium such that a concentration of 1 x 10s cells per ml was obtained. The cells which had been infected in this way were then pipetted into the wells of 96-well microtiter plates in the amount of 1 x 104 cells/well. The first vertical row of the microtiter plate contained only growth medium and cells which had not been infected 5 but which had otherwise been treated exactly as described above (cell control). The second vertical row of the microtiter plate contained only HIV-infected cells (virus control) in growth medium. The remaining wells contained the compounds according to the invention in differing 10 concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the substances under test were diluted up to 210 times in doubling dilution steps. The test samples were incubated at 37 °C until the 15 synctium formation which is typical for HIV appeared in the untreated virus control (between day 3 and day 6 following infection), at which time the syncytium formation was evaluated microscopically. Under these test conditions, approximately 20 syncytia arose in the 2 0 untreated virus control, while no syncytia were evident in the untreated cell control. Each IC50 value was determined as the concentration of the compound according to the invention at which 50% (about 10 syncytia) of the virus-induced syncytia were sup-25 pressed by treatment with the compound according to the invention. Lu A fill - 25 - I <• :! . It was found that the compounds according to the invention protect HIV-infected cells from virus-induced cell destruction. Table A: 10 15 Ex. No. IC50 (jim) 8 3 14 0.7 20 0.2 23 0.4 31 0.7 39 0.25 50 0.5 51 0.2 69 0.7 92 0.6 113 2 146 0.7 The compounds according to the invention represent 20 valuable active compounds for the treatment and prophylaxis of diseases in human and veterinary medicine which are caused by retroviruses. Those areas of indication in human medicine which may be mentioned by way of example are: 25 1.) The treatment and prophylaxis of human retroviral infections. 2.) For the treatment or prophylaxis of diseases (AIDS) caused by HIV I (human immunodeficiency virus; previously termed HTLV III/LAV) and HIV II, and the Ul h BO - 26 - ■J $ } stages associated therewith, such as ARC (AIDS-related complex) and LAS (lymphadenopathy syndrome), as well as of the immune weakness and encephalopathy caused by this virus. 5 3.) For the treatment or prophylaxis of an HTLV-I or HTLV-II infection. 4.) For the treatment or prophylaxis of the AIDS-carrier condition. Those indications in veterinary medicine which may be 10 listed by way of example are: Infections with a) Maedi-visna (in sheep and goats) b) progressive pneumonia virus (PPV) (in sheep and goats) 15 c) caprine arthritis-encephalitis virus (in sheep and goats) d) zwoegersiekte virus (in sheep) e) equine infectious anaemia virus (of the horse) f) infections caused by feline leukaemia virus 20 g) infections caused by feline immunodeficiency virus (FIV) h) infections caused by simian immunodeficiency virus (SIV) The above listed points 2, 3 and 4 from the areas of 25 indication in human medicine are preferred. The present invention includes pharmaceutical Ll ft CO 010 - 27 - 25 A preparations which, in addition to non-toxic, inert and pharmaceutically appropriate excipients, contain one or more compounds of the formula (I) , or which consist of one or more active compounds of the formula (I), as well as processes for producing these preparations. The active compounds of the formula (I) are preferably intended to be present in the above listed pharmaceutical preparations at a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95, % by weight of the total mixture. In addition to the compounds of the formula (I) , the above listed pharmaceutical preparations may also contain further pharmaceutical active compounds. The above listed pharmaceutical preparations are produced in a customary manner in accordance with known methods, for example by mixing the active compound(s) with the excipient(s). In general, it has proved to be advantageous both in human and veterinary medicine, in order to obtain the desired results, to administer the active compound(s) according to the invention in total quantities of about 0.5 to about 500, preferably 1 to 100, mg/kg of body weight every 24 hours, optionally in the form of several individual doses. An individual dose preferably contains the active compound(s) in quantities of about 1 to about 80, in particular 1 to 30, mg/kg of body weight. It may, Lu ft ti - 28 - however, be necessary to deviate from the said dosages, namely in dependence on the nature and the body weight of the subject to be treated, on the nature and severity of the disease, on the nature of the preparation and the mode of administration of the medicament, and on the period or interval within which administration takes place. Starting compounds Example I a. 2-(4-Nitrobenzyl)-2H-1,2,3-triazole 15.6 g (0.072 mol) of 4-nitrobenzyl bromide are heated to reflux for 6 hours in 70 ml of acetone together with 5.0 g (0.072 mol) of 1,2,3-triazole and 20.2 g (0.15 mol) of potassium carbonate. After cooling, the mixture is filtered and the solvent is removed in vacuo. The crude product is purified by column chromatography (silica gel, methylene chloride/methanol 98/2). 2- (4-Aminobenzyl) -2H-1,2,3-triazole NH2 Yield: 3.87 g (26% of theory) Melting point: 96-100°C b. 2-(4-Aminobenzyl)-2-H-l,2,3-triazole 3.5 g (0.017 mol) of 2-(4-nitrobenzyl)-2H-1,2,3-triazole are hydrogenated under atmospheric pressure in 50 ml of ethyl acetate and in the presence of 1 g of Pd/C (10%) . The catalyst is filtered off and subsequently washed thoroughly with dime thyl f ormamide. The solvents are removed in vacuo. Yield: 2.1 g (72% of theory) ^-MMR (d6-DMSO) : s 5.4 (2H) ; d 6.5 (2H) ; d7.0 (2H); s 7.7 (2H). Example II and Example III 1-(3-Aminobenzyl)-1H-1,2,3-triazole (II) and 2-(3-Aminobenzyl)-2H-1,2,3-triazole (III) nh2 nh2 a. 1-(3-Nitrobenzyl)-1H-1,2,3-triazole and 5 2 -(3-nitrobenzyl)-2H-1,2,3 -triazole 12.3 g (0.072 mol) of 3-nitrobenzyl chloride and 5.0 g of 1,2,3-triazole are heated to reflux for 6 hours in 70 ml of acetone together with 20.2 g (0.15 mol) of potassium carbonate. The cooled mixture is filtered and the solvent 10 is removed in vacuo. The crude product is fractionated by column chromatography (silica gel, methylene chloride/ methanol 96/4). Yield: 4.1 g of 1-(3-nitrobenzyl)-1H-1,2,3-triazole (28% of theory) 15 Melting point: 96-97°C and 4.6 g of 2-(3-nitrobenzyl)-2H-1,2,3-triazole (31% of theory) A 09 DIP - 31 - M=' fa ^ ^ ?, '! : -/ W' 'ij V, ,1'> Melting point: 91-93°C 4.1 g (0.02 mol) of 1-(3-nitrobenzyl)-1H-1,2,3-triazole are hydrogenated under atmospheric pressure in 100 ml of ethyl acetate together with 1 g of Pd/C (10%) . The catalyst is filtered off and then washed thoroughly with dimethylformamide. The solvents are removed in vacuo. Yield: 3.2 g (94% of theory) (Example II) ^-NMR (CDC1,) : 5.4 (2H); m 6.5-6.7 (3H); t 7.15 (1H); s 7.50 (1H); s 7.70 (1H). 10 4.6 g (0.023 mol) of 2-(3-nitrobenzyl)-2H-1,2,3-triazole are hydrogenated in an analogous manner to Example II. Yield: 3.9 g (97% of theory) (Example III) Example IV and Example V 15 1- (2-Aminobenzyl) -1H-1,2,3-triazole (XV) and 2- (2-aminobenzyl) -2H-1,2,3-triazole (V) (IV) (V) a . 1-(2-Nitrobenzyl)-1H-1,2,3-triazole and 2-(2-nitro-benzyl)-2H-1,2,3-triazole 15.5 g (0.072 mol) of 2-nitrobenzyl bromide and 5.0 g Jiu A DO - 32 - (0.072 mol) of 1,2,3-triazole are heated to reflux for 4 hours in 70 ml of acetone together with 2 0.2 g (0.15 mol) of potassium carbonate. The cooled mixture is filtered and the solvent is removed in vacuo. The crude 5 product is fractionated by column chromatography (silica gel, methylene chloride/methanol 96/4). Yield: 3.0 g of 2-(2-nitrobenzyl)-2H-1,2,3-triazole (20% of theory) Melting point: 77-80°C 10 and 6.8 g of 1-(2-nitrobenzyl)-1H-1,2 , 3-triazole (46% of theory) Melting point: 110-115°C b. 1-(2-Aminobenzyl)-1H-1,2,3 -triazole 15 6.8 g (0.033 mol) of 1-(2-nitrobenzyl)-1H-1,2,3-triazole are hydrogenated under atmospheric pressure in 100 ml of ethyl acetate and in the presence of 1 g of Pd/C (10%). The catalyst is filtered off and then washed thoroughly with dimethylf ormamide. The solvents are removed in 20 vacuo. Yield: 5.6 g (97% of theory) 'H-NMR (CDClj) : s 5.45 (2H) ; m 6.65-6.85 (2H) ; m 7.10-7.25 (2H); s 7.50 (1H); s 7.70 (1H) 3.0 g (0.015 mol) of 2-(2-nitrobenzyl)-2H-1,2,3-triazole 25 are hydrogenated in an analogous manner to Example b^. Yield: 2.4 g (91% of theory) ^-NMR (CDClj) : s 5.50 (2H) ; m 6.60-6.85 .vl', *1 11 y u (2H) ; m 7 .05-7.35 (2H) ; s 7.55 (2H) Example VI 6,7-Difluoro-1, 4-dihydro-4-oxo-l- [4- (1H-1, 2,3-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylic acid O 0 5 a_j. Ethyl 2-(2, 4, 5-trifluorobenzoyl)-3 -[4-(1H-1,2,3 - triazol-l-yl-methyl)-phenylamino]-acrylate 11.5 g (0.038 mol) of ethyl 3-ethoxy-2-(2, 4,5-trifluoro-benzoyl)-acrylate are initially introduced into 75 ml of ethanol and 6.7 g (0.038 mol) of 1-(4-aminobenzyl)-1H-10 1,2, 3 - triazole are added dropwise. The mixture is sub sequently stirred at room temperaure for 12 hours and the solvent is then removed in vacuo. Crude yield: 15.8 g b. Ethyl 6,7-Difluoro-l,4-dihydro-4-oxo-l-[4-(1H-1,2,3-15 triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylate 15 g (0.035 mol) of the product obtained under a^_ are heated at 100 °C for 5 hours in 7 0 ml of dimethylformamide together with 5.7 g (0.041 mol) of potassium carbonate. The solvent is removed in vacuo and the residue is stirred up with water. Drying then takes place at about 100°C. Yield: 13.2 g (92% of theory) Melting point: 183-185°C 10 g (24 mmol) of the ester obtained under bj. are stirred, together with 0.6 g (24 mmol) of lithium hydroxide, at room temperature for three days in a mixture consisting of 100 ml of tetrahydrofuran, 5 ml of dimethylf ormamide and 5 ml of water. Subsequently, filtration with suction takes place and the residue is stirred up thoroughly with iso-propanol and then dried at about 100°C. Yield: 8.2 g (89% of theory) Melting point: >280°C Example VII Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-1,8-naphthyridine-3 -carboxylate 0 0 5 a^ Ethyl 2-(2,5-dichloro-4-fluoro-nicotinoyl)-3-[4-(1H- 1,2,3-triazol-l-yl-methyl)-phenylamino]-acrylate 2.9 g (8.6 mmol) of ethyl 3-ethoxy-2-(2,5-dichloro-4-fluoro-nicotinoyl)-acrylate and 1.5 g (8.6 mmol) of l-(4-aminobenzyl)-1H-1,2,3-triazole are stirred at room 10 temperature for 12 hours in 20 ml of ethanol. The solvent is then removed in vacuo. Yield: 3.65 g (91% of theory) Melting point: 153-158°C 3.5 g (7.5 mmol) of the product obtained under a^. are 15 heated at 120°C for 5 hours in 20 ml of dime thy lformamide together with 1.3 g (9.4 mmol) of potassium carbonate. 15 ' K A o o - The cooled mixture is added to ice water and the precipitated product is isolated. It is dried at about 100°C. Yield: 3.05 g (94% of theory) Melting point: 216-220°C Example VIII Ethyl 6,7-difluoro-l,4-dihydro-4-oxo-l-[4-(2H-1,2,3-triazol-2-yl-methyl) -phenyl] -3-quinolinecarboxylate O O OEt V" .N •fxN N: a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3 -[4-(2H-1,2,3-triazol-2-yl-methyl)-phenylamino]-acrylate 3.6 g (0.012 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl) -acrylate and 2.1 g (0.038 mol) of 2-(4-amino-benzyl)-2H-1,2,3-triazole are stirred at room temperature overnight in 25 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 5.0 g (97% of theory) Melting point: 108-110°C 09 SiB - 37 - 1 U '! f ' ti ^ '*-* V-' i * 5.0 g (0.012 mol) of the product obtained under a_;_ are heated at 100°C for 5 hours in 25 ml of dimethylf ormamide together with 1.9 g (0.014 mol) of potassium carbonate. The cooled mixture is then added to ice water and the precipitated product is isolated. It is dried at about 100°C. Yield: 4.0 g (85% of theory) Melting point: 203-206°C He A 13 Wff - 38 - '"1 y £v) Example IX Ethyl 6,7-difluoro-l,4-dihydro-4-oxo-l- [4- (1H-1,2,4-triazol-l-yl-methyl) -phenyl] -3-quin.olinecarboxylate 0 0 OEt N" U .N -N a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3- [4-(1H-1,2,4-triazol-l-yl-methyl) -phenylamino] -acrylate 10 17.2 g (0.052 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl) -acrylate and 10.0 g (0.057 mol) of 1-(4-amino-benzyl)-lH-l,2,4-triazole are stirred at room temperature overnight in 100 ml of ethanol. The precipitated product is isolated and washed with ethanol. Yield: 20.2 g (82% of theory) Melting point: 137-139°C 15 4.5 g (0.011 mol) of the product obtained under a^ are heated at 100°C for seven hours in 25 ml of dimethyl-formamide together with 1.9 g (0.014 mol) of potassium carbonate. The cooled mixture is added to ice water and ft flQ - 39 - the precipitated product is isolated, about 100°C. Yield: 2.94 g (68% of theory) Melting point: 226-228°C It is dried at Example X Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-l- [4- (1H-1,2,4-triazol-1-yl-methyl)-phenyl] -1,8-naphthyridine-3 ■ carboxylate 0 O cr^N 10 a. Ethyl 2-(2, 5-dichloro-4-fluoro-nicotinoyl)-3-[4-(1H-1,2,4-triazol-l-yl-methyl)-phenylamino]-acrylate 15 9.7 g (0.029 mol) of ethyl 3-ethoxy-2-(2,5-dichloro-4-f luoro-nicotinoyl)-acrylate and 5.0 g (0.029 mol) of 1-(4-aminobenzyl)-1H-1,2,4-triazole are stirred at room temperature for three hours in 60 ml of ethanol. The solvent is removed in vacuo. Yield: 13.5 g of crude product La h AO fefrft - 40 - 15 13.3 g {28 mmol) of the product obtained under a_;_ are heated at 100°C for four hours in 70 ml of dimethylformamide together with 5.0 g (36 mmol) of potassium carbonate. The cooled mixture is added to ice water and the precipitated product is isolated. It is dried at about 100°C. Yield: 10.8 g (85% of theory) Melting point: 225-228°C Example XI 6 , 7 -Difluoro-1,4-dihydro-l-[4-(N-imidazolyl-methyl)-phenyl]-4-oxo-3-quinolinecarboxylic acid IN a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3-[4-(N-imidazolyl-methyl) - phenyl amino] -acrylate 17.2 g (0.057 mol) of ethyl 3-ethoxy-2-(2,4, 5-trifluoro-benzoyl)-acrylate and 10.0 g (0.057 mol) of N- (4-amino-benzyl)-imidazole are stirred at room temperature - 41 - overnight in 100 ml of ethanol. All the volatile components are removed in vacuo. Yield: 24.0 g of crude product b. Ethyl 6,7-Difluoro-l,4-dihydro-l-[4-(N-imidazolyl-5 methyl)-phenyl]-4-oxo-3-quinolinecarboxylate 24.0 g of the product obtained under a_^ are heated at 100 °C for six hours in 200 ml of dimethylf ormcimide together with 14.3 g (0.1 mol) of potassium carbonate. All the volatile components are removed in vacuo and the 10 residue is purified by column chromatography (silica gel, methylene chloride/methanol 96/4) . Yield: 15.3 g (65% of theory over two steps) Melting point: 251-254°C 200 mg (0.49 mmol) of the ester obtained under b_;_ are 15 heated at 80°C for two hours in a mixture consisting of 1 ml of acetic acid, 1 ml of water and 0.1 ml of concentrated sulphuric acid. After cooling, the mixture is added to a little ice water and the product is isolated. Yield: 180 mg (96% of theory) 20 Melting point: >280°C Example XII Ethyl 6,7-difluoro-l,4-dihydro-4-oxo-l-[3-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylate iiu ft BO - 42 - a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3- [3- (1H-1,2,3-triazol-l-yl-methyl) -phenylamino] -acrylate 5.9 g (0.019 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl) -acrylate and 3.4 g (0.019 mol) of l-(3-amino-5 benzyl)-1H-1,2,3-triazole are stirred overnight in 40 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 7.8 g (92% of theory) Melting point: 126-128°C 10 7.7 g (0.018 mol) of the product obtained under a^_ are heated at 100°C for four hours in 45 ml of dimethylformamide together with 3.1 g (0.022 mol) of potassium carbonate. The cooled mixture is added to 180 ml of ice water and the precipitated product is isolated. It is 15 dried at a about 100°C. Yield: 6.2 g (85% of theory) Melting point: 187-189°C Example XIII 9 r - Ethyl 6,7-difluoro-1,4-dihydro-l-[3-(2H-1,2,3-triazol-2-yl-methyl) -phenyl] -4-oxo-3-quinolinecarboxylate O O II a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3 -[3-2H-1,2,3-triazol-2-yl-methyl)-phenylamino]-acrylate 10 4.0 g (0.013 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluoro-benzoyl)-acrylate and 2.3 g (0.013 mol) of 2-(3-amino-benzyl)-2H-1,2, 3-triazole are stirred overnight in 25 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 5.5 g of crude product 15 5.5 g (0.013 mol) of the product obtained under a^. are heated at 100 °C for four hours in 30 ml of dimethylf ormamide together with 2.3 g (0.017 mol) of potassium carbonate. The cooled mixture is added to 180 ml of ice water and the precipitated product is isolated. It is dried at about 100°C. Yield: 4.5 g (86% of theory) Melting point: 144-146°C Example XIV liu ft 00 - 44 - Ethyl 6,7-difluoro-l,4-dihydro-l-[3-(1H-1,2,4-triazol-l-yl-methyl)-phenyl]-4-oxo-3-quinolinecarboxylate 0 0 a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3-[3-(1H-1,2,4- triazo-l-yl-methyl)-phenylamino]-acrylate 8.7 g (0.029 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl) -acrylate and 5.0 g (0.029 mol) of l-(3-amino-benzyl)-1H-1,2,4-triazole are stirred overnight in 60 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 12.4 g of crude product 12.4 g (0.013 mol) of the product obtained under are heated at 100 °C for two hours in 80 ml of dimethylformamide together with 5.4 g (0.039 mol) of potassium carbonate. The cooled mixture is added to ice water, and then this mixture is extracted with methylene chloride and the solvent removed on a rotary evaporator. Drying takes place at about 100°C. Yield: 10.0 g (84% of theory) Melting point: 175-180°C ao oio - 45 - 2 Example XV Ethyl 7-chloro-6-fluoro-1,4-dihycLro-4-oxo-1 - [3- (1H-1,2,4-triazol-l-yl-methyl)-phenyl]-1,8-naphthyridine-3-carboxylate a. Ethyl 2-(2,5-dichloro-4-fluoro-nicotinoyl)-3-[3-(1H-1,2,4-triazol-l-yl-methyl)-phenylamino]-acrylate 5.7 g (0.017 mol) of ethyl 3-ethoxy-2-(2,5-dichloro-4-f luoro-nicotinoyl)-acrylate and 3.0 g (0.017 mol) of 1-(3-aminobenzyl)-1H-1,2,4-triazole are stirred at room temperature overnight in 35 ml of ethanol. The solvent is then removed in vacuo. Yield: 7.7 g of crude product 7.7 g (16 mmol) of the product obtained under a^. are heated at 100°C for two hours in 50 ml of dimethylform-amide together with 3.4 g (24 mmol) of potassium carbonate. The cooled mixture is added to ice water and this mixture is then extracted with methylene chloride and the organic phase is then dried over sodium sulphate and evaporated off on a rotary evaporator. Drying takes place hm fc afl H* - 46 - at about 100°C. Yield: 4.9 g (67% of theory over two steps) Melting point: 186-189°C Example XVI 6, 7- Dif luoro-1, 4-dihydro-l- [3 - (N-imidazolyl-methyl) -phenyl] -4-oxo-3-quinolinecarboxylic acid 0 0 a. Ethyl 2-(2, 4, 5-trif luorobenzoyl) -3-[3-(N-imidazolyl -methyl) -phenylaunino] -acrylate 8.7 g (0.029 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluoro-benzoyl)-acrylate auid 5.0 g (0.029 mol) of N-(3-aminobenzyl) -imidazol are stirred at room temperature overnight in 60 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 12.3 of crude product b. Ethyl 6, 7-dif luoro-1, 4-dihydro-l- [3- (N-imidazolyl-methyl) -phenyl] -4-oxo-3-quinolinecarboxylate 12.3 g of the product obtained under a^. are heated at ijl a OP - 47 - 100 °C for two hours in 70 ml of dimethylf ormamide together with 5 g (0.03 6 mol) of potassium carbonate. The cooled mixture is added to ice water and this mixture is then extracted with methylene chloride and the solvent is then removed in a rotary evaporator. The crude product is purified by column chromatography (silica gel, methylene chloride/methanol 96/4). Yield: 3.3 g (2 8% of theory over two steps) Melting point: 193-194°C 2 00 mg (0.49 mmol) of the ester obtained under b^. are heated at 80°C for two hours in a mixture consisting of 1 ml of acetic acid, 1 ml of water and 0.1 ml of concentrated sulphuric acid. After cooling, the mixture is added to a little ice water and the product is isolated. Yield: 130 mg (68% of theory) Melting point: >280°C Example XVII Ethyl 6,7-difluoro-1,4-dihydro-4-oxo-l-[2-(1H-1,2,3- triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylate O O 250 "t a. Ethyl 2 -(2 , 4,5-trifluorobenzoyl)- 3 - [2 -(1H-1,2,3 -triazol-l-yl-methyl)-phenylamino]-acrylate 5.0 g (0.016 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluoro-benzoyl)-acrylate and 2.8 g (0.016 mol) of l-(2-amino-5 benzyl)-1H-1,2,3-triazole are stirred overnight in 30 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 6.4 g of crude product Melting point: 124-126°C 10 6.0 g (0.014 mol) of the product obtained under are heated at 100°C for four hours in 35 ml of dimethyl form -amide together with 2.4 g (0.017 mol) of potassium carbonate. The cooled mixture is added to 180 ml of ice water and the precipitated product is isolated. It is 15 dried at about 100°C. Yield: 3.9 g (68% of theory) Melting point: 224-226°C Example XVIII Ethyl 6,7-difluoro-l,4-dihydro-4-oxo-l-[2-(2H-1,2,3-20 triazol-2-yl-methyl) -phenyl] -3-quinolinecarboxylate ha M 8P UA - 49 - * I I J k _>s 4 w u 0 ^ .) a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3- [2-(2H,-1,2,3-triazol-2-yl-methyl)-phenylamino]-acrylate 3.9 g (0.013 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl) -acrylate and 2.3 g (0.013 mol) of 2-(3-amino-benzyl)-2H-1,2,3-triazole are stirred overnight in 25 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 4.9 g (89% of theory) Melting point: 98-99°C 10 4.5 g (0.011 mol) of the product obtained under a^. are heated at 100°C for four hours in 25 ml of dimethylformamide together with 1.7 g (0.012 mol) of potassium carbonate. The cooled mixture is added to 180 ml of ice water and the precipitated product is isolated. It is 15 dried at about 100°C. Yield: 3.7 g (88% of theory) Melting point: 144-145°C iiin ft at) Efrft - 50 - Example XIX Ethyl 6,7-difluoro-1,4-dihydro-4-oxo-l-[2-(1H-1,2,4- triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylate 0 0 a . Ethyl 2- (2,4,5-trifluorobenzoyl)-3-[2-(1H,-1,2,4-triazol-l-yl-methyl) -phenylamino] -acrylate 8.7 g (0.029 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluoro-benzoyl)-acrylate and 5.0 g (0.029 mol) of l-(3-amino-benzyl)-1H-1,2,4-triazole are stirred overnight in 60 ml of ethanol. All the volatile components are then removed in vacuo. Yield: 14.3 g of crude product 12.4 g of the product obtained under su. are heated at 100°C for 3.5 hours in 80 ml of dimethylf ormamide together with 5.7 g (0.04 mol) of potassium carbonate. The cooled mixture is added to ice water and this mixture is then extracted with methylene chloride and the solvent then removed on a rotary evaporator. The crude product is purified by column chromatography (silica gel, methylene chloride/methanol 96/4). Yield: 6.5 g (54% of theory) Melting point: 214-216°C Example XX 6, 7-Difluoro-1,4-dihydro-l-[2-(N-imidazolyl-methyl) -phenyl]-4-oxo-3-quinolinecarboxylic acid a. Ethyl 2 -(2,4,5-trifluorobenzoyl)- 3 -[2-N-imidazolyl-methyl) -phenylamino]-acrylate 7.85 g (0.026 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl) -acrylate and 4.5 g (0.026 mol) of N-(2-amino-benzyl)-imidazole are stirred at room temperature overnight in 50 ml of ethanol. All the volatile components are removed in vacuo and the residue is purified by chromatography. Yield: 7.87 g (70% of theory) b. Ethyl 6,7-difluoro-l,4-dihydro-l-[2 -(N-imidazolyl-methyl) -phenyl]-4-oxo-3-quinolinecarboxylate 7.8 g (0.018 mol) of the product obtained under a^_ are km ft BP SAA - 52 - g*\ ) E™ -c;, heated at 100°C for 3.5 hours in 45 ml of dimethylformamide together with 3.1 g (0.022 mol) of potassium carbonate. The cooled mixture is added to ice water and this mixture is then extracted with methylene chloride 5 and the solvent removed on a rotary evaporator. The crude product is purified by column chromatography (silica gel, methylene chloride/methanol 96/4). Yield: 4.7 g (64% of theory) Melting point: 225-227°C 10 200 mg (0.49 mmol) of the ester obtained under b_;_ are heated at 80°C for two hours in a mixture consisting of 1 ml of acetic acid, 1 ml of water and 0.1 ml of concentrated sulphuric acid. After cooling, the mixture is neutralized with dilute sodium hydroxide solution and 15 then extracted with methylene chloride and the solvent removed on a rotary evaporator. Yield: 67 mg (37% of theory) Melting point: 210-214°C (with decomposition) Example XXI 20 6,7, 8-Trifluoro-1,4-dihydro-4-oxo-l- [4- (lH-l,2,3-triazol- 1-yl-methyl) -phenyl] -3-quinolinecarboxylic acid BP DIP - 53 - £ 5 0 & < W v.,' /, o o 'n \\ N a. Ethyl 2-(2,3,4, 5-tetrafluorobenzoyl)-3 - [4-(1H-1,2,3-triazol-l-yl-methyl)-phenylamino]-acrylate 10 12 g (0.069 mol) of 1-(4-aminobenzyl)-1H-1,2,3-triazole are initially introduced into 120 ml of ethanol and 22.0 g (0.069 mol) of ethyl 3-ethoxy-2-(2,3,4,5-tetra-fluorobenzoyl)-acrylate in 30 ml of methylene chloride are added at room temperature. The mixture is subsequently stirred at room temperature for 12 hours and the solvent is then removed in vacuo. Crude yield: 3 0.8 g b. Ethyl 6,7,8-Trifluoro-1,4-dihydro-4-oxo-1-[4 -(1H-1, 2, 3-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylate 15 30.8 g (0.069 mol) of the product obtained under au are heated at 90 °C for three hours in 130 ml of dimethyl form-amide together with 4.4 g (0.076 mol) of potassium fluoride. The solvent is then removed in vacuo and the fall M DP «p» - 54 - residue is taken up in methylene chloride/water. After back extraction, the combined organic phases are washed with water until neutral and then dried over sodium sulphate. After removing the solvent in vacuo, the residue is stirred up with ethyl acetate/isooctane 1:1. Yield: 23.2 g (79% of theory) Melting point: 170-172°C 23.2 g (54.2 mmol) of the ester obtained under b^ are stirred at room temperature overnight together with 1.3 g (54.2 mmol) of lithium hydroxide in a mixture consisting of 240 ml of tetrahydrofuran, 100 ml of dimethylf ormamide and 12 ml of water. After removing the solvents in vacuo, the crude product is purified by column chromatography (silica gel, methylene chloride/methanol 95/5). Yield: 10.7 g (89% of theory) Melting point: 170-172°C 15 Example XXII 8-Chloro-6, 7-difluoro-l,4-dihydro-4-oxo-l- [4- (1H-1, 2, 3-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylic acid 0 0 a. Ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-[4-(1H-1,2, 3-triazol-l-yl-methyl)-phenylamino]-acrylate 8 g (0.046 mol) of 1-(4-aminobenzyl)-1H-1,2,3-triazole are initially introduced into 80 ml of ethanol and 14.7 g (0.046 mol) of ethyl 3-ethoxy-2-(3-chloro-2,4,5-tri-fluorobenzolyl)-acrylate in 4 ml of methylene chloride are then added at room temperature. The mixture is subsequently stirred at room temperature for 12 hours and the solvent is then removed in vacuo. Crude yield: 21.3 g b. Ethyl 8-chloro-6,7-difluoro-l,4-dihydro-4-oxo-l-[4-(1H-1, 2 , 3 -triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylate ha ft DO -W - 56 - v,,, J k v.' t- 21.3 g (0 .069 mol) of the product obtained under a_;_ are heated at 90°C for three hours in 90 ml of dimethylform-amide together with 4.9 g (0.050 mol) of potassium fluoride. The solvent is removed in vacuo and the residue 5 is then taken up in methylene chloride/water. After back extraction, the combined organic phases are washed with water until neutral and then dried over sodium sulphate. The solvent is removed in vacuo. Yield: 12.2 g (60% of theory) 10 Melting point: 120-122°C 12.0 g (27 mmol) of the ester obtained under b_;_ are stirred at room temperature for three days together with 7 00 mg (27 mmol) of lithium hydroxide in a mixture consisting of 120 ml of tetrahydrofuran, 50 ml of dimethyl-15 formsunide and 6 ml of water. After removing the solvents in vacuo, the crude product is purified by column chromatography (silica gel, methylene chloride/methanol/ acetic acid 10/1/0.5). Yield: 9.4 g (84% of theory) 20 Melting point: 201-203°C BP DIP - 57 - P r ^ V 2 5 -It, V, J, Example XXIII 8-Chloro-6, 7-difluoro-l, 4-dihydro-4-oxo-1- [4- (2H-1,2,3-triazol-2-yl-methyl)-phenyl] -3-quinolinecarboxylic acid 0 0 ii The title compound was obtained in analogy with Example XXII. Melting point: >250°C ■He A i9 ■3*6' - 58 - 15 Example XXIV 6, 7, 8-Trif luoro-1,4-dihydro-4-oxo-l- [4- (1H-1,2,4-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylic acid a. Ethyl 2- (2, 3,4,5-tetrafluorobenzoyl)-3-[4-(1H-1,2,4-triazol-l-yl-methyl) -phenylamino] -acrylate 3.9 g (0.022 mol) of 1- (4-aminobenzyl)-1H-1,2,4-triazole are initially introduced into 40 ml of ethanol and 7.2 g (0.022 mol) of ethyl 3-ethoxy-2-(2,3,4,5-tetrafluoro-benzoyl) -acrylate in 2 ml of methylene chloride are then added at room temperature. The mixture is subsequently stirred at room temperature for 12 hours and the solvent is then removed in vacuo. Crude yield: 10.0 g b. Ethyl 6,7,8-trifluoro-l,4-dihydro-4-oxo-l-[4-(1H-1, 2, 4-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylate Lu ft 09 5*» - 59 - <n> :• ... ftiv, .v . , 10.0 g (0.022 mol) of the product obtained under a_^ are heated at 90°C for three hours in 50 ml of dimethylformamide together with 1.4 g (0.025 mol) of potassium fluoride. The solvent is removed in vacuo and the residue 5 is then taken up in methylene chloride/water. After back extraction, the combined organic phases are washed with water until neutral and then dried over sodium sulphate. The crude product is purified by column chromatography (silica gel, methylene chloride/methanol 95:5). 10 Yield: 8.9 g (94% of theory) Melting point: 160-162°C 8.9 g (20.8 mmol) of the ester obtained under b_;_ are stirred at room temperature overnight together with 500 mg (20.8 mmol) of lithium hydroxide in a mixture 15 consisting of 90 ml of tetrahydrofuran, 4.5 ml of di- methylformamide and 4.5 ml of water. After removing the solvent in vacuo, the crude product is purified by column chromatography (silica gel, methylene chloride/methanol 95/5) . 20 Yield: 6.2 g (75% of theory) Melting point: 256-258°C ft BP AAA - 60 - v r.,: n / - \ t 1 ; '• > ~i w v? : / ' w\ Example XXV 8-Chloro-6,7 -dif luoro-1, 4-dihydro-4-oxo-1 - [4- (1H-1,2,4-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylic acid 0 0 The title compound was obtained in analogy with Example XXIV. Melting point: 232-234°C tiu ft BP M-ft - 61 - *» V Example XXVI N-Isopropyl- [6, 7-difluoro-l, 4-dihydro-4-oxo-l- [4- (1H-1, 2, 3-triazol-l-yl-methyl) -phenyl] -3-quinolinecarbox-amide] 0 0 5 2.67 g (7.0 mmol) of 6,7-difluoro-1,4-dihydro-4-oxo-l-[4- (1H-1,2,3 - triazol-1-yl-methyl)-phenyl]- 3-quinolinecarboxylic acid are suspended in 25 ml of dry toluene and the suspension is boiled for drying on a water separator. Subsequently, 0.55 ml (7.5 mmol) of thionyl chloride is 10 added to the cooled suspension, which is then boiled until gas evolution ceases; 1.3 ml (15 mmol) of isopro-pylamine are then added at room temperature and boiling is subsequently continued for a further two hours. For the working up, the cooled solution is stirred into 15 IN hydrochloric acid and then extracted with methylene chloride. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. Following drying over uu h bp - 62 - sodium sulphate, the solution is evaporated on a rotary- evaporator and purification is then carried out using column chromatography (silica gel, methylene chloride/ methanol 9/1). Yield: 0.7 g (24% of theory) Melting point: 223-225°C Example XXVII N,N-Diisopropyl- [6,7-difluoro-1,4-dihydro-4-axo-l- [4- (1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarbox-amide] 0.28 ml (2.7 mmol) of triethylamine is added at 0°C to 0.95 g (2.5 mmol) of 6, 7-dif luoro-1,4-dihydro-4-oxo-l- [4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylic acid in 10 ml of acetone. Subsequently, 0.38 ml (2.7 mmol) of ethyl chloroformate is added drop-wise at this temperature within the space of 30 minutes. After adding 0.38 ml (2.7 mmol) of diisopropylamine, the fi B0 DIP - 63 - mixture is boiled under reflux for one hour. For the working up, the mixture is added to saturated sodium hydrogen carbonate solution and this mixture is then extracted with ethyl acetate. The combined organic phases 5 are washed with saturated sodium chloride solution and dried over sodium sulphate. Yield: 1.1 g (95% of theory) Melting point: 85-87°C The compounds listed in Table I are obtained in analogy 10 with Example XXVII: Ex. No. Rs M.p. [°C] XXVIII -NHC(CHJOH)3CH3 171-173 XXIX -NHCH,CH(OH)CH3 75-77 15 XXX -NHCI^CILjOH 90-92 XXXI - NHCELj CHj OCH3 156-158 15 Example XXXII Ethyl 7-chloro-1,4-dihydro-4-oxo-l-[4-(1H-1,2,4-triazol-l-yl-methyl) phenyl] -1,8-naphthyridine-3-carboxylate 0 a. Diethyl (2,6-dichloronicotinoyl)malonate 7.21 g (0.075 mol) of magnesium chloride are initially introduced at 0°C into 75 ml of absolute acetonitrile and 12.12 g (0.075 mol) of diethyl malonate are added drop-wise while cooling in an ice bath. Subsequently, 15.34 g (0.150 mol) of triethylaunine are added dropwise at 0°C, as are, after subsequently stirring for 60 minutes, 17.0 g (0.075 mol) of 2,6-dichloronicotinoyl chloride (Helvetica Chimica Acta 59, 222 (1976)); the mixture is then stirred overnight while being heated to room temperature. 80 ml of 18% strength hydrochloric acid are subsequently added and the mixture is extracted with methyl tert-butyl ether, followed by drying over sodium sulphate and concentration in vacuo. iiu ft t3 dip - 65 - rv. b. Ethyl (2,6-dichloronicotinoyl)acetate The crude diethyl (2,6-dichloronicotinoyl)-malonate is heated to reflux for 2 hours in 45 ml of water containing 90 mg of p-toluenesulphonic acid. The mixture is extrac-5 ted with methylene chloride, followed by washing with water, drying over sodium sulphate and concentration in vacuo. The crude product is purified on silica gel (eluent, dichloromethane). Yield: 14.2 g (72% of theory over two steps). 10 Ci Ethyl 2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate 43 g (0.162 mol) of the product from b^_ are heated at 150-160°C for two hours in 38.1 g (0.26 mol) of ethyl orthoformate and 42.4 g (0.42 mol) of acetic anhydride. All the readily volatile constituents are distilled off 15 under high vacuum at a bath temperature of up to 100°C and the crude product is used directly for further reaction. Crude yield: 50.5 g d. Ethyl 2-(2,5-dichloronicotinoyl)-3-[4-(1H-1,2, 4-20 triazol-l-yl-methyl)phenylamino]-acrylate 7 g (0.022 mol) of the product obtained under c^ and 3.8 g (0.022 mol) of 1-(4-aminobenzyl)-1H-1,2,4-triazole are stirred at room temperature overnight in 40 ml of ethanol. The solvent is removed in vacuo. 25 Yield: 9.7 g of crude product - 66 - k 2 h .a o 9 -7 3 4 J 26.0 g (0.058 mol) of the product obtained in d^_ are heated at 80°C for four hours in 140 ml of dimethylform-amide together with 9.5 g (0.066 mol) of potassium carbonate. The cooled mixture is added to ice water and the precipitated product is isolated and dried at about 100°C. Yield: 18.7 g (78% of theory) M.p.: 253-256°C B8 Oii - 67 - Preparation examples: Example 1: Ethyl 6-fluoro-7- [4- (4-fluorophenyl) -piperazin-l-yl] -1,4-di hydro - 4 -oxo-1 - [4 - (lH-l,2,3-triazol -1 - yl-methyl) -phenyl]-3-quinolinecarboxylate COOEt 490 mg (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-4-oxo-1-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylate are heated at 140°C for eight hours in 12 ml of N-methylpyrrolidone together with 650 mg 10 (3.6 mmol) of N-(4-fluorophenyl)-piperazine. All the volatile components are removed under high vacuum and the residue is stirred up with iso-propanol and dried at about 100°C. Yield: 580 mg (84% of theory) 15 Melting point: 128-130°C CD DIP 68 - v" vi Example 2 : Ethyl 6-fluoro-l, 4-dihydro-4-oxo-7- (3-phenylpiperazin-1-yl) -1-[4-(1H-1, 2, 3-triazol-l-yl-methyl)-phenyl] -3-quinolinecarboxylate o F >1 .COOEt The title compound is obtained in analogy with Example 1 by reacting with 3-phenylpiperazine after stirring up in acetonitrile. Melting point: 219-221°C Example 3 : 6-Fluoro-l,4-dihydro-4-oxo-7-(4-phenylpiperazin-l-yl)-1-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylic acid 5 286 mg (0.75 mmol) of 6,7-difluoro-1,4-dihydro-4-oxo-1- [4- (lH-l,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylic acid and 364 mg (2.25 mmol) of N-phenyl-piperazine are heated at 120°C for one hour in 7.5 ml of N-methylpyrrolidone. All the volatile constituents 10 are removed under high vacuum and the residue is stirred up with acetonitrile and dried at about 100°C. Yield: 150 mg (38% of theory) Melting point: >290°C The compounds listed in Table 1 are prepared in analogy 15 with the directions in Example 3: 2508? Table 1: Ex. No. Reaction cond. Isolated from M.p.[°C] 1 h / 140"C Iso-prop 225-227 F^\\ // C! d- 1 h / 120"C Iso-prop > 280 ,oe 16 h / RT Acetonitrile > 280 /Et 6- MeO N w // 1 h /100"C Acetonitrile 138-140 1 h / 100'C Acetonitrilc > 280 3 h / 60*C DMF/water 236 - 238 10 1 h / 120"C Iso-prop 217-219 u-4 S /j fcl Example 11 6-Fluoro-1,4-dihydro-4-oxo-7- (3-phenylpiperazin-l-yl)-1- [4- (1H-1,2,3-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboacylic acid 286 mg (0.75 mmol) of 6,7-difluoro-1,4-dihydro-4-oxo-l-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylic acid and 3 65 mg (2.25 mmol) of 3-phenyl-piperazine are heated at 120°C for one hour in 7.5 ml of N-methylpyrrolidone. All the volatile components are removed in vacuo and the residue is stirred up with iso-propanol and dried at about 100°C. Yield: 210 mg (53% of theory) Melting point: 163-165°C iiu n - 72 - Example 12 6-Fluoro-1,4-dihydro-4-oxo-7-[4-(4-hydroxypheny1)-piperazin-l-yl]-1-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylic acid o F ^ A COOH 5 286 mg (0.75 mmol) of 6,7-difluoro-1,4-dihydro-4-oxo-l- [4-(lH-l,2,3-triazol-l-yl-methyl)-phenyl]-3-quinoline-carboxylic acid are heated at 120°C for two hours in 7.5 ml of N-methylpyrrolidone together with 290 mg (0.86 mmol) of N-(4-hydroxypheny1)-piperazine and 385 10 mg (3.4 mmol) of diazabicyclo [2.2.2]octane. All the volatile components are removed under high vacuvim and the residue is stirred up with water and dried at about 100°C. Yield: 390 mg (96% of theory) 15 Melting point: 269-271°C The compounds listed in Table 2 are prepared in analogy with the directions in Example 12: Table 2: , A o '7 w (j £=. R8 COOH Ex. No. Isolated from M.p.[°C] R8 13 14 15 Iso-prop Water Water 248-250 133-135 254-256 \\ // S-CsHs 2 0 Examp1e 16 Ethyl 6-fluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl)-1-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-1,8-naphthyridine-3 -carboxylate o F >1 COOEt 5 0.5 g (1.2 mmol) of ethyl 7-chloro-6-fluoro-l,4- dihydro-4-oxo-l- [4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-1,8-naphthyridine-3-carboxylate are heated at 120°C for four hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine 10 and 460 mg (4.1 nunol) of diazabicyclo [2 .2 .2] octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 430 mg (66% of theory) 15 Melting point: 201-203°C The compounds listed in Table 3 are prepared in analogy with the directions in Example 16: Table 3 d f- : o i i i N. R8 Ex. No. M.p.[°C] 17 180-183 18 115-117 19 86-89 O :" ■ ■ Example 2 0 6-Fluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl] -1, 8-naphthyridine-3-carboxylic acid o f il COOH 300 mg (0.5 mmol) of the ester from Example 16 are heated at 50°C for 1.5 hours together with 1 ml of 1 N sodium hydroxide solution in a mixture consisting of 5 ml of ethanol and 5 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 240 mg (85% of theory) Melting point: 279-281°C (with decomposition) The compounds listed in Table 4 are prepared in analogy with the directions in Example 20: 10 15 hu ft B0 ■»*» - 77 - Table 4: R8 Ex. No. M.p.[°C] 21 225-227 (decomp.) F 22 238-240 (decomp.) CI 23 200-204 (decomp.) r\ r, r ( *. •' , y' ' v-1, v.,- Example 24 Ethyl 6-f luoro-1, 4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl)-1- [4-(2H-1, 2, 3-triazol-2-yl-methyl)-phenyl]-3-quinoline-carboxylate 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-4-oxo-1- [4-(2H-1,2, 3-triazol-2-yl-methyl)-phenyl]-3-quinolinecarboxylate are heated at 120°C for three hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicylco[2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 580 mg (80% of theory) Melting point: 230-232°C The compounds listed in Table 5 are prepared in analogy with the directions in Example 24: BP DIP - 79 - ti ■ i in - 80 - o Example 2 8 6-Fluoro-l,4-dihydro-4-oxo-7-(4-phenylpiperazin-l-yl)-1-[4-(2H-1,2,3-triazol-2-yl-methyl)-phenyl] - 3-quinoline-carboxylic acid 0.5 g (0.9 mmol) of the ester obtained in Example 20 are heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 0.39 g (82% of theory) Melting point: 208-210°C The compounds listed in Table 6 are prepared in analogy with the directions in Example 28: 81 250823 • 15 £ Example 3 2 Ethyl 6-fluoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl) -1- [4- (1H-1,2, 4-triazol-l-yl-methyl) -phenyl] -3-quinoline-carboxylate o F ii COOEt 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-4-oxo-1- [4-(1H-1,2,4-triazol-l-yl-methyl)-phenyl]-3 -quinoline-carboxylate are heated at 120°C for three hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicyclo[2.2.2] octane. All the volatile components are then removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 600 mg (89% of theory) Melting point: 217-218°C The compounds listed in Table 7 are prepared in analogy with the directions in Example 32: ifcu h 00 - 83 - Table 7 : COOEt ex. no. 33 34 35 36 37 38 m.p. [°c] 72-74 98-100 110-112 128-130 126-128 221-225 W /, a fsc- w /, 9 a- w /, f3c £ o ' i t' ,f 1 ') Example 3 9 6-Fluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1- [4- (1H-1,2,4-triazol-l-yl-methyl)phenyl] -3-quinolinecarboxylic acid cooh 10 0.5 g (0.9 mmol) of the ester obtained in Example 32 are heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 0.46 g (82% of theory) Melting point: 234-236°C 15 The compounds listed in Table 8 are prepared in analogy with the directions in Example 39: Iiu ft BO - 85 - Table 8: cooh ex. no, 40 m.p. [°c] 246-248 41 42 244-246 179-181 cl £ ci 43 44 45 264-268 239-241 198-202 F'C-\\ f3c ci- C:;: Example 46 Ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl)-1- [4-(1H-1,2,4-triazol-l-yl-methyl)phenyl] -1,8-naphthyridine- 3 -carboxylate o F il COOEt 5 0.5 g (1.2 mmol) of ethyl 7-chloro-6-fluoro-1, 4- dihydro-4-oxo-l-[4-(1H-1,2,4-triazol-l-yl-methyl)-phenyl]-1,8-naphthyridine-3-carboxylate are heated at 120°C for six hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 nmiol) of N-phenylpiperazine 10 and 460 mg (4.1 mmol) of diazabicyclo[2.2.2]octane. All the volatile components are removed under high vacuum. The residue is stirred up with water and purified by column chromatography (silica gel, methylene chloride/methanol 96/4). 15 Yield: 500 mg (78% of theory) Melting point: 179-180°C The compounds listed in Table 9 are prepared in analogy with the directions in Example 46: Example 50 250823 6-Fluoro-l,4-dihydro-4-oxo-7-(4-phenylpiperazin-l-yl)-1-[4-(1H-1,2,4-triazol-l-yl-methyl)phenyl]-1,8-naphthyxidine-3-carboxylic acid 5 0.45 g (0.8 mmol) of the ester from Example 46 is heated at 50°C for 1.5 hours together with 1.6 ml of 1 N sodium hydroxide solution in a mixture consisting of 8 ml of ethanol and 8 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the 10 solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 0.39 mg (90% of theory) Melting point: 234-238°C (with decomposition) 15 The compounds listed in Table 10 are prepared in analogy with the directions in Example 50: Examp1e 54 25 0 Ethyl 6-fluoro-l,4-dih.ydro-l- [4-(N-imidazolyl-methyl)phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinoline-carboxylate 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-1-[4- (N-imidazolyl-methyl) -phenyl] -4-oxo-3-quinolinecarboxylate is heated at 120°C for five hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicyclo[2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 580 mg (86% of theory) Melting point: 130-133°C The compounds listed in Table 11 are prepared in analogy with the directions in Example 54: o Table 11: Ex. No. M.p. [ °C] R8 55 180-184 56 187-188 57 155-159 ci Example 5 8 6-Fluoro-l, 4-dihydro-l- [4- (N-imidazolyl-methyl) -phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinoline-carboxylic acid o P. .COOH 5 0.5 g (0.9 mmol) of the ester obtained in Example 55 is heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the 10 solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 0.42 g (89% of theory) Melting point: 248-251°C 15 The compounds listed in Table 12 are prepared in analogy with the directions in Example 58: Table 12: 250823 ri r8-n\/ COOH n xs w Ex. No. M.p.[°C] 59 202-205 (decomp.) f 60 242-246 (dccorap.) C! 61 224-227 (dccomp.) CI at -< Example 62 Ethyl 6 - fluoro-1,4-dihydro- 4 -oxo- 7 - (4-phenylpiperazin-1-yl)-1-[3-(1H-1,2,3-triazol-l-yl-methyl)phenyl] -3-quinoline-carboxylate COOEt 5 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-4- oxo-1-[3-(lH-1,2,3-triazol-l-yl-methyl)-phenyl] - 3-quinolinecarboxylate is heated at 12 0°C for three hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) 10 of diazabicyclo[2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at cibout 100°C. Yield: 650 mg (97% of theory) 15 Melting point: 170-172°C The compounds listed in Table 13 are prepared in analogy with the directions in Example 62: - 95 - Excunp 1 e 66 6-Fluoro-l#4-dihydro-4-oxo-7- (4-phenylpiperazi.n-l-yl) -1- [3-(lH-l,2,3-triazol-l-yl-methyl)phenyl] -3-quinoline-carboxylic acid 0.55 g (0.9 mxnol) of the ester obtained in Example 62 is heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1) . Yield: 0.31 g (64% of theory) Melting point: 243-245°C The compounds listed in Table 14 are prepared in analogy with the directions in Example 66: fcu ft 00 - 97 - Table 14: Example 7 0 Ethyl 6-fluoro-l, 4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl) -1- [3 - (2H-1, 2,3- triazol-2-yl-methyl) phenyl] - 3-quinoline-carboxylate 0.5 g (1.2 xranol) of ethyl 6,7-difluoro-l,4-dihydro-4-oxo-1- [3 - (2H-1,2,3 -triazol-2-yl-methyl)phenyl] - 3-quinolinecarboxylate is heated at 120°C for three hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 huhoI) of diazabicyclo[2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 590 mg (89% of theory) Melting point: 112-115°C The compounds listed in Table 15 are prepared in analogy with the directions in Example 70: h B0 DIP - 99 - Example 74 6-Fluoro-l, 4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1- [3- (2H-1, 2,3-triazol-2-yl-methyl)phenyl] -3-quinoline-carboxylic acid 0.5 g (0.9 mmol) of the ester obtained in Example 70 is heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1) . Yield: 0.2 g (42% of theory) Melting point: 233-235°C The compounds listed in Table 16 are prepared in analogy with the directions in Example 74: iia * aa - 101 - Table 16: 0 L , Example 7 8 EtJtiyl 6-fluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl) -1- [3- (1H-1,2,4-triazol-l-yl-methyl) phenyl] -3-quinoline-carboxylate 5 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1, 4-dihydro-4- oxo-1 - [3 - (1H,1,2,4 -triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylate is heated at 120°C for six hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) 10 of diazabicyclo [2 . 2 .2] octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 600 mg (89% of theory) 15 Melting point: 160-162°C The compounds listed in Table 17 are prepared in analogy with the directions in Example 78: - 103 - Example 82 6-Fluoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1- [3- (1H-1, 2, 4-triazol-l-yl-methyl)phenyl] -3-quinoline-carboxylic acid 0.5 g (0.9 mmol) of the ester obtained in Example 7 8 is heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 0.44 g (93% of theory) Melting point: 256-260°C The compounds listed in Table 18 are prepared in analogy with the directions in Example 82: * ao bio - 105 - Table 18: .COOH r:xx>' •° CUS- Ex. No. 83 84 85 M.p. [°C] 202-206 264-268 221-225 R8 ) ci Example 8 6 Ethyl 6- fluoro-1,4-dihydro-4-oxo- 7 - (4-phenylpiperazin-1-yl) -1-[3-{lE-l,2,4-triazol-l-yl-methyl)phenyl]-1,8-naphthyridine- 3 - carboxylate 0.5 g (1.2 mmol) of ethyl 7-chloro-6-fluoro-l,4-dihydro-4-oxo-l- [3- (1H-1,2,4-triazol-l-yl-methyl) -phenyl]-1,8-naphthyridine-3-carboxylate is heated at 120°C for 4 hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicyclo [2.2.2]octane. All the volatile components are removed under high vacuum. The residue is stirred up with water and purified by column chromatography (silica gel, methylene chloride/methanol 9/1) . Yield: 280 mg (43% of theory) Melting point: 109-111°C The compounds listed in Table 19 are prepared in analogy with the directions in Example 86: ii bib - 107 - Example 90 6-Fluoro-l,4-dihydro-4-oxo-7-(4-phenylpiperazin-l-yl)-1-[3-(1H-1,2,4-triazol-1-yl-methyl)phenyl]-1,8-naphthyridine-3-carboxylic acid 0.25 g (0.4 mmol) of the ester from Example 46 is heated at 50°C for 1.5 hours together with 0.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 4 ml of ethanol and 4 ml of water. This mixture is then neturalized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1) . Yield: 0.21 g (90% of theory) Melting point: 264-268°C (with decomposition) The compounds listed in Table 20 are prepared in analogy with the directions in Example 90: BO DIP - 109 - Table 20: r Examp1e 94 Ethyl 6-fluoro-l,4-dihydro-l- [3- (N-imidazolyl-methyl) • phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinoline- carboacylate 5 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-1- [3- (N-imidazolyl-methyl) -phenyl] -4-oxo-3-quinoline-carboxylate is heated at 120°C for four hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of 10 diazabicyclo[2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 590 mg (88% of theory) Melting point: 187-190°C 15 The compounds listed in Table 21 are prepared in analogy with the directions in Example 94: ifcu a no - Ill - Table 21: Ex. No. M.p.[°C] R 95 163-170 96 226-229 97 190-193 250823 CI paa Vtf? Example 9 8 0 o 1 ? 3 6-Fluoro-l,4-dihydro-l- [3- (N-imidazolyl-methyl)phenyl] -4-OXO-7-(4-phenylpiperazin-l-yl)-3-quinoline-carboxylic acid COOH 10 0.5 g (0.9 mmol) of the ester obtained in Example 95 is heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 0.45 g (95% of theory) Melting point: 207-210°C 15 The compounds listed in Table 22 are prepared in analogy with the directions in Example 98: T - « C"IQ - 113 - Table 22: COOH ex. no. 99 100 101 m.p. [°c] 190-192 >300 260-263 Cl I.A u S ft .f ?■ J Example 102 Ethyl 6-fluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl)-1-[2-(1H-1,2,3-triazol-1-yl-methyl) phenyl]-3-quinoline-carboxylate 5 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-4- oxo-1-[2-(lH-l,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylate is heated at 120°C for three hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of M-phenylpiperazine and 460 mg (4.1 mmol) 10 of diazabicylco[2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 580 mg (86% of theory) 15 Melting point: 138-141°C The compounds listed in Table 23 are prepared in analogy with the directions in Example 102: hm Ik ap m - 115 - Table 23: Example 10 6 6-Fluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1-[2-(lH-l,2,3-triazol-l-yl-jnethyl)phenyl]-3-quinoline-carboxylic acid 0.5 g (0.9 mmol) of the ester obtained in Example 102 is heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neturalized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 83 mg (18% of theory) Melting point: 235-238°C (with decomposition) The compounds listed in Table 24 are prepared in analogy with the directions in Example 106 fcb ft 00 - 117 - * Example 110 Ethyl 6-fluoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1- [2- (2H-1,2, 3- triazol-2-yl-methyl)phenyl] -3-quinoline-carboxylate 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-4-oxo-1- [2-(2H-1,2,3-triazol-2-yl-methyl)-phenyl]-3-quinolinecarboxylate is heated at 120°C for three hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicylco [2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water amd dried at about 100°C. Yield: 590 mg (80% of theory) Melting point: 198-200°C The compounds listed in Table 25 are prepared in analogy with the directions in Exaimple 110: fci » aii m - 119 - Table 25: R8 ■o Ex. No. M.p.[°C] R8 111 112 113 217-219 208-210 167-168 c! r-, C Example 114 10 6-Fluoro-l,4-dihydro-4-oxo-7-(4-phenylpiperazin-l-yl)-1-[3-(2H-1,2,3-triazol-2-yl-methyl)phenyl]-3-quinoline-carboxylic acid COOH N | 1 , N r* J N=/ 0.5 g (0.9 mmol) of the ester obtained in Example 110 is heated at 50°C for 1.5 hours together with 1.8 ml of 1 N sodium hydroxide solution in a mixture consisting of 9 ml of ethanol and 9 ml of water. This mixture is then neturalized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 280 mg (60% of theory) Melting point: 270-273°C 15 The compounds listed in Table 26 are prepared in analogy with the directions in Example 114 Mm * BP - 121 - Table 26: 116 117 r8'nn^ Ex. No. M.p.C°C] 115 r9 271-272 291-295 273-276 « n .o 23 Example 118 Ethyl 6-fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-l-yl) -1-[2-(1H-1,2,4-triazol-1-yl-methyl)phenyl]-3 -quinoline-carboxylate 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-4-oxo-1-[2-(1H-1,2,4-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylate is heated at 12 0°C for four hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicyclo [2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100°C. Yield: 420 mg (62% of theory) Melting point: 214-217°C The compounds listed in Table 27 are prepared in analogy with the directions in Example 118: inn * ae - 123 - Table 27: cooet r Ex. No. M.p.[°C] 119 120 121 229-232 222-225 213-216 ii»i ip flfl - 124 - V- <> ■? f'V.3 Example 122 10 6-Fluoro-l, 4-dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) - 1- [2- (1H-1, 2,4-triazol-l-yl-methyl)phenyl] -3-quinoline- carboxylic acid COOH N | JL . ^ N V J 0.3 5 g (0.6 mmol) of the ester obtained in Example 118 is heated at 50°C for two hours together with 1.2 ml of 1 N sodium hydroxide solution in a mixture consisting of 6 ml of ethanol and 6 ml of water. This mixture is then neturalized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1) . Yield: 280 mg (89% of theory) Melting point: 270-274°C 15 The compounds listed in Table 28 are prepared in analogy with the directions in Example 122 ail fillB - 125 - Table 28: Ex. No. M.p.[°C] 123 227-229 124 257-258 125 258-261 cl Example 126 Ethyl 6-fluoro-l, 4-dihydro-l- [2- (N-imidazolyl-methyl) - phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinoline- carboxylate 0.5 g (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-l-[2- (N-imidazolyl-methyl) -phenyl] -4-oxo-3-quinolinecarboxylate is heated at 120 °C for two hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicyclo [2 .2 .2] octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at eibout 100°C. Yield: 470 mg (71% of theory) Melting point: 117-119°C The compounds listed in Table 29 are prepared in analogy with the directions in Example 126: o o Example 13 0 6-Fluoro-1,4-dihydro-1- [2- (N-imidazolyl-methyl) -phenyl] - 4 - oxo - 7 - (4-phenylpiperazin-l-yl) -3-quinoline-carboxylic acid 0.4 g (0.7 mmol) of the ester obtained in Example 126 is heated at 50°C for 1.5 hours together with 1.4 ml of 1 N sodium hydroxide solution in a mixture consisting of 7 ml of ethanol and 7 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol 9/1). Yield: 0.29 mg (79% of theory) Melting point: 260-263°C The compounds listed in Table 30 are prepared in analogy with the directions in Example 130: - 129 - Table 30: Ex. No. M.p. [°C] R8 131 258-262 132 250-254 133 275-278 Li fli 20 5*6- - 130 - tf \\ Example 13 4 6,8-Difluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin-l- yl)-1-[4-(1H-1,2,3 -triazol-1-yl-methyl)phenyl]-3- quinoline-carboxylic acid COOH 5 300 mg (0.75 mmol) of 6,7,8-trifluoro-1,4-dihydro-4- oxo-1- [4- (1H-1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxylic acid are heated at 100°C in 8 ml of DMSO together with 410 mg (2.25 mmol) of N-(4-fluoro-phenyl)-piperazine. All the volatile components are 10 removed under high vacuum and the residue is stirred up with iso-propanol and the resulting solid is isolated. Washing is repeated with iso-propanol and diethyl ether and drying then takes place at about 100°C. Yield: 3 87 mg (92% of theory) 15 Melting point: 222-224°C The compounds listed in Table 31 are prepared in analogy with the directions in Example 134: hm ft 8ci - 131 - Table 31: r8 COOH Ex. No. M.p.[°C] 135 136 137 138 200-202 194-196 220-222 225-227 139 226-228 H 140 248-250 Me o • C -'iti vv' V '4'i Example 141 8-Chloro-6-fluoro-1,4-dihydro-4-oxo-7-[4-(4- fluorophenyl)-piperazin-l-yl] -1-[4-(1H-1,2,3-triazol-l- yl-methyl) -phenyl] -3-qu.inoline-carboxylic acid COOH 10 The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-l,4-dihydro-4-oxo-1- [4- (1H-1,2,3-triazol-1-yl-methyl)-phenyl]-3-quinolinecarboxylic acid with N-(4-fluorophenyl)-piperazine. Melting point: 128-130°C bp fflft - 133 - Example 142 9 h (\ O 8-Chloro-6-fluoro-1,4-dihydro-4-oxo-7-[4-(2- chlorophenyl)-piperazin-l-yl]-1-[4-(1H-1,2,3-triazol-l- yl-methyl)phenyl]-3-quinoline-carboxylic acid COOH 10 The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-1-[4-(1H-1,2,3-triazol-1-yl-methyl)-phenyl] -3-quinolinecarboxylic acid with N-(2-chlorophenyl)-piperazine. Melting point: 158-160°C cm - 134 - Example 14 3 8-Ch.loro-6-f luoro-1, 4-dihydro-4-oxo-7- [4- (4- fluorophenyl)-piperazin-l-yl]-1-[4-(2H-1,2,3-triazol-2 yl-methyl)phenyl] -3-quinoline-carboxylic acid COOH y S yT ! a Ai V 5 The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-1,4-dihydro-4- oxo-1- [4-(2H-1,2,3-triazol-2-yl-methyl)-phenyl] - 3- quinolinecarboxylic acid with N-(4-fluorophenyl)- piperazine. 10 Melting point: 213-215°C c o f' Example 14 4 8-Chloro-6-fluoro-1, 4-dihydro-4-oxo-7- [4- (2-chlorophenyl) -piperazin-l-yl] -1- [4- (2H-1,2,3-triazol-2-yl-methyl)phenyl] -3-quinoline-carboxylic acid The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-l,4-dihydro-4-oxo-1- [4- (2H-1,2,3-triazol-2-yl-methyl)-phenyl] -3-quinolinecarboxylic acid with N-(2-chlorophenyl)-piperazine. Melting point: 228-230°C (under decomposition) In analogy with the directions in Example 144, 6,7,8-trifluoro-1,4-dihydro-4-oxo-l-[4-(1H-1,2,4-triazol-l-yl-methyl)-phenyl] -3-quinolinecarboxylic acid reacts to give the following products: o Ex. No. M.p.[°C] 145 Oil 146 147 148 297 (dccomp.) 278-280 217-219 oe! 149 222-224 -CsH5 Example 150 8-Chloro-6-fluoro-1, 4-dihydro-4-oxo-7- [4- (4- fluorophenyl) -piperazin-l-yl] -1- [4- (1H-1,2#4-triazol-l- yl-methyl)phenyl] -3-quinoline-carboxylic acid o F 11 COOH 5 The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-l,4-dihydro-4- oxo-1-[4-(1H-1,2,4-triazol-l-yl-methyl)-phenyl]-3- quinolinecarboxylic acid with N-(4-fluorophenyl)- piperazine. 10 Melting point: 248-250°C 1. Example 151 8-Chloro-6-fluoro-l,4-dihydro-4-oxo-7- [4- (2- chlorophenyl)-piperazin-l-yl]-1-[4-(1H-1,2,4-triazol-1- yl-methyl)phenyl] -3-quinoline-carboxylic acid COOH 10 The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-l,4-dihydro-4-oxo-1-[4-(1H-1,2,4-triazol-1-yl-methyl)-phenyl]-3 -quinolinecarboxylic acid with N-(2-chlorophenyl)-piperazine. Melting point: 248-250°C fca ft 8fl OA - 139 - # Example 152 6-Fluoro-l,4-dihydro-4-oxo-7-[4-(4-fluorophenyl)-piperazin-l-yl]-1-[4-(1H-1,2,3-triazol-1-yl -methyl)phenyl]-3-quinolinecarboxylic acid propylamide 0.46 ml (3.3 mmol) of triethylamine is added at 0°C to 1.32 g (3 mmol) of 6-fluoro-l,4-dihydro-4-oxo-7-[4-(4-fluorophenyl)-piperazin-l-yl] -1-[4-(1H-1,2,3 -triazol-1-yl-methyl)-phenyl]-3-quinolinecarboxylic acid in 10 ml of acetone. Subsequently, 0.34 ml of ethyl chloroformate is added dropwise at this temperature within the space of 30 minutes. After adding 0.30 ml (3.6 mmol) of propylamine, the mixture is boiled under reflux for 1.5 hours. For the working up, the mixture is added to saturated sodium hydrogen carbonate solution, and then extracted with methylene chloride followed by drying over sodium sulphate. The crude product obtained by evaporation is chromatographed on silica gel (methylene chloride/ methanol 96/4). ft in fclA - 140 - Yield: 0.8 g (57% of theory) Melting point: 202-204°C The compounds listed in Table 3 3 are prepared analogy with the directions in Example 152: Table 33: 0 o jCr° Ex. No. M.p.[°C] 153 194-196 -N N-CH, 154 152-154 -nhch2ch2och3 155 110-112 -N 0 156 223-225 -nhch2ch2oh Example 157 Benzyl 6-fluoro-1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) -piperazin-l-yl] -1- [4- (1H-1,2,3-triazol-l-yl -methyl) phenyl ] - 3 - quinolinecarboxylate 0.14 ml (1.2 mmol) of triethylamine is added at 0°C to 0.44 g (1.0 mmol) of 6-fluoro-1,4-dihydro-4-oxo-7-[4-(4-fluorophenyl)-piperazin-l-yl]-1-[4-(lH-1,2,3-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylic acid in 10 ml of acetone. Subsequently, 0.14 ml (1.2 mmol) of ethyl chloroformate is added dropwise at this temperature within 30 minutes. After adding 0.30 ml (3.6 mmol) of benzyl alcohol, the mixture is boiled under reflux for 2 hours. For the working up, the mixture is added to saturated sodium hydrogen carbonate solution and this mixture is then extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution amd dried over sodium sulphate. The crude product obtained by evaporation is chromatographed on 00 010 - 142 - silica gel 6 0 (eluent: methylene chloride/methanol 9/1) • Yield: 0.35 g (55% of theory) Melting point: 226-228°C The compounds listed in Table 34 are prepared in analogy with the directions in Example 157: Table 34: o o Ex. No. M.p. [°C] 158 > 235 -och3 159 198-200 -OCH2CH2CI 160 >235 1 o. o k,c chj 161 163-165 Example 162 Ethyl 1,4- dihydr o - 4 - oxo - 7 - (4-phenylpiperazin-l-yl) -1-[4- (1H-1,2,4-triazol-1-yl-methyl)phenyl] -1,8-naphthyridinecarboxylate 0.5 g (1.2 mmol) of ethyl 7-chloro-l,4-dihydro-4-oxo-1-[4-(1H-1,2,4-triazol-1-yl-methyl)-phenyl]-1,8-naphthyridine-3-carboxylate is stirred at room temperature overnight in 12 ml of dimethyl sulphoxide together with 0.58 g (3.6 mmol) of N-methylpiperazine. All the volatile components are then removed under high vacuum. The residue is added to water and the mixture is extracted with dichloromethane. The crude product obtained after rotary evaporation is purified on silica gel (eluent dichloromethane/methanol 96/4) . Yield: 475 mg (73% of theory) M.p.: 170-171°C - 144 - Example 163 Ethyl 7- [4- (4-fluorophenyl)piperazin-l-yl] -1,4-dihydro-4-oxo-l- [4- (1H-1,2,4-triazol-l-yl-methyl)phenyl] -1, 8-naphthyr idine- 3 - carboxylate cooc^ The title compound is obtained in analogy with Example 162 by reacting with 1-(4-fluorophenyl)piperazine. M.p.: 176-178°C •BUB—ftP-frO DIP' - 145 - jf- u : "• !■ ■; h . , * • ■> Example 164 1,4-Dihydro-4-oxo-7- (4-phenylpiperazin-l-yl) -1- [4- (1H- 1,2, 4-triazol-l-yl-methyl)phenyl] -1, 8-naphthyridine-3- carboxylic acid COOH 10 0.45 g (0.84 nnnol) of the ester obtained in Example 162 is stirred at 50°C for one hour together with 1.68 ml of 1 N sodium hydroxide solution in a mixture consisting of 8 ml of ethanol and 8 ml of water. This mixture is then neutralized with dilute hydrochloric acid and the solvents are removed in vacuo. The residue is purified on silica gel (eluent, dichloromethane/methanol 96/4) . Yield: 158 mg (37% of theory) M.p.: 286-287°C Uu ft 0 0 - 146 - </div>

Claims

<div class="application article clearfix printTableText" id="claims"> O •-* •• ,, / . i i ' ^ > y fvvj „ ; £ J , Example 165 7- [4- (4-Fluorophenyl)piperazin-l-yl] -1,4-dihydro-4-oxo-1-[4-(lH-l,2,4-triazol-l-yl-methyl)phenyl] -1,8-naph-thyridine-3-carboxylic acid COOH In analogy with Example 164, the ester from Example 163 reacts to give the title compound. M.p.: 284-285°C Mm to 801 - 147 - 250 WHAT WE CLAIM IS 1. Derivatives of quinolonecarboxylic acid and naph- thyridonecarboxylic acid of the general formula (I) (I) 5 in which R1 represents hydrogen, hydroxyl, mercapto, halogen, straight-chain or branched alkyl having up to 3 carbon atoms, perfluoroalkyl having up to 3 carbon atoms, straight-chain 10 or branched alkoxy or alkylthio having in each case up to 6 carbon atoms, arylthio having 6 to 10 carbon atoms, or the group of the formula -NR7R8, in which 15 R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon v>' o r tuaa R* atoms, represents hydrogen, nitro or halogen. R3 represents a residue of the formula r9 _n n — VI/ ' \ R'° in which R and R1 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, or a residue of the formula R" R1 // ^ — n N \ 10 •N // \\ ; N or in which R11, R12 and R13 are identical or different / r. 1 ^ l_ h ip-fc - 149 - o 15 250823 and denote hydrogen, halogen, nitro, hydroxyl, cyano, mercapto, arylthio having 6 to 10 carbon atoms, straight-chain or branched alkyl, 5 alkoxy, acyl or alkylthio having in each case up to 5 carbon atoms, or perfluoroalkyl having up to 4 carbon atoms, A represents a nitrogen atom or represents the 10 group of the formula -CR14, in which R14 denotes hydrogen, halogen, methyl, hydroxyl, methoxy, vinyl or alkinyl, R4 represents a residue of the formula R15 / -(ch2)a_n \is in which a denotes a number 1, 2, 3 or 4, and R15 and R1S, together with the nitrogen atom, form an imidazolyl, pyrrolyl, 1,2,3- triazol-l-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-i-yl, 1,2,4-triazol-4-yl or tetrazolyl ring, represents hydrogen, hydroxyl, halogen, or straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, represents hydroxyl, benzyloxy, morpholino, straight-chain or branched alkoxy having up to 6 carbon atoms, which can be substituted identically or differently up to 3 times by halogen, hydroxyl, or a heterocyclic residue of the represents a group of the formula -NR17R18, in which R17 and R18 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon formula or 25 OR?1 atoms, which is optionally substituted identically or differently up to 3 times by hydroxyl or straight-chain or branched alkoxy having up to 6 carbon 5 atoms, or represents a residue of the formula N ' N-R19, in which 10 R19 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and D represents hydrogen, amino, phenyl, cyano , or hydroxyl, or represents straight-chain or 15 branched alkenyl, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, or represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by straight-chain or 2 0 branched alkoxycarbonyl having up to 4 carbon atoms, and hydrates and salts thereof, optionally in an ,y..T jr. ■ a/" f isomeric form. 2- Derivatives of the general formula (I) according to Claim 1, in which R1 represents hydrogen, hydroxyl, mercapto, fluorine, chlorine, bromine, straight-chain or branched alkyl having up to 3 carbon atoms, trifluoromethyl, straight-chain or branched alkoxy or alkylthio having in each case up to 4 carbon atoms, phenylthio, or the group of the formula -NR7RS, in which R7 and R8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R2 represents hydrogen, nitro, fluorine, chlorine or bromine, R3 represents a residue of the formula /~a R9 -N N — v_y DlO 2r 082 in which R5 and R10 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or R" a residue of the formula °~§y- o- d13 • /—n r w : N or in which 10 15 R11, R12 and R13 are identical or different and denote hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, cyano, phenylthio, straight-chain or branched alkyl, alkoxy, acyl or alkylthio having in each case up to 4 carbon atoms, or trifluoromethyl, represents a nitrogen atom or represents the group of the formula -CR14, ?.*? n q 9 in which R14 denotes hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, vinyl or alkinyl, R4 represents a residue of the formula r15 / ■(CH2)a—N ^r16 in which a denotes a number 1, 2 or 3, and R15 and R1S, together with the nitrogen atom, 10 form an imidazxolyl, pyrrolyl, 1,2,3- triazol-l-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-l-yl, 1, 2,4-triazol-4-yl or tetrazolyl ring, R5 represents hydrogen, hydroxyl, fluorine, 15 chlorine, bromine, or straight- chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, OK c f represents hydroxyl, benzyloxy, morpholino, straight-chain or branched alkoxy having up to 5 carbon atoms, which can be sxibstituted identically or differently up to 2 times by halogen, hydroxyl, or a heterocyclic residue of the formula -o ch3 / lo^ch3 ' represents a group of the formula -NR17R18, in which 10 R17 and Ria are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted identically or differently up to 2 times 15 by hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, or Rfi represents a residue of the formula ft 20 S19. - 156 - /<- t V <*- ^ a — N N-R19, y_/ in which R13 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and D represents methyl, vinyl, phenyl or hydrogen, and hydrates amd salts thereof, optionally in an isomeric form. 3. Derivatives of the general formula (I) according to Claim 1, in which R1 represents hydrogen, fluorine, chlorine, bromine or methyl, R2 represents hydrogen, fluorine or chlorine, R3 represents a residue of the formula ^ r / \ r9 _ n N — v_y R10 in which R® and R10 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, or denote a residue of the formula "k-. o-.v R13 •N N- \\_ or // ^ or : N in which R11, R12 and R13 are identical or different and denote hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, cyano, phenylthio, straight-chain or branched alkyl, alkoxy, acyl or alkylthio having in each case up to 3 carbon atoms, or trifluoromethyl, represents a nitrogen atom or represents the group of the formula -CR14, in which R14 denotes hydrogen, fluorine or chlorine, represents a residue of the formula Ft15 / -CH2 N ^r16 in which R15 and R15, together with the nitrogen atom, form an imidazolyl, pyrrolyl, 1,2,3-triazol-l-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-l-yl or 1,2,4-triazol-4-yl ring, represents hydrogen, represents hydroxyl, benzyloxy, morpholino, straight-chain or branched alkoxy having «.o y o up to 4 carbon atoms, which can optionally be substituted by fluorine, chlorine, bromine, hydroxyl, or by a residue 1-0 CHa kch , j—q ch3 of the formula 5 or represents a group of the formula -NR17R1B, in which R17 and R18 are identical or different and denote hydrogen, or straight-chain or branched alkyl having up to 4 carbon 10 atoms, which is optionally sxibstituted identically or differently up to 2 times by hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms, 15 or 25 R represents a residue of the formula ■N N-R'9 w in which R1 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and D represents hydrogen, and hydrates and salts thereof, optionally in an isomeric form. 4. Process for preparing a compound of the general formula (I) according to Claim 1, characterized in that a compound of the general formula (II) CO- R6 (D) in which R1, R3, R4, R5, Rs, A and D are as defined in claim 1 and E represents halogen, is reacted with a compound of the general formula (III) R3-H (III) in which R3 is as defined in claim 1, in one or more inert solvents, optionally in the presence of an acid-capturing agent , and, in the case of the acid , the ester is hydrolyzed, amd, in the case of the ester , the acid is reacted with the corresponding alcohol according to customary methods, and, in the case of the amide , the acid is amidated, optionally after prior activation and in t ■ : O mm < T the presence of a base and/or auxiliary substance. A process according to claim 4. wherein the halogen is selected from the group comprising chlorine and fluorine. 6- Medicament containing one or more compounds as claimed in any one of claims 1 to 3. 7. Use of the compounds as claimed in any one of claims 1 to 3 for preparing medicaments. 8. Compounds of the general formula (II) (II) in which R1, RJ, R\ R5, Rs, A and D have the meaning given in any one of claims 1 to 3, and E represents halogen. 9. A compound according to claim 8, wherein the halogen is selected from the group comprising chlorine and fluorine. 10. Process for preparing a compound of the general formula (II) according to claim 8, characterised in that a compound of the general formula (IV) R1 O in which R1, Rs, A and E have the meaning given in Claim 8, L represents halogen, R5' represents C1-C4-alkyl, and R1S represents C,-C4-alkoxy or C1-C4-dialkylamino, is initially converted, by reaction with an amine of the general formula (V), NH2 R4 in which r* and Rs are as defined in claim 8, in a solvent, into a compound Qf the general formula (VI) r1 0 r2 E A L NH co-r6' (vi) in which R, R , R\ R5, A, E, L and R6 have the above-mentioned meaning, and, in a final step, the compound of formula(VI) is cyclized in a solvent and a base. A compound of the formula (I) according to claim 1 substantially as herein described or exemplified. A process according to claim A substantially as herein described or exemplified. A compound of the formula (II) according to claim 8 substantially as herein described or exemplified. A process according to ciaiir 10 substantially as herein described or exemplified . BAYER AKTIENGESELLSCHAFT By Their Attorneys henry hughes ^t;p " . "c neys hu fl. do 5*» 165 m \ ^ i- _ ,.o </div>