AU670470B2 - Novel derivatives of quinolonecarboxylic acid and naphthyridonecarboxylic acid - Google Patents

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

Our Ref: 494696 P/00/011 Regulation 3:2

AUSTRALIA

Patents Act 1990

ORIGINAL

COMPLETE SPECIFICATION STANDARD PATENT

D

Applicant(s): Bayer Aktiengesellschaft D-51368 LEVERKUSEN

GERMANY

S* S S Address for Service: Invention Title: DAVIES COLLISON CAVE Patent Trade Mark Attorneys Level 10, 10 Barrack Street SYDNEY NSW 2000 Novel derivatives of quinolonecarboxylic acid and naphthyridonecarboxylic acid The following statement is a full description of this invention, including the best method of performing it known to me:- 5020 The present invention relates to novel derivatives of quinolonecarboxylic acid and napthyridonecarboxylic acid, processes for their preparation and their use as medicaments, in particular as antiviral agents.

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 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.

The present invention now relates to novel derivatives of quinolonecarboxylic acid and napthyridonecarboxylic acid of the general formula (I)

R,

1 0 R RI O

S

CO-R R3 A N

D

Le A 29 518 1 in which

R

1 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 alkylthio having in each case up to 6 carbon atoms, arylthio having 6 to 10 carbon atoms, or represents the group of the formula -NRR 8 in which

R

7 and R 8 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

R

2 represents hydrogen, nitro or halogen, 10 in which

S

and R are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, or a residue of R represents a residue of the formula Ro Le A 29 518 2

R

11 N

N

in which

R"

1

R

1 and R" are identical or different and denote hydrogen, halogen, nitro, hydroxyl, cyano, mercapto, arylthio hav- ing 6 to 10 carbon atoms, straight-chain or branched alkyl, alkoxy, acyl or alkylthio 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 -CR 1 4 in which

R

14 denotes hydrogen, halogen, methyl, hydroxyl, methoxy, vinyl or alkinyl,

R

1

R

4 represents a residue of the formula -(CH 2 )a-N

R

1 6 Le A 29 518 3 d in which a denotes a number 1, 2, 3 or 4,

R

15 and R 16 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-1-yl, 1,2,4-triazol-4-yl or tetrazolyl ring,

R

5 represents hydrogen, hydroxyl, halogen, or represents straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms,

R

6 represents hydroxyl, benzyloxy, morpholino, or straight-chain or branched alkoxy having up to 6 carbon atoms, where the latter can be substituted identically or differently up to 3 times by halogen, hydroxyl, or by a heterocyclic residue of the O CH.

formula 0 or -O CH represents a group of the formula -NR 17

R

18 in which R"1 and R 1 are identical or different and denote Le A 29 518 4 _I 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 by straight-chain or branched alkoxy having up to 6 carbon atoms, or

R

6 represents a residue of the formula -N N-R 19 in which

R'

9 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, D represents hydrogen, amino, phenyl, cyano, hydroxyl, or represents straight-chain or 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 branched alkoxycarbonyl having up to 4 carbon atoms, and hydrates and salts thereof, optionally in an isomeric form.

Physiologically harmless salts of the compounds according Le A 29 518 5 I- 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, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic 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 are preferred i*; in which

R

1 represents hydrogen, hydroxyl, mercapto, fluorine, chlorine, bromine, straight-chain cr 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, phenyl- i"" thio, or represents the group of the formula -NRR 8 in which

R

7 and R 8 are identical or different and denote hydrogen or straight-chain or branched alkyl Le A 29 518 6 having up to 4 carbon atoms,

R

2 represents hydrogen, nitro, fluorine, chlorine or bromine,

R

3 represents a residue of the formula

N-

R -N N Rio in which

R

9 and R 10 are identical or different and denote hydrogen, straight-chain or b.ranched alkyl having up to 4 carbon atoms, or denote a residue of the formula r

N

N02 r N

N

r 0 or in which Le A 29 518 7

R

11 and R 12 and R" are identical or different and denote hydrogen, fluo e, 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, A represents a nitrogen atom or represents the group of the formula -CR 14 in which denotes hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, vinyl or alkinyl, a se seesee se

R

4 represents a residue of the formula -(CH 2 )a-N o as in which a denotes a number 1, 2 or 3,

R

15 and R 16 together with the nitrogen atom, form an imidazolyl, pyrrolyl, 1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-l-yl, Le A 29 518 8 1,2,4-triazol-4-yl or tetrazolyl ring,

R

5 represents hydrogen, hydroxyl, fluorine, chlorine, bromine, or represents straight-chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms,

R

6 represents hydroxyl, benzyloxy, morpholino, or straight-chain or branched alkoxy having up to 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 O- CH 3 CH represents a group of the formula -NR 17

R

1 8 in which R" and R 18 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, Le A 29 518 9

R

6 represents a residue of the formula -N N-R19, in which

R

1 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and oa D represents methyl, vinyl, phenyl or hydrogen, and hydrates and salts thereof, optionally in an isomeric form.

Compounds of the general formula are particularly preferred *0 in which

*SSS

R

1 represents hydrogen, fluorine, chlorine, bromine or methyl,

R

2 represents hydrogen, fluorine or chlorine, Le A 29 518 10

R

3 represents a residue of the formula

R

9 -N N- RIo in which

R

9 and R 10 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

RI,

R

12

R

13

O-N

u

CN

N

or in which

R

11

R

12 and R 13 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, Le A 29 518 11

I

A represents a nitrogen atom or represents the group of the formula -CR 14 in which

R

14 denotes hydrogen, fluorine or chlorine, R1 5 R represents a residue of the formula -C

R

4 represents a residue of the formula -CHr___N in which

R

15 and R 16 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,

R

5 represents hydrogen,

R

6 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, Le A 29 518 12- O CH 3 hydroxyl, or by a residue of the formula ,CH O CH, 3 or represents a group of the formula -NR"7R 18 in which

R

17 and R 18 are identical or different and denote hydrogen, or straight-chain or branched alkyl having up to 4 carbon atoms, which is option- ally substituted identically or differently up to 2 times by hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms, or

R

6 represents a residue of the formula -N N-R, 1 9 in which

R

19 denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, and D represents hydrogen, Le A 29 518 13 and hydrates and salts thereof, optionally in an isomeric form.

In addition, a process for preparing the compounds of the general formula according to the invention has been found which is characterized in that compounds of the general formula (II)

CO-R

6 o* e o II f in which

R

I

R

2

R

4

R

5

R

6 A and D have the abovementioned meaning and E represents halogen, fluorine, preferably chlorine an ~1 are reacted with compounds of the general formula (III) R -H (III) in which Le A 29 518 14

R

3 has the abovementioned meaning, in inert solvents, optionally in the presence of acidcapturing 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: r CO02H C N-H C-H--H N-H 6 s o Le A 29 518 15

CO

2

H

C

2

HSOH

NN

N

0 1) CA)OGZHs N(C 2

H

5 3 2) H 2

N-(CH

2 2 -0H 3 0 F C0 2

C

2

HS

F N Le A 29 518 L-j

S.

o S 54 S S S

CH

5 -H \/N-H 16 CO 2

C

2

HS

OH-

'N

N-

N

0 1)cAJoc;,H. N(C 2

H

5 3 o 0 F C-NH(CH 1) 2

-CH,

NN

2) H 2

N-(CH

2 2

.CH

3 0 0*0* *0 0*000* 0000 The customary inert solvents, which a1re 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 ethers, 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- dime thyl formanide, hexamethylphosphoric triamide, suipholane, ethyl acetate, pyridine, Le A 29 518 17 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.

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, diisopropylethylamine or N-methylpiperidine, or bicyclic amidines, such as 1,4-diazabicyclo[2.2.2]octane (DABCO), diazabicyclo [4.3.0]non-5-ene (DBN) or [5.4.0]undec-5-ene (DBU) Diisopropylethylamine and DABCO are preferred.

The bases are in general employed in a quantity of 1 to 3 mol, preferably of 1 to 1.5 mol, based on 1 mol of the corresponding carboxylic acid.

The process is generally carried out in a temperature range of +0°C to +160°C, preferably of +0 0 C to +140 0

C.

In general, atmospheric pressure is employed. However, it is also possible to carry out the process under negative pressure or under excess pressure in a range from to 5 bar). Suitable solvents to use for the hydrolysis are water or water in combination with a customary organic solvent.

The latter preferably include alcohols, such as methanol, Le A 29 518 18 ethanol, propanol, isopropanol or butanol, or ethers, such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulphoxide. The use of alcohols, such as methanol, ethanol, propanol or isopropanol, is particularly 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 dimethylformamide, 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.

The hydrolysis is generally carried out in a temperature range of 0°C to +130 0 C, preferably of +20 0 C to +1100C. 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 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 mol, based on 1 mol of the ester. The use of molar quantities of the reactants is particularly preterred.

Le A 29 518 19 The hydrolysis of tert-butyl esters is generally effected using acids, such as, for example, hydrochloric acid or trifluoroacetic 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 Cl-CO 2

C

2

H

5 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 In the case of one of the above listed bases, which is inert under the reaction conditions, such as, for example, trithylamine, pyridine or bicyclic amidines, 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 and 0.5 2, preferably 1 1,5, mol of catalyst in the case of in Le A 29 518 20 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, tetrachloromethane, 1,2- dichloroethane, trichloroethane, tetrachloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petro- leum fractions, nitromethane, dimethylformamide, 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 0 C, preferably at 25°C to 40 0

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 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 mol, based on 1 mol of the carboxylic acid.

Le A 29 518 21 The compounds of the general formula (II) are novel and can be prepared by first converting compounds of the general formula (IV) RI 0 R 2

C

2

O-R

6

(IV)

E A L R 16 in which

R

1

R

2 A and E have the abovementioned meaning, L represents halogen, preferably chlorine or fluorine,

R

6 represents C 1

-C

4 -alkyl, and

R

16 represents C 1

-C

4 -alkoxy or Ci-C 4 -dialkylamino, by reaction with amines of the general formula (V)

NH

2

RM

R4 in which

R

4 and R 5 have the abovementioned meaning, in one of the above listed solvents, preferably ethanol, Le A 29 518 22 into the compounds of the general formula (VI)

R

1

O

R, CO-R' I 0 E A L NH

(VI)

R4

R

in which

R

1

R

2

R

4

R

5 A, E, L and R 6 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 K 2

CO

3 /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 0 C to +150 0 C, preferably of +OOC to +120 0

C.

In general, atmospheric pressure is employed. However, it is also possible to carry out the process under negative pressure or under excess pressure in a range from 0.5 to 5 bar).

The compounds of the general formulae (IV) and are Le A 29 518 23 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.

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 The HIV test was carried out according to the method of Pauwels et al [cf. Journal of Virological Methods (1988), 309-321] with minor modifications. Normal human blood lymphocytes (PBL's) were enriched on Ficoll-Hypaque and stimulated with phytohaemagglutinin (90 Ag/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 37 0 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 10 s cells per ml was obtained. The cells which had been infected in this way Le A 29 518 24 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 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 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 0 C until the 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 untreated virus control, while no syncytia were evident in the untreated cell control.

Each IC, 0 value was determined as the concentration of the compound according to the invention at which 50% (about syncytia) of the virus-induced syncytia were sup- pressed by treatment with the compound according to the invention.

Le A 29 518 25 It was found that the compounds according to the invention protect HIV-infected cells from virus-induced cell destruction.

Table A: Ex. No. ICso (Jm) 3 0.7 0.2 0.4 0.7 0.25 0.2 0.7 0.6 2 0.7 69 92 113 146 s The compounds according to the invention represent valuable active compounds for the treatment and prophyiaxis 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: The treatment and prophylaxis of human retroviral infections.

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 r Le A 29 518 26 stages associated therewith, such as ARC (AIDSrelated complex) and LAS (lymphadenopathy syndrome), as well as of the immune weakness and encephalopathy caused by this virus.

For the treatment or prophylaxis of an HTLV-I or HTLV-II infection.

For the treatment or prophylaxis of the AIDS-carrier condition.

Those indications in veterinary medicine which may be listed by way of example are: Infections with a) Maedi-visna (in sheep and goats) b) progressive pneumonia virus (PPV) (in sheep and goats) 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 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 indication in human medicine are preferred.

The present invention includes pharmaceutical Le A 29 518 27 preparations which, in addition to non-toxic, inert and pharmaceutically appropriate excipients, contain one or more compounds of the formula or which consist of one or more active compounds of tha formula as well as processes for producing these preparations.

The active compounds of the formula 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 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 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 in particular 1 to 30, mg/kg of body weight. It may, Le A 29 518 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 2-(4-Aminobenzyl)-2H-1,2,3-triazole

NH

2

N

N/N

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 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).

Le A 29 518 29 Yield: 3.87 g (26% of theory) Melting point: 96-100*C b. 2- (4-Aminobenzyl)-2-H-1,2,3-triazole g (0.017 mol) of 2-(4-nitrobenzyl)-2H-l,2,3-triazole are hydrogenated under atmospheric pressure in 50 ml of ethyl acetate and in the presence of 1g of Pd/C The catalyst is filtered off and ubseguently washed thoroughly with dimethylformanide. The solvents are removed in vacuo.

Yield: 2.1 g (72% of theory) 'H-NMR (dg-DMSO) 5. 4 d 6. 5 (2H) ;d 7. 0 (2H1); s 7.7 (2H).

Le A 29 518 30 Example II and Example III 1- (3-Aminobenzyl) -1H-1,2,3-triazole (II) and 2- (3-Aminobenzyl) -2H-1,2,3-triazole (III)

NH

2

NH

2 a. l-(3-Nitrobenzyl)-lH-1,2,3-triazole and 2-(3-nitrobenzyl)-2H-l,2,3-triazole 12.3 g (0.072 mol) of 3-nitrobenzyl chloride and 5.0 g of 1,2,3-triazole azce 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 is removed in vacuo. The crude product is fractionated by column chromatography (silica gel, methylene chloride/ methanol 96/4).

Yield: 4.1 g of l-(3-nitrobenzyl)-1H-l,2,3-triazole (28% of theory) Melting point: 96-97'C and 4.6 g of 2-(3-nitrobenzyl)-2H-1,2,3-triazole (31% of theory) Le A 29 518 -31- Melting point: 91-931C 4.1 g (0.02 mol) of 1-(3-nitrobenzyl)-lH-l,2,3-triazole are hydrogenated under atmospheric pressure in 100 ml of ethyl acetate together with 1 g of Pd/c 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 11) 1 H{NMR (CDCl 3 8 5.4 m 6.5-6.7 (3 t 7. 15 (1H) s 7. 50 (1H) s 7. 70 (lH).

4.6 g (0.023 mol) of 2-(3-nitrobenzyl)-2H-l,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 1- (2-1Aminobenzy1)-1H-1,2,3-triazole (IV) and 2- (2-aminobenzyl) -2H-1,2,,3-triazole (V) NH NH N

N

(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 Le A 29 518 32 (0.072 mol) of 1,2,3-triazole are heated to reflux for 4 hours in 70 ml of acetone together with 20.2 c (0.15 mol) of potassium carbonate. The cooled mixture is filtered and the solvent is removed in vacuo. The crude 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 of theory) Melting point: 77-80°C 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 6.8 g (0.033 mol) of l-(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 The catalyst is filtered off and then washed thoroughly with dimethylformamide. The solvents are removed in vacuo.

Yield: 5.6 g (97% of theory) 'H-NMR (CDC13) s 5.45 m 6.65-6.85 m 7.10-7.25 s 7.50 s 7.70 (1H) g (0.015 mol) of 2-(2-nitrobenzyl)-2H-1,2,3-triazole are hydrogenated in an analogous manner to Lxample b Yield: 2.4 g (91% of theory) 'H-NMR (CDC1 3 s 5.50 m 6.60-6.85 Le A 29 518 33 m 7.05-7.35 (2H1); s 7.55 (2H1) ExajMle VI 6,7-Difluoro-1,4-dihydro-4-oxo-1- (1H-1,2,3-triazol-1yl-methyl) -phenyl] -3-quinolinecarboxylic acid O 0

F

I I

OH

F) &N N Ety 2.-(2,4,5-trifluorobenzoyl)i-3-[4-(lH-1,2,3triazol-1-yl-methyl) -phenylaiino] -acrylate 11.5 g (0.038 mci) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl)-acrylate are initially introduced into 75 ml of ethanol and 6.7 g (0.038 mol) of. 1-(4-aminobenzyl)-I-- o*.

1,2,3-triazole are added dropwise. The mixture is subsequently 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-1,4-dihydro-4-oxo-1- 14- (11-1,2,3triazol-1-yl-methyl) -ph~tnylJ -3-quinolinecarboxylate Le A 29 518- 4. 34 g (0.035 mol) of the product obtained under a. are heated at 100 0 C for 5 hours in 70 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 1000C.

Yield: 13.2 g (32% of theory) Melting poin-: 1.3-185°C g (24 mmol) of the ester obtained under b. 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 dimethylformamide 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 6 e Le A 29 518 35 Example VII Ethiyl 7-chloro-6-fluoro-1,4-dihydro-4--oxo-1- (1H-1,2,3triazol-l-yl-methyl) -phenyl] 8-naphthyridine-3carboxylate, 0 0

F

QEt C1 N N a. Ethyl 2- (2,5-dichloro-4-fluoro-nicotinoyl) (1H- 1,2, 3-triazol-1-yl-methyl) -phenylamino] -acrylate 2.9 g (8.6 inmol) of ethyl 3-ethoxy-2-(2,5-dichloro-4fluoro-nicotinoyl)-acrylate and 1.5 g (8.6 mmol) of 1-(4aminobenzyl)-1H-1,2,3-triazole are stirred at room 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 5 mmol) of the product obtained under a. are heated at 120*C for 5 hours in 20 ml of dime thyl formamide together with 1.3 g (9.4 mmol) of potassium carbonate.

Le A29 518 36- The cooled mixture is added to ice water and the precipitated product is isolated. It is dried at about 100 0

C.

Yield: 3.05 g (94% of theory) Melting point: 216-220*C Example VIII Ethyl 6,7-difluoro-1,4-dihydro-4-oxo-l- (2H-l,2,3triazol-2-yl-methyl) -phenyl] -3 -quinolinecarboxylate 0 0 a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3-[4-(2H-1,2,3triazol-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-aminobenzyl) -2H- 1,2, 3 -triazole are stirred at room t emperature 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 0 Le A 29 518 37 g (0.012 mol) of the product obtained under a. are heated at 100 0 C for 5 hours in 25 ml of dimethylformamide 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 1000C.

Yield: 4.0 g (85% of theory) Melting point: 203-206 0

C

*9 Le A 29 518 38 Example IX Ethyl 6,7-difluoro-1,4-dihylro-4-oxo-l- (1H-1,2,4triazol-1-yl-methyl) -phenyl 3-quinolinecarboxylate 0 0

F

QEt F N

N

a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3-[4-(lH-l,2,4triazol-1-yl-methyl) 'phenylamino] -acrylate 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-aminobenzyl) -1H-1,2,4-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 g (0.011 mol) of the product obtained under a. are heated at 100 0 C for seven hours in 25 ml of dimethylformaniide together with 1.9 g (0.014 mol) of potassium carbonate. The cooled mixture is added to ice water and Le A 29 518 39 the precipitated product is isolated. It is dried at about 100'C.

Yield: 2.94 g (68% of theory) Melting point: 226-228'C Example X Ethyl 7-chloro-6-fluoro-1,4-dihydro-4-oxo-l- (lH-1,2,4triazol-l-yl-methyl) -phenyl] -1,8-naphthyridine-3carboxylate 0 0

F

NI I I C1 N N N- N, a. Ethyl 2- (2,5-dichloro-4-fluoro-nicotinoyl) (11- 1, 2,4-triazol- 1-yl-methyl) -phenylamino] -acrylate 9.7 g (0.029 mol) of ethyl 3-ethoxy-2-(2,5-dichloro-4fluoro-nicotinoyl)-acrylate and 5.0 g (0.029 mol) of 1- (4-aminobenzyl) -lH-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 Le A29 518

S

S*

%S*

13.3 g (28 inmol) 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 1000c.

Yield: 10.8 g (85% of theory) Melting point: 225-228*C Example XI 6,7-Difluoro-1,4-dihydro-1- (N-imidazolyl-methyl) plienyl] -4-oxo-3-quiinolinecarboxylic acid 0 0

F

OH

F N

N

N

A. Ethyl 2-(2,4,5-trifluorobenzoyl)-3- (N-imidazolylmethyl) -phenylamino] -acrylate 17.2 g (0.057 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl)-acrylate and 10.0 g (0.057 mol) of N-(4-aminobenzyl) -imidazole are stirred at room temperature Le A 29 518 -441 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-imidazolylmethyl)-phenyl]-4-oxo-3-quinolinecarboxylate 24.0 g of the product obtained under a. are heated at 100 0 C for six hours in 200 ml of dimethylformamide together with 14.3 g (0.1 mol) of potassium carbonate.

All the volatile components are removed in vacuo and the 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 0 C 200 mg (0.49 mmol) of the ester obtained under b. are heated at 80 0 C for two hours in a mixture consisting of 1 ml of acetic acid, 1 ml of water and 0.1 ml of concen- trated sulphuric acid. After cooling, the mixture is added to a little ice water and the product is isolated.

Yield: 180 mg (96% of theory) Melting point: >280 0

C

Example XII Ethyl 6,7-difluoro-1,4-dihydro-4-oxo-l-[3-(1H-1,2,3triazol-1-yl-methyl) -phenyl]-3-quinolinecarboxylate Le A 29 518 42 O O

F

OEt S I N F N a. Ethyl 2'-(2,4,5-trifluorobenzoyl)-3-[3-(1H-1,2,3triazol-1-yl-methyl) -phenylamino] -acrylate 5.9 g (0.019 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluoro- O benzoyl)-acrylate and 3.4 g (0.019 mol) of l-(3-amino- 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 0 C 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 dried at a about 1000C.

Yield: 6.2 g (85% of theory) Melting point: 187-189°C Example XIII Le A 29 518 43 Ethyl 6,7-dif luoro-1, 4-dihydro-l- (2H-1, 2,3-triazol-2yl-methyl) -phenyl] -4-oxo-3 -guinolinecarboxylate 0 0

F

OEt F N

ND/

a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3-[3-2H-1,2,3triazol-2-yl-methyl) -phenylaminol -acrylate 4.0 g (0.013 mol) of ethyl 3-ethoxy-2-(1,4,5-trifluorobenzoyl)-acrylate and 2.3 g (0.013 mol) of 2-(3-aminobenzyl)-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 g (0.013 mol) of the product obtained under a. are heated at 1001C for four hours in 30 mI of dimethylformamide 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 100WC.

Yield: 4.5 g (86% of theory) Melting point: 144-146WC Example XIV Le A 29 518 44 Ethyl 6,7-difluoro-l,4-dihydro-l-[3-(lH-1,2,4-triazol-lyl-methyl) -phenyl] -4-oxo-3 -quinolinecarboxLylate 0 0

F

1 1 1C E t F N a. Ethyl 2 5- trif luorobenzoyl) 3-[3 (1H-1, 2,4 triazo-1-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-aminobenzyl)-1I--1,2,4-triazole are stirred overnight in 60 ml of ethanol. All the volatile components are then removed in vco J.0 Yield: 12.4 g of crude product 12.4 g (0.013 mol) of the product obtained under a. are heated at 100 0 C for two hours in 80 ml of dimethylform- amide 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 0

C.

Yield: 10.0 g (84% of theory) Melting point: 175-180*C Le A 29 518 45 Example XV Ethyl 7-ch:Loro-6-fluoro-l,4-dihydro-4-oxo-l- E3-(l-H-l,2,4triazol-1-yl-methyl) -phenyl] 8-naphthyridine-3carboxylate 0 0

F

CEt C1 N N I N a. Ethyl 2-(2,5-dichloro-4-fluoro-nicotinoyl) [3-(lHl,2,4-triazol-1-yl-methyl) -phenylamino] -acrylate 5.7 g (0.017 mol) of ethyl 3-ethoxy-2-(2,5-dichloro-4fluoro-nicotinoyl)-acrylate and 3.0 g (0.017 mol) of 1-(3-aminobenzyl)-1H-l,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 0 C for two hours in 50 ml of dimethylformamide 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 Le A 29 518 46 at about 100 0

C.

Yield: 4.9 g (67% of theory over two steps) Melting point: 186-189'C Example XVI 6,7-Difluoro--1,4-dihydro-1- (N-imidazolyl-methyl) phenyl] -4-oxo-3-quinolinecarboxyic acid 0 0

OH

F

I

F NN

NN

a. Ethyl 2- (2,4,5-triflu-orobenzoyl) (N-imidazolylmethyl) -phenylamino] -acrylate 8.7 g (0.029 mol) of ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyi-acrylate and 5.0 g (0.029 mol) of N-(3-amino- benzyl)-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-difluoro-1,4-dihydro-l-[3-(N-imidazolylmethyl) -phenyl) -4-oxo-3-quinolinecarboxylate 12.3 g of the product obtained under a. are heated at Le A 29 518 -4 47 100°C for two hours in 70 ml of dimethylformamide together with 5 g (0.036 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 (28% of theory over two steps) Melting point: 193-194°C 200 mg (0.49 mmol) of the ester obtained under b. are heated at 80 0 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 0

C

Example XVII Ethyl 6,7-difluoro-l,4-dihydro-4-oxo-l-[2 -(lH-l,2,3triazol-1-yl-methyl) -phenyl] -3-quinolinecarboxylate O O

F

OEt F N: N

N

N, Le A 29 518 48 a Ethyl 2-(2,4,5-trifluorobenzoyl)-3-(2-(lH-1,2,3triazol-l-yl-m .hyl) -phenylamino] -acrylate g (0.016 mol) of ethyl 3-ethoxy.-2-(2,4,5-trifluorobenzoyl)-acrylate and 2.8 g (0.016 mol) of 1-(2-aminobenzyl)-lH-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 6.0 g (0.014 mol) of the product obtained under a. are heated at 100 0 C for four hours in 35 ml, of dimethylformamide 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 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-1- (2H-l,2,3triazol-2-yl-methyl) -phenyl] -3-quiinolinecarboxylate Le A 29 518 -449 0 0

F

O

Et F 'N

N

N==y bNa. Ethyl 2-(2,4,5-trifluorobenzoyl)-3-[2-(2H,-1,2,3triazol-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-aminobenzyl)-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 0 C 4.5 g (0.011 mol) of the product obtained under a. are heated at 100°C for four hours in 25 ml of dimethylform- amide 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 dried at about 100 0 C. Yield: 3.7 g (88% of theory) Melting point: 144-145°C Le A 29 518 50 Example XIX Ethyl 6,7-difluoro-1,4-dihydro-4-oxo-l-[2-(IH-1,2,4triazol-1-yl-methyl)-phenyl]-3-quinolinecarboxylate 0 0 "OEt

N

N

a. Ethyl 2-(2,4,5-trifluorobenzoyl)-3-[2-(1H,-1,2,4triazol-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-aminobenzyl)-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 a. are heated at 100 0 C for 3.5 hours in 80 ml of dimethylformamide 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).

Le A 29 518 51- Yield: 6.5 g (54% of theory) Melting point: 214-216WC Example XX 6,7-Difluoro-1,4-dihydro-1- (N-imidazolyl-methyl) phenyl] -4-oxo-3-quinolinecarboxylic acid 0 0 A. Ethyl 2 4, 5- trif luorobenzoyl) 3- (2 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-aininobenzyl)*-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- (N-imidazolylmethyl) -phenyl] -4-oxo-3-quinolinecarboxylate 7.8 g (0.018 mol) of the product obtained under a. are Le A29 518 52-

V:

heated at 100 0 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 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 0

C

200 mg (0.49 mmol) of the ester obtained under b. are heated at 80 0 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 then extracted with methylene chloride and the solvent removed on a rotary evaporator.

Yield: 67 mg (37% of theory) Melting point: 210-214 0 C (with decomposition) Example XXI 6,7,8-Trifluoro-1,4-dihydro-4-oxo-l- (IH-1,2,3-triazol- 1-yl-methyl)-phenyl]-3-quinolinecarboxylic acid a e r Le A 29 518 53 O 0

F

OH

F N

F

N)

N a. Ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-[4-(1H-l,2,3triazol- l-yl-methyl) -phenylamino] -acrylate 12 g (0.069 mol) of 1-(4-aminobenzyl)-1H-l,2,3-triazole are initially introduced into 120 ml of ethanol and 0 22.0 g (0.069 mol) of ethyl 3 -ethoxy-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: 30.8 g Ethyl 6,7,8-Trifluoro-1,4-dihydro-4-oxo-1- [4-(1H- 1, 2, 3 -triazol -l1-yl -methyl) -phenyl] 3-quinolinecarboxylate 30.8 g (0.069 mol) of the product obtained under a. are heated at 90*C for three hours in 130 ml of dimethylfornamide together with 4.4 g (0.076 mci) of potassium fluoride. The solvent is then removed in vacuo and the Le A 29 518 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 dimethylformamide 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 0 C e o Le A 29 518 55 Example XXII 8-Chloro-6,7-difluoro-1,4-dihydro-4-oxo-1- (1H-1,2,3triazol-1-yl-methyl) -phenyl] -3-quinolinecarboxylic acid 0 0

F

N OH F NY

CI

N

N

a. Ethyl 2- (3-chloro-2,4,5-trifluorobenzoyl) (lH- 00 1,2, 3-triazol-1-yl-methyl) -phenylamino] -acrylate V: 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-trif luorobenzolyl) -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 a* b. Ethyl 8-chloro-6,7--dif luoro-l,4-dihydro-4-oxo-l- £4- (lH-1,2,3-triazol-1-yl-methyl)-phenyl)-3-quinolinecarboxylate Le A 29 518 -556 21.3 g (0.069 mol) of the product obtained under a. are heated at 90 0 C for three hours in 90 ml of dimethylformamide together with 4.9 g (0.050 mol) of potassium fluoride. The solvent is removed in vacuo and the residue 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) Melting point: 120-122 0

C

12.0 g (27 mmol) of the ester obtained under b. are stirred at room temperature for three days together with 700 mg (27 mmol) of lithium hydroxide in a mixture consisting of 120 ml of tetrahydrofuran, 50 ml of dimethylformamide and 6 ml of water. After removing the solvents in vacuo, the crude product is purified by column chro- matography (silica gel, methylene chloride/methanol/ acetic acid 10/1/0.5). Yield: 9.4 g (84% of theory) Melting point: 201-203°C

V

0* oo 0000 0 Le A 29 518 57 Example XXIII 8-Chloro-6,7-difluoro-1,4-diy.dro-4-oxo-1- (2H-1,2,3triazol-2-yl-methyl) -phenyl] -3-quinolinecarboxylic acid 0 0

*N

The title compound 'was obtained in analogy with Example

XXII.

Melting point: >250 0

C

S

S

S.

S

Le A 29 518 58 Example XXIV 6,7,8-Trifluoro-l,4-dihydro-4-oxo--- (lH-1,2,4-triazol- 1-yl -methyl) -phenyl] -3 -quinoliuecarboxylic acid 0 0

F

OH

F

N

N'

N

N

a- Ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-[4-(1H-l,2,4triazol-1-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-tetrafluorobenzoyl)-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-1,4-dihydro-4-oxo-l-[4-(1H- 1, 2,4-triazoJ.-l-yl-methyl) -phenyl] -3-quinolinecarboxylate Le A 29 518 59 10.0 g (0.022 mol) of the product obtained under a. are heated at 90 0 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 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).

Yield: 8.9 g (94% of theory) Melting point: 160-162 0

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 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). Yield: 6.2 g (75% of theory) Melting point: 256-258 0 C o Le A 29 518 60 Example XXV 8-Chloro-6,7-difluoro-1,4-dihydro-4-oxo-1- (1H-1,2,4triazol-1--yl-methyl) -phenyl] -3-quinolinecarboxylic acid 0 0 The title compound was obtained in analogy with Example

XXIV.

Melting point: 232-234*C ft. ft ft 0*ft* ft..

ft ft *4*ftftft ft...

Le A 29 518 -661 Example XXVI N-Isopropyl-[6,7-ditluoro-1,4-dihydro-4-oxo-l (H- 1,2,3-triazol-l-yl-methyl)-phenyl]-3-quinolinecarboxamide] O O

F

F N H

N

N*

2.67 g (7.0 mmol) of 6,7-difluoro-l,4-dihydro-4-oxo-1-[4- (1H-1,2,3-triazol-l-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 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 1N hydrochloric acid and then extracted with methylene chloride. The combined organic phases are washed with saturated sodium hydrogen carbonate solution and satura- ted sodium chloride solution. Following drying over Le A 29 518 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-dif luoro-1,4-dihydro-4-oxo-1- (1H- 1, 2,3 -triazol-1-yl-methyl) -phenyl] -3 -quinolinecarboxamidel 0 0

FN

F N F N *fee ml(.*ml ftityaiei de tOCt 0.95g o 6,7difuoro1,4-ihyro-ooxo..e4 (IH-,2,-trazo-1-y-mehyl-phnyll3-qinoin0 150.28 ml (2.7 iml of tethylaminrfoae is added tdr o 0.95r gdin (2.5 ml(27cl) of 6,-iloo14dihydpro-4-oxole, th Le A 29 518 -663 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 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 with Example XXVII: Table I: o o 'N Ex. No.

XXVIII

XXIX

XXX

XXXI

R

6 -NHC (CHOH) 2

CH

3

-NHCH

2 CH (OH) CH 3

-NHCH

2

CH

2

OH

-NHCH

2

CHOCH

3 M.p. 171-173 75-77 90-92 156-158 Le A 29 518 64 Example XXXII Ethyl 7-chloro-l,4-dihydro-4-oxo-l-[4-(1H-1,2,4-triazoll-yl-methyl)phenyl]-1,8-naphthyridine-3-carboxylate 0 SCOOC 2

H

CI N N N

N'

SN

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 dropwise while cooling in an ice bath. Subsequently, 15.34 g (0.150 mol) of triethylamine are added dropwise at 0°C, as are, after subsequently stirring ior 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 tem- perature. 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.

Le A 29 518 65 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 mg of p-toluenesulphonic acid. The mixture is extracted 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).

c. Ethyl 2-(2,6-dichloronicotinoyl)-3-ethoxyacrylate 43 g (0.162 mol) of the product from b. are heated at 150-160 0 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 under high vacuum at a bath temperature of up to 100 0

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-1,2,4triazol-l-yl-methyl)phenylamino]-acrylate 7 g (0.022 mol) of the product obtained under c. and 3.8 g (0.022 mol) of l-(4-aminobenzyl)-1H-1,2,4-triazole are stirred at room temperature overnight in 40 ml of ethanol. The solvent is removed in vacuo.

Yield: 9.7 g of crude product Le A 29 518 66 26.0 g (0.058 mol) of the product obtained in d. are heated at 80 0 C for four hours in 140 ml of dimethylformamide 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 1000C.

Yield: 18.7 g (78% of theory) 253-256 0

C

o Le A 29 518 67 Preparation examples: Example 1: Ethyl 6-fluoro-7- (4-fluoropiienyl) -piperazin-l-yl] -1,4dihydro-4-oxo-1- (1H-1, 2, 3-triazol-1-yl--methyl) phenylJ -3 -quinolinecarboxylate 0 F COQOt

NJN

F

N 490 mg (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-4- oxo-l- (lH-1,2,3-triazol-l-yl-methyl)-phenyll -3-quinolinecarboxylate are heated at 140 0 C for eight hours in 12 ml of N-methylpyrrolidone together with 650 mg (3.6 nmol) 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 0

C.

Yield: 580 mg (84% of theory) Melting point: 128-130 0

C

Le A 29 518 68 Example 2: Ethyl 6-f luoro-l,4-dihydro-4-oxo-7- (3-phenylpiperazinl-yl) 4- (1H-l,2,3-tciazol-l-yl-methyl) -phenylJ -3quinolinecarboxylate 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

V:

Le A 29 518 -669 Example 3: 6-Fluoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl) 1- (1H-1,2,3-triazol-1-yl-methyl) -phenyl] -3quinolinecarboxylic acid 0 F COOH N ON

N

286 mg (0.75 mmol) of 6,7-difluoro-1,4-dihydro-4-oxo-1- (1H-l,2,3-triazol-l-yl-methyl) -phenyl] -3-quinolinecarboxylic acid and 364 mg (2.25 nmol) of N-phenylpiperazine are heated at 120 0 C for one hour in 7.5 ml of N-methylpyrrolidone. All the volatile constituents are removed under high vacuum and the residue is stirred up with acetonitrile and dried at about 100 0

C.

Yield: 150 mg (38% of theory) Melting point: >290*C The compounds listed in Table 1 are prepared in analogy with the directions in Example 3: Le A 29 518 70 Table 1:

*COOH

R a Ex. No. Reaction cond.

1 h/140C 1 h/120'C 16 h RT 1 h/l00*C 1 h/1000C 3 hI60*C 1 h 120'C Isolated Iso-prop Iso-prop Acetonitrile Acetonitrile Acetonitrile DMF/water Iso-prop from M.p. 0

C]

225 -227 280 280 133-140 280 236 -238 21 7-219

F

dOEt OEt MeO N\

N

N

*9 9 Le A 29 518 71 Example 11 6-Fluoro-1,4-dihydro-4-oxo-7- (3-phenylpiperazin-1-yl) 1- (1H-1,2,3-triazol-1-yl-methyl) -phenyl] -3quinolinecarboxylic acid 0 F COOH

NI

N NN 286 mg (0.75 inmol) of 6,7-difluoro-l,4-dihydro-4-oxo-l- (1H-1,2,3-triazol-1-yl-methyl) -phenyl] -3-quinolinecarboxylic acid and 365 mg (2.25 mmol) of 3-phenylpiperazine are heated at 120 0 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 0 C.

V

Yield: 210 mg (53% of theory) Melting point: 163-165*C Le A 29 518 72 Example 12 6-Fluoro-1,4-dihydro-4-oxo-7- (4-hydroxyphenyl) piperazin-1-yl] (1H-1, 2,3 -triazol-1-yl-methyl) phenyl] -3 -quinolinecarboxylic acid 0 F COOH

IN

N):

HO"' rN

N\\

286 mg (0.75 mmol) of 6,7-difluoro-l,4-dihydro-4-oxo-1- (1H-l,2,3-triazol-1-yl-methyl) -phenyl] -3-quinolinecarboxylic acid are heated at 120*C for two hours in ml of N-methylpyrrolidone together with 290 mg (0.86 mmol) of N-(4-hydroxyphenyl)-piperazine and 385 mg (3.4 =imol) of diazabicyclo octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 1000c.* Yield: 390 mg (96% of theory) Melting point: 269-271*C The compounds listed in Table 2 are prepared in analogy with the directions in Example 12: Le A 29 518 73 Table 2:

F.

N'N

rC01

IN~

Ex. No. Isolated from M.P. 0

C]

ISO-prop Water Water 248-250 133-1 35 254-256

Q-

C I H S. S S SS Le A 29 518 74 Example 16 Ethyl 6-f luoro-1,4-dihydro-4--oxo-7- (4-pheimylpiperazinl-yl) 4- (lH-1,2,3-triazol-l-yl-methyl) -phenyl] -1,8naphthyridine- 3- carboxylate 0 F COOEt N N N

N

K-

N

NI

0.5 g (1.2 mmol) of ethyl 7-chloro-6-fluoro-l,4dihydro-4-oxo-1- (1H-1,2,3-triazol-1-yl-methyl)phenyl] 8-naphthyridine-3-carboxylate are heated at 1200C for four hours in 12 ml of dimethyl suiphoxide together with 190 mg (1.2 mmnol) 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 1001C.

Yield: 430 mg (66% of theory) Melting point: 201-203 0

C

The compounds listed in Table 3 are prepared in analogy with the directions in Example 16: Le A 29 518 -775 Table 3: r

N"

NN

N

Ex. No. M.P.[ 0 C] R 17 180-183 F 18 115-117 C 19 86-89 V\09

C[

*t to.99 Le A 29 518 76 I 111( Example 6-Fluoro-l,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl)- 1-[4-(1H-1,2,3-triazol-l-yl-methyl)-phenyl]-1,8naphthyridine-3-carboxylic acid o F COOH N N N

N

N

300 mg (0.5 mmol) of the ester from Example 16 are heated at 50 0 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 Yield: 240 mg (85% of theory) Melting point: 279-281 0 C (with decomposition) *e The compounds listed in Table 4 are prepared in analogy with the directions in Example Le A 29 518 77 Table 4: 0 N N Ex. No.

21 22 23 M.P. (C]C 225-227 (decom p.) 238-240 (decomp.) 200-204 (deco mp.) F 0 cI 6* 0 0000 0*0* 00..

000*

CO

~0

C

0**0*0 0000 Le A 29 518 78 Example 24 Ethyl 6-f luoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazinl-yl) 4- (2H-1,2 .3-triazol-2-yl-methyl) -phenyl] -3quinoline -carboxylate 0 F COOEt

N

NN

NN

N J- .5g 12 mo) fetyl6,-ifuoo-,-dhyr74 m.5g (1.2 mmol) of Npehyl 6,-difluorand46d0hmgro41 mmol) of diazabicylco[2.2.2Joctane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100 0

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: Le A 29 518 -779 Table Ex. No.

26 27 M.P. V 0

CJ

227-229 187-1 89 189-1 90 F-0

CI

Le A 29 518 8 80 I 11 Example 28 6-Fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl) 1-[4-(2H-1,2,3-triazol-2-yl-methyl)-phenyl]-3quinoline-carboxylic acid o F COOH

N.N

N

I-

N

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 "nared in analogy with the directions in Example 28: Le A 29 518 81 Table 6: Ex. No.

29 31 M.P. E 0

C]

247-249 246-248 197-201 F-0 c l Le A 29 518 82 Example 32 Ethyl 6-f luoro-l,4-dihydro-4 -oxo-7- (4-phenylpiperazinl-yl) 4- (1H-1,2,4-triazol-1-yl-methyl) -phenyl] -3quinoline- carboxylate 0 0.5 g (1.2 mmo)) of ethyl 6,7-difluoro-l,4-dihydro-4oxo-1- (lH-l,2,4-triazol-1-yl-methyl) -phenyl] -3quinoline-carboxylate are heated at 120*C for three hours in 12 ml of dimethyl suiphoxide 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 0

C.

Yield: 600 mg (89% of theory) Melting point: 217-2181C The compounds listed in Table 7 are prepared in analogy with the directions in Example 32: Le A29 518 83 Table 7: OCOOEt Ex. No.

33 34 36 37 38 M.P. E 0 Cl 72-74 98-1 00 110-112 128-1 126-1 28 221 -225 F 0

C

F

3

C

p

V:

Le A 29 518 84 Example 39 6-Fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl)- 1-[4-(1H-1,2,4-triazol-l-yl-methyl)phenyl]-3-quinolinecarboxylic acid o F COOH ^Nr N

N

N

N

N 0.5 g (0.9 mmol) of the ester obtained in Example 32 are heated at 50 0 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 Yield: 0.46 g (82% of theory) Melting point: 234-2360C The compounds listed in Table 8 are prepared in analogy with the directions in Example 39: Le A 29 518 85 Table 8:

*COOH

N

N'

L N Ex. No.

41 42 43 44 Le A 29 518 M.P. E 0

C]

246-248 244-246 179-1 81 264-268 239-241 198-202

F

C,

F

3

C

b-~

C

C C C. S 86 Example 46 Ethyl 6-f luoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin- 1-yl) (1H-l,2,4-triazol-1-yl-methyl)phenyl] -1,8naphthy-ridine carboxylate 0 F COQEt

N

NI

N N N

NN

0.5 g (1.2 mmol) of ethyl 7-chloro-6-fluoro-l,4dihydro-4-oxo-1- (lH-l,2,4-triazol-l-yl-meth,,yl) phenyl] 8-naphthyridine-3-carbox-ylate are heated at 120 0 C for six hours in 12 ml of dimethyl suiphoxide together with 190 mg (1.2 inmol) 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 96/4).

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: Le A 29 518 -887 Table 9:

CN

Ex. No.

47 48 49 M.P. 0

C]

201-203 183-1 170-1 72 F 0

CI

too.

V:.

to Le A 29 518 88 I Example 6-Fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl) 1-[4-(1H-1,2,4-triazol-1-yl-methyl)phenyl]-1,8naphthyridine-3-carboxylic acid 0 F. ,COOH N

'N

N 0.45 g (0.8 mmol) of the ester from Example 46 is heated at 50 0 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 solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol Yield: 0.39 mg (90% of theory) Melting point: 234-238 0 C (with decomposition) The compounds listed in Table 10 are prepared in analogy with the directions in Example Le A 29 518 89 Table

N<N

N

Ex. No.

51 52 53 M.P. 0

CJ

252-256 212-214 217-220

R

8 F-0 /l 0

CA/

S

S

Le A 29 518 -990 Example 54 Ethyl 6-fluoro-1,4-dihydro-l- (N-imidazolylmethyl)phenylJ -4-oxo-7- (4-phenylpiperazin-l-yl) -3quinoline -carboxylate 0 F COOEt N N

N

N

N

0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-l- (N-imidazolyl-methyl) -phenyl] -4-oxo-3quinolinecarboxylate is heated at 1201C 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 diazabicycloE2.2.2]octane. All the volatile components are removed under high vacuum and the.

residue is stirred up with water and dried at about 1000C. 9.

Yield: 580 mg (86% of theory) Melting point: 130-133WC The compounds listed in Table 11 are prepared in analogy with the directions in Example 54: Le A 29 518 91 Table 11: 0 N .COOEt

NN

Ex. No.

56 57 M.P. 0 Cl 180-1 84 187-1 88 155-1 59

R

8 F 0 cI too.

V..

to Le A 29 518 92 Example 58 6-Fluoro-1,4-dihydro-l- [4-(N-imidazolyl-methyl) phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinolinecarboxylic acid o F COOH 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 solvents are removed in vacuo. The residue is purified by column chromatography (silica gel, methylene chloride/methanol Yield: 0.42 g (89% of theory) Melting point: 248-251 0 °C The compounds listed in Table 12 are prepared in analogy with the directions in Example 58: Le A 29 518 93 Table 12:

F,

N

COOH

N

NI:

Ex. No.

59 61 M.P. E 0

C]

202-205 (decomp.) 242-246 (decomp.) 224-227 (decomp.) F 0 cI .i Le A 29 518 94 Exjiple 62 Ethyl 6-f luoro-1,4-dihydro-4-oxo-7- (4-phenylpiperaznl-yl) -1-[3-(lH-l,2,3-triazol-l-yl-methyl)phenyl] -3quinoline- carboxylate 0 F COOEt N N& N N N

I

0.5 g (1.2 mmnol) of ethyl 6,7-difluoro-l,4-dihydro-4oxo-1- [3-(1H-1,2,3-triazol-1-yl-methyl) -phenyl] -3quinolinecarboxylate is heated at 120 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)* of diazabicyclo[2.2.2loctane. All the volatileVcomponents are removed under high vacuum and the residue is stirred up with water and dried at about 1000c.

Yield: 650 mg (97% of theory) Melting point: 170-172*C The compounds listed in Table 13 are prepared in analogy with the directions in Example 62: Le A 29 518 95 Table 13: N-

N

N

Ex. No.

63 64 M.P. 0

C]

117-119 128-1 174-175 F4

S

Le A 29 518 -9 96 Example 66 6-Fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl)- 1-[3-(1H-1,2,3-triazol-1-yl-methyl)phenyl]-3-quinolinecarboxylic acid 0 F COOH SN N

N

N:N

0.55 g (0.9 mmol) of the ester obtained in Example 62 is heated at 50 0 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 0

C

The compounds listed in Table 14 are prepared in analogy with the directions in Example 66: Le A 29 518 97 Table 14:t

N-N

N

Ex. No.

67 68 69 M.P. 0

CJ

233-234 250-253 238-241 F 0 cI *5* a. Le A 29 518 -998 Example Ethyl 6-f luoro-1, 4-dihydro--4-oxo-7- (4-phenylpiperazin- 1-yl) (2H-1,2,3-triazol,-2-yl-methyl)phenyl] -3quinoline- carboxylate 0 F COQEt N N

N,

N

0.5 g (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-4quinolinecarboxylate is heated at 120*C for three hours in 12 ml of dimethyl suiphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 nimol) 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 0 c. S.

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 Le A 29 518 -999 Table 0 F COQEt N N N SIN

N

Ex. No.

71 72 73 M.P. [ICJ 139-1 42 108-110 110-112 F 0

CI

V:

Le A 29 518-10 100 Example 74 6-Fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-l-yl)- 1- (2H-1,2,3-triazol-2-yl-methyl)phenyl] -3-quinolinecarboxylic acid o F COOH N N

N

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 *.1 solvents are removed in vacuo. The residue is purified i by column chromatography (silica gel, methylene chloride/methanol Yield: 0.2 g (42% of theory) Melting point: 233-235 0

C

The compounds listed in Table 16 are prepared in analogy with the directions in Example 74: Le29 518 Le A 29 518 101 Table 16: Ex. No.

76 77 M.P. l 0

C]

208-210 259-263 20 2-208 F 0 cl Le A 29 518-10 102 Example 78 Ethyl 6-f luoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazinl-yl) (1H-1,2,4-triazol-l-yl-methyl)phenylI -3quinoline- carboxylate 0 F OOR N N N:r

N

N

N.,

0.5 g (3.2 mmol) of ethyl 6,7-difluoro--l,4-dihydro-4quinolinecarboxylate is heated at 120*C for six hours in 12 ml of dimethyl suiphoxide together with 190 mg (1.2 inmol) 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 1000c.

Yield: 600 mg (89% of theory) Melting point: 160-162 0

C

The compounds listed in Table 17 are prepared in aa~logy with the directions in Example 78: Le A 29 518-10 103 Table 17: 0 F COOR

N

Ex. No.

79 61 M.P. E 0

CJ

160-162 158-1 134-135 F 0 cI

I.

I

I I

I

*1II I. I 6 Le A 29 518-14- 104 Example 82 6-Fluoro-1,4-dihydro-4-oxo-- (4-phenylpiperazin--yl) (H-1,2,4-triazol-1-yl-methyl)phenyl]-3-quinolinecarboxylic acid o F C

O

OH

N I N

N

0.5 g (0.9 mmol) of the ester obtained in Example 78 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 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: Le A 29 518 105 Table 18: 0 F COOH N NN

R

8 I N Ex. No.

83 84 M.P. V 0

C]

202-206 264-268 221-225

R

8 F 0 cI *9 a a.

Le A 29 518-16- 106 Example 86 Ethyl 6-f luoro-1, 4-dihydro-4-oxo-7- (4-phen~ylpiperazinl-yl) 3- (1H-l,2,4-triazol-1-yl-methyl)phenyl] -1,8naphthyridine carboxylate 0 F COORt l N N N I N

N

0.5 g (1.2 mmol) of ethyl 7-chloro-6-fluoro-1,4dihydro-4-oxo-1- (lH-1,2,4-triazol-1-yl-methyl) phen.ylJ -1,8-naphthyridine-3-carboxylate is heated at 1200C for 4 hours in 12 ml of dimethyl suiphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 inmol) of diazabicyclo[2.2.2Joctane. 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 0

C%

The compounds listed in Table 19 are prepared in analogy with the directions in Example 86: Le A 29 518-10 107 Table 19: 0 F COOEt N N N

IN

Ex. No.

87 88 89 M.P. 0

C]

205-207 1 6-138 133-1 35 Ra F 0

CA

Le A 29 518-10 108 Example 6-Fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl)- 1-[3-(1H-1,2,4-triazol-l-yl-methyl)phenyl]-1,8naphthyridine-3-carboxylic acid o N1 N sodium hydroxide N

NN

II N

N,

0.25 g (0.4 mmol) of the ester from Example 46 is heated at 50 0 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 pur. ied 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 Le A 29 518 109r

I

o r

I

D

Table 0 F GOOH N N N

N.

Ex. No.

91 92 93 M.P. 0

C]

21 3-218 200-202 246-250 Fl a Le A 29 518-10- 110 Example 94 Ethyl 6-fluoro-l,4-dihydro-l- (N-imidazolyl-methyl) phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinolinecarboxylate 0 F COQEt rl NO

NY

(:N

0.5 g (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-l- (N-imidazolyl-methyl) -phenyl] -4-oxo-3-quinolinecarboxylate, is heated at 120WC for four hours in 12 ml, of dimethyl sulphoxide together with 190 mg (1.2 rnmol) of N-phen1peazine and 460 mg(4.1 1'ol 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 0

C.

Yield: 590 mg (88% of theory) Melting point: 187-190*C The compounds listed in Table 21 are prepared in

V

analogy with the directions in Example 94: Le A 29 518-11 ill Table 21:

F

N

N Ex. No.

96 97 M.P. V 0

C]

168-1 70 226-229 190-1 93 F 0 C l Le A 29 518-12- 112 Example 98 6-Fluoro-, 4-dihydro-l-[3-(N-imidazolyl-methyl)phenyl]- 4-oxo-7-(4-phenylpiperazin-l-yl)-3-quinoline-carboxylic acid o F COOH N N N Nf\ 0 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 The compounds listed in Table 22 are prepared in analogy with the directions in Example 98: *e Le A 29 518 113 Table 22:

N

Re Ex. No.

99 100 101 M.P. 0

C]

190-1 92 300 260-263 R 8 F 0 C l *0 S

S..

S

S S

SS

Le A 29 518-14- 114 Example 102 Ethyl 6-f luoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazinl-yl) 2- (lH-l,2,3-triazol-l-yl-methyl)phenyl] -3quinoline- carboxylate 0

NN

L-/

0.5 g (1.2 mmol) of ethyl 6,7-difluoro-1,4-dihydro-4oxo-1- (1H-1,2,3-triazol-1-yl-methyl) -phenyll -3quinolinecarboxylate is heated at 1200C for three hours in 12 ml of dimethyl suiphoxide together with 190 mg (1.2 mmol) of N-pheny-lpiperazine and 460 mng (4.1 immol) of diazabicylco(2.2.2Joctane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 1000oc.

Yield: 580 mg (86% of theory) Melting point: 138-141*C The compounds listed in Table 23 are prepared in analogy with the directions in Example 102: Le A 29 518-15- 115 Table 23: 0 F COOEt

N.

N N Ex. No. M.P. 0

C]

103 119-121 F -0/ 104 128-131 c- 0" 105 125-128\/ Le A 29 518 11 116 Example 106 6-Fluoro-1,4-dihydro -4-oxo-7-(4-phenylpiperazin-1-yl)- 1-[2-(IE-1,2,3-triazol-l-yl-mehyl)phenyl]-3-quinolinecarboxylic acid r r N 1- 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 *0q* 0a 00** Le A 29 518 117 Table 24: F. ICOOH N N N Ex. No.

107 108 109 M.P. CO0] 209-211 208-211 228-231 F 0 C 4-

S

0*SS S S*

S

Le A 29 518-18- 118 Example 110 Ethyl 6-f luoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazinl-yl) (2H-1,2,3 triazol-2-yl-methyl)phenyl] -3quinoline -carboxylate 0 F COOE N N

N

0.5 g (1.2 rnmol) of ethyl 6,7-difluoro-1,4-dihydro-4oxo-1- (2H-l,2,3-triazol-2-yl-methyl) -phenyl] -3quinolinecarbozcylate is heated at 120 0 C for three hours in 12 ml of dimethyl sulphoxide together with 190 mg (1.2 inmol) 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 1000.

Yield: 590 mg (80% of theory) Melting point: 198-200*C

V

The compounds li.sted in Table 25 are prepared in analogy with the directions in Example 110: Le A 29 518-19- 119 Table

N-OON

Ex. No. M.P.[ 0

CJ

21 7-219 208-210 167-168 F 0 cI

V:*

Le A 29 518-12 120 Example 114 6-Fluoro-1,4-dihydro-4-oxo-7-(4-phenylpiperazin-1-yl) 1- (2H-1,2,3-triazol-2-yl-methyl)phenyl] -3-quinolinecarboxylic acid o F COOH

N

N

0.5 g (0.9 mmol) of the ester obtained in Example 110 is heated at 50 0 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 The compounds listed in Table 26 are prepared in analogy with the directions in Example 114 n Le A 29 518 121 Table 26:

F.

RN

IN

COOH

N Ex. No. M.P.[ 0

CJ

271-272 291-295 273-276 F 0

V.

Le A 29 518-12 122 Example 118 Ethyl 6-fluoro-l,4-dihydro-4-oxo-7- (4-phenylpiperazin- 1-yl) (lH-1,2,4-triazol-1-yl-methyl)phenyl] -3quiinoline- carboxylate 0 FD OOEt

NN

Q N N

N

0.5 g (1.2 inmol) of ethyl 6,7-difluoro-1,4-dihydro-4-: oxo-l- (1H-1,2,4-triazol-1-yl-methyl) -phenyll -3quinolinecarboxylate is heated at 1201C 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 diazabicycloE2.2.2]octane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 1000c.

Yield: 420 *mg (62% of theory) Melting point: 214-217*C Tha compounds listed in Table 27 are prepared in analogy with the directions in Example 118: Le A 29 518-12 123 Table 27:

N

Ex. No.

119 120 121 M.P. 0 Cj 229-232 222-225 213-216

R

8 F -0

CI

*e S. Le A 29 518-12 124 Example 122 6-Fluoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazin--yl) 1-[2-(1H-1,2,4-triazol-1-yl-methyl)phenyl]-3-quinolinecarboxylic acid o F COOH N. N

N*

0.35 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 0 C The compounds listed in Table 28 are prepared in analogy with the directions in Example 122 C C Le A 29 518 125 Table 28: 0 F GOOH r N

N

Ex. No. M.P. 0 C] Re 123 227-229 F 0/ 124 257-258 CI 125 258-61 cl Le A 29 518-12 126 Example 126 Ethyl 6-f luoro-1, 4-dihydro-l- (N-imid-Azolyl-methy1) phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinolinecarboxylate 0 F COOEt N NY

(:N

0.5 g (1.2 mmol) of ethyl 6,7-difluoro-l,4-dihydro-l- (N-imidazolyl-methyl) -phenyl] -4-oxo-3quinolinecarboxylate is heated at 120*C for two hours in 12 ml of dimethyl suiphoxide together with 190 mg (1.2 mmol) of N-phenylpiperazine and 460 mg (4.1 mmol) of diazabicyclo(2.2.2Joctane. All the volatile components are removed under high vacuum and the residue is stirred up with water and dried at about 100 0

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: Le A 29 518-12 127 Table 29: F, -CQOEt Ex. No.

127 128 129 M.P. [OCI 122-1 24 123-1 107-1 09

R

8 F 0

S

Le A 29 518-12 128 Example 130 6-Fluoro-1,4-dihydro-l- (N-imidazolyl-methyl) phenyl] -4-oxo-7- (4-phenylpiperazin-l-yl) -3-quinolinecarboxylic acid o F K COOH N N

NLN

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 Yield: 0.29 mg (79% of theory) Melting point: 260-2630C The compounds listed in Table 30 are prepared in analogy with the directions in Example 130: Le A 29 518 129 Table

,COOH

Ex. No. M.p.[VC] 258-262 250-254 275-278 F 0 c l Le A 29 51813 130 Example 134 6, 8-Difluoro-1,4-dihydro-4-oxo-7- (4-phenylpiperazn-lyl) (1-H-1,2,3-triazol-1-yl-methyl)phenylI -3quinoline-carboxylic acid 0 F COOH N #N N F

N

300 mg (0.75 mmol) of 6,7,8-trifluoro-1,4-dihydro-4oxo-l- [4-(lH-1,2,3--triazol-l-yl-methyl) -phenyll -3quinolinecarboxylic acid are heated at 100 0 C in 8 ml of DMSO together with 410 mg (2.25 mmol) of N- (4-f luorophenyl) -piperazine. All the volatile components are removed under high vacuum and the residue is stirred up with iso-propanol and the resulting volid is isolated.

Washing is repeated with iso-propanol and diethyl either and drying then takes place at about 100 0

C.

Yield: 387 mg (92% of theory) Melting point: 222-224*C The compounds listed in Table 31 are prepared in analogy with the directions in Example 134: Le A 29 518-13 131 Table 31:

CIIOH

'NNN

N-

Ex. No. M.P.EC1C 200-202 194-1 96 220-222 MeO Et

C'

H

Me 225-227 226-228 248-250 *0 0 a Le A 29 518-12- 132 rA- fA- I Example 141 a. a a ~a fluorophenyl) -piperazira-1-yl] (1H-1, 2,3-triazolyl-methyl) -phenyl] -3-quinoline-carboxylic acid N

N-

The title compound is obtained in ana~logy with Example 134 by reacting 8-chloro-6,7-difluoro-1,4-dihydro-4oxo-1- (1H-1, 2,3-triazol-1-yl-methyl) -phenyl] -3quinolinecarboxylic acid with N- (4 f luorophenyl) piperazine.

Melting point: 128-130 0

C

C.

C

C.

S

C

C

C

C

eC C C Le A 29 518-13- 133 Example 142 8-Chloro-6-fluoro-1,4-dihydro-4-oxo-7- (2chiorophenyl) -piperazin-l-yl (lH-l,2,3-triazol-lyl-methyl)phenyl] -3-quinoline-carboxylic acid ac"I, The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-1,4-dihydro-4oxo-l- (1H-1,2,3-triazol-1-yl-methyl) -phenyll -3quinolinecarboxylic acid with N-(2-chlorophenyl)piperazine.

Melting point: 158-160 0

C

4 4.

44** .4 V:4* Le A 29 518-14- 134 Example 143 8-chloro-6-fluoro-l,4-dihydro-4-oxo-7- (4fluorophenyl) -piperazin-1-yl] 4- (2H-1,2,3-triazol-2yl-methyl) phenyl] -3-quinoline-carboxylic acid The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-1,4-dihydro-4oxo-l- (2H-1,2,3-triazol-2-yl-methyl) -phenyl] -3quinolinecarboxylic acid with N- fluorophenyl) piperazine.

Melting point: 213-2151C no...

S

S 0*

S

OSSSSS

5 0 500

OS

55S555

S

*SSS

55

SO

Le A 29 518-13 135 Example 144 8-Chloro-6-fluoro-1, 4-dihydro-4-oxo-7- (2chiorophenyl) -piperazin-l1-yl] 1- [4 (2H- 1,2, 3- triazol -2 yl-methyl) phenyl] -3 -quinoline-carboxylic acid 0 The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-1,4-dihydro-4oxo-1- (2H-l,2,3-triazol-2-yl-methyl) -phenyl] -3quinolinecarboxylic acid with N- (2 -chiorophenyl) 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-1- (lH-1,2,4triazol-1-yl-methyl) -phenyl] -3-quinoliiiecarboxylic acid reacts to give the following products: 0* 0 0 00 *00* 0 0000 *00000 00 0 0 0000 0000 0000 000 00 0* 0 0 0* 00 00 0 000000 0000 00 0 0 00 00 0 Le A 29 518-13 136 Table 32:

-CQOH

Ex. No.

145 M.P. 1 0 C1 oil 297 (deco mp.)

R

8

H

QEt Et

C

-C

6

H

278-280 21 7-219 222-224

V:*

Le A 29 518-13 137 Example 150 8-Chloro-6-fluoro-1,4-dihydro-4-oxo-7- (4fluorophenyl) -piperazin-1-yl (1H-1,2,4-triazol-1yl-methyl)phenyl] -3-cruinoline-carboxylic acid I COOH The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-l,4-dihydro-4oxo-1- (lH-1,2,4-triazol-1-yl-methyl) -phenyl] -3quinolinecarboxylic acid with N- fluorophenyl) piperazine.

Melting point: 248-250*C

V:

Le A 29 518-13 138 Example 151 8-Chloro-6-fluoro-1,4-dihydro-4-oxo-7- (2chiorophenyl) -piperazin-1-yl (1H-1,2,4-triazol-lyl-methyl)phenyl] -3-quinoline-carboxylic acid 0 F COOH

N)N

N C1

NN

N

The title compound is obtained in analogy with Example 134 by reacting 8-chloro-6,7-difluoro-1,4-dihydro-4quinolinecarboxylic acid with N-(2-chlorophenyl)piperazine.

Melting point: 248-250 0

C

Le A 29 518-13 139 Example 2152 6-Fluoro-l,4-dihydro-4-oxo-7- (4-f luorophenyl) piperazin-1-yl (lH-l,2,3-triazol-l-ylmethyl) phenyl] -3-quinolinecarboxylic acid propylamide 0 0

F

N N

H

F NCN1 N

N

0.46 ml (3.3 mmol) of triethylamine is added at 0 0 C to 1.32 g (3 mmol) of 6-fluoro-l,4-dihydro-4-oxo-7-[4-(4fluorophenyl) -piperazin-l-yl (lH-l,2,3-triazol-1yl-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 obtaixied by evaporation is chromatographed on silica gel (methylene chloride/ methanol 96/4).

Le A 29 518-14 140 Yield: 0.8 g (57% of theory) Melting point: 202-204*C The compou-nds listed in Table 33 are prepared in analogy with the directions in Example 152: Table 33: 0 0 0N" 9 Ex. No. M.p.[ 0 C1 194-1 96 152-1 54 110-112 223-225 R 6 -N N-O 3

-NHCH

2

CH

2

OCH

3 -N 0

-NHCH

2

CH

2

OH

Le A 29 518-14 141 Example 157 Benzyl 6-fluoro-1,4-dihydro-4-oxo-7- 4-(4fluorophenyl)-piperazin-1-ylJ-1-[4-(1H-1,2,3-triazol-1yl-methyl)phenyl]-3-quinolinecarboxylate o o

F

F J J K -rN j N N

NN

0.14 ml (1.2 mmol) of triethylamine is added at OOC to 0.44 g (1.0 mmol) of 6-fluoro-1,4-dihydro-4-oxo-7-[4- (4-fluorophenyl)-piperazin-1-yl]-l-[4-(1H-1,2,3triazol-1-yl-methyl)-phenyll-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 1 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 and dried over sodium sulphate. The crude product obtained by evaporation is chromatographed on Le A 29 518 142 silica gel 60 (eluent: methylene chloride/methanol 9/1).

Yield: 0.35 g (55% of theory) Melting point: 226-228 0

C

The compounds listed in Table 34 are prepared in analogy with the directions in Example 157: Table 34: 0 0 Ex. No. M.p.[ 0

C]

235 198-200 235 163-1 65 Ra

-OCH

3

-OCH

2

CHZCI

0 0

H

3 C CH 3

CH

3 -0

C;;

Le A 29 518-14 143 Example 162 Ethyl 1,4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl) -1- (1H-1,2,4-triazol-1-yl-methyl)phenyl] -1,8naphthyridinecarboxylate, 0

COOC

2

H

N N N

NN

0.5 g (1.2 mmol) of ethyl 7-chloro-1,4-dihydro-4-oxo-l- (4-(1H-l,2,4-triazol-1-yl-methyl)-phenylJ -1,8naphthyridine-3-carboxylate is stirred at room tempzarature overnight in 12 ml of dimethyl sulphoxide together with 0.58 g (3.6 mmnol) 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 dichioromethane. The crude product obtained after rotary evaporation is purified on silica gel (eluent dichloromethane/methanol 96/4).

Yield: 475 mg (73% of theory) Mop.: 170-171 0 C o Le A 29 518-14 144 ExaLmple 163 Ethyl 7- (4-fluoropohenyl)piperazin-1-yl] -1,4-dihydro- 4-oxo-l- (1H-1,2.4-triazol-1-yl-methyl)plienylj -1,8naphthyridine- 3-carboxylate ,000C 2

HS

The title compound is obtained in analogy with Example 162 by reacting with l-(4-fluorophenyl)piperazine.

176-178'C

C

C

C.

Le A 29 518-14 145 Example 154 1,4-Dihydro-4-oxo-7- (4-phenylpiperazin-1-yl) (1H- 1,2, 4-triazol-1-yl-methyl)phenyl] 8-naphthyridine-3carboxylic acid 0.45 g (0.84 mmol) of the ester obtained in Example 162 is stirred at 501C 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, dichioromethane/methanol 96/4).

Yield: 158 mg (37% of theory) 286-287*C o 0* 0* 0 0**00* Le A 29 518-14 146 Example 165 7- (4-Fluo~eophenyl)piperazin-1-yl] -l,4-dihydro-4-oxo- 1- (1H-1,2.4-triazol-1-yl-.methyl)phenyl] -1,8-naphthyridine-3 -carboxylic acid In analogy with Example 164, the ester from Example 163 reacts to give the title compound.

284-285 0

C

Le A 29 518-14 147

Claims (5)

1. Derivatives of quinolonecarboxylic acid and naph- thyridonecarboxylic acid of the general formula (I) RI 0 R, CO-R 6 R 3 A N D (I) R, in which R 1 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 alkylthio having in each case up to 6 carbon atoms, arylthio having 6 to 10 carbon atoms, or represents the group of the formula -NR 7 R 8 in which R 7 and R' are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon Le A 29 518 148 atoms, R 2 represents hydrogen, nitro or halogen, R 3 represents a residue of the formula R-N N- Ri1 in which R 9 and R 10 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, or a residue of the formula S %00% t oo S R 12 N S CN N No or -N .o t o S *5 in which R 11 R 12 and R 13 are identical or different Le A 29 518 149 and denote hydrogen, halogen, nitro, hydroxyl, cyano, mercapto, arylthio having 6 to 10 carbon atoms, straight-chain or branched alkyl, alkoxy, acyl or alkylthio 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 -CR 1 4 in which R 14 denotes hydrogen, halogen, methyl, hydroxyl, methoxy, vinyl or ethinyl, R 4 represents a residue of the formula R 1 15 -(CH 2 )a-N \R16 in which Sa denotes a number 1, 2, 3 or 4, and R16, together with the nitrogen atom, form an imidazolyl, pyrrolyl, 1,2,3- S Le A 29 518 -150- triazol-l-yl, 1,2,3-triazol-2-yl, 1,2,4- triazol-1-yl, 1,2,4-triazol-4-yl or tetrazolyl ring, R 5 represents hydrogen, hydroxyl, halogen, or represents straight-chain or branched alkyl or alkoxy having in each case up to 6 carbon atoms, R 6 represents hydroxyl, benzyloxy, morpholino, or straight-chain or branched alkoxy having up to 6 carbon atoms, where the latter can be substituted identically or differently up to 3 times by halogen, hydroxyl, or by a hetero- cyclic residue of the r- 0 CH3 formula O CHx or represents a group of the formula -NRR 1 8 in which R1 7 and R 18 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon Le A 29 518 151 atoms, which is optionally substituted identically or differently up to 3 times by hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms, or R 6 represents a residue of the formula -NA N N-R19 in which R 9 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, D represents hydrogen, amino, phenyl, cyano, hydroxyl, or represents straight-chain or 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 option- ally substituted by straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, and hydrates and salts thereof, optionally in an Le A 29 518 152 isomeric form. 10

2. Compounds of the general formula according to Claim 1, in which R 1 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 represents the group of the formula -NR'R 8 in which R 7 and R' are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R 2 represents hydrogen, nitro, fluorine, chlorine or bromine, R 3 represents a residue of the formula R 9 -N N- RIO D o o o Le A 29 518 153 in which R 9 and R 10 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 R11 R 13 N N S\ or N "-N in which R 11 and R 1 2 and R 13 are identical or dif- ferent 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, A represents a nitrogen atom or represents the group of the formula -CR 14 Le A 29 518 154 in which R 14 denotes hydrogen, fluorine, chlorine, bromine, methyl, hydroxyl, methoxy, vinyl or alkinyl, R 4 represents a residue of the formula -(CH 2 )a-N R 16 in which a denotes a number 1, 2 or 3, R 15 and R 16 together with the nitrogen atom, form an imidazxolyl, pyrrolyl, 1,2,3- triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4- triazol-1-yl, 1,2,4-triazol-4-yl or tetrazolyl ring, R s represents hydrogen, hydroxyl, fluorine, chlorine, bromine, or represents straight- chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, Le A 29 518 155- o e r o r R 6 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 hetero- cyclic residue of the formula OCH, or O CH3 represents a group of the formula -NR 17 R 18 in which R 1 and R 18 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, or R 6 represents a residue of the formula Le A 29 518 156- -N N-R19, in which R 19 denotes hydrogen or straight-chain or branched 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.

3. Compounds of the general formula according to Claim 1, in which R 1 represents hydrogen, fluorine, chlorine, bro- mine or methyl, R 2 represents hydrogen, fluorine or chlorine, R 3 represents a residue of the formula Le A 29 518 157- I I e~ R 9 -N N- in which R 9 and R" 1 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 R 1 1 R12 R13 O-N No-- r er r r r -N \=N Nor or __N o o o*~ in which R 11 R 12 and are identical or different and denote hydrogen, fluorine, chlorine, bromine, nitro, hydroxyl, cyano, phenylthio, straight-chain or Le A 29 518 158 L- branched alkyl, alkoxy, acyl or alkylthio having in each case up to 3 carbon atoms, or trifluoromethyl, A represents a nitrogen atom or represents the group of the formula -CR 14 in which R 14 denotes hydrogen, fluorine or chlorine, R 4 represents a residue of the formula R 1 5 0 ,o 16 in which R" and R 6 together with the nitrogen atom, form an imidazolyl, pyrrolyl, 1,2,3- triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,4- triazol-1-yl or 1,2,4-triazol-4-yl ring, R 5 represents hydrogen, R 6 represents hydroxyl, benzyloxy, morpholino or, straight-chain or branched alkoxy having Le A 29 518 159 l"i up to 4 carbon atoms, where the latter can optionally be substituted by fluorine, chlorine, bromine, hydroxyl, or by a residue -0 CH 3 of the formula OCH, O- CH, or represents a group of the formula -NR 7 R 1 in which R 17 and R 1 8 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, or e* o Le A 29 518 160 I R 6 represents a residue of the formula -N N-R19, in which R 19 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 the compounds of the general formula according to Claim 1, characterized in that compounds of the general formula (II) r R, O CO-R 6 Le A 29 518 161 in which S S S R R 2 R 4 R s R 6 A and D have the meaning given in clairs 1 to 3 and E represents halogen, preferably chlorine and fluorine, are reacted with compounds of the general formula (III) R -H (III) in which R 3 has the meaning given in claims 1 to 3 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 amdated, optionally after prior activation and in hi; A 0j Le A 29 518 162 1';%WPDOQSA(;RA494696 KD I 1715,;6

163- the presence of a base and/or auxiliary substance. A composition containing one or more compounds from Claims 1 to 3 in combination with one or more non-toxic, inert and pharmaceutically appropriate excipients. 6. A method for the production of medicaments characterized in that compounds of Claims 1 to 3 and/or one of their physiologically acceptable salts are brought into a suitable dosage form together with at least one pharmaceutically appropriate excipient. 7. Compounds of the general formula (II) E A N D (H) R4 15R in which R, R 4 R 5 A and D have the meaning given in Claims 1 to 3, and E represents halogen, preferably chlorine and fluorine. 8. Process for preparing the compounds of the general 1 D -Os -t 3 oe i formula characterized in that compounds of the general formula (IV) R 1 0 R 2 C0-R 6 (IV) E A L R 16 in which R 1 R 2 A and E have the meaning given in Claim 7, L represents halogen, preferably chlorine or fluorine, R 6 represents C 1 -C 4 -alkyl, and el• R 1 6 represents C 1 -C 4 -alkoxy or Cl-C 4 -dialkylamino, are initially converted, by reaction with amines of the general formula NH 2 2 *0* R R4 in which R 4 and R 5 have the meaning given in claims 1 to 3, Le A 29 518 164 VT oV0' in one of the above listed solvents, preferably ethanol, into the compounds of the general formula (VI) R 0 R 2 CO-R E A L NH (VI) r n r in which R 1 R 2 R 4 R 5 A, E, L and R 6 have the meaning given in claims 1 to 3, and, in a final step, are cyclized in one of the above listed solvents and one of the above listed bases, preferably DMF and K 2 CO 3 /KF, and, in the case where D H, these substituents are varied in accordance with customary methods. i Le A 29 518 v '4 QI;TC' 165 166 9. 'Compounds of the formula methods for their manufacture or pharmaceutical compositions or methods of treatment involving/containing them, substantially as hereinbefore described with reference to the Examples 1 to 165. A method for the treatment of disease which comprises administering to a subject in need of such treatment a therapeutically effective amount of at least ore compound according to anyone of Claim 1 to 4, optionally in association with one or more pharamaceutically acceptable carriers. DATED this 22nd day of May, 1996. o i BAYER AKTIENGESELLSCHAFT By Its Patent Attorneys DAVIES COLLISON CAVE oo* Novel derivatives of quinolonecarboxylic acid and naph- thyridonecarboxylic acid Abstract The invention relates to novel derivatives of quinolonecarboxylic acid and naphthyridonecarboxylic acid of the general formula in which the substituents have the meaning given in the description, to processes for their preparation, and to their use as medicaments, particularly as antiviral agents. p o p* p. o p 4* p oo p p p p o• oo p a *r Le A 29 518