DE4425649A1 - New 1- [4- (aminomethyl) phenyl] substituted quinolonecarboxylic acids - Google Patents

Abstract

The invention provides novel compounds of the general formula (I) in which the symbols have the meanings given in the description, and processes for their production and their use as antiviral agents.

Description

The present invention relates to novel 1- [4- (aminomethyl) phenyl] substituted Quinolonecarboxylic acids, process for their preparation and their use as Medicines, in particular as antiviral agents.

The publication EP 422 485 already contains antiviral quinolone carbon known acid derivatives.

The present invention now relates to novel 1- [4-aminomethyl) phenyl] substituted Quinolonecarboxylic acids of the general formula (I)

in which
A is hydrogen or methyl,
X represents a nitrogen atom or a group of the formula -CH, CF or C-Cl,
R¹ is phenyl, naphthyl, pyridyl, pyrimidyl or pyrazinyl optionally substituted up to 3 times, identically or differently, by nitro, trifluoromethyl, halogen, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio each having up to 8 carbon atoms are,
R² is hydrogen or fluorine,
R³ and R⁴ are the same or different and are hydrogen, an amino protecting group or straight-chain or branched alkyl, alkoxycarbonyl or acyl having in each case up to 8 carbon atoms, or
R³ and R⁴ together with the nitrogen atom form a 6-membered saturated heterocycle, which may also contain another heteroatom from the series N, S or O.
and their hydrates and salts, optionally in an isomeric form.

Physiologically acceptable salts of the compounds of the invention can Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids his. Particular preference is z. Salts with hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, Toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, Propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically harmless salts can also alkali, alkaline earth, silver and Guanidinium salts of the compounds of the invention.

Amino-protective group in the invention are the usual in peptide chemistry used amino protecting groups.  

These preferably include: benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert.butoxycarbonyl, Allyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, fluorenyl-9- methoxycarbonyl, formyl, acetyl, 2-chloroacetyl, 2,2,2-trifluoroacetyl, 2,2,2-tri chloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, Phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4- Dinitrobenzyl, 4-nitrophenyl, 4-methoxyphenyl or triphenylmethyl.

Preference is given to compounds of the general formula (I) in which
A is hydrogen or methyl,
X represents a nitrogen atom or a group of the formula -CH, CF or C-Cl,
R¹ is phenyl, pyridyl, pyrimidyl or pyrazinyl, optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio each having up to 6 Carbon atoms are substituted.
R² is hydrogen or fluorine,
R³ and R⁴ are the same or different and are hydrogen, tert.-butoxycarbonyl, benzyloxycarbonyl or straight-chain or branched alkyl, alkoxycarbonyl or acyl having in each case up to 6 carbon atoms, or
R³ and R⁴ together with the nitrogen atom form a morpholine or piperidine ring,
and their hydrates and salts, optionally in an isomeric form.

Particular preference is given to compounds of the general formula (I) in which
A is hydrogen or methyl,
X represents a nitrogen atom or a group of the formula -CH, CF or C-Cl,
R¹ is phenyl or pyridyl, which are optionally substituted identically or differently up to 2 times by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio having in each case up to 4 carbon atoms,
R² is hydrogen or fluorine,
R³ and R⁴ are the same or different and are hydrogen, tert.-butoxycarbonyl, benzyloxycarbonyl or straight-chain or branched alkyl, alkoxycarbonyl or acyl having in each case up to 4 carbon atoms, or
R³ and R⁴ together with the nitrogen atom form a morpholine ring,
and their hydrates and salts, optionally in an isomeric form.

In addition, a process for the preparation of the compounds of general formula (I) according to the invention was found, characterized in that
Compounds of the general formula (II)

in which
R², R³, R⁴ and X have the abovementioned meaning and
R⁵ is halogen, preferably fluorine or chlorine,
with compounds of the general formula (III)

in which
A and R¹ have the abovementioned meaning,
in inert solvents, if appropriate in the presence of acid scavengers.

The process of the invention can be exemplified by the following equation be explained:  

Suitable solvents are the usual inert solvents for all process steps, which do not change under the reaction conditions. These include preferably organic solvents such as ethers z. As diethyl ether, dioxane or Tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons, such as methylene chloride, Chloroform, carbon tetrachloride, or dimethyl sulfoxide, N, N-dimethylformamide, Hexamethylphosphoric triamide, sulfolane, ethyl acetate, pyridine, acetonitrile, Triethylamine, N-methylpyrrolidone, anisole or picoline. It is also possible Use mixtures of the solvents mentioned. Preference is given to dimethyl sulfoxide and acetonitrile.

Suitable bases for individual reaction steps are the customary basic ones Links. These include, for example, alkali or alkaline earth hydroxides, Pyridine, triethylamine, diisopropylethylamine or N-methylpiperidine, or bicyclic amidines such as diazabicyclo [2,2,3] octane, 1,5-diazabicyclo [3,4,0] -nonenes-5 (DBN) or 1,5-diazabicyclo [3,4,0] undecene-5 (DBU). Is preferred Diisopropylethylamine.  

The bases are generally used in an amount of 1 to 3 mol, preferably from 1 to 1.5 mol, based on 1 mol of the corresponding carboxylic acid used.

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

In general, working at atmospheric pressure. But it is also possible that Procedure at negative pressure or at overpressure (eg in a Range from 0.5 to 5 bar).

The compounds of the general formula (II) are known or new in part and can be prepared by first making compounds of general formula (IV)

in which
X, R 2 and R⁵ have the abovementioned meaning,
R⁶ is C₁-C₄-alkyl,
R⁷ is C₁-C₄ alkoxy or C₁-C₄ dialkylamino, and
Y is halogen, preferably chlorine or fluorine,
by reaction with amines of the general formula (V)

in which
R³ and R⁴ have the abovementioned meaning,
one of the abovementioned solvents, preferably ethanol,
into the compounds of general formula (VI)

in which
R², R³, R⁴, R⁵, R⁶, X and Y have the abovementioned meaning,
transferred, and in a last step in one of the abovementioned solvents and a base mentioned there, preferably cyclized DMF and K₂CO₃,
and the esters saponified.

The process is generally carried out in a temperature range from + 0 ° C to + 150 ° C, preferably from + 0 ° C to + 120 ° C performed.  

In general, working at atmospheric pressure. But it is also possible that Procedure at negative pressure or at overpressure (eg in a Range from 0.5 to 5 bar).

The saponification is generally carried out in a mixture of glacial acetic acid / water and in Presence of an inorganic acid, preferably sulfuric acid or Hydrochloric acid, in a temperature range of 50-100 ° C, preferably at 100 ° C.

The compounds of the general formula (IV) and (V) are known per se or can be prepared according to published methods.

The compounds of the general formula (VI) are new and can then for example, as described above.

Surprisingly, the compounds of the invention showed activity in Lentivirus infected cell cultures. This was demonstrated by the example of the HIV virus become.

HIV infection in cell culture

The HIV test was done with minor modifications by the method of Pauwels et al. (see Journal of Virological Methods 20 [1988], 309-321).

Normal human blood lymphocytes (PBLs) were enriched by Ficoll-Hypaque and in RPMI 1640, 20% fetal calf serum with phytoagglutinin (90 μg / ml) and interleukin-2 (40 U / ml). Infection with the infectious HIV PBLs were pelleted and the cell pellet was subsequently resuspended in 1 ml of HIV. Virus adsorption solution and incubated for 1 hour at 37 ° C.

The virus adsorption solution was centrifuged and the infected cell pellet in Growth medium was added so that 1 × 10⁵ cells were set per ml. The thus-infected cells became 1 × 10⁴ cells / well in wells of 96-well Microtiter plates pipetted.  

The first vertical row of the microtiter plate contained only growth medium and Cells that are not infected, but otherwise treated exactly as described above had been (cell control). The second vertical row of the microtiter plate received only HIV-infected cells (virus control) in growth medium. The The remaining dishes contained the compounds of the invention in different concentrations, starting from the wells of the 3rd vertical Series of microtiter plate from which the test substances in 2-step 2¹⁰fach be diluted.

The test mixtures were incubated at 37 ° C until untreated Virus control, which was typical of HIV syncytia formation (between day 3 and 6 after infection), which was then evaluated microscopically. In the untreated virus control resulted in about 20 under these test conditions Syncytia while the untreated cell control had no syncytia.

The IC₅₀ values were given as the concentration of the treated and infected Cells detected in the 50% (about 10 syncytia) of virus-induced syncytia were suppressed by the treatment with the compound of the invention.

It has now been found that the compounds of the invention HIV infected Protect cells from virus-induced cell destruction.

Expl IC₅₀ (μM) 5 0.3 61 0.3 189 0,002 204 0.3 213 0.03 214 0,015 215 0.03 216 0.3

The compounds of the invention are valuable drugs for treatment and prophylaxis of diseases caused by retroviruses in the Human and veterinary medicine dar.

As indications in human medicine, for example, may be mentioned become:

• 1.) The treatment and prophylaxis of human retrovirus infections.
• 2.) For the treatment or prophylaxis of HIV I (virus of the human immunodeficiency; formerly called HTLV III / LAV) and HIV II Diseases (AIDS) and the associated stages such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome) as well as by This virus caused immunodeficiency and encephalopathy.
• 3.) For the treatment or prophylaxis of HTLV-I or HTLV-II Infection.
• 4.) For the treatment or prophylaxis of AIDS carrier condition (AIDS transmitter state).

Examples of indications in veterinary medicine include:
Infections with

• a) Maedivisna (in sheep and goats)
• b) progressive pneumonia virus (PPV) (in sheep and goats)
• c) caprine arthritis encephalitis virus (in sheep and goats)
• d) Zwoegerziekte virus (in sheep)
• e) infectious anemia (horse) virus
• f) infections caused by the feline leukemia virus
• g) infections caused by the virus of cat immunodeficiency (FIV)
• h) Infections caused by the Monkey Immunodeficiency Virus (SIV)

From the field of indication in human medicine, the above are preferred listed items 2, 3 and 4.

The present invention includes pharmaceutical preparations in addition to non-toxic, inert pharmaceutically acceptable excipients one or a plurality of compounds of the formula (I) or consisting of one or more Active ingredients of the formula (I) exist, as well as processes for the preparation of these Preparations.

The active compounds of the formula (I) are intended in the abovementioned pharmaceutical Preparations, preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 95% by weight of the total mixture.

The pharmaceutical compositions listed above may, in addition to the compounds of the formula (I) also contain other active pharmaceutical ingredients.

The preparation of the pharmaceutical preparations listed above takes place in usual way by known methods, for. B. by mixing the or the active ingredients with the carrier (s).

In general, it has in both the human and the Veterinary medicine proved to be advantageous, the invention or the Active ingredients in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg body weight per 24 hours, optionally in the form of several Single doses to give the desired results. A Single dose preferably contains the active ingredient (s) in amounts of about one to about 80, especially 1 to 30 mg / kg of body weight. It can, however be required to deviate from the stated dosages, in Dependence on the type and body weight of the object to be treated, the nature and severity of the disease, the method of preparation and the Application of the drug as well as the period or interval, within which the administration takes place.  

Explanations to the experimental part:

DC systems Stationary phase

Merck DC Finished Plates Kieselgel 60 F-254, 5 × 10 cm, layer thickness 0.25 mm, Item No. 5719th

Mobile phases (in the test as "DC system")

I: CH₂CL₂ / MeOH 9: 1
II: CH₂Cl₂ / MeOH 95: 5
III: NH₃ / CH₂Cl₂ / MeOH 0.2: 9: 1
IV: acetic acid / CH₂Cl₂ / MeOH 0.2: 9: 1
V: CH₂Cl₂ / MeOH 10: 1
VI: toluene / ethanol 5: 1
VII: Petroleum ether / ethyl acetate 6: 1
VIII: NH₃ / CH₂Cl₂ / MeOH 2: 80: 20
IX: HOAc / CH₂Cl₂ / MeOH 0.1: 10: 1
X: toluene / acetone 2: 1
XI: CH₂Cl₂ / MeOH / NH₃ 95: 5: 0.2
XII: CH₂Cl₂
XIII: CH₂Cl₂ / MeOH 80:20
XIV: chloroform / MeOH / water / acetic acid 100: 50: 2: 2
XV: glacial acetic acid / n-butanol / water 1: 3: 1
XVI: toluene / ethanol 1: 1

HPLC system

Column Nucleosil 102-5 C 18.5 μm, 125 × 4 mm eluent;
A = 0.01 M H₃PO₄, B = acetonitrile
Eluentenprogramm.
0-1 min: 10% B
1-9 min: gradient with 10% B / min
9-13 minutes: 90% B
Flow: 2 ml / min, room temperature
5 μl, amount of sample approx. 1 mg / ml
Detection: UV diode array at 210 nm

The retention indices refer to a series of homologous 2-alkanones (Methyl n-alkyl ketones): C3 = 300, C4 = 400, C16 = 1600

starting compounds Example I 4- (N-tert-butyloxycarbonylaminomethyl) nitrobenzene

50 g (0.265 mol) of 4-nitrobenzylamine hydrochloride (Aldrich) and 73.5 ml (0.53 mol) of triethylamine are suspended in 600 ml of dioxane and stirred for 30 minutes at room temperature. 63.5 ml (0.291 mol) of di-tert-butyl dicarbonate (Boc₂O) are added dropwise with ice-cooling and stirring, and the mixture is allowed to come to room temperature overnight. The precipitate is filtered off with suction and the filtrate is concentrated to dryness. The residue is taken up in 500 ml of diethyl ether and the organic phase is extracted by shaking three times with 300 ml of water. The organic phase is dried over sodium sulfate and freed from the solvent on a rotary evaporator. The residue is thoroughly stirred in 300 ml of n-hexane, filtered off with suction, washed with n-hexane and dried at 30 ° C. in a high vacuum.
Yield: 51.8 g (77.5% of theory)
DC system XI: R _f = 0.91
MS (DCI): m / z 253 (M + H); m / z 197; m / z 153 (base peak)
1 H-NMR (CDCl₃): δ = 1.47 (s, 9H); 4.41 (d, 2H); 5.05 (s, (broad) 1H); 7.45 (m, 2H) and 8.20 (m, 2H), AB system.

Example II 4- (t-tert.Butoxycarbonylaminomethyl) aniline hydrochloride

14 g (55.5 mmol) of the compound from Example I are dissolved in 150 ml of methanol and treated with 55.5 ml (55.5 mmol) of 1 normal aqueous hydrochloric acid. After addition of 2 g of palladium on carbon (10%) is hydrogenated at atmospheric pressure until the completion of hydrogen uptake. The batch is filtered through a diatomaceous earth layer to remove the catalyst. It is washed with methanol and concentrated the combined organic phase on a rotary evaporator at a bath temperature of 35 ° C to dryness. The residue is triturated with 200 ml of diethyl ether, filtered off, washed with diethyl ether and dried at 30 ° C under high vacuum.
Yield: 13.3 g (92.9% of theory)
DC system XI: R _f = 0.64
MS-DCI: m / z 223 (M + H); m / z 106 (base peak)
Hydrochloride 1 H-NMR (CD₃OD): δ = 1.41 (s, 9H); 4.25 (s, 2H), 4.88 (s, broad, 3 + 1H); 7.31-7.47 (m, 4H)
Free base 1 H-NMR (CDCl₃): δ = 1.46 (s, 9H); 3.64 (s, broad, 2H); 4.18 (d, 2H); 4.74 (s, broad, 1H); 6.64 and 7.06 (each 2 H, arom. AB system)

Example III 4- (morpholinomethyl) aniline hydrochloride

10.6 g (47.7 mmol) of 4- (morpholinomethyl) -nitrobenzene (obtainable by reacting 4-nitrobenzylchloride with morpholine) are dissolved in 50 ml of dimethylformamide. The mixture is mixed with 25 .mu.l of 1 normal aqueous hydrochloric acid and hydrogenated after addition of 1 g of palladium on carbon (10%) for 2 days at 3 bar. The catalyst is separated on a kieselgurbett and the filtrate is concentrated to dryness in a high vacuum. The residue is taken up in 200 ml of dichloromethane and the solution extracted four times with water, which is adjusted to pH 5 with 1 normal hydrochloric acid during each extraction. The combined aqueous phases are washed at pH 5 with dichloromethane and concentrated in a high vacuum to dryness. The yellow residue is triturated with 300 ml of diethyl ether, filtered off with suction and dried after washing with diethyl ether at 30 ° C under high vacuum.
Yield: 5.3 g (48.5% of theory)
DC system IV: R _f = 0.20
DC system I: R _f = 0.49
MS-EI: m / z 192 (M⁺); m / z 106 (base peak)
1 H-NMR (DMSO): δ = 2.88-3.22 (m, 8H); 4.12 (s, 2H); 6.78 (2H) nd 7.34 (2H); AB system (3.82 (broad, H₂O + NH₂ × HCl group)

Example IV 7-fluoro-1,4-dihydro-4-oxo-1- [4- (N-tert-butoxycarbonyl-methyl) phenyl] - 3-quinolinecarboxylic acid

a) 2- (2,4-Difluorobenzoyl) -3- [4- (N-tert-butoxycarbonylmethyl) phenyl amino] acrylic acid ethyl ester

13 g (50 mmol) of the compound from Example II are stirred with 6.9 ml (50 mmol) of triethylamine in 100 ml of ethanol for 15 minutes. Under ice-cooling, a solution of 14.8 g (52 mmol) of ethyl 3-ethoxy-2- (2,4-difluorobenzoyl) -arylate in 100 ml of ethanol is added dropwise to the suspension. It is stirred for three hours in an ice bath and allowed to come to Raumtemperataur overnight. The solvent is stripped off and the residue is triturated with 300 ml of diethyl ether, filtered off and dried. The crude product (22.7 g) is reacted directly to the next stage.
DC system VI: R _f = 0.38

b) 7-Fluoro-1,4-dihydro-4-oxo-1- [4- (N-tert-butoxycarbonyl-methyl) -phenyl] -3- quinolinecarboxylate

22.6 g of the crude product from a) are stirred with 34 g (0.346 mol) of potassium carbonate in 100 ml of dimethylformamide for 8 hours at room temperature. It sucks from the insoluble and washed the residue with ethanol. The combined filtrates are concentrated to dryness in a high vacuum. The residue is triturated with diethyl ether, filtered off with suction and dried under high vacuum.
Yield: 16.2 g (73.6% of theory with respect to Example II)
DC system VI: R _f = 0.46
MS-DCI: m / z 441 (M + H)

2.3 g (5 mmol) of the ester from b) are dissolved in 15 ml of dioxane and treated with 7.5 ml (15 mmol) of a 2 normal aqueous solution of lithium hydroxide. The suspension is stirred for 4 hours at room temperature (TLC). The mixture is adjusted to pH 3 by addition of 1 normal aqueous hydrochloric acid and stirred for 10 minutes. It is suctioned off and the residue is washed first with water, then with n-pentane and finally dried at 30 ° C in a high vacuum.
Yield: 1.76 g (85.4% of theory)
DC system III: R _f = 0.16
MS-DCI: m / z 413 (M + H) ⁺; m / z 368 (M-CO₂); m / z 313 (+) FAB-MS; m / z 413 (M + H); m / z 435 (M + Na); m / z 519 (M + Ag)
1 H-NMR (DCOOD): δ = 1.52 (s, 9H); 4.68 (s, 2H); 7.06 (m, H); 7.57 (m, 1H); 7.78 (m, 2H) and 7.96 (m, 2H); AB-system; 8.28 (s, 1H); 8.66 (m, 1H); 9.13 (s, H)

Example V 6,7,8-trifluoro-1,4-dihydro-4-oxo-1- [4- (N-tert-butoxycarbonyl-methyl) phenyl] -3- quinolinecarboxylic

The title compound is prepared analogously to Example IV starting from ethyl 3-ethoxy-2- (2,3,4,5-tetrafluorobenzoyl) acrylate and the compound from Example II.
DC system III: R _f = 0.31
HPLC system I: R _f = 6.956 min
(+) FAB-MS: m / z 475 (M + H)
1 H-NMR (CF₃COOD): δ = 1.66 (s, 9H); 4.64 (d, 2H); 7.70-7.95 (m, 4 + 1H); 8.45 (m, 1H); 9.30 (s, 1H)
Analytical data of the precursors:

• Va) 2- (2,3,4,5-tetrafluorobenzoyl) -3- [4- (N-tert-butoxycarbonyl-methyl) -ph-enyl-amino] -acrylic acid ethyl ester
  DC system XII: R _f = 0.21
  (+) FAB-MS: m / z 497 (M + H)
• Vb) ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxo-1- [4- (N-tert-butoxycarbonylamino-methyl) -phenyl-3-quinolinecarboxylate
  DC system II: R _f = 0.81
  (+) FAB-MS: m / z 477 (M + H); m / z 499 (M + Na)
  1 H-NMR (DMSO): δ = 1.22 (t, 3H); 4.15-4.30 (m, 2 + 2H); 7.41 (2H); and 7.65 (2H) AB system; 7.52 (m, 1H); 8.02 (m, 1H); 8.31 (s, 1H)

Example VI 6,7-difluoro-1,4-dihydro-4-oxo-1 [4- (N-t-butyloxycarbonyl-aminometh-yl) phenyl] - 3-quinolinecarboxylic

The title compound is prepared analogously to Example IV starting from 3-ethoxy-2- (2,4,5- Trifluorbenzoyl) -acrylic acid ethyl ester and the compound of Example II manufactured.

Example VII 8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-1- [4- (N-tert.butyloxycarbonyla-mino-methyl) - phenyl] -3-quinolinecarboxylic acid

The title compound is prepared analogously to Example IV starting from 3-ethoxy-2- (3-chloro 2,4,5-trifluorobenzoyl) -acrylic acid ethyl ester and the compound from Example II manufactured.

Example VIII 7-chloro-1,4-dihydro-4-oxo-1- [4- (N-tert-butoxycarbonylamino-methyl) -p-henyl] -1,8- naphthyridine-3-carboxylic acid

The title compound is prepared analogously to Example IV starting from 2- (2,6- Dichlornicotinoyl) -3-ethoxyacrylsäureethylester and the compound of Example II manufactured.  

Example IX 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- [4- (N-tert-butoxycarbonylamino-m-ethyl) - phenyl] -1,8-naphthyridine-3-carboxylic acid

The title compound is prepared analogously to Example IV starting from 3-ethoxy-2- (2.5- dichloro-4-fluoro-nicotinoyl) -acrylic acid ethyl ester and the compound of the Example II.

Example X 7-fluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylamino-methyl) -phenyl] -ch inolin-3- carboxylic acid hydrochloride a) 2- (2,4-Difluorobenzoyl) -3- [4- (N, N-dimethylamino-methyl) -phenylamino] - acrylic acid ethyl ester

44.8 g (0.158 mol) of ethyl 3-ethoxy- (2,4-difluorobenzoyl) acrylate are dissolved in 100 ml of ethanol and, with ice-cooling and stirring, a solution of 23.88 g (0.158 mmol) of 4- (N, N- Dimethylaminomethyl) aniline (BAYER) dissolved in 50 ml of ethanol. The mixture is stirred for 3 hours at room temperature, the solvent removed in vacuo and the oily crude product directly to the next stage.
Yield: 67 g of oil
DC system I: R _f = 0.50

b) 7-Fluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylamino-methyl) -phenyl] -3- quinolinecarboxylate

67 g (assuming 0.158 mol) of the crude product from a) are stirred with 88 g (0.158 mol × 4.03) of potassium carbonate in 180 ml of dimethoxyethane for 7 hours at room temperature. It is filtered off from the undissolved and the residue is washed several times with dichloromethane. The combined organic phases are concentrated to dryness in vacuo and the resulting crude oily product is dried to constant weight under high vacuum. The crude product is transferred directly to the next stage.
Yield: 65 g of oil
DC system IV: R _f 0.33

65 g (assumed 0.158 mol) of the crude ester from b) are stirred for 1.5 hours with 180 ml of 4 normal aqueous hydrochloric acid at 110 ° C at reflux. It is allowed to come to room temperature and sucks. The filter cake is first washed twice with the filtrate, then with a little water (30 ml). The solid is washed with 50 ml of diethyl ether and then worked up on the filter with 100 ml of diethyl ether. It is suctioned off and washed three times with 100 ml of diethyl ether. The product is dried at 35 ° C in vacuo over calcium chloride.
Yield: 39.2 g (62.5% of theory)
DC system III: R _f = 0.33
DC system XIII: R _f = 0.64
(+) FAB-MS: m / z 341 (M + H); m / z 447 (M + Ag)
1 H-NMR (CDOOD): δ = 3.15 (s, 6H), 4.67 (s, 2H); 7.19 (dd, 1H); 7.65 (m, 1H); 7.82-8.08 (m, 4H); 8.71 (dd, 1H); 9.27 (s, 1H)

Example XI 6,7-difluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylamino-methyl) phenyl] - 3- quinolinecarboxylic acid hydrochloride

The title compound is prepared analogously to Example X starting from ethyl 3-ethoxy- (2,4,5-trifluorobenzoyl) acrylate and 4- (N, N-dimethylamino-methyl) -aniline.
DC System VIII: 0.32
(+) FAB-MS: m / z 359 (M + H)
1 H-NMR (DCOOD): δ = 3.10 (s, 6H); 4.62 (s, 2H); 7.32 (m, 1H); 7.88-8.02 (m, 4H); 8.40 (m, 1H); 9.19 (s, 1H); [8.24 and 10.60 DCOOD].

Example XII 6,7,8-trifluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylamino-methyl) phen yl] -3- quinoline-carboxylic acid hydrochloride

The title compound is prepared analogously to Example X starting from 3-ethoxy- (2,3,4,5- tetrafluorobenzoyl) -acrylic acid ethyl ester and 4- (N, N-dimethylaminomethyl) aniline manufactured.

Example XIII 8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylaminomethyl) - phenyl] -3- quinoline-carboxylate a) 2- (3-Chloro-2,4,5-trifluorobenzoyl) -3- [4- (N, N-dimethylamino-methyl) -] phenylamino] acrylic acid ethyl ester

6.4 g (19 mmol) of ethyl 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) acrylate are dissolved in 11 ml of ethanol. A solution of 2.86 g (19 mmol) of 4- (N, N-dimethylaminomethyl) aniline in 6 ml of ethanol is added dropwise with stirring. The mixture is stirred for 3 hours at room temperature, the solvent is evaporated off in vacuo and the oily crude product is dried on the high vacuum pump. The resulting residue (9.1 g) is converted directly to the title compound.
DC system I: R _f = 0.54
DC system XIII: R _f = 0.84

9.1 g (19 mmol) of the crude product from a) are stirred for 21 hours at room temperature with 11 g (19 mmol × 4.2) of potassium carbonate in 60 ml of dichloromethane and 25 ml of dimethylformamide. The residue is filtered off with suction and the residue is washed twice with 10 ml of dimethylformamide each time and three times with 30 ml of dichloromethane each time. The filtrates are combined and concentrated to dryness in vacuo. The evaporation residue is dried under high vacuum and then stirred with 50 ml of n-pentane. The resulting crystals are filtered off with suction and dried in vacuo.
Yield: 7.46 g (93.2% of theory)
DC system IV: R _f = 0.37
MS-EI: m / z420 (M⁺)
1 H NMR (CDCl₃, TMS): δ = 1.38 (t, 3H); 2.26 (s, 6H); 3.49 (s, 2H); 4.38 (q, 2H); 7.22-7.52 (m, 4H); 8.35 (m, 1H); 8.48 (s, 1H)

Example XIV 8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylaminomethyl) -phenyl] -3- quinolinecarboxylic acid hydrochloride

7.15 g (17 mmol) of the ethyl ester from Example XII are stirred in 21 ml of 4 N aqueous hydrochloric acid for 2¼ hours at 105 ° C. It is allowed to come to room temperature and sucks off the crystals. The product is washed first with 10 ml of water, then three times with 30 ml of diethyl ether and finally dried over calcium chloride under reduced pressure.
Yield: 7.11 g (97.4% of theory)
DC system III: R _f = 0.22
DC system XIII: R _f = 0.46
(+) FAB-MS: m / z 393 (M + H)
1 H-NMR (DCOOD / TMS): δ = 3.05 (m, 6H), 4.56 (m, 2H); 7.22-7.91 (m, 4H); 8.46 (m, 1H); 9.13 (s, 1H)

Example XV 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylaminomkethyl) phe nyl-] -1,8- naphthyridine-3-carboxylate a) 2- (2,5-dichloro-4-fluoro-nicotinoyl) -3- [4- (N, N-dimethylaminomethyl) -] phenylamino] -acrylate

2.42 g (7.17 mmol) of ethyl 3-ethoxy-2- (2,5-dichloro-4-fluoro-nicotinoyl) acrylate are dissolved in 20 ml of ethanol and stirred at 0 ° C. with a solution of 1 ml a 1 molar solution of 4- (N, N-dimethylmethyl) -aniline in ethanol. It is allowed to come to room temperature and stirred for 2 hours. All volatiles are distilled off in a high vacuum and the residue is azeotroped several times with ethyl acetate. The crude product is introduced into the subsequent reaction without further purification.
DC system VI: R _f = 0.42

The crude product from a) is stirred with 3 g (43 mmol) of potassium carbonate in 60 ml of dimethoxyethane for 20 hours at room temperature. From the undissolved is filtered off and the filtrate is concentrated in vacuo to dryness. The residue is heated to boiling with 100 ml of ethyl acetate, filtered hot and the filtrate is concentrated to dryness. The product obtained is triturated with 30 ml of ethyl acetate and the suspension is mixed with 30 ml of petroleum ether. It is suctioned off, washed with petroleum ether and dried in vacuo.
Yield: 1.3 g (45% of theory)
DC system XVI: R _f = 0.43
1 H-NMR (CDCl₃ / TMS): δ = 1.41 (t, 3H); 2.30 (s, 6H); 3.52 (s, 2H); 4.40 (q, 2H); 7.25-7.58 (m, 4H); 8.49 (d, 1H); 8.67 (s, 1H)

Example XVI 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylaminomethyl) phen yl] -1,8- naphthyridine-3-carboxylic acid hydrochloride

The title compound is prepared analogously to Example XIV by acid hydrolysis of Ethyl ester prepared from Example XV.  

Example XVII 7-chloro-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylaminomethyl) phenyl] -1,8-- naphthyridincarbonsäureethylester

The title compound is prepared analogously to Example XV starting from 2- (2,6- Dichlornicotinoyl) -3-ethoxyacrylsäureethylester and 4- (N, N Dimethylaminomethyl) aniline.

Example XVIII 7-chloro-1,4-dihydro-4-oxo-1- [4-N, N-dimethylaminomethyl) -phenyl] -1,8- naphthyridine carboxylic acid hydrochloride

The title compound is prepared analogously to Example XIV by acid hydrolysis of Ethyl ester prepared from Example XVII.

Example XIX 7-fluoro-1,4-dihydro-4-oxo-1- [4- (morpholinomethyl) phenyl] -3-quinoline-carboxylic acid hydrochloride

The title compound is prepared analogously to Example XX starting from 3-ethoxy- (2,4- difluorobenzoyl) ethyl acrylate and the compound of Example III.  

Example XX 6,7-difluoro-1,4-dihydro-4-oxo-1- [4- (morpholino-methyl) phenyl] -3- quinolinecarboxylic acid hydrochloride a) 2- (2,4,5-trifluorobenzoyl) -3- [4- (morpholinomethyl) phenylamino] - acrylic acid ethyl ester

2.5 g (11 mmol) of the compound from Example III are stirred with 2.3 ml (13.2 mmol) of N, N-diisopropylethylamine in 8 ml of ethanol for 10 minutes at room temperature. While stirring and cooling with ice, a solution of 3.22 g (11 mmol) of ethyl 3-ethoxy-2- (2,4,5-trifluorobenzoyl) acrylate in 7 ml of ethanol is added dropwise to the suspension. The mixture is stirred for one hour at room temperature, filtered off with suction and the residue is washed twice with 15 ml of ice-cold ethanol and three times with 20 ml of pentane. The product is dried on the oil pump.
Yield: 4.58 g (92.9% of theory)
DC system I: R _f = 0.61
DC system II: R _f = 0.34

b) 6,7-Difluoro-1,4-dihydro-4-oxo-1- [4- (morpholino-methyl) -phenyl] -3- quinolinecarboxylate

4.5 g (10 mmol) of the product from a) are stirred with 6 g (43.4 mmol) of potassium carbonate in 35 ml of dichloromethane and 15 ml of dimethylformamide for 26 hours at room temperature. The suspension is heated to 45 ° C (water bath) and filtered with suction. The residue is washed three times with 50 ml of warm dichloromethane (45 ° C). The combined filtrates are concentrated to dryness in vacuo. The evaporation residue is triturated with 30 ml of diethyl ether, filtered off, washed with diethyl ether and n-pentane and dried in vacuo.
Yield: 4.17 g (97.3% of theory)
DC system II: R _f = 0.26
DC system VIII: R _f = 0.87

4 g (9.34 mmol) of the ethyl ester from b) are stirred for 4 hours at 110 ° C. to 115 ° C. in 20 ml of 4 N aqueous hydrochloric acid. For dilution add directly 5 ml of water, after 3 hours add another 5 ml of water. It is allowed to come to room temperature and sucks. The residue is washed thoroughly first with ethanol, then with diethyl ether and dried in vacuo over potassium hydroxide.
Yield: 3.88 g (95.1 d.
DC System VIII: R _f = 0.56
1 H-NMR (DCOOD / TMS): δ = 3.52 (m, 2H); 3.78 (m, 2H); 4.03 (m, 2H); 4.81 (m, 2H); 4.77 (s, 2H); 7.35 (m, 1H); 7.88 (2H) and 8.04 (2H); para-aromat. AB system; 8.45 (m, 1H); 9.18 (s, 1H)

Example XXI 6,7,8-trifluoro-1,4-dihydro-4-oxo-1- [4- (morpholinomethyl) phenyl] -3- quinolinecarboxylic acid hydrochloride

The title compound is prepared analogously to Example XX starting from 3-ethoxy- (2,3,4,5- tetrafluorobenzoyl) -acrylic acid ethyl ester and the compound from Example III manufactured.

Example XXII 8-chloro-6,7-difluoro-1,4-dihydro-4-oxo-1- [4- (morpholinomethyl) phenyl] - 3- quinolinecarboxylic acid hydrochloride

The title compound is prepared analogously to Example XX starting from ethyl 3-ethoxy-2- (3-chloro-2,4,5-trifluorobenzoyl) acrylate and 4- (morpholinomethyl) aniline hydrochloride (Example III)
DC system VIII: R _f = 0.67
(+) FAB-MS: m / z 435/437 (M + H)
1 H-NMR (DCOOD / TMS): δ = 3.52 (m, 2H); 3.75 (m, 2H); 4.03 (m, 2H); 4.33 (m, 2H); 4.71 (s, 2H); 7.75-7.95 (m, 4H; p-arom. AB system); 8.48 (m, 1H); 9.04 (s, 1H)

Example XXIII 7-chloro-1,4-dihydro-4-oxo- [4- (morpholinomethyl) phenyl] -1,8-naphthyridine-din carboxylic acid hydrochloride

The title compound is prepared analogously to Example XX starting from 2- (2,6- Dichlornicotinoyl) -3-ethoxy-ethyl acrylate and the compound of Example III produced.

Example XXIV 7-chloro-6-fluoro-1,4-dihydro-4-oxo-1- [4- (morpholino-methyl) phenyl] -1, 8- naphthyridine carboxylic acid hydrochloride

The title compound is prepared analogously to Example XX starting from 3-ethoxy- (2.5- dichloro-4-fluornicotinoyl) ethyl acrylate and the compound of Example III manufactured.

Preparation Examples example 1 1,4-dihydro-4-oxo-7- (4-phenylpiperazin-1-yl) -1- [4- (N, N-dimethylamino-methyl) - phenyl] -3-quinolinecarboxylic acid

1.51 g (4 mmol) of the compound from Example X are stirred at 110 ° C. for 3 hours with 1 g (6 mmol) of N-phenylpiperazine and 3.6 ml (20 mmol) of N, N-diisopropylethylamine in 8 ml of dimethyl sulfoxide. It is allowed to come to room temperature and the batch is mixed with 4 ml of ether and 2 ml of 1,2-dimethoxyethane. The crystals formed are filtered off with suction and washed with 1,2-dimethoxyethane / diethyl ether 1: 1. The residue is briefly dried and stirred with 10 ml of water. It is filtered off and the product is washed three times with a little water (3 ml each), then three times with 30 ml of diethyl ether and finally dried in vacuo over calcium chloride.
Yield: 1.25 g (64.5% of theory)
DC System VIII: R _f = 0.54
HPLC system I: Rt = 5.199 min
MS-EI: m / z 482 (M⁺)
1 H-NMR (CDCl₃ / TMS): δ: 2.27 (s, 6H); 3.20-3.42 (m, 8H); 3.53 (s, 2H); 6.25 (dd, 1H); 6.90 (m, 3H); 7.15 (dd, 1H); 7.22-7.65 (m, 6H); 8.37 (d, 1H); 8.65 (s, 1H); 15.32 (s, wide, 1H)

Example 2 6-fluoro-1,4-dihydro-4-oxo-7- [4- (2-thiomethylphenyl) piperazine-1-yl] -1 - [4- (N, N- dimethylaminomethyl) phenyl] -3-quinolinecarboxylic acid

290 mg (736 μmol) of the compound from Example XI are mixed with 229 mg (1.1 mmol) of 1- (2-methylmercaptophenyl) piperazine and 0.9 ml (5.15 mmol) of N, N-diisopropylethylamine in 3.7 ml Dimethylsulfoxide stirred at 100 ° C for 3 hours. All volatile components are removed in vacuo. The evaporation residue is dissolved in 100 ml of dichloromethane and shaken twice with 50 ml of 0.1 normal aqueous hydrochloric acid. The organic phase is dried over sodium sulfate and concentrated on a rotary evaporator. The residue is triturated with 5 ml of isopropanol, filtered off, washed with diethyl ether and dried in vacuo.
Yield: 320 mg (79.6% of theory)
DC System VIII: R _f = 0.41
HPLC system I: Rt = 7.155 min
(+) FAB-MS: m / z 547 (M + H)

Example 3 8-chloro-6-fluoro-1,4-dihydro-4-oxo-7 [4- (2-methoxyphenyl) piperazin-1-yl -] - 1- [4- (N, N-dimethylaminomethyl) phenyl] -3-quinolinecarboxylic acid

150 mg (350 .mu.mol) of the compound from Example XIV are stirred for 3 hours at 100.degree. C. with 160 mg (700 .mu.mol) of o-methoxyphenylpiperazine hydrochloride and 304 .mu.l (1.75 mol) of N, N-diisopropylethylamine in 3 ml of dimethyl sulphoxide. The batch is allowed to come to room temperature and diluted with 30 ml of water. The aqueous phase is extracted three times with 30 ml of toluene. The organic phase is washed with citrate buffer pH 4 (Merck Article No. 9435.1000), dried over sodium sulfate and concentrated in vacuo. The crude product (144 mg) is chromatographed on silica gel with the eluent mixtures chloroform / methanol / water / acetic acid 100: 50: 2: 2. The product-containing fractions are combined, concentrated on a rotary evaporator, azeotroped with toluene and dried under high vacuum over potassium hydroxide.
Yield: 135 mg (68% of theory)
DC system XIV: R _f = 0.20
HPLC system I: Rt = 5.605 min
(+) FAB-MS: m / z 565 (M + H)

Example 4 6-fluoro-1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) piperazin-1-yl] -1- [4-- (Morpholinomethyl) phenyl] -3-quinolinecarboxylic acid

218 mg (0.5 mmol) of the compound from Example XX are mixed with 135 mg (0.75 mmol) of 1- (4-fluorophenyl) piperazine and 0.88 ml (5 mmol) of N, N-diisopropylethylamine in 3 ml of dimethyl sulfoxide 3 Stirred at 100 ° C hours. All volatile components are removed in a high vacuum and the residue is stirred with 5 ml of ethanol. It is filtered off with suction and the resulting crystals are triturated with 5 ml of water. The product is filtered, washed successively with water, ethanol and diethyl ether and dried in vacuo
Yield: 215 mg (76.8% of theory)
DC system VIII: R _f = 0.64
HPLC system I: Rt = 6.225 min
(+) FAB-MS: m / z 561 (M + H)

Example 5 6-fluoro-1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) piperazin-1-yl] -1- [4 - (N, N- dimethylaminomethyl) -phenyl] -1,8-naphthyridine-3-carboxylic acid-trihydro-chloride a) 6-Fluoro-1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) piperazin-1-yl] -1- [4 - (- N, N- dimethylaminomethyl) phenyl] -1,8-naphthyridine-3-carbonsäureethylester-

150 m (372 μmol) of the compound from Example XV are reacted with 134 mg (741 mol) of 1- (4-flurophenyl) piperazine and 194 μl (1.1 mmol) of N, N-diisopropylethylamine in 2 ml of dimethyl sulfoxide at 100 ° for 4 hours C stirred. It is allowed to come to room temperature and 8 ml of water are added to the batch. The precipitate formed is filtered off, taken up in 2 ml of dichloromethane and the solution is mixed with 8 ml of diethyl ether. The insoluble material is filtered off, the filtrate is concentrated to dryness and the residue is chromatographed on silica gel with the mobile phase mixture dichloromethane / methanol 10: 1. The product-containing fractions are combined and evaporated to dryness in vacuo.
Yield: 114 mg (55.8% of theory)
DC system V: R _f = 0.59
(+) FAB-MS: m / z 548 (M + H)

60 mg (109.2 .mu.mol) of the ethyl ester from a) are heated at 100.degree. C. for 3 hours with 2 ml of 6N aqueous hydrochloric acid and 2 ml of water. It is concentrated to dryness and azeotroped twice with toluene. The residue is suspended in diethyl ether, filtered off with suction and dried in vacuo over potassium hydroxide.
Yield: 41.3 mg (73% of theory)
DC system XIV: R _f = 0.45
HPLC system I: Rt = 5.921 min
(+) FAB-MS: m / z 520 (M + H)

Example 6 1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) piperazin-1-yl] -1- [4- (N- tert-butoxycarbonylamino-methyl) -phenyl] -3-quinolinecarboxylic acid

1.2 g (2.9 mmol) of the compound from Example IV are mixed with 821 mg (4.36 mmol) of 4-fluorophenylpiperazine and 5 ml (29.1 mmol) of N, N-diisopropylethylamine in 10 ml of acetonitrile and 5 ml of dimethylformamide Stirred at 110 ° C for 11 hours. The mixture is allowed to come to room temperature with stirring, stirred for two hours and filtered off with suction. The residue is triturated with 50 ml of diethyl ether and filtered. The procedure is repeated twice more, the purified product is finally dried in vacuo.
Yield: 1.11 g (66.8% of theory)
DC system I: R _f = 0.84
HPLC system I: Rt = 7.548 min
(+) FAB-MS: m / z 573 (M + H)

Example 7 1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) piperazin-1-yl] -1- [4-aminometh-yl) phenyl] - 3-quinolinecarboxylic trihydrochloride

0.8 g (1.7 mmol) of the compound from Example 6 are dissolved in 1 ml of ethanol and treated with 7 ml of a 4 molar solution of hydrogen chloride gas in dioxane. The mixture is stirred for 5 hours at room temperature and the mixture is diluted with 8 ml of diethyl ether. The precipitate formed is filtered off with suction and triturated with diethyl ether. After re-aspirating and washing the residue with diethyl ether and n-pentane is dried under high vacuum at 30 ° C over potassium hydroxide.
Yield: 810 mg (99.4% of theory)
DC system III: R _f = 0.23
DC system XV: R _f = 0.33
(+) FAB-MS: m / z 473 (M + H); m / z 495 (M + H); m / z 579 (M + Ag)

Example 8 1,4-dihydro-4-oxo-7- [4- (4-fluorophenyl) piperazin-1-yl] -1- [4- (N-acetyl- aminomethyl) phenyl] -3-quinolinecarboxylic acid

200 mg (344 μmol) of the compound from Example 7 are stirred for 14 hours at room temperature with 598 μl (3.43 mmol) of N, N-diisopropylethylamine and 65 μl (687 μmol) of acetic anhydride. The precipitate formed is filtered off with suction, washed thoroughly with diethyl ether and dried under high vacuum at 30 ° C.
Yield: 106 mg (59.9% of theory)
DC system I: R _f = 0.44
HPLC system I: Rt 6.016 min
(+) FAB-MS: m / z 515 (M + H)

The examples listed in the following tables are analogous to Examples 1-4, 6 by reacting the respective carboxylic acids with the corresponding piperazine derivatives. Alternatively, analogously to Example 5 the reaction can also be carried out with the respective carboxylic acid esters, which are saponified after intermediate isolation or directly to the title compounds can. The piperazine derivatives used are commercially available (Aldrich, Emka, Janssen) or can be prepared by known methods.

The tert-butoxycarbonylaminomethyl compounds of Tables 12, 15, 18 and 21 can analogously to Example 7 to the title compounds of Tables 13, 16, 19 and 22 and also analogously to Example 8 to the title compounds of Tables 14, 17, 20 and 23 are acylated.  

Example 188 6-fluoro-1,4-dihydro-4-oxo-7- (4-phenyl-2-methyl-piperazin-1-yl) -1- [4 - (N, N- dimethylaminomethyl) phenyl] -3-quinolinecarboxylic acid trihydrochloride

100 mg (195 .mu.mol) of the compound from Example 36 are dissolved in 1 ml of dichloromethane and treated with 1 ml of a 4 molar solution of hydrogen chloride gas in dioxane and stirred for 10 minutes at room temperature. All volatile components are removed in vacuo. The residue is stirred for 2 hours with 5 ml of diethyl ether, filtered off, washed with diethyl ether and dried in vacuo over potassium hydroxide.
Yield: 90 mg (74% of theory)
(+) FAB-MS: m / z 515 (M + H)

Example 189 6-fluoro-1,4-dihydro-4-oxo-7- (4-phenyl-2-methyl-piperazin-1-yl) -1- [4 - N, N- dimethylaminomethyl) phenyl] -3-quinolinecarboxylic acid Trimethansulfonat

100 mg (195 .mu.mol) of the compound from Example 36 are dissolved in 1 ml of dichloromethane and admixed with 0.58 ml (580 .mu.mol) of a 1 molar solution of methanesulphonic acid in dichloromethane. The mixture is concentrated and the evaporation residue is stirred for 2 hours in 5 ml of diethyl ether. The product is filtered off, washed with diethyl ether and dried in vacuo over potassium hydroxide.
Yield: 95 mg (60.7% of theory)
(+) FAB-MS: m / z 515 (M + H)

Claims (6)

1. Compounds of the general formula (I) in which
A is hydrogen or methyl,
X represents a nitrogen atom or a group of the formula -CH, CF or C-Cl,
R¹ is phenyl, naphthyl, pyridyl, pyrimidyl or pyrazinyl optionally substituted up to 3 times, identically or differently, by nitro, trifluoromethyl, halogen, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio each having up to 8 carbon atoms are,
R² is hydrogen or fluorine,
R³ and R⁴ are the same or different and are hydrogen, an amino protecting group or straight-chain or branched alkyl, alkoxycarbonyl or acyl having in each case up to 8 carbon atoms, or
R³ and R⁴ together with the nitrogen atom form a 6-membered saturated heterocycle, which may also contain another heteroatom from the series N, S or O.
and their hydrates and salts, optionally in an isomeric form. 2. Compounds of general formula (I) according to claim 1, in which
A is hydrogen or methyl,
X represents a nitrogen atom or a group of the formula -CH, CF or C-Cl,
R¹ is phenyl, pyridyl, pyrimidyl or pyrazinyl, optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio each having up to 6 Carbon atoms are substituted,
R² is hydrogen or fluorine,
R³ and R⁴ are the same or different and are hydrogen, tert.-butoxycarbonyl, benzyloxycarbonyl or straight-chain or branched alkyl, alkoxycarbonyl or acyl having in each case up to 6 carbon atoms, or
R³ and R⁴ together with the nitrogen atom form a morpholine or piperidine ring,
and their hydrates and salts, optionally in an isomeric form. 3. Compounds of general formula (I) according to claims 1 or 2, in which
A is hydrogen or methyl,
X represents a nitrogen atom or a group of the formula -CH, CF or C-Cl,
R¹ is phenyl or pyridyl, which are optionally substituted identically or differently up to 2 times by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio having in each case up to 4 carbon atoms,
R² is hydrogen or fluorine,
R³ and R⁴ are the same or different and are hydrogen, tert.-butoxycarbonyl, benzyloxycarbonyl or straight-chain or branched alkyl, alkoxycarbonyl or acyl having in each case up to 4 carbon atoms, or
R³ and R⁴ together with the nitrogen atom form a morpholine ring,
and their hydrates and salts, optionally in an isomeric form. 4. A process for the preparation of compounds of general formula (I) according to claim 1, characterized in that
Compounds of the general formula (II) in which
R², R³, R⁴ and X are as defined in claim 1 and
R⁵ is halogen, preferably fluorine or chlorine,
with compounds of the general formula (III) in which
A and R¹ have the meaning given in claim 1,
in inert solvents, if appropriate in the presence of acid scavengers. 5. Medicaments containing at least one compound of the formula (I) according to Claim 1.   6. Use of compounds of formula (I) according to claim 1 in the Fight against diseases.