DE4425659A1 - New N1-diverse 6-fluoro-8-difluoromethoxy substituted quinolonecarboxylic acids - Google Patents

Abstract

N1 diverse 6-fluorine-8-difluoromethoxy substituted quinolone carboxylic acids of the general formula (I) in which A is hydrogen or methyl, R<1> is phenyl, pyridyl, pyrimidyl or pyrazinyl, which may be substituted up to triply, equally or differently, by nitro, trifluoromethyl, halogen, cyano, hydroxy or by straight-chained or branched alkyl, acyl, alkoxy or alkylthio with up to 8 carbon atoms, R<2> is hydrogen or a straight-chained or branched alkyl with up to 6 carbon atoms, D or E is hydrogen and D is morpholino or E is a radical of the formula -CH2-L, in which L is morpholino or a 5-membered heteroaromatic bonded via N with up to 3 further nitrogen atoms or a group of the formula NR<3>R<4>, in which R<3> and R<4> are the same or different and are hydrogen, straight-chained or branched alkyl with up to 6 carbon atoms or an amino protective group, process for their production and their use as medicaments, especially antiviral agents.

Description

The present invention relates to new N₁-diverse 6-fluoro-8-difluoromethoxy substituted quinolonecarboxylic acids, processes for their preparation, and their use as a drug, especially as an antiviral.

From publication EP 422 485 are quinolonecarboxylic acid derivatives with antiviral activity known.

The present invention relates to new N₁-diverse 6-fluoro-8-difluoromethoxy substituted Quinolonecarboxylic acids of the general formula (I),

in which
A represents hydrogen or methyl,
R1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally substituted up to 3 times identically or differently by nitro, trifluoromethyl, halogen, cyano, hydroxyl or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each having up to 8 carbon atoms,
R² represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
D or E represent hydrogen or
D stands for Morpholino
or
E represents a radical of the formula -CH₂-L,
wherein
L means morpholino, or an N-bonded 5-membered heteroaromatic with up to 3 further nitrogen atoms, or a group of the formula -NR³R⁴,
wherein
R³ and R⁴ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or an amino protecting group,
and their hydrates and salts, optionally in an isomeric form.

Physiologically acceptable salts of the compounds according to the invention can Salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids his. Z are particularly preferred. B. 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 acceptable salts can also be alkali, alkaline earth, silver and Guanidinium salts of the compounds of the invention.

An N-linked 5-membered heteroaromatic is within the scope of the invention generally for an imidazolyl, pyrrolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl or 1,2,4-triazol-4-yl or tetrazolyl ring. 1,2,4-Triazol-1-yl is preferred.

Amino protecting groups in the context of the invention are the usual ones in peptide chemistry amino protecting groups used.

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-trichloroacetyl, Benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, Isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl, 4-nitrophenyl, 4-methoxyphenyl or triphenylmethyl.

Compounds of the general formula (I) are preferred
in which
A represents hydrogen or methyl,
R¹ is phenyl, pyridyl, pyrimidyl or pyrazinyl, which may optionally be 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 with up to 6 Carbon atoms are substituted,
R² represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
D or E represent hydrogen or
D stands for Morpholino
or
E represents a radical of the formula -CH₂-L,
wherein
L means morpholino, imidazolyl, pyrrolyl, 1,2,3-triazolyl-1-yl, 1,2,4-triazolyl-1-yl, 1,2,4-triazolyl-4-yl or tetrazolyl, or a group of Formula -NR³R⁴ means
wherein
R³ and R⁴ are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyloxycarbonyl or tert.butoxycarbonyl,
and their hydrates and salts, optionally in an isomeric form.

Compounds of the general formula (I) are particularly preferred
in which
A represents hydrogen or methyl,
R¹ represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which may optionally be 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 with up to 4 Carbon atoms are substituted,
R² represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
D or E represent hydrogen or
D stands for Morpholino
or
E represents a radical of the formula -CH₂-L,
wherein
L denotes morpholino or 1,2,4-triazolyl-1-yl, or denotes a group of the formula -NR³R⁴,
wherein
R³ and R⁴ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyloxycarbonyl,
and their hydrates and salts, optionally in an isomeric form.

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

in which
R², D and E have the meaning given above,
R⁵ represents halogen, preferably fluorine or chlorine,
with compounds of the general formula (III)

in which
A and R¹ have the meaning given above,
in inert solvents, if appropriate in the presence of acid scavengers,
and in the case of acids, the esters are saponified,
and in the case of the esters, the acids are reacted with the corresponding alcohols by customary methods.

The method according to the invention can be exemplified by the following formula are explained:

The usual inert solvents are suitable as solvents for all process steps, that do not change under the reaction conditions. This includes preferably organic solvents such as ether z. B. 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 to mix to use the solvent mentioned. Dimethyl sulfoxide and Acetonitrile.

The usual basic ones are suitable as bases for individual reaction steps Links. These include, for example, alkali or alkaline earth metal hydroxides, Pyridine, triethylamine, diisopropylethylamine or N-methylpiperidine, or bicyclic Amidines such as diazabicyclo [2,2,3] octane, 1,5-diazabicyclo [3,4,0] -nonene-5 (DBN) or 1,5-diazabicyclo [3,4,0] undecene-5 (DBU). Diisopropylethylamine is preferred.  

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

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

In general, normal pressure is used. But it is also possible that Carry out procedures under negative pressure or overpressure (e.g. in one area 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 (II) are new and can be prepared by first using compounds of the general formula (IV)

in which
R⁵ has the meaning given above,
R⁶ represents C₁-C₄ alkyl,
R⁷ represents C₁-C₄ alkoxy or C₁-C₄ dialkylamino,
and
T represents halogen, preferably chlorine or fluorine,
by reaction with amines of the general formula (V)

in which
D and E have the meaning given above,
in one of the solvents listed above, preferably ethanol,
into the compounds of the general formula (VI)

in which
T, R⁵, R⁶, D and E have the meaning given above,
transferred, and in a last step cyclized in one of the solvents listed above and a base mentioned there, preferably DMF and K₂CO₃,
and saponified the esters.

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

In general, normal pressure is used. But it is also possible that Carry out procedures under negative pressure or overpressure (e.g. 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 100 ° C.

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

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

Surprisingly, the compounds according to the invention showed activity in Lentivirus infected cell cultures. This was shown by the example of the HIV virus will.

HIV infection in cell culture

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

Normal human blood lymphocytes (PBL's) were enriched via Ficoll-Hypaque and in RPMI 1640, 20% fetal calf serum with phythema agglutinin (90 µg / ml) and Interleukin-2 (40 U / ml) stimulated. For infection with the infectious HIV were pelleted into PBL's and the cell pellet was then placed in 1 ml of HIV virus adsorption solution suspended and incubated for 1 hour at 37 ° C.

The virus adsorption solution was centrifuged and the infected cell pellet in Growth medium added so that 1 × 10⁵ cells per ml were set.  

The cells infected in this way were 1 × 10⁴ cells / well in the 96 wells Pipetted microtiter plates.

The first vertical row of the microtiter plate contained only growth medium and Cells that are not infected but are 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 other wells contained the compounds of the invention in different Concentrations starting from the wells of the 3rd vertical row of the Microtiter plate, from which the test substances are diluted 2 × in 2 steps were.

The test batches were incubated at 37 ° C. until the untreated one Virus control that occurred for HIV-typical syncytia formation (between day 3 and 6 after infection), which was then evaluated microscopically. In the untreated virus control resulted in approximately 20 under these test conditions Syncytia, while the untreated cell control showed no syncytia.

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

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

The compounds according to the invention are valuable active substances for treatment and prophylaxis of diseases caused by retoviruses in which Human and veterinary medicine.  

As indication areas in human medicine, for example will:

• 1. The treatment and prophylaxis of human retrovirus infections.
• 2. For the treatment or prophylaxis of HIV I (virus of 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 encyphalopathy.
• 3. For the treatment or prophylaxis of an HTLV-I or HTLV-II infection.
• 44. For the treatment or prophylaxis of the AIDS carrier condition (AIDS carrier condition).

Examples of indications in veterinary medicine are:

Infections with

• a) Maedivisna (for sheep and goats)
• b) progressive pneumonia virus (PPV) (in sheep and goats)
• c) caprine arthritis encephalitis virus (in sheep and goats)
• d) Zwoegerziezte virus (in sheep)
• e) infectious anemia (horse) virus
• f) infections caused by the feline leukemia virus
• G) infections caused by the virus of the cat immune difference (FIV)
• h) infections caused by the monkey immunodeficiency virus (SIV)

From the indication area in human medicine, the above are preferred points 2, 3 and 4.

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

The active compounds of the formula (I) are intended to be used in the pharmaceuticals listed above 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.

In addition to the compounds, the pharmaceutical preparations listed above can of formula (I) also contain other active pharmaceutical ingredients.

The pharmaceutical preparations listed above are produced in customarily by known methods, e.g. B. by mixing the active ingredient (s) with the carrier or carriers.

In general, it has been found in both human and veterinary medicine proven to be advantageous in the active ingredient (s) according to the invention in Total amounts from about 0.5 to about 500, preferably 1 to 100 mg / kg body weight 24 hours each, possibly in the form of several individual doses, to achieve to deliver the desired results. A single dose contains the or the active ingredients preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary from the diverge mentioned dosages, depending on the type and the body weight of the object to be treated, the type and severity of the Disease, the type of preparation and the application of the drug as well the period or interval within which the administration takes place.  

Explanation of the experimental part:
DC systems
Stationary phase
Merck DC pre-assembled silica gel 60 F-254 plates, 5 × 10 cm, layer thickness 0.25 mm, item no. 5719.

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
XVII: toluene / acetone 80:20
XVII: CH₂Cl₂ / MeOH 98: 2

HPLC system I
Nucleosil 120-5 C 18.5 µm column, 125 x 4 mm eluent;
A = 0.01 M H₃PO₄, B = acetonitrile
Eluent program:
0-1 min: 10% B
1-9 min: gradient at 10% b / min
9-13 min: 90% B
Flow: 2 ml / min, room temperature
5 µl, sample amount approx. 1 mg / ml
Detection: UV diode array at 210 nm

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

Output connections Example I 1- (4-nitrobenzyl) -1H-1,2,4-triazole

99.2 mg (0.58 mol) of 4-nitrobenzyl chloride and 40.0 g (0.58 mol) of 1H-1,2,4-triazole are with 162 g (1.17 mol) of potassium carbonate in 1000 ml of acetone for two hours heated under reflux. The cooled batch is filtered and the solvent in Vacuum removed. The residue is extracted hot with toluene. From the filtrate the product crystallizes out after cooling to room temperature. You suck off rinses with diethyl ether and dries in a high vacuum.

Yield: 83 g (70% of theory)
DC system VI: R _f = 0.30
MS-EI: m / z 205 (M + H) ⁺

Example II 1- (4-aminobenzyl) -1H-1,2,4-triazole

10.9 mg (53.4 mmol) of the compound from Example I are dissolved in 200 ml Dissolved ethyl acetate. After adding 4 g of Pd / C (10% Pd, Aldrich) the mixture is hydrogenated for 4.5 hours at a hydrogen pressure of 3.5 bar. Of the The catalyst is filtered off and washed with 100 ml of ethyl acetate. The combined filtrates are evaporated to dryness in vacuo. Of the The residue is triturated with diethyl ether, suction filtered and in a high vacuum dried.

Yield: 8.8 g (94% of theory)
DC system VI: R _f = 0.23
MS-EI: m / z 175 (M + H) ⁺

Example III (3-morpholino) nitrobenzene

29 g (107 mmol) 3-nitrophenyl trifluoromethanesulfonate (Synthesis, 12 (1990) pp. 1145 ff.) In 150 ml (1.72 mol) morpholine under argon for 16 h in a 130 ° C bath touched. The excess morpholine is removed in a high vacuum on a rotavapor and the resulting oil on silica gel with petroleum ether / ethyl acetate 3: 1 chromatographed.

Yield: 14.5 g of oil (= 65% of theory)  

Example IV 3- morpholinoaniline

25 g (120.2 mmol) of the compound from Example III are in 700 ml of ethyl acetate dissolved and on 2 g pd catalyst (10% Pd on activated carbon) for 4 hours at 3.2 bar hydrated. The catalyst is separated off, the filtrate is evaporated and the Residue dissolved in a little ethyl acetate. The product is precipitated with petroleum ether and recrystallized from ethyl acetate.

Yield: 17.74 g (41% of theory)

Example V 4- (morpholinomethyl) aniline hydrochloride

10.6 g (47.7 mmol) of 4- (morpholinomethyl) nitrobenzene (obtainable by reaction of 4-nitro-benzyl chloride with morpholine) in 50 ml of dimethylformamide solved. 25 μl of 1 normal aqueous hydrochloric acid and hydrogenated after adding 1 g of palladium on carbon (10%) for 2 days at 3 bar. Of the Catalyst is separated off on a diatomaceous earth bed and the filtrate on High vacuum concentrated to dryness. The residue is in 200 ml Dichloromethane added and the solution extracted four times with water, the adjust to pH 5 with 1 normal hydrochloric acid during each extraction. The combined aqueous phases are washed at pH 5 with dichloromethane and evaporated to dryness under high vacuum. The yellow residue is 300 ml  Diethyl ether triturated, suction filtered and after washing with diethyl ether dried at 30 ° C in a 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 (base peak)
1 H-NMR (DMSO): δ = 2.88-3.22 (m, 8H); 4.12 (s, 2H); 6.78 (2H) and 7.34 (2H); AB system; (3.82 (broad, H₂O + NH₂ × HCl group)

Example VI 4- (N-tert-butyloxycarbonylaminomethyl-nitrobenzene

50 g (0.265 mol) 4-nitrobenzylamine hydrochloride (Aldrich) and 73.5 ml (0.53 mol) Triethylamine are suspended in 600 ml of dioxane and added for 30 minutes Room temperature stirred. 63.5 ml (0.291 mol) are added dropwise with ice cooling and stirring Add di-tert-butyl dicarbonate (Boc₂O) and leave to room temperature overnight come. The precipitate is filtered off and the filtrate Dry evaporated. The residue is taken up in 500 ml of diethyl ether and the organic phase was shaken three times with 300 ml of water. The organic phase is dried over sodium sulfate and on a rotary evaporator freed from the solvent. The residue is thoroughly stirred in 300 ml of n-hexane, filtered off, 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 VII 4- (N-tert-butoxycarbonylaminomethyl) aniline hydrochloride

14 g (55.5 mmol) of the compound from Example VI are in 150 ml of methanol dissolved and mixed with 55.5 ml (55.5 mmol) of 1 normal aqueous hydrochloric acid. To Add 2 g of palladium on carbon (10%) at normal pressure up to Hydrogen uptake ceased. The approach is to remove of the catalyst filtered through a layer of diatomaceous earth. It is washed with methanol and the combined organic phase on a rotary evaporator at one Bath temperature of 35 ° C to dryness. The residue is mixed with 200 ml Diethyl ether triturated, suction filtered, washed with diethyl ether and at 30 ° C. dried in a high vacuum.

Yield: 1.33 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); (see broad, 2H); 4.18 (d. 2H); 4.74 (s, broad, 1H); 6.64 and 7.06 (each 2H, aromatic AB system)

Example VIII 3-Ethoxy-2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl) acrylic acid ethyl ester

13 g (41 mmol) of 2,4,5-trifluoro-3-difluoromethoxybenzoyl-ethyl acetate (EP 0 572 259 A1, UBE INDUSTRIES, p. 58, ref. Example 1, lines 1-39) with 13.9 ml (82 mmol) triethyl orthoformate in 50 ml acetic anhydride for 1.5 hours stirred at reflux at a bath temperature of 140 ° C. All volatile components are removed at a heating bath temperature of 65 ° C in a vacuum. The residue is three times with 25 ml of toluene p. A. distilled off in vacuo. The oily The crude product is dried in a high vacuum and without further purification in the Subsequent steps implemented with the respective substituted anilines.

Yield: 16.2 g (107.3% of theory)
The raw product is 93%
DC system VII: R _f = 0.20 (starting material β-ketoester R _f = 0.57)
DC system XVII: R _f = 0.73

Example IX 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- [4- (1H-1,2,4-triazo-l-1-yl- methyl) phenyl] -3-quinolinecarboxylic acid hydrochloride a) 2- (2,4,5-Trifluoro-3-difluoromethoxybenzoyl) -3- [4- (1H-1,2,4-triazol-1 - yl- methyl) phenylamino] acrylic acid ethyl ester

4 g (10 mmol) of the 93% crude product from Example VIII are in 20 ml Dissolved ethanol and in portions with stirring with 1.57 g (9 mmol) Compound from Example II added. The mixture is diluted with 5 ml of ethanol  and stirred for 2.5 hours at room temperature. The product is suctioned off and rinsed three times with its filtrate. The residue is twice with 20 ml n-pentane, once with 20 ml of n-pentane / ethanol 1: 1 and another four times with 20 ml each Washed n-pentane and dried in vacuo on the oil pump.

Yield: 3.74 g (75.4% of theory based on Example VIII)
[Another 425 mg (8.5% of theory) are obtained by processing the mother liquors]
DC system II: R _f = 0.43

b) 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- [4- (1H-1,2,4-triazo-l-1-yl- methyl) phenyl] -3-quinolinecarboxylic acid ethyl ester

4.01 g (8 mmol) of the enamino compound from a) are mixed with 5 g (36.16 mmol) Potassium carbonate in 50 ml of dimethoxyethane for 20.5 hours at room temperature touched. A further 1.15 g (8.32 mmol) of potassium carbonate are added and stirred for a further 20.75 hours. Then the batch is 2.75 hours at 45 ° C. stirred and allowed to come to room temperature. It is added in portions with 0.328 g (6.07 mmol) of sodium methylate and stirred for 2.25 hours Room temperature after. The mixture is diluted with 50 ml dichloromethane, suction filtered and the residue washed with dichloromethane. The residue is successively with 100 ml of dichloromethane and with 25 ml of ethanol / 50 ml Boiled dichloromethane, vacuumed warm and several times with a total of 200 ml Washed dichloromethane. The combined filtrates are vacuumed from exempted from all volatile components. The evaporation residue (4.02 g, crystalline) is stirred with 20 ml of diethyl ether, suction filtered and dried in vacuo.

Yield: 3.9 g (100% of theory)
DC system II: R _f = 0.35
DC system VIII: R _f = 0.92
(+) FAB-MS: m / z 477 (M + H)

3.8 g (8 mmol) of the ester from b) are mixed with 25 ml of 4 normal aqueous hydrochloric acid for 2 hours stirred at 110 ° C. It is allowed to come to room temperature and the is sucked Crystals. These are mixed twice with 40 ml ethanol / diethyl ether 1: 3 and Washed twice with 50 ml of diethyl ether each and vacuum Calcium chloride dried.

Yield: 3.47 g (89.5% of theory)
DC system VIII: R _f = 0.20
HPLC system I: Rt = 6.484 min
(+) FAB-MS: m / z 449 (M + H)
1 H-NMR (DCOOD / TMS): δ = 5.95 (s, 2H); 6.09, 6.37, 6.68 (t, 1/2 // 1), 1H, (OCHF₂); 7.70-7.88 (m, 4H); 8.45 (m. 1H); 9.04 (s, 2H); 9.93 (s, 1H)

Example X 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylamino-no-methyl) - phenyl] -3-quinolinecarboxylic acid hydrochloride a) 2- (2,4,5-Trifluoro-3-difluoromethoxybenzoyl) -3- [4- (N, N-dimethylamino- methyl) phenylamino] acrylic acid ethyl ester

1.8 g (about 4.4 mmol) of the 93% crude product from Example VIII are in 10 l ethanol dissolved and with stirring at room temperature with a solution of 0.661 g (4.4 mmol) of 4- (N, N-dimethylamino-methyl) aniline in 10 ml of ethanol transferred. The mixture is stirred for 3 hours and all volatile constituents are removed High vacuum at a bath temperature of 45 ° C. The oily raw product becomes direct implemented in the next stage.

Yield: 2.28 g
DC system XVII: R _f = 0.49

b) 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylamino-no- methyl) phenyl] -3-quinolinecarboxylic acid ethyl ester

2.28 g (4.4 mmol) of the crude product from a) are dissolved in 8 ml of dimethoxyethane and with stirring and cooling in portions with a total of 0.362 g (6.67 mmol) Sodium methylate added. The mixture is stirred at room temperature for 7 hours and vaporizes all volatiles in a vacuum at a bath temperature of 38 ° C. The residue is coevaporated with diethyl ether and dichloromethane, dried on the oil pump and without further cleaning to the target connection implemented.

Yield: 2.25 g of crude product
DC system XVII: 0.36

2.25 g (4.4 mmol) of the crude ester from b) become more aqueous in 10 ml Hydrochloric acid stirred at 110 ° C for 2 hours. Allow to come to room temperature and stir the mixture with 15 ml of diethyl ether. You suck over one Sinter plate and stir the crystal slurry on the suction filter with 4 ml of dimethoxyethane and 2 ml of diethyl ether. After thorough dry vacuuming the product washed with diethyl ether and dried in vacuo.

Yield: 1.35 g (66% of theory with respect to Example VIII over 3 stages)
DC system VIII: = 0.38
HPLC system I: Rt = 4.492 min
(+) FAB-MS: m / z 425 (M + H)

Example XI 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-44-oxo-1- [3- (morpholino) phe-nyl] -3- quinoline carboxylic acid hydrochloride a) 2- (2,4,5-Trifluoro-3-difluoromethoxybenzoyl) -3- [3- (morpholino) phenylamino] - acrylic acid ethyl ester

1.8 g (about 4.4 mmol) of the 93% crude product from Example VIII are in 20 ml of ethanol dissolved and in portions with stirring at room temperature 0.784 g (4.4 mmol) of the compound from Example IV are added in portions. The mixture is stirred for 3 hours and all volatile components are removed in the High vacuum at a bath temperature of 45 ° C. The oily raw product becomes direct implemented to the next level.

Yield: 2.47 g
DC system II: R _f = 0.86
DC system XII: R _f = 0.11
DC system XVIII: R _f = 0.68

b) 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- [3- (morpholino) -phenyl] - 3-quinoline carboxylic acid ethyl ester

2.46 g (4.4 mmol) of the crude product from a) are dissolved in 8 ml of dimethoxyethane and with stirring and cooling in portions with a total of 0.353 g (6.52 mmol) Sodium methylate added. The mixture is stirred at room temperature for 7 hours and vaporizes all volatiles in a vacuum at a bath temperature of 38 ° C. The crude ester is converted to the title compound without further purification.

Yield: 2.5 g
DC system XII: R _f = 0.19
DC system XVIII: R _f = 0.28
(+) FAB-MS: m / z 481 (M + H)

2.45 g (4.4 mmol) of the crude ester from b) become more aqueous in 10 ml Hydrochloric acid stirred at 110 ° C for 2 hours. Allow to come to room temperature and stir the mixture with 15 ml of diethyl ether. You suck over one Sinter plate and rinse the residue with 20 ml of ethanol / diethyl ether 1: 1. The product is on the suction filter in succession with three times 20 ml of diethyl ether stirred and suctioned off, and finally in a vacuum over calcium chloride dried.

Yield: 1.73 g (80.3% of theory with respect to Example VIII over 3 steps)
DC system II: R _f = 0.52
DC system VIII: R _f = 0.50
HPLC system I: Rt = 6.484 min
(+) FAB-MS: m / z 453 (M + H)

Manufacturing examples example 1 6-fluoro-8-difluoromethoxy-7- [4- (2-methoxyphenyl) piperazin-1-yl] -1- [4 - (1H-1,2,4- triazol-1-yl-methyl) phenyl] -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid -

212 mg (437 µmol) of the compound from Example IX are mixed with 110 mg (560 µmol) 1- (2-methoxyphenyl) piperazine and 0.5 ml (2.88 mmol) N, N-diisopropylethylamine in 0.4 ml of dimethyl sulfoxide for 3.5 hours at 110 ° C. All volatile components are in a high vacuum at a bath temperature up to 93 ° C away. The evaporation residue (0.533 g) is stirred with 1 ml of water. The crystals formed are suctioned off and successively twice with 1 ml of water, three times with 1 ml of diethyl ether, once with 1.5 ml of ethanol / ether 1:10 and finally washed with 1.5 ml of diethyl ether. The crude product (267 mg) Dried overnight under high vacuum over potassium hydroxide and from 1 ml 1,2-dimethoxyethane recrystallized, suction filtered, washed with diethyl ether and dried.

Yield: 187 mg (69% of theory)
DC system VIII: R _f = 0.69
HPLC system I: Rt = 6.406 min
(+) FAB-MS: m / z 621 (M + H)

Example 2 6-fluoro-8-difluoromethoxy-7- [4- (phenyl) piperazin-1-yl] -1- [4- (N, N-dime-thylamino- methyl) phenyl] -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

212 mg (460 µmol) of the compound from Example X are mixed with 100 mg (598 µmol) N-phenylpiperazine and 0.5 ml (2.85 mmol) of N, N-diisopropylethylamine in 0.4 ml of dimethyl sulfoxide stirred at 110 ° C for 7 hours. All volatile components are removed in a high vacuum at a bath temperature of up to 93 ° C. Of the Evaporation residue is distributed between 50 ml dichloromethane and 6 ml water. The organic phase is saturated with 10 ml of water, then with 10 ml Washed saline, dried over sodium sulfate and dried constricted. The crude product is triturated with 5 ml of ether / n-pentane 1: 1, suction filtered, washed with ether and n-pentane and dried in vacuo.

Yield: 225 mg (86% of theory)
DC system VIII: R _f = 0.51
HPLC system I: Rt = 6.325 min
(+) FAB-MS: m / z 537 (M + H)

Example 3 6-fluoro-8-difluoromethoxy-7- [4- (2-methoxyphenyl) piperazin-1-yl] -1- [3-- (morpholino) phenyl] -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid

225 mg (460 μmol) of the compound from Example XI are mixed with 113 mg (575 μmol) 4- (2-methoxyphenyl) piperazine and 0.5 ml (2.85 mmol) N, N-diisopropylethylamine stirred in 0.4 ml of dimethyl sulfoxide at 110 ° C for 6 hours. Man Allows to come to room temperature and adds 2 ml of diethyl ether to the mixture. The crystals formed are suction filtered and twice with 1 ml of diethyl ether washed. The residue is dried on an oil pump (254 mg) and mix it with 1 ml of water, suction and wash successively with 1 ml of water each (twice), 0.5 ml of dimethoxyethane (twice) and 1 ml of diethyl ether (three times). The The product is dried under high vacuum.

Yield: 189 mg (65.8% of theory)
DC system VIII: R _f = 0.66
HPLC system I: Rt = 7.244 min
(+) FAB-MS: m / z 625 (M + H); m / z 647 (M + Na)

Example 4 6-fluoro-8-difluoromethoxy-7- [4- (phenyl) piperazin-1-yl] -1- [4- (N, N-dime-thylamino- methyl) phenyl] -1,4-dihydro-4-oxo-quinoline-3-carboxylic acid trihydrochloride

200 mg (353 mmol) of the compound from Example 2 are in 3 ml Dichloromethane and 1 ml of ethanol dissolved. 0.46 ml of a 4 N solution are added of dry hydrogen chloride gas in dioxane and removes all volatile Components in a vacuum. The oily evaporation residue is used for crystallization 3 ml of diethyl ether and 0.3 ml of ethanol were added and stirred. The product is left sit down and decant the supernatant. After filling with 5 ml of n-pentane is stirred for 10 minutes, suction filtered and washed with n-pentane. The The target compound is dried overnight under high vacuum over potassium hydroxide.

Yield: 179 mg (75% of theory)
(+) FAB-MS: m / z 567 (M + H)

The examples listed in Tables 1 to 3 below become analogous Example 1-3 from the respective acids of the starting compounds IX, X and XI and the corresponding piperazine derivatives. These can be bought (Aldrich, Emka, Janssen) or can be obtained by known methods. The salts listed in Tables 4 and 5 are analogous to Example 4 from the receive respective free bases.  

Claims (6)

1. N₁-diverse 6-fluoro-8-difluoromethoxy substituted quinolonecarboxylic acids of the general formula (I), in which
A represents hydrogen or methyl,
R1 represents phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally substituted up to 3 times identically or differently by nitro, trifluoromethyl, halogen, cyano, hydroxyl or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each having up to 8 carbon atoms,
R² represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
D or E represent hydrogen or
D stands for Morpholino
or
E represents a radical of the formula -CH₂-L,
wherein
L means morpholino, or an N-linked 5-membered heteroaromatic with up to 3 further nitrogen atoms, or
is a group of the formula -NR³R⁴,
wherein
R³ and R⁴ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms or an amino protecting group,
and their hydrates and salts, optionally in an isomeric form. 2. Compounds of general formula (I) according to claim 1, in which
A represents hydrogen or methyl,
R¹ is phenyl, pyridyl, pyrimidyl or pyrazinyl, which may optionally be 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 with up to 6 Carbon atoms are substituted,
R² represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
D or E represent hydrogen or
D stands for Morpholino
or
E represents a radical of the formula -CH₂-L,
wherein
L is morpholino, imidazolyl, pyrrolyl, 1,2,3-triazolyl-1-yl, 1,2,4-triazolyl-1-yl, 1,2,4-triazolyl-4-yl or tetrazolyl, or
is a group of the formula -NR³R⁴,
wherein
R³ and R⁴ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyloxycarbonyl or tert-butoxycarbonyl,
and their hydrates and salts, optionally in an isomeric form. 3. Compounds of general formula (I) according to claim 1, in which
A represents hydrogen or methyl,
R¹ is phenyl, pyrridyl, pyrimidyl or pyrazinyl, which may optionally be 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 with up to 4 Carbon atoms are substituted,
R² represents hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
D or E represent hydrogen or
D stands for Morpholino
or
E represents a radical of the formula -CH₂-L,
wherein
L denotes morpholino or 1,2,4-triazolyl-1-yl, or denotes a group of the formula -NR³R⁴,
wherein
R³ and R⁴ are the same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms, benzyloxycarbonyl,
and their hydrates and salts, optionally in an isomeric form. 4. A process for the preparation of the compounds of general formula (I) according to claim 1, characterized in that
Compounds of the general formula (II) in which
R², D and E have the meaning given above,
R⁵ represents halogen, preferably fluorine or chlorine,
with compounds of the general formula (III) in which
A and R¹ have the meaning given above,
in inert solvents, if appropriate in the presence of acid scavengers,
and in the case of acids, the esters are saponified,
and in the case of the esters, the acids are reacted with the corresponding alcohols by customary methods. 5. Medicaments containing one or more compounds from the Claims 1 to 3. 6. Use of the compounds from claims 1 to 3 for the preparation of antiviral drugs.