WO1996002511A1

WO1996002511A1 - Novel n1 diverse 6-fluorine-8-difluoromethoxy substituted quinolone carboxylic acids

Info

Publication number: WO1996002511A1
Application number: PCT/EP1995/002645
Authority: WO
Inventors: Wolfgang Bender; Wolfgang RÖBEN; Arnold Paessens; Stephan Bartel
Original assignee: Bayer Aktiengesellschaft
Priority date: 1994-07-20
Filing date: 1995-07-07
Publication date: 1996-02-01
Also published as: DE4425659A1; IL114621A0; ZA955966B; AU2928095A

Abstract

N1 diverse 6-fluorine-8-difluoromethoxy substituted quinolone carboxylic acids of the general formula (I) in which A is hydrogen or methyl, R1 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, R2 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 -CH¿2?-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?3R4¿, in which R?3 and R4¿ 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

New N _j -various 6-fluoro-8-difluoromethoxy substituted quinolonecarboxylic acids

The present invention relates to new N, diverse 6-fluoro-8-difluoromethoxy-substituted quinolonecarboxylic acids, processes for their preparation and their use as medicaments, in particular as antiviral agents.

Antiviral quinolonecarboxylic acid derivatives are known from publication EP 422 485.

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

in which

A represents hydrogen or methyl,

R ^{1 represents} phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, halogen, Cyano, hydroxy or substituted by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each with up to 8 carbon atoms,

R ^{2 represents} hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,

D or E represents hydrogen and

D stands for Morpholino

or

E represents a radical of the formula -CH ₂ -L,

wherein

L means morpholino, or an N-linked 5-membered heteroaromatic with up to 3 further nitrogen atoms, or a group of the formula -NR ³ R ⁴ ,

wherein

R ³ and R ^{4 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 be salts of the substances according to the invention with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, 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 according to the invention.

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

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

These preferably include: benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, fluorenyl-9-methoxycaibonyl, foπnyl, acetyl, 2- 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,

R ^{1 represents} phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxyl or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio with each up to 6 carbon atoms are substituted,

R ² for hydrogen or for straight-chain or branched alkyl with up to 4

Carbon atoms, D or E represents hydrogen and

D stands for Moφholino

or

E represents a radical of the formula -CH ₂ -L,

wherein

L means morpholino, imidazolyl, pyrrolyl, 1,2,3-triazol-l-yl, 1,2,4-triazolyl-1-yl, l, 2,4-triazolyl-4-yl or tetrazolyl, or a group of Formula -NR ³ R ⁴ means

wherein

R ³ and R ^{4 are} identical 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.

Compounds of the general formula (I) are particularly preferred

in which

A represents hydrogen or methyl,

R ^{1 represents} phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched

Alkyl, acyl, alkoxy or alkylthio each having up to 4 carbon atoms, R ^{2 represents} hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

D or E represents hydrogen and

D stands for Morpholino

or

E represents a radical of the formula -CH ₂ -L,

wherein

L denotes morpholino or 1,2,4-triazol-l-yl, or denotes a group of the formula -NR ³ R ⁴ ,

wherein

R ³ and R ^{4 are the} same or different and are hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or 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

R, D and E have the meaning given above,

R 5 is halogen, preferably fluorine or chlorine,

with compounds of the general formula (HI)

in which

A and R ^{1 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 process according to the invention can be illustrated by the following formula scheme:

Suitable solvents for all process steps are the customary inert solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers e.g. 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 acid triamide, sulfolane, acetic ester, acetic ester, acetic ester Triethylamine, N-methylpyrrolidone, anisole or picoline. It is also possible to use mixtures of the solvents mentioned. Dimethyl sulfoxide and acetonitrile are preferred.

The usual basic compounds are suitable as bases for individual reaction steps. These include, for example, alkali or alkaline earth metal hydroxides, pyridine, triethylamine, diisopropylethylamine or N-methylpiperidine, or bicyclic amidines such as 1,4-diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [3,4,0] ~ nonenes -5 (DBN) or 1,5-diazabicyclo [3,4,0] undecene-5 (DBU). Diisopropylethylamine is preferred. The bases are generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the corresponding carboxylic acid.

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

In general, work is carried out at normal pressure. It is also possible, however

Carry out the process under reduced 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 the presence of an inorganic acid, preferably sulfuric acid or hydrochloric acid, in a temperature range from 50 to 100 ° C., preferably at 100 ° C.

The compounds of the general formula (II) are new and can be prepared by first preparing compounds of the general formula (IV)

in which

R ^{5 has} the meaning given above,

R ⁶ for C _! -C ₄ alkyl,

R ^{7 represents} C _j -C ₄ alkoxy or C ₁ -C ₄ 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, R ⁵ , R ⁶ , 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 K ₂ CO ₃ ,

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

In general, normal pressure is used. However, it is also possible to carry out the process under negative pressure or under positive pressure (e.g. in a range from 0.5 to 5 bar).

The saponification is generally carried out in a mixture of glacial acetic acid / water and in the presence of an inorganic acid, preferably sulfuric acid or hydrochloric acid, in a temperature range from 50 to 100 ° C., preferably 100 ° C.

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

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

Surprisingly, the compounds according to the invention showed activity in cell cultures infected with lentivirus. This could be shown using the example of the HTV virus.

HIV infection in cell culture

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

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

The virus adsorption solution was centrifuged and the infected cell pellet was taken up in growth medium so that 1 × 10 ⁵ cells per ml were set. The cells infected in this way were pipetted into the wells of 96-well microtiter plates at 1 × 10 ⁴ cells / well.

The first vertical row of the microtiter plate contained only growth medium and cells that were not infected but were otherwise treated exactly as described above (cell control). The second vertical row of the microtiter plate received only HTV-infected cells (virus control) in growth medium. The other wells contained the compounds according to the invention in different concentrations, starting from the wells of the third vertical row of the microtiter plate, from which the test substances were diluted 2 to ¹⁰ times in steps of two.

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

The IC ₅₀ values were determined as the concentration of the treated and infected cells at which 50% (approx. 10 syncytia) of the virus-induced syncytia were suppressed by the treatment with the compound according to the invention.

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

The compounds according to the invention are valuable active substances for the treatment and prophylaxis of diseases caused by retroviruses in human and veterinary medicine. Areas of indication in human medicine include:

1.) The treatment and prophylaxis of human retrovirus infections.

2.) For the treatment or prophylaxis of those caused by HIV I (Human Immunodeficiency Virus; 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 the immune deficiency and encephalopathy caused by this virus.

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

4.) For the treatment or prophylaxis of the AIDS carrier state (AIDS carrier state).

Examples of indications in veterinary medicine are:

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) Zwoegersiekte virus (in sheep) e) infectious virus of anemia (of the horse) f) infections caused by the feline leukemia virus g) infections caused by the virus of the cat immunodeficiency (FIV) h) infections caused by the virus of the monkey immunodeficiency (SIV)

Points 2, 3 and 4 from the indication area in human medicine are preferred.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds of the formula (I) or which consist of one or more active compounds of the formula (I), and processes for the preparation of these preparations. The active compounds of the formula (I) should be present in the pharmaceutical preparations listed above in a concentration of about 0.1 to 99.5%, preferably about 0.5 to 95% by weight, of the total mixture.

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

The pharmaceutical preparations listed above are prepared in a customary manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

In general, it has proven to be advantageous in both human and veterinary medicine to use the active ingredient (s) according to the invention in total amounts of about 0.5 to about 500, preferably 1 to 100 mg / kg of body weight per 24 hours. if necessary, in the form of several single doses to achieve the desired results. A single dose contains the active ingredient (s) preferably in amounts of about 1 to about 80, in particular 1 to 30 mg / kg body weight. However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place.

Explanation of the experimental part:

DC systems

Stationary phase

Merck DC pre-assembled silica gel 60 F-254, 5 x 10 cm, layer thickness 0.25 mm, art. 5719.

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

I: CH ₂ C1 ₂ / MeOH 9: 1 u: CH ₂ C1 ₂ / MeOH 95: 5

HI: NH ₃ / CH ₂ C1 ₂ / MeOH 0.2: 9: 1 IV: acetic acid / CH ₂ C1 ₂ / MeOH 0.2: 9: 1

V: CH ₂ C1 ₂ / MeOH 10: 1

VI: toluene / ethanol 5: 1

VII: Petroleum ether / ethyl acetate 6: 1

Vπi: NH ₃ / CH ₂ C1 ₂ / MeOH 2:80:20 IX: HOAc / CH ₂ C1 ₂ / MeOH 0, 1: 10: 1

X: toluene / acetone 2: 1

XI: CH ₂ C1 ₂ / MeOH / NH ₃ 95: 5: 0.2

XII: CH ₂ C1 ₂

XIII: CH ₂ Cl ₂ / 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

XVIII: CH ₂ C1 ₂ / MeOH 98: 2

HPLC system I:

Nucleosil 120-5 C 18.5 µm column, 125 x 4 mm; Eluents: A = 0.01 MH ₃ PO ₄ , B = acetonitrile eluent program: 0-1 min: 10% B 1-9 min: gradient with 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 refer to a series of homologous 2-alkanones (methyl-n-alkyl ketones): C3 = 300, C4 = 400, C16 = 1600

Analytical HPLC under standard conditions:

Column: GROMSIL OOSB, 5 μm, 250 x 4.6 mm eluent: A = 0.01 m H ₃ PO ₄ , B = acetonitrile

Eluent program: 0 - 1 min .: 10% B

1 - 9 min .: gradient with 10% b / min. 9 - 13 min .: 90% B

Flow: 2 ml / min. Temperature: room temperature injection volume: 5 μl sample: approx. 1 mg / ml detection: UV diode array at 210 nm

Outgoing connections

Example I

1 - (4-nitrobenzyl) - 1H-1, 2,4-triazole

99.2 g (0.58 mol) of 4-nitrobenzyl chloride and 40.0 g (0.58 mol) of 1H-l, 2,4-triazole are mixed 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 is removed in vacuo. The residue is extracted hot with toluene. After cooling to room temperature, the product crystallizes out of the filtrate. It is suctioned off, washed with diethyl ether and dried in a high vacuum. Yield: 83 g (70% of theory) TLC system VI: R _f = 0.30 MS-EI: m / z 205 (M + H) ⁺

Example II

1- (4-aminobenzyl) -IH-l, 2,4-triazole

10.9 g (53.4 mmol) of the compound from Example I are dissolved in 200 ml of 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. The catalyst is filtered off and washed with 100 ml of ethyl acetate. The combined filtrates are evaporated to dryness in vacuo. The residue is triturated with diethyl ether, suction filtered and dried under a high vacuum.

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

Example m

(3-Moφholino) nitrobenzene

29 g (107 mmol) 3-nitrophenyl trifluoromethanesulfonate (Synthesis, 12 (1990) pp.

1145 ff.) Are stirred in 150 ml (1.72 mol) Moφholin under argon for 16 h in a 130 ° C bath. The Moφholin excess is removed in a high vacuum on a Rotavapor and the resulting oil on silica gel with petroleum ether / ethyl acetate 3: 1 chromatographies. Yield: 14.5 g of oil (= 65% of theory) Example IV

3 -Moφholinoaniline

25 g (120.2 mmol) of the compound from Example ni are dissolved in 700 ml of ethyl acetate and hydrogenated over 2 g of Pd catalyst (10% Pd on activated carbon) at 3.2 bar for 4 hours. The catalyst is separated off, the filtrate is evaporated and the residue is 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- (Moφholinomethyl) aniline hydrochloride

10.6 g (47.7 mmol) of 4- (Mθφholinomethyl) nitrobenzene (obtainable by reacting 4-nitro-benzyl chloride with Moφholin) are dissolved in 50 ml of dimethylformamide. 25 μl of 1 normal aqueous hydrochloric acid are added to the mixture and, after addition of 1 g of palladium on carbon (10%), the mixture is hydrogenated at 3 bar for 2 days. The catalyst is separated off on a bed of diatomaceous earth and the filtrate is evaporated to dryness in a high vacuum. The residue is taken up in 200 ml of dichloromethane and the solution is 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 evaporated to dryness in a high vacuum. The yellow residue is 300 ml Diethyl ether triturated, suction filtered and dried after washing with diethyl ether 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 106 (base peak)

1H 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, H ₂ O + NH ₂ x HCl group))

Example VI

4- (N-tert-butyloxy carbonylaminomethyl) 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. Under ice cooling and stirring, is added dropwise 63.5 ml (0.291 mol) of di-tert.-butyl dicarbonate (Boc _j O) and left overnight to come Raum¬ temperature. The precipitate is filtered off and the filtrate is evaporated to dryness. The residue is taken up in 500 ml of diethyl ether and the organic phase is extracted 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, suction filtered, 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) 1H-NMR (CDC1 ₃ ): 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 dissolved in 150 ml of methanol and 55.5 ml (55.5 mmol) of 1 normal aqueous hydrochloric acid are added. To

Add 2 g of palladium on carbon (10%) at normal pressure up to

Hydrogen uptake ceased. The batch is filtered through a layer of diatomaceous earth to remove the catalyst. It is washed with methanol and the combined organic phase is evaporated to dryness on a rotary evaporator at a bath temperature of 35 ° C. The residue is mixed with 200 ml

Triturated diethyl ether, suction filtered, washed with diethyl ether and dried at 30 ° C 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 1H-NMR (CD ₃ OD): δ = 1.41 (s, 9H); 4.25 (s, 2H), 4.88 (s, broad, 3

+ 1H); 7.31 - 7.47 (m, 4H).

Free base 1H-NMR (CDC1 ₃ ): δ = 1.46 (s, 9H); 3.64 (s, broad, 2H); 4.18 (d. 2H);

4.74 (s, broad, 1H); 6.64 and 7.06 (2 H each, aromatic AB system)

Example Vm

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

13 g (41 mmol) of 2,4,5-trifluoro-3-difluoromethoxybenzoyl-acetic acid ethyl ester (EP 0 572 259 AI, ÜBE INDUSTRIES, p. 58, ref.Example 1, lines 1-39) are mixed with 13.9 ml ( 82 mmol) of triethyl orthoformate in 50 ml of acetic anhydride were stirred at a bath temperature of 140 ° C. under reflux for 1.5 hours. All volatile components are removed in a vacuum at a heating bath temperature of 65 ° C. The residue is distilled off three times with 25 ml of toluene pA in vacuo. The oily crude product is dried in a high vacuum and reacted with the substituted anilines in the subsequent steps without further purification. Yield: 16.2 g (107.3% of theory). The crude product is 93%

DC system VII: R _f = 0.20 (starting material β-ketoester Rf = 0.57) DC system XVII: R _f = 0.73

Example IX

6,7-difluoro-8-difluoromethoxy-l, 4-dihydro-4-oxo-l- [4- (lH-l, 2,4-triazol-l-ylmethyl) phenyl] -3-quinolinecarboxylic acid hydrochloride

a) Ethyl 2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl) -3- [4- (1H-1, 2,4-triazole-1-yl-methyl) -phenylamino] acrylic acid

4 g (10 mmol) of the 93% crude product from Example VIII are dissolved in 20 ml of ethanol and in portions with stirring with 1.57 g (9 mmol) of

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 washed twice with 20 ml of n-pentane, once with 20 ml of n-pentane / ethanol 1: 1 and a further four times with 20 ml of n-pentane and dried in an oil pump in vacuo. Yield: 3.74 g (75.4% of theory based on the example VÜI)

[A further 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-triazole-1-yl-methyl) -phenyl] -3- quinoline carboxylic acid ethyl ester

4.01 g (8 mmol) of the enamino compound from a) are stirred with 5 g (36.16 mmol) of potassium carbonate in 50 ml of dimethoxyethane at room temperature for 20.5 hours. A further 1.15 g (8.32 mmol) of potassium carbonate are added and the mixture is stirred for a further 20.75 hours. The mixture is then stirred at 45 ° C. for 2.75 hours and allowed to come to room temperature. 0.328 g (6.07 mmol) of sodium methylate are added in portions and the mixture is subsequently stirred at room temperature for 2.25 hours. The mixture is diluted with 50 ml of dichloromethane, suction filtered and the residue is washed with dichloromethane. The residue is boiled in succession with 100 ml of dichloromethane and with 25 ml of ethanol / 50 ml of dichloromethane, suction filtered while warm and several times with a total of 200 ml

Washed dichloromethane. The combined filtrates are freed of all volatile components in vacuo. 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) of DC system II: R _f = 0.35

VÜI DC system. R _f 0.92 (+) FAB-MS: m / z 477 (M + H)

3.8 g (8 mmol) of the ester from b) are stirred with 25 ml of 4 normal aqueous hydrochloric acid at 110 ° C. for 2 hours. The mixture is allowed to come to room temperature and the crystals are filtered off with suction. These are washed twice with 40 ml of ethanol / diethyl ether 1: 3 and twice with 50 ml of diethyl ether and dried in vacuo over calcium chloride. 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)

1H-NMR (DCOOD TMS): δ = 5.95 (s, 2H); 6.09, 6.37, 6.68 (t, 1/2/1), 1H,

(OCHF ₂ ); 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-methyl) phenyl] -3-quinolinecarboxylic acid hydrochloride

a) Ethyl 2- (2,4,5-trifluoro-3-difluoromethoxybenzoyl) -3- [4- (N, N-dimethylamino-methyl) -phenylamino] -acrylic acid

1.8 g (approx. 4.4 mmol) of the 93% crude product from Example VÜI are dissolved in 10 1 of ethanol 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. The mixture is stirred for 3 hours and all volatile constituents are removed under high vacuum at a bath temperature of 45 ° C. The oily crude product is implemented directly in the next stage. Yield: 2.28 g of DC system XVII: R _f = 0.49 b) 6,7-difluoro-8-difluoromethoxy-1,4-dihydro-4-oxo-1- [4- (N, N-dimethylamino-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 a total of 0.362 g (6.67 mmol) of sodium methylate are added in portions with stirring and cooling. The mixture is stirred for 7 hours at room temperature and all volatile constituents are evaporated off in vacuo at a bath temperature of 38.degree. The residue is coevaporated with diethyl ether and dichloromethane, dried on an oil pump and converted into the target compound without further purification. Yield: 2.25 g of crude product

DC system XVII: 0.36

2.25 g (4.4 mmol) of the crude ester from b) are stirred in 10 ml of 4 normal aqueous hydrochloric acid at 110 ° C. for 2 hours. The mixture is allowed to come to room temperature and the mixture is stirred with 15 ml of diethyl ether. It is suctioned off over a sinter plate and the crystal slurry is stirred on the suction filter with 4 ml of dimethoxyethane and 2 ml of diethyl ether. After thorough drying, the product is washed with diethyl ether and dried in vacuo. Yield: 1.35 g (66% of theory with respect to Example VIII over 3 steps) DC system VÜI: = 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-4-oxo-1- [3- (morpholino) phenyl] -3-quinolinecarboxylic acid hydrochloride

a) 2- (2,4,5-Trifluoro-3-difluoromethoxybenzoyl) -3- [3- (moφholino) phenylamino] - acrylic 1-ethyl ester

1.8 g (approx. 4.4 mmol) of the 93% crude product from Example VÜI are dissolved in 20 ml of ethanol and 0.784 g (4.4 mmol) of the compound from Example IV are added in portions with stirring at room temperature. The mixture is stirred for 3 hours and all volatile components are removed in a high vacuum at a bath temperature of 45 ° C. The oily crude product is implemented directly in the next stage. Yield: 2.47 g of DC system II: R _f = 0.86 DC system Xu: R _f O, ll DC system XvTH: R _f = 0.68

b) 6,7-difluoro-8-difluoromethoxy-l, 4-dihydro-4-oxo-l - [3- (moφholino) phenyl] - 3-quinolinecarboxylic acid, ethyl ester

2.46 g (4.4 mmol) of the crude product from a) are dissolved in 8 ml of dimethoxyethane and a total of 0.353 g (6.52 mmol) of sodium methylate are added in portions with stirring and cooling. The mixture is stirred for 7 hours at room temperature and all volatile constituents are evaporated off in vacuo at a bath temperature of 38.degree. 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 4 normal aqueous in 10 ml

Hydrochloric acid stirred at 110 ° C for 2 hours. The mixture is allowed to come to room temperature and the mixture is stirred with 15 ml of diethyl ether. It is suctioned off over a sinter plate and the residue is rinsed with 20 ml of ethanol / diethyl ether 1: 1. The product is stirred on the suction filter in succession with three times 20 ml of diethyl ether and suction filtered, and finally dried in vacuo over calcium chloride.

Yield: 1.73 g (80.3% of theory with respect to Example VIII over 3 stages) 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-l-yl] -l- [4- (lH-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) of 1- (2-methoxyphenylene) piperazine and 0.5 ml (2.88 mmol) of N, N-diisopropylethylamine in 0.4 ml of dimethyl sulfoxide was stirred at 110 ° C. for 3.5 hours. All volatile components are removed in a high vacuum at a bath temperature of up to 93 ° C. The evaporation residue (0.533 g) is stirred with 1 ml of water. The crystals formed are filtered off with suction and washed 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 with 1.5 ml of diethyl ether. The crude product (267 mg) is dried overnight under high vacuum over potassium hydroxide and recrystallized from 1 ml 1,2-dimethoxyethane, suction filtered, washed with diethyl ether and dried.

Yield: 187 mg (69% of theory) DC system VÜI: 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-dimethylamino-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) of N-phenylpiperazine and 0.5 ml (2.85 mmol) of N, N-diisopropylethylamine in 0.4 ml of dimethyl sulfoxide at 110 ° for 7 hours C stirred. All volatile components are removed in a high vacuum at a bath temperature of up to 93 ° C. The evaporation residue is distributed between 50 ml dichloromethane and 6 ml water. The organic phase is washed with 10 ml of water, then with 10 ml of semi-saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness. 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) of DC system VIII: R _f = 0.51

HPLC system I: Rt = 6.325 min. (+) FAB-MS: m / z 567 (M + H)

Example 3

6-fluoro-8-difluoromethoxy-7- [4- (2-methoxyphenyl) piperazin-l -yl] - l - [3- (morpholino) phenyl] -l, 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) of 4- (2-methoxyphenyl) piperazine and 0.5 ml (2.85 mmol) of N, N-diisopropylethylamine in 0.4 ml of dimethyl sulfoxide stirred at 110 ° C for 6 hours. The mixture is allowed to come to room temperature and 2 ml of diethyl ether are added to the mixture. The crystals formed are filtered off and washed twice with 1 ml of diethyl ether. The residue is dried on an oil pump (254 mg) and stirred with 1 ml of water, suction filtered and washed successively with 1 ml of water (twice), 0.5 ml of dimethoxyethane (twice) and 1 ml of diethyl ether (three times). The product is dried under high vacuum. Yield: 189 mg (65.8% of theory) DC system VIH: 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-dimethylamino-methyl) phenyl] - 1, 4-dihydro-4-oxo- quinoline-3-carboxylic acid trihydrochloride

200 mg (353 mmol) of the compound from Example 2 are dissolved in 3 ml of dichloromethane and 1 ml of ethanol. 0.46 ml of a 4 N solution of dry hydrogen chloride gas in dioxane are added and all volatile constituents are removed in vacuo. For the crystallization, the oily evaporation residue is mixed with 3 ml of diethyl ether and 0.3 ml of ethanol and stirred. Allow the product to settle and decant the supernatant. After filling with 5 ml of n-pentane, the mixture is stirred for 10 minutes, suction filtered and washed with n-pentane. 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 are prepared analogously to Examples 1-3 from the respective acids of the starting compounds IX, X and XI and the corresponding piperazine derivatives. These are commercially available (Aldrich, Emka, Janssen) or can be obtained using known methods. The salts listed in Tables 4 and 5 are obtained analogously to Example 4 from the respective free bases.

Table General formula eductic acid

XI

Table 3:

E.g. no. R (+) FAB-MS DC system / RfΛVert HPLC system / Rt value

19 m / z 623 (M + H) I: 0.69 H: 9.498 min

20 m / z 609 (M + H) I: 0.73 II: 7.269 min

21 m / z 596 (M + H) I: 0.64 II: 4.749 min

Table 4:

Table 5:

Claims

claims

1. N _] various 6-fluoro-8-difluoromethoxy-substituted quinolonecarboxylic acids of the general formula (I),

in which

represents hydrogen or methyl,

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 ,

D or E represents hydrogen and

stands for Morpholino

or

represents a radical of the formula -CH ₂ -L,

wherein L Moφholino, or a 5-membered via N-bond

Means heteroaromatics with up to 3 further nitrogen atoms, or means a group of the formula -NR ³ R ⁴ ,

wherein

R ³ and R ^{4 are} identical or different and denote 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,

R ^{1 represents} phenyl, pyridyl, pyrimidyl or pyrazinyl, optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl , Alkoxy or alkylthio are each substituted with up to 6 carbon atoms,

R ^{2 represents} hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,

D or E represents hydrogen and

D stands for Morpholino

or

E represents a radical of the formula -CH ₂ -L,

wherein L Moφholino, imidazolyl, pyrrolyl, 1,2,3-triazolyl-l-yl, 1,2,4-

Triazol-1-yl, l, 2,4-triazol-4-yl or tetrazolyl, or a group of the formula -NR ³ R ⁴ ,

wherein

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,

R ^{1 represents} phenyl, pyridyl, pyrimidyl or pyrazinyl, which are optionally up to 3 times the same or different by nitro, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio with each up to 4 carbon atoms are substituted,

R ^{2 represents} hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,

D or E represents hydrogen and

D stands for Moφholino

or

E represents a radical of the formula -CH ₂ -L,

wherein L denotes morpholino or 1,2,4-triazol-l-yl, or denotes a group of the formula -NR ³ R ⁴ ,

wherein

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

R ² , D and E have the meaning given in claim 1,

R represents halogen, preferably fluorine or chlorine,

with compounds of the general formula (III)

1 / \ R ¹ -N N- H

VW ⁽ π-O in which

A and R ^{1 have} the meaning given in claim 1,

in inert solvents, if appropriate in the presence of acid scavengers,

and in the case of acids, the esters are saponified,

5. Medicament containing one or more compounds from claims 1 to 3.

6. Use of the compounds from claims 1 to 3 for the preparation of antivirally active drugs.