DE4425660A1 - 7-Substituted 1- [4- (1H-1,2,4-triazol-1-yl-methyl) phenyl] substituted quinolone carboxylic acids - Google Patents

Abstract

The present invention concerns 7-substituted 1-[4-(1H-1,2,4-triazol-1-yl-methyl)phenyl] substituted quinolone carboxylic acids of general formula (I), in which the substituents have the meanings given in the description. The invention further concerns a process for their preparation and their use as drugs, in particular as antiviral agents.

Description

The present invention relates to 7-substituted 1- [4- (1H-1,2,4-triazol-1-yl- methyl) phenyl] substituted quinolonecarboxylic acids, process for their preparation and their use as medicines, especially as antivirals.

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

The present invention now relates to 7-substituted 1- [4- (1H-1,2,4-triazol-1-yl- methyl) phenyl] substituted quinolonecarboxylic acids of the general formula (I),

in which
A represents hydrogen or methyl,
R¹ represents phenyl, naphthyl, pyridyl, pyrimidyl or pyrazinyl, which may optionally be up to 3 times the same or different by nitro, trifluoromethyl, halogen, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each with up to 8 Carbon atoms or by a radical of the formula

are substituted,
or
R¹ for a radical of the formula

stands,
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.

Compounds of the general formula (I) are preferred
in which
A represents hydrogen or methyl,
R¹ is phenyl, naphthyl, pyridyl, pyrimidyl or pyrazinyl, which may 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 up to 6 carbon atoms or by a radical of the formula

are substituted,
or
R¹ for a radical of the formula

stands,
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 is phenyl, naphthyl, pyridyl, pyrimidyl or pyrazinyl, which may 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 up to 4 carbon atoms or by a radical of the formula

are substituted,
or
R¹ for a radical of the formula

stands,
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 represents halogen, preferably chlorine or bromine,
with compounds of the general formula (III)

in which
A and R¹ have the meaning given above,
in inert solvents, optionally in the presence of acid scavengers.

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 use mixtures of the solvents mentioned. Dimethyl sulfoxide is preferred 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 a Range from 0.5 to 5 bar).

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

in which
R² has the meaning given above,
R³ represents C₁-C₄-alkyl,
R⁴ represents C₁-C₄ alkoxy or C₁-C₄ dialkylamino,
and
D represents halogen, preferably chlorine or fluorine,
by reaction with amines of the general formula (V)

in one of the solvents listed above, preferably ethanol,
into the compounds of the general formula (VI)

in which
D and R² 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 at 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 using 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 in PBL's and the cell pellet was then 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 became 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 the microtiter plate, from which the test substances are diluted 2½ times in steps of two were.

The test batches were incubated at 37 ° C. until the untreated one Virus control the syncytia formation typical of HIV occurred (between day 3 and 6 after infection), which was then evaluated microscopically. In the untreated virus control results in about 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 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 retroviruses 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 encephalopathy.
• 3. For the treatment or prophylaxis of an HTLV-I or HTLV-II Infection.  
• 4. For the treatment or prophylaxis of the AIDS carrier condition (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 cat immunodeficiency (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, and methods for producing them 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 in both human and Veterinary medicine has proven advantageous, the one or more Active ingredients in total amounts from about 0.5 to about 500, preferably 1 to 100 mg / kg body weight per 24 hours, possibly in the form of several single doses, to achieve the desired results. A single gift contains the active ingredient (s) preferably in amounts of about 1 to about 80, especially 1 to 30 mg / kg body weight. However, it may be necessary deviate from the doses mentioned, depending on the Type and body weight of the object to be treated, the type and the Severity of the disease, the type of preparation and the application 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 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: NH₂ / CH₂Cl₂ / MeOH 2:80:20

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 g (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 g (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 2- (2,4-difluorobenzyl) -3- [4- (1H-1,2,4-triazol-1-ylmethyl) phenylamine-o] - acrylic acid methyl ester a) Ethyl 3- (2,4-difluorophenyl) -3-oxo-propionate

100 g (0.874 mol) of magnesium ethylate (Aldrich) are placed under argon in 800 ml Ethanol p.A. suspended. 141.5 ml are added dropwise to the mixture with stirring (0.932 mol) diethyl malonate, dissolved in 800 ml toluene p.A. and 250 ml Ethanol p.A. The batch is heated at 70 ° C. for 1.5 hours and is left on Come to room temperature and then cools to -15 ° C. At this temperature a solution of 71 ml (0.582 mol) of 2,4-difluorobenzoyl chloride (Aldrich) is added dropwise dissolved in 250 ml toluene p.A. quickly. The approach is at room temperature Let come, stir for four hours and let stand overnight. Of the The batch is cooled to 10 ° C. and mixed vigorously with vigorous stirring 195 ml (3.49 mol) of concentrated sulfuric acid and 200 ml of water were added. Man allows to come to room temperature and adds 500 ml of water to the batch. The Phases are separated and the aqueous phase is washed twice with 500 ml of toluene washed out. The combined organic phases are twice with 300 ml saturated saline, dried over sodium sulfate and am Rotary evaporator concentrated. The residue (426 g) is in 1500 ml of water suspended. After adding 20.25 g of p-toluenesulfonic acid hydrate Batch refluxed for 8 hours. After cooling, the phases Cut. The aqueous phase is extracted twice with 300 ml dichloromethane. The combined organic phase is washed with brine, over Dried sodium sulfate and evaporated to dryness on a rotary evaporator.

Crude yield: 253.8 g
DC system VII: R _f = 0.61
MS-EI: m / z 229 (M + H) ⁺

b) 3-Ethoxy-2- (2,4-difluorobenzoyl) acrylic acid ethyl ester

The crude product obtained under a) (253.8 g) is in argon in 650 ml Acetic anhydride dissolved, mixed with 225 ml (1.324 mol) of triethyl orthoformate and 3 Stirred at 135 ° C for hours. The solvents are removed in a high vacuum and the residue twice with 300 ml of toluene p.A. coevaporated. The Crude product is dried under high vacuum and directly to the title compound of Example III implemented.

Crude yield: 258.7 g
DC system VII: R _f = 0.18
DC system VI: R _f = 0.60
MS / EI: m / z 284 (M + H) ⁺

The crude product obtained under a) (258.7 g) is in argon in 700 ml of ethanol p.A. solved. 73 g (0.42 mol) of the compound are then carried into the mixture from Example II. The mixture is stirred at room temperature, initially one Solution forms, but from which a precipitate precipitates after about 10 minutes begins. The suspension is stirred overnight at room temperature. Of the Product precipitate is suctioned off, washed well with ethanol and pentane and dried in a high vacuum.

Yield: 157 g (0.38 mol; 90.9% of theory with respect to Example II; 65.3% of theory Th. Regarding 2,4-difluorobenzoyl chloride)

Another 10.2 g of the title compound crystallize out of the mother liquor.

DC system VI: R _f = 0.43
MS-DCI: m / z 413 (M + H) ⁺

Example IV 7-fluoro-1,4-dihydro-4-oxo-1- [4- (1H-1,2,4-triazol-1-ylmethyl) phenyl] -3 quinoline carboxylic acid ethyl ester

157 g (0.38 mol) of the compound from Example III are in a mixture of 1 l Dichloromethane and 300 ml of dimethylformamide dissolved. One gives to the solution 210 g (1.5 mol) of potassium carbonate and stirred overnight at room temperature. Man sucks off the solid and washes well with dichloromethane / dimethylformamide to. The combined filtrates are evaporated to dryness in vacuo. Of the  The residue is triturated three times with 500 ml of diethyl ether, suction filtered and 30 ° C dried in a high vacuum.

Yield: 146 g (98% of theory)
DC system VI: R _f = 0.21
MS-EI: m / z 392 (M⁺)
1 H-NMR (CDCl₃): δ = 1.38 (t, 3H); 4.37 (q, 2H); 5.53 (s, 2H); 6.62 (dd, 1H); 7.12 (m, 1H); 7.52 (m. 4H); 8.07 (s, 1H); 8.28 (s, 1H); 8.42 (s, 1H); 8.52 (dd, 1H).

Example V 7-fluoro-1,4-dihydro-4-oxo-1- [4- (1H-1,2,4-triazol-1-ylmethyl) phenyl] -3 quinoline carboxylic acid hydrochloride

145.6 g (0.371 mol) of the compound from Example IV are dissolved in 600 ml of 4N aqueous hydrochloric acid (2.4 mol) suspended and two hours at 110 ° C at reflux touched. A clear solution is obtained after 30 minutes and starts after 35 minutes the product fail. The mixture is allowed to cool, diluted with 500 ml of water and sucked from. The filter cake is washed first with water, then with pentane and dried at 30 ° C in a high vacuum over potassium hydroxide.

Yield: 141.5 g (95.2% of theory)
DC system I: R _f = 0.41
(+) FAB-MS: m / z 365 (M + H) ⁺, m / z 387 (M + Na) ⁺ m / z 471 (M + Ag) ⁺
1 H-NMR (DCOOD): δ = 5.98 (s, 2H); 7.13 (dd, 1H); 7.57 (m. 1H); 7.72-7.97 (m, 4H); 8.66 (dd, 1H); 9.04 (s, 1H); 9.18 (s. 1H); 10.0 (s, 1H); 10.7 (s, 1H); [8.30 (s, DCOOD)].

Manufacturing examples Example 1 7- [4- (2-fluorophenyl) piperazin-1-yl] -1,4-dihydro-4-oxo-1- [4- (1H-1,2,4-triazol-1-yl- methyl) phenyl] -3-quinoline carboxylic acid

2 g (5 mmol) of the compound from Example V are mixed with 1.35 g (7.5 mmol) of 1- (o- Fluorophenyl) piperazine and 4.45 ml (2.25 mmol) diisopropylethylamine in 8 ml Dimethyl sulfoxide heated to 120 ° C for four hours with stirring. You let go Come to room temperature and sucks off the precipitated product. The residue is stirred with 30 ml of water and filtered off. The crystals obtained are stirred with 50 ml of diethyl ether, filtered and dried at 30 ° C in a high vacuum.

Yield: 2.5 g (95.4% of theory)
DC system I: R _f = 0.52
HPLC system I: Rt = 6.390 min
(+) FAB-MS: m / z 525 (M + H); m / z 631 (M + Ag)

Example 2 7- (4-phenyl-3-methyl-piperazin-1-yl) -1,4-dihydro-4-oxo-1- [4-1,2,4-tr-iazol-1-yl- methyl) phenyl] -3-quinolinecarboxylic acid

2 g (5 mmol) of the compound from Example V are mixed with 1.32 g (7.5 mol) of 2- Methyl 1-phenyl-piperazine and 8.8 ml (50 mmol) diisopropylethylamine in 20 ml Dimethyl sulfoxide stirred for four hours at a temperature of 120 ° C. All volatile components are in a high vacuum at a bath temperature of 90 ° C. distilled off. The crude product is dissolved in 10 ml of ethanol and by adding 30 ml of diethyl ether precipitated. It is suctioned off and the residue is stirred with 30 ml Water. The product is filtered and stirred with 50 ml of diethyl ether. To Vacuum drying the residue at 30 ° C in a high vacuum.

Yield: 2.44 g (93.8% of theory)
DC system I: R _f = 0.48
HPLC system I: Rt = 6.409 min
(+) FAB-MS: m / z 521 (M + H)

Examples 3 to 60 are analogous to that in Table 1 below Instructions of Examples 1 and 2 from the starting compound of Example V and the corresponding piperazines. These can be bought (Aldrich, Janssen, Maybridge, Lancaster) or can be prepared by known methods will.

Example 61 7- [4- (2-fluorophenyl) piperazin-1-yl] -4-dihydro-4-oxo-1- [4- (1H-1,2,4 - triazol-1-yl- methyl) phenyl] -3-quinolinecarboxylic acid trihydrochloride

200 mg (0.38 mmol) of the compound from Example 1 are mixed out 5 ml dichloromethane and 5 ml methanol dissolved and with 2 ml (8 mmol) of a 4 N Solution of dry hydrogen chloride gas mixed with dioxane. All fleeting Components are spun off and the residue with 5 ml of 1,2- Dimethoxyethane stirred. It is suctioned off, washed with 1,2-dimethoxyethane and Diethyl ether and dried in a high vacuum over potassium hydroxide.

Yield: 202 mg (83.6% of theory)
(+) FAB-MS: m / z 525 (M + H)

Example 62 7- (4-phenyl-3-methyl-piperazin-1-yl) -1,4-dihydro-4-oxo-1- [4- (1H-1,2,4-triazol-1-yl- methyl) phenyl] -3-quinolinecarboxylic acid trimethanesulfonate

450 mg (0.86 mmol) of the compound from Example 2 are in 5 ml of dichloromethane dissolved and with 2.58 ml (2.58 mmol) of a 1 N solution of methanesulfonic acid added in dichloromethane. You pull all volatile components in a high vacuum and the residue is stirred with 10 ml of diethyl ether. The ether will evaporated and the residue dried over potassium hydroxide in a desiccator. The The crude product is stirred with ether / petroleum ether, suction filtered and in a high vacuum dried.

Yield: 600 mg (86.3% of theory)
(+) FAB-MS: m / z 521 (M + H)

The salts listed in Tables 3 and 4 are analogous to Examples 61 and 62 from the corresponding free bases listed in the tables and the respective acids.

Claims (6)

1. 7-substituted 1- [4- (1H-1,2,4-triazol-1-yl-methyl) phenyl] substituted quinolonecarboxylic acids of the general formula (I), in which
A represents hydrogen or methyl,
R¹ represents phenyl, naphthyl, pyridyl, pyrimidyl or pyrazinyl, which may optionally be up to 3 times the same or different by nitro, trifluoromethyl, halogen, cyano, hydroxy or by straight-chain or branched alkyl, acyl, alkoxy or alkylthio, each with up to 8 Carbon atoms or by a radical of the formula are substituted,
or
R¹ for a radical of the formula stands,
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, naphthyl, pyridyl, pyrimidyl or pyrazinyl, which may 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 up to 6 carbon atoms or by a radical of the formula are substituted,
or
R¹ for a radical of the formula stands,
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, naphthyl, pyridyl, pyrimidyl or pyrazinyl, which may 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 up to 4 carbon atoms or by a radical of the formula are substituted,
or
R¹ for a radical of the formula stands,
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 represents halogen, preferably chlorine or bromine,
with compounds of the general formula (III) in which
A and R¹ have the meaning given in claim 1,
in inert solvents, optionally in the presence of acid scavengers. 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.