DE19802437A1 - Use of N-aminophenyl sulfonamides for treating or preventing viral infections, particularly herpes - Google Patents

Abstract

Use of N-aminophenyl benzenesulfonamide derivatives (I), or their stereoisomeric mixtures or salts, for treating or preventing viral infections is new. (I) are of formula A and D = hydrogen, fluoro, chloro, nitro, cyano, hydroxy or linear or branched 1-3C alkyl, alkoxy or alkoxycarbonyl; R<1> = phenyl, optionally substituted by 1-3 of halo, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, carboxy, 1-8C linear or branched alkoxycarbonyl, 1-6C linear or branched alkyl or alkoxy, and/or by phenyl or phenoxy (themselves optionally substituted by up to 3 of halo, trifluoromethyl, hydroxy or 1-4C linear or branched alkyl or alkoxy) and/or by a group -(NH)aSO2-NR<4>R<5> or 4-phenyl-1,2,3-triazol-2-yl; a = 0 or 1; R<4> and R<5> = hydrogen or 1-6C linear or branched alkyl or alkoxy; R<2> = hydrogen or methyl; R<3> = COR<6>; R<6> = 2-6C linear or branched alkenyl, 1-8C linear or branched alkyl (optionally substituted by 1-3 of hydroxy, halo, cyano, 1-5C linear or branched alkyl or phenyl (itself optionally substituted by 1-3 of halo, hydroxy, trifluoromethyl, trifluoromethoxy or 1-5C linear or branched alkyl or alkoxy)). An Independent claim is also included for a pharmaceutical composition containing one or more (I).

Description

The present invention relates to the use of substituted sulfonamides as antiviral agents, especially against cytomegaloviruses, as well as new substances and Process for their production.

Benzenesulfonamides are already from many medical and phototechnical publications cations known [cf. see JP 0915806172; US WO 94/24095].

Various classes of nucleosides and are available as classes of compounds with anti-cytomegalyactivity Nucleotide analogs, anthraquinone derivatives, cobalt complexes, macrolides and Acyl peptides [e.g. B. EP 488 041] known.

Surprisingly, it has now been found that the compounds of the general formula (I) according to the invention

in which
A and D are the same or different and represent hydrogen, fluorine, chlorine, nitro, cyano, hydroxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
R ^{1 represents} phenyl which may be up to 3 times identical or different through halogen, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms, or
is substituted by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
and / or is substituted by phenyl or phenoxy, which in turn can be substituted up to 3 times identically or differently by halogen, trifluoromethyl, hydroxy, straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
and / or by a group of the formula - (NH) _a -SO ₂ -NR ⁴ R ⁵ or

is substituted, wherein
a represents a number 0 or 1,
R ⁴ and R ^{5 are} identical or different and denote hydrogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
R ^{2 represents} hydrogen or methyl,
R ^{3 represents} a radical of the formula -CO-R ⁶ ,
wherein
R ⁶ denotes straight-chain or branched alkenyl having up to 6 carbon atoms, or
straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted up to 3 times identically or differently by hydroxyl, halogen, cyano, straight-chain or branched alkyl having up to 5 carbon atoms or by phenyl, which in turn is up to 3 times the same or different is substituted by halogen, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
have an antiviral effect on representatives of the group of herpes viridae, especially on the human cytomegalovirus (HCMV) and are therefore suitable for the treatment and prophylaxis of diseases caused by human cytomegaloviruses.

Compounds of the general formula (I) according to the invention are preferably used,
in which
A and D are the same or different and represent hydrogen, fluorine, chlorine, nitro, cyano, hydroxy or methoxy,
R ^{1 represents} phenyl, which is optionally up to 3 times the same or different by fluorine, chlorine, bromine, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or
is substituted by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
and / or is substituted by phenyl or phenoxy, which in turn can be substituted up to 2 times, identically or differently, by fluorine, chlorine, nitro, trifluoromethyl, hydroxy, straight-chain or branched alkyl or alkoxy, each having up to 3 carbon atoms,
and / or by a group of the formula - (NH) _a -SO ₂ -NR ⁴ R ⁵ or

is substituted,
wherein
a represents a number 0 or 1,
R ⁴ and R ^{5 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R ^{2 represents} hydrogen or methyl,
R ^{3 represents} a radical of the formula -CO-R ⁶ ,
wherein
R ⁶ denotes straight-chain or branched alkenyl having up to 5 carbon atoms, or
straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally up to 3 times the same or differently substituted by hydroxy, fluorine, chlorine, bromine, cyano or by phenyl, which in turn is up to 2 times the same or different by fluorine , Chlorine, bromine, hydroxyl or substituted by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
and their salts
as an antiviral, especially against cytomegaloviruses.

Compounds of the general formula (I) according to the invention are particularly preferably used,
in which
A and D are the same or different and represent hydrogen, fluorine, chlorine, hydroxy or methoxy,
R ^{1 represents} phenyl which may be up to 3 times the same or different by fluorine, chlorine, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or
is substituted by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
and / or is substituted by phenyl or phenoxy, which in turn can be substituted up to 2 times in the same or different manner by fluorine, chlorine, nitro, trifluoromethyl or hydroxy, and / or by a group of the formula - (NH) _a -SO ₂ -NR ⁴ R ⁵ or

is substituted, wherein
a represents a number 0 or 1,
R ⁴ and R ^{5 are the} same or different and are hydrogen or methyl,
R ^{2 represents} hydrogen or methyl,
R ^{3 represents} a radical of the formula -CO-R ⁶ ,
wherein
R ⁶ denotes straight-chain or branched alkenyl having up to 5 carbon atoms, or
straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally up to 2-fold identical or different by hydroxy, fluorine, chlorine, bromine, cyano, straight-chain or branched alkyl having up to 4 carbon atoms or by phenyl sub-substituted is in turn up to 2 times the same or different is substituted by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
and their salts
as an antiviral, especially against cytomegaloviruses.

The substances according to the invention can also be present as salts. As part of the Invention physiologically acceptable salts are preferred.

Physiologically acceptable salts can be salts of the compound according to the invention with inorganic or organic acids. Salts are preferred with inorganic acids such as hydrochloric acid, hydrobromic acid, Phosphoric acid or sulfuric acid, or salts with organic carbon or Sulfonic acids such as acetic acid, maleic acid, fumaric acid, malic acid, Citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulfonic acid, Ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfone acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Z are particularly preferred. B. Well trium, potassium, magnesium or calcium salts, as well as ammonium salts are guided by ammonia, or organic amines, such as ethyl amine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, di methylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.  

The compounds of general formula (I) according to the invention can be found in ver different stereochemical forms occur, which are either like image and Mirror image (enantiomers), or which are not like image and mirror image (Diastereo mere) behave. The invention relates to both the antipodes and the racem shape as well as the diastereomer mixtures. The racemic shapes can also be used as the diastereomers in a known manner in the stereoisomerically uniform Be separate components.

In the context of the invention, the compounds of the general formula (I) according to the invention can be linked to the respective phenyl ring with respect to the —SO ₂ —NH group and the —NR ² R ³ group in the o-, m- or p-position .

The -SO ₂ -NH group and the -NR ² R ³ group are preferably bonded to the phenyl radical in the m or p position.

The -SO ₂ -NH group and the -NR ² R ³ group in the p-position are particularly preferably linked to the phenyl radical.

The present invention also relates to new substances listed in Table A. are:  

Table A

The examples listed in Table B are very particularly preferred:

Table B

The compounds of general formula (I) according to the invention and the new substances can be prepared by:
[A] compounds of the general formula (II)

in which
A, D and R ^{1 have} the meaning given above,
first by catalytic hydrogenation with palladium / C or by reduction with SnCl ₂ in inert solvents into the compounds of the general formula (III)

in which
A, D and R ^{1 have} the meaning given above,
convicted,
and finally with compounds of the general formula (IV)

LR ³ (IV)

in which
R ^{3 has} the meaning given above
and
L represents hydroxy or halogen, preferably chlorine,
in inert solvents, if appropriate in the presence of a base and / or an auxiliary,
and in the case of R ² ≠ H, optionally including an alkylation by customary methods,
or
[B] compounds of the general formula (V)

in which
A, D and R ^{3 have} the meaning given above,
initially as described under [A] by hydrogenation on Pd / C or by reduction with SnCl ₂ in inert solvents into the compounds of the general formula (VI)

in which
A, D and R ^{3 have} the meaning given above,
transferred
and then with compounds of the general formula (VII)

R ¹ -SO ₂ -E (VII)

in which
R ^{1 has} the meaning given above
and
E represents halogen, preferably chlorine,
in inert solvents, optionally in the presence of a base and / or auxiliary agent.

The processes according to the invention can be exemplified by the following formula schemes:

The usual inert solvents are suitable as solvents for all process steps, that do not change under the reaction conditions. These preferably include organic solvents such as ether z. B. diethyl ether, glycol mono- or dimethyl 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, dimethyl form amide, hexamethylphosphoric triamide, ethyl acetate, pyridine, triethylamine or Picolin. It is also possible to use mixtures of the solvents mentioned, if appropriate can also be used with water. Methylene chloride and tetra are particularly preferred hydrofuran, dioxane and dioxane / water.

Suitable bases are organic amines (trialkyl (C ₁ -C ₆ ) amines such as triethylamine or heterocycles such as pyridine, methylpiperidine, piperidine or N-methylmorpholine. Triethylamine and N-methylmorpholine are preferred.

The bases are generally preferred in an amount of 0.1 mol to 5 mol from 1 mol to 3 mol in each case based on 1 mol of the compounds of the general Formulas (III) and (VIII) used.

Suitable auxiliaries are carbodiimides such as diisopropylcarbodiimide, Dicyclohexylcarbodiimide or N- (3-dimethylainopropyl) -N'-ethylcarbodiimide- Hydrochloride or carbonyl compounds such as carbonyldiimidazole or 1,2-oxa zolidum compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate or propane phosphoric anhydride or isobutyl chloroformate or benzotriazolyloxy-tris- (di methylamino) phosphonium hexyfluorophosphate or phosphonic acid diphenyl ester amide or methanesulfonic acid chloride, optionally in the presence of bases such as Triethylamine or N-ethylmorpholine or N-methylpiperidine or dicyclohexylcarbo diimide and N-hydroxysuccinimide.

The reactions can be carried out at normal pressure, but also at elevated or low pressure (e.g. 0.5 to 3 bar). Generally one works at Normal pressure.  

The reactions are preferred in a temperature range from 0 ° C to 100 ° C as carried out at 0 ° C to 30 ° C and at normal pressure.

The reductions can generally by hydrogen in water or in inert organic solvents such as alcohols, ethers or halogenated hydrocarbons, or mixtures thereof, with catalysts such as SnCl ₂ , Raney nickel, palladium, palladium on animal charcoal or platinum, or with hydrides or boranes in inert solvents, optionally carried out in the presence of a catalyst. Palladium on animal charcoal or SnCl _{2 is} preferred.

The reaction can be carried out at normal, elevated or reduced pressure out (e.g. 0.5 to 5 bar). Generally one works at normal pressure.

The reductions are generally in a temperature range from 0 ° C to + 60 ° C, preferably at + 10 ° C to + 40 ° C.

Customary organic solvents which are suitable as solvents for the acylation are do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, or hydrocarbon substances such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, or Halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, Dichlorethylene, trichlorethylene or chlorobenzene, or ethyl acetate, or triethylamine, Pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, Acetonitrile, acetone or nitromethane. It is also possible to mix the ge to use named solvents. Dichloromethane and pyridine are preferred.

The acylation is carried out in the solvents listed above at temperatures of 0 ° C to + 150 ° C, preferably at room temperature to + 100 ° C and at normal pressure carried out.

The compounds of the general formulas (II), (III), (IV), (V), (VI) and (VII) are known per se or can be produced by methods known from the literature.  

The compounds of the general formula (I) according to the invention do not show one predictable surprising spectrum of action. They have an antiviral effect to representatives of the group of herpes viridae, especially to the human cytomegalovirus (HCMV). They are therefore for treatment and prophylaxis of diseases caused by herpes viridza, especially diseases caused by caused by human cytomegaloviruses.

The anti-HCMV activity was determined in a screening test system in 96-well micro titer plates with the help of human embryonic pulmonary fibroblasts (HELF) cell cultures determined. The influence of substances on the spread of the cytopathogenic effect was compared to the reference substance ganciclovir (Cymevene® sodium), a clinically approved anti-HCMV chemotherapeuti cum, definitely.

The substances (50 mM) dissolved in DMSO (dimethyl sulfoxide) are examined on micro-titer plates (96-well) in final concentrations of 250-0.4 µM (micromolar) in duplicate determinations (4 substances / plate). Toxic and cytostatic effects are also included. After the corresponding substance dilutions (1: 2) on the microtiter plate, a suspension of 50-100 HCMV-infected HELF cells and 30 × 10 ⁴ non-infected HELF cells in Eagle's MEM with 10% fetal calf serum is added to each well, and the Incubate plates at 37 ° C in a CO ₂ incubator for 6 days. After this time, the cell lawn in the substance-free virus controls, starting from 50-100 infectious centers, is completely destroyed by the cytopathogenic effect of HCMV (100% CPE). After staining with neutral red and fixation with formalin / methanol, the plates are evaluated using a projection microscope (plaque viewer). The results for some compounds are summarized in the following table:
It has been found that the compounds according to the invention increase the HCMV in HELF cells in z. Inhibit T. concentrations 10-50 times lower than Cymevene® sodium and have a selectivity index that is several times higher.

The compounds according to the invention thus represent valuable active substances for the treatment and prophylaxis of diseases of human cytomegalovirus infections. The following can be mentioned as areas of indication:

• 1) Treatment and prophylaxis of HCMV infections in AIDS patients (Retinitis, pneumonitis, gastrointestinal infections).
• 2) Treatment and prophylaxis of cytomegalovirus infections in bones marrow and organ transplant patients suffering from HCMV pneumonitis, -Encephalitis, as well as gastrointestinal and systemic HCMV infections cations often become life-threatening.
• 3) Treatment and prophylaxis of HCMV infections in newborns and Toddlers.

In vivo effect Animals

Male mice 5 weeks old, strain NOD / LtSz-Prkdc (scid) / J, were from one commercial breeders (The jackson Lab., Bar Harbor). The animals were kept in isolators under sterile conditions (including bedding and feed).

Virus / infection

Murine cytomegalovirus (MCMV), Smith strain, was passaged in vivo (BALB / c) and purified by fractional centrifugation. The titer was examined using a plaque assay for primary embryonic mouse fibroblasts. The mice were infected with a dose of 5 × 10 ⁵ pfu in a total volume of 0.2 ml intraperitoneally. This dose leads to death in 100% of the infected animals after approx. 11 days.

Treatment / evaluation

24 hours after infection, the mice were exposed for 8 days Treated with os twice a day (morning and evening). The dose  was 25 mg / kg body mass, the application volume 10 ml / kg body mass. The The substances were formulated in the form of a 0.5% tylose suspension. 16 The animals were killed painlessly hours after the last substance application and saliva, liver and kidney.

Genomic DNA was purified from 25 mg of the tissue by phenol / chloroform extraction. The DNA was quantified photometrically and using the formula OD ₂₆₀ × 50 = mg / ml.

The purity of the DNA was checked using the quotient OD ₂₆₀ / OD ₂₈₀ and the DNA was then adjusted to pH = 8.0 with Tris-EDTA.

The MCMV-DNA was quantified using DNA dot blot hybridization. A digoxygenin-labeled (Boehringer-Mannheim, also listed buffer, unless otherwise described) 1.2 kb fragment from the MCMV range, Smith, HindIII J, was used as the probe. The signals were detected by means of chemiluminescence. For this, the membrane was washed in 1 × digoxygenin washing buffer 1 for 3 minutes. The filters were then incubated for 30 minutes at room temperature with shaking in 1 × digoxygenin blocking solution. The filters were then incubated for 30 minutes in 20 ml / 100 cm ² membrane with the anti-DIG alkaline phosphatase conjugate solution (1: 20,000 in 1 × digoxygenin blocking solution). Two 15-minute washing steps with 1 × digoxygenin washing buffer followed. This was followed by equilibration of the filters in 1 × digoxygenin detection buffer for 5 minutes and detection by means of 1 ml / 100 cm ² membrane area 1: 100 diluted CDP-Star solution. After spreading out the CDP-Star solution and incubating for 5 minutes in a dark box, the chemoluminescence was detected or evaluated using X-ray film (Kodak) or LumiImager (Boehringer Mannheim).

All results were backed up statistically (analysis of variance using statistics; StatSoft Inc.).  

The new active ingredients can be introduced into the usual formulations in a known manner are transferred, such as tablets, dragees, pills, granules, aerosols, syrups, emuls ions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable carriers or solvents. This is where the therapeu Table active compound in a concentration of about 0.5 to 90% by weight of the total mixture is present, d. H. in amounts that are sufficient are in order to achieve the specified dosage range.

The formulations are prepared, for example, by stretching the active ingredients substances with solvents and / or carriers, optionally using Emulsifiers and / or dispersants, z. B. in the case of using Water as a diluent and optionally organic solvents as auxiliary solvents tel can be used.

The application is carried out in the usual way, preferably orally, parenterally or topically, especially perlingually or intravenously.

In the case of parenteral use, solutions of the active ingredients can be found below Use of suitable liquid carrier materials can be used.

In general, it has proven to be advantageous for intravenous administration Amounts from about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg body weight to give effective results, and oral appli cation is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg Body weight.

Nevertheless, it may be necessary to deviate from the quantities mentioned give way, depending on the body weight or the type of application path, from individual behavior towards the drug, the type of its formulation and the time or interval at which the administr submission takes place. So in some cases it may be sufficient to use less than that the aforementioned minimum quantity, while in other cases the aforementioned upper limit must be exceeded. In the case of application of larger quantities  it may be advisable to mix these in several single doses throughout the day divide.

Output connections Example I Benzenesulfonic acid- [4-nitroanilide]

80 g (0.58 mol) of 4-nitroaniline are stirred in 1.6 l in 3 l three-neck flasks Dissolved dioxane and added 117 ml (1.45 mol) of pyridine. Under cold water cooling 88.5 ml (0.70 mol) of benzenesulfonyl chloride are added dropwise at 20-25 ° C. and Stirred at RT for 20 h. DC control PE / EE 1: 1.

The suspension is poured into 9 l of water, stirred well for 3 h, the crystals are suctioned off, washed with 2 ml of water and then washed with pentane. The crystals are then dried.
Yield: 160 g (99% of theory).

Example II Benzenesulfonic acid- [4-aminoanilide]

80 g (0.29 mol) of the compound from Example I are in a 2 l round neck flask with 1 l Dioxane submitted with stirring. Then it is covered with argon and the Catalyst added. It is hydrogenated for 48 h at RT and normal pressure. DC control PE / EE 1: 1.  

The catalyst is suctioned off through kieselguhr and the mother liquor is poured onto 7 l of water. The mixture is then stirred well for 2 h. The crystals are filtered off and washed with 2 l of water. Then it is washed with pentane and the crystals are dried.
Yield: 68 g (95%).

Manufacturing examples example 1 Benzenesulfonic acid- [4- (2,2-mono-fluoromethyl] propion-antrazonyl] -3-nitrile

20 ml of dioxane are placed in a 100 ml round-bottomed flask and 1.00 g (4.027 mol) of the compound from Example II is dissolved therein with stirring. Then 0.81 ml (10.068 mmol) of pyridine and then 0.76 g (4.833 mmol) of 3,3-difluoropivaloyl chloride are added. After 20 h of stirring, the completeness of the reaction is checked by DC control (PE / EE 1: 1). 80 ml of water are poured in and stirred vigorously for 3 h. The deposited crystals are filtered off and washed with 100 ml of water and 50 ml of pentane. The crystals are dried at 1 mm on the oil pump.
Yield: 1.2 g (80.9%).

Analog to the rule of Example 1, the Ver listed in Table 1 bindings made:  

Table 1

Claims (7)

1. Use of compounds of the general formula (I)
in which
A and D are the same or different and represent hydrogen, fluorine, chlorine, nitro, cyano, hydroxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 3 carbon atoms,
R ^{1 represents} phenyl, which is optionally up to 3 times the same or different by halogen, nitro, hydroxyl, trifluoromethyl, trifluoromoxy, carboxyl, straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms, or
is substituted by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
and / or is substituted by phenyl or phenoxy, which in turn can be substituted up to 3 times identically or differently by halogen, trifluoromethyl, hydroxyl, straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms,
and / or by a group of the formula - (NH) _a -SO ₂ -NR ⁴ R ⁵ or
is substituted,
wherein
a represents a number 0 or 1,
R ⁴ and R ^{5 are} identical or different and are hydrogen or straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
R ^{2 represents} hydrogen or methyl,
R ^{3 represents} a radical of the formula -CO-R ⁶ ,
wherein
R ⁶ denotes straight-chain or branched alkenyl having up to 6 carbon atoms, or
straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted up to 3 times identically or differently by hydroxyl, halogen, cyano, straight-chain or branched alkyl having up to 5 carbon atoms or by phenyl, which in turn is up to 3- is the same or differently substituted by halogen, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
or of their stereoisomeric mixtures or salts for the prophylaxis or treatment of viral diseases. 2. Use of compounds of general formula (I) according to claim 1, in which
A and D are the same or different and represent hydrogen, fluorine, chlorine, nitro, cyano, hydroxy or methoxy,
R ^{1 represents} phenyl which may be up to 3 times the same or different from fluorine, chlorine, bromine, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms, or
is substituted by straight-chain or branched alkyl or alkoxy each having up to 5 carbon atoms,
and / or is substituted by phenyl or phenoxy, which in turn can be substituted up to 2 times, identically or differently, by fluorine, chlorine, nitro, trifluoromethyl, hydroxy, straight-chain or branched alkyl or alkoxy, each having up to 3 carbon atoms,
and / or by a group of the formula - (NH) _a -SO ₂ -NR ⁴ R ⁵ or
is substituted,
wherein
a represents a number 0 or 1,
R ⁴ and R ^{5 are} identical or different and denote hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms,
R ^{2 represents} hydrogen or methyl,
R ^{3 represents} a radical of the formula -CO-R ⁶ ,
wherein
R ⁶ denotes straight-chain or branched alkenyl having up to 5 carbon atoms, or
straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally up to 3 times the same or different substituted by hydroxy, fluorine, chlorine, bromine, cyano or by phenyl, which in turn is up to 2 times the same or different by fluorine , Chlorine, bromine, hydroxy or is substituted by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
or of their stereoisomeric mixtures and / or salts. 3. Use of compounds of general formula (I) according to claim 1, in which
A and D are the same or different and represent hydrogen, fluorine, chlorine, hydroxy or methoxy,
R ^{1 represents} phenyl which may be up to 3 times the same or different by fluorine, chlorine, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkoxycarbonyl having up to 3 carbon atoms, or
is substituted by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
and / or is substituted by phenyl or phenoxy, which in turn can be substituted up to 2 times by the same or different means by fluorine, chlorine, nitro, trifluoromethyl or hydroxy,
and / or by a group of the formula - (NH) _a -SO ₂ -NR ⁴ R ⁵ or
is substituted,
wherein
a represents a number 0 or 1,
R ⁴ and R ^{5 are} identical or different and are hydrogen or methyl,
R ^{2 represents} hydrogen or methyl,
R ^{3 represents} a radical of the formula -CO-R ⁶ ,
wherein
R ⁶ denotes straight-chain or branched alkenyl having up to 5 carbon atoms, or
straight-chain or branched alkyl having up to 5 carbon atoms, which is optionally up to 2-fold identical or different by hydroxy, fluorine, chlorine, bromine, cyano, straight-chain or branched alkyl having up to 4 carbon atoms or substituted by phenyl, which is in turn up to 2-fold identical or differently substituted by fluorine, chlorine, bromine, hydroxy, trifluoromethyl, trifluoromethoxy or by straight-chain or branched alkyl or alkoxy each having up to 3 carbon atoms,
or of their stereoisomeric mixtures and / or salts. 4. Use of compounds of general formula (I) according to claim 1 for the manufacture of medicinal products for the treatment and prophylaxis of human cytomegalovirus infections.   5. Connections of the formulas
6. Medicaments containing compounds of the general formula (I) according to Claim 1. 7. Medicament according to claim 6, characterized in that it is one or contain several compounds according to claim 5.