HK1115385B - Heterocyclylamide-substituted thiazoles, pyrroles and thiophenes - Google Patents

Abstract

The invention relates to heterocyclylamide-substituted thiazoles, pyrroles and thiophenes and to processes for preparing them, to their use for the treatment and/or prophylaxis of diseases, and to their use for the production of medicaments for the treatment and/or prophylaxis of diseases, particularly for use as antiviral agents, especially against cytomegaloviruses.

Description

The invention relates to heterocyclylamide substituted thiazoles, pyrroles and thiophenes and methods of their manufacture, their use in the treatment and/or prophylaxis of diseases and their use in the manufacture of medicinal products for the treatment and/or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegalovirus.

WO 99/23091 describes aromatic heterocyclic compounds as anti-inflammatory agents which may be useful, inter alia, for the treatment of viral infections and WO 04/052852 describes 3-pyrrolyl urea derivatives as antiviral agents carrying a carbocyclic substituent on the urea.

Although structurally different antiviral agents are available on the market, the currently available therapies with ganciclovir, valganciclovir, foscamet and cidofovir are associated with serious side effects such as nephrotoxicity, neutropenia or thrombocytopenia.

One purpose of the present invention is therefore to provide new compounds with equal or improved antiviral activity for the treatment of viral infectious diseases in humans and animals.

Surprisingly, the substituted heterocycles described in this study were found to be highly effective antiviral agents.

The present invention relates to compounds of the formula Other in which R1 for a group of the formula is * stands for the carbonyl group,R3 stands for phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, the substituents being independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluormethoxy, difluormethoxy, monofluormethoxy, trifluoromethyl, C1-C6-alkyl, C1-C6-alkoxy, hydroxy phenyl, heteroxy, C1-C6-alkoxy, amino, C1-C6-alkylamino, phenyl, and C1-cyl, wherein 5- or 6-membered halogen, or 3-membered halogen, may be independently selected from the group and substituted with 1 to 6 substitutes, andHydroxy, oxo, nitro, cyano, trifluoromethy, difluoromethy, trifluormethoxy, difluormethoxy, monofluormethoxy, trifluormethylo, C1-C6 alkyl, C1-C6 alkoxy, hydroxycarbonyl, C1-C6-alkoxycarbonyl, amino, C1-C6-alkylamino, aminocarbonyl and C1-C6-alkylaminocarbonyl, whether or not in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the form of a solution in the solution in the form of a solution in the form of a solution in the form of a solution in the solution in the form of a solution in the form of a solution in the solution in the form of a solution in the solution in the form of a solution in the solution in the form of a solution in the solution in the form of a solution in the solution in the form of a solution in the solution in and Other R5 and R6 stand for hydrogen, methyl or ethyl, independently of each other, R2 stands for phenyl, wherein phenyl can be substituted with 1 to 3 substitutes, the substitutes being independently selected from the group consisting of halogens, hydroxy, trifluoromethy, difluormethy, trifluormethoxy, difluormethoxy, monofluormethoxy, trifluormethy, trifluorethyo, C1-C6-alkyl and C1-C6-alkoxy, for a group of formula Other is where* stands for the carbonyl group,# stands for the nitrogen atom of the urea,R7 stands for C1-C6-alkyl, where the alkyl can be substituted with a substituent, the substituent being selected from the group consisting of C3-C6-cycloalkyl,C6-C10-aryl and 5- or 6-membered heteroaryl, where cycloalkyl, aryl and heteroaryl can be substituted with 1 to 3 substituents, the substituents being independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethyl, difluormethyl, monofluormethyl, trifluoromethyl thio, C1-C6-alkyl, C1-C6-alkoxy, hydroxycarbonyl, C1-C6-alkoxycarbonyl, amino, C1-C6-alkylamino, aminocarbonyl and C1-C6-alkylaminocarbonyl, andR8 and R9 are independently of each other hydrogen, halogens or C1-C6-alkyl, where the alkyl can be substituted with a substituent, the substituent being selected from the group consisting of C3-C6-cycloalkyl, C6-C10-aryl and 5- or 6-membered heteroaryl, where cycloalkyl, aryl and heteroaryl can be substituted with 1 to 3 substitutes, the substitutes being independently selected from the group,consisting of a halogen, a hydroxy, an oxo, a nitro, a cyano, a trifluoromethyl, a difluoromethyl, a trifluormethyl, a difluormethyl, a monofluormethyl, a trifluormethyl, a trifluormethyl thio, a C1-C6-alkyl, a C1-C6-alkoxy, a hydroxycarbonyl, a C1-C6-alkoxycarbonyl, an amino, a C1-C6-alkylamino, an aminocarbonyl and a C1-C6-alkylaminocarbonyl, and their salts, their solvates and their solvates.

The compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates of salts; the compounds of formula (I) and their salts, solvates and solvates of salts, and the compounds of formula (I) and their salts, solvates and solvates of salts, and the compounds of formula (I) and their salts, solvates and solvates of salts, insofar as the compounds of formula (I) and their salts, solvates and solvates of salts are not already salts, solvates and solvates of salts, are the compounds of the invention.

The compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers) depending on their structure. The invention therefore concerns the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers the stereoisomeric single components can be isolated in a known manner.

If the compounds of the invention can be found in more than one tautomeric form, the present invention covers all tautomeric forms.

The salts of the present invention are physiologically harmless salts of the compounds of the invention, but also include salts which are not suitable for pharmaceutical applications but can be used, for example, for the isolation or purification of the compounds of the invention.

Physiologically safe salts of the compounds of the invention include acid addition salts of mineral acids, carbonic acids and sulphonic acids, e.g. salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethanesulphonic acid, toluene sulphonic acid, benzene sulphonic acid, naphthalindisulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically safe salts of the compounds of the invention include salts of common bases, such as, and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C atoms, such as, and preferably, ethylene, diethylamine, triethylamine, ethyldiisopropylamine, monoethylene, diethanolamine, triethylamine, diclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, n-methylpyramidamine, arginine, l-aminolamine, n-methylene, and n-methylpermethylamine.

For the purposes of the invention, solvates are defined as forms of the compounds of the invention which, in the solid or liquid state, form a complex by coordination with solvent molecules.

Err1:Expecting ',' delimiter: line 1 column 148 (char 147)

For the purposes of the present invention, the substitutes have the following meanings, unless otherwise specified:

Err1:Expecting ',' delimiter: line 1 column 60 (char 59)

Alkoxy is an example and preferably an abbreviation of methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamine is an alkylamine residue with one or two alkylate substituents (independently selected), e.g. and preferably methyllamine, ethyllamine, n-propylamine, isopropylamine, tert-butylamine, n-pentylamine, n-hexylamine, N,N-dimethylamine, N,N-diethylamine, N-ethyl-N-methylamine, N-methyl-N-n-propylamine, N-isopropyl-N-n-propylamine, N-t-butyl-N-methylamine, N-ethyl-N-n-pentylamine and N-n-n-exyl-N-methylamine. C1-C3-alkylamine is an alkylate mono-residue containing 1 to 3 carbon atoms or a diethyl alcohol containing 1 to 3 carbon atoms.

Alkoxycarbonyl is an example and preferably an abbreviation of methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Allaminocarbonyl is an alkylaminocarbonyl residue with one or two alkyl substituents (independently selected), as an example and preferably for methyllaminocarbonyl, ethyllaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methylaminocarbonyl, N-propylaminocarbonyl, N-propylaminocarbonyl, N-propylaminocarbonyl, N-propylaminocarbonyl, N-propylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-propylaminocarbonyl, N-propylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylaminocarbonyl, N-methylamine, N-methylamine, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-methyl, N-meth

Aryl is a monocyclic or bicyclic aromatic carbocyclic residue, usually 6 to 10 carbon atoms; examples and preferences are phenyl and naphthyl.

The five- or six-membered heteroaryl is generally an aromatic monocyclic residue with five or six ring atoms and up to four heteroatoms from the S, O and/or N series. The heteroaryl residue may be bound by a carbon or a heteroatom. For example, and preferably, the names are thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazine.

Cycloalkyl means a cycloalkyl group with usually 3 to 6 carbon atoms, for example and preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Halogen is short for fluorine, chlorine, bromine and iodine.

For the purposes of the present invention, compounds of formula (I) are preferred. in which R1 for a group of the formula Other is where* stands for the carbonyl group,R3 stands for phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl can be substituted with 1 to 3 substitutes, the substitutes being independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluormethyl, trifluormethoxy, difluormethoxy, monofluormethoxy, trifluormethyl thio, C1-C6-alkyl, C1-C6-alkoxy, hydroxycarbonyl, C1-C6-alkoxycarbonyl, amino, C1-C6-alkylamino, aminocarbonyl and C1-C6-allaminocarbonyl,R2 stands for phenyl, wherein the phenyl can be substituted with 1 to 3 substitutes, the substitutes being selected independently from the group consisting of halogens, hydroxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluormethoxy,Monofluoromethoxy, trifluoromethyloxy, C1-C6-alkyl and C1-C6-alkoxy,for a group with formula Other is where* stands for the carbonyl group,# stands for the nitrogen atom of the urea,R7 stands for C1-C6-alkyl, where the alkyl can be substituted with a substituent, the substituent being selected from the group consisting of C3-C6-cycloalkyl, C6-C10-aryl and 5- or 6-membered heteroaryl, where cycloalkyl, aryl and heteroaryl can be substituted with 1 to 3 substituents, the substituents being independently selected from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethyl, difluormethyl, monofluormethyl, trifluoromethyl thio, C1-C6-alkyl, C1-C6-alkoxy, hydroxycarbonyl, C1-C6-alkoxycarbonyl, amino, C1-C6-alkylamino, aminocarbonyl and C1-C6-alkylaminocarbonyl, andR8 and R9 are independently of each other hydrogen, halogens or C1-C6-alkyl,Other and their salts, their solvates and their solvates.

The present invention also prefers compounds of formula (I), in which R1 for a group of the formula Other is where* stands for the carbonyl group linkage,R3 stands for phenyl or pyridyl, wherein phenyl and pyridyl can be substituted with 1 to 3 substitutes, the substitutes being selected independently from the group consisting of halogen, nitro, cyano, trifluormethyl, difluormethyl, trifluormethoxy, difluormethoxy, monofluormethoxy, C1-C4-alkyl and C1-C4-alkoxy,R2 stands for phenyl, wherein phenyl can be substituted with 1 to 3 substitutes, the substitutes being selected independently from the group consisting of fluorine, chlorine, trifluoromethoxy, difluormethoxy, trifluoromethyloethyl and methyl, for a group of the formula Other Other Standing up where* stands for the carbonyl group,# stands for the nitrogen atom of the urea,R7 stands for methyl, ethyl or n-butyl, where methyl, ethyl and n-butyl can be substituted with a substituent, the substituent being selected from the group consisting of cyclopropyl and phenyl, wherein the phenyl can be substituted with a substituent trifluoromethyl, andR8 and R9 stand independently for hydrogen, bromine, chlorine, methyl or ethyl, and their salts, their solvates and their solvates.

The present invention also prefers compounds of formula (I) in which R1 is given for a group of compounds of formula (I) and (I) is wherein * stands for the carbonyl group linkage and R3 stands for phenyl or pyridyl, wherein phenyl and pyridyl can be substituted with 1 to 3 substitutes, the substitutes being independently selected from the group consisting of halogen, nitro, cyano, trifluoromethyl, difluoromethyl, trifluormethoxy, difluormethoxy, monofluormethoxy, C1-C4-alkyl and C1-C4-alkoxy.

The present invention also prefers compounds of formula (I) where R2 is for phenyl, whereby phenyl may be substituted with 1 to 3 substitutes, the substitutes being selected independently from the group consisting of fluorine, chlorine, trifluoromethoxy, difluormethoxy, trifluoromethyloethyl and methyl.

The present invention also prefers compounds of formula (I), in which A for a group of Other is wherein * stands for the carbonyl group,# stands for the nitrogen atom of the urea,R7 stands for methyl, ethyl or n-butyl, where methyl, ethyl and n-butyl can be substituted with a substituent, the substituent being selected from the group consisting of cyclopropyl and phenyl, wherein phenyl can be substituted with a substituent trifluoromethyl,R8 stands for hydrogen, bromine, chlorine or methyl, and R9 stands for hydrogen.

The invention is furthermore a process for the production of compounds of formula (I), wherein

Method according to [A] Compounds of formula Other in which R1 has the meaning given above, in the first step with a reducing agent and in the second step in the presence of a carbonate derivative with compounds of the formula Other The following shall be added to the list of substances: Other in which R2 has the meaning given above, or Method [B] Compounds of formula (II) in the first step with a reducing agent and in the second step with compounds of formula Other the following point (a) is inserted: Other in which R2 has the meaning given above, or Method of [C] Compounds of formula Other in which R2 has the meaning given above and R10 stands for methyl or ethyl, a thickness of not more than 0,05 mm, Other R1-H (VI), Other in which R1 has the meaning given above, The test chemical is used to determine the concentration of the test chemical in the test medium.

The compounds of formulae (III), (IV) and (VI) are known or can be synthesized from the corresponding edicts by known processes.

For procedures [A] and [B] Stage 1:

The implementation is generally inert solvents, preferably in a temperature range of 0°C to the solvent backflow at normal pressure up to 3 bar.

For example, reducing agents are palladium to activated carbon and hydrogen, formic acid/triethylamine/palladium to activated carbon, zinc, zinc/saltic acid, iron, iron/saltic acid, iron-II sulphate/saltic acid, sodium sulphide, sodium disulfide, sodium dithionite, ammonium polysulfide, sodium borohydride/nickel chloride, zinc dichloride, titanium triethylamine or Raney nickel and aqueous hydrazine solution, preferably Raney nickel and aqueous hydrazine solution, palladium to activated carbon and hydrogen or formic acid/triethylamine/palladium.

Inert solvents include, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycoldimethyl ether or diethyl glycoldimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylol, toluol, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethyl formate, dimethyl amide, acetonite or pyridine, in the case of water-miscible solvents also mixtures of the same with water, as solvent, methanol, methanol, ethanol-propanol or methanol-N-hydracetyl and hydrazine in the case of hydracetyl ether and hydrazine.

For procedure [A] Stage 2 the following applies:

The implementation is generally in inert solvents, preferably in a temperature range from room temperature to 40°C at normal pressure.

The carbonic acid derivatives are for example N,N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, chlorophyll phenylester or chlorophyll-4-nitrophenyl ester, with N,N-carbonyldiimidazole being preferred.

Inert solvents include, for example, hydrocarbons such as methyl chloride, trichloromethane, tetrachloromethane, trichlorethane, tetrachlorethane, 1,2-dichloromethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycoldimethyl ether or diethyl glycoldimethyl ether, hydrocarbons such as benzene, xylol, toluol, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetic acid, acetone, dimethylformidine, dimethyl acetate, 2-butane, dimethylfoxide, acetonitrile or pyrethyl acetate, which is also acceptable in the case of water solvents, including dimethyl sulphate.

For procedure [B] Stage 2 the following applies:

The implementation is generally in inert solvents, where appropriate in the presence of a base, preferably in a temperature range from room temperature to the return of solvents at normal pressure.

Inert solvents include, for example, hydrocarbons such as methyl chloride, trichloromethane, tetrachloromethane, trichlorethane, tetrachlorethane, 1,2-dichlorethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycoldimethyl ether or diethyl glycoldimethyl ether, hydrocarbons such as benzene, xylol, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, tetrahydramethylformidine, dimethylacetamide, 2-butane, dimethyl oxide, aceton or pyrethyl chloride, or pyrethyl sulphate or methane.

Bases are, for example, alkali carbonates such as caesium carbonate, sodium or potassium carbonate, or potassium tert-butylate, or other bases such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferably triethylamine.

For procedure [C] stage 1, the following shall apply:

The implementation is generally inert solvents, preferably in a temperature range of 0°C to the return of solvents at normal pressure.

Bases are, for example, alkali hydroxides such as sodium, lithium or potassium hydroxide, or alkali carbonates such as caesium carbonate, sodium or potassium carbonate, preferably sodium hydroxide.

Inert solvents include, for example, hydrocarbons such as methyl chloride, trichloromethane, tetrachloromethane, trichlorethane, tetrachlorethane, 1,2-dichloromethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycoldimethyl ether or diethyl glycoldimethyl ether, alcohols such as methanol, ethanol, n-propanol, ethanol-propanol, n-bolol or tert-butyl ether, hydrocarbons such as benzene, xylol, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethyl acetate, dimethyl acetate, dimethyl or pyridoxal, and isoglucose, and isoglucose, and isoglucose, and isoglucose, and isoglucose.

For procedure [C] Stage 2 the following applies:

The implementation is generally carried out in inert solvents, where necessary in the presence of a base, preferably in a temperature range of -70°C to 40°C at normal pressure.

For example, carbodiimides such as N,N'-diethyl, N,N,'dipropyl, N,N'-diisopropyl, N,N'-dicyclohexylcarbodiimide, N- ((3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-n'-propyloxymethyl polystyrene (PS-carbodiver) or carbonyl compounds such as carbonyl dihydramidazole, or 1,2-dioxyzoyl compounds such as 2-ethyltetrahydroxyethyltetrahydramine-1-tetrahydroxy-fluoroxy-3-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluoroxy-fluor-fluor-fluor-fluor-fluor-fluor-fluor-fluor-fluor-fluor-fluor-fluor-fluor-fluor

Bases are, for example, alkali carbonates, such as sodium or potassium carbonate, or hydrogen carbonate, or organic bases such as trialkylamines, such as triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine (DMAP) or diisopropylethylamine, or DBU, DBN, pyridine, preferably triethylamine.

Preferably, the condensation is carried out with TBTU and DMAP.

Inert solvents include, for example, hydrocarbons such as methyl chloride, trichloromethane, tetrachloromethane, trichlorethane, tetrachlorethane, 1,2-dichlorethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycoldimethyl ether or diethyl glycoldimethyl ether, hydrocarbons such as benzene, xylol, toluol, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetic acid, acetone, dimethyl formate, dimethyl acetate, 2-butane, dimethyl oxide, acetonitrile or, in the case of water solvents, dimethyl formate, which is also acceptable with the dimethyl formate.

In an alternative process, the carbon acids obtained from the first step of process [C] can be converted in the second step first by a chlorination reagent such as thionyl chloride to carbonic acid chloride and then by compounds of formula (VI) in the presence of a base to compounds of formula (I).

The compounds of formula (II) are known or can be prepared by the reaction of compounds of formula (II) Other in which R10 has the meaning given above,

be carried out in the first step with a base and in the second step with compounds of formula (VI) in the presence of dehydrating reagents.

The implementation shall be as described in procedure [C].

The compounds of formula (VII) are known or can be prepared by the reaction of compounds of formula (VII) Other in which R10 has the meaning given above, be prepared with smoking sulphuric acid, concentrated sulphuric acid, nitric acid or other mixtures of sulphuric acid and sulphuric acid, where appropriate in acetone hydride as solvent, preferably in a temperature range from room temperature to 60 °C at standard pressure.

The compounds of formula (VIII) are known or can be synthesized from the corresponding edicts by known processes.

The compounds of formula (V) are known or can be prepared by converting compounds of formula (VII) in the first step with a reducing agent and in the second step in the presence of a carbonic acid derivative with compounds of formula (III) or in the second step with compounds of formula (IV).

The implementation shall be as described in procedures [A] and [B].

The compounds of the invention of general formula (I) have an unpredictable and surprising spectrum of action. They exhibit an antiviral effect against members of the group of herpes viridae (herpes viruses), especially against cytomegalovirus (CMV), especially against human cytomegalovirus (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases, especially infections with viruses, especially the viruses mentioned above, and the infectious diseases caused by them.

The compounds of generic formula (I) can be used for the manufacture of medicinal products suitable for the prophylaxis and/or treatment of diseases, in particular viral infections, due to their special properties.

The following areas may be identified 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 bone marrow and organ transplant patients who are suffering from HCMV pneumonitis, encephalitis, and gastrointestinal and systemic HCMV infections, often life-threatening.3) treatment and prophylaxis of HCMV infections in newborns and infants.4) treatment of acute HCMV infection in pregnant women.5) treatment of HCMV infection progression in immunocompromised patients with cancer and cancerTherapy.6) treatment of HCMV-positive tumors targeted by HCMV et al., 2004, JEMS, CEMS, F. 59-77.

The compounds of the invention are preferably used for the manufacture of medicinal products suitable for the prophylaxis and/or treatment of infections with a representative of the group of herpes viridae, in particular a cytomegaly virus, in particular the human cytomegaly virus.

The compounds of the invention may, due to their pharmacological properties, be used alone or, if necessary, in combination with other active substances, in particular antiviral agents such as ganciclovir, valganciclovir or aciclovir, for the treatment and/or prevention of viral infections, in particular HCMV infections.

The present invention also relates to the use of the compounds of the invention for the treatment and/or prophylaxis of diseases, preferably viral infections, in particular infections with the human cytomegalovirus (HCMV) or another member of the herpes viridae family.

The present invention also relates to the use of the compounds of the invention for the treatment and/or prophylaxis of diseases, in particular the diseases mentioned above.

The present invention also relates to the use of the compounds of the invention for the manufacture of a medicinal product for the treatment and/or prophylaxis of diseases, particularly those mentioned above.

The twists of the invention may be systemic and/or local in nature and may be applied in appropriate ways, such as orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, ottically or as an implant or stent.

For these applications, the compounds of the invention may be administered in suitable application forms.

For oral application, fast-acting and/or modified forms of application according to the state of the art, containing the compounds of the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (uncoated or coated tablets, for example with stomach-resistant or delayed dissolution or insoluble coatings, controlling the release of the compound of the invention), tablets or films/ointments, films/lyophilisates, capsules (for example, hard or soft capsules), droplets, granules, pulses, emulsions, solutions, aerosols or suspensions, which decompose rapidly in the oral cavity.

Parenteral administration may be bypass an absorption step (e. g. intravenous, intra-arterial, intra-cardial, intraspinal or intralumbar) or include absorption (e. g. intramuscular, subcutaneous, intracutan, percutan or intraperitoneal).

Other routes of application include inhalation formulations (including powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films/foils or capsules, suppositories, ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shakes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems, milk, pastes, foams, powders, implants or stents, to be applied lingually, sublingually or orally.

The compounds of the invention may be converted into the above applications by means of known in-house mixtures with inert, non-toxic, pharmaceutically suitable excipients, including carriers (e.g. microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersing or net agents (e.g. sodium dodecyl sulphate, polyoxysorbitanoleate), binders (e.g. polyvinylpyrrolidone), synthetic and natural polymers (e.g. albumin), stabilizers (e.g. antioxidants), ascorbic acid (e.g. ascorbic acid) and pigments (e.g. ascorbic acid) and anti-oxidants (e.g. anti-oxidants).

The present invention also covers medicinal products containing at least one compound of the invention, usually together with one or more inert non-toxic excipients suitable for pharmaceutical use, and their use for the purposes described above.

In general, intravenous doses of approximately 0.001 to 10 mg/ kg, preferably 0.01 to 5 mg/ kg body weight, have been shown to be beneficial for effective results, and oral doses of approximately 0.01 to 25 mg/ kg, preferably 0.1 to 10 mg/ kg body weight.

However, it may be necessary to deviate from the amounts mentioned, depending on body weight, route of application, individual behaviour with the active substance, type of preparation and time or interval of application. In some cases, it may be sufficient to use less than the minimum amount mentioned above, while in other cases the upper limit mentioned above may have to be exceeded.

The percentages in the following tests and examples are percentages by weight, parts by weight, solvent ratios, dilution ratios and liquid/liquid solution concentration ratios are all related to volume.

A. Examples Abbreviations used:

The test chemical is a chemical that is used to determine the concentration of a substance in a solution, and is used to determine the concentration of a substance in a solution, and to determine the concentration of a substance in a solution, and to determine the concentration of a substance in a solution.

HPLC and LC-MS methods:

Method 1 (LC-MS): Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2795; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 11 water + 0.5 mL 50% formic acid, Eluent B: 11 acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90%A → 2.5 min 30%A → 3.0 min 5%A → 4.5 min 5%A; Flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; Furnace: 50°C; UV detection: 210 nm.

Method 2 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent series 1100; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 11 water + 0.5 mL 50% formic acid, Eluent B: 11 acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90%A → 2.5 min 30%A → 3.0 min 5%A → 4.5 min 5%A; Flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; Furnace: 50°C; UV detection: 208 to 400 nm.

Method 3 (LC-MS): Device type MS: Micromass ZQ; Device type HPLC: HP 1100 Series; UV DAD; Column: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm x 4 mm; Eluent A: 11 water + 0.5 mL 50% formic acid, Eluent B: 11 acetonitrile + 0.5 mL 50% formic acid; Gradient: 0.0 min 90%A → 2.5 min 30%A → 3.0 min 5%A → 4.5 min 5%A; Flow: 0.0 min 1 mL/min, 2.5 min/3.0 min/4.5 min 2 mL/min; Furnace: 50°C; UV detection: 210 nm. The method is based on the following equation:

Exit connections Example 1A The following substances are to be classified in the same heading as the active substance:

1.09 mL (12.3 mmol) of trichloracetyl chloride is presented in 5 mL DCM with argon and a solution of N-methylimidazole is dripped into 3 mL DCM in RT within 30 min. Production: 2.12 g (76% of the total) The test chemical is then applied to the test chemical and the test chemical is removed.

Example 2A The following substances are to be classified in the same heading as the active substance:

2.12 g (9.34 mmol) 1-Methyl-2-trichloracetyl-1H-pyrrol is dissolved in 9.5 mL acetane hydride, cooled to -20°C and mixed with 0.43 mL (9.34 mmol) hydrochloric acid. RT is heated slowly, stirred for 1 h at RT. The reaction mixture is poured on 95 g of ice and stirred vigorously for 2.5 h (first oily deposition, then crystallization). Production: 1.71 g (67% of the total) The test chemical is then applied to the test chemical. The mean value of the test chemical is calculated as the mean value of the test chemical in the range of 0 to 100 mg/kg.

Example 3A Ethyl esters of 1-methyl-4-nitro-1H-pyrrol-2-carbonic acid

0.50 g (1.84 mmol) 1-Methyl-4-nitro-2-trichloracetyl-1H-pyrrol is presented in 5 ml of ethanol, mixed with 0.26 ml (1.84 mmol) triethylamine and stirred at RT 2 h. The reaction mixture is mixed with 5 ml of water, stirred at 0 °C for 30 min, and then vacuum-dried. The yield is 321 mg (88% by weight) The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 4A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

After cooling, filter over silica, rinse with ethanol and remove the filtrate from the solvent in the vacuum. Dissolve the residue in 6 mL THF, dissolve with 374 mg (1.84 mmol) 4-triluorhoxyphenylisocyanate and stir for 1 h at RT 304. The reaction solution is pressed and the residue is pressed with RHP-PLC (acetyl-PLC) to obtain a purified solid. The yield is 486 mg (85% d.j.) The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 5A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

470 mg (1.27 mmol) 1-Methyl-4-[[[[[[[4-[trifluormethoxy) phenyl]amino}carbonyl) amino]-1H-pyrrol-2-carboxylic acid ethyl ester is presented in 5 mL THF, 152 mg (6.33 mmol) lithium hydroxide is added to 1 mL water and stirred overnight under return flow. The yield is 429 mg (98% by weight) The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 6A 1-5- ((methylpyridine-2-yl) piperazine

Stage 1 The following substances are to be classified in the same heading as the active substance:

Under an argon atmosphere, dissolve 2.50 g (19.6 mmol) 2-methyl-5-chlorpyridine and 4.38 g (23.5 mmol) N-tert-butyl-oxycarbonyl) piperazine in 50 ml of absolute toluene. Then add 2.26 g (23.5 mmol) sodium butylate, 0.37 g (0.59 mmol) BINAP and 0.36 g (0.39 mmol) trisodium dipaladium and heat to 70 °C for 12 h. After cooling, the reaction mixture is saturated with diethyl ether, washed with a slightly saturated sodium chloride solution, dehydrated with sodium ether and vacuum cleaned. The flash (cycloacetate/cycloacetate) was cleaned in the 9:1 position. The yield is 5.27 g (97% of the dry weight). The test chemical is used to determine the concentration of the test chemical in the test chemical.

Stage 2 1-5- ((methylpyridine-2-yl) piperazine

3.47 g (12.5 mmol) 1-tert-butyl-pyridine-2-yl) piperazine is dissolved in 10 ml of dioxan and added to 31 ml (125 mmol) of hydrochloric acid in dioxan (4 molar). Stir for 2 h at RT. Then compress, alkalize with 1 ml of baking soda and extract several times with dichloromethane. The combined organic phases are dried using sodium sulphate, compressed and vacuum-dried. The yield is 2.18 g (98% of the dry weight). The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 7A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of example 5A. The test chemical is used to determine the concentration of the test substance in the test medium.

Example 8A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of example 5A. The mean of the measurements is calculated by multiplying the mean of the measurements by the mean of the measurements.

Example 9A Cyclic aromatic hydrocarbons having carbon numbers predominantly in the range of C1 through C5 and boiling in the range of approximately -15 oC to -15 oC (- 37 oF to -15 oF).

The manufacture is analogous to that of example 5A. The test chemical is used to determine the concentration of the active substance in the test chemical and to determine the concentration of the active substance in the test chemical.

Example 10A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of examples 4A and 5A from 4-aminothiophen-2-carboxylic acid methyl esters (synthesised according to A. A. Kiryano et al., Tetrahedron Lett.2001, (42), 8797-8800). The test chemical is used to determine the concentration of the test chemical in the test medium. The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 11A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of 4A and 5A from 2-amino-1,3-thiazol-4-carboxylic acid ethyl ester (commercially available from ACROS). The test chemical is used to determine the concentration of the test chemical in the test medium. The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 12A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of e.g. 4A and 5A from 2-amino-5-methyl-1,3-thiazol-4-carboxylic acid methyl ester (commercially available from Tyger Scientific). The test chemical is used to determine the concentration of the test chemical in the test medium. The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 13A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of examples 4A and 5A from 2-amino-5-chlorine-1,3-thiazole-4-carboxylic acid ethyl ester (synthesis described in K. J. Hodgett et al., Org. Lett.2002, (4), 1363-1366). The yield is 365 mg (89% of the total, 2 steps) The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 14A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of examples 4A and 5A from 2-amino-5-bromo-1,3-thiazole-4-carboxylic acid ethyl ester (synthesis described in J. F. Okonya et al., Tetrahedron Lett.,2002, (43), 7051-7054). The yield is 343 mg (74% of the total, 2 steps) The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Example 15A It consists predominantly of hydrocarbons having carbon numbers predominantly in the range of C1 through C5.]

The manufacture is analogous to that of examples 4A and 5A from 2-amino-1,3-thiazol-5-carboxylic acid ethyl ester (commercially available from RareChem). The test chemical is used to determine the concentration of the test chemical in the test medium. The test chemical is then applied to the test chemical and the test chemical is then removed from the test chemical.

Examples of implementation Example 1 The substance is to be classified in the immediate vicinity of the product.

50 mg (0.15 mmol) 1-Methyl-4-phenyl-[[[[[4-[trifluormethoxy) amino]carbonyl) amino]-1H-pyrrolic-carbonic acid (Example 5A) is presented in 1 mL DMF and mixed with 56 mg (0.18 mmol) O- (benzotriazole-1-yl) N,N,N',N'-tetramethyluronium tetrafluoroborate (TU) and 8.9 mg (0.07 mmol) 4-Dimethylamino) pyridine (DMAP). Then 29 mg (0.18 mmol) 1- (1-) 2-pyridyl) pyrazine is added and 8 TB is added to RT. The reaction solution is purified by RHPPLC (acetonyl/water). The yield is 54 mg (76% by weight) The mean of the measurements is calculated by multiplying the mean of the measurements by the mean of the measurements.

Example 2 The substance is to be classified in the immediate vicinity of the product.

The manufacture is analogous to example 1 from examples 5A and 6A. The following information is provided for the purpose of the calculation of the yield: The mean of the measurements performed was approximately the same as the mean of the measurements performed at the same time, i.e. the mean of the measurements performed at the same time was approximately the same as the mean of the measurements performed at the same time.

The Commission N-{1-ethyl-5-[[[4-pyridine-2-ylpiperazine-l-yl) carbonyl]-1H-pyrrol-3-yl}-N'-[4-trifluormethoxy) -phenyl]uric acid

The manufacture is analogous to example 1 from examples 7A and 6A. The yield is 29 mg (43% d.j.) The mean of the measurements performed was approximately the same as the mean of the measurements performed at the same time, i.e. the mean of the measurements performed at the same time was approximately the same as the mean of the measurements performed at the same time.

Example 4 N- ((1-Ethyl-5-{[4-(5-methylpyridine-2-yl)piperazine-l-yl]carbonyl}-1H-pyrrol-3-yl) -N'-[4-(trifluoromethoxy)phenyl]uric acid

The manufacture is analogous to example 1 from examples 7A and 6A. The following table shows the results of the analysis: The mean of the measurements performed was approximately the same as the mean of the measurements performed at the same time, i.e. the mean of the measurements performed at the same time was approximately the same as the mean of the measurements performed at the same time.

Example 5 N-{- ((1-butyl-5-[(4-pyridine-2-ylpiperazine-1-yl) carbonyl]-1H-pyrrol-3-yl) }-N'-[4-trifluormethoxy) -phenyl] urea

The manufacture is carried out in analogy with example 1 from example 8A. The yield is 41 mg (69% d.j.) The LC-MS (Method 2): Rt = 2.11 min.; MS (ESI+): m/z = 531 (M+H) + 1H-NMR (400MHz, DMSO-d6): δ = 8.75 (bs, 1H), 8.33 (bs, 1H), 8.12 (d, 1H), 7.58 (m, 1H), 7.54 (d, 2H), 7.26 (d, 2H), 7.07 (d, 1H), 6.87 (d, 1H), 6.68 (dd, 1H), 6.26 (d, 1H), 4.02 (t, 2H), 3.72 (m, 4H), 3.53 (m, 4H), 1.59 (quint., 2H), 1.18 (sext., 2H), 0.84 (t, 3H).

Example 6 The substance is to be classified in the immediate vicinity of the product.

The manufacture is analogous to example 1 from examples 8A and 6A. The following information is provided for the purpose of the calculation of the yield: The LC-MS (Method 2): Rt = 1.97 min.; MS (ESI+): m/z = 545 (M+H) + 1H-NMR (300MHz, DMSO-d6): δ = 8.74 (bs, 1H), 8.32 (bs, 1H), 7.98 (d, 1H), 7.53 (d, 2H), 7.41 (dd, 1H), 7.25 (d, 2H), 7.07 (d, 1H), 6.80 (d, 1H), 6.25 (d, 1H), 4.02 (t, 2H), 3.72 (m, 4H), 3.47 (m, 4H), 2.16 (s, 3H), 1.59 (quint., 2H), 1.18 (sext., 2H), 0.83 (t, 3H).

Example 7 The substance is to be classified in the immediate vicinity of the product.

The manufacture is carried out in analogy with example 1 from example 9A. The yield is 51 mg (86% by weight) The mean of the measurements performed was approximately the same as the mean of the measurements performed at the same time, i.e. the mean of the measurements performed at the same time was approximately the same as the mean of the measurements performed at the same time.

Example 8 The substance is to be classified in the immediate vicinity of the product.

The manufacture is analogous to example 1 from examples 9A and 6A. The following information is provided for the purpose of the calculation of the yield: The mean of the measurements performed was approximately the same as the mean of the measurements performed at the same time, i.e. the mean of the measurements performed at the same time was approximately the same as the mean of the measurements performed at the same time.

Example 9 The substance is to be classified in the immediate vicinity of the product.

The manufacture is analogous to example 1 from examples 10A and 6A. The yield is 60 mg (63% d.j.) The mean of the measurements performed was approximately the same as the mean of the measurements performed at the same time, i.e. the mean of the measurements performed at the same time was approximately the same as the mean of the measurements performed at the same time.

The following compounds are synthesised from the corresponding starting compounds in analogy with example 1: Other

10		Beispiel 11A	36 mg (51% d. Th.)	1.95 (Methode 3)	493
11		Beispiel 11A	49 mg (67% d. Th.)	2.02 (Methode 3)	507
12		Beispiel 11A	43 mg (58% d. Th.)	2.52 (Methode 3)	518
13		Beispiel 12A	33 mg (48% d. Th.)	2.00 (Methode 3)	507

14		Beispiel 12A	50 mg (70% d. Th.)	2.01 (Methode 3)	521
15		Beispiel 12A	52 mg (71% d. Th.)	2.60 (Methode 3)	532
16		Beispiel 13A	43 mg (58% d. Th.)	2.21 (Methode 3)	527
17		Beispiel 13A	35 mg (49% d. Th.)	2.24 (Methode 3)	541
18		Beispiel 13A	42 mg (52% d. Th.)	2.76 (Methode 3)	552
19		Beispiel 14A	45 mg (59% d. Th.)	2.22 (Methode 3)	571
20		Beispiel 14A	50 mg (68% d. Th.)	2.27 (Methode 3)	585
21		Beispiel 14A	41 mg (50% d. Th.)	2.77 (Methode 3)	596
22		Beispiel 15A	34 mg (49% d. Th.)	1.90 (Methode 3)	493
23		Beispiel 15A	47 mg (65% d. Th.)	1.93 (Methode 3)	507
24		Beispiel 15A	47 mg (64% d. Th.)	2.53 (Methode 3)	518

B. Evaluation of physiological efficacy

The in vitro effect of the compounds of the invention can be demonstrated by the following assays:

The test chemical is used to determine the concentration of the active substance in the test chemical.

The test compounds are used as 50 millimolar (mM) solutions in dimethysulfoxide (DMSO). Ganciclovir, foscarnet and cidofovir are used as reference compounds. After adding 2 μl each of the 50, 5, 0.5 and 0.05 mM DMSO stock solutions to 98 μl of cell culture medium in series 2 A-H in double determination, 1:2 dilutions of 50 μl each of medium are passed to row 11 of the 96-well plate. The wells in rows 1 and 12 contain 50 μl each of medium. The wells are then filled with 150 μl of a suspension of 1 x 104 cells (pre-dermal fibroblasts [DF]) (NH1 = 1 series) or with a double-cell controlled line of unrefined NH12 and NHCM-MDF.The final test concentrations are 250 - 0.0005 μM. The plates are incubated for 6 days at 37°C / 5% CO2, i.e. until all cells are infected in the virus controls (100% cytopathogenic effect [CPE]). The wells are then fixed and stained (30 minutes) by adding a mixture of formalin and Giemsa's dye, washed with aqua bidest. and dried in the dry washer at 50°C. The plates are then visually evaluated with an overhead microscope (technomaraque's multiplier).

The following data can be obtained from the test plates: CC50 (NHDF) = maximum concentration of substance in μM where no visible cytostatic effects on cells are observed compared to untreated cell control;EC50 (HCMV) = concentration of substance in μM where the CPE (cytopathic effect) is inhibited by 50% compared to untreated viral control;

Representative in vitro data for the compounds of the invention are given in Table A:

	21	0.0007	28767
	21	0.0059	3559
	11	0.0016	7333
	11	0.0054	2637

The suitability of the compounds of the invention for the treatment of HCMV infections can be demonstrated in the following animal model:

The test chemical shall be used for the determination of the concentration of the test chemical in the test chemical. Other animals:

3-4 week old female immunodeficient mice (16-18 g), Fox Chase SCID or Fox Chase SCID-NOD or SCID beige are obtained from commercial breeders (Bomholtgaard, Jackson) and kept in isolation in sterile conditions (including spraying and feeding).

The virus is:

Human cytomegalovirus (HCMV), Davis strain, is cultured in vitro on human embryonic prefrontal fibroblasts (NHDF cells). Following infection of the NHDF cells with a multiplicity of infection (M.O.I) of 0.01, the virus-infected cells are harvested 5-7 days later and stored in the presence of Minimal Essential Medium (MEM), 10% foetal calf serum (FKS) with 10% DMSO at -40°C. After serial dilution of the virus-infected cells in ten steps, the T-titer determination is performed on 24-fluoroplate confluent NHDF cells after vitalising with red or F-fixation and dyeing with a gel gel gel (as described above).

Preparation of the sponges, transplantation, treatment and evaluation:

1 x 1 cm collagen sponges (Gelfoam®; Fa. Peasel & Lorey, Best-No. 407534; K.T. Chong et al., Abstracts of 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p. 439; P.M. Kraemer et al., Cancer Research 1983, (43): 4822-4827) are first moistened with phosphate-buffered saline (PBS), the air bubbles are removed by degassing and then retained in MEM + 10 % FKS. 1 x 106 virus-infected NHDF cells (infection with HCM-Davis M.O.I. = 0.01) are removed 3 hours after infection and dissolved in 20 μl, 10 μl of FBS, 10 μl of FBS on a moist basis.1% BSA/1 mM DTT applied and incubated for 1 hour. For transplantation, the immunodeficient mice are anesthetized with avertine or a mixture of azepromazine-xylazine and ketamine, the spine is removed with a dry razor, the epidermis is opened 1-2 cm, relieved and the moist sponges are transplanted under the spine. The surgical wound is closed with tissue adhesive. 24 hours after transplantation, the mice are treated with the substance three times daily (7.00 a.m. and 14.00 a.m. and 19.00 p.m.) twice daily (8.00 a.m. and 17.00 p.m.) or once daily (14.00 p.m.) orally for 8 days. The dose is 3 or 10 or 30 mg or 100 kg body weight,The virus-infected cells are removed from the sponge by collagenase digestion (330 U / 1.5 mL) and stored in the presence of MEM, 10 per cent foetal calf serum, 10 per cent DMSO at -140°C. Evaluation is performed after serial dilution of the virus-infected cells in ten steps by titration on 24-well plates of confluent NHDF-vital cells with neural red staining or filamentary red staining and a formula as described above (Fixin).The number of infectious virus particles after treatment with the substance is measured compared to the placebo control group.

C. Examples of pharmaceutical formulations

The compounds of the invention may be converted into pharmaceutical preparations as follows:

The tablets: The composition:

The test chemical is a mixture of 100 mg of example 1,50 mg lactose (monohydrate), 50 mg cornstarch (native), 10 mg polyvinylpyrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

The tablet weighs 212 mg, has a diameter of 8 mm and a bulb radius of 12 mm.

Manufacture:

The mixture of active substance, lactose and starch is granulated with a 5% solution (m/m) of PVP in water. After drying, the granulate is mixed with the magnesium stearate for 5 min. This mixture is pressed with a standard tablet press (tablets format see above).

Suspension for oral use: The composition:

1000 mg of the compound of example 1, 1000 mg ethanol (96%), 400 mg rhodigel (xanthan gum from the Fa. FMC, Pennsylvania, USA) and 99 g water.

A single dose of 100 mg of the compound of the invention corresponds to 10 ml of oral suspension.

Manufacture:

The rodigel is suspended in ethanol, the active substance is added to the suspension, the water is added during stirring, and the rodigel is stirred for about 6 h until the fermentation is complete.

Intravenous solution for use: The composition:

1 mg of the example 1, 15 g polyethylene glycol 400 and 250 g water for injections.

Manufacture:

The compound of the invention is dissolved in water by stirring together with polyethylene glycol 400, sterilized (pores 0,22 μm in diameter) and filled under aseptic conditions in heat-sterilized infusion bottles, which are closed with infusion caps and nozzles.

Claims (9)

1. A compound having the formula in which

   R¹ denotes a group having the formula where

   * denotes the point of attachment to the carbonyl group

   R³ denotes phenyl or 5 or 6-membered heteroaryl wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, amino, C₁-C₆-alkylamino, aminocarbonyl and C₁-C₆-alkylaminocarbonyl,

   R⁴ denotes phenyl or 5 or 6-membered heteroaryl, wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, amino, C₁-C₆-alkylamino, aminocarbonyl and C₁-C₆-alkylaminocarbonyl, and R⁵ and R⁶ denote, independently of each other, hydrogen, methyl or ethyl

   R² denotes phenyl wherein phenyl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl and C₁-C₆-alkoxy

   A denotes a group having the formula where

   * denotes the point of attachment to the carbonyl group

   # denotes the point of attachment to the nitrogen atom of the urea

   R⁷ denotes C₁-C₆-alkyl wherein alkyl can be substituted by a substituent, said substituent being chosen from the group consisting of C₃-C₆-cycloalkyl, C₆-C₁₀-aryl and 5 or 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, amino, C₁-C₆-alkylamino, aminocarbonyl and C₁-C₆-alkylaminocarbonyl, and R⁸ and R⁹ denote, independently of each other, hydrogen, halogen or C₁-C₆-alkyl, wherein alkyl may be substituted by a substituent, the substituent being chosen from the group consisting of C₃-C₆-cycloalkyl, C₆-C₁₀-aryl and 5 or 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, amino, C₁-C₆-alkylamino, aminocarbonyl and C₁-C₆-alkylaminocarbonyl,

   or one of its salts, its solvates, or solvates of its salts.
2. A compound according to Claim 1, characterized in that

   R¹ denotes a group having the formula where

   * denotes the point of attachment to the carbonyl group

   R³ denotes phenyl or 5 or 6-membered heteroaryl wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, C₁-C₆-alkoxycarbonyl, amino, C₁-C₆-alkylamino, aminocarbonyl and C₁-C₆-alkylaminocarbonyl

   R² denotes phenyl wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl and C₁-C₆-alkoxy,

   A denotes a group having the formula where

   * denotes the point of attachment to the carbonyl group

   # denotes the point of attachment to the nitrogen atom of the urea

   R⁷ denotes C₁-C₆-alkyl wherein alkyl may be substituted by a substituent, said substituent being chosen from the group consisting of C₃-C₆-cycloalkyl, C₆-C₁₀-aryl and 5 or 6-membered heteroaryl, wherein cycloalkyl, aryl and heteroaryl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, hydroxy, oxo, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, trifluoromethylthio, C₁-C₆-alkyl, C₁-C₆-alkoxy, hydroxycarbonyl, C ₁-C₆-alkoxycarbonyl, amino, C₁-C₆-alkylamino, aminocarbonyl and C₁-C₆-alkylaminocarbonyl, and

   R⁸ and R⁹ denote, independently of each other, hydrogen, halogen or C₁-C₆-alkyl

   or one of its salts, its solvates, or the solvates of its salts.
3. A compound according to Claim 1 or 2, characterized in that

   R¹ denotes a group having the formula where

   * denotes the point of attachment to the carbonyl group

   R³ denotes phenyl or pyridyl wherein phenyl and pyridyl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of halogen, nitro, cyano, trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy, monofluoromethoxy, C₁-C₄-alkyl and C₁-C₄-alkoxy,

   R² denotes phenyl wherein phenyl may be substituted by 1 to 3 substituents, said substituents being chosen independently of each other from the group consisting of fluorine, chlorine, trifluoromethoxy, difluoromethoxy, trifluoromethylthio and methyl,

   A denotes a group having the formula where

   * denotes the point of attachment to the carbonyl group

   # denotes the point of attachment to the nitrogen atom of the urea

   R⁷ denotes methyl, ethyl or n-butyl wherein methyl, ethyl and n-butyl may be substituted by a substituent, said substituent being chosen from the group consisting of cyclopropyl and phenyl wherein phenyl may be substituted by a substituent, trifluoromethyl, and

   R⁸ and R⁹ denote, independently of each other, hydrogen, bromine, chlorine, methyl or ethyl

   or one of its salts, its solvates, or the solvates of its salts.
4. A method for producing a compound having the formula (I) according to Claim 1, characterized in that in accordance with method [A] a compound having the formula in which

   R¹ has the same meaning as that given in Claim 1,

   is reacted in the first step with a reducing agent and in the second step is reacted in the presence of a carbonic acid derivative with a compound having the formula         H₂N-R²     (III) in which

   R² has the same meaning as that given in Claim 1

   or in accordance with method [B] a compound having the formula (II) is reacted in the first stage with a reducing agent and in the second stage is reacted with a compound having the formula         OCN-R²     (IV), in which

   R² has the same meaning as that given in Claim 1,

   or in accordance with method [C] a compound having the formula in which

   R² has the same meaning as that given in Claim 1, and

   R¹⁰ denotes methyl or ethyl

   is reacted in the first stage with a base and in the second stage with a compound having the formula         R¹-H     (VI) in which

   R¹ has the same meaning as that given in Claim 1,

   said reactions occurring in the presence of dehydrating reagents.
5. A compound according to any of Claims 1 to 3 for the treatment and/or prophylaxis of diseases.
6. A medication containing a compound according to any of the Claims 1 to 3 in combination with at least one inert, non-toxic, pharmaceutically suitable excipient.
7. The use of a compound according to any of Claims 1 to 3 for producing a medication for the treatment and/or prophylaxis of viral infections.
8. The use according to Claim 7, characterized in that the viral infection is an infection with the human cytomegalovirus (HCMV) or another representative of the Herpes viridae group.
9. A medication according to Claim 6 for the treatment and/or prophylaxis of viral infections.