EP1507757A1 - Lactams used as anti-viral agents - Google Patents

Abstract

The invention relates to lactams, to methods for producing the same and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for use as anti-viral agents specifically against cytomegaloviruses.

Description

 LACTA E AS AN ANTIVIRAL AGENT

The invention relates to lactams and processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegaloviruses.

Although there are structurally different antiviral agents on the market, resistance development can regularly occur. New means of effective therapy are therefore desirable.

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

Surprisingly, it was found that the lactams described in the present invention are antiviral.

The invention relates to compounds of the formula

in which

the remainder -NHC (D) NHR ² is bound to the aromatic system via one of the positions 2 or 3, D represents oxygen or sulfur,

R ^{1 represents} hydrogen or -CC ₆ - alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, Ci-C _δ -alkoxy, C _ö -Cio-aryl, 5- to 6-membered heteroaryl, amino and Ci-Cβ- alkylamino,

or

R ¹ and R ⁴ together with the carbon atom to which they are attached form a C ₃ -C 6 cycloalkyl ring, where the cycloalkyl ring can be substituted with 0, 1, 2 or 3 substituents independently of one another the group consisting of halogen, hydroxy,

Ci-C _ö alkyl, -C-C ₆ alkoxy, C _ö -Cio aryl, 5- to 6-membered heteroaryl, amino and -Cö-alkylamino,

R ^{2 represents} C ₃ -C] ₀ -cycloalkyl or C ₆ -C ₁₀ -aryl, where cycloalkyl and aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, nitro , Cyano, Ci-C _ö alkoxy, hydroxycarbonyl, Ci-C _δ alkoxycarbonyl; Amino, Ci-C _ö alkylamino, Cι-C ₆ alkylamino carbonyl and Cι-C ₆ - alkyl,

R ^{3 represents} hydrogen or Ci-C _ö -alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, C ₁ -C ₆ alkoxy, C _ß -Cio-aryl, 5- to 6-membered heteroaryl, amino and -CC ₆ - alkylamino, or

R ³ and R ⁶ together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl ring, where the cycloalkyl ring can be substituted with 0, 1, 2 or 3 substituents selected independently of one another from the group consisting of halogen, hydroxy, Ci-C _ö -alkyl, C ₆ alkoxy, Ce o-aryl, 5- to 6-membered heteroaryl, amino and Ci-C _ö alkylamino,

R ^{4 represents} hydrogen or -CC ₆ - alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, CC _ö -alkoxy, C _ö -Cio Aryl, amino and Ci-C _ö alkylamino,

R ⁵ for hydrogen, halogen, hydroxy, cyano, -CC ₆ alkoxy, carboxy,

Benzyl, Ci-Cβ-alkoxycarbonyl, aminocarbonyl, Cι-C ₆ -All yl-armno-carbonyl, C ₆ -Cιo-arylaminocarbonyl, 5- to 6-membered heteroaryl-aminocarbonyl, Cι-C ₆ alkylcarbonylamino, C ₆ -Cιo -Aryl-carbonyl-amino, amino, CrCö-alkylamino or -CC ₆ alkyl.

R ^{6 represents} hydrogen or -CC ₆ alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, Ci-Ce-alkoxy, Ce-Cio Aryl, amino and Ci-C _ö alkylamino,

R ^{7 represents} hydrogen or -CC ₆ alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, hydroxycarbonyl, aminocarbonyl, -C-C ₆ - alkoxy, C ₆ -CiQ-aryl, 5- to 6- membered heteroaryl, amino, _Cι-C6 alkylamino, Ci-Cβ-alkoxy carbonyl, C ₁ -C ₆ ^{alkylaminocarbonyl,} C ₆ -Cιo-Axylaminocarbonyl, -C-C ₆ -AU yl-carbonylamino, C ₆ -Cι ₀ -axyl-carbonylamino, Cι-C ₆ - alkylcarbonyloxy, C _ό -Cio-arylcarbonyloxy, Cι-C ₆ -alkylamino-carbonyloxy and C ₆ -Cιo-arylaminocarbonyloxy,

and

R ¹ , R ³ , R ⁴ and R ^{6 are} not all hydrogen at the same time.

The compounds according to the invention can also be present in the form of their salts, solvates or solvates of the salts.

Depending on their structure, the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). The invention therefore relates to the enantiomers or diastereomers and their respective mixtures. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and / or diastereomers.

Depending on the structure of the compounds, the invention also relates to tautomers of the compounds.

In the context of the invention, preferred salts are physiologically acceptable salts of the compounds according to the invention.

Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, Fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds (I) also include salts of common bases, such as, for example and preferably, alkali metal salts (for example sodium and potassium salts), alkaline earth metal salts (for example calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines with 1 to 16 C Atoms such as, for example and preferably, emylamine, diethylamine, trie yla in, ethyldiisopropylamine, monoemanolamine, diemanolamine, trie anolamine, dicyclohexylamine, dimethylaminoethanol, procaine, diibylamine, N-memylmorpholine, dehydroabginylamine, arylamine , Emylenamine and methylpiperidine.

In the context of the invention, solvates are those forms of the compounds which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvate, in which coordination takes place with water.

In the context of the present invention, unless otherwise specified, the substituents have the following meaning:

Alkyl per se and "alk" and "alkyl" in alkoxy, alkylamino, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyloxy, all ylaminocarbonyloxy and alkoxycarbonyl represent a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably for methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, for example and preferably for memylamino, ethylarnino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylarnino, N, N-dimemylamino, N , N-diemylamino, N-emyl-N-memylamino, N- Memyl-Nn-propylamino, N-isopropyl-Nn-propylamino; N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, by way of example and preferably for methylaminocarbonyl, emylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-penrylaminocarbonyl, n-hexylaminocarbon , N-dimemylaminocarbonyl, N, N-diemylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-memyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylamino-carbonyl, N-tert-butyl-N-memylamite carbonyl, N-ethyl-Nn-pentylamino-carbonyl and Nn-hexyl-N-memylaminocarbonyl.

Alkylarninocarbonyloxy stands for an alkylaminocarbonyloxy radical with one or two (independently selected) alkyl substituents, for example and preferably for memylaminocarbonyloxy, emylaminocarbonyloxy, n-propylaminocarbonyloxy, isopropylaminocarbonyloxy, tert.-butylaminocarbonyloxy, n-pentylamino-nyl-pentylamino, n-pentylamino, n-pentylamino, , N, N-Dimemylaminocarbonyloxy, N, N-Diethylaminocarbonyloxy, N-Emyl-N-memylaminocarbonyloxy, N-Methyl-Nn-propylarninocarbonyloxy, N-Isopropyl-Nn-propylaminocarbonyloxy, N-tert.-Butyl-N-methylaminocarbonyloxy, N- Emyl-Nn-pentylaminocarbonyloxy and Nn-hexyl-N-memylarninocarbonyloxy.

Aiylarninocarbonyl stands for an arylaminocarbonyl radical with an aryl substituent and optionally another substituent, such as. B. aryl or alkyl, for example and preferably for phenylaminocarbonyl, phenylmemylaminocarbonyl, biphenylaminocarbonyl, Νaphthylaminocarbonyl and Νaphthylmethylaminocarbonyl.

Heteroarylaminocarbonyl stands for a Heteroarylaminocarbonylrest with one

Heteroaryl substituents and optionally another substituent, such as. B. aryl or alkyl, for example and preferably for thienylaminocarbonyl, furylaminocarbonyl, furylmethylaminocarbonyl, pyrrolylarriinocarbonyl, TMazolylamino carbonyl, oxazolylaminocarbonyl, imidazolylaminocarbonyl, pyridylamino-carbonyl, pyridylmethylaminocarbonyl, pyrimidyl-aniinocarbonyl, pyridazinylammocarbonyl, indolylaminocarbonyl, dazolylaminocarbonyl, benzofuranylamino-carbonyl, benzo-thiophenylaminocaminylaminocylylaminolaminocaminyl.

Arylaminocarbonyloxy stands for an Arylarmnocarbonyloxyrest with an aryl substituent and optionally another substituent, such as. B. aryl or alkyl, for example and preferably for phenylaminocarbonyloxy, phenylmethylaminocarbonyloxy, biphenylaminocarbonyloxy, naphthylaminocarbonyloxy and naphthylmethylaminocarbonyloxy.

Alkylcarbonylamino stands for an alkylcarbonylamino radical with an alkyl substituent, for example and preferably for memylcarbonylamino, emylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylarnino and n-hexylcarbonylamino.

Arylcarbonylamino stands for an arylcarbonylamino radical with an aryl substituent, for example and preferably for phenylcarbonylamino, naphmylcarbonylamino and phenantaenylcarbonylamino.

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

Alkylcarbonyloxy stands for an alkylcarbonyloxy radical with an alkyl substituent, for example and preferably for methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy and n-hexylcarbonyloxy.

Arylcarbonyloxy stands for an arylcarbonyloxy radical with an aryl substituent, for example and preferably for phenylcarbonyloxy and naphthylcarbonyloxy. Cycloalkyl stands for a cycloalkyl group with generally 3 to 10, preferably 5 to 10 carbon atoms, by way of example and preferably for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl and norbornyl.

Aryl stands for a mono- to tricyclic aromatic, carbocyclic radical with generally 6 to 14 carbon atoms; exemplary and preferably for phenyl, naphthyl and phenanthrenyl.

Heteroaryl represents an aromatic, mono- or bicyclic radical in the

Rule 5 to 10, preferably 5 to 6 ring atoms and up to 5, preferably up to 4 heteroatoms from the series S, O and N, by way of example and preferably for thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl , Indolyl, indazolyl, benzofuranyl, benzothiophenyl, quinolinyl and isoquinolinyl.

Halogen stands for fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

A symbol * on a carbon atom means that the compound is present in enantiomerically pure form with regard to the configuration on this carbon atom, including an enantiomeric excess in the context of the present invention

(enantiomeric excess) of more than 90% is understood (> 90% ee).

In other words, the fact that R ¹ , R ³ , R ⁴ and R ⁶ should not all be hydrogen at the same time means that at least one of the radicals R ¹ , R ³ , R ⁴ and R ^{6 is not} equal to hydrogen.

Preferred compounds are those in which

the rest -NHC (D) NHR ^{2 is} attached to the aromatic system via position 3,

D stands for oxygen, R ^{1 represents} Ci-C _ό alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, Ci-C _ö alkoxy, C ₆ -Cιo-aryl , Amino and Ci-C _ß - alkylamino,

R _{* stands} for C ₃ -Cιo-cycloalkyl or Cö-Cio-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and Cι-C ₆ alkyl,

R ^{3 represents} hydrogen or Ci-C _ö alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, Ci-Ce-alkoxy, C _ö - Cio-aryl, amino and Cι-C ₆ - alkylamino,

R ^{4 represents} hydrogen or -CC ₆ - alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxyl, C _I -C _O - alkoxy, Ce-Cio Aryl, amino and CrC _ö alkylamino,

R ⁵ represents hydrogen, fluorine, chlorine, hydroxyl, amino, Ci-C _ö alkylamino, Ci-Cβ-alkylcarbonylamino or C _ö alkyl;

R ⁶ is hydrogen or Ci-C _ö alkyl, where alkyl may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, Ci-C _ö -Al- koxy, Cβ- Cio-aryl, Arnino and -CC ₆ alkylamino,

and R ^{7 represents} hydrogen or Ci-C _ö alkyl, where alkyl can be substituted with 0 or 1 substituents selected from the group consisting of hydroxy and -CC6-alkylaminocarbonyloxy.

Preference is also given to those compounds in which

the rest -NHC (D) NHR ^{2 is} attached to the aromatic system via position 3,

D stands for oxygen,

R ^{1 represents} Ci-Ce-alkyl,

R ² represents phenyl or adamantyl, wherein phenyl may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano and Ci-C _ö alkyl,

R ^{3 represents} hydrogen,

R ^{4 represents} hydrogen or -CC ₆ alkyl,

R ^{5 represents} hydrogen, hydroxy, fluorine, chlorine or methyl,

R ^{6 represents} hydrogen, •

and

R ^{7 represents} hydrogen or -CC ₃ alkyl, where alkyl can be substituted with 0 or 1 substituents selected from the group consisting of hydroxy and Ci-Cβ-alkylaminocarbonyloxy.

Preference is also given to those compounds in which the rest -NHC (D) NHR ² is bound to the aromatics via one of the positions 2, 3, 5 or 6,

D represents oxygen or sulfur,

R ^{1 stands} for hydrogen or -CC ₆ alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, Ci-C _ö alkoxy, Cö- Cio-aryl, amino and -CC6-alkylamino,

or

R ¹ and R ⁴ together with the carbon atom to which they are attached form a C ₃ -C 6 cycloalkyl ring, it being possible for the cycloalkyl ring to be substituted by 0, 1, 2 or 3 substituents selected independently of one another from the group consisting of halogen, hydroxy, Ci-C _δ -alkyl, C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C] arnino -C ₆ alkyl,

R ^{2 represents} C ₃ -C ₀ cycloalkyl or C _ö -Cio-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, Cι -C ₆ - alkoxy, hydroxycarbonyl, -C-C ₆ - alkoxycarbonyl, A ino, Cι-C ₆ - alkylamino, Cι-C ₆ -alkyιιιι inocarbonyl and Cι-C ₆ -

alkyl,

R ³ represents hydrogen or Ci-C _ö -alkyl, where alkyl may be substituted with 0, 1, 2 or 3 substituents independently excluded selected from the group consisting of fluorine, chlorine, hydroxyl, Cι-C ₆ -Al- koxy, Cö-Cio-aryl, amino and Ci-C _ö -alkylamino, or

R ³ and R ⁶ together with the carbon atom to which they are attached form a C ₃ -Cό cycloalkyl ring, where the cycloalkyl ring can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, Ci-C _ö alkyl, Ci-C _ö alkoxy, C ₆ -Cι ₀ aryl, amino, and amino Cι-C ₆ alkyl,

R ⁴ is hydrogen or Ci-C _ö -alkyl, where alkyl may be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, Cι-C -alkoxy ₆ -Al-, C _ö -Cio-aryl, Arnino and Ci-Cg- alkylamino,

R ⁵ for hydrogen, halogen, hydroxy, cyano, Ci-C _ö alkoxy, carboxy, Ci-C _ö alkoxycarbonyl, aminocarbonyl, Ci-C _ö alkylaminocarbonyl, amino, Ci-C _ö alkylamino or Ci-C _ö - Alkyl stands.

R ^{6 represents} hydrogen or Ci-C _ό- alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of fluorine, chlorine, hydroxyl, Ci-C _ό -alkoxy, C _ö -Cio aryl, amino and Ci-C _ö alkylamino,

R ^{7 represents} hydrogen or Ci-C _ö -alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, hydroxycarbonyl, aminocarbonyl, Ci-C _ö - Alkoxy, C _ö -Cio-aryl, amino, Cι-C ₆ -alkylamino, Ci-C _ö -alkoxycarbonyl, Ci-C _ö -alkylaminocarbonyl, Ci- C _ό -alkylcarbonylamino and C _δ -Cio-arylcarbonylamino, and

R ¹ , R ³ , R ⁴ and R ^{6 are} not all hydrogen at the same time.

Preference is also given to those compounds in which

the rest -NHC (D) NHR ^{2 is} attached to the aromatic system via position 3,

D stands for oxygen,

R ^{1 represents} Ci-Cö-alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, Ci-C _ö alkoxy, C _ö -Cio aryl, Amino and Ci-C _δ alkylamino,

R ^{2 stands} for C ₃ -Cιo-cycloalkyl or C _ö -Cio-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and Ci-Cβ-alkyl,

R ^{3 represents} hydrogen or C _I -C _Ö - alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, C _I -C _Ö alkoxy, C _ö -Cio-aryl, amino and Ci-C _ö alkylamino,

R ^{4 represents} Ci-Cö-alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, Ci-C _ö alkoxy, C _δ -Cio aryl, Ainino and Ci-C _ö alkylamino, R ⁵ represents ₆ alkyl, hydrogen, halogen, hydroxy, amino, Ci-C _ö alkylamino or Cι-C,

R ^{6 represents} hydrogen or -CC ₆ alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, -C _Ö -AI- koxy, C _ö - Cio-aryl, amino and Ci-C _ö alkylamino,

and

R ^{7 represents} hydrogen.

Preference is also given to those compounds in which

the rest -NHC (D) NHR ^{2 is} attached to the aromatic system via position 3,

D stands for oxygen,

R ^{1 represents} Ci-C _ö alkyl,

R ² represents phenyl or adamantyl, wherein phenyl may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano and Ci-C _ö alkyl,

R ^{3 represents} hydrogen,

R ^{4 represents} Ci-Cö-alkyl,

R ^{5 represents} hydrogen, hydroxy, fluorine, chlorine or methyl,

R ^{6 represents} hydrogen, and

R ^{7 represents} hydrogen.

Preference is also given to those compounds in which the -NHC (D) NHR ² radical is bonded to the aromatics via position 3.

Compounds in which D represents oxygen are also preferred.

Compounds in which R ^{1 represents} methyl are also preferred.

Also preferred are those compounds in which R ^{2 is} adamantyl or phenyl, where phenyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano and

Methyl. R ² particularly preferably represents phenyl which is substituted by 1 or 2 substituents, and in the case of 2 substituents these preferably occupy the ortho and pr positions or the meta and ^ αra positions.

Compounds in which R ^{3 represents} hydrogen are also preferred.

Compounds in which R ^{4 represents} hydrogen or methyl, in particular methyl, are also preferred.

Compounds in which R ^{5 represents} hydrogen or fluorine, in particular fluorine, are also preferred.

Compounds in which R represents hydrogen are also preferred.

Also preferred are those compounds in which R ⁵ , in particular fluorine, is bonded to the aromatics via position 6. Those are particularly preferred Compounds in which the residue -NHC (O) NHR ^{2 is} simultaneously bonded to the aromatic system via position 3.

Compounds in which R ^{6 is} hydrogen are also preferred.

Also preferred are those compounds in which R ^{7 represents} hydrogen or methyl, in particular hydrogen.

Also preferred are those compounds in which R ¹ and R ^{4 are} methyl.

The radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of a different combination, regardless of the respectively specified combinations of the radicals.

Combinations of two or more of the preferred ranges mentioned above are very particularly preferred.

The invention furthermore relates to a process for the preparation of the compounds of the formula (I), compounds of the formula

in which

-NH ₂ is bound to the aromatics via one of the positions 2 or 3, and R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given above,

with compounds of the formula

DCN - R ² (TU), in which

R ² and D have the meaning given above,

be implemented.

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran or diethylene glycol ether - Koldimethylether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran, methylene chloride or ethyl acetate are preferred ,

Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or other bases such as triethylamine or diisopropylemylamine, diisopropylethylamine or triethylamine are preferred.

The compounds of the formula (DT) are known or can be synthesized from the corresponding starting materials by known processes. The compounds of formula (IT) can be prepared by compounds of the formula

in which

-ΝO ₂ is bound to the aromatics via one of the positions 2 or 3, and

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given above,

be reduced, e.g. with palladium on carbon in a hydrogen atmosphere or with tin (II) chloride or tin in hydrochloric acid, palladium on carbon in a hydrogen atmosphere is preferred.

The reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure to 3 bar.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n -Butanol or tert-butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine, ethanol, iso-propanol, ethyl acetate or in the case of Tin dichloride in dimethylformamide, dioxane or methanol. The compounds of formula (TV) can be prepared by compounds of the formula

in which

-NO ₂ is bound to the aromatics via one of the positions 2 or 3, and

R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given above, and

R ^{8 represents} alkyl, preferably methyl or ethyl,

with compounds of the formula

R "NH ₂ (VI), in which

R ^{7 has} the meaning given above,

or with the formates of the compounds of the formula (VT)

be implemented. The reaction is generally carried out in inert solvents or in formic acid, preferably in a temperature range from 50 ° C. to 200 ° C. at normal pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine. It is preferred to carry out in formic acid:

The compounds of the formula (VI) are known or can be synthesized from the corresponding starting materials by known processes.

The compounds of formula (V) can be prepared by compounds of the formula

in which

-NO ₂ is bound to the aromatics via one of the positions 2 or 3, and

R, R, R, R and R have the meaning given above,

with compounds of the formula R-OH (VJJI), in which

R ^{8 has} the meaning given above, are implemented.

The reaction is generally carried out in inert solvents or in compounds of the formula (VTET), optionally in the presence of an acid, preferably in a temperature range from room temperature to the reflux of the solvents at atmospheric pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or methylene glycol dimethyl ether, or other solvents such as dimethylformamide, dimethyl acetamide, acetonitrile, ethyl acetate or pyridine. Solvents of the formula (VTET), for example ethanol or methanol, are preferred.

Acids are, for example, hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, sulfuric acid is preferred.

The compounds of the formula (VW) are known or can be synthesized from the corresponding starting materials by known processes.

The compounds of formula (VE) can be prepared by compounds of formula in which

R »1, R τ> 3, τ R, 4, τ Rj5 and R have the meaning given above,

with fuming nitric acid, concentrated nitric acid, nitrating acid or other mixing ratios of sulfuric acid and nitric acid, preferably in a temperature range from -30 ° C to 0 ° C at normal pressure.

The compounds of formula (IX) can be prepared by compounds of formula

in which

R has the meaning given above,

with compounds of the formula

in which

R »1, τ R> 3, _n R4 and R have the meaning given above, are implemented.

The reaction is generally carried out in inert solvents, if appropriate in

Presence of a Lewis acid, preferably in a temperature range from -10 ° C to room temperature at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as hexane or cyclohexane, or other solvents such as acetonitrile or pyridine, 1,2-dichloroethane is preferred.

Lewis acids are, for example, aluminum trichloride or titanium tetrachloride; aluminum trichloride is preferred.

The compounds of the formulas (X) and (XI) are known or can be synthesized from the corresponding starting materials by known processes.

In an alternative synthetic method, compounds of formula (IX) can be prepared by using compounds of formula

in which

R> 1, R τ> 4 and J τ R> 5 have the meaning given above, with compounds of the general formula

in which

R ³ , R ⁶ and R ^{8 have} the meaning given above, and

L ^{1 represents} halogen, preferably bromine or iodine,

be implemented.

The reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from -78 ° C. to room temperature at atmospheric pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1, 2rDhnethoxyethan, dioxane, tetrahydrofuran, glycol dimethyl ether _. or ethylene glycol dimethyl ether, hydrocarbons such as benzene, ethylbenzene, xylene, toluene, preferably tetrahydrofuran or toluene.

Bases are, for example, amides such as sodium amide, lithium diisopropylamide, or other bases such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hydride, DBU or diisopropylethylamine, preferably sodium amide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide.

The compounds of the general formulas (XU) and (XIII) are known or can be synthesized from the corresponding starting materials by known processes (for (XE) cf. MR Schneider, H. Ball, J. Med. Chem. 1986, 29, 75 -79). In an alternative synthetic method, compounds of formula (Va), which are compounds of formula (V), can be used in which

R ^{6 represents} hydrogen,

are prepared by compounds of the formula

in which

R, R, R, R and R have the meaning given above,

by the method described for the preparation of the compounds of the formula (VE).

The compounds of formula (XTV) can be prepared by compounds of the formula

in which R, R, R, and R have the meaning given above,

be reacted with tetrabutylammonium fluoride.

The reaction is generally carried out in inert solvents, preferably in a temperature range from 0 ° C. to room temperature at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-

Dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso-propanol, n-butanol or tert. -Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran is preferred.

The compounds of formula (XV) can be prepared by compounds of the formula

in which

R ^{s has} the meaning given above,

with compounds of the formula in which

R, R, R and R have the meaning given above, are implemented.

The reaction is generally carried out in inert solvents, in the presence of a base, preferably in a temperature range from -78 ° C. to room temperature at atmospheric pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, ethylbenzene, xylene, toluene, hexane, heptane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide or dimethylacetamide, or mixtures of the solvents, preferred are diethyl ether, tetrahydrofuran, heptane and / or ethylbenzene.

Bases are, for example, sodium or potassium methanolate, or sodium or potassium ethanolate or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenylhthium, or others Bases such as sodium hydride, DBU,

Triethylamine or diisopropylethylamine, lithium diisopropylamide is preferred.

The compounds of the formula (XVTT) are known or can be synthesized from the corresponding starting materials by known processes.

The compounds of formula (XVI) can be prepared by compounds of the formula in which

R has the meaning given above,

be reacted with trimethylsilyl cyanide and zinc iodide.

The reaction is optionally carried out in inert solvents, preferably in a temperature range from room temperature to 100 ° C. at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol ethyl dimethyl ether or glycol ethylenedimethyl ether , Hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylforrnamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or pyridine, tetrahydrofuran is preferred.

The compounds of the formula (XVEI) are known or can be prepared according to known ones

Synthesize processes from the corresponding starting materials.

In an alternative synthetic procedure, the compounds of formula (IV) can be prepared by using compounds of formula

in which

-NO ₂ is bound to the aromatics via one of the positions 2 or 3, and

R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given above,

with compounds of the formula

R ⁷ -X ^x (XIX),

in which

R ^{7 has} the meaning given above, and

X ^{1 represents} halogen, preferably iodine or bromine,

be implemented.

The reaction is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from -10 ° C. to room temperature at atmospheric pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide or pyridine, tetrahydrofuran is preferred.

Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or potassium tert-butoxide, or other bases such as sodium hydride, DBU, triethylamine or diisopropylemylarnine, sodium hydride being preferred.

The compounds of the formula (XIX) are known or can be synthesized from the corresponding starting materials by known processes.

The compounds of formula (IVa) can be prepared by compounds of formula

in which

R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given above,

with fuming nitric acid, concentrated nitric acid, nitrating acid or other mixing ratios of sulfuric acid and nitric acid, preferably in a temperature range from -30 ° C to 0 ° C at normal pressure.

The compounds of formula (XX) can be prepared by compounds of the formula

in which

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{8 have} the meaning given above,

be reacted with ammonium formate.

The reaction is generally carried out in the melt or in inert solvents or in formic acid, preferably in a temperature range from 50 ° C. to 200 ° C. at normal pressure.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine. Execution in formic acid is preferred.

The compounds of the formula (XXI) are known or can be synthesized from the corresponding starting materials by known processes.

The preparation of the compounds according to the invention can be illustrated by the following synthesis scheme. Synthesis scheme 1: basic body synthesis

Synthesis scheme 2: basic body synthesis

Synthesis scheme 3: Synthesis of lactams I

Synthesis scheme 4: synthesis of lactams II

Synthesis Scheme 5: Synthesis of Lactams III

Synthesis scheme 6: alkylated lactams

R = Me, -CH ₂ C0 ₂ Et

The compounds of formula (I) according to the invention show an unpredictable, surprising spectrum of action. They show an antiviral activity against representatives of the group of herpes viridae (herpes viruses), especially against cytomegaloviruses (CMV), especially against human cytomegalovirus (HCMV). They are therefore suitable for the treatment and / or prophylaxis of diseases, in particular infections with viruses, in particular the viruses mentioned above, and the hip diseases caused thereby. A virus infection is understood below to mean both an infection with a virus and an illness caused by an infection with a virus.

Due to their special properties, the compounds of the formula (I) can be used to prepare medicaments for the prophylaxis and / or treatment of

Diseases, especially viral infections, are suitable.

The following can be mentioned as indication areas: 1) Treatment and prophylaxis of HCMV infections in ATDS patients (retinitis, pneumonitis, gastrointestinal infections).

2) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients suffering from HCMV pneumonitis,

-Encephalitis, as well as gastrointestinal and systemic HCMV infections, often life-threatening.

3) Treatment and prophylaxis of HCMV infections. Newborn and toddlers.

4) Treatment of acute HCMV infection in pregnant women.

5) Treatment of HCMV infection in immunosuppressed patients with cancer and cancer therapy.

The compounds according to the invention are preferably used for the production of medicaments which are suitable for the prophylaxis and / or treatment of infections with a representative of the group of herpes viridae, in particular a cytomegalovirus, in particular the human cytomegalovirus.

Because of their pharmacological properties, the compounds according to the invention can be used alone and, if necessary, in combination with other active ingredients, in particular antiviral active ingredients such as, for example, gancyclovir or acyclovir, for the treatment and / or prevention of viral infections, in particular

HCMV infections.

The present invention further relates to medicaments which contain at least one compound according to the invention, preferably together with one or more pharmacologically acceptable excipients or other auxiliaries, and their use for the purposes mentioned above. The active substance can act systemically and / or locally. For this purpose, it can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, otically, intravitreally or as an implant.

The active ingredient can be administered in suitable administration forms for these administration routes.

Known application forms which release the active ingredient quickly and / or modified, such as e.g. Tablets (non-coated and coated tablets, e.g. tablets or film-coated tablets provided with enteric coatings), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.

Parenteral administration can be done by bypassing an absorption step (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or by switching on absorption (intramuscularly, subcutaneously, intracutaneously, percutaneously, or intraperitoneally). Application forms suitable for parenteral administration include: Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes, e.g. Inhaled drug forms (e.g. powder inhalers, nebulizers), nasal drops / solutions, sprays; Tablets or capsules to be administered lingually, sublingually or buccally, suppositories, ear and eye preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or implants.

The active compounds can be converted into the administration forms mentioned in a manner known per se. This is done using inert non-toxic, pharmaceutically suitable excipients. These include carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. polyvinyl pyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), dyes ( eg inorganic pigments such as

Iron oxides) or taste and / or smell.

In general, it has proven to be advantageous to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg body weight in the case of intravenous administration, in order to achieve effective results, and the dosage is about 0.01 to for oral administration 50 mg / kg, preferably 0.1 to 25 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the quantities mentioned, depending on body weight, route of administration, individual behavior towards the active ingredient, type of preparation and time or interval at which the application is carried out. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day.

The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume. Examples

Abbreviations:

TLC thin layer chromatography

DCI direct chemical ionization (for MS)

DCM dichloromethane

DIEA N, N-diisopropylethylamine

DMSO dimethyl sulfoxide

DMF N, N-dimethylformamide d. Th. Of theory

EE ethyl acetate (ethyl acetate)

EI electron impact ionization (for MS)

ESI electrospray ionization (for MS)

Mp melting point sat. saturated h hour

HPLC high pressure, high performance liquid chromatography conc. concentrated

LC-MS liquid chromatography-coupled mass spectroscopy

LDA lithium diisopropylamide

MS mass spectroscopy

NMR Keπiresonanzspektoskopie perc. percent

RP-HPLC reverse phase HPLC

RT room temperature

Rt retention time (with HPLC)

THF tetrahydrofuran General methods LC-MS and HPLC:

HPLC parameters:

Method 1 (HPLC):

Column: Kromasil C18 60 * 2 mm; Temperature: 30 ° C; River: 0.75 min ¹ ; Eluent A: 0.005 M HClO ₄ , eluent B: acetonitrile; Gradient: - »0.5 min 98% A, -» 4.5 min 10% A, → 6.5 min 10% A.

Method 2 (preparative HPLC, enantiomer separation):

Column: packing material KBD 6371 (250 * 20 mm); Temperature: 23 ° C; Eluent: ethyl acetate; Flow: 25 min ^"1 ; compound dissolved in ethyl acetate.

Method 3 (preparative HPLC, enantiomer separation): column: packing material KBD 6371 (250 * 20 mm); Temperature: 23 ° C; eluent:

ethyl acetate; Flow: 25 mlmin ^"1 ; compound dissolved in ethyl acetate / tetrahydrofuran (l: l (v / v)).

Method 4 (preparative HPLC, enantiomer separation): column: packing material KBD 6136 (250 * 20 mm); Temperature: 23 ° C; Eluent:.

ethyl acetate; Flow: 25 mlmin ^"1 ; compound dissolved in ethyl acetate.

Method 5 (preparative HPLC, enantiomer separation):

Column: packing material KBD 4922 (250 * 20 mm); Temperature: 23 ° C; Eluent: i-hexane / ethyl acetate (65:35 v / v); Flow: 25 mlmin ^"1 ; compound dissolved in

Ethyl acetate.

Method 6 (HPLC):

Column: Kromasil C18 60 * 2 mm; Temperature: 30 ° C; Flow: 0.75 mlmin ^"1 , eluent A: 0.005 M HClO ₄ , eluent B: acetomtrile; gradient: → 0.5 min 98% A, → 4.5 min

10% A, → 15 min 10% A. Method 7 (preparative RP-HPLC):

Column: CromSil C18, 250 x 30 mm; Flow: 50 ml / min; Running time: 38 min; Detection at 210 nm; Eluent A: water, eluent B: acetomtril, gradient: 10% B (3 min) -> 90% B (31 min) -> 90% B (34 min) -> 10% B (34.01 min).

Method 8 (preparative HPLC, enantiomer separation):

Column: packing material KBD 5326 (250 * 30 mm); Temperature: 23 ° C; Step gradient elution: ethyl acetate (100%) - methanol (100%) ethyl acetate (100%); Flow: 25 ml / min; Compound dissolved in tetrahydrofuran / ethyl acetate (1: 1).

starting compounds

Example 1A

1 - (2-fluorophenyl) -2-methyl-1-propanone

5.10 g of 2-fluorobenzonitrile are placed in 50 ml of diethyl ether, and 25.27 ml of 2-propylmagnesium chloride are added at 0 ° C. After stirring overnight at room temperature, 60 ml 10 percent at 0 ° C. Dropped in hydrochloric acid and stirred for an hour. It is extracted with diethyl ether and, after chromatographic purification on silica gel (cyclohexane / ethyl acetate 9/1), the target compound is obtained in a yield of 4.8 g (68%). HPLC (method 1): R _t = 4.5 min

MS (DCT / H3): m / z = 184 (M + NSj) *

Example 2A

4- (2-Fluo henyl) -3,3-dimethyl-4-oxobutanoic acid

1.75 g of l- (2-fluorophenyl) -2-methyl-1-propanone are dissolved in tetrahydrofuran and 13.00 ml of lithium hexamethyldisilazide are added. After stirring for two hours at room temperature, 3.77 g of ethyl iodoacetate are added dropwise. After four Hours stirring at room temperature, 50 ml 20 percent. Sodium hydroxide solution added and stirred overnight. The solvent is distilled off and water is added to the residue. Then it is washed with diethyl ether and the aqueous phase with conc. Acidified hydrochloric acid. After extraction with ethyl acetate and washing with saturated sodium chloride solution, the organic phase is separated off and, after the solvent has been distilled off and recrystallized from diisopropyl ether, the product is obtained in a yield of 30% (0.6 g). HPLC (method 1): R _t = 4.1 min MS (DCI / MH ₃ ): m / z = 242 (M + NIL ^"1"

Example 3A

4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid

10.0 g of 4- (2-fluorophene) -3,3-dimethyl-4-oxobutanoic acid are placed in 25 ml of sulfuric acid and a mixture of 13 ml of conc. Sulfuric acid and 3.4 ml conc. Added dropwise nitric acid. After 60 min, 400 ml of ice water are added, the product is filtered off with suction, washed with water and then dried. This gives 12 g (quantitative) target compound.

HPLC (method 1): R _t = 4.0 min MS (DCI / NH ₃ ): m / z = 287 (M + NEW Example 4A

4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoate

12 g of 4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid are dissolved in 140 ml of methanol and concentrated with 10 drops. Sulfuric acid added. After 7 hours under reflux, the methanol is distilled off and the residue is saturated. Sodium bicarbonate solution, water and sat. Washed sodium chloride solution. After drying, 12.5 g (99%) of the target compound are obtained. HPLC (method 1): R _t = 4.55 min MS (DCI / NH ₃ ): m / z = 301 (M + NELt) *

Example 5A

5- (2-fluoro-5-rLitrophenyl) -4,4-dimethyl-2-pyrrolidinone

At 200 ° C, 283.25 mg (1.00 mmol) of methyl 4- (2-fluoro-5-mttophenyl) -3,3-dimethyl-4-oxobutanoate are stirred with 1,766 g (28 mmol) of ammonium formate for two hours. Then water and ethyl acetate are added and the organic phase is separated off. After drying the organic phase over magnesium sulfate, the solvent is distilled off and the residue is purified chromatographically on silica gel (dichloromethane, dichloromethane / ethyl acetate). ester 3: 1, 1: 1). The product is crystallized from diethyl ether and washed with ethyl acetate. The yield is 29 mg (12%).

Alternative reaction instructions for the preparation of Example 5A: 4.24 g (20.5 mmol) of 5- (2-fluo-henyl) -4,4-dimethyl-2-pyrrolidinone are dissolved in 20 ml of concentrated sulfuric acid and the solution obtained is cooled to -10 ° C.

Separately, 2.6 ml of concentrated sulfuric acid are added dropwise to 1.7 ml of concentrated nitric acid at -10 ° C. This nitrating acid is then added dropwise to the reaction mixture. The mixture is stirred at -5 ° C. until a reaction check by means of analytical HPLC shows complete conversion.

Then it is carefully poured into ice water and extracted 3 times with dichloromethane.

After drying over magnesium sulfate, filtration and concentration of the solvent, the residue is crystallized from cyclohexane ethyl acetate 7: 3. It will

3.26 g (63% of theory) of product obtained. HPLC (method 1): R _t = 3.83 min

MS (DCI): m / z = 253 (M + H) ⁺

Example 6A

5- (5-amino-2-fluoφhenyl) -4,4-dimethyl-2-pyrrolidinone

675 mg (2.68 mmol) of 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyl-2-pyrrolidinone are placed in 20 ml of ethanol, and 3.49 g (29.44 mmol) of tin are added at room temperature. 14 ml of concentrated hydrochloric acid are added dropwise and the whole is refluxed for one hour. It is then filtered and the solvent is distilled off. After mixing with ethyl acetate and water, it becomes basic with nanium bicarbonate and filtered through Celite. The organic phase is separated off and the aqueous phase is extracted twice more with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off. It is recrystallized from diethyl ether. The yield is 529 mg (89%).

HPLC (method 1): R _t = 3.19 min MS (ESI): m / z = 223 (M + H) ⁺

Alternative reaction procedure for the preparation of Example 6A: 290 mg (1.15 mmol) 5- (2-fluoro-5-mttophenyl) -4,4-dimemyl-2-pynolidinone are suspended in 5 ml ethanol and mixed with 122 mg palladium on carbon (5th %) stirred in a hydrogen atmosphere until a TLC check shows complete conversion. The catalyst is filtered off through Celite. It is washed with ethanol and crystallized after concentration of the solvent. 240 mg (94% of theory) of product are obtained.

Example 7A

4- (2-Fluoφhenyl) -3,3-dimethyl-4-oxobutansäureethylester

5.28 g (31.76 mmol) of l- (2-fluorophenyl) -2-methyl-l-propanone are dissolved in 100 ml of dry THF at RT and then quickly mixed with 43 ml of a 1 molar hexamethyldisilazide solution in THF. The mixture is stirred at RT for a further 2 hours before 12.6 g (59 mmol) of ethyl iodoacetate are added. A slight warming of the reaction mixture occurs during the addition. The mixture is then left to stir for 2-4 hours at RT. It is then carefully quenched with 1N hydrochloric acid and extracted three times with ethyl acetate. After drying the combined organic phases over magnesium sulfate, filtration and evaporation of the solvent, the residue is purified by column chromatography (silica gel: cyclohexane / ethyl acetate 20: 1). 4.97 g (60% of theory) of product are obtained. HPLC (method 1): R _t = 4.74 min MS (ESIpos): m / z = 253 (M + H) ⁺

Example 8A

5 - (2-Fluoφhenyl) -4,4-dimethyl-2-pyrrolidinone

2.49 g (9.85 mmol) of 4- (2-fluorophenyl) -3,3-dimethyl-4-oxobutanoate are mixed with 17.4 g (276 mmol) of ammonium formate and stirred at a bath temperature of 200 ° C. until a TLC check is complete Displays sales. After cooling, water is added and extracted three times with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and concentrated. This gives 1.74 g (85% of theory) of product which can be used in the next step without further purification.

HPLC (method 1): R _t = 3.91 min MS (ESIpos): m / z = 207 (M + H) ⁺ Example 9A

(5S) -5- (2-fluoro-5-mttophenyl) -4,4-dimethyl-2-pyrrolidinone

Enantiomer separation on a chiral HPLC phase (Method 8) gives 2.2 g (46% of theory) from 4.8 g of racemic 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyl-2-pynolidinone (Example 5A) . Th.) Enantiomerically pure product.

Example 10A

(5iS) -5- (5-A rmno-2-fluoφhenyl) -4,4-άimethyl-2-pyrrolidinone

200 mg (0.79 mmol) (5S) -5- (2-fluoro-5-nitrophenyl) -4,4-dimethyl-2-pyrrolidinone (Example 9A) are suspended in 5 ml of ethanol and 84 mg of palladium on carbon (5 %) stirred in a hydrogen atmosphere until a TLC check shows complete conversion. The catalyst is filtered off through Celite. It is washed with ethanol and crystallized after concentration of the solvent. 172 mg (97% of theory) of product are obtained. HPLC (method 1): R _t = 3.14 min MS (ESIpos): m / z = 223 (M + H) ⁺ General working procedure A: alkylation of the lactams

1 equivalent of 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyl-2-pyrrolidinone (Example 5A) is dissolved in dry THF (0.16 molar solution) and at 0 ° C to a suspension of 1.1-1.5 equivalents Sodium hydride dropped in THF (0.2 molar).

The mixture is stirred for a further 30 min at RT and then 1.2-2.5 equivalents of the corresponding alkylating agent are added. The mixture is stirred at RT or reflux overnight, then water is carefully added and the mixture is extracted three times with diethyl ether. The combined organic phases are dried over magnesium sulfate. Filtration and concentration ^"of the solvent provides the product for the next

Synthetic step of sufficient purity.

Example 11A

5- (2-fluoro-5-nitrophenyl) -l, 4,4-trimethyl-2-pyrrolidmon

In accordance with general working procedure A, 200 (0.79 mmol) 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyl-2-pyrrolidinone (Example 5A), 35 mg (0.87 mmol) sodium hydride and 281 mg ( 1.98 mmol) of methyl iodide 157 mg (74% of theory) of product.

HPLC (method 1): R _t = 3.97 min MS (DCI): m / z = 267 (M + H) ⁺ Example 12A

(5S) -5- (2-fluoro-5-nitrophenyl) -l, 4,4-trimethyl-2-pyrrolidmon

According to general working procedure A, 200 mg (0.79 mmol) (5S) -5-

(2-fluoro-5-nitrophenyl) -4,4-dimethyl-2-pyrrolidinone. (Example 9A), 35 mg

(0.87 mmol) sodium hydride and 281 mg (1.98 mmol) methyl iodide 210 mg (99% of theory

Th.) Product received.

HPLC (method 1): R _t = 3.94 min

MS (ESIpos): m / z = 267 (M + H) ⁺

Example 13A

[2- (2-fluoro-5-rüttophenyl) -3,3-dimethyl-5-oxo-l-pyrrolidinyl] essigsäιιreethylester

According to general working procedure A, 200 (0.79 mmol) 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyl-2-pyrrolidinone (Example 5A), 48 mg (1.19 mmol) sodium hydride and 159 mg ( 0.95 mmol) ethyl bromoacetate 265 mg (98% of theory) of product. HPLC (method 1): R _t = 4.28 min MS (ESIpos): m / z = 339 (M + H) ⁺

Example 14A

[(2S) -2- (2-fluoro-5-mtrophenyl) -3,3-dimethyl-5-oxo-l-pyrrolidinyl] ethyl acetate θyθ _v ^CH 3

According to the general working procedure A with 195 mg (0.77 mmol) (55) -5- (2-fluoro-5-mttophenyl) -4,4-dimemyl-2-pynolidinone (Example 9A), 24 mg (1.00 mmol) sodium hydride and 248 mg (1.16 mmol) ethyl iodoacetate 139 mg (51% of theory) of product. HPLC (method 1): R _t = 4.41 min MS (ESIpos): m / z = 339 (M + H) ⁺

Example 15A

5- (5-amino-2-fluoφhenyl) -l, 4,4-trimethyl-2-pyrrolidinone

148 mg (0.56 mmol) of 5- (2-fluoro-5-mtrophenyl) -1,4,4-tτimethyl-2-pyrrolidinone are suspended in 5 ml of ethanol and stirred with 59 mg of palladium on carbon (5%) in a hydrogen atmosphere until a DC control shows complete conversion. The catalyst is filtered off through Celite. It is washed with ethanol and crystallized after concentration of the solvent. 96 mg (78% of theory) of product are obtained. Mp .: 178.5 ° C

HPLC (method 1): R _t = 3.27 min MS (ESIpos): m / z = 237 (M + H) ⁺

Example 16A

(55) -5- (5-Amino-2-fluorophene) - 1,4,4-trimethyl-2-pyrrolidinone

206.3 mg (0.77 mmol) (5S) -5- (2-fluoro-5-mtrophenyl) -l, 4,4-trimethyl-2-pyrrolidinone

(Example 12A) are suspended in 5 ml of ethanol and stirred with 82 mg of palladium on carbon (5%) in a hydrogen atmosphere until a TLC check shows complete conversion. The catalyst is filtered off through Celite. It is washed with ethanol and crystallized after concentration of the solvent. This gives 178 mg (96% of theory) of product.

HPLC (method 1): R _t = 3.30 min Example 17A

[2- (5-Amino-2-fluoφhenyl) -3, 3-dimethyl-5-oxo-1-pyrrolidinyl] ethyl acetate

260 mg (0.77 mmol) [2- (2-fluoro-5-mttophenyl) -3,3-dimethyl-5-oxo-l-pyrrolidinyl] - ethyl acetate are suspended in 3.6 ml ethanol and mixed with 82 mg palladium on carbon (5th %) stirred in a hydrogen atmosphere until a TLC check shows complete conversion. The catalyst is filtered off through Celite. It is washed with ethanol and concentrated. 225 mg (89% of theory) of product are obtained. HPLC (method 1): R _t = 3.58 min MS (ESIpos): m / z = 309 (M + H) ⁺

Example 18A

[(2 ₁ S) -2- (5-Amio-2-fluoφhenyl) -3,3-dimethyl-5-oxo-l-pynolidinyl] ethyl acetate

132 mg (0.39 mmol) [(2S) -2- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-5-oxo-l-pyrrolidinyl] ethyl acetate (Example 14A) are dissolved in 5 ml of ethanol and mixed with 41 mg of palladium on carbon (10%) stirred in a hydrogen atmosphere until a TLC check shows complete conversion. The catalyst is filtered off through Celite. It is washed with ethanol and concentrated. 119 mg (84% of theory) of product are obtained. HPLC (method 1): R _t = 3.66 min MS (ESIpos): m / z = 309 (M + H) ⁺

Example 19A

1 - (2-Fluoφhenyl) - 1-propanone

5 g (41..3 mmol) of 2-fluorobenzonitrile in 82 ml of dry diethyl ether are placed under an argon atmosphere and at RT 41.3 ml of a 2 molar ethyl Magnesium chloride solution (in THF) slowly added dropwise. The realdione mixture is then left to stir at RT overnight, then cooled to 0 ° C. and carefully hydrolyzed with about 100 ml of 10% hydrochloric acid. The mixture is stirred for a further 30 min and then the aqueous phase is extracted three times with diethyl ether. The combined extracts are dried over magnesium sulfate. After filtration and evaporation of the solvent, 3.32 g (53% of theory) of product are obtained, which is not further purified. HPLC (method 1): R _t = 4.41 min MS (DCI): m / z = 170 (M + NE) ⁺

Example 20A

4- (2-Fluoφhenyl) -3-methyl-4-oxobutansäureethylester

3.31 g (21.8 mmol) of l- (2-fluorophenyl) -l-propanone are initially introduced at RT into 70 ml of THF and 21.8 ml of a 1 molar lithium hexamethyldisilazide solution (in THF) are added rapidly. The mixture is stirred at RT for 2 hours and then 3.81 g (22.8 mmol) of ethyl bromoacetate are added dropwise. The mixture is stirred at RT overnight and then carefully hydrolyzed with 1 N hydrochloric acid. The aqueous phase is three times with

Extracted ethyl acetate. After drying over magnesium sulfate, filtration and concentration of the solvent, the residue is purified by column chromatography (silica gel: cyclohexane / ethyl acetate 8: 2). This gives 1.94 g (24% of theory) of product. HPLC (method 1): R _t = 4.63 min

MS (DCI): m / z = 256 (M + NELι) ⁺ Example 21A

5- (2-fluorophene) -4-methyl-l, 5-dihydro-2H-pyrrol-2-one and 5- (2-fluorophene) -4-ethyl-1,3-dihydro-2H-pyrrole-2- on

1.93 g (8.61 mmol) of 4- (2-fluorophenyl) -3-methyl-4-oxobutanoic acid ethyl ester are allowed to stir together with 15.2 g (241 mmol) of ammonium formate at a bath temperature of 200 ° C. for 4 hours. After the reaction mixture has cooled to RT, water is added and the mixture is then extracted three times with ethyl acetate. The combined organic phases are washed three times with water and then dried over magnesium sulfate. After filtration and evaporation of the solvent, the residue obtained is purified by column chromatography (silica gel: cyclohexane / ethyl acetate 1: 1). 0.21 g (8% of theory) of 5- (2-fluorophene) -4-methyl-l, 5- Obtained dihydro-2H-pyrrol-2-one. ΗPLC (method 1): R _t = 3.78 min

MS (ESIpos): m / z = 192 (M + Η) ⁺

At the same time, 0.24 g (13% of theory) of 5- (2-fluorophenyl) -4-methyl-1,3-dihydro-2H-pyrrol-2-one is obtained. ΗPLC (method 1): R _t = 3.63 min MS (ESIpos): m / z = 192 (M + Η) ⁺ Example 22A

5- (2-Fluoφhenyl) -4-methyl-2-pyrrolidinone

450 mg (2.35 mmol) of a mixture of 5- (2-fluorophene) -4-methyl-l, 5-dihydro-2H-pyrrol-2-one and 5- (2-fluorophene) -4-methyl-1,3 dihydro-2H-pyrrol-2-one are dissolved in ethanol and 125 mg of palladium on carbon (10%) are added. The mixture is stirred under a hydrogen atmosphere until a reaction is checked by means of

DC shows full sales. The reaction mixture is filtered through Celite, washed well with ethanol and the filtrate is then concentrated. 320 mg (67% of theory) of product (mixture of diastereomers) are obtained. ΗPLC (method 1): R _t = 3.74 min MS (DCI): m / z = 194 (M + Η) ⁺ , 211 (M + NEL,) ^"1"

Example 23A

5- (2-fluoro-5-nitrophenyl) -4-methyl-2-pyrrolidmon

320 mg (1.66 mmol) of 5- (2-Fluoφhenyl) -4-methyl-2-pyrrolidinone are dissolved in 2 ml of concentrated sulfuric acid and the solution is cooled to -10 ° C. Separately, 0.22 ml of concentrated nitric acid is also added dropwise at -10 ° C with 1.65 ml of concentrated sulfuric acid. This nitrating acid is then added dropwise to the reaction mixture at -10 ° C. The mixture is stirred for a further 90 min at -5 ° C., then carefully poured onto ice water and extracted three times with dichloromethane. The combined extracts are dried over magnesium sulfate. After filtration and evaporation of the solvent, 243 mg (60% of theory) of product (mixture of diastereomers) are obtained. HPLC (method 1): R _t = 3.64 min

MS (ESIpos): m / z = 239 (M + H) ⁺

Example 24A

5- (5-amino-2-fluoφhenyl) -4-methyl-2-pyrrolidinone

233 mg (0.96 mmol) of 5- (2-fluoro-5-nitrophenyl) -4-methyl-2-pyrrolidinone are suspended in 7 ml of ethanol and 51 mg of palladium on carbon (10%) are added under an inert gas atmosphere. Under a hydrogen atmosphere, the mixture is stirred at RT until a TLC check indicates complete conversion. The reaction mixture is then filtered through Celite and washed well with ethanol, and the filtrate is finally concentrated. 199 mg (99% of theory) of product (mixture of diastereomers) are obtained. HPLC (method 1): R _t = 2.97 min

MS (ESIpos): m / z = 209 (M + H) ⁺ Ausfflhrungsbeispiele

example 1

N- (4-Chloro-2-methylphenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluorophenyl] urea

250.00 mg (1.12 mmol) of 5- (5-amino-2-fluorophenyl) -4,4-dimethyl-2-pyrrolidinone are dissolved in 10 ml of dichloromethane, and 226.21 mg (1.35 mmol) of 4-chloro-2-methylphenyl isocyanate are added. After one hour under reflux, the precipitate is filtered off, washed with dichloromethane and dried. The yield is 404 mg (92% of theory). HPLC (method 1): R _t = 4.5 min MS (ESI): mz = 390 (M + H) ^{+ J} H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.65 (s, 3 H); 1.2 (s, 3H); 2.1 (d, 2H); 2.21 (s,

3H); 4.6 (s, IH), 7.1-7.3 (m, 4H); 7.45-7.55 (m, IH); 7.85-7.80 (m, 3H); 9.2 (br.s, IH).

Example 2

N- (4-CMor-2-methylphenyl) -N '- [3- (3,3-dimemyl-5-oxo-2-pyιolidolidinyl) -4-fluorophenyl-urea (enantiomer of Example 1)

Chromatographic separation of enantiomers of 300 mg racemate of N- (4-chloro-2-memylphenyl) -N '- [3- (3,3-ά methyl-5-oxo-2-pyrrolidinyl) -4-fluorophenyl] - Urea (example 1) on silica gel is carried out by HPLC method 2. After primary crystallization from ethyl acetate, the yield is 108 mg (36% of theory).

Example 3

N- (4-Cyano-2-methylphenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluorophenyl] urea

254.00 mg (1.14 mmol) of 5- (5-amino-2-fluoφhenyl) -4,4-dimethyl-2-pyrrolidinone are placed in 10 ml of dichloromethane and 216.89 mg (1.37 mmol) of 4-isocyanato-3-methylbenzonitrile are introduced for one hour heated under reflux. After vacuuming with Washed dichloromethane and dried at 60 ° C in a vacuum. The yield is 388 mg (89% of theory). HPLC (method 1): R _t = 4.3 min MS (ESI): mz = 381 (M + H) ^{+ X} H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.7 (s, 3H); 1.21 (s, 3H); 2.1 (s, 2H); 2.3 (s,

3H); 4.6 (s, 1H); 7.1-7.3 (m, 2H); 7.5-7.7 (m, 3H); 7.95-8.4 (m, 3H); 9.45 (s, IH).

Example 4

N- (4-Cyano-2-ylphenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluorophenyl] urea (enantiomer of Example 3)

Chromatographic separation of enantiomers of 300 mg of racemate of N- (4-cyano-2-methylphenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidmyl) -4-fluorophenyl] - Urea (example 3) on silica gel is carried out by HPLC method 3. After recrystallization from ethyl acetate, the yield is 110 mg (37% of theory).

General working procedure B: synthesis of ureas

1 equivalent of the aniline is dissolved in ethyl acetate (0.1-0.25 M solution) and 1.1 equivalents of the corresponding isocyanate are added. The reaction mixture is stirred at room temperature overnight. The purification is carried out by recrystallization, column chromatography (silica gel: cyclohexane / ethyl acetate) or by preparative RP-HPLC (method 7).

Example 5

N- (4-CMor-2-methylphenyl) -N '- [4-fluoro-3- (1,3,3-trimethyl-5-oxo-2-pyrrolidinyl) phenyl] urea

According to general regulation B, 5- (5-amino-)

2-fluoφhenyl) -l, 4,4-trimethyl-2-pyrrolidinone (Example 15A) and 66 mg (0.39 mmol)

4-Chloro-2-methylphenyl isocyanate obtained after crystallization 114 mg (79% of theory) of product.

Mp: 215.0 ° C

HPLC (method 1): R _t = 4.59 min

MS (ESIpos): m / z = 404 (M + H) ⁺

Example 6

N- (4-Chloro-2-methylρhenyl) -N '- {4-fluoro-3 - [(2S) -l, 3,3-tτimethyl-5-oxo-2-pyrrolidinyl] phenyl} urea

According to general regulation B, 155 mg (0.66 mmol) (5S) -5- (5-

Amino-2-fluoφhenyl) -l, 4,4-trimethyl-2-pynoüdinon (Example 16A) and 121 mg

(0.72 mmol) 4-chloro-2-methylphenyl isocyanate after crystallization 191 mg (72% of theory

Th.) Product received.

HPLC (method 1): R _t = 4.67 min

^X H NMR (300 MHz, DMSO-d ₆ ): δ = 0.70 (s, 3 H), 1.23 (s, 3 H), 2.07 (d, 1 H), 2.23

(s, 3 H), 2.25 (d, 1 H), 2.66 (s, 3 H), 4.54 (s, 1 H), 6.95 (d, 1 H), 7.16-7.26 (m, 3 H),

7.51 (m, 1 H), 7.86 (d, 1 H), 7.90 (s, 1 H), 9.14 (s, 1 H)

Example 7

N- (2,4-Dimethylphenyl) -N '- {4-fluoro-3 - [(2S) -l, 3,3-trimethyl-5-oxo-2-pyrrolidinyl] phenyl urea

According to general procedure B, 157 mg (0.66 mmol) of (55) -5- (5- Ammo-2-fluoφhenyl) -l, 4,4-1rimemyl-2-pynolidinone (Example 16A) and 108 mg (0.73 mmol ) 2,4-dimethylphenyl isocyanate after chromatographic purification (method 7) 133 mg (52% of theory) of product obtained.

HPLC (method 1): R _t = 4.49 min MS (ESIpos): m / z = 384 (M + H) ⁺

^T H-ΝMR (300MHz, DMSO-de): δ = 0.69 (s, 3 H), 1.23 (s, 3 H), 2.07 (d, 1 H), 2.19 (s, 3 H), 2.22 (s, 3 H), 2.26 (d, 1 H), 2.66 (s, 3 H), 4.53 (s, 1 H), 6.92-6.98 (m, 3 H), 7.18 (t, 1 H), 7.52 (m, 1 H), 7.63 (d, 1 H), 7.77 (s, 1 H), 9.05 (s, 1 H). Example 8

{(2S) -2- [5 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) -2-fluoropheneyl] -3,3-dimethyl-5-oxo-l-pyrrolidinyl} ethyl acetate

According to the general procedure B, ethyl acetate (Example 18A) and 119 mg (0.39 mmol) of [(2S) -2- (5-Amio-2-fluorophene) -3,3-dimemyl-5-oxo-1-pyrrolidinyl] 71 mg (0.42 mmol) of 4-chloro-2-methylphenyl isocyanate after chromatographic purification (method 7) 88 mg (48% of theory) of product were obtained. HPLC (method 1): R _t = 4.87 min MS (ESIpos): mz = 476 (M + H) ⁺

Example 9

N- (4-CMor-2-me phenyl) -N '- {4-fluoro-3 - [(2S) -l- (2-hydroxyethyl) -3,3-dimethyl-5-oxo-2-pyrrolidinyl] phenyl} -urea

According to a regulation by KA Scheidt et al, Bioorganic & Medicinal Chemistry 1998, 2477-2494, 38 mg calcium chloride are suspended in 1 ml ethanol and the suspension is cooled to -5 ° C. A solution of 82 mg (0.17 mmol) {(2S) -2- [5 - ({[(4-chloro-2-ylphenyl) ammo] carbonyl} amino) -2- fluoφhenyl] -3, 3-dimethyl-5-oxo-l-pyrrolidinyl} ethyl acetate (Example 8) in 2 ml of tetrahydrofuran. The mixture is stirred for a further 5 minutes and then 26 mg of sodium borohydride are added in one portion. The reaction mixture is allowed to warm up slowly to RT and stirred at this temperature overnight. Then 1 M citric acid is added to the reaction mixture and extracted three times with ethyl acetate. The combined organic extracts are washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and then dried over magnesium sulfate. After filtration and evaporation of the solvent, the cleaning is carried out by RP-HPLC, 73 mg (96% of theory) of product being obtained.

HPLC (method 1): R _t = 4.38 min MS (ESIpos): m / z = 434 (M + H) ⁺

Example 10

N- (4-Chloro-2-methylphenyl) -N '- [4-fluoro-3- (3-methyl-5-oxo-2-pyrrolidinyl) phenyl] urea

According to general regulation B, 196 mg (0.94 mmol) of 5- (5-amino-2-fluoφhenyl) -4-methyl-2-pyrrolidinone and 189 mg (1.13 mmol) of 4-chloro-2-methylphenyl isocyanate are chromatographically Cleaning (method 7) 184 mg (52% of theory) of product (mixture of diastereomers). HPLC (method 1): R _t = 4.36 min MS (ESIpos): m / z = 376 (M + H) ⁺

Example 11

N- (3-chloro-phenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoro-phenyl] urea

In analogy to Example 1, the target compound is obtained from 0.18 mmol of 5- (5-amino-2-fluoro-phenyl) -4,4-dimethyl-2-pyrrolidinone and 0.22 mmol of 3-chloro-phenyl isocyanate.

Yield: 74% of theory Th. HPLC (method 1): R _t = 4.4 min MS (ESI): m / z = 376 (M + H) ⁺

^! H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.65 (s, 3 H); 1.2 (s, 3H); 2.1 (s, 2H); 4.6 (s, 1H); 6.95 -7.5 (m, 6H); 7.7 (s, 1H); 8.0 (s, 1H); 8.8 (s, 1H); 8.9 (s, IH). Example 12

N- (3-Chlθφhenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoφhenyl] urea

The target structure is obtained as enantiomer B by chromatographic separation of enantiomers from Example 11 by HPLC method 5.

Example 13

N- [3- (3,3-Dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoropheneyl] -N '- (4-fluoro-2-me-phenyl) urea

In analogy to Example 1, the target compound is obtained from 0.18 mmol of 5- (5-amino-2-fluorophenyl) -4,4-dimethyl-2-pyrroüdinon and 0.22 mmol of 4-fluoro-2-methylphenyl isocyanate.

Yield: 95% of theory Th.

HPLC (method 6): R _t = 4.2 min

MS (ESI): m / z = 374 (M + H) ⁺

1H NMR (200 MHz, DMSO-d ₆ ): δ = 0.65 (s, 3 H); 1.2 (s, 3H); 2.1 (s, 2H); 2.2 (s, 3rd

H); 4.6 (s, 1H); 6.9-7.3 (m, 4H); 7.4-7.6 (m, 1H); 7.65-7.8 (m, 1H); 7.85 (s, 1H);

8.0 (s, IH); 9.1 (s, IH).

Example 14

N- [3- (3,3-Dimethyl-5-oxo-2-pyrrolidrnyl) -4-fluoro-phenyl] -N '- (4-fluoro-2-methylphenyl) urea

The target structure is obtained as enantiomer B by chromatographic separation of enantiomers from Example 13 by HPLC method 4. Example 15

N- (2,4-Difluoφhenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoφhenyl] urea

In analogy to Example 1, the target compound is obtained from 0.14 mmol of 5- (5-amino-2-fluoro-phenyl) -4,4-dimethyl-2-pyrrolidinone and 0.16 mmol of 2,4-difluoro-phenyl isocyanate. Yield: 59% of theory Th.

HPLC (method 1): R _t = 4.2 min

MS (ESI): m / z = 378 (M + H) ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 0.65 (s, 3H); 1.2 (s, 3H); 2.1 (s, 1H); 4.6 (s,

IH); 6.95-7.55 (m, 5H); 7.9-8.15 (m, 2H); 8.4 (s, IH); 9.15 (s, IH).

Example 16

N- (2,4-Difluoφhenyl) -N '- [3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoφhenyl] urea

The target structure is obtained as the enantiomer B by chromatographic separation of the enantiomers of Example 15 by HPLC method 4.

Example 17

N- [3- (3,3-Dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoφhenyl] -N ^, - (3-fluoφhenyl) urea

In analogy to Example 1, the target compound is obtained from 0.14 mmol of 5- (5-amino-2-fluoro-phenyl) -4,4-dimethyl-2-pyrrolidinone and 0.16 mmol of 3-fluoro-phenyl isocyanate. Yield: 74% of theory Th.

HPLC (method 1): R _t = 4.2 min

MS (ESI): m / z = 360 (M + H) ⁺ -NMR (200 MHz, DMSO-d ₆ ): δ = 0.65 (s, 3 H); 1.2 (s, 3H); 2.1 (s, 2H); 4.55 (s,

1 H); 6.7-6.9 (m, 1H); 7.05-7.6 (m, 6H); 8.0 (s, 1H); 8.8 (s, 1H); 8.9 (s, 1H).

Example 18

N- [3- (3,3-Dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoφhenyl] -N '- (3-fluoφhenyl) urea

The target structure is obtained as the enantiomer B by chromatographic separation of the enantiomers of Example 17 by HPLC method 4.

Example 19

N- [3- (3,3-Dimethyl-5-oxo-2-pynolidmyl) -4-fluoropheneyl] -N '- (2,4-dimethylphenyl) urea

In analogy to Example 1, the target compound is obtained from 0.18 mmol of 5- (5-arnino-2-fluorophene) -4,4-dimethyl-2-pyrrolidone and 0.22 mmol of 2,4-dimethylphenyl isocyanate.

Yield: 71% of theory Th.

HPLC (method 1): R _t = 4.3 min

MS (ESI): m / z = 370 (M + H) ⁺

Η NMR (200 MHz, DMSO-d ₆ ): δ = 0.65 (s, 3 H); 1.2 (s, 3H); 2.1 (s, 2H); 2.15 (s,

3 H); 2.2 (s, 3H); 4.6 (s, 1H), 6.9-7.3 (m, 4H); 7.4-7.6 (m, 1H); 7.65 (d. 1H); 7.8

(s, 1H); 8.0 (s, IH); 9.05 (s, IH).

Example 20

N-f3- (3,3-dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoro-phenyl] -N '- (2,4-dimethylphenyl) urea

The target structure is obtained as the enantiomer B by chromatographic separation of the enantiomers of Example 19 by HPLC method 4.

Example 21

N- [3- (3,3-Dimethyl-5-oxo-2-pynolidinyl) -4-fluoropheneyl] -N '- [3- (trifluoromethyl) phenyl] urea

In analogy to Example 1, the target compound is obtained from 0.18 mmol of 5- (5-amino-2-fluoro-phenyl) -4,4-dimethyl-2-pyrrolidinone and 0.22 mmol of 3-trifluoromethylphenyl isocyanate.

Yield: 91% of theory Th.

HPLC (method 1): R _t = 4.5 min

MS (ESI): mz = 410 (M + H) ⁺

^! H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.65 (s, 3 H); 1.2 (s, 3H); 2.1 (s, 2H); 4.6 (s, 1

H); 7.1-7.7 (m, 6H); 8.0 (s, 2H); 9.0 (s, 2H).

Example 22

N- [3- (3,3-Dimethyl-5-oxo-2-pyrrolidinyl) -4-fluoropheneyl] -N '- [3- (trifluoromethyl) phenyl] urea

The target structure is determined by chromatographic enantiomer separation from example

21 obtained as enantiomer B by HPLC method 4. B. Assessment of physiological effectiveness

The in vitro activity of the compounds according to the invention can be shown in the following assays:

Anti-HCMV (Anti-Human Cytomegalo Virus) zvtopathogenicity tests

The test compounds are used as 50 millimolar (mM) solutions in dimethysulfoxide (DMSO). Ganciclovir ^® , Foscarnet ^® and Cidofovir ^® serve as reference compounds. After adding 2 μl of the 50, 5, 0.5 and 0.05 mM DMSO stock solutions to 98 μl cell culture medium in the 2 AH series in duplicate, 1: 2 dilutions with 50 μl medium each are carried out up to the 11 series the 96-well plate. The wells in rows 1 and 12 each contain 50 μl medium. 150 μl of a suspension of 1 × 10 ⁴ cells (human foreskin fibroblasts [NHDF]) are then pipetted into the wells (row 1 = cell control) or a mixture of HCMV-infected and non-infected NHDF- in rows 2-12

Cells (MOI = 0.001 - 0.002), ie 1-2 infected cells per 1000 uninfected cells. Row 12 (without substance) serves as a virus control. The final test concentrations are 250 - 0.0005 μM. The plates are incubated for 6 days at 37 ° C / 5% CO ₂ , ie until all cells in the virus controls are infected (100% cytopathogenic effect [CPE]). The wells are then removed by adding a mixture of

Formalin and Giemsa's. Dye. fixed and colored (30 minutes), with aqua bidest. washed and dried in a drying cabinet at 50 ° C. The plates are then visually evaluated using an overhead microscope (Techno ara plaque multiplier).

The following data can be obtained from the test plates:

CC ₅₀ (NHDF) = substance concentration in μM at which no visible cytotoxic effects on the cells can be seen in comparison to the untreated cell control; EC ₅ 0 (HCMV) = substance concentration in μM which inhibits the CPE (cytopathic effect) by 50% compared to the untreated virus control; SI (selectivity index) = CC ₅₀ (NHDF) / EC ₅₀ (HCMV). _,

Representative in vitro activity data for the compounds according to the invention are shown in Table A:

Table A

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

HCMV Xenograft-Gelfoanr model

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 (Taconic M + B, Jackson, USA). The animals are kept in isolators under sterile conditions (including litter and feed). Virus Growing:

Human cytomegalovirus (HCMV), Davis strain or AD 169, is grown in vitro on human foreskin fibroblasts (NHDF cells). After infection of the NHDF cells with a multiplicity of infection (MOI) of 0.01-0.03, the virus-infected cells are harvested 5-10 days later and in the presence of Minimal Essential Medium (MEM), 10% fetal calf serum (FKS) stored with 10% DMSO at -40 ° C. After serial dilution of the virus-infected cells in steps of ten, the titer is determined on 24-well plates of confluent NHDF cells after vital staining with neutral red. ■ ^"

Preparation of the sponges, transplantation, treatment and evaluation: collagen sponges measuring 1 x 1 x 1 cm (Gelfoam ^® ; Peasel & Lorey, order no. 407534; KT Chong et al., Abstracts of 39 ^th Interscience Conference on Antimicrobial Agents and Chemotherapy , 1999, p. 439) are first wetted with phosphate-buffered saline (PBS), the enclosed air bubbles are removed by degassing and then stored in MEM + 10% FCS. 1 x 10 ⁶ virus-infected NHDF cells (infection with HCMV-Davis or HCMV AD 169 MOI = 0.03) are detached 3 hours after infection and dropped in 20 μl MEM, 10% FCS onto a damp sponge. Approximately 16 hours later, the infected sponges are incubated with 25 μl PBS / 0.1% BSA / 1 mM DTT with 5 ng / μl basic fibroblast growth factor (bFGF). For transplantation, the immunodeficient mice are anesthetized with avertine or with a ketamine / xylazine azepromazine mixture, the back skin is removed with the help of a razor, the epidermis is opened 1-2 cm, relieved and the moist sponges are transplanted under the back skin. The surgical wound is closed with tissue adhesive. The mice can be treated for the first time 6 hours after the transplant (once on the day of the operation). On the following days, the patient is treated orally with substance three times a day (7 a.m. and 2 p.m. and 7 p.m.), twice a day (8 a.m. and 6 p.m.) or once a day (2 p.m.) over a period of 8 days. The daily dose is, for example, 3 or 10 or 30 or 60 or 100 mg / kg body weight, the application volume 10 ml / kg body weight. The substances are formulated in the form a 0.5% tylose suspension with 2% DMSO or a 0.5% tylose suspension. 9 days after the transplant and 16 hours after the last substance application, the animals are killed painlessly and the sponge is removed. The virus-infected cells are released from the sponge by KoUagenase digestion (330 U / 1.5 ml) and in the presence of MEM, 10% fetal calf serum,

10% DMSO stored at -140 ° C. The evaluation is carried out after serial dilution of the virus-infected cells in steps of ten by titer determination on 24-well plates of confluent NHDF cells after vital staining with neutral red. The number of infectious virus particles after substance treatment is determined in comparison to the placebo-treated control group.

C. Examples of pharmaceutical compositions

The compounds according to the invention can be converted into pharmaceutical preparations as follows:

Tablet:

Composition:

100 mg of the compound from Example 1, 50 mg lactose (monohydrate), 50 mg corn starch (native), 10 mg polyvinylpyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The mixture of active ingredient, lactose and starch is granulated with a 5% solution (m / m) of the PVP in water. The granules are dried with the magnesium stearate for 5 min. mixed. This mixture is veφresst with a conventional tablet press (format of the tablet see above). A pressing force of 15 kN is used as a guideline for the compression.

Oral suspension:

Composition:

1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the compound according to the invention corresponds to 10 ml of oral suspension.

production:

The Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stirred for about 6 hours. Solution that can be administered intravenously:

Composition:

10-200 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for injections.

production:

The compound of Example 1 is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile filtered (pore diameter 0.22 μm) and filled into heat-sterilized infusion bottles under aseptic conditions. These are closed with infusion stoppers and crimp caps.

Claims

claims

1. Connections of the formula

in which

the remainder -NHC (D) NHR ² is bound to the aromatic system via one of the positions 2 or 3,

D represents oxygen or sulfur,

R ^{1 represents} hydrogen or CrCe-alkyl, where alkyl can be substituted by 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, C ₁ -C ₆ -alkoxy, C _ö -Cio- Aryl, 5- to 6-membered heteroaryl, amino and -CC ₆ - alkylamino,

or

R ¹ and R ⁴ together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl ring, where the cycloalkyl ring can be substituted with 0, 1, 2 or 3 substituents independently of one another from the Group consisting of halogen, hydroxy, Ci-Cö-alkyl, Ci-C _ö -alkoxy, C ₆ -Cιo-aryl, 5- to 6-membered heteroaryl, amino and Ci-Cβ- alkylamino, R ^{2 represents} C ₃ -Cιo-cycloalkyl or C ₆ -Cιo-aryl, where cycloalkyl and aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, C _I -C _Ö - alkoxy, hydroxycarbonyl,

Ci-C _δ alkoxycarbonyl, amino, Cι-C ₆ alkylamino, Ci-C _ö alkylaminocarbonyl and Cι-C ₆ alkyl,

R ^{3 represents} hydrogen or Ci-Cö-alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, C _I -C _Ö -AI- koxy, C _ό -Cιo-aryl, 5- to 6-membered heteroaryl, amino and CI-C _Ö - alkylamino,

or

R ³ and R ⁶ together with the carbon atom to which they are attached form a C ₃ -C _ό cycloalkyl ring, which cycloalkyl ring may be substituted with 0, 1, 2 or 3 substituents selected independently of one another from the group consisting of halogen, hydroxy,

Ci-Cö-alkyl, Ci-C _ö alkoxy, C ₆ -Cιo-aryl, 5- to 6-membered heteroaryl, amino and Ci-Cö-alkylamino,

R ^{4 represents} hydrogen or CI-C _Ö - alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, Ci-Cό-alkoxy, C _ό - Cιo-aryl, amino and Ci-C _ö alkylamino,

R ⁵ for hydrogen, halogen, hydroxy, cyano, CI-C _Ö - alkoxy, carboxy, benzyl, C _I -C _Ö - alkoxycarbonyl, - aminocarbonyl, CI-C _Ö - alkyl-amino-carbonyl, Cö-Cio-arylaminocarbonyl, 5- to 6-core heteroaryl aminocarbonyl, Ci-C _ö -AUcylcarbonylamino, C _ö -Cio-arylcarbonylamino, amino, Ci-C _ö alkylamino or Ci-C _ό alkyl.

R ^{6 represents} hydrogen or -CC ₆ alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, Ci-C _ό -alkoxy, C _ö -Cio-aryl, amino and Ci-C _ö alkylamino,

R ^{7 represents} hydrogen or Ci-C _ö -alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, hydroxycarbonyl, aminocarbonyl, Ci-C _ö - Alkoxy, C _ό -Cio aryl, 5- to 6-membered heteroaryl, amino, Ci-C _ö alkylamino, Ci-C _ό alkoxycarbonyl, Ci-C _ö alkylaminocarbonyl, C _ö -Cio arylaminocarbonyl, - C _ό -alkylcarbonylamino, C _ö -Cio-arylcarbonylamino, Ci-C _ö - alkylcarbonyloxy, C _ö -Cio-arylcarbonyloxy, Ci-C _ό -alkylaminocarbonyloxy and C _ö -Cio-arylaminocarbonyloxy,

R ¹ , R ³ , R ⁴ and R ^{6 are} not all hydrogen at the same time,

and their salts, solvates and solvates of the salts.

2. Compounds according to claim 1, characterized in that

the rest -NHC (D) NHR ^{2 is} attached to the aromatic system via position 3,

D stands for oxygen,

R ^{1 represents} C _I -C _Ö alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, Ci-C _ö alkoxy, C _ö -Cio-aryl, amino and Ci-Cö-alkylamino,

R ^{2 represents} C ₃ -Cιo-cycloalkyl or C _ö -Cio-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and C _I -C _Ö - alkyl,

R ^{3 represents} hydrogen or Ci-C _ö -alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, C ₁ -C ₀ -AI- koxy, Cö -Cio-aryl, amino and Ci-Cö-alkylamino,

R ^{4 represents} hydrogen or C ₁ -C ₀ -alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxyl, C ₁ -C ₀ -alkoxy, C _ö -Cio-aryl, amino and Ci-C _ö alkylamino,

R ^{5 represents} hydrogen, fluorine, chlorine, hydroxy, amino, Ci-Cö-alkylamino, Ci-C _δ -Alkylcarbonylamino or Ci-C _ό -alkyl,

R ^{6 represents} hydrogen or C1-C0-alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, C ₁ -C ₀ -AI- koxy, Cδ- Cio-aryl, amino and Ci-C _ö alkylamino,

and

R ^{7 represents} hydrogen or Ci-Cδ- alkyl, where alkyl can be substituted with 0 or 1 substituent - selected from the group consisting of hydroxy and Ci-C _δ -alkylaminocarbonyloxy.

3. Compounds according to one of claims 1 or 2, characterized in that

the rest -NHC (D) NHR ^{2 is} attached to the aromatic system via position 3,

D stands for oxygen,

R ^{1 represents} Ci-C _ö alkyl,

R ² represents phenyl or adamantyl, wherein phenyl may be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano and Ci-C _ö alkyl,

R ^{J represents} hydrogen,

R represents hydrogen or Ci-C _ό alkyl,

R ^{5 represents} hydrogen, hydroxy, fluorine, chlorine or methyl,

R ^{6 represents} hydrogen,

and

R ^{7 represents} hydrogen or -CC ₃ alkyl, where alkyl can be substituted with 0 or 1 substituents selected from the group consisting of hydroxy and Ci-C _ό -alkylaminocarbonyloxy.

4. Compounds according to claim 1, characterized in that the residue -NHC (D) NHR ² is bonded to the aromatics via position 3.

5. Compounds according to one of claims 1 or 4, characterized in that D represents oxygen.

6. Compounds according to any one of claims 1 to 5, characterized in that R ^{1 is} methyl.

7. Compounds according to any one of claims 1 to 6, characterized in that R ^{2 is} adamantyl or phenyl, where phenyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano and methyl ,

8. Compounds according to any one of claims 1, 2 or 4 to 7, characterized in that R ^{3 is} hydrogen.

9. Compounds according to any one of claims 1 to 8, characterized in that R ^{4 represents} hydrogen or methyl.

10. Compounds according to any one of claims 1 to 9, characterized in that R ^{5 represents} hydrogen or fluorine.

11. Compounds according to any one of claims 1, 2 or 4 to 10, characterized in that R ^{6 is} hydrogen.

12. Compounds according to any one of claims 1 to 11, characterized in that R ^{7 represents} hydrogen or methyl.

13. A process for the preparation of compounds of formula (I) according to claim 1, characterized in that compounds of formula

in which

-NH ₂ is bound to the aromatics via one of the positions 2 or 3, and

R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given in claim 1,

with compounds of the formula

DCN— FC (HI), in which

R and D have the meaning given in claim 1,

be implemented.

14. Compounds according to any one of claims 1 to 12 for the treatment and / or prophylaxis of diseases. ^•

15. Medicament containing at least one compound according to one of claims 1 to 12 in combination with at least one pharmaceutically acceptable, pharmaceutically acceptable carrier or other excipient.

16. Use of compounds according to one of claims 1 to 12 for the manufacture of a medicament for the treatment and / or prophylaxis of viral infections.

17. Use according to claim 16, characterized in that the virus infection is an infection with the human cytomegalovirus (HCMV) or another representative of the group of Heφes viridae.

18. Medicament according to claim 15 for the treatment and / or prophylaxis of viral infections.

19. A method for combating vi sinfections in humans and animals by administering an antivirally effective amount of at least one compound according to one of claims 1 to 12