EP1499603A1 - Antiviral lactone-ureas - Google Patents

Abstract

The invention relates to lactones and to a method for their production, in addition to their use for producing medicaments for the treatment and/or prophylaxis of diseases, particularly to their use as anti-viral agents in particular against cytomegaloviruses.

Description

 ANTIVIRAL LACTON UREAS

The invention relates to lactones 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.

A. Martinez, A. Castro, C. Gil, C. Perez describe: "Recent Strategies in the Development of New Human Cytomegalovirus Inhibitors", Med. Res. Rev. 2001, 21 (3), 227-244 and A. Castro, A. Martinez: "Patent focus on antiviral agents: June-

November 2000 ", Exp. Opin. Ther. Pat. 2001, 11 (2), 165-176 antiviral agents. However, resistance can regularly develop. New agents for effective therapy are therefore desirable.

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

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

The present invention relates to compounds of the formula

in which the remainder -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 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, Ci-C ₆ alkoxy, Cβ-Cio- Aryl, 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 selected from the Group consisting of halogen, hydroxyl, -CC ₆ -alkyl, -C-C ₆ -

Alkoxy, C _ö -Cio-aryl, amino and -C-C ₆ alkylamino,

R ^{2 represents} C ₃ -Cιo-cycloalkyl or C ₆ -Cιo-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, Ci C ₆ alkoxy,

Hydroxycarbonyl, Ci-C _ö alkoxycarbonyl, amino, C _t -Cs alkylamino, Cι-C ₆ -

Alkylaminocarbonyl and -CC ₆ alkyl,

R ^{3 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 fluorine, chlorine, hydroxy, -C-C ₆ alkoxy, C ₆ -C ₁₀ aryl,. Amino and C ₁ -C 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 independently selected from the Group consisting of halogen, hydroxy, -CC ₆ alkyl, -C ₆ -alkoxy, Cg-do-aryl, amino and Ci-C _ö alkylamino,

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 ₆ - alkoxy, Amino and C ₁ -C ₆ -alkylamino,

R ^{5 represents} hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ -alkoxy, carboxy, CrC ₆ - alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkylaminocarbonyl, amino, C ds-alkylamino or C 1 -C ₆ -alkyl.

R ^{6 represents} hydrogen or C Cβ-alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, C ₁ -C ₆ alkoxy, C ₆ -Cιo Aryl, amino and C ₁ -C ₆ -AH **. Ylamino.

and

R ¹ , R ³ , R ⁴ and R ^{6 are} not simultaneously hydrogen.

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

Solvates of the salts are present.

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. Out Such mixtures of enantiomers and / or diastereomers can isolate the stereoisomerically uniform constituents in a known manner.

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 compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid. Naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds (T) also include salts of conventional bases, such as, for example and by way of preference, 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, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoelhanolamine, diethanolamine, triethanolamine, dicyclo-hexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dehydroabietylamine and methylamine, arginine diamine, arginine diamine.

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 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 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 of one another) alkyl substituents, for example and preferably for methylamino, ethylamino, n-propylamino, isopropylarnino, tert-butylamino, n-pentylamino, n-

Hexylamino, NN-dimethylamino, NN-diethylamino, N-ethyl-N-methylamino, N- me yl-Nn-propylan-ino, N-isopropyl-Nn-propylamino, N-tert.-butyl-N-mefhylamino, N- Ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Alkylaminocarbonyl stands for an alkylarninocarbonyl radical with one or two (independently selected) alkyl substituents, by way of example and preferably for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert.-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, n-hexylaminocarbonyl , N, N-Die1hylaminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylamino-carbonyl, N-tert.-butyl-N-methylaminocarbonyl, N-ethyl- Nn-pentylamino-carbonyl and Nn-hexyl-N-methylaminocarbonyl.

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

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

Heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic heterocyclic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO ₂ . The heterocyclyl residues can be saturated or partially unsaturated. 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the are preferred

Series O, N and S, such as, for example and preferably, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, piperidinyl, morpholinyl, perhydroazepinyl.

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

Compounds of the formula (I) are preferred

in which

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

D stands for oxygen,

R ^{1 represents} CrC ₆ alkyl, where alkyl can be substituted by 0, 1 or 2

Substituents independently selected from the group consisting from fluorine, chlorine; Hydroxy, CrCβ-alkoxy, Cö-Cio-aryl, amino and Cι-C ₆ - alkylamino,

R ^{2 represents} C ₃ -Cιo-cycloalkyl or C ₆ -Cιo-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 C ₁ -C 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 ₁ -C ₆ -alkoxy, Cö-Cio -Aryl, amino and

C ₁ -C ₆ - alkylamino,

R ⁴ represents C ₁ -C 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 ₁ -C ₆ -alkoxy, C ₆ -Cιo-aryl , Amino and Cι-C ₆ -

alkylamino,

R ^{5 represents} hydrogen, halogen, hydroxy, amino, C ₁ -C ₆ -alkylamino or C ₁ -C ₆ -alkyl,

and

R ^{6 represents} hydrogen or CrC 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 ₁ -C ₆ -alkoxy, C ₆ -Cιo-aryl , Amino and

CrC _ö alkylamino.

Preference is furthermore given to compounds of the formula (I)

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

D stands for oxygen,

R ¹ . represents d-Ce-alkyl,

R represents phenyl or adamantyl, 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 C ₁ -C ₆ -alkyl,

R represents hydrogen,

R ^{4 represents} Ci-Cβ-alkyl,

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

and

R ^{6 represents} hydrogen.

Preference is furthermore given to compounds of the formula (I)

in which

the rest -NHC (D) NHR ² is bound to the aromatic system via position 3.

Preference is furthermore given to compounds of the formula (I)

in which

R stands for hydrogen. Preference is furthermore given to compounds of the formula (I)

in which

R ^{5 stands} for hydroxyl, fluorine, chlorine or methyl and is bound via the 6 position to the aromatics.

Preference is furthermore given to compounds of the formula (I)

in which

D stands for oxygen.

Preference is furthermore given to compounds of the formula (I)

in which

R ^{1 represents} methyl.

Preference is furthermore given to compounds of the formula (I)

in which

R ^{2 stands} for 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.

Preference is furthermore given to compounds of the formula (I)

in which R stands for hydrogen.

Preference is furthermore given to compounds of the formula (I)

in which

R ^{4 represents} methyl.

Preference is furthermore given to compounds of the formula (I)

in which

R ^{4 represents} benzyl.

Preference is furthermore given to compounds of the formula (I)

in which

R ^{6 represents} hydrogen.

Preference is furthermore given to compounds of the formula (I)

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 further relates to processes for the preparation of the compounds of

Formula (I), characterized in that compounds of the formula

in which

-NHC (D) NHR> 2 is bound to the aromatics via one of the positions 2, 3, 5 or 6,

D, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given above, and

R ^{7 represents} alkyl, preferably methyl or ethyl,

be implemented with reducing agents

or

that according to method [B] compounds of the formula in which

-NH ₂ is bound to the aromatics via one of the positions 2, 3, 5 or 6, and

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

with compounds of the formula

D = C = N - R ² (IV) in which

D and R ^{2 have} the meaning given above,

be implemented.

The reaction according to Verfaliren [A] is generally carried out in a solvent, preferably in a temperature range from τl0 ° C to room temperature at normal pressure.

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, iso-propanol, n-

Butanol or tert-butanol, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, preferred are methanol, diethyl ether or mixtures of methanol and diethyl ether or ethanol and tetrahydrofuran. Reducing agents are, for example, sodium borohydride, lithium borohydride, tetrabutylammonium borohydride or sodium cyanoborohydride, preferably sodium borohydride.

The reaction according to process [B] 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 dimethyl ether - Glycol dimethyl ether, 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 potassium tert-butoxide, or other bases such as sodium hydride,

DBU, triethylamine or diisopropylethylamine, preferred are diisopropylethylamine and triethylamine.

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

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

in which

NH ₂ is bound to the aromatics via one of the positions 2, 3, 5 or 6, and

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

be reacted with compounds of the formula (IV).

The reaction is generally carried out under the conditions described in process [B].

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

in which N0 ₂ is bound to the aromatics via one of the positions 2, 3, 5 or 6, and

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

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

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, iso-

Propanol, 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, isopropanol, ethyl acetate or im are preferred Case of tin dichloride in dimethylformamide, ethanol or dioxane.

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, 3, 5 or 6, and

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

with compounds of the formula

R-OH (VII), in which

R ^{7 has} the meaning given above, are implemented.

The reaction is generally carried out in inert solvents or in compounds of the formula (VII), if appropriate 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 diethylene glycol dimethyl ether, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine, ethanol being preferred or methanol.

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

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

in which

R ^{5 has} the meaning given above,

with compounds of the formula

in which

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

The reaction is generally carried out in merten solvents, optionally in the 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 or glycol Diethylene glycol dimethyl ether, hydrocarbons such as hexane or cyclohexane, or others

Solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, 1,2-dichloroethane is preferred.

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

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

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

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

with compounds of the general formula

in which

R> 3 ^J , τ R> 6 °. U.N-. d R 'have the meaning given above, and

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

implemented and then converted into compounds of formula (VIII) (acid) by saponification of the ester group (-C (= O) OR ⁷ ) by methods known to those skilled in the art.

The reaction is generally carried out in inert solvents, if appropriate 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, preferably tetrahydrofuran or toluene. Bases are, for example, amides such as sodium amide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, lithium diisopropylamide, or other bases such as sodium hydride, DBU or diisopropylethylamine, preferably sodium amide, lithium hexamethyldisilazide, potassium hexamethyldisilazide or lithium diisopropylamide.

The compounds of the general formulas (XVIII) and (XEX) are known or can be synthesized from the corresponding starting materials by known processes (for (XVIII) cf. MR Schneider, H. Ball, J. Med. Chem. 1986, 29, 75 -79).

In an alternative synthetic method, compounds of the formula (Va), which are compounds of the formula (V), in which

R ^{6 represents} hydrogen,

are prepared by compounds of the formula

in which

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

are implemented by the process described for the preparation of the compounds of the formula (VI). The compounds of formula (XI) can be prepared by compounds of the formula

in which

R, 1, 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 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, 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 nitromethane, ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran is preferred.

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

R ^{5 has} the meaning given above,

with compounds of the formula (XTV),

in which

R> 1, r R »3, R n 4 - and J R τ, l have the meaning given above, are implemented.

The reaction is generally carried out in inert solvents, if appropriate 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, diethyl ether, tetrahydrofuran, heptane and / or ethylbenzene are preferred. Bases are, for example, sodium or potassium methoxide, or sodium or potassium ethoxide or potassium tert-butoxide, or amides such as sodium amide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, or organometallic compounds such as butyllithium or phenyllithium, or other bases such as sodium hydride , DBU, triethylamine or diisopropylethylamine, lithium diisopropylamide is preferred.

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

The compounds of formula (XIII) 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 dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclo- hexane or petroleum fractions, or other solvents such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine, preferably tetrahydrofuran or methylene chloride.

The compounds of formula (XV) are known or can be made according to known ones

Synthesize processes from the corresponding starting materials.

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

in which

-NO ₂ is bound to the aromatics via one of the positions 2, 3, 5 or 6, and

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

be reduced, e.g. with tin (II) chloride or tin in hydrochloric acid.

The reaction is generally carried out according to that for the compounds of the formula

(III) conditions described.

The compounds of formula (XVII) can be prepared by reacting compounds of formula (V) according to the conditions described in process [A]. In an alternative synthetic method, compounds of formula (EU) can be prepared by using compounds of formula

in which

N-diallyl is bonded to the aromatics via one of the positions 2, 3, 5 or 6, and

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

with 1,3-dimethylbarbituric acid, triphenylphosphine and tettakis (ttiphenylphosphine) palladium (O).

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.

Inert solvents are, for example, hydrocarbons such as benzene, ethylbenzene, xylene, toluene, or other solvents such as ethyl acetate, dimethylformamide or dimethylacetamide or mixtures of these solvents, preferably dimethylformamide, toluene or a mixture of dimethylformamide and toluene. The compounds of the formula (XX) can be synthesized from the corresponding NN-diallylamino-substituted starting materials by the alternative synthetic process described for the formula (VIII) or 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: synthesis of the ß-dimethyllactones

Synthesis scheme 3: Synthesis of the α-dimethyllactones

The compounds of the general formula (I) according to the invention show an unforeseeable surprising spectrum of action. They show an antiviral effect against representatives of the group of herpes viridae, especially against the human cytomegalovirus (HCMV). They are therefore suitable for the treatment and prophylaxis of diseases caused by herpes viridae, in particular diseases caused by human cytomegaloviruses.

Because of their special properties, the compounds of the general formula (I) can be used for the production of medicaments which are suitable for the prophylaxis or treatment of diseases, in particular viral diseases.

Due to their properties, the compounds according to the invention are valuable active substances for the treatment and prophylaxis of human cytomegalovirus infections and diseases caused thereby. Examples of indications which may be mentioned are:

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 often suffer from life-threatening HCMV pneumonitis, encephalitis, and gastrointestinal and systemic HCMV infections.

3) Treatment and prophylaxis of HCMV infections in newborns and young children.

4) Treatment of acute HCMV infection in pregnant women. 5) Treatment of HCMV infection in immunosuppressed patients with cancer and cancer therapy.

The new active ingredients can be used alone and, if necessary, in combination with other antiviral active ingredients such as Gancyclovir or Acyclovir.

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 auxiliaries or excipients, and to 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 way, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, topical or as

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). For parenteral administration, the following are suitable form 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, shake 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. polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments) such as iron oxides) or taste and / or smell.

In general, it has proven to be advantageous for intravenous administration

To administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg body weight to achieve effective results, and in the case of oral administration, the dosage is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be necessary to deviate from the amounts 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 takes place. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the upper limit mentioned is exceeded got to. 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.

A. Examples

Abbreviations:

TLC thin layer chromatography

DCI direct chemical ionization (for MS)

DCM dichloromethane

DIEA NN-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 LitMim diisopropylamide

MS mass spectroscopy

NMR nuclear magnetic resonance proc. 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:

Column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow = 0.75 min ^"1 , eluent: A = 0.005 M HClO ₄ , B = CH ₃ CN, gradient: → 0.5 min 98% A -» 4.5 min 10 % A - »6.5 min 10% A

Method 2:

Pillar: packing material KBD 6371 (250 * 20); Temperature: 23 ° C; Eluent: ethyl acetate; Compound dissolved in ethyl acetate.

Method 3: Column: packing material 6371 (250 * 20); Temperature: 23 ° C; Eluent: ethyl acetate; Compound dissolved in ethyl acetate / tetrahydrofuran (1: 1 (v / v)).

LCMS parameters:

Method 4:

Instrument: Waters AUiance 2790 LC; Column: Symmetry C18, 50mm x 2.1, 3.5μm; Eluent: A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 5% B - »5.0 min 10% B -> 6.0 min 10% B; Temperature: 50 ° C; Flow: 1.0 ml / min; UV detection: 210 n. starting compounds

Example 1A

(4-bromophenyl) - [(trimethylsilyl) oxy] acetonitrile

According to a regulation by K. Deuchert, U. Hertenstein, S. Hünig, G. Wehner, Chem. Ber. 1979, 112, 2045-2061, 2.73 g (27.5 mmol) of trimethylsilyl cyanide are mixed with a small spatula tip of zinc iodide as a catalyst under an argon atmosphere and heated to 60.degree. At this temperature, 4.23 g (25 mmol) of 4-bromobenzaldehyde are added in portions as a solid. The temperature is then raised to 95 ° C and held for 8 hours. Cleaning is then carried out by bulb tube distillation in a high vacuum (220-230 ° C). 6.11 g (85% of theory) of product are obtained.

HPLC (method 1): R _t = 3.88 min MS (ESIpos): m / z = 306 (M + Na) ⁺

Example 2A

4- (4-bromophenyl) -4-cyano-3,3-dimethyl-4- [trimethylsilyl) oxy] butansäuremethylester

According to a regulation by S. Hünig, G. Wehner, Chem. Ber. 1980, 113, 302-323 6 g (21.11 mmol) (4-bromophenyl) - [(trimethylsilyl) oxy] acetonitrile are dissolved in 21 ml dry diethyl ether under an argon atmosphere and the solution obtained is cooled to -78 ° C. 11.1 ml (22.2 mmol) of a 2 molar lithium diisopropylamide solution are added dropwise within 20 min. After 30 min, a solution of 2.48 g (21.11 mmol) of 3-methyl-2-butenoic acid methyl ester in 2 ml of dry diethyl ether is added dropwise. The reaction mixture is allowed to slowly warm to room temperature in the cooling bath within 4-5 hours. Then 40 ml of saturated ammonium chloride solution are added and the mixture is stirred at room temperature for a further 10 min. After the phases have been separated, it is dried over magnesium sulfate. After filtration and evaporation of the solvent, 9.48 g of crude product are obtained, which is used for the next synthesis without further purification. HPLC (method 1): R _t = 5.72 min MS (EI): m / z = 397 (M) ⁺ Example 3A

Methyl 4- (4-bromophenyl) -3, 3-dimethyl-4-oxobutanoate

Under an argon atmosphere, 8.65 g of 4- (4-bromophenyl) -4-cyano-3,3-dimethyl-4- [trimethylsilyl) oxy] butanoic acid (crude product) are dissolved in 87 ml of dry tetrahydrofuran and the solution in an ice bath to 0 ° C cooled. At this temperature, 21.7 ml (21.7 mmol) of a 1 molar tetrabutylammonium fluoride solution are slowly added dropwise. After 4.5 hours at 0 ° C with

75 ml of water are added and the mixture is extracted 3 times with dichloromethane. The combined organic phases are dried over magnesium sulfate. After filtration and evaporation of the solvent, the purification is carried out by column chromatography (silica gel: cyclohexane / ethyl acetate 85:15), 4.25 g (57% of theory over 2 stages) of product being obtained.

HPLC (method 1): R _t = 4.84 min MS (EI): m / z = 298 (M) ⁺

Example 4A

4- (4-bromo-3-nitrophenyl) -3,3-dimethyl-4-oxobutanoate

Under argon, 6 ml of fuming nitric acid are cooled to -30 ° C. and 3.71 g (12.4 mmol) of 4- (4-bromophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester are added dropwise at this temperature. The mixture is stirred for 1 hour at -30 ° C before pouring onto ice and extracted 3 times with dichloromethane. The combined organic extracts are dried over magnesium sulfate. After filtration and

Evaporation of the solvent is purified by column chromatography (silica gel: cyclohexane, ethyl acetate 9: 1). 2.83 g (66% of theory) of product are obtained.

HPLC (method 1): R _t = 4.75 min MS (DCI): m / z = 361 (M + NIL;) ⁺

Example 5A

4- (3-Anιinophenyl) -3,3-dimethyl-4-oxobutanoate

0.85 g (2.46 mmol) of 4- (4-bromo-3-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester are dissolved in 12 ml of degassed ethanol, and 131 mg of palladium on carbon (10%) are added and stirred under a hydrogen atmosphere until reaction control shows complete conversion using analytical HPLC. It is filtered through kieselguhr and the solvent is evaporated. The backlog is in

Ethyl acetate taken up and washed with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulfate. After filtration and concentration of the solvent, 0.52 g (83% of theory) of product is obtained, which is used as a crude product for the further syntheses. HPLC (method 1): R _t = 3.35 min

MS (ESIpos): m / z = 236 (M + H) ⁺ , Example 6A

4-phenyl-2,2-dimethyl-4-oxobutanoic acid

In an argon atmosphere, 23.8 g (178.4 mmol) aluminum trichloride are mixed with 100 ml 1,2-dichloroethane and the suspension obtained is cooled to 0 ° C. in an ice bath. At this temperature, 10 g (78 mmol) of 3,3-dimethyldihydro-2,5-furandione are added dropwise. When the addition is complete, the mixture is stirred at 0 ° C. for a further 10 min and then 5.81 g (74.3 mmol) of benzene are added. The cooling bath is removed and the mixture is stirred at RT for 5 hours. Then it is carefully hydrolyzed with ice and the precipitate formed by adding a little conc. Hydrochloric acid brought back into solution. The phases are separated and the aqueous phase is extracted twice with dichloromethane. The combined organic phases are washed 3 times with water and dried over magnesium sulfate. When the

The solution precipitates a colorless precipitate, which is filtered off and washed with cyclohexane. After drying in vacuo, 12.6 g (82% of theory) of product are obtained. Mp .: 174 ° C HPLC (method 1): R _t = 3.93 min

MS (DCI): m / z = 207 (M + H) ⁺

Example 7A

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

Under an argon atmosphere, 50 ml of fuming nitric acid are cooled to -30 ° C. and then a total of 18.05 g (87.5 mmol) of 4-phenyl-2,2-dimethyl-4-oxobutanoic acid are slowly added in portions. When the addition is complete, the mixture is stirred at -30 ° C. for a further 30 min and then carefully poured onto ice. A colorless precipitate precipitates, which is filtered off, washed with water and then dried in vacuo. 21.6 g (67% of theory) of product are obtained as a mixture of regioisomers (70% of m-product contained). HPLC (method 1): R _t = 4.10 min MS (DCI): m / z = 269 (M + NH

Example 8A

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

1.5 g (6 mmol) 4- (3-nitrophenyl) -2,2-dimethyl-4-oxobutanoic acid (regioisomer mixture) are dissolved in 10 ml methanol and concentrated with a few drops. Sulfuric acid added. The mixture is heated to reflux until the DC control shows complete conversion. The solvent is evaporated, the residue is taken up in ethyl acetate and the organic phase is washed with saturated sodium bicarbonate solution and water. The drying takes place over Magnesium sulfate. After filtration and concentration, the purification is carried out by column chromatography (silica gel: cyclohexane / ethyl acetate 8: 2). 620 mg (33% of theory) of product are obtained. HPLC (method 1): R _t = 4.24 min MS (DCI): m / z = 266 (M + H) ⁺

Example 9A

4- (3-aminophenyl) -2,2-dimethyl-4-oxobutanoate

619 mg (2.33 mmol) of methyl 4- (3-nitrophenyl) -2,2-dimethyl-4-oxobutanoate are dissolved in 10 ml of ethyl acetate, 124 mg of palladium on activated carbon (10%) are added and the mixture is then stirred in a hydrogen atmosphere until DC- Control indicates complete implementation (approx. 5 hours). The mixture is then filtered through Celite, the filtrate is concentrated and the residue is crystallized from cyclohexane / ethyl acetate 7: 3. The precipitate is filtered off and dried in vacuo. This gives 152 mg (23% of theory) of product. HPLC (method 1): R _t = 3.38 min MS (DCI): m / z = 236 (M + H) ⁺ Example 10A

4- (2-Fluoro-5-nitrophenyl) -3, 3-dimethyl-4-oxobutanoic acid, methyl ester

3 g (11.14 mmol) 4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid are concentrated together with a few drops. Sulfuric acid and 15 ml of methanol heated to reflux overnight. The solvent is then evaporated, the residue is taken up in ethyl acetate and the organic phase is washed lx with water and lx with saturated sodium bicarbonate solution. It is dried over magnesium sulfate, then filtered, concentrated and dried in vacuo. 2.85 g (90% of theory) of product are obtained. HPLC (method 1): R _t = 4.62 min MS (DCI): m / z = 301 (M + NH- ^"1"

Example 11A

4- (5-Amino-2-fluorophenyl) -3, 3-dimethyl-4-oxobutanoic acid, methyl ester

2.85 g (10 mmol) of 4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester are dissolved in 15 ml of ethanol. After evacuating and establishing a protective gas atmosphere, 535 mg palladium on activated carbon (10%) are added. The mixture is then stirred under a hydrogen atmosphere until TLC control shows complete conversion (about 3 hours). It is filtered off through Celite and concentrated. This gives 1.9 g (75% of theory) of product which is used as a crude product. General working procedure A: synthesis of ureas

1 equivalent of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester 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 reaction mixture can be washed with saturated ammonium chloride solution. The organic phase is then dried over magnesium sulfate. After filtration and evaporation of the solvent, the purification can be carried out by recrystallization, column chromatography (silica gel: cyclohexane / ethyl acetate 7: 3) or by preparative RP-HPLC.

Examples 12A to 21A are produced according to general working procedure A.

Example 12A

4- [3 - ({[(4-Chloro-2-methylphenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid, methyl ester

Starting with 0.51 g (2.17 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester, 0.41 (2.39 mmol) of 4-chloro-2-methylphenyl isocyanate after crystallization 0.71 g (76 % of theory) Product received.

HPLC (method 1): R _t = 4.80 min MS (ESIpos): m / z = 403 (M + H) ⁺ Example 13A

Methyl 4- [3 - ({[(3-chloro-4-fluorophenyl) amino] carbonyl} amino) phenyl] -3, 3-dimethyl-4-oxobutanoate

Starting from 156 mg (0.66 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid * methyl ester, with 125 mg (0.73 mmol) of 3-chloro-4-fluorophenyl isocyanate 164 mg (61% d. Th.) Product received. HPLC (method 1): R _t = 4.73 min MS (ESIpos): m / z = 407 (M + H) ⁺

Example 14A

Methyl 4- [3 - ({[(3-fluorophenyl) amino] carbonyl} amino) phenyl] -3, 3-dimethyl-4-oxobutanoate

Starting from 156 mg (0.66 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid, methyl ester with 100 mg (0.73 mmol) of 3-fluorophenyl isocyanate 162 mg

(65% of theory) Product received. HPLC (method 1): R _t = 4.56 min MS (ESIpos): m / z = 373 (M + H) ⁺ Example 15A

Methyl 4- [3 - ({[(3-chlorophenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoate

Based on 156 mg (0.66 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid, methyl ester with 197 mg (0.73 mmol) of 3-chlorophenyl isocyanate 197 mg (76% of theory) Received product. HPLC (method 1): R _t = 4.72 min MS (ESIpos): mz = 389 (M + H) ⁺

Example 16A

Methyl 4- [3 - ({[(4-fluoro-2-methylphenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoate

Based on 156 mg (0.66 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester, 110 mg (0.73 mmol) of 4-fluoro-2-methylphenyl isocyanate

178 mg (70% of theory) of product obtained. HPLC (method 1): R _t = 4.52 min MS (ESIpos): m / z = 387 (M + H) ⁺ Example 17A

4- [3 - ({[(1 - Adamantyl) amino] carbonyl} amino) phenyl] -3, 3-dimethyl-4-oxobutanoic acid, methyl ester

110 mg (0.47 mmol)) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester are dissolved in a mixture of 1 ml of THF and 1 ml of DMF, mixed with 91.2 mg (0.51 mmol) of adamantyl isocyanate and for 72 hours heated to 80 ° C. After removing the solvent, it is taken up in DMSO and purified by RP-HPLC. 54.5 mg (28% of theory) of product are obtained. HPLC (method 1): R _t = 5.05 min MS (ESIpos): m / z = 413 (M + H) ⁺

Example 18A

Methyl 4- [3 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) ρhenyl] -2,2-dimethyl-4-oxobutanoate

Starting from 150 mg (0.64 mmol) of 4- (3-aminophenyl) -2,2-dimethyl-4-oxobutanoic acid methyl ester with 117.5 mg (0.70 mmol) of 4-chloro-2-methylphenyl isocyanate in accordance with the general working instructions received 52.6 mg (20% of theory) of product for the synthesis of ureas. HPLC (method 1): R _t = 4.93 min MS (ESIpos): m / z = 403 (M + H) ⁺

Example 19A

Methyl 4- [2-fluoro-5 - ({[l-adamantylamino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutane

100 mg (0.39 mmol) of 4- (5-amino-2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester are combined with 77 mg (0.43 mmol) of 1-adamantyl isocyanate in 2 ml of DMF at 50 ° C stirred overnight. The cleaning is done directly by RP-HPLC. 76.7 mg (45% of theory) of product are obtained. HPLC (method 1): R _t = 5.16 min MS (ESIpos): m / z = 431 (M + H) ⁺

Example 20A

4- [2-Fluoro-5 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester

Starting from 100 mg (0.39 mmol) of 4- (5-amino-2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester, 118 mg are obtained with 73 mg (0.43 mmol) of 4-chloro-2-methylphenyl isocyanate (71% of theory) Product received. HPLC (method 1): R _t = 5.03 min MS (ESIpos): m / z = 421 (M + H) ⁺

Example 21A

Methyl 4- [2-fluoro-5 - ({[(3-fluorophenyl) amino] carbonyl} amino) phenyl] -3, 3-dimethyl-4-oxobutanoate

Starting from 100 mg (0.39 mmol) of 4- (5-amino-2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester with 59.6 mg (0.43 mmol) of 3-fluorophenyl isocyanate

97.4 mg (51% of theory) of product were obtained. HPLC (method 1): R _t = 4.82 min MS (ESIpos): m / z = 391 (M + H) ⁺

Example 22A

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

5.10 g of 2-fluorobenzonitrile are placed in 50 ml of diethyl ether and at 0 ° C. with

25.27 ml of 2-propyl magnesium chloride are added. 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 67.9% (4.8 g). HPLC (method 1): R _t = 4.5 min MS (DCI / NH ₃ ): m / z = 184 (M + NHt) ⁺

Example 23A 4- (2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid

1.75 g of l- (2-fluorophenyl) -2-methyl-l-propanone are dissolved in tetrahydrofuran and 13.00 ml of lithium hexamethyldisilazide are added. After stirring for two hours

3.77 g of ethyl iodoacetate are added dropwise at room temperature. After four hours of stirring at room temperature, 50 ml of 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 + NH ₄ ) ⁺

Example 24A

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

10.0 g of 4- (2-fluorophenyl) -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 + NBL0

Example 25A

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 10 drops of conc. Sulfuric acid added. After 7 hours under

The methanol is refluxed and the residue is saturated with sat. 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 + NH-.) ⁺

Example 26A 5 - (2-Fluoro-5-nitrophenyl) -4,4-dimethyldihydro-2 (3 H) -furan

In 40 ml of methanol / diethyl ether, 4.53 g of 4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester are added at -20 ° C. with 0.73 g of sodium borohydride.

After DC control, acidify with IN hydrochloric acid. Ethyl acetate and water are added and the organic phase is separated off. After washing with saturated sodium chloride solution, drying over magnesium sulfate and distilling off the solvent, the residue is dissolved in 40 ml of dichloromethane and 1.85 ml of TFA are added at room temperature. After 30 min with water and 10 percent. Washed sodium acetate solution and dried over magnesium sulfate. After the solvent has been distilled off, the target product is obtained by recrystallization from diethyl ether / n-pentane in a yield of 3.2 g (79%). HPLC (method 1): R _t = 4.2 min MS (ESI): m / z = 254 (M + H) ⁺ Example 27A

5- (5-amino-2-fluorophenyl) -4,4-dimethyldihydro-2 (3H) -ftιranon

In 90 ml of ethanol, 3.55 g of 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyldihydro- 2 (3H) -fiιran at room temperature with 18.28 g of tin and 75 ml of conc. Hydrochloric acid added. After stirring for one hour under reflux, the solvent is distilled off, ethyl acetate and water are added and the mixture is made basic with sodium bicarbonate. It is suction filtered through Celite and the organic phase with sat. Washed sodium chloride solution. After drying over magnesium sulfate, the product crystallized from the solution in a yield of 2.97 g (95%). HPLC (method 1): R _t = 3.4 min MS (ESI): m / z = 224 (M + H) ⁺

Example 28A

3-Diallylaminobenzonitrile

50 g (423.23 mmol) 3 aminobenzonitrile are dissolved in 1 1 dry tetrahydrofuran. With cooling, 221.2 ml (1270 mmol) of N, N-diisopropylamine and 183.1 ml (2116 mmol) of allyl bromide are added dropwise within 1 hour. When the addition is complete, the mixture is heated to reflux and stirred at reflux for 60 hours. After evaporation of the solvent, the residue is taken up in a mixture of ethyl acetate and water. The aqueous phase is extracted 3 times with ethyl acetate and the combined organic phases are dried over magnesium sulfate. After concentration again, the residue is taken up in methylene chloride and filtered through a frit filled with silica gel. 80 g (95% of theory) of product are obtained, which is used for the next synthesis without further purification. HPLC (method 1): R _t = 4.87 min MS (ESIpos): m / z = 199 (M + H) ⁺

Example 29A 1- [3- (Diallylamino) phenyl] -2-methyl-1-propanone

80 g (403.5 mmol) of 3-diallylaminobenzonitrile are dissolved in 800 ml of dry diethyl ether under an argon atmosphere. At room temperature, 404 ml (807 mmol) of 2-propyl magnesium chloride are added dropwise as a 2 molar solution in diethyl ether. When the addition is complete, the mixture is heated to boiling and stirred under reflux overnight. Allow to cool and then slowly dropwise drop 250 ml of a 10% hydrochloric acid while cooling with ice. The mixture is stirred for a further 30 min and then extracted aqueous phase 3x with diethyl ether. The combined extracts are dried over magnesium sulfate. After evaporation of the solvent, the mixture is dried under high vacuum and 76.7 g (75% of theory) of crude product are obtained, which is used without further purification. HPLC (method 1): R _t = 4.63 min MS (DCI): m / z = 244 (M + H) ⁺

Example 30A

4- (3-Diallylaminophenyl) -3, 3-dimethyl-4-oxobutanoic acid ethyl ester

The LDA solution required to carry out this reaction is freshly prepared. For this purpose, 21.4 ml (153 mmol) of diisopropylamine are dissolved in 25 ml of dry THF under an argon atmosphere and cooled to -20 ° C. At this temperature, 61.2 ml (153 mmol) of n-butyllithium are added dropwise as a 2.5 molar solution. The solution obtained is then stirred for a further 30 min with heating to 0.degree. 12.4 g (51 mmol) of l- [3- (diallylamino) phenyl] -2-methyl-l-propanone are also dissolved in 10 ml of dry THF under an argon atmosphere. After cooling to -78 ° C, the freshly prepared LDA solution is slowly added dropwise. It will be at 1 hour

-78 ° C. before 43.6 g (204 mmol) of ethyl iodoacetate, dissolved in 30 ml of THF, are added dropwise. The mixture is stirred overnight with slow warming to room temperature. The reaction is then hydrolyzed with 1N hydrochloric acid and the product is extracted 3 times with ethyl acetate. The combined organic phases are dried over magnesium sulfate. After filtration and evaporation of the solution the residue is purified by column chromatography (silica gel: petroleum ether / ethyl acetate 95: 5). 7.23 g (37% of theory) of product are obtained. HPLC (method 1): R _t = 4.71 min MS (ESIpos): m / z = 330 (M + H) ⁺

Example 31A

4- (3-aminophenyl) -3,3-dimethyl-4-oxobutansäureethylester

8.27 g (53 mmol) of 1,3-dimethylbarbituric acid, 204 mg (0.18 mmol) of TefraMs (ttiphenylphosphine) palladium (0) and 185 mg (0.71 mmol) of triphenylphosphine in a mixture of 30 ml of toluene and 10 ml of DMF are added under argon solved. This catalyst solution is added to a solution of 2.91 g (8.83 mmol) of ethyl 4- (3-diallylamino-phenyl) -3,3-dimethyl-4-oxobutanoate in 30 ml of toluene. The mixture is stirred at 80 ° C. overnight, then the toluene is evaporated, the residue is taken up in ethyl acetate and washed twice with saturated sodium carbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. Assuming a complete implementation, the crude product is obtained, which is used for further synthesis without further purification.

HPLC (method 1): R _t = 3.69 min MS (DCI): m / z = 250 (M + H) ⁺ Example 32A

1 - [3 - (Diallylamino) phenyl] -3-phenyl-1-propanone

5 g (25.22 mmol) of 3-diallylaminobenzonitrile are dissolved in 50 ml of dry diethyl ether under an argon atmosphere. 25.22 ml (50.44 mmol) of 2-phenylethylmagnisium chloride are then added dropwise as a 2 molar solution in diethyl ether at room temperature. The mixture is heated to reflux for 9 hours. After cooling to room temperature, it is carefully hydrolyzed with 20% hydrochloric acid.

After stirring for 30 min, the phases are separated and the aqueous phase is extracted 3 times with diethyl ether. The combined organic phases are then dried over magnesium sulfate. After filtration and concentration of the solvent, the residue obtained is purified by column chromatography (silica gel: methylene chloride / petroleum ether 5: 1). 3.53 g (46% of theory) of product are obtained.

HPLC (method 1): R _t = 5.30 min MS (DCI): m / z = 306 (M + H) ⁺

Example 33A

3-Benzyl-4- [3- (diallylamino) phenyl] -4-oxobutanoate

A fresh LDA solution is prepared from 1.15 g (11.38 mmol) of diisopropylamine and 4.55 ml of a 2.5 molar n-butyllithium solution in 15 ml of dry THF under an argon atmosphere. In the meantime, 3.16 g (10.35 mmol) are dissolved in 30 ml THF under an argon atmosphere and the solution obtained is cooled to -78 ° C. The Irish-made LDA solution is slowly added dropwise to this solution at -78 ° C. The mixture is stirred for a further hour at -78 ° C. before 4.75 g (31 mmol) of methyl bromoacetate in 15 ml of THF are added dropwise. The reaction mixture is allowed to warm up slowly to room temperature and is stirred for a further 4 hours at RT. Then 14 ml of 1N hydrochloric acid, 70 ml of water and 100 ml of methylene chloride are added. The phases are separated and the aqueous phase is extracted 3 times with methylene chloride. The combined organic phases are dried over magnesium sulfate. After filtration and evaporation of the solvent, the residue is purified by column chromatography (silica gel: cyclohexane / methylene chloride 2: 1 then 1: 1 and finally with pure methylene chloride). 1.17 g (28% of theory) of product are obtained.

HPLC (method 1): R _t = 5.11 mhϊ MS (ESIpos): m / z = 378 (M + H) ⁺ Example 34A

4-Ben- ^ 1-5 [3- (diallyIamino) phenyl] d ydro-2 (3H) -furanone

823.4 mg (2.18 mmol) of methyl 3-benzyl-4- [3- (diallylamino) phenyl] -4-oxobutanoate are dissolved in 4 ml of methanol and 4 ml of diethyl ether and cooled to 0 ° C. Now 90.8 mg (2.4 mmol) of solid sodium borohydride are added. The mixture is allowed to warm slowly to room temperature and is stirred overnight. The solvents are evaporated and the residue is washed with 1N hydrochloric acid,

Water and ethyl acetate are added. The aqueous phase is extracted twice with ethyl acetate and then the combined organic phases are dried over magnesium sulfate. The cleaning is done by RP-ΗPLC. 383.2 mg (49% of theory) of product are obtained as a mixture of diastereomers, which is not separated into the diastereomers.

ΗPLC (method 1): R _t = 4.52 min MS (ESIpos): m / z = 348 (M + Η) ⁺ Example 35A

5- (3-Ammophenyl) -4-benzyldihydro-2 (3H) -furanone

433 mg (1.25 mmol) of 4-benzyl-5- [3- (diallylamino) phenyl] dihydro-2 (3H) -furanone are dissolved in 2 ml of dry TΗF and mixed with a solution of 14.4 mg (0.01 mmol) of tetrakis (ttiphenylphosphine) palladium (0) and 584 mg (3.74 mmol) 1,3-dimethylbarbituric acid in 2 ml TΗF. It is heated to reflux for 20 hours. Since the conversion is not yet complete, another 14 mg of palladium catalyst are added and the mixture is heated to boiling for a further 2 hours. The solvent is then removed, the residue is dissolved in 20 ml of ethyl acetate and the organic phase is washed 3 times with 10 ml of saturated sodium hydrogen carbonate solution. The organic phases are dried over magnesium sulfate and, after filtration, concentrated and dried. This gives 487 mg (93% of theory) of crude product which is used for the next syntheses without further purification. ΗPLC (method 1): R _t = 3.67 min MS (DCI): m / z = 285 (M + NΗ- ⁺ embodiments

General working procedure B: synthesis of the lactones

Analogous to a regulation by A. L. Gutman, K. Zuobi, T. Bravdo, J. Org. Che. 1990, 55, 3546-3552, 1 equivalent of the 4-oxo compound to be reacted is dissolved in a 1: 1 mixture of diethyl ether and methanol. The mixture is cooled to 0 ° C. in an ice bath and then 1 equivalent of solid sodium borohydride is added (for larger batches, the sodium borohydride is dissolved in water). The mixture is stirred at 0 ° C. until the TLC check indicates complete conversion, then IN hydrochloric acid is added, diluted with water and then extracted 3 times with ethyl acetate. The combined organic phases are then washed with saturated sodium bicarbonate solution and water, then dried over magnesium sulfate. After filtration and removal of the solvent, the residue obtained is purified by preparative RP-HPLC.

Examples 1 to 10 are produced according to general working procedure B.

example 1

N- (4-Chloro-2-methylphenyl) -N '- [3- (3,3-dime yl-5-oxotettahydro-2-furanyl) phenyl] urea

Starting from 650 mg (1.61 mmol) of 4- [3 - ({[(4-chloro-2-methylphenyl) amino] - carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester with 62 mg (1.61 mmol) sodium borohydride in 0.22 ml water 426 mg (71% of theory)

Received product. HPLC (method 1): R _t = 4.81 min MS (ESIpos): m / z = 373 (M + H) ⁺

1H-NMR (200 MHz, DMSO): δ = 0.63 (s, 3H), 1.21 (s, 3H), 2.24 (s, 3H), 2.41 (d, IH), 2.74 (d, IH), 5.28 (s , IH), 6.87 (d, IH), 7.19 (dd, IH), 7.27 (m, IH), 7.33 (d, IH), 7.42 (m, IH), 7.90 (d, IH), 7.96 (s, IH), 9.20 (s, IH)

Example 2

N- (3-Fluoι Jhenyl) -N '- [3- (3,3-dimemyl-5-oxotettahydro-2-fiαranyl) phenyl] urea

Starting from 142 mg (0.38 mmol) of 4- [3 - ({[(3-fluorophenyl) amino] carbonyl} - amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester with 14 mg (0.38 mmol) of sodium borohydride 104 mg (80% of theory) of product were obtained. HPLC (method 1): R _t = 4.58 min MS (ESIpos): m / z = 343 (M + H) ⁺

Example 3

N- (3-Chlorophenyl) -N - [3 - (3,3-dimethyl-5-oxotetrahydro-2-furanyl) phenyl] urea

Starting from 170 mg (0.44 mmol) of 4- [3 - ({[(3-chlorophenyl) amino] carbonyl} - amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester with 17 mg (0.44 mmol) of sodium borohydride 119 mg (76% of theory) were obtained. HPLC (method 1): R _t = 4.41 min MS (ESIpos): m / z = 359 (M + H) ⁺

Example 4

N- (4-Fluoro-2-ylphenyl) -N '- [3- (3,3-dimemyl-5-oxotettahydro-2-furanyl) phenyl] urea

Starting from 154 mg (0.40 mmol) of 4- [3 - ({[(4-fluoro-2-methylphenyl) amino] - carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester, 15 mg (0.40 mmol) sodium borohydride 85 mg (60% of theory) of product.

HPLC (method 1): R _t = 4.38 min MS (ESIpos): m / z = 357 (M + H) ⁺

Example 5 N- (3-Cωor-4-fluorophenyl) -N '- [3- (3,3-dimemyl-5-oxotettahydro-2-furanyl) phenyl] urea

Starting from 153 mg (0.38 mmol) of 4- [3 - ({[(3-chloro-4-fluoromethylphenyl) amino] - carbonyl} -amino) phenyl] -3, 3-dimethyl-4-oxobutanoic acid methyl ester with 14 mg (0.38 mmol) sodium borohydride 81 mg (57% of theory) of product. HPLC (method 1): R _t = 4.62 min MS (ESIpos): m / z = 377 (M + H) ⁺

Example 6 '

N- (l-Adaman1yl) -N '- [3- (3,3-dimemyl-5-oxotettahydro-2-furanyl) phenyl] -urea

Starting from 47.3 mg (0.11 mmol) of 4- [3 - ({[(l-adamantyl) amino] carbonyl} - amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester with 4.5 mg (0.11 mmol) of sodium borohydride 36.5 mg (83% of theory) of product obtained.

HPLC (method 1): R _t = 4.93 min MS (ESIpos): m / z = 383 (M + H) ⁺

Example 7 N- (4-Chloro-2-methylρhenyl) -N '- [3- (2,2-dimethyl-5-oxotetrahydro-2-furanyl) phenyl] urea

Starting from 52.6 mg (0.13 mmol) of 4- [3 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) phenyl] -2,2-dimethyl-4-oxobutanoic acid methyl ester are mixed with 5 mg (0.13 mmol) sodium borohydride 20.5 mg (42% of theory) of product. HPLC (method 1): R _t = 4.81 min

MS (ESIpos): m / z = 373 (M + H) ⁺

Example 8

N- (4-Chloro-2-ylphenyl) -N '- [3- (3,3-dimemyl-5-oxote1ϊahydro-2-furanyl) -4-fluorophenyl urea

Starting from .117 mg (0.28 mmol) of 4- [2-fluoro-5 - ({[(4-chloro-2-methylphenyl) - amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester obtained with 10.5 mg (0.28 mmol) sodium borohydride 40.7 mg (37% of theory) of product.

HPLC (method 1): R _t = 4.88 min

MS (ESIpos): m / z = ^' 391 (M + H) ⁺

1H-NMR (200 MHz, DMSO): δ = 0.74 (s, 3H), 1.21 (d, 3H), 2.23 (s, 3H), 2.45 (d, IH), 2.76 (d, IH), 5.55 (s , IH), 7.15-7.28 (m, 3H), 7.39-7.52 (m, 2H), 7.82 (d ,. IH),

7.94 (s „lH), 9.22 (s, IH) Example 9

N- [3- (3,3-Dimemyl-5-oxotettahydro-2-furanyl) -4-fluorophenyl] -N '- (3-fluorophenyl) urea

Starting from 97 mg (0.20 mmol) of 4- [2-fluoro-5 - ({[(3-fluorophenyl) amino] carbonyl} - amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester, 7.5 mg (0.20 mmol) of sodium borohydride 40 mg (56% of theory) of product. HPLC (method 1): R _t = 4.67 min MS (ESIpos): m / z = 361 (M + H) ⁺

Example 10

N- (1 -Adamantyl) -N'- [3 - (3,3-dimethyl-5-oxotettahydro-2-furanyl) -4-fluorophenyl] urea

Starting from 63 mg (0.15 mmol) of 4- [2-fluoro-5 - ({[l-adamantylamino] carbonyl} - amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester, 5.5 mg

(0.15 mmol) sodium borohydride 10.5 mg (18% of theory) of product. 1H-NMR (200 MHz, DMSO): δ = 0.72 (s, 3H), 1.92 (d, 3H), 1.63 (s _br , 6H), 1.92 (s _br , 6H), 2.02 (s _br , 3H), 2.43 (d, IH), 2.79 (d, IH), 5.50 (s, IH), 5.79 (s, IH), 7.27 (m, 2H), 7.35 (dd, IH), 8.41 (s, IH).

Example 11

N- (4-Cyano-2-methylphenyl) -N'- [3 - (3, 3-dimethyl-5-oxotetrahydro-2-furanyl) -4-fluorophenyl urea

In 20 ml of dichloromethane, 0.67 g of 5- (5-amino-2-fluorophenyl) -4,4-dimethyldihydro-2 (3H) -furanone are stirred with 0.57 g of 4-isocyanato-2-methylbenzonitrile under reflux for one hour and then Purified over silica gel (cyclohexane / ethyl acetate 3/1; 2/1). 1.02 g (89%) of the target compound are obtained. HPLC (method 1): R _t = 4.6 min MS (ESI): m / z = 382 (M + H) ⁺ Example 12

N- (4-Cyano-2-methylphenyl) -N '- [3- (3,3-dimethyl-5-oxotetrahydro-2-furanyl) -4-fluorophenyl urea

After chromatographic separation of the enantiomers of example 11 (method 2), 154 mg (31%) of enantiomer B are obtained. HPLC (method 2): R _t = 4.62 min MS (ESI): mz = 382 (M + H) ⁺

Example 13

N- (4-Fluoro-2-methylphenyl) -N '- [3- (3,3-dimemyl-5-oxotettahydro-2-furanyl) -4-fluorophenyl] urea

0.67 g of 5- (5-amino-2-fluorophenyl) -4,4-dimethyldihydro-2 (3H) -furanone is dissolved in 10 ml of dichloromethane, and 0.54 g of 4-fluoro-2-methylphenyl isocyanate is added. After one hour under reflux, the product crystallizes out by adding 10 ml of diethyl ether and, after drying, is obtained in a yield of 1.1 g (98%).

HPLC (method 1): R _t = 4.6 min MS (ESI): m / z = 375 (M + H) ⁺

Example 14

N- (4-Fluoro-2-methylphenyl) -N'- [3 - (3, 3-dimethyl-5-oxotetrahydro-2-furanyl) -4-fluorophenyl urea

After chromatographic separation of the enantiomers of compound from Example 13 (Method 3), 157 mg (31%) of Entiomer B are obtained. HPLC (method 2): R _t = 4.5 min MS (ESI): m / z = 375 (M + H) ⁺

The examples listed in Table 1 are prepared analogously to the examples listed above.

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 cytopathogenicity tests

The test compounds are used as 50 millimolar (mM) solutions in dimethyl sulfoxide (DMSO). Ganciclovir, foscarnet and cidofovir serve as reference compounds. After adding 2 μl each of the 50, 5, 0.5 and 0.05 mM

DMSO stock solutions with 98 μl cell culture medium in the 2 AH series in duplicate are carried out 1: 2 dilutions with 50 μl medium each up to the 11 series of 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 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 fixed by adding a mixture of formalin and Giemsa's dye and colored (30 minutes), with aqua bidest. washed and dried in a drying cabinet at 50 ° C. Then the plates are visually evaluated with an overhead microscope (plaque multiplier from Technomara).

The following data can be obtained from the test plates:

CC ₅₀ (NHDF) = substance concentration in μM at which no visible cytostatic effects on the cells can be seen compared to the untreated cell control; EC50 (HCMV) = substance concentration in μM that 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 Xeno _g raft-GeIfoam ^® -ModeIl

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). The animals are kept in isolators under sterile conditions (including litter and feed).

Virus Growing:

Human cytomegalovirus (HCMV), DavisSmith strain, is grown in vitro on human embryonic foreskin fibroblasts (NHDF cells). After infection of the

NHDF cells with an infection multiplicity (MOI) of 0.01, the virus-infected cells are harvested 5-7 days later and in the presence of Minimal Essential Medium (MEM), 10% Fetal Calf Serum (FCS) with 10% DMSO at -40 ° C stored. 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 ^ft Interscience Conference on Anti-microbial 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 × 10 ⁶ virus-infected NHDF cells (infection with HCMV-Davis MOI = 0.01) are detached 3 hours after infection and dropped onto a moist sponge in 20 μl MEM, 10% FCS. 12-13

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, the dorsal coat removed with the help of a dry razor, the epidermis opened 1-2 cm, relieved and the moist sponges transplanted under the dorsal skin. The surgical wound is closed with tissue glue. 24 hours after the transplant the mice were treated orally with substance three times a day for 8 days (7 a.m. and 2 p.m. and 7 p.m.). The dose is 7 or 15 or 30 or 60 mg / kg body weight, the application volume 10 ml / kg body weight. The substances are formulated in the form of a 0.5% tylose suspension with 2% DMSO. 9 days after the transplant and 16 hours after the last one

^'' Substance application kills the animals painlessly and removes the sponge. The virus-infected cells are released from the sponge by collagenase digestion (330 U / 1.5 ml) and stored at -140 ° C. in the presence of MEM, 10% fetal calf serum, 10% DMSO. The evaluation takes place 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 Neutrahot. The number of infectious virus particles after substance treatment compared to the placebo-treated control group is determined.

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 of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg of 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 compressed with a conventional tablet press (tablet format see above). A pressing force of 15 kN is used as a guideline for the pressing.

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 present compound ^'correspond to 10 ml of oral suspension.

Manufacturing: ^•

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.

Claims

Patentansprtiche

1. Compounds of the formula

in which

the remainder -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 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, C C-3-

Alkoxy, C _ö -Cio-aryl, amino and CrC 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 selected from the group consisting of halogen, hydroxy, _Cι-C6 alkyl, Ci-C ₆ alkoxy, C ₆ amino -Cι ₀ aryl, amino and Ci-C ₆ alkyl, R ^{2 stands} for C ₃ -Cio-cycloalkyl or C ₆ -Cιo-aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, nitro,

Cyano, -C ₆ alkoxy, hydroxycarbonyl, -C ₆ alkoxycarbonyl, amino, -C ₆ alkylamino. Ci-C _ö alkylaminocarbonyl and Cι-C ₆ -

Alkyl,.

R ^{3 represents} hydrogen or CC _δ- alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, hydroxy, C ₁ -C ₆ -

Alkoxy, C _ö -Cio aryl, amino and CrC _ö alkylamino,

or

R and R 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 selected from the group consisting of from halogen, hydroxy, CrC ₆ -alkyl, CrCβ-alkoxy, C ₆ -Cιo-aryl, amino and CrC _ό -alkyl-amino,

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, -C ₆ -alkoxy, C ₆ -C ₁₀ aryl, amino and CrC ₆ alkylamino,

R ^{5 represents} hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ -alkoxy, carboxy, C ₁ -C ₆ -alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkylaminocarbonyl, amino, -C _Ö - alkylamino or C ₁ -C ₆ -alkyl , R ⁶ 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 fluorine, chlorine, hydroxyl, Cι-C ₆ - alkoxy, C ₆ -Cιo-aryl, amino and Ci-C _ö alkylamino,

and

R ¹ , R ³ , R ⁴ and R ^{6 are} not simultaneously hydrogen.

2. Compounds according to claim 1, wherein

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

D stands for oxygen,

R ^{1 stands} for Ci-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 _! -C ₆ alkoxy, C ₆ -Cι ₀ aryl, amino, and Cι-C ₆ -alkylamino,

R ^{2 represents} C ₃ -C ₁₀ cycloalkyl or C ₆ -Cι ₀ 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 stands} for 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 ₆ -alkoxy, C ₆ -C _10- aryl, amino and Ci-Ce-alkylamino, R ⁴ represents C ₁ -C 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 ₁ -C ₆ -alkoxy, C ₆ -Cιo-aryl , Amino and Ci-Cö-alkylamino,

R ^{5 represents} hydrogen, halogen, hydroxy, amino, Ci-Cö-alkylamino or Ci-Cβ-al yl,

R ^{6 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 ₆ -C alkoxy, C _ö -Cio -Aryl, amino and dC _ö alkylamino.

3. Compounds according to claim 1, wherein

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

D stands for oxygen,

R ^{1 represents} dC _ö alkyl,

R ^{2 represents} phenyl or adamantyl, 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 C ₁ -C ₆ alkyl,

R ^{3 represents} hydrogen,

R ^{4 represents} dC _ö alkyl, R ^{5 represents} hydrogen, hydroxy, fluorine, chlorine or methyl,

R ^{6 represents} hydrogen.

4. Verbindungsimgen according to claim 1, 2 or 3, wherein the rest -NHC (D) NHR ² is bound via the position 3 to the aromatics.

5. Compounds according to claim 1, 2 or 3, wherein R ^{5 is} hydrogen.

6. Compounds according to claim 1, 2 or 3, wherein R ^{5 is} hydroxy, fluorine, chlorine or methyl and is bonded via the 6 position to the aromatics.

7. Compounds according to claim 1, 2 or 3, wherein D represents oxygen.

8. Compounds according to claim 1, 2 or 3, wherein R ^{1 is} methyl.

9. Compounds according to claim 1, 2 or 3, wherein 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.

10. Compounds according to claim 1, 2 or 3, wherein R ^{3 is} hydrogen.

11. Compounds according to claim 1, 2 or 3, wherein R ^{4 is} methyl.

12. Compounds according to claim 1, 2 or 3, wherein R ^{4 is} benzyl.

13. Compounds according to claim 1, 2 or 3, wherein R ^{6 is} hydrogen.

14. Compounds according to claim 1, 2 or 3, wherein R ¹ and R ^{4 are} methyl.

15. A process for the preparation of compounds according to claim 1, characterized in that according to process [A] compounds of the formula

in which

-NHC (D) NHR> 2 is bound to the aromatics via one of the positions 2, 3, 5 or 6,

D, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 have} the meaning given in Claim 1, and

R ^{7 represents} alkyl, preferably methyl or ethyl,

be implemented with reducing agents

or

that according to method [B] compounds of the formula

in which

-NH ₂ is bound to the aromatics via one of the positions 2, 3, 5 or 6, and

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

with compounds of the formula

D = C = N-FΓ (IV) in which

D and R ^{2 have} the meaning given in claim 1,

be implemented.

16. Compounds according to any one of claims 1 to 3 for the treatment and / or prophylaxis of viral diseases.

17. Medicament containing at least one compound according to one of claims 1 to 3 in combination with at least one pharmaceutically acceptable, pharmaceutically acceptable carrier or excipient.

18. Use of compounds according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment and or prophylaxis of viral diseases.

19. Medicament according to claim 17 for the treatment and / or prophylaxis of viral diseases.

20. A method for combating viral diseases in humans and animals by administering an antivirally effective amount of at least one compound according to one of claims 1 to 3.