DE10217518A1 - lactones - Google Patents

Abstract

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.

Description

The invention relates to lactones and processes for their preparation and their Use for the manufacture of medicaments for treatment and / or prophylaxis 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 Medium. However, resistance can develop regularly. New Means for effective therapy are therefore desirable.

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

Surprisingly, it has been found that in the present invention Lactones described are antiviral.

The present invention relates to compounds of the formula


in which
the rest -NHC (D) NHR ² is bound to the aromatic system via one of the positions 2, 3, 5 or 6,
D represents oxygen or sulfur,
R ^{1 represents} hydrogen or C ₁ -C 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 ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C 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, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ^{2 represents} C ₃ -C ₁₀ cycloalkyl or C ₆ -C ₁₀ 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 ₁ -C ₆ alkoxy, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl and C ₁ -C ₆ alkyl,
R ^{3 is} hydrogen C ₁ -C ₆ 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 -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, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ^{4 represents} hydrogen or C ₁ -C 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 ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ⁵ for hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ alkoxy, carboxy, C ₁ -C ₆ alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, amino, C ₁ -C ₆ - alkylamino or C ₁ -C ₆ alkyl.
R ^{6 represents} hydrogen or C ₁ -C ₆ 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 -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino, 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 be in Stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or diastereomers and their respective mixtures.

From such mixtures of enantiomers and / or diastereomers, the Isolate 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, salts which are physiologically acceptable are the salts Compounds of the invention preferred.

Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. B. 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 (I) also include salts more commonly Bases, such as, by way of example and by way of preference, alkali metal salts (e.g. sodium and Potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and Ammonium salts, derived from ammonia or organic amines with 1 to 16 carbon atoms, such as by way of example and preferably ethylamine, diethylamine, triethylamine, Ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclo-hexylamine, Dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, Dehydroabietylamine, arginine, lysine, ethylenediamine and methylpiperidine.

Such forms of the compounds are considered as solvates in the context of the invention referred to, which in the solid or liquid state by coordination with Solvent molecules form a complex. Hydrates are a special form of solvate, where 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 stand for 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 alkyl substituents selected from one another, by way of example and preferably for methylamino, Ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n- Hexylamino, N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N- Methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.

Alkylaminocarbonyl represents an alkylaminocarbonyl 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, N-dimethylaminocarbonyl, N, N-diethylaminocarbonyl, N-ethyl-N- methylaminocarbonyl, N-methyl-N-n-propylaminocarbonyl, N-isopropyl-N-n-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-N-n-pentylaminocarbonyl and N-n-hexyl-N-methylaminocarbonyl.

Alkoxycarbonyl is exemplary and preferably methoxycarbonyl, Ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Cycloalkyl stands for a cycloalkyl group with usually 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 in 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. Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the O, N and S series, 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 formula (I) are preferred, wherein
the remainder -NHC (D) NHR ² is bound to the aromatic system via position 3,
D stands for oxygen,
R ^{1 stands} for C ₁ -C ₆ alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, C ₁ -C ₆ alkoxy, C ₆ -C _10- aryl, amino and C ₁ -C ₆ -alkylamino,
R ^{2 represents} C ₃ -C ₁₀ cycloalkyl or C ₆ -C ₁₀ aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and C ₁ -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, hydroxy, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ^{4 stands} for 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 -C _10- aryl, amino and C ₁ -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 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 -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino.

Also preferred are compounds of formula (I), wherein
the remainder -NHC (D) NHR ² is bound to the aromatic system via position 3,
D stands for oxygen,
R ^{1 represents} C ₁ -C ₆ 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} C ₁ -C ₆ alkyl,
R ^{5 represents} hydrogen, hydroxy, fluorine, chlorine or methyl, and
R ^{6 represents} hydrogen.

Also preferred are compounds of formula (I), wherein
the rest -NHC (D) NHR ² is bound to the aromatic system via position 3.

Compounds of the formula (I) are furthermore preferred, where R ^{5 is} hydrogen.

Preference is furthermore given to compounds of the formula (I) where R ^{5 is} hydroxyl, fluorine, chlorine or methyl and is bonded to the aromatics via position 6.

Preference is furthermore given to compounds of the formula (I) in which D stands for oxygen.

Compounds of the formula (I) are furthermore preferred, where R ^{1 is} methyl.

Preference is furthermore given to compounds of the formula (I) where R ^{2 is} adamantyl or phenyl, where phenyl can be substituted by 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano and methyl.

Compounds of the formula (I) are furthermore preferred, where R ^{3 is} hydrogen.

Compounds of the formula (I) are furthermore preferred, where R ^{4 is} methyl.

Preference is furthermore given to compounds of the formula (I), where R ^{4 is} benzyl.

Compounds of the formula (I) are furthermore preferred, where R ^{6 is} hydrogen.

Compounds of the formula (I) are furthermore preferred, where R ¹ and R ^{4 are} methyl.

Those in the respective combinations or preferred combinations of residues radical definitions specified in detail are independent of the respective specified combinations of the residues arbitrarily also by residue definitions other combination replaced.

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

The invention further relates to processes for the preparation of the compounds of the formula (I), 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 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

DCN-R ² (IV)

in which
D has the meaning given above,
be implemented.

The reaction according to process [A] is generally carried out in an inert manner Solvents, preferably in a temperature range from -10 ° C to room temperature 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, 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.

Reducing agents are, for example, sodium borohydride, lithium borohydride, Tetrabutylammonium borohydride or sodium cyanoborohydride, preferred Sodium borohydride.

The reaction according to process [B] is generally carried out in an inert manner Solvents, if appropriate in the presence of a base, preferably in a Temperature range from room temperature to the reflux of solvents at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as Methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 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, 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 are preferred Diisopropylethylamine and triethylamine.

The compounds of formula (IV) are known or can be made according to known ones Synthesize processes from the corresponding starting materials.

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 ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 have} the meaning given above,
be reacted with compounds of the formula (IV).

The reaction is generally carried out according to that described in process [B] Conditions.

The compounds of formula (III) can be prepared by compounds of 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 , R ⁶ and R ^{7 have} the meaning given above,
be reduced, e.g. B. 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 normal pressure up 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 are preferred are ethanol, iso-propanol, ethyl acetate or in the case of tin dichloride Dimethylformamide 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 ⁷ -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 formula (VII), optionally in the presence of an acid, preferably in a temperature range from room temperature to the reflux of the solvents 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, ethyl acetate or pyridine, ethanol or are preferred Methanol.

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

The compounds of formula (VII) are known or can be made according to known ones Synthesize processes from the corresponding starting materials.

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 ¹ , R ³ , R ⁴ and R ^{6 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, carbon tetrachloride, 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 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, aluminum trichloride is preferred.

The compounds of the formulas (IX) and (X) are known or can be reduced synthesize known processes from the corresponding starting materials.

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 , R ⁶ and R ^{7 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, if appropriate in Presence of a base, preferably in a temperature range from -78 ° C to Room temperature 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, hydrocarbons such as benzene, ethylbenzene, xylene, Toluene, preferably tetrahydrofuran or toluene.

Bases are, for example, amides such as sodium amide, lithium hexamethyl disilazide, Potassium hexamethyl disilazide, lithium diisopropylamide, or other bases such as Sodium hydride, DBU or diisopropylethylamine, preferably sodium amide, Lithium hexamethyl disilazide, potassium hexamethyl disilazide or lithium diisopropylamide.

The compounds of the general formulas (XVIII) and (XIX) are known or can be synthesized from the corresponding starting materials by known processes (for (XVIII) see M. R. 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 ¹ , R ³ , R ⁴ , R ⁵ and R ^{7 have} the meaning given above, are reacted 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 ³ , R ⁴ , R ⁵ and R ^{7 have} the meaning given above, are 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, carbon tetrachloride, 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 (XII) can be prepared by compounds of the formula


in which
R ^{5 has} the meaning given above,
with compounds of the formula (XIV),


in which
R ¹ , R ³ , R ⁴ and R ^{7 have} the meaning given above, are implemented.

The reaction is generally carried out in inert solvents, if appropriate in Presence of a base, preferably in a temperature range from -78 ° C to Room temperature 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, 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 ethanolate 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 is preferred Lithium.

The compounds of formula (XIV) are known or can be made according to known ones Synthesize processes from the corresponding starting materials.

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


in which
R ^{5 has} the meaning given above,
be reacted with trimethylsilyl cyanide and zinc iodide.

The reaction is optionally carried out in inert solvents, preferably in one 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, carbon tetrachloride, 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, Cyclohexane or petroleum fractions, or other solvents such as dimethylformamide, Dimethylacetamide, dimethyl sulfoxide, acetonitrile or pyridine is preferred Tetrahydrofuran.

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, are reduced, for. B. 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 Compounds of formula (V) according to the conditions described in process [A] be implemented.

In an alternative synthetic method, compounds of formula (III) 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, are reacted with 1,3-dimethylbarbituric acid, triphenylphosphine and tetrakis (triphenylphosphine) palladium (0).

The reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at normal 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 prepared according to the formula (VIII) described alternative synthetic methods or known methods from the synthesize corresponding N, N-diallylamino-substituted starting materials.

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 β-dimethyllactones

Synthesis Scheme 3 Synthesis of α-dimethyllactones

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

The compounds of general formula (I) can because of their particular Properties for the manufacture of medicinal products for prophylaxis or Treatment of diseases, especially viral diseases, are used become.

• 1. Behandlung und Prophylaxe von HCMV-Infektionen bei AIDS-Patienten (Retinitis, Pneumonitis, gastrointestinale Infektionen).
• 2. Behandlung und Prophylaxe von Cytomegalovirus-Infektionen bei Knochenmark- und Organtransplantationspatienten, die an einer HCMV-Pneumonitis, -Enzephalitis, sowie an gastrointestinalen und systemischen HCMV-Infektionen oft lebensbedrohlich erkranken.
• 3. Behandlung und Prophylaxe von HCMV-Infektionen bei Neugeborenen und Kleinkindern.
• 4. Behandlung einer akuten HCMV-Infektion bei Schwangeren.
• 5. Behandlung der HCMV-Infektion bei immunsupprimierten Patienten bei Krebs und Krebs-Therapie.

Because of 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 can 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 agents such as Gancyclovir or Acyclovir used become.

The present invention furthermore relates to medicaments which at least a compound according to the invention, preferably together with an or contain several pharmacologically acceptable auxiliaries or carriers, and their use for the aforementioned purposes.

The active substance can act systemically and / or locally. For this purpose, he can be applied in a suitable manner, such as. B. 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 be administered.

Known active ingredients are quick and / or suitable for oral administration modified dispensing application forms, such as. B. tablets (uncoated as well as coated tablets, e.g. B. provided with enteric coatings Tablets or film-coated tablets), capsules, coated tablets, granules, pellets, powder, Emulsions, suspensions, solutions and aerosols.

Parenteral administration can be done by bypassing an absorption step happen (intravenously, intraarterially, intracardially, intraspinally or intralumbally) or with absorption (intramuscular, subcutaneous, intracutaneous, percutaneous, or intraperitoneally). For parenteral administration are suitable as Application forms and. a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates and sterile powders.

For the other application routes, z. B. Inhalation Drugs (et al. Powder inhalers, nebulizers), nose drops / solutions, sprays; lingual, sublingual or buccal tablets or capsules, suppositories, ear and Eye preparations, vaginal capsules, aqueous suspensions (lotions, Shake mixes), lipophilic suspensions, ointments, creams, milk, pastes, powder or Implants.

The active substances can be incorporated into the listed substances in a manner known per se Application forms are transferred. This is done using inert non-toxic, pharmaceutically suitable excipients. These include u. a. 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 Amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg Body weight for effective results, and oral Application is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg Body weight.

Nevertheless, it may be necessary from the amounts mentioned deviate, depending on body weight, application route, individual behavior towards the active ingredient, type of preparation and Time or interval at which the application takes place. So it may be in some Cases are sufficient, with less than the aforementioned minimum amount get along, 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 store them in to distribute several single doses throughout the day.

The percentages in the following tests and examples are, unless otherwise stated, 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 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
ges. 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
proc. percent
NMR nuclear magnetic resonance proc. percent
RP-HPLC reverse phase HPLC
RT room temperature
R _t 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 mlmin ^-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 6371 (250.20); Temperature: 23 ° C; eluent: ethyl acetate; Compound dissolved in ethyl acetate.

Method 3

Pillar: 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 Alliance 2790 LC; Column: Symmetry C18, 50 mm × 2.1, 3.5 µm; 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 nm. 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] butanoic acid methyl ester

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 minutes, a solution of 2.48 g (21.11 mmol) of methyl 3-methyl-2-butenate 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 for a further 10 min at room temperature. After the phases have been separated, the mixture 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 4- (4-bromophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester

Under an argon atmosphere, 8.65 g of methyl 4- (4-bromophenyl) -4-cyano-3,3-dimethyl-4- [trimethylsilyl) oxy] butanoate (crude product) are dissolved in 87 ml of dry tetrahydrofuran and the solution in an ice bath at 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., 75 ml of water are added and the mixture is extracted 3 × 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-oxobutanoic acid methyl ester

6 ml of fuming nitric acid are cooled to -30 ° C. under argon 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 at -30 ° C for 1 hour before pouring onto ice and extracted 3 × with dichloromethane. The combined organic extracts are dried over magnesium sulfate. After filtration and evaporation of the solvent, it 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 + NH ₄ ) ⁺ Example 5A methyl 4- (3-aminophenyl) -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, 131 mg of palladium on carbon (10%) are added and the mixture is kept under stirred in a hydrogen atmosphere until reaction control using analytical HPLC indicates complete conversion. It is filtered through diatomaceous earth and the solvent is evaporated. The residue is taken up in ethyl acetate 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) of aluminum trichloride are mixed with 100 ml of 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 2 × with dichloromethane. The combined organic phases are washed 3 × with water and dried over magnesium sulfate. When the solution is concentrated, a colorless precipitate precipitates, 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. After the addition has ended, the mixture is stirred at -30 ° C. for a further 30 min and then carefully poured onto ice. A colorless precipitate is formed, 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 ₄ ) ⁺ Example 8A 4- (3-nitrophenyl) -2,2-dimethyl-4-oxobutanoic acid methyl ester

1.5 g (6 mmol) of 4- (3-nitrophenyl) -2,2-dimethyl-4-oxobutanoic acid (regioisomer mixture) are dissolved in 10 ml of 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-oxobutanoic acid methyl ester

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). Then it is filtered off through Celite, the filtrate is concentrated and 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 off, the residue is taken up in ethyl acetate and the organic phase is washed 1 × with water and 1 × 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 ₄ ) ⁺ Example 11A 4- (5-Amino-2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester

2.85 g (10 mmol) Methyl 4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoate are dissolved in 15 ml ethanol. After evacuating and establishing one A protective gas atmosphere is added to 535 mg palladium on activated carbon (10%). The mixture is then stirred under a hydrogen atmosphere until DC- Control shows complete sales (approx. 3 hours). It is about Celite filtered off and concentrated. In this way 1.9 g (75% of theory) of product are obtained, which as Raw product is used.

General working instructions A Synthesis of ureas

1 equivalent of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester is in Ethyl acetate dissolved (0.1-0.25 M solution) and with 1.1 equivalents of corresponding isocyanates added. The reaction mixture is at room temperature stirred overnight. The reaction mixture can be saturated Ammonium chloride solution. The organic phase is then over Magnesium sulfate dried. After filtration and evaporation of the solvent, the Purification by recrystallization, column chromatography (silica gel: Cyclohexane / ethyl acetate 7: 3) or by preparative RP-HPLC become.

Examples 12A to 21A are produced according to general working procedure A. Example 12A Methyl 4- [3 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoate

Starting from 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 . Th.) Product received.
HPLC (method 1): R _t = 4.80 min
MS (ESIpos): m / z = 403 (M + H) ⁺ Example 13A 4- [3 - ({[(3-chloro-4-fluorophenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl- 4-oxobutanoic acid methyl ester

Starting from methyl methyl 156 mg (0.66 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoate, 164 mg (61% of theory) are obtained with 125 mg (0.73 mmol) of 3-chloro-4-fluorophenyl isocyanate .) Product received.
HPLC (method 1): R _t = 4.73 min
MS (ESIpos): m / z = 407 (M + H) ⁺ Example 14A 4- [3 - ({[(3-fluorophenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid- methylester

Starting from methyl methyl 156 mg (0.66 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoate, 162 mg (65% of theory) of product are obtained with 100 mg (0.73 mmol) of 3-fluorophenyl isocyanate ,
HPLC (method 1): R _t = z 4.56 min
MS (ESIpos): m / z = 373 (M + H) ⁺ Example 15A 4- [3 - ({[(3-chlorophenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid- methylester

Starting from methyl methyl 156 mg (0.66 mmol) of 4- (3-aminophenyl) -3,3-dimethyl-4-oxobutanoate, 197 mg (76% of theory) of product are obtained with 112 mg (0.73 mmol) of 3-chlorophenyl isocyanate ,
HPLC (method 1): R _t = 4.72 min
MS (ESIpos): m / z = 389 (M + H) ⁺ Example 16A 4- [3 - ({[(4-fluoro-2-methylphenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl- 4-oxobutanoic acid methyl ester

Starting from 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 are used to obtain 178 mg (70% of theory) .) Product received.
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- methylester

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

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 according to the general procedure for the synthesis of Urea 52.6 mg (20% of theory) product obtained.
HPLC (method 1): R _t = 4.93 min
MS (ESIpos): m / z = 403 (M + H) ⁺ Example 19A 4- [2-fluoro-5 - ({[1-adamantylamino] carbonyl} amino) phenyl] -3,3-dimethyl-4-oxobutane -säuremethylester

100 mg (0.39 mmol) of methyl 4- (5-amino-2-fluorophenyl) -3,3-dimethyl-4-oxobutanoate are stirred together with 77 mg (0.43 mmol) of 1-adamantyl isocyanate in 2 ml of DMF at 50 ° C. 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-oxobutanoate

Starting from 100 mg (0.39 mmol) of 4- (5-amino-2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester, 73 mg (0.43 mmol) of 4-chloro-2-methylphenyl isocyanate are added to 118 mg (71 % of theory) Product received.
HPLC (method 1): R _t = 5.03 min
MS (ESIpos): m / z = 421 (M + H) ⁺ Example 21A 4- [2-fluoro-5 - ({[(3-fluorophenyl) amino] carbonyl} amino) phenyl] -3,3-dimethyl- 4-oxobutane acid methyl ester

Starting from 100 mg (0.39 mmol) of 4- (5-amino-2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid, 59.4 mg (0.43 mmol) of 3-fluorophenyl isocyanate 97.4 mg (51% of theory .) Product received.
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 25.27 ml of 2-propylmagnesium chloride are added at 0.degree. After stirring overnight at room temperature, 60 ml 10 percent at 0 ° C. Hydrochloric acid added dropwise 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 + NH ₄ ) ⁺ Example 23A 4- (2-fluorophenyl) -3,3-dimethyl-4-oxobutanoic acid

1.75 g of 1- (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 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 + NH ₄ ) ⁺ Example 25A 4- (2-fluoro-5-nitrophenyl) -3,3-dimethyl-4-oxobutanoic acid methyl ester

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 + NH ₄ ) ⁺ Example 26A 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyldihydro-2 (3H) 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 checking by TLC, acidify with 1 N 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 in a yield of 3.2 g (79%) by recrystallization from diethyl ether / n-pentane.
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) -furanone

In 90 ml of ethanol, 3.55 g of 5- (2-fluoro-5-nitrophenyl) -4,4-dimethyldihydro-2 (3H) furan are concentrated 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 suctioned off 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) of 3-aminobenzonitrile are dissolved in 1 l of 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. After the addition has ended, 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 × 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 the aqueous phase is extracted 3 × 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 minutes while heating to 0.degree. 12.4 g (51 mmol) of 1- [3- (diallylamino) phenyl] -2-methyl-1-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. The mixture is stirred for a further 1 hour at -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 extracted 3 × with ethyl acetate. 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: 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-oxobutanoic acid ethyl ester

8.27 g (53 mmol) of 1,3-dimethylbarbituric acid, 204 mg (0.18 mmol) of tetrakis (triphenylphosphine) palladium (0) and 185 mg (0.71 mmol) of triphenylphosphine are dissolved in a mixture of 30 ml of toluene and 10 ml of DMF under argon. This catalyst solution is added to a solution of 2.91 g (8.83 mmol) of 4- (3-diallylaminophenyl) -3,3-dimethyl-4-oxobutanoic acid ethyl ester 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 × 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-oxobutanoic acid, methyl ester

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 freshly prepared 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 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 × 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 min
MS (ESIpos): m / z = 378 (M + H) ⁺ Example 34A 4-benzyl-5- [3- (diallylamino) phenyl] dihydro-2 (3H) -furanone

823.4 mg (2.18 mmol) of 3-benzyl-4- [3- (diallylamino) phenyl] -4-oxobutanoic acid methyl ester 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 1N hydrochloric acid, water and ethyl acetate are added to the residue. 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-HPLC. 383.2 mg (49% of theory) of product are obtained as a mixture of diastereomers, which is not separated into the diastereomers.
HPLC (method 1): R _t = 4.52 min
MS (ESIpos): m / z = 348 (M + H) ⁺ Example 35A 5- (3-aminophenyl) -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 THF and mixed with a solution of 14.4 mg (0.01 mmol) of tetrakis (triphenylphosphine) palladium (0) and 584 mg (3.74 mmol) 1,3-dimethylbarbituric acid in 2 ml THF. 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 × with 10 ml of saturated sodium bicarbonate solution. The organic phases are dried over magnesium sulfate and, after filtration, concentrated and dried. 487 mg (93% of theory) of crude product are obtained, which is used for the next syntheses without further purification.
HPLC (method 1): R _t = 3.67 min
MS (DCI): m / z = 285 (M + NH ₄ ) ⁺

embodiments General working instructions B Synthesis of lactones

Analogous to a regulation by A. L. Gutman, K. Zuobi, T. Bravdo, J. Org. Chem. 1990, 55, 3546-3552 becomes 1 equivalent of the 4-oxo compound to be reacted in a 1: 1 mixture of diethyl ether and methanol. The mixture is in Cooled ice bath to 0 ° C and then with 1 equivalent of solid sodium borohydride added (for larger batches, the sodium borohydride is dissolved in water). you can be stirred at 0 ° C until DC control shows complete conversion, there then 1N hydrochloric acid, diluted with water and then extracted 3 × with Ethyl acetate. The combined organic phases are then with saturated sodium bicarbonate solution and water, then washed over Magnesium sulfate dried. 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-dimethyl-5-oxotetrahydro-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) product.
HPLC (method 1): R _t = 4.81 min
MS (ESIpos): m / z = 373 (M + H) ^+
1 H-NMR (200 MHz, DMSO): δ = 0.63 (s, 3H), 1.21 (s, 3H), 2.24 (s, 3H), 2.41 (d, 1H), 2.74 (d, 1H), 5.28 ( s, 1H), 6.87 (d, 1H), 7.19 (dd, 1H), 7.27 (m, 1H), 7.33 (d, 1H), 7.42 (m, 1H), 7.90 (d, 1H), 7.96 (s , 1H), 9.20 (s, 1H) Example 2 N- (3-fluorophenyl) -N '- [3- (3,3-dimethyl-5-oxotetrahydro-2-furanyl) 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-methylphenyl) -N '- [3- (3,3-dimethyl-5-oxotetrahydro-2-furanyl ) phenyl] urea

Starting with 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-chloro-4-fluorophenyl) -N '- [3- (3,3-dimethyl-5-oxotetrahydro-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, 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- (1-Adamantyl) -N '- [3- (3,3-dimethyl-5-oxotetrahydro-2-furanyl) phenyl] - urea

Starting from 47.3 mg (0.11 mmol) of 4- [3 - ({[(1-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 received.
HPLC (method 1): R _t = 4.93 min
MS (ESIpos): m / z = 383 (M + H) ⁺ Example 7 N- (4-chloro-2-methylphenyl) -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-methylphenyl) -N '- [3- (3,3-dimethyl-5-oxotetrahydro-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 10.5 mg (0.28 mmol) sodium borohydride 40.7 mg (37% of theory) product obtained.
HPLC (method 1): R _t = 4.88 min
MS (ESIpos): m / z = 391 (M + H) ^+
1 H-NMR (200 MHz, DMSO): δ = 0.74 (s, 3H), 1.21 (d, 3H), 2.23 (s, 3H), 2.45 (d, 1H), 2.76 (d, 1H), 5.55 ( s, 1H), 7.15-7.28 (m, 3H), 7.39-7.52 (m, 2H), 7.82 (d, 1H), 7.94 (s, 1H), 9.22 (s, 1H) Example 9 N- [3- (3,3-Dimethyl-5-oxotetrahydro-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-oxotetrahydro-2-furanyl) -4- fluorophenyl] - urea

Starting from 63 mg (0.15 mmol) of 4- [2-fluoro-5 - ({[1-adamantylamino] carbonyl} - amino) phenyl] -3,3-dimethyl-4-oxobutanoic acid methyl ester with 5.5 mg (0.15 mmol) of sodium borohydride 10.5 mg (18% of theory) of product obtained.
¹ H-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, 1H), 2.79 (d, 1H), 5.50 (s, 1H), 5.79 (s, 1H), 7.27 (m, 2H), 7.35 (dd, 1H), 8.41 (s, 1H). 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 over silica gel (Cyclohexane / ethyl acetate 3/1; 2/1) cleaned. 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): m / z = 382 (M + H) ⁺ Example 13 N- (4-fluoro-2-methylphenyl) -N '- [3- (3,3-dimethyl-5-oxotetrahydro-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 of 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 seen in the following Assays are shown:

Anti-HCMV (Anti-Human Cytomegalo Virus) cytopathogenicity 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 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 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. The plates are then visually evaluated using an overhead microscope (plaque multiplier from Technomara).

The following data can be obtained from the test plates:
CC ₅₀ (MIDF) = substance concentration in µM at which no visible cytostatic effects on the cells can be seen compared to the untreated cell control;
EC ₅₀ (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 Xenograft Gelfoam® model animals

3-4 week old female immunodeficient mice (16-18 g), Fox Chase SCID or Fox Chase SCID-NOD or SCID-beige are used by commercial breeders (Bomholtgaard, Jackson). The animals are under sterile conditions (including litter and feed) kept in isolators.

virus growing

Human cytomegalovirus (HCMV), strain DavisSmith, is in vitro on human Embryonic foreskin fibroblasts (NHDF cells) grown. After infection of the NHDF cells with an infection multiplicity (M.O.I) of 0.01 are the virus-infected cells harvested 5-7 days later and in the presence of minimal Essential Medium (MEM), 10% Fetal Calf Serum (FKS) with 10% DMSO Store at -40 ° C. After serial dilution of the virus infected cells in The titer is determined in steps of ten on 24-well plates of confluent NHDF cells after vital staining with neutral red.

Preparation of the sponges, transplantation, treatment and evaluation

1 × 1 × 1 cm collagen sponges (Gelfoam®; Peasel & Lorey, Order No. 407534; KT Chong et al., Abstracts of 39 ^th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p. 439) first wetted with phosphate buffered saline (PBS), the enclosed air bubbles 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 the 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 are 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 substance application, the animals are killed painlessly and the sponge is removed. The virus-infected cells are released from the sponge by collagenase digestion (330 U / 1.5 ml) and stored in the presence of MEM, 10% fetal calf serum, 10% DMSO 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. Embodiments of pharmaceutical compositions

The compounds of the invention can be pharmaceutical as follows Preparations are transferred:

tablet composition

100 mg of the compound of Example 1.50 mg lactose (monohydrate), 50 mg Corn starch (native), 10 mg polyvinyl pyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

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

manufacturing

The mixture of active ingredient, lactose and starch is made with a 5% solution (m / m) of the PVP granulated in water. After drying, the granules are mixed with the magnesium stearate for 5 min. mixed. This mixture comes with a usual Tablet press pressed (for tablet format see above). As a guide for the Pressing a pressure of 15 kN is used.

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.

Correspond to a single dose of 100 mg of the compound according to the invention 10 ml oral suspension.

manufacturing

The Rhodigel is suspended in ethanol, the active ingredient becomes the suspension added. The water is added with stirring. Until swelling is complete of the Rhodigel is stirred for about 6 hours.

Claims (20)

1. Compounds of the formula


in which
the rest -NHC (D) NHR ² is bound to the aromatic system via one of the positions 2, 3, 5 or 6,
D represents oxygen or sulfur,
R ^{1 represents} hydrogen or C ₁ -C 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 ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C 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, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ^{2 represents} C ₃ -C ₁₀ cycloalkyl or C ₆ -C ₁₀ 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 ₁ -C ₆ alkoxy, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylaminocarbonyl and C ₁ -C ₆ alkyl,
R ^{3 represents} hydrogen or C ₁ -C ₆ 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 -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, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ^{4 represents} hydrogen or C ₁ -C 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 ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ⁵ for hydrogen, halogen, hydroxy, cyano, C ₁ -C ₆ alkoxy, carboxy, C ₁ -C ₆ alkoxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkylaminocarbonyl, amino, C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkyl.
R ^{6 represents} hydrogen or C ₁ -C ₆ 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 -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino, and
R ¹ , R ³ , R ⁴ and R ^{6 are} not simultaneously hydrogen. 2. Compounds according to claim 1, wherein
the remainder -NHC (D) NHR ² is bound to the aromatic system via position 3,
D stands for oxygen,
R ^{1 stands} for C ₁ -C ₆ alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, hydroxy, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ^{2 represents} C ₃ -C ₁₀ cycloalkyl or C ₆ -C ₁₀ aryl, where aryl can be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano and C ₁ -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, hydroxy, C ₁ -C ₆ alkoxy, C ₆ -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino,
R ^{4 stands} for 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 -C ₁₀ aryl, amino and C ₁ -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 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 -C ₁₀ aryl, amino and C ₁ -C ₆ alkylamino. 3. Compounds according to claim 1, wherein
the remainder -NHC (D) NHR ² is bound to the aromatic system via position 3,
D stands for oxygen,
R ^{1 represents} C ₁ -C ₆ 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} C ₁ -C ₆ alkyl,
R ^{5 represents} hydrogen, hydroxy, fluorine, chlorine or methyl, and
R ^{6 represents} hydrogen. 4. Compounds according to claim 1, 2 or 3, wherein the radical -NHC (D) NHR ² is bonded 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 = NR ² (IV)

in which
D and R ^{2 have} the meaning given above,
be implemented. 16. Compounds according to any one of claims 1 to 3 for treatment and / or Prophylaxis of viral diseases. 17. Medicament containing at least one compound according to one of the Claims 1 to 3 in combination with at least one pharmaceutical compatible, pharmaceutically acceptable carrier or excipient. 18. Use of compounds according to one of claims 1 to 3 for 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. Methods for combating viral diseases in humans and Animals by administration of an antivirally effective amount at least a connection according to one of claims 1 to 3.