WO2004052363A1 - Oxazolidinones used as antiviral agents, in particular for fighting against cytomegalovirus - Google Patents

Abstract

The invention relates to oxazolidinones, methods for the preparation and use thereof for producing drugs for treating and/or preventing diseases and which are used, in particular in the form of antiviral agents, especially for fighting against cytomegalovirus.

Description

OXAZOLIDINONE AS AN ANTIVIRAL AGENT, ESPECIALLY AGAINST CYTOMEGALOVIRES

The invention relates to oxazolidinones and processes for their preparation and their use for the manufacture of medicaments for treatment and / or

Prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegaloviruses.

Although there are structurally different antiviral agents on the market, resistance can regularly develop. New

Means 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 infectious diseases in humans and animals.

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

The invention relates to compounds of the formula

in welcher

in which

the remainder -NHC (O) NHR ² is bound to the aromatic system via one of the positions 2 or 3, R stands for hydrogen or -CC ₆ alkyl, where alkyl can be substituted with 0, 1, 2 or 3 substituents independently of one another selected from the group consisting of halogen, hydroxy, hydroxycarbonyl, aminocarbonyl, -C ₆ alkoxy, Co -Cio-aryl, amino, CrC ₆ -alkylamino, -C-C ₆ -alkoxy- carbonyl, CrC _ö -alkylaminocarbonyl, CrC ₆ -alkylcarbonylamino and C ₆ -C ₁₀ - arylcarbonylamino,

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

-C-C ₆ alkoxy, hydroxycarbonyl, Ci-C _ö alkoxycarbonyl, amino, CrC ₆ -

Alkylamino, CrC _ö alkylaminocarbonyl and C] -C ₆ alkyl,

R ^{3 represents} dC ₆ alkyl, where alkyl can be substituted by 0, 1, 2 or 3

Substituents selected independently of one another from the group consisting of halogen, hydroxy, C ₁ -C ₆ -alkoxy, Ce-Cio-aryl, amino and C Cβ-alkylamino,

R ^{4 represents} hydrogen or -C ₆ alkyl, where alkyl can be substituted by

0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, Cι-C ₆ -alkoxy, C ₆ -Cι ₀ aryl, amino, and Cι-C ₆ alkylamino, and

R ⁵ for hydrogen, halogen, hydroxy, cyano, d-Cö-alkoxy, carboxy, C Cö-

Alkoxycarbonyl, aminocarbonyl, CrC _ö alkylaminocarbonyl, amino, C ₁ -C ₆ alkylamino or C ₆ -C ₆ alkyl,

and their salts, solvates or solvates of the salts. Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts; the compounds of the formulas encompassed by the formula (I) and their salts, solvates and solvates of the salts, and the compounds encompassed by the formula (I), hereinafter referred to as exemplary embodiments, and the salts, solvates and solvates of the salts, to the extent that are included the compounds mentioned in the formula (I) below are not already salts, solvates and solvates of the salts.

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

If the compounds according to the invention can occur in tautomeric forms, the present invention encompasses all tautomeric forms.

In the context of the present invention, preferred salts are physiologically acceptable salts of the compounds according to the invention. However, salts are also included which are not themselves suitable for pharmaceutical applications but can be used for example for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds of the invention 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, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, such as, by way of 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 carbon atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine,

Ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Within the scope of the invention, such forms of the invention are considered as solvates

Refers to compounds that 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 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 selected) alkyl substituents. (-C ~ C ₃ ) alkylamino stands for example for a monoalkylamino radical having 1 to 3 carbon atoms or for a dialkylamino radical each having 1 to 3 carbon atoms per alkyl substituent. The following may be mentioned by way of example and preferably: methylamino, ethylamino, n-propylamino, isopropyl amino, tert-butylamino, n-pentylamino, n-hexylamino, NN-dimethylamino, NN-diethyla ino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N- tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents. (-C-C ₃ ) -alkylaminocarbonyl stands for example for a monoalkylaminocarbonyl radical with 1 to 3 carbon atoms or for a dialkylaminocarbonyl radical with 1 to 3 carbon atoms per alkyl substituent. Examples and preferably are:

Methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, NN-dimethylaminocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methylamino-carbonyl-propyl , N-isopropyl-Nn-propylamino-carbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylamino-carbonyl and Nn-hexyl-N-methylaminocarbonyl.

Alkylcarbonylamino stands for an alkylcarbonylamino radical with an alkyl substituent, for example and preferably for methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, n-

Pentylcarbonylamino and n-hexylcarbonylamino.

Arylcarbonylamino stands for an arylcarbonylamino radical with an aryl substituent, for example and preferably for phenylcarbonylamino, Νaphthylcarbonylamino and phenanthrenylcarbonylamino.

Alkoxycarbonyl exemplifies and preferably represents 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 generally 6 to 14 carbon atoms; exemplary and preferably for phenyl, naphthyl and phenanthrenyl.

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

A symbol * on a carbon atom means that the Nerbinding is in enantiomerically pure form with regard to the configuration on this carbon atom, which in the context of the present invention means an enantiomeric excess of more than 90% (> 90% ee).

Preferred compounds are those in which

the remainder -CHC (O) ΝHR ² is bound to the aromatics via position 3,

R ^{1 represents} hydrogen or -CC ₃ alkyl, where alkyl can be substituted with

0, 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, aminocarbonyl, Q-COE-alkoxy, C ₆ -Cι ₀ aryl, amino, dC ₆ alkylamino, _Cι-C6 alkoxycarbonyl, Ci- Ce-alkylamino-carbonyl, Ci-C _ö alkylcarbonylamino and C ₆ -do-arylcarbonylarnino,

R ² is C ₃ -Cι is ₀ -cycloalkyl or phenyl, where phenyl may be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, trifluoromethyl and dC _ö - alkyl,

R ^{3 is} C ₁ -C ³ -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 -alkoxy, C6-C ₁₀ -aryl, amino and dC _ö -alkylamino,

R ^{4 represents} hydrogen or dC 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, dC ₆ -alkoxy, C ₆ -Cι ₀ -aryl, Amino and -CC ₆ alkylamino, and

R ^{5 represents} hydrogen, halogen or -CC ₆ alkyl,

and their salts, solvates or solvates of the salts.

Preference is also given to those compounds in which

the remainder -NHC (O) NHR ² is bound to the aromatic system via position 3,

R ^{1 represents} hydrogen or -CC ₃ alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of hydroxy, dC ₃ alkoxy, amino and dC ₃ alkylamino,

R ^{2 represents} phenyl or adamantyl, where phenyl can be substituted by 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl and dC ₃ alkyl,

R ³ represents C ₁ -C ₃ -alkyl,

R ^{4 represents} hydrogen or -CC ₃ alkyl, and

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

and their salts, solvates or solvates of the salts. Preference is also given to those compounds in which the --NHC (O) NHR ² radical is bonded to the aromatic system via position 3.

Also preferred are those compounds in which R ^{1 is} hydrogen or d

C ₃ alkyl, where alkyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, dC ₃ - alkoxy, amino and C ₁ -C ₃ alkylamino. Examples of such R ¹ include hydrogen, methyl, ethyl, CH ₂ CH ₂ OH, CH ₂ CH ₂ NHCH ₃ and CH ₂ CH ₂ NH ₂ .

Also preferred are those compounds in which R ^{2 is} adamantyl or phenyl, where phenyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl and methyl. R ² particularly preferably represents phenyl which is substituted by 1 or 2 substituents, and in the case of 2 substituents these preferably occupy the ortho and .αr positions or the meta and αr positions.

Compounds in which R ^{3 is} methyl are also preferred.

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

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

Also preferred are those compounds in which R ⁵ , in particular fluorine, is bonded to the aromatics via position 6. Compounds in which the radical —NHC (O) NHR ^{2 is} simultaneously bonded to the aromatic system via position 3 are particularly preferred. The radical definitions specified in detail in the respective combinations or preferred combinations of radicals are also replaced by radical definitions of another 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 a process for the preparation of the compounds of the formula (I), wherein compounds of the formula

in welcher

in which

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

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

with compounds of the formula

OCN - F, T ₂ (III) in which

R ^{2 has} the meaning given above, are reacted and the resulting compounds of the formula (I) are reacted, if appropriate, with the corresponding (i) solvents and / or (ii) bases or acids to give their salts, solvates and / or solvates of the salts.

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

Presence of a base, preferably in a temperature range from room temperature to the reflux of the 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 acetic acid - Ethyl ester, 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, diisopropylethylamine and triethylamine are preferred.

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

in welcherThe compounds of formula (II) can be prepared by compounds of formula

in which

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

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

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

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

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert .-Butanol, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as

Dimethylformamide, dimethylacetamide, acetonitrile, ethyl acetate or pyridine, ethanol, methanol, isopropanol or ethyl acetate are preferred, or in the case of tin dichloride in dimethylformamide, dioxane or methanol.

in welcherThe compounds of formula (IV) can be prepared by compounds of formula

in which

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

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

with compounds of the formula

R ^ X ¹ (V), in which

R ^{1 has} the meaning given above, and

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

be implemented.

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

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

Bases are, for example, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, or potassium tert-butoxide, or other bases such as sodium hydride,

DBU, triethylamine or diisopropylethylamine, sodium hydride is preferred.

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

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

in welcher

in which

R .1, R, R and R have the meaning given above,

with fuming nitric acid, concentrated nitric acid, nitric acid or other mixing ratios of sulfuric acid and nitric acid, preferably in one

Temperature range from -30 ° C to 0 ° C at normal pressure.

in welcherThe compounds of formula (VI) can be prepared by compounds of the formula

in which

R, 3, R and R have the meaning given above

be implemented with bases.

The reaction is generally carried out in inert solvents, preferably in a temperature range from -10 ° 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, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as dimethylformamide , Dimethylacetamid, or pyridine, tetrahydrofuran is preferred.

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

The compounds of the formula (VII) are known or can be synthesized from the corresponding starting materials by known processes (cf. SD Bull, SG Davies, S. Jones, HH Sanganee, J. Chem. Soc. Perkin Trans 1 1999, 387; MP Sibi et al., Synthetic Communications 1995, 5 (8), 1255-1264). The preparation of the compounds according to the invention can be illustrated by the following synthesis schemes.

Synthesis scheme 1: basic body synthesis

Synthesis scheme 2: basic body synthesis

Syntheseschema 3: Synthese der Oxazolidinone

Synthesis scheme 3: Synthesis of the oxazolidinones

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 (herpes viruses), especially against cytomegaloviruses (CMV), especially against the human cytomegalovirus (HCMV). They are therefore suitable for the treatment and / or prophylaxis of diseases, especially infections with viruses, in particular the viruses mentioned above, and the infectious diseases caused thereby. In the following, a virus infection is understood to mean both an infection with a virus and a disease caused by an infection with a virus.

The compounds of general formula (I) can because of their particular

Properties for the production of medicaments which are suitable for the prophylaxis and / or treatment of diseases, in particular viral infections, are used.

The following areas of indication can be mentioned, for example: 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 suffering from HCMV pneumonitis,

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

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

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

HCMV infections.

The compounds according to the invention can act systemically and / or locally. For this purpose, they can be applied in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent. For these administration routes, the compounds according to the invention can be administered in suitable administration forms.

For oral administration, the state-of-the-art that works quickly and / or modifies the application forms which give off the compounds according to the invention and which contain the compounds according to the invention in crystalline and / or amorphized and / or dissolved form, such as, for example, Tablets (non-coated or coated tablets, for example with gastric juice-resistant or delayed dissolving or insoluble coatings which control the release of the compound according to the invention), rapidly disintegrating tablets or films / wafers in the oral cavity, films / lyophilisates, capsules (for example hard or soft gelatin capsules), dragées , Granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be done by bypassing an absorption step (e.g. intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (e.g. intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable forms of application for parenteral administration include: Injection and infusion preparations in the form of

Solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other application routes, e.g. Inhaled drug forms (including powder inhalers, nebulizers), nasal drops, solutions, sprays; tablets, films / wafers or capsules, suppositories to be applied lingually, sublingually or buccally,

Ear or eye preparations, vaginal capsules, aqueous suspensions (lotions, shake mixes), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (such as plasters), milk, pastes, foams, powder, implants or stents. The compounds according to the invention can be converted into the administration forms mentioned. This can be done in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable auxiliaries. These auxiliaries include, inter alia, carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersing or wetting agents (for example sodium dodecyl sulfate, polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example Albumin), stabilizers (for example antioxidants such as ascorbic acid), dyes (for example inorganic pigments such as iron oxides) and taste and / or odor correctors.

The present invention further relates to medicaments which contain at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable auxiliaries, and to their use for the purposes mentioned above.

In general, it has proven to be advantageous to administer amounts of approximately 0.001 to 10 mg / kg, preferably approximately 0.01 to 5 mg / kg of body weight in the case of intravenous administration, in order to achieve effective results, and the dosage is approximately in the case of oral administration 0.01 to 50 mg / kg, preferably 0.1 to 25 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 is carried out. In some cases it may be sufficient to make do with less than the aforementioned minimum quantity, while in other cases the above upper limit must be exceeded. In the case of application of larger quantities, it may be advisable to distribute them in several individual doses over the day. The percentages in the following tests and examples are, unless stated otherwise, percentages by weight; Parts are parts by weight. Solvent ratios, dilution ratios and concentration details of liquid / liquid solutions each relate to the volume.

A. Examples

Abkürzunεen:

TLC thin layer chromatography

DCI direct chemical ionization (for MS)

DCM dichloromethane

DIEA N N-diisopropylethylamine

DMSO dimethyl sulfoxide

DMF N N-dimethylformamide d. Th. Of theory

EE ethyl acetate (ethyl acetate)

EI electron impact ionization (for MS)

ESI electrospray ionization (for MS)

Mp melting point sat. Saturated h hour

HPLC high pressure, high performance liquid chromatography conc. Concentrated

LC-MS liquid chromatography-coupled mass spectroscopy

LDA lithium diisopropylamide

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

Pd-C Palladium on carbon percent. Percent

RP-HPLC reverse phase HPLC

RT room temperature

Rt retention time (with HPLC)

THF tetrahydrofuran General methods LC-MS and HPLC:

Method 1 (HPLC):

Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm x 2 mm, 3.5 μ; Eluent A: 5 ml HClO ₄ / l water, eluent B: acetonitrile; Gradient: 0 min

2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; Flow: 0.75 ml / min; Oven: 30 ° C; UN detection: 210 nm.

Method 2 (HPLC, preparative separation): column: CromSil C18, 250 mm x 30 mm; Eluent A: water, Eluent B: acetonitrile,

Gradient: 3 min 10% B -> 31 min 90% B -> 34 min 90% B -> 34.01 min 10% B; Flow: 50 ml / min; Running time: 38 min; UN detection: 210 nm.

Method 3 (HPLC, enantiomer separations): Selector: silica gel phase KBD 5326 based on the optically active monomer Ν-

Methacrylolyl-L-leucine - (+) - (3 S) -pinanylamide; Eluent: ethyl acetate, whereby methanol is used for the later eluting enantiomer (fraction 2) (step-gradient procedure: ethyl acetate, methanol, ethyl acetate).

Method 4 (LCMS):

Device type MS: Micromass ZQ; Device type HPLC: Waters Alliance 2790; Column: Grom-Sil 120 ODS-4 HE 50 mm x 2 mm, 3.0 μm; Eluent B: acetonitrile + 0.05% formic acid, eluent A: water + 0.05% formic acid; Gradient: 0.0 min 5% B -> 2.0 min 40% B ^ 4.5 min 90% B ^ 5.5 min 90% B; Oven: 45 ° C; Flow: 0.0 min 0.75 ml / min ^• 4.5 min 0.75 ml / min- 5.5 min 1.25 ml / min; UN detection: 210 nm. starting compounds

Example 1A

Amino- (2-fluorophenyl) acetate hydrochloride

Analogous to a regulation by S. D. Bull, S. G. Davies, S. Jones, H. H. Sanganee, J. Chem. Soc. Perkin Trans. 1, 1999, 387, 2.24 g (10.9 mmol) of amino- (2-fluorophenyl) acetic acid hydrochloride are suspended in 22 ml of methanol and at 0 ° C. (cooling in an ice bath) 1.19 ml (16.34 mmol) of thionyl chloride are added dropwise added. The reaction mixture is stirred at RT overnight. After evaporation of the solvent, the residue is crystallized from methanol by precipitation with diethyl ether. 2.39 g (83% of theory) of crude product are obtained.

HPLC (method 1): R _t = 2.82 min MS (ESIpos): m / z = 184 (M + H) ⁺ (molar mass of the free amine)

Example 2A

Amino (4-bromophenyl) -acetic acid methyl ester hydrochloride

Die Reaktion wird wie bei Beispiel 1A beschrieben durchgeführt. Mit 12.72 g

The reaction is carried out as described in Example 1A. At 12.72 g

(47.7 mmol) amino- (4-bromophenyl) acetic acid hydrochloride are mixed with 5.22 ml

(71.6 mmol) of thionyl chloride in 100 ml of methanol 14.25 g (97% of theory) of crude product.

HPLC (method 1): R _t = 3.40 min

MS (DCI): m / z = 244 (M + H) ⁺ (molar mass of the free amine)

Example 3A

[(tert-Butoxycarbonyl) amino] - (2-fluorohenyl) acetic acid

According to a regulation by E. Ponnusamy et al., Synthesis 1986, 48, 5 g

(29.56 mmol) of DL-2-fluorophenylglycine suspended in 50 ml of dry methanol. 10.3 ml (59.12 mmol) of N, N-diisopropylethylamine and 12.90 g (59.12 mmol) of di-tert-butyl dicarbonate are then added in succession at RT. The mixture is stirred at RT overnight and the solvent is then removed on a rotary evaporator. The residue is stirred for 10 min with ice-cooled 1N hydrochloric acid and then extracted three times with ethyl acetate. The combined extracts are dried over magnesium sulfate. After filtration and evaporation of the solvent, 10 g (quant.) Of crude product are obtained. HPLC (method 1): R _t = 4.14 min MS (ESIpos): m / z = 270 (M + H) ⁺ Example 4A

[(Tert-butoxycarbonyl) amino] - (2-fluorophenyl) acetate

2.39 g (10.9 mmol) methyl amino (2-fluorophenyl) acetic acid hydrochloride are dissolved in 25 ml methanol and successively at RT with 2.84 ml (16.3 mmol) N, N-diisopropylethylamine and 3.56 g (16.3 mmol) di-tert- butyl dicarbonate added. The mixture is stirred at RT overnight. After removing the solvent

Residue taken up in chloroform and the solution washed twice with 1N hydrochloric acid and saturated sodium chloride solution. It is dried over magnesium sulfate, then filtered and the solvent is evaporated. 3.34 g (92% of theory) of crude product are obtained, which can be used without further purification.

HPLC (method 1): R _t = 4.53 min MS (ESIpos): m / z = 284 (M + H) ⁺

Example 5A

[(Tert-butoxycarbonyl) amino] - (4-bromophenyl) -acetic acid methyl ester

Analog zu der für Beispiel 3A beschriebenen Reaktion werden mit 14.25 g (50.8 mmol) Amino-(4-bromphenyl)-essigsäuremethylester-hydrochlorid, 13.3 ml (76.2 mmol) N,N-Diisopropylethylamin und 16.6 g (76.2 mmol) Di-tert-butyl- dicarbonat 17.2 g (93 % d. Th.) Rohprodukt erhalten, welches ohne weitere Aufreinigung weiterverwendet wird. HPLC (Methode 1): R_t= 4.74 min MS (DCI): m/z = 361 (M+NH₄)⁺

Analogously to the reaction described for Example 3A, 14.25 g (50.8 mmol) of methyl amino (4-bromophenyl) acetate hydrochloride, 13.3 ml (76.2 mmol) of N, N-diisopropylethylamine and 16.6 g (76.2 mmol) of di-tert. Butyl dicarbonate 17.2 g (93% of theory) of crude product, which is used without further purification. HPLC (method 1): R _t = 4.74 min MS (DCI): m / z = 361 (M + NH ₄ ) ⁺

Example 6A

tert-Bu1yl-l- (2-fluorophenyl) -2- [methoxy (methyl) amino] -2-oxoethylcarbamate

According to a regulation by MP Sibi et al., Synthetic Communications 1995, 25 (8), 1255-1264, 10 g (36.4 mmol) of [(tert-butoxycarbonyl) amino] - (2-fluorophenyl) acetic acid (crude product), 3.55 g (36.4 mmol) of N, O-dimethylhydroxylamine hydrochloride and 11.15 g (43.6 mmol) of 2-chloro-l-methylpyridinium iodide are suspended in 100 ml of methylene chloride and then 21.5 ml (123.7 mmol) of N, N-diisopropylethylamine are added dropwise. The mixture is heated to boiling and allowed to stir at reflux overnight. 100 ml of water are then added to the reaction mixture, the phases are separated and the aqueous phase is added three times

Extracted methylene chloride. After drying the combined organic phases over magnesium sulfate, filtration and concentration of the solvent, the residue obtained is stirred with a mixture of diethyl ether and ethyl acetate, the product crystallizing. This gives 7.88 g (69% of theory) of product. HPLC (method 1): R _t = 4.43 min

MS (ESIpos): m / z = 313 (M + H) ⁺ Example 7A tert-Butyl-1 - (2-fluorophene) -2-hydroxy-2-methylpropyl carbamate

According to a regulation by S. D. Bull, S. G. Davies, S. Jones, H. H. Sanganee, J. Chem. Soc. Perkin Trans 1 1999, 387 are dissolved in an argon atmosphere 35.7 g (110 mmol) of [(tert-butoxycarbonyl) amino] - (2-fluorophenyl) -acetic acid methyl ester in 400 ml of tetrahydrofuran, cooled to 0 ° C. and then slowly with 143.5 ml

(430 mmol) of a 3 molar methylmagnesium bromide solution (in diethyl ether) was added. The mixture is allowed to warm up slowly to RT and is then stirred overnight at this temperature. After cooling again to 0 ° C., saturated ammonium chloride solution is carefully added and extracted three times with diethyl ether. The combined organic extracts are washed with saturated sodium chloride solution and then dried over magnesium sulfate. After filtration and concentration of the solvent, 30.4 g (73% of theory) of crude product are obtained, which is not further purified. HPLC (method 1): R _t = 4.43 min MS (ESIpos): m / z = 284 (M + H) ⁺ Example 8A

tert-Butyl-1 - (4-bromophenyl) -2-hydroxy-2-methylpropyl carbamate

Analogously to the reaction described in Example 7A, 2 g (5.81 mmol) of methyl [(tert-butoxycarbonyl) amino] - (4-bromophenyl) acetic acid and 7.75 ml (23.2 mmol) of methyl magnesium bromide as a 3 molar solution (in diethyl ether) in 35 ml of tetrahydrofuran as solvent 1.67 g (71% of theory) of crude product, which is not further purified. HPLC (method 1): R _t = 4.69 min MS (DCI): m / z = 344 (M + H) ⁺

Example 9A

tert-butyl-1 - (2-fluorophenyl) -2-oxopropyl carbamate

Under an argon atmosphere, a solution of 1.48 g (4.75 mmol) of tert-butyl-1- (2-fluorophenyl) -2- [methoxy (methyl) amino] -2-oxoethyl carbamate (crude product) in 20 ml of absolute THF is brought to 0 ° C cooled and slowly at this temperature with 3.17 ml (9.5 mmol) of a 3 molar solution of methyl magnesium bromide in diethyl ether added. The mixture is stirred at RT overnight, then the suspension obtained is cooled to 0 ° C. in an ice bath and carefully hydrolyzed with saturated ammonium chloride solution. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are then washed with saturated sodium chloride solution and finally dried over magnesium sulfate. After filtration and evaporation of the solvent, 1.18 g (87% of theory) of crude product are obtained. HPLC (method 1): R _t = 4.54 min MS (DCI): m / z = 268 (M + H) ⁺

Example 10A

tert-Butyl-1 - (2-fluorophenyl) -2-hydroxypropyl carbamate

2.29 g (7.69 mmol) of tert-butyl-l- (2-fluorophenyl) -2-oxopropylcarbamate (crude product) are dissolved in a mixture of 10 ml of methanol and 10 ml of diethyl ether and the solution obtained is cooled to 0.degree. At this temperature, 290 mg (7.69 mmol) sodium borohydride are added in portions. The reaction mixture is stirred at 0 ° C for 2 hours before being hydrolyzed with 1N hydrochloric acid. It will be with

Diluted water and extracted three times with ethyl acetate. The combined organic phases are then washed with saturated sodium bicarbonate solution and water and dried over magnesium sulfate. After filtration and evaporation of the solvent, 1.98 g (85% of theory) of crude product (mixture of diastereomers) are obtained.

HPLC (method 1): R _t = 4.24 min MS (ESIpos): m / z = 270 (M + H) ⁺ Example 11 A

4- (2-fluorophenyl) -5,5-dimethyl-1,3-oxazolidin-2-one

According to a modified regulation by S. D. Bull, S. G. Davies, S. Jones, H. H.

Sanganee, J. Chem. Soc. Perkin Trans 1 1999, 387, 1.16 g (4.11 mmol) of tert-butyl-l- (2-fluorophenyl) -2-hydroxy-2-methylpropylcarbamate are dissolved in 15 ml of tetrahydrofuran and at 0 ° C in portions with 0.2 g (4.93 mmol) sodium hydride (60% in paraffin oil) was added. The mixture is stirred until a DC control is complete

Displays sales. The solvent is evaporated and the obtained one is taken

Residue in ethyl acetate. It is washed with saturated ammonium chloride solution and saturated sodium chloride solution. Then over

Magnesium sulfate dried. After filtration and evaporation of the solvent, 797 mg (87% of theory) of product are obtained.

HPLC (method 1): R _t = 3.82 min

MS (ESIpos): m / z = 210 (M + H) ⁺

Example 12A

4- (4-bromophenyl) -5,5-dimethyl-1,3-oxazolidin-2-one

Analogously to the procedure described for Example HA, 8.73 g (25.4 mmol) of tert-butyl l- (4-bromophenyl) -2-hydroxy-2-methylpropylcarbamate and 1.22 g (30.4 mmol) of sodium hydride (60% in paraffin oil) are added 120 ml of tetrahydrofuran after crystallization, 2.5 g (36% of theory) of product were obtained.

HPLC (method 1): R _t = 4.17 min MS (ESIpos): m / z = 270 (M + H) ⁺

Example 13A

4- (2-fluorophenyl) -5-methyl-1,3-oxazolidin-2-one

A solution of 1.98 g (7.35 mmol) of tert-butyl-l- (2-fluorophenyl) -2-hydroxypropyl-carbamate (crude product) in 36 ml of THF is cooled to 0 ° C and added in portions with 350 mg (8.81 mmol) of sodium hydride ( 60% in paraffin oil). After the evolution of gas has subsided, the mixture is heated to 40 ° C. and stirred at this temperature overnight. Since the reaction is not yet complete, another 147 mg of sodium hydride (60% in paraffin oil) are added and again at 40 ° C. for 12 hours heated. The solvent is then evaporated, the residue taken up in ethyl acetate and washed with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate. After filtration and evaporation of the solvent, 1.42 g (87% of theory) of crude product (mixture of diastereomers) are obtained. HPLC (method 1): R _t = 3.64 min MS (DCI): m / z = 213 (M + NH ₄ ) ⁺

Example 14A

4- (2-fluoro-5-nitrophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-on

593 mg (2.83 mmol) 4- (2-Fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one are dissolved in 7 ml concentrated sulfuric acid and the solution cooled to -10 ° C.

0.27 ml of concentrated nitric acid are added dropwise with 0.35 ml of concentrated sulfuric acid. The nitrating acid thus obtained is added dropwise to the reaction solution at -10 ° C. The mixture is stirred for a further 30 minutes at -5 ° C., then poured carefully onto ice water and extracted three times with ethyl acetate. The combined extracts are dried over magnesium sulfate. To

Filtration and concentration is crystallized, 542 mg (75% of theory) of product being obtained. Mp .: 201.3 ° C

HPLC (method 1): R _t = 3.73 min MS (ESIpos): m / z = 255 (M + H) ⁺ Example 15A

4- (2-fluoro-5-nitrophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-on

This compound is obtained by preparative HPLC separation of the enantiomer mixture / racemate from Example 14A on a chiral phase (Method 3) as the later eluting enantiomer. HPLC (method 1): R _t = 3.80 min

Example 16A

4- (4-bromo-3-nitrophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-on

2.12 g (7.83 mmol) of 4- (4-bromophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one are dissolved in 6 ml of concentrated sulfuric acid and cooled to -10 ° C. in the solution. Separately, 1 ml of concentrated nitric acid is mixed with 2 ml of sulfuric acid at -10 ° C. This nitrating acid is then added dropwise to the reaction mixture. Then allowed to stir for 1.5 hours at -5 ° C, then carefully poured onto ice and extracted three times with dichloromethane. The united organic Phases are dried over magnesium sulfate, then filtered and the solvent evaporated. The residue is crystallized from ethyl acetate / cyclohexane 1: 1. 1.17 g (47% of theory) of product are obtained. HPLC (method 1): R _t = 4.10 min MS (DCI): m / z = 315 (M + H) ⁺

Example 17A

4- (2-fluoro-5-nitrophenyl) -5-methyl-l, 3-oxazolidin-2-on

1.42 g (7.26 mmol) of 4- (2-fluorophene) -5-methyl-l, 3-oxazolidin-2-one (crude product) are dissolved in 15 ml of concentrated sulfuric acid and the solution obtained is cooled to -10 ° C. At the same time, 0.9 ml of concentrated sulfuric acid is also added to 0.69 ml of concentrated nitric acid at -10 ° C. The reaction mixture is then added dropwise at -10 ° C. with the nitrating acid and stirred at -5 ° C. for a further 30 min. It is carefully poured onto ice water and extracted three times with methylene chloride. The combined extracts are dried over magnesium sulfate. After filtration and evaporation of the solvent, the residue obtained is stirred with diethyl ether. This gives 0.458 g (25% of theory) of product

(Mixture of diastereomers). HPLC (method 1): R _t = 3.61 min MS (ESIpos): m / z = 241 (M + H) ⁺ Example 18A

4- (2-fluoro-5-nitrophenyl) -3, 5,5-trimethyl-1,3-oxazolidin-2-one

350 mg (8.65 mmol) of sodium hydride (60% in paraffin oil) are suspended in 5 ml of THF under an argon atmosphere and the suspension obtained is cooled to 0.degree. At the same time, 2 g (7.87 mmol) of 4- (2-fluoro-5-nitrophenyl) -5,5-dimethyl-1,3-oxazolidin-2-one (Example 15A) are dissolved in 15 ml of THF and added at 0.degree added to the sodium hydride suspension. The mixture is allowed to warm up slowly to RT and stirred at RT for a further 30 min. Then 2.79 g (19.7 mmol) of methyl iodide are added dropwise. The mixture is stirred at RT overnight, then the reaction mixture is mixed with water and extracted three times with diethyl ether. The combined organic phases are dried over magnesium sulfate. After filtration and evaporation of the solvent, 1.95 g (92% of theory) of product are obtained. HPLC (method 1): R _t = 3.98 min MS (ESIpos): m / z = 269 (M + H) ⁺

Example 19A

[4- (2-Fluoro-5-nitrophenyl) -5,5-dimethyl-2-oxo-l, 3-oxazolidin-3-yl] ethyl acetate

520 mg (13 mmol) sodium hydride (60% dispersion in mineral oil) are suspended in 2 ml dry THF. The suspension is cooled to 0 ° C. under an argon atmosphere and then with 3 g (11.8 mmol) of 4- (2-fluoro-5-nitrophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one ( Example 15A) dissolved in 20 ml of dry THF added dropwise. After the evolution of gas has ended, the mixture is stirred at RT for a further 30 min and then 3.79 g (17.7 mmol) of ethyl iodoacetate are added. After stirring for 24 hours, water is added and the mixture is extracted three times with diethyl ether. The combined organic phases are dried over magnesium sulfate. Purification is carried out by column chromatography (silica gel: cyclohexane / ethyl acetate 1: 1).

2.78 g (69% of theory) of product are obtained. HPLC (method 1): R _t = 4.38 min MS (ESIpos): m / z = 341 (M + H) ⁺ Example 20A

4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-on

407 mg (1.6 mmol) of 4- (2-fluoro-5-nitrophenyl) -5,5-dimethyl-1,3-oxazolidin-2-one (Example 14A) are dissolved in 10 ml of ethanol and treated with 171 mg of Pd-C (5%) stirred under a hydrogen atmosphere until a TLC check shows complete conversion. The reaction mixture is filtered through kieselguhr, washed with ethanol, concentrated and the residue is purified by RP-HPLC. 247 mg (69% of theory) of product are obtained. HPLC (method 1): R _t = 3.08 min MS (ESIpos): m / z = 225 (M + H) ⁺

Example 21A

4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-on

1 g (3.93 mmol) 4- (2-fluoro-5-nifrophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (Example 15A) are dissolved in 20 ml ethanol and with 210 mg Pd-C (10%) under one Hydrogen atmosphere stirred until a TLC check shows complete conversion. The reaction mixture is filtered through Celite, washed with ethanol and the solvent is evaporated off. 825 mg (87% of theory) of crude product are obtained, which is processed without further purification. HPLC (method 1): R _t = 3.08 min MS (ESIpos): m / z = 225 (M + H) ⁺

Example 22A

4- (3-aminophenyl) -5,5-dimethyl-1,3-oxazolidin-2-one

1.17 g (3.71 mmol) of 4- (4-bromo-3-nitrophenyl) -5,5-dimethyl-1,3-oxazolidin-2-one (Example 16A) are suspended in 15 ml of ethanol and treated with 198 mg of Pd-C (10%) stirred under a hydrogen atmosphere until reaction control indicates complete conversion by means of analytical HPLC. The reaction mixture is filtered through Celite, washed well with ethanol and concentrated on a rotary evaporator. The residue is taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. After drying over magnesium sulfate, filtration and evaporation of the solvent, 1.08 g (quant.) Of crude product are obtained, which is further processed without further purification. HPLC (method 1): R _t = 2.71 min MS (ESIpos): m / z = 207 (M + H) ⁺ Example 23A

4- (5-amino-2-fluoφhenyl) -5-methyl-l, 3-oxazolidin-2-on

460 mg (1.91 mmol) of 4- (2-fluoro-5-nitrophenyl) -5-methyl-l, 3-oxazolidin-2-one (Example 17A) are suspended in 10 ml of ethanol and exposed to 100 mg of palladium under an inert gas atmosphere Coal (10%) added. The mixture is then stirred at RT under a hydrogen atmosphere until a TLC check shows complete conversion. The reaction mixture is filtered through Celite. It is washed with ethanol and then the solvent is removed on a rotary evaporator. This gives 385 mg (96% of theory) of product (mixture of diastereomers). HPLC (method 1): R _t = 2.70 min

MS (ESIpos): m / z = 211 (M + H) ⁺

Example 24A

4- (5-amino-2-fluoφhenyl) -3,5,5-frimethyl-l, 3-oxazolidin-2-one

1.94 g (7.22 mmol) 4-(2-Fluor-5-nitrophenyl)-3,5,5-trimethyl-l,3-oxazolidin-2-on (Beispiel 18A) werden in 50 ml Ethanol gelöst, mit 380 mg Pd-C (10%ig) versetzt und bei RT unter einer Wasserstoffatmosphäre gerührt bis eine DC-Kontrolle vollständigen Umsatz anzeigt. Die Reaktionsmischung wird über Celite filtriert. Es wird gut mit Ethanol nachgewaschen und anschließend das Lösungsmittel am Rotationsverdampfer entfernt. Dabei werden 1.72 g (quant.) Rohprodukt erhalten. Dieses Rohprodukt wird ohne weitere Aufreinigung weiterverarbeitet. HPLC (Methode 1): R_t= 3.16 min MS (ESIpos): m/z - 239 (M+H)⁺

1.94 g (7.22 mmol) 4- (2-fluoro-5-nitrophenyl) -3,5,5-trimethyl-l, 3-oxazolidin-2-one (Example 18A) are dissolved in 50 ml ethanol, with 380 mg Pd -C (10%) and stirred at RT under a hydrogen atmosphere until a TLC check shows complete conversion. The reaction mixture is filtered through Celite. It is washed well with ethanol and then the solvent is removed on a rotary evaporator. 1.72 g (quant.) Of crude product are obtained. This raw product is processed without further purification. HPLC (method 1): R _t = 3.16 min MS (ESIpos): m / z - 239 (M + H) ⁺

Example 25A

[4- (5-Amino-2-fluoφhenyl) -5,5-dimethyl-2-oxo-l, 3-oxazolidin-3-yl] ethyl acetate

2.78 g (8.18 mmol) [4- (2-fluoro-5-nitrophenyl) -5,5-dimethyl-2-oxo-l, 3-oxazolidin-3-yl-acetic acid ethyl ester are dissolved in 50 ml absolute ethanol, with 440 mg Pd -C (10%) and stirred at RT under a hydrogen atmosphere until TLC control shows complete conversion. The reaction mixture is filtered through Celite and washed well with ethanol and then the solvent is removed on a rotary evaporator. 2.53 g (quant.) Of crude product are obtained, which is further processed without further purification. HPLC (method 1): R _t = 3.60 min MS (ESIpos): m / z = 311 (M + H) ⁺ Example 26A

{4- [5 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) -2-fluoropheneyl] -5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl} acetate

According to the general working procedure [A], starting from 2.53 g (8.15 mmol) of [4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-2-oxo-1,3-oxazolidin-3 - yl-acetic acid, ethyl ester (Example 25A) with 1.5 g (8.97 mmol) of 4-chloro-2-methylphenyl isocyanate after crystallization gave 3.48 g (89% of theory) of product. HPLC (method 1): R _t = 4.89 min MS (DCI): m / z = 478 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.97 (s, 3 H), 1.19 (t, 3 H), 1.61 (s, 3 H), 2.23 (s, 3 H), 3.62 (d , 1 H), 4.08-4.27 (m, 3 H), 4.97 (s, 1 H), 7.18-7.27 (m, 4 H), 7.52 (m, 1 H), 7.86 (d, 1 H), 7.97 (s, 1H), 9.19 (s, 1H)

Example 27A

2- {4- [5 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) -2-fluoropheneyl] -5,5-dimethyl-2-oxo-1,3-oxazolidin-3 - yl} ethyl 4-methylbenzenesulfonate

1.00 g (2.29 mmol) of alcohol from Example 18 and 929 mg (9.18 mmol) of triethylamine are dissolved in 15 ml of dichloromethane, the solution is cooled to 0 ° C. and 875 mg (4.59 mmol) of p-toluenesulfonic acid chloride are then added. You leave them

Slowly warm the reaction mixture to RT and stir at RT for 16 h. The mixture is then diluted with dichloromethane, the organic phase is washed with 1M hydrochloric acid and saturated sodium bicarbonate solution, the organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified chromatographically on silica gel using cyclohexane / ethyl acetate mixtures. 1.25 g (90% of theory) of product are obtained. HPLC (method 1): R _t = 5.11 min MS (DCI): m / z = 590 (M + H) ⁺ 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.92 (s, 3 H), 1.45 (s, 3H), 2.23 (s, 3H), 2.41 (s, 3H); 2.90-3.00 (m, 1H), 3.70-3.80 (m, 1H), 4.13-4.19 (m, 2H); 4.85 (s, 1H), April 7th

7.28 (m, 4H), 7.44-7.55 (m, 3H), 7.74 (d, 2H), 7.85 (d, 1H), 7.94 (s, 1H), 9.21 (s, 1H). Exemplary embodiments

General working specification [A]: Synthesis of ureas

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

example 1

N- (4-Chloro-2-methylphenyl) -N '- [3- (5,5-dimethyl-2-oxo-l, 3-oxazolidin-4-yl) -4-fluoropheneyl] urea

According to the general working instructions [A] starting from 247 mg

(1.1 mmol) 4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (Example 20A) with 203 mg (1.21 mmol) 4-chloro-2-methylphenyl isocyanate crystallization

195 mg (45% of theory) of product were obtained.

Mp .: 235.4 ° C

HPLC (method 1): R _t = 4.43 min

MS (ESIpos): m / z = 392 (M + H) ⁺ 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.92 (s, 3 H), 1.53 (s, 3 H), 2.24 (s , 3 H), 4.85

(s, 1 H), 7.13-7.28 (m, 3 H), 7.38 (dd, 1 H), 7.53 (m, 1 H), 7.87 (s, 1 H), 7.92 (d,

1 H), 8.07 (s, 1 H), 9.25 (s, 1 H) Example 2

N- (4-Chloro-2-methylphenyl) -N '- [3- (5,5-dimethyl-2-oxo-l, 3-oxazolidin-4-yl) -4-fluoro-phenylj-urea

According to the general working procedure [A], starting from 5.19 g (23.15 mmol) of 4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (example

20A) with 4.27 g (25.46 mmol) of 4-chloro-2-methylphenyl isocyanate after crystallization, 8 g (88% of theory) of racemic product.

2 g of this racemate are subjected to the enantiomer separation on a chiral HPLC phase and 416.3 mg (21% of theory) of the active enantiomer are obtained.

HPLC (method 1): R _t = 4.49 min

Enantiomerentrennung:

Selector: ZWE 840 silica gel phase based on the optically active monomer N-

Methacryloyl-L-leucine dicyclopropylamid

Eluent: ethyl acetate, whereby methanol is used for the later eluting enantiomer (fraction 2) (step-gradient procedure: ethyl acetate, methanol, ethyl acetate). Example 3

N- [3- (5,5-Dimethyl-2-oxo-l, 3-oxazolidin-4-yl) -4-fluoropheneyl] -N- (4-fluoro-2-methylphenyl) urea

According to the general working procedure [A] starting from 100 mg

(0.45 mmol) 4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (Example 20A) with 74 mg (0.49 mmol) of 4-fluoro-2-methylphenyl isocyanate crystallization

96 mg (58% of theory) of product were obtained.

Mp .: 252.9 ° C

HPLC (method 1): R _t = 4.18 min

MS (ESIpos): m / z = 376 (M + H) ⁺ 1H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.92 (s, 3 H), 1.53 (s, 3 H), 2.24 (s , 3 H), 4.83

(s, 1 H), 6.98 (m, 1 H), 7.06 (m, 1 H), 7.17 (t, 1 H), 7.38 (d, 1 H), 7.53 (m, 1 H), 7.73

(dd, 1 H), 7.86 (s, 1 H), 8.04 (s, 1 H), 9.14 (s, 1 H)

Example 4

N- (3-Chloro-4-fluoφhenyl) -N '- [3- (5,5-dimethyl-2-oxo-l, 3-oxazolidin-4-yl) -4-fluoφhenyl] urea

Nach der allgemeinen Arbeitsvorschrift [A] werden ausgehend von 100 mg (0.45 mmol) 4-(5-Amino-2-fluoφhenyl)-5,5-dimethyl-l,3-oxazolidin-2-on (Beispiel 20A) mit 84 mg (0.49 mmol) 3-Chlor-4-fluoφhenylisocyanat nach Kristallisation 145 mg (82 % d. Th.) Produkt erhalten. Fp.: 253.0°C

According to the general working procedure [A], starting from 100 mg (0.45 mmol) of 4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (Example 20A) with 84 mg (0.49 mmol) 3-chloro-4-fluoφhenyl isocyanate after crystallization 145 mg (82% of theory) Product obtained. Mp .: 253.0 ° C

HPLC (method 1): R _t = 4.40 min MS (ESIpos): m / z = 396 (M + H) ⁺

1H-NMR (400 MHz, DMSO-d ₆ ): δ - 0.92 (s, 3 H), 1.53 (s, 3 H), 4.84 (s, 1 H), 7.17 (t, 1 H), 7.32 (m , 2 H), 7.45 (m, 2 H), 7.79 (d, 1 H), 8.04 (s, 1 H), 8.80 (s, 1 H), 8.96 (s, 1 H)

Example 5

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

According to the general working procedure [A] starting from 100 mg

(0.45 mmol) 4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (Example 20A) with 67 mg (0.49 mmol) 3-fluoφhenyl isocyanate after crystallization 123 mg ( 76

% d. Th.) Product received.

Mp .: 220.1 ° C

HPLC (method 1): R _t = 4.22 min

MS (ESIpos): mz = 362 (M + H) ⁺ 1H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.92 (s, 3 H), 1.53 (s, 3 H), 4.84 (s, 1 H), 6.78

(t, 1 H), 7.12 (d, 1 H), 7.18 (t, 1 H), 7.30 (dd, 1 H), 7.43-7.49 (m, 3 H), 8.05 (s, 1 H),

8.83 (s, 1 H), 8.94 (s, 1 H) Example 6

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

According to the general working instructions [A], starting from 430 mg (1.9 mmol) of 4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (example

20A) with 310 mg (2.09 mmol) 2,4-dimethylphenyl isocyanate after cleaning with

RP-HPLC 162 mg (23% of theory) of product obtained.

Mp: 215.3 ° C

HPLC (method 1): R _t = 4.37 min MS (ESIpos): m / z = 372 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.92 (s, 3 H), 1.53 (s, 3 H), 2.19 (s, 3 H), 2.22

(s, 3 H), 4.83 (s, 1 H), 6.93-6.99 (m, 2 H), 7.16 (dd, 1 H), 7.37 (dd, 1 H), 7.53 (m, 1

H), 7.65 (d, 1 H), 7.78 (s, 1 H), 8.06 (s, 1 H), 9.12 (s, 1 H)

Example 7

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

Nach der allgemeinen Arbeitsvorschrift [A] werden ausgehend von 800 mg (3.57 mmol) 4-(5-Amino-2-fluoφhenyl)-5,5-dimethyl-l,3-oxazolidin-2-on (Beispiel 21A) mit 580 mg (3.92 mmol) 2,4-Dimethylphenylisocyanat nach Kristallisation 969.2 mg (73% d. Th.) Produkt erhalten. HPLC (Methode 1): R_t = 4.36 min

According to the general working procedure [A], starting from 800 mg (3.57 mmol) of 4- (5-amino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (Example 21A) with 580 mg (3.92 mmol) 2,4-dimethylphenyl isocyanate after crystallization 969.2 mg (73% of theory) of product. HPLC (method 1): R _t = 4.36 min

MS (ESIpos): m / z = 372 (M + H) ⁺

Example 8

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

According to the general working procedure [A], starting from 100 mg (0.45 mmol) of 4- (5-ajnino-2-fluoφhenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (example

20A) with 75 mg (0.49 mmol) 3-chloro-phenyl isocyanate after crystallization 141 mg

(84% of theory) Product received.

Mp: 244.6 ° C

HPLC (method 1): R _t = 4.36 min MS (ESIpos): m / z = 378 (M + H) ⁺

1H-NMR (400 MHz, DMSO-d ₆ ): δ = 0.92 (s, 3 H), 1.53 (s, 3 H), 4.84 (s, 1 H), 7.02

(d, 1 H), 7.18 (t, 1 H), 7.28-7.32 (m, 2 H), 7.46 (m, 2 H), 7.70 (s, 1 H), 8.05 (s, 1 H),

8.81 (s, 1 H), 8.95 (s, 1 H) Example 9

N- (4-Chloro-2-methylphenyl) -N- [3- (5,5-dimethyl-2-oxo-l, 3-oxa2; olidin-4-yl) phenyl] urea

According to the general working instructions [A] starting from 150 mg

(0.73 mmol) 4- (3-aminophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (crude product)

(Example 22 A) with 134 mg (0.8 mmol) of 4-chloro-2-methylphenyl isocyanate after cleaning by RP-HPLC 51.7 mg (19% of theory) of product.

Mp .: 206.1 ° C

HPLC (method 1): R _t = 4.41 min

MS (ESIpos): m / z = 374 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.83 (s, 3 H), 1.51 (s, 3 H), 2.24 (s, 3 H), 4.61 (s, 1 H), 6.89 (d , 1 H), 7.19 (dd, 1 H), 7.26-7.36 (m, 3 H), 7.47 (d, 1 H), 7.91 (d, 1

H), 7.96 (s, 1 H), 8.04 (s, 1 H), 9.20 (s, 1 H)

Example 10

N- [3- (5,5-Dimethyl-2-oxo-l, 3-oxazolidin-4-yl) ρhenyl] -N '- (4-fluoro-2-methylphenyl) urea

Nach der allgemeinen Arbeitsvorschrift [A] werden ausgehend von 150 mg (0.73 mmol) 4-(3-Aminophenyl)-5,5-dimethyl-l,3-oxazolidin-2-on (Rohprodukt) (Beispiel 22A) mit 121 mg (0.80 mmol) 4-Fluor-2-methylphenylisocyanat nach Reinigung mittels RP-HPLC 48.3 mg (19 % d. Th.) Produkt erhalten. Fp.: 205.9°C

According to the general working procedure [A], starting from 150 mg (0.73 mmol) of 4- (3-aminophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (crude product) (Example 22A) with 121 mg ( 0.80 mmol) of 4-fluoro-2-methylphenyl isocyanate after purification by RP-HPLC 48.3 mg (19% of theory) of product. Mp: 205.9 ° C

HPLC (method 1): R _t = 4.16 min MS (ESIpos): m / z = 358 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.83 (s, 3 H), 1.51 (s, 3 H), 2.24 (s, 3 H), 4.60 (s, 1 H), 6.86-7.10 (m, 3 H), 7.25-7.35 (m, 2 H), 7.47 (m, 1 H), 7.76 (dd, 1 H), 7.90 (s, 1 H), 8.03 (s, 1 H), 9.09 (s, 1 H)

Example 11

N- (3-Chloro-4-fluoφhenyl) -N '- [3- (5,5-dimethyl-2-oxo-l, 3-oxazolidin-4-yl) phenyl] urea

According to the general working procedure [A], starting from 150 mg (0.73 mmol) of 4- (3-aminophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (crude product)

(Example 22A) with 137 mg (0.80 mmol) of 3-chloro-4-fluoφhenyl isocyanate

Obtain purification using RP-HPLC 93.9 mg (34% of theory) of product.

Mp: 223.2 ° C

HPLC (method 1): R _t = 4.39 min MS (ESIpos): m / z = 378 (M + H) ⁺ 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.83 (s, 3 H), 1.51 (s, 3 H), 4.61 (s, 1 H), 6.90 (d, 1 H), 7.26-7.34 (m, 3 H), 7.40-7.43 (m, 2 H), 7.80 (m, 1 H), 8.03 (s, 1 H), 8.83 (s, 1 H), 8.90 (s, 1 H)

Example 12

N- [3- (5,5-dimethyl-2-oxo-l, 3-oxazolidin-4-yl) phenyl] -N '- (3-fluoφhenyl) -urea

According to the general working procedure [A], starting from 150 mg (0.73 mmol) of 4- (3-aminophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (crude product) (Example 22A) with 110 mg ( 0.80 mmol) 3-Fluoφhenylisocyanat after cleaning by RP-HPLC 88 mg (35% of theory) Product obtained. Mp: 198.1 ° C

HPLC (method 1): R _t = 4.19 min

MS (ESIpos): m / z = 344 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.83 (s, 3 H), 1.52 (s, 3 H), 4.61 (s, 1 H), 6.78

(m, 1 H), 6.90 (d, 1 H), 7.11 (m, 1 H), 7.25-7.40 (m, 4 H), 7.48 (m, 1 H), 8.03 (s, 1 H), 8.86 (s, 1H), 8.87 (s, 1H) Example 13

N- [3- (5,5-dimethyl-2-oxo-l, 3-oxazolidin-4-yl) phenyl] -N- (2,4-dimethylphenyl) urea

According to the general procedure [A], starting from 150 mg (0.73 mmol) of 4- (3-aminophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (crude product) (Example 22A) with 117 mg ( 0.80 mmol) of 2,4-dimethylphenyl isocyanate

Obtain purification by means of RP-HPLC 8.5 mg (3% of theory) of product. 1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.83 (s, 3 H), 1.51 (s, 3 H), 2.20 (s, 3 H), 2.23 (s, 3 H), 4.60 (s , 1 H), 6.85-6.99 (m, 3 H), 7.25-7.35 (m, 2 H), 7.46 (m, 1 H), 7.67 (d, 1 H), 7.81 (s, 1 H), 8.03 (s, 1 H), 9.06 (s, 1 H)

Example 14

N- (3-Chloφhenyl) -N- [3- (5,5-dimethyl-2-oxo-l, 3-oxazolidin-4-yl) phenyl] urea

According to the general working procedure [A], starting from 150 mg (0.73 mmol) of 4- (3-aminophenyl) -5,5-dimethyl-l, 3-oxazolidin-2-one (crude product) (Example 22A) with 123 mg (0.80 mmol) of 3-chloro-phenyl isocyanate after cleaning by RP-HPLC 98.2 mg (38% of theory) of product. Mp: 219.6 ° C

HPLC (method 1): R _t = 4.36 min MS (ESIpos): m / z = 360 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.83 (s, 3 H), 1.52 (s, 3 H), 4.61 (s, 1 H), 6.90 (d, 1 H), 7.02 (German , 1 H), 7.26-7.43 (m, 5 H), 7.72 (m, 1 H), 8.03 (s, 1 H), 8.84 (s, 1 H), 8.88 (s, 1 H)

Example 15

N- (4-Chloro-2-methylphenyl) -N- [4-fluoro-3- (5-methyl-2-oxo-l, 3-oxazolidin-4-yl) phenyl] urea

According to the general working procedure [A], starting from 380 mg (1.83 mmol) of 4- (5-amino-2-fluoφhenyl) -5-methyl-l, 3-oxazolidin-2-one (Example 23 A) with 340 mg ( 2 mmol) of 4-chloro-2-methylphenyl isocyanate after crystallization, 543 mg (76% of theory) of product (mixture of diastereomers) were obtained.

HPLC (method 1): R _t = 4.32 min MS (ESIpos): mz = 378 (M + H) ⁺ Example 16

N- (4-Chloro-2-methylphenyl) -N '- [4-fluoro-3- (3,5,5-trimethyl-2-oxo-l, 3-oxazolidin-4-yl) phenyl] urea

According to the general working instructions [A] starting from 850 mg

(3.59 mmol) 4- (5-amino-2-fluoro-phenyl) -3,5,5-trimethyl-l, 3-oxazolidin-2-one (example 24A) with 660 mg (3.94 mmol) 4-chloro- 2-methylphenyl isocyanate after

Crystallization from ethyl acetate diethyl ether obtained 1.04 g (72% of theory) of product.

Mp .: 113.5 ° C

HPLC (method 1): R _t = 4.63 min MS (ESIpos): m / z = 406 (M + H) ⁺

1H-NMR (300 MHz, DMSO-d ₆ ): δ = 0.93 (s, 3 H), 1.52 (s, 3 H), 2.24 (s, 3 H), 2.71

(s, 3 H), 4.84 (s _br , 1 H), 7.17-7.27 (m, 4 H), 7.49 (m, 1 H), 7.86 (d, 1 H), 7.93 (s, 1

H), 9.19 (s, l H)

Example 17

N- (2,4-Dimethylphenyl) -N '- [4-fluoro-3- (3,5,5-trimethyl-2-oxo-l, 3-oxazolidin-4-yl) phenyl] urea

Nach der allgemeinen Arbeitsvorschrift [A] werden ausgehend von 813 mg (3.41 mmol) 4-(5-Amino-2-fluoφhenyl)-3,5,5-trimethyl-l,3-oxazolidin-2-on (Beispiel 24A) mit 553 mg (3.75 mmol) 2,4-Dimethylphenylisocyanat nach Kristallisation 930 mg (71 % d. Th.) Produkt erhalten. Fp.: 166.1°C

According to the general working procedure [A], starting from 813 mg (3.41 mmol) of 4- (5-amino-2-fluoφhenyl) -3,5,5-trimethyl-l, 3-oxazolidin-2-one (Example 24A) 553 mg (3.75 mmol) of 2,4-dimethylphenyl isocyanate after crystallization, 930 mg (71% of theory) of product were obtained. Mp: 166.1 ° C

HPLC (method 1): R _t = 4.49 min MS (DCI): m / z = 386 (M + H) ⁺

1H-NMR (200 MHz, DMSO-d ₆ ): δ = 0.93 (s, 3 H), 1.52 (s, 3 H), 2.19 (s, 3 H), 2.22 (s, 3 H), 2.71 (s , 3 H), 4.85 (s _br , 1 H), 6.93-6.98 (m, 2 H), 7.16-7.25 (m, 2 H), 7.49 (m, 1 H), 7.63 (d, 1 H), 7.79 (s, 1 H), 9.10 (s, 1 H)

Example 18

N- (4-chloro-2-methylphenyl) -N- {4-fluoro-3- [3- (2-hydroxyethyl) -5,5-dimethyl-2-oxo-1,3-oxazolidin-4-yl] phenyl} urea

According to a regulation by KA Scheidt et al., Bioorg. Med. Chem. 1998, 6, 2477-2494, 1.54 g (13.9 mmol) of calcium chloride are suspended in 10 ml of ethanol and the suspension is cooled to -5 ° C. 3.31 g (6.93 mmol) {4- [5 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) -2-fluoφhenyl] -5,5-dimethyl-2-oxol, 3-oxazolidin-3-yl} ethyl acetate, suspended in THF / ethanol, added. The mixture is stirred for 5 min at -5 ° C. and then 1.05 g (27.7 mmol) sodium borohydride is added in one portion. The mixture is slowly warmed to RT and stirred at this temperature overnight. After evaporation of the solvent, the residue obtained is taken up in ethyl acetate and successively in each case washed once with an IM citric acid solution in water, saturated sodium hydrogen carbonate solution and saturated sodium chloride solution. It is dried over magnesium sulphate and, after filtration and evaporating the solvent, 2.98 g (97% of theory) are obtained as a crude product which is processed without further purification.

HPLC (method 1): R _t = 4.38 min MS (DCI): m / z = 436 (M + H) ⁺

1H-ΝMR (200 MHz, DMSO-d ₆ ): δ - 0.93 (s, 3 H), 1.54 (s, 3 H), 2.23 (s, 3 H), 2.76 (m, 1 H), 3.37-3.62 (m, 3 H), 4.83 (t, 1 H), 5.03 (s, 1 H), 7.11-7.27 (m, 4 H), 7.50- 7.58 (m, 1 H), 7.87 (d, 1 H) , 7.93 (s, 1 H), 9.24 (s, 1 H)

Example 19

N- (4-chloro-2-methylphenyl) -N- (3- {5,5-dimethyl-3- [2- (methylamino) ethyl] -2-oxo-1,3-oxazolidin-4-yl} - 4-fluoφhenyl) urea

100 mg (0.17 mmol) of tosylate from Example 27A and 47 mg (0.34 mmol) of potassium carbonate in DMSO are initially charged, 0.85 ml of a 2M solution of methylamine in THF is added and the mixture is stirred in a sealed glass tube at 50 ° C. for 16 hours. The product is then cleaned by means of preparative HPLC (method 2) without further purification. 40 mg (53% of theory) of product are obtained.

HPLC (method 1): R _t = 4.28 min

MS (DCI): m / z = 449.0 (M + H) ⁺ 1H-NMR (400 MHz, CDC1 ₃ ): δ = 1.04 (s, 3H), 1.42 (s, 2H), 1.61 (s, 3H); 2.27 (s, 3H), 2.36 (s, 3H); 2.74 (t, 2H), 2.94 (dt, 1H), 3.70-3.77 (m, 1H); 5.02 (s, 1H), 6.59 (dd, 1H); 7.09 (7, 2H), 7.16-7.19 (m, 2H), 7.85 (d, 1H), 8.14-8.18 (m, 1H), 8.41 (s, 1H).

Examples 20 to 26 of Table 1 can be prepared by the methods described above. The starting material given in Table 1 determines the stereochemistry in the case of Examples 21 to 26. Example 20 is one of four stereoisomers, which are two mutually diastereomeric pairs of enantiomers, and is obtained after the enantiomer separation described in Example 2 as the later eluting enantiomer of the two first eluting enantiomers.

Table 1

B. Bewertung der physiologischen Wirksamkeit

B. Assessment of physiological effectiveness

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

Anti-HCMN (Anti-Human Cytomegalo-Virus) cytopathogenicity tests

The test compounds are used as 50 millimolar (mM) solutions in dimethyl sulfoxide (DMSO). Ganciclovir ^® , Foscamet ^® 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 ner dilutions with 50 μl medium each are carried out up to the 11 series the 96-well plate. The wells in rows 1 and 12 each contain 50 μl medium. Then 150 μl of a suspension of 1 x 10 ⁴ cells (human nortal fibroblasts [ΝHDF]) are pipetted into the wells (row 1 = cell control) or a mixture of HCMN-infected and uninfected in rows 2-12

ΝHDF 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 added by adding a

Mixture of formalin and Giemsa's dye fixed and colored (30 minutes) with aqua bidest. washed and dried in a drying cabinet at 50 ° C. The plates are then visually evaluated using an overhead microscope (Plaque Multiplier from Technomara).

The following data can be obtained from the test plates:

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

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

Table A

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

HCMV Xenograft-GelfoaπT-ModeU

Animals:

3-4 week old female immunodeficient mice (16-18 g), Fox Chase SCID or Fox Chase SCID-NOD or SCID-beige are obtained from commercial breeders (Taconic M + B, Jackson, USA). The animals are kept in isolators under sterile conditions (including litter and feed). Nirusanzucht:

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

Preparation of the Sponges, Transplantation, Treatment and Evaluation:.. Lxlxl cm collagen sponges (Gelfoam ^® Fa Peasel & Lorey, order no 407534; KT Chong et al, Abstracts of 39 Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p. . 439) are first wetted with phosphate-buffered saline (PBS), the trapped air bubbles

Degassing removed and then stored in MEM + 10% FCS. 1 x 10 ⁶ virus-infected NHDF cells (infection with HCMV-Davis or HCMV AD169 MOI = 0.03) are detached 3 hours after infection and dropped in 20 μl MEM, 10% FCS onto a damp sponge. Approximately 16 hours later, the infected sponges are treated with 25 μl PBS / 0.1% BSA / 1 mM DTT with 5 ng / μl basic fibroblast

Growth Factor (bFGF) incubated. For transplantation, the immunodeficient mice are anesthetized with avertine or with a ketamine / xylazine / azepromazine mixture, the back skin is removed with the help of a razor, the epidermis is opened 1-2 cm, relieved and the moist sponges are transplanted under the back skin. The surgical wound is closed with tissue glue. 6 hours after the

Transplant mice can be treated for the first time (once on the day of surgery). On the following days, the patient is treated orally with substance three times a day (7:00 a.m. and 2:00 p.m. and 7:00 p.m.), twice a day (8:00 a.m. and 6:00 p.m.) or once a day (2:00 p.m.) The daily dose is, for example, 3 or 10 or 30 or 60 or 100 mg / kg body weight, the application volume 10 ml / kg body weight. The substances are formulated in the form of a 0.5% tylose suspension with 2% DMSO or a 0.5% tylose suspension. 9 days after the transplant and 16 hours after the last substance application, the animals are killed painlessly and the sponge is removed. The virus-infected cells are released from the sponge by KoUagenase digestion (330 U / 1.5 ml) and 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 according to vital color 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 polyvinylpyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate. Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

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

Composition:

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

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

Production: The Rhodigel is suspended in ethanol, the active ingredient is added to the suspension. The water is added with stirring. The swelling of the Rhodigel is stirred for about 6 hours.

Claims

Patentansprflche 1. Compound of the formula

in which the remainder -NHC (O) NHR ² is bound to the aromatic system via one of the positions 2 or 3, 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, hydroxycarbonyl, aminocarbonyl, -Cö-alkoxy, C ₆ -C ₁₀ aryl, amino, C _Ö - alkylamino, C _ϊ -C ₆ alkoxycarbonyl, CC ₆ - alkylaminocarbonyl, Ci- C ₆ -alkylcarbonylamino and C ₆ -Cιo-arylcarbonylamino, R ^{2 represents} C ₃ -C ₀ -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, trifluoromethyl, Cι-C ₆ -alkoxy, hydroxycarbonyl, Ci-C _ö -Alk- oxycarbonyl, amino, Cι-C ₆ - alkylamino, Ci-Ce-alkylaminocarbonyl and d-Ce-alkyl, R ³ is dC _ö - represents 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, C ₆ -Cι ₀ aryl, amino, and Cι-C ₆ -alkylamino, R ⁴ . 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 ₆ - alkoxy, Cö-Cio-aryl, amino and C _t -Ce- alkylamino, and R ⁵ for hydrogen, halogen, hydroxyl, cyano, C ₁ -C ₆ alkoxy, carboxy, C _ϊ -C _ö alkoxycarbonyl, aminocarbonyl, C _t -C _ö alkylaminocarbonyl, Amino, -CC ₆ - alkylamino or -CC ₆ alkyl, or one of their salts, their solvates or the solvates of their salts. Connection according to claim 1, characterized in that the remainder -NHC (O) NHR ² is bound to the aromatic system via position 3, R ¹ is hydrogen or _Cι-C3 alkyl, where alkyl may be substituted with 0, 1, 2 or 3 substituents independently selected from the group consisting of hydroxy, aminocarbonyl, Ci- C ₆ alkoxy, C -C _{ö ö-} aryl, amino, C _Ϊ -C ₆ -alkylamino, -Cβ-alk-oxycarbonyl, Cι-C ₆ - alkylaminocarbonyl, CrC _ö -alkylcarbonylamino and C _ö - o-arylcarbonylamino, R ^{2 represents} C ₃ -C ₀ cycloalkyl or phenyl, where phenyl can be substituted by 0, 1, 2 or 3 substituents independently selected from the group consisting of halogen, cyano, trifluoromethyl and -Cβ-alkyl, R ³ represents C 1 -C 4 -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- ₀ -aryl , Amino and -CC ₆ - alkylamino, R ^{4 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 -Ciö Aryl, amino and Ci-Ce alkylamino, and R ^{5 represents} hydrogen, halogen or -CC ₆ alkyl, or one of their salts, their solvates or the solvates of their salts. 3. A compound according to claim 1 or 2, characterized in that the rest -NHC (O) NHR is attached to the aromatic system via position 3, R ^{1 represents} hydrogen or -Cs-alk l, where alkyl can be substituted with 0, 1 or 2 substituents independently of one another selected from the group consisting of hydroxy, C ₁ -C ₃ -alkoxy, amino and Ci-Cs-alkylamino, 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, trifluoromethyl and C ₁ -C ₃ -alkyl, R ³ represents C ₁ -C ₃ -alkyl, R ^{4 represents} hydrogen or -CC ₃ alkyl, and R represents hydrogen, fluorine, chlorine or methyl, or one of their salts, their solvates or the solvates of their salts. 4. A compound according to claim 1, characterized in that the residue -NHC (O) NHR ² is bonded to the aromatics via position 3. 5. A compound according to claim 1, 2 or 4, characterized in that R ^{1 represents} hydrogen or -CC ₃ alkyl, where alkyl can be substituted by 0, 1 or 2 substituents independently selected from the group consisting of hydroxy, -CC ₃ alkoxy, amino and -Cs alkylamino. 6. A compound according to any one of claims 1 to 5, characterized in that R ^{2 is} adamantyl or phenyl, where phenyl can be substituted with 0, 1 or 2 substituents independently selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl and methyl. 7. A compound according to any one of claims 1 to 6, characterized in that R ^{3 is} methyl. 8. A compound according to any one of claims 1 to 7, characterized in that R ^{4 is} methyl. 9. Connection according to one of claims 1 to 8, characterized in that R ^{5 represents} hydrogen or fluorine. 10. A method for producing a compound of formula (I) according to claim 1, characterized in that a compound of formula

in which -NH is bound to the aromatics via one of the positions 2, 3, 5 or 6, and R ¹ , R ³ , R ⁴ and R ^{5 have} the same meaning as in formula (I), with a compound of the formula OCN - R ² (m) in which R ^{2 has} the same meaning as in formula (I), is reacted and the resulting compound of the formula (I) is reacted, if appropriate with the corresponding (i) solvents and / or (ii) bases or acids, to give one of its salts, its solvates or the solvates of its salts. 11. A compound according to any one of claims 1 to 9 for the treatment and / or prophylaxis of diseases. 12. Medicament containing a compound according to any one of claims 1 to 9 in combination with an inert, non-toxic, pharmaceutically suitable excipient. 13. Use of a compound according to one of claims 1 to 9 for Manufacture of a medicament for the treatment and / or prophylaxis of viral infections. 14. Use according to claim 13, characterized in that the virus infection is an infection with the human cytomegalovirus (HCMV) or another representative of the group of Heφes viridae. 15. Medicament according to claim 12 for the treatment and / or prophylaxis of viral infections. 16. A method for combating viral infections in humans and animals by administering an antivirally effective amount of at least one compound according to one of claims 1 to 9, a medicament according to claim 12 or a medicament obtained according to claim 13 or 14.