HK1199033B - Sulfonic acid salts of heterocyclylamide-substituted imidazoles - Google Patents

Abstract

The invention relates to sulfonic acid salts of heterocyclylamide-substituted imidazoles, and to solvates and hydrates thereof, to the use thereof for treating and/or preventing diseases, and to use thereof for producing drugs for treating and/or preventing diseases, in particular for use as antiviral agents, in particular against cytomegaloviruses.

Description

Sulfonate salts of heterocyclylamide-substituted imidazoles

The present invention relates to salts of compounds of the general formula:

wherein

R¹Represents methyl, ethyl, butyl or cyclopropylmethyl,

R²represents phenyl, wherein the phenyl is substituted by a substituent selected from the group consisting of trifluoromethoxy and difluoromethoxy, and

R³represents hydrogen, methyl, chlorine, methoxy or trifluoromethyl.

The invention also relates to methods for the production thereof, to the use thereof for the treatment and/or prophylaxis of diseases, and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular as antiviral agents, in particular against cytomegaloviruses.

Compounds of general formula (I) are known from, for example, WO2006/089664 and are developed by the applicant as candidates for promising antiviral active substances, in particular for combating Human Cytomegalovirus (HCMV) infections. However, in development, it has been shown that substances in aqueous solvents and strongly polar solvents exhibit insufficient solubility. The problem with respect to solubility is also increasing, since the compounds also exhibit insufficient solubility in the conditions present in the human stomach (about 0.1M HCl, pH-1), wherein the process may start with the in situ formation of the HCl salt.

It was therefore an object of the present invention to describe salts which exhibit a significantly improved solubility compared to the free base of the compounds of the general formula (I). In addition, these salts should also be stable for long periods of time under ordinary storage conditions. In particular, the compounds should not exhibit an increase in deliquescence. Moreover, the salts present in the dilute HCl solution should only be slowly converted to HCl salts to ensure as rapid and uniform a release as possible even under conditions such as those present in the human stomach.

It was found, surprisingly enough, that the organic sulfonate salts of the compounds of formula (I) exhibit excellent solubility compared to the free base, as well as a broad spectrum of other salts of the compounds of formula (I). In addition, these salts also exhibit the long-term stability necessary for use in pharmaceuticals. Furthermore, it has been shown that the salts of the present invention also exhibit high and uniform solubility under conditions equivalent to those in the human stomach.

The invention relates to salts of compounds of general formula (I) having an organic sulfonic acid or solvates or hydrates thereof.

Within the scope of the present invention, organic sulfonates are adducts of compounds of the general formula (I) reacted with organic sulfonic acids. In this regard, the compound of formula (I) and the organic sulfonic acid may be present in any ratio. In this case, the ratio is preferably an integer (e.g., 1:1,1:2,1:3,3:1,2: 1). In this case, these salts may be prepared by direct reaction of the compound of formula (I) with an organic sulphonic acid or by preparation of other acid salts of the compound of formula (I) followed by exchange of the counterion.

Within the scope of the present invention, those forms of the compounds of the invention which form complexes by coordination with solvent molecules are referred to as solvates. Hydrates are a special form of solvates in which coordination with water is carried out.

Within the scope of the present invention, preference is given to salts in which the organic sulfonic acid is methanesulfonic acid.

Within the scope of the present invention, the dimesylate salt is particularly preferred.

Within the scope of the present invention, salts having the following general formula are preferred:

within the scope of the present invention, particular preference is given to crystalline N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxyphenyl ] urea dimesylate which shows characteristic peaks in the powder-XRD diffractogram at about 6.37, 11.77, 12.56, 17.17, 18.81, 20.34, 21.47, 23.04, 35.46 degrees 2-theta.

Also preferred within the scope of the present invention is crystalline N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxy-phenyl ] urea bis-mesylate, which shows a powder-XRD diffractogram substantially as depicted in figure 1.

In general, the salts of the invention are prepared by reacting a compound of formula (I) with an organic sulfonic acid in a solvent.

The salts of the invention may also be prepared by reacting an acid salt of a compound of formula (I) with a source of the sulfonate anion of an organic sulfonic acid in a solvent, wherein the acid salt is not an organic sulfonate.

In the latter case, the source of the sulfonate anion may be an organic sulfonic acid or organic sulfonate.

The subject of the present invention is therefore also a process for the preparation of an organic sulfonate of a compound of the general formula (I), which comprises reacting a compound of the general formula (I) or a salt of a compound of the general formula (I) with a source of organic sulfonic acid or organic sulfonate anion in a solvent, wherein the salt of the compound of the general formula (I) is not an acid salt of an organic sulfonic acid.

The solvent is preferably selected in such a way that: which provides a good balance between the solubility of the compound of formula (I) or a salt of the compound of formula (I) which is not an organic sulphonate and the source of the organic sulphonic acid or sulphonate anion. Preferably, the salts of the invention should be as poorly soluble as possible in the solvent used. Optionally, however, the salts of the invention may also be precipitated by addition of a counter-solvent.

Examples of solvents used to prepare the salts of the present invention include the following: that is, alcohols such as methanol, ethanol, n-propanol, isopropanol, and butanol; ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane or tetrahydrofuran; hydrocarbons such as benzene or toluene; or other solvents such as acetone, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, heptane, dimethyl sulfoxide, or dimethylformamide.

Optionally, a counter solvent is added to precipitate the salts of the invention. Examples of such counter solvents include the following: i.e. water and alcohols such as methanol, ethanol or propanol.

The thus obtained salts of the invention may optionally be further processed, such as recrystallized or micronised, to further adapt their physical properties to the application.

Heterocyclyl amide substituted imidazoles useful for preparing the salts of the present invention are known and may be prepared, for example, according to the methods described in WO 2006/089664.

In particular, the preparation of the heterocyclylamide-substituted imidazoles used is carried out by means of the following, i.e. compounds of the general formula

Wherein

R¹And R²As defined above, and

R⁴represents a methyl group or an ethyl group,

in a first stage with a base and in a second stage with a compound of the general formula

Wherein

R³As defined above.

The reaction of the first stage is generally carried out in an inert solvent at atmospheric pressure, preferably at a temperature ranging from 0 ℃ up to the temperature at which reflux of the solvent occurs.

For example, the base is an alkali metal hydroxide such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or an alkali metal carbonate such as cesium carbonate, sodium carbonate or potassium carbonate. In this case, sodium hydroxide is preferred.

For example, the inert solvent is a halogenated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; ethers such as diethyl ether, methyl-tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene 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 crude oil fractions; or other solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile or pyridine, or mixtures of solvents with water. As the solvent, a mixture of ethanol and water is preferred.

The reaction of the second stage is generally carried out in an inert solvent, optionally in the presence of a base, preferably at atmospheric pressure, at a temperature in the range from-70 ℃ to 40 ℃.

For this, as the dehydrating reagent, suitable are, for example, carbodiimides such as N, N '-diethyl-, N' -dipropyl-, N '-diisopropyl-, N' -dicyclohexyl-carbodiimides, N- (3-dimethylaminoisopropyl) -N '-ethylcarbodiimide-hydrochloride (EDC), N-cyclohexylcarbodiimides-N' -propoxymethyl-polystyrene (PS-carbodiimides); or carbonyl compounds such as carbonyldiimidazole; or 1, 2-oxazolium compounds such as 2-ethyl-5-phenyl-1, 2-oxazolium-3-sulfate or 2-tert-butyl-5-methyl-isoxazolium-perchlorate; or an amido compound such as 2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloroformate, or bis- (2-oxo-3-oxazolidinyl) phosphoryl chloride or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HBTU), 2- (2-oxo-1- (2H) -pyridinyl) -1,1,3, 3-tetramethylurea hexafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), or 1-hydroxy-benzotriazole (HOBt) or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOB) or mixtures of the latter with bases.

For example, the base is an alkali metal carbonate such as sodium or potassium carbonate or bicarbonate, or an organic base such as a trialkylamine, for example triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine, or diisopropylethylamine or DBU, DBN, or pyridine; n-methylmorpholine is preferred.

The condensation with propanephosphonic anhydride (T3P) is preferably carried out in the presence of N-methylmorpholine (NMM).

For example, the inert solvent is a halogenated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane, or crude oil fractions; or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethylsulfoxide, acetonitrile or pyridine, in the case of water-soluble solvents, the inert solvent is also a mixture thereof with water; dimethylformamide is preferred.

The compounds of the formula (II) are known or can be prepared by reacting compounds of the formula (IV)

Wherein

R¹And R⁴As defined above, the above-mentioned,

in a first stage with a reducing agent and in a second stage, in the presence of a carbonic acid derivative, with a compound of the general formula

H₂N-R²(V)

Wherein

R²As defined above, the above-mentioned,

or in a second stage with a compound of the general formula

OCN-R²(VI),

Wherein

R²As defined above.

In this case, in the first stage, the reaction is generally carried out in an inert solvent, preferably at atmospheric pressure up to 3 bar, at a temperature ranging from 0 ℃ up to the temperature at which reflux of the solvent occurs.

For example, the reducing agent is palladium activated carbon and hydrogen, formic acid/triethylamine/palladium activated carbon, zinc/hydrochloric acid, iron/hydrochloric acid, iron (II) sulfate/hydrochloric acid, sodium sulfide, sodium disulfide, sodium hydrosulfite, ammonium polysulfide, sodium borohydride/nickel chloride, tin dichloride, titanium trichloride, or raney nickel and hydrazine aqueous solution; preferably raney nickel and hydrazine in water, palladium activated carbon and hydrogen, or formic acid/triethylamine/palladium activated carbon.

For example, the inert solvent is an ether such as diethyl ether, methyl t-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene 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 crude oil fractions; or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, in the case of water-soluble solvents, also in mixtures with water. As the solvent, methanol, ethanol, isopropanol, or in the case of aqueous solution of raney nickel and hydrazine, tetrahydrofuran is preferable.

The second stage of the reaction of the first variant is generally carried out in an inert solvent, preferably at atmospheric pressure, at a temperature ranging from room temperature up to 40 ℃.

For example, the carbonic acid derivative is N, N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, phenyl chloroformate, or 4-nitrophenyl chloroformate; n, N-carbonyldiimidazole is preferred.

For example, the inert solvent is a halogenated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or crude oil fractions; or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethylsulfoxide, acetonitrile or pyridine, and in the case of water-soluble solvents, the inert solvent is also a mixture thereof with water; dimethyl sulfoxide is preferred.

The second stage of the reaction of the second variant is generally carried out in an inert solvent, optionally in the presence of a base, preferably at atmospheric pressure, at room temperature up to a temperature at which reflux of the solvent occurs.

For example, the inert solvent is a halogenated hydrocarbon such as dichloromethane, trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1, 2-dichloroethane or trichloroethylene; ethers such as diethyl ether, methyl tert-butyl ether, 1, 2-dimethoxyethane, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether; hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or crude oil fractions; or other solvents such as ethyl acetate, acetone, dimethylformamide, dimethylacetamide, 2-butanone, dimethylsulfoxide, acetonitrile, or pyridine; tetrahydrofuran or dichloromethane is preferred.

The base is, for example, an alkali metal carbonate such as cesium carbonate, sodium carbonate or potassium carbonate, or potassium tert-butoxide, or another base such as sodium hydride, DBU, triethylamine or diisopropylethylamine, preferably triethylamine.

The compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula

Wherein

R¹And R⁴As defined herein, the amount of the compound in the composition,

optionally in acetic anhydride as solvent, preferably at atmospheric pressure, at temperatures in the range from room temperature up to 60 ℃, with fuming nitric acid, concentrated nitric acid, nitrating acid, or other mixed proportions of sulfuric and nitric acids.

The compounds of the formulae (III), (IV), (V), (VII) are known or can be synthesized according to known methods from the corresponding educts.

The preparation of heterocyclylamide substituted imidazoles for use in the preparation of the salts of the present invention is illustrated in more detail by the following examples of synthetic figures. In this regard, the composite map is defined by way of example only, and is in no way limiting.

Synthesis of a graph:

[ symbol: ]

Aceton ═ acetone

The salts of the invention exhibit an antiviral action on representatives of the group of the herpesviridae (herpesviruses), mainly on Cytomegalovirus (CMV), in particular on Human Cytomegalovirus (HCMV). They are therefore suitable for the treatment and/or prophylaxis of diseases, primarily infections with viruses, in particular the viruses mentioned herein, and infectious diseases resulting therefrom. Herein, viral infection is defined as infection by a virus and a disease caused by the viral infection.

The salts of the invention can be used, on the basis of their properties, for the preparation of medicaments suitable for the prophylaxis and/or treatment of diseases, in particular viral infections.

According to the type of indication, the following may be mentioned:

1) treatment and prevention of HCMV infection (retinitis, pneumonia, gastrointestinal infection) in AIDS patients.

2) Treatment and prevention of cytomegalovirus infections in bone marrow and organ transplant patients who are frequently infected with HCMV pneumonia, HCMV encephalitis, and life-threatening variants (versions) of gastrointestinal and systemic HCMV infections.

3) Treatment and prevention of HCMV infection in newborns and young children.

4) Treatment and prevention of acute HCMV infection in pregnant women.

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

Treatment of HCMV-positive cancer patients (review j. cinatl et al, FEMS Microbiology Reviews 2004,28,59-77) in order to slow the progression of HCMV-mediated tumors.

The salts according to the invention are preferably used for producing medicaments which are suitable for the prophylaxis and/or treatment of infections of representatives of the family herpesviridae, in particular of cytomegaloviruses, especially human cytomegaloviruses.

The salts of the present invention can be used for the treatment and/or prophylaxis of viral infections, in particular HCMV infections, based on their individual pharmacological properties and, if necessary, also in combination with other active ingredients, in particular antiviral active ingredients, such as valganciclovir (valganciclovir), ganciclovir (ganciclovir), valacyclovir (valacyclovir), acyclovir (acyclovir), foscarnet (foscarnet), cidofovir (cidofovir) and related derivatives.

Another subject of the invention is the use of the salts of the invention in a method for the treatment and/or prevention of a disease, preferably a viral infection, in particular an infection of Human Cytomegalovirus (HCMV) or representatives of the group of other herpesviridae.

A further subject of the present invention is the use of the salts according to the invention for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

A further subject of the present invention is the use of the salts according to the invention for the preparation of a medicament for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases.

A further subject of the invention is a method for the treatment and/or prophylaxis of diseases, in particular of the abovementioned diseases, using an antiviral effective amount of a salt according to the invention.

The salts of the invention may have systemic and/or local effects. For this purpose, they can be administered in a suitable manner, such as by, for example, buccal, parenteral, pulmonary, intranasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, aural or as an implant or stent.

For these methods of administration, the salts of the invention may be administered in a suitable form of administration.

For oral administration, administration forms which deliver the salts of the invention in a rapid-acting and/or modified manner and which comprise the compounds of the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (uncoated or coated tablets, for example coated with a gastric juice-resistant or slowly soluble or insoluble coating which controls the release of the compounds of the invention), tablets which dissolve rapidly in the oral cavity or films/wafers (wafers), films/lyophilisates (lyophilites), capsules (for example hard or soft gelatin capsules), coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solvents, are suitable, according to the state of the art.

Parenteral administration can be accomplished by bypassing the resorption step (e.g., by intravenous, intra-arterial, intra-cardiac, intra-spinal or intra-lumbar means) or by including resorption (e.g., by intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal means). For parenteral administration, in particular, injectable and infusible preparations in the form of solutions, suspensions, emulsions, lyophilized powders or sterile powders are suitable as administration forms.

For other methods of administration, suitable are, for example, inhalation forms of medicaments (in particular powder inhalers, nebulizers), nasal drops, nasal solutions, nasal sprays; tablets for lingual, sublingual or buccal administration; film/wafer or capsule, suppository, ear or eye preparation, vaginal capsule, aqueous suspension (lotion, shaking mix), lipophilic suspension, ointment, cream, transdermal therapeutic system, cream (milk), paste, foam, dispersion (scraped powder), implant or stent.

The salts of the invention can be converted into the cited administration forms. This can be done in a manner known in the art by mixing with inert, non-toxic, pharmaceutically suitable adjuvants. These adjuvants include, inter alia, carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium lauryl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants such as ascorbic acid), dyes (e.g., inorganic pigments such as iron oxide), and flavoring and/or odor modifiers.

Within the scope of the present invention, agents with 5-12.5mg/ml of the salt according to the invention, 50-150mg/ml of hydroxypropyl- β -cyclodextrin, 0.5-2.0mg/ml of sodium acetate and water, and optionally with other pharmaceutically harmless adjuvants, are preferred.

Further subjects of the invention are pharmaceutical agents comprising at least one salt according to the invention, usually together with one or more inert, non-toxic, pharmaceutically suitable adjuvants, and their use for the above-mentioned purposes.

In general, it has been shown that in the case of intravenous administration, an amount of about 0.001-10mg/kg, preferably about 0.001-5mg/kg of body weight, relative to the pure active ingredient, is advantageous to obtain effective results. In the case of oral administration, the dosage is generally about 0.01 to 25mg/kg, preferably 0.1 to 10mg/kg, of body weight.

However, optionally, it may be necessary to deviate from the above amounts, particularly based on body weight, administration method, individual behavior with respect to the active ingredient, type of formulation, and time or interval at which administration is carried out. Thus, in some cases, less than the minimum amount described above may be sufficient, while in other cases, the upper limit described above must be exceeded. In the case of larger amounts, it is advisable to divide the latter into several separate administrations during the day.

The invention will now be explained in more detail below on the basis of embodiments and with reference to the drawings. Here:

FIG. 1: the powder-XRD diffractogram of the salt of example 1 is shown.

Unless otherwise indicated, percentages in the following tests and examples are percentages by weight; parts are parts by weight. In each case, the solvent ratio, dilution ratio, and concentration information of the liquid/liquid solution are related to volume.

Examples

Abbreviations used

Ex. examples

TLC thin layer chromatography

DMF N, N-dimethylformamide

DMSO dimethyl sulfoxide

Th.th. theoretical

EI Electron bombardment ionization (MS middle)

ESI electrospray ionization (MS middle)

h hours

HPLC high pressure high performance liquid chromatography

LC-MS liquid chromatography-mass spectrometry combination

MS Mass Spectrometry

NMR nuclear magnetic resonance spectrum

RP-HPLC reversed phase HPLC

RT Room temperature

R_tRetention time (for HPLC)

TBTU O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylhexafluoro-boronic acid urea

THF tetrahydrofuran

HPLC and LC-MS methods:

method 1(LC-MS): the instrument comprises the following steps: micromass QuattROLCZ loaded with HPLC Agilent Series 1100; column: phenomenex Synergi 2. mu. Hydro-RP Mercury 20mm x 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l of acetonitrile +0.5ml of 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min,2.5min/3.0min/4.5min 2 ml/min; oven: 50 ℃; and (4) UV detection: 208-400 nm.

Method 2 (LC-MS):the instrument comprises the following steps: micromass platform for LCZ loaded with HPLC Agilent Series 1100; column: phenomenex Synergi 2. mu. Hydro-RP Mercury 20mm x 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l of acetonitrile +0.5ml of 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min,2.5min/3.0min/4.5min 2 ml/min; oven: 50 ℃; and UV detection is 210 nm.

Method 3 (LC-MS):MS device type: micromass ZQ; HPLC apparatus type: waters Alliance 2795; column: phenomenex Synergi 2. mu. Hydro-RP Mercury 20mm x 4 mm; eluent A: 1l of water +0.5ml50% formic acid, eluent B: 1l of acetonitrile +0.5ml of 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min,2.5min/3.0min/4.5min 2 ml/min; oven: 50 ℃; and UV detection is 210 nm.

Method 4 (LC-MS):MS device type: micromass ZQ; HPLC apparatus type: HP 1100 Series; UVDAD; column: phenomenex Synergi 2. mu. Hydro-RP Mercury 20mm x 4 mm; eluent A: 1l of water +0.5ml of 50% formic acid, eluent B: 1l of acetonitrile +0.5ml of 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min,2.5min/3.0min/4.5min 2 ml/min; oven: 50 ℃; and (4) UV detection: 210 nm.

Method 5 (analytical HPLC):column: kromasil 100RP-18,60mm x 2.1mm,3.5 μm; eluent A: water + 0.5% perchloric acid (70%), eluent B: acetonitrile; gradient: 0min 2% B,0.5min 2% B,4.5min 90% B,9min 90% B,9.2min 2% B,10min 2% B; the flow rate is 0.75 ml/min; column temperature: 30 ℃; and (3) detection: UV 210 nm.

Starting compounds

Example 1A

1- (cyclopropylmethyl) -4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1H-imidazole-2-carboxylic acid

Stage 1

1- (cyclopropylmethyl) -4-nitro-1H-imidazole-2-carboxylic acid ethyl ester

15g (81mmol) of ethyl 4-nitro-1H-imidazole-2-carboxylate are stirred under argon at 80 ℃ together with 13.13g (97.2mmol) of cyclopropylmethyl bromide and 22.4g (162mmol) of potassium carbonate in 165ml of DMF for 1H. After cooling, the reaction mixture was diluted with water and extracted 4 times with ethyl acetate. The combined organic phases were washed 1 time with water and 3 times with saturated sodium chloride solution, dried over magnesium sulfate and concentrated by evaporation in vacuo. The crystalline residue was immediately reused for the next reaction.

Yield: 17.59g (70% of theory)

LC-MS (method 1) R_t＝2.02min.

MS(ESI⁺):m/z＝240[M+H]⁺

¹H-NMR(300MHz,DMSO-d₆):＝8.2(s,1H),4.4(q,2H),4.3(d,2H),1.4(m,4H),0.55(q,2H),0.45(q,2H)ppm。

Stage 2

4-amino-1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester

3.89g (16.26mmol) of 1- (cyclopropylmethyl) -4-nitro-1H-imidazole-2-carboxylic acid ethyl ester were dissolved in 50ml of THF and mixed with one full shovel of Raney nickel. The reaction mixture was hydrogenated with hydrogen in a hydrogenation unit at room temperature. The catalyst was filtered off and the filtrate was concentrated by evaporation in vacuo. The evaporation residue was immediately reused for the next reaction.

Yield 3.46g (100% of theory)

LC-MS (method 2) R_t＝1.21min.

MS(ESI⁺):m/z＝210[M+H]⁺

¹H-NMR(300MHz,DMSO-d₆):＝6.55(s,1H),4.55(s,2H),4.2(q,2H),4.1(d,2H),1.25(tr,3H),1.2(m,1H),0.5(q,2H),0.3(q,2H)ppm。

Stage 3

4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester

7.49g (35.8mmol) of 4-amino-1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid ethyl ester are mixed with 6g (35.8mmol) of 4- (trifluoromethoxy) phenyl isocyanate in 18ml of THF under argon and stirred at room temperature for 4 hours. The reaction mixture is concentrated by evaporation in vacuo, and the product crystallized in this case is stirred in 40ml of ethyl acetate and sucked off.

Yield 11.1g (82% of theory)

LC-MS (method 1) R_t＝2.66min.

MS(ESI⁺):m/z＝376[M+H]⁺

¹H-NMR(300MHz,DMSO-d₆):＝9.45(s,1H),8.0(d,1H),7.35(s,1H),7.3(d,1H),7.2(dd,1H),4.3(q,2H),4.25(d,2H),2.25(s,3H),1.3(tr,3H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm。

Stage 4

4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1- (cyclopropylmethyl) -1H-imidazole-2-carboxylic acid

10.6g (28.1mmol) ethyl 4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1- (cyclopropylmethyl) -1H-imidazole-2-carboxylate are suspended in 158ml ethanol. While cooling with ice, 16.4ml of water and 6ml (112mmol) of a 50% aqueous solution of sodium hydroxide were added. The reaction mixture was stirred at room temperature for 1 hour and then concentrated by evaporation in vacuo. The residue was dissolved in 100ml of isopropanol and mixed with 100ml of 1N hydrochloric acid while cooling with ice. The crystals were aspirated and dried in vacuo at 40 ℃.

Yield 9.85g (100% of theory)

LC-MS (method 3) R_t＝1.74min

MS(ESI⁺):m/z＝349[M+H]⁺

¹H-NMR(400MHz,DMSO-d₆):＝9.4(s,1H),8.0(d,1H),7.3(s,1H),7.25(d,1H),7.2(dd,1H),4.25(d,2H),2.25(s,3H),1.25(m,1H),0.55(q,2H),0.35(q,2H)ppm。

Example 2A

1-butyl-4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1H-imidazole-2-carboxylic acid

The preparation was carried out analogously to example 1A.

Yield 2.05g (96% of theory)

LC-MS (method 3) R_t＝1.96min.

MS(ESI⁺):m/z＝387[M+H]⁺

¹H-NMR(300MHz,DMSO-d₆) 9.0(s,1H),8.9(s,1H),7.55(d,2H),7.3(s,1H),7.25(d,1H),4.35(tr,2H),1.7 (quintet, 2H),1.25 (sextet, 2H),0.9(tr,3H) ppm.

Example 3A

1-methyl-4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1H-imidazole-2-carboxylic acid ethyl ester

1.22g (3.61mmol) of ethyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (synthesis analogous to example 1A, stage 3, or otherwise according to Tetrahedron Lett.2003,44,1607 and the references cited therein) are mixed with 1.46g (7.21mmol) of 4- (trifluoromethoxy) phenylisocyanate in 50ml of THF under argon and stirred at room temperature overnight. The reaction mixture was filtered, the filtrate was concentrated by evaporation in vacuo and purified by chromatography.

Yield 860mg (62% of theory)

LC-MS (method 4) R_t＝2.41min.

MS(ESI+):m/z＝373[M+H]+

¹H-NMR(300MHz,DMSO-d₆):＝8.98(bs,2H),7.55(m,2H),7.36(s,1H),7.29(m,2H),4.28(q,2H),3.91(s,3H),1.30(t,3H)。

Example 4A

1-methyl-4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1H-imidazole-2-carboxylic acid

835mg (2.13mmol) of ethyl 1-methyl-4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1H-imidazole-2-carboxylate (example 3A) are suspended in 5ml of ethanol and 12ml of tetrahydrofuran. While cooling with ice, 2ml (25mmol) of a 50% aqueous sodium hydroxide solution was added. The reaction mixture was stirred at room temperature overnight and then acidified with 1N hydrochloric acid while cooling with ice. The solution was extracted with dichloromethane. The organic phase was concentrated by vacuum evaporation. The residue was purified by preparative HPLC.

Yield 346mg (44% of theory)

LC-MS (method 3) R_t＝1.62min.

MS(ESI⁺):m/z＝345[M+H]⁺

¹H-NMR(400MHz,DMSO-d₆):＝9.33(bs,1H),8.98(bs,1H),7.55(m,2H),7.30(s,1H),7.28(m,2H),3.90(s,3H)。

Example 5A

1-ethyl-4- [ ({ [4- (trifluoromethoxy) phenyl ] amino } carbonyl) amino ] -1H-imidazole-2-carboxylic acid

The preparation was carried out analogously to example 4A.

Yield 425mg (91% of theory)

LC-MS (method 4) R_t＝1.94min.

MS(ESI⁺):m/z＝359[M+H]⁺

¹H-NMR(300MHz,DMSO-d₆):＝10.3(bs,1H),7.67(m,2H),7.24(s,1H),7.20(m,2H),4.45(q,2H),1.33(t,3H)。

Example 6A

4- [ ({ [4- (difluoromethoxy) phenyl ] amino } carbonyl) amino ] -1-methyl-1H-imidazole-2-carboxylic acid

The preparation was carried out analogously to example 4A.

Yield 964mg (81% of theory)

HPLC (method 5) R_t＝3.57min.

MS(ESI⁺):m/z＝327[M+H]⁺

¹H-NMR(400MHz,CDCl₃):＝8.9(s,1H),8.8(s,1H),7.5(d,2H),7.3(s,2H),7.1(t,1H),7.09(d,2H),3.9(s,3H)。

Example 7A

1- (5-methylpyridin-2-yl) piperazine

Stage 1

1- (tert-butyloxycarbonyl) -4- (5-methylpyridin-2-yl) piperazine

2.50g (19.6mmol) of 2-methyl-5-chloropyridine and 4.38g (23.5mmol) of N- (tert-butoxycarbonyl) -piperazine were dissolved in 50ml of anhydrous toluene under an argon atmosphere. Then, 2.26g (23.5mmol) of sodium tert-butylate, 0.37g (0.59mmol) of BINAP and 0.36g (0.39mmol) of tris (dibenzylideneacetone) dipalladium were added and heated at 70 ℃ for 12 hours. After cooling, the reaction mixture was mixed with diethyl ether, washed 3 times with saturated sodium chloride solution, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was purified by flash chromatography (cyclohexane/ethyl acetate 9: 1).

Alternatively, the coupling reaction may be carried out using palladium- (II) -acetate as a catalyst.

Yield 5.27g (97% of theory)

LC-MS (method 3) R_t＝1.26min.

MS(ESI⁺):m/z＝278[M+H]⁺

¹H-NMR(300MHz,CDCl₃):＝8.02(d,1H),7.34(dd,1H),6.59(d,1H),3.55(m,4H),3.45(m,4H),2.21(s,3H),1.49(s,9H)。

Stage 2

1- (5-methylpyridin-2-yl) piperazine

3.47g (12.5mmol) of 1- (tert-butoxycarbonyl) -4- (5-methylpyridin-2-yl) piperazine were dissolved in 10ml of dioxane and combined with 31ml (125mmol) of dioxane (4mol) containing hydrogen chloride. It was allowed to stir at room temperature for 2 hours. Then, it is concentrated by evaporation, the residue is basified with 1M sodium hydroxide solution and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, concentrated by evaporation and dried in vacuo.

Alternatively, the compound of example 7A can also be isolated as a hydrochloride salt.

Yield: 2.18g (98% of theory)

LC-MS (method 4) R_t＝0.38min.

MS(ESI⁺):m/z＝177[M+H]⁺

¹H-NMR(300MHz,CDCl₃):＝8.02(d,1H),7.32(dd,1H),6.59(d,1H),3.45(m,4H),3.00(m,4H),2.20(s,3H)。

Example 8A

N- { 1-methyl-2- [ (4-pyridin-2-yl-piperazin-1-yl) carbonyl ] -1H-imidazol-4-yl } -N' - [4- (trifluoromethoxy) phenyl ] urea

1.50g (4.36mmol) of the compound from example 4A are dissolved in30 ml of DMF and combined with 1.82g (5.66mmol) O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyltetrafluoroboric acid urea (TBTU) and 266mg (2.18mmol) of 4-dimethylaminopyridine. 925mg (5.66mmol) of 1- (pyridin-2-yl) piperazine was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was purified by RP-HPLC.

Yield 1.79g (83% of theory)

LC-MS (method 1) R_t＝1.83min.

MS(ESI⁺):m/z＝490[M+H]⁺

¹H-NMR(400MHz,DMSO-d₆):＝8.89(bs,2H),8.12(d,1H),7.55(m,3H),7.29(m,2H),7.20(s,1H),6.88(d,1H),6.68(dd,1H),4.02(bs,2H),3.77(s,3H),3.71(bs,2H),3.58(bs,4H)。

Example 9A

N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] carbonyl } -1H-imidazol-4-yl) -N' - [4- (trifluoromethoxy) phenyl ] urea

5.6g (26.14mmol) of the compound of example 7A and 13.22g (130.7mmol) of N-methylmorpholine are added to a solution of 9.0g (26.14mmol) of the compound of example 4A in 110ml of ethyl acetate and the reaction mixture is cooled to 0 ℃. 16.63g (52.26mmol) of propanephosphonic anhydride (T3P) are added to the reaction solution over a period of 90 minutes, and the resulting suspension is stirred at this temperature for a further 10 minutes. The reaction mixture was then heated to 20 ℃ for 60 minutes and stirred at this temperature overnight. Unreacted T3P was quenched by the addition of 45ml water and the reaction mixture was stirred for an additional 10 minutes. Then, the phases were separated and the organic phase was washed several times with water (3X 45ml) set to pH 5. The combined aqueous phases were washed 1 more time with ethyl acetate and the combined organic phases were washed 2 times with 45ml of aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated by evaporation. The crude product obtained was recrystallized from ethanol, after which the final product was obtained as a light yellow solid.

Yield 8.42g (64% of theory)

LC-MS (method 4) R_t＝2.01min.

MS(ESI⁺):m/z＝504[M+H]⁺

¹H-NMR(300MHz,DMSO-d₆):＝8.92(bs,2H),7.99(d,1H),7.54(m,2H),7.42(dd,1H),7.28(m,2H),7.20(s,1H),6.80(d,1H),4.00(bs,2H),3.77(s,3H),3.72(bs,2H),3.51(bs,4H),2.16(s,3H)。

Example 10A

N- (2- { [4- (5-chloropyridin-2-yl) piperazin-1-yl ] carbonyl } -1-ethyl-1H-imidazol-4-yl) -N' - [4- (trifluoromethoxy) phenyl ] urea

Preparation was carried out from example 5A analogously to example 9A.

Yield 55mg (68% of theory)

LC-MS (method 4) R_t＝2.76min.

MS(ESI⁺):m/z＝538[M+H]⁺

¹H-NMR(300MHz,DMSO-d₆):＝8.97(bs,1H),8.92(bs,1H),8.14(d,1H),7.65(dd,1H),7.54(m,2H),7.28(m,2H),7.24(s,1H),6.92(d,1H),4.16(q,2H),3.97(bs,2H),3.72(bs,2H),3.59(bs,4H),1.32(t,3H)。

Example 11A

N- (2- { [4- (4-methoxyphenyl) piperazin-1-yl ] carbonyl } -1-methyl-1H-imidazol-4-yl) -N' - [4- (trifluoromethoxy) phenyl ] urea

From example 4A, the preparation was carried out analogously to example 9A.

Yield 35mg (58% of theory)

LC-MS (method 3) R_t＝2.24min.

MS(ESI⁺):m/z＝519[M+H]⁺

¹H-NMR(400MHz,DMSO-d₆):＝8.89(bs,2H),7.53(m,2H),7.28(m,2H),7.19(s,1H),6.92(m,2H),6.84(m,2H),4.05(bs,2H),3.75(m,5H),3.69(s,3H),3.08(bs,4H)。

Example 12A

N- [4- (difluoromethoxy) phenyl ] -N' - (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) urea

From example 6A, the preparation was carried out analogously to example 9A.

Yield 17mg (29% of theory)

LC-MS (method 4) R_t＝1.70min.

MS(ESI⁺):m/z＝486[M+H]⁺

¹H-NMR(400MHz,DMSO-d₆):＝8.84(bs,1H),8.77(bs,1H),7.98(d,1H),7.47(m,2H),7.42(dd,1H),7.18(s,1H),7.11(t,1H),7.10(m,2H),6.80(d,1H),4.01(bs,2H),3.77(s,3H),3.71(bs,2H),3.50(bs,4H),2.16(s,3H)。

The examples of table 1 were prepared similarly to example 8A.

TABLE 1

Detailed description of the preferred embodiments

Example 1

N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxyphenyl ] urea disulphonate

All operations were carried out under a nitrogen capping gas atmosphere. In a reaction vessel, 3,202g of the compound of example 9A (6.36mol,1 equivalent) are mixed with a mixture consisting of 15 l of THF and 1l of water. The resulting suspension was slowly heated to 60 ℃ and then stirred at this temperature for 30 minutes. 1,252g methanesulfonic acid (13.03mol,2.05eq.) was added to the resulting pale yellow solution, followed by incubation with N- (1-methyl-2- { [4- (5-methyl-pyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxyphenyl ] urea dimesylate. Over a period of 2 hours, a further 30 l of THF were added to the suspension resulting from the crystallization of N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxyphenyl ] urea disulphonate. The suspension was slowly cooled to 20 ℃ and then stirred at this temperature for a further 12 hours. The crystals formed were collected by vacuum filtration and the reactor was flushed sequentially with THF and n-heptane, whereby these organic phases were subsequently used to wash the crystals. Finally, the crystals were dried on a filter under vacuum and under a stream of nitrogen. 4,262g (yield: 96.4%, purity > 99%) of the desired bis-mesylate salt were obtained.

¹H-NMR(400MHz,DMSO-d₆):＝9.07(s,1H),8.98(s,1H),7.99(s,1H),7.92(d,1H),7.56(d,2H),7.41(d,1H),7.33-7.24(m,3H),4.18(s,br.,2H),3.92-3.69(m,9H),2.43-2.39(s,6H),2.25(s,3H)。

The X-ray diffraction pattern described in figure 1 was recorded using a Rigaku MiniFlex powder-XRD spectrometer.

The compounds of example 8A and examples 10A-15A can be similarly converted to the bis-mesylate salt.

Solubility study

20mg of the compound of example 1, and the citrate, maleate, sulfate and tartrate salts of the compound of example 9A used for comparison, and the chloride salts of the compound of example 9A with 1,2 and 4 equivalents of hydrochloric acid, and free bases, were weighed into an HPLC glassware equipped with a magnetic stirrer. 1ml of H was added to each₂O, and sealing the HPLC glassware. The resulting suspension was stirred at 25 ℃ overnight. To assess the amount of dissolved material, the suspension was filtered through a pipette microfilter and the resulting filtrate was diluted 1:4 and analyzed by HPLC. HPLC analysis was performed on a Dionex LunaRP18(100A) column with the following dimensions: 5 μm 50X 4.6mm using a 3:7 ratio of acetonitrile and H₂An isocratic mixture of O + 0.1% TFA.

As a result of the solubility measurement, the values described in table 2 below were determined.

TABLE 2

Compound (I)	Solubility [ mg/ml ]]
		Example 9A, free base	0.004
Example 9A, citrate salt	0.42
		Example 9A, maleate salt	0.12
Example 9A, sulfate salt	0.18
		Example 9A, tartrate salt	0.72
Example 9A, chloride, 1eq.	0.19
		Example 9A, chloride, 2eq.	0.07
Example 9A, chloride, 4eq.	0.11
		Example 1	>9.70

These values clearly show the excellent solubility of the salt of example 1 in aqueous media relative to the salts of the other compounds of example 9A.

Solubility in simulated human stomach conditions

To determine the solubility under simulated human stomach conditions, the salt of example 1 as well as the citrate and tartrate salts of example 9A and the corresponding free base in aqueous sodium chloride solution (0.2% by weight), which was set to pH 1.2 with hydrochloric acid, were stirred for 5 hours. The sample is then processed as described above. And the amount of free base in the solution was determined by HPLC. Table 3 below shows the corresponding values of solubility under simulated human stomach conditions.

TABLE 3

The table clearly shows the significantly better solubility of the salts of the invention under simulated human gastric conditions. In this regard, it should be noted that a freshly emerging suspension can be observed after allowing the solution to stand for an extended period of time. It is expected that the latter results from the formation of the poorly soluble chloride salt of example 9A. This observed formation of insoluble chloride salts is believed to be not severe, however, since the latter-mainly when used according to example 1-has a delayed access, so that initially a metastable supersaturated solution is present. This further demonstrates the advantages that can be obtained by using the salts of the invention for the preparation of a medicament.

Deliquescence property

The deliquescence of the salts according to the invention was measured by storing the salt of example 1 in pure form at about 46% relative atmospheric humidity and 24 ℃. In this case, the salt of example 1 exhibited a weight gain of less than 0.11% after about 2 days of storage time, which represents acceptable deliquescence for use in medicine.

B. Assessment of physiological efficacy

The in vitro effect of the compounds of the invention on the replication of HCMV (human cytomegalovirus) can be demonstrated in the following antiviral assays:

HCMV fluorescence reduction assay

The test compounds were used as a 50 millimolar (mM) solution in dimethyl sulfoxide (DMSO). As reference compounds, it is possible to use, for exampleOr other compound of example 9A the day before the start of the test, 1.5 × 10⁴Human foreskin fibroblasts (NHDF cells)/well were seeded in 200. mu.l cell culture medium in B2-G11 wells (black translucent bottom) of a 96 well plate. The wells at the edge positions of each 96-well plate were only filled with 200. mu.l of medium to avoid edge effects. On the day of testing, cell culture medium was aspirated from B2-G11 wells of each 96-well plate and replaced with 100. mu.l of virus suspension (multiplicity of infection (MOI): 0.1-0.2). The virus used was a recombinant HCMV incorporating an expression module for Green Fluorescent Protein (GFP) in the viral genome (HCMV AD 169 RV-HG, E.M.Borst, K.Wagner, A.Binz, B.Sodeik, and M.Messerle,2008, J.Virol.82: 2065-. At 37 deg.C, 5% CO₂After 2 hours of incubation, the virus was aspirated and all wells except column 3 wells were filled with 200 μ l of cell culture medium. Column 2 was not further treated and used as a virus control. In each case, the wells of column 3 were filled with 300 μ l of the test substance (diluted in cell culture medium) in a two-pass assay format. The concentration of the respective antiviral substances in column 3 is the EC expected in each case₅₀About 27 times the concentration of the value. The test substance in column 3 was diluted in 8 steps 1:3 across a 96-well plate by transferring 100 μ l of the column in each case into the right-hand column in each case — and mixing there with the existing 200 μ l of cell culture medium. With the sameIn this way, three antiviral substances were tested in a two-time assay format. 37 ℃/5% CO₂The plate was incubated for 7 days, then, all wells of the plate were washed with PBS (phosphate buffered saline) 3 × and filled with 50. mu.l of PBS, then, the GFP intensity of each well of the 96-well plate was determined by a fluorescence reader (FluoBox; Bayer technology Services GmbH; filter parameters: GFP, Ex 480nm, Em 520 nm.) thus, the EC against HCMV substances could be determined from the thus obtained measurement values₅₀：

EC₅₀(GFP-RA) ═ substance concentration in μ M, reduced GFP fluorescence in infected cells by 50% compared to untreated virus controls.

Representative in vitro activity data for the compounds of the invention are reproduced in table 4:

TABLE 4

Embodiments of the pharmaceutical composition

The compounds of the invention can be converted into the following pharmaceutical preparations:

tablet formulation：

Composition of：

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

The tablet weight is 212 mg. The diameter is 8mm, and the curvature radius is 12 mm.

Preparation:

the mixture of active ingredient, lactose and starch was granulated with a 5% solution of PVP in water (m/m). After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture is compressed using a conventional tablet press (tablet format, see above). A pressure of 15kN was used as a guide value for pressing.

Suspensions that can be administered orally:

consists of the following components:

1,000mg of the compound of example 1,1,000 mg of ethanol (96%), 400mg of Rhodigel (xanthan gum, FMC company, Pennsylvania, USA) and 99g of water.

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

Preparation:

rhodigel is suspended in ethanol and the active ingredient is added to the suspension. While stirring, water was added. It is stirred for about 6 hours until the swelling of the Rhodigel is complete.

Solutions that can be administered intravenously:

consists of the following components:

5.53g of the compound of example 1,1,000 g of water for injection purposes (which contains 10% (w/v) hydroxypropyl-. beta. -cyclodextrin (Aldrich)), and 985mg of sodium acetate.

Preparation:

the compound of the invention was dissolved in water with stirring and the pH of the solution was adjusted to about pH 3.94 with sodium acetate. The solution was sterilized by filtration (pore size 0.22 μm) and poured under sterile conditions into heat sterilized infusion bottles. The latter are sealed with infusion stoppers and flanged caps (flanges caps).

Claims (9)

1. A salt of a compound of formula (I):

wherein the salt is crystalline N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxyphenyl ] urea dimesylate, wherein the powder-XRD diffractogram shows characteristic peaks at 6.37, 11.77, 12.56, 17.17, 18.81, 20.34, 21.47, 23.04 and 35.46 degrees 2 theta.

2. The salt of claim 1, wherein the salt is crystalline N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxyphenyl ] urea dimesylate, characterized by the powder-XRD diffractogram as depicted in figure 1.

3. A process for the preparation of a salt of a compound of formula (I) as claimed in claim 1 or 2, which comprises reacting the compound N- (1-methyl-2- { [4- (5-methylpyridin-2-yl) piperazin-1-yl ] -carbonyl } -1H-imidazol-4-yl) -N' - [ 4-trifluoromethoxyphenyl ] urea with methanesulfonic acid.

4. A medicament comprising a salt according to claim 1 or 2 and at least one inert, non-toxic, pharmaceutically suitable adjuvant.

5. The medicament according to claim 4, wherein it comprises 5-12.5mg/ml of the salt according to claim 1 or 2, 50-150mg/ml of hydroxypropyl- β -cyclodextrin, 0.5-2.0mg/ml of sodium acetate and water, and optionally other pharmaceutically harmless adjuvants.

6. The medicament of claim 4 or 5 for the treatment and/or prevention of a viral infection.

7. The medicament of claim 6, wherein the viral infection is an infection of HCMV or another representative of the group of herpesviridae.

8. Use of a salt according to claim 1 or 2 for the preparation of a medicament for the treatment and/or prevention of a viral infection, wherein the viral infection is an infection of HCMV or another representative of the group of herpesviridae.

9. The use of claim 8, wherein the medicament comprises an antiviral effective amount of a salt of claim 1 or 2.