WO2003064394A1 - 5-ring heterocycles used as antiviral agents - Google Patents

Abstract

The invention relates to 5-ring heterocycles, methods for the production thereof, and the use thereof for the production of medicines used for treating or preventing diseases, particularly medicines used as antiviral agents, particularly against cytomegaloviruses.

Description

 5-RING HETEROCYCLE FOR USE AS ANTIVIRAL MEDIUM

The invention relates to 5-ring heterocycles and processes for their preparation and their use for the manufacture of medicaments for the treatment and / or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegaloviruses.

EP-A-8391 describes benzimidazole substituted pyridazinones for cardiovascular diseases and with antiviral activity.

The synthesis of diaryl-l, 2,4- (4H) -triazol-5-ones is described in P. Hewawasam et al, Bioorg. Med. Chem. Lett. 2002, 12, 1117-1120.

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

Means for better and more effective therapy are therefore desirable.

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

Surprisingly, it was found that the 5-ring heterocycles described in the present invention are highly effective antivirally.

The present invention relates to compounds of the formula

in which

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

X for -N (R) - or a group

stands,

D represents oxygen or sulfur,

R ^{1 represents} Ce-Cio-aryl or CrC ₆ -alkyl, where alkyl can optionally be substituted with up to three substituents independently selected from the group consisting of hydroxy, C] _. -C ₆ -alkoxy, amino, Ci-C ₆ -alkylamino, Ci-C _ö -alkylcarbonylamino, hydroxycarbonyl, -C-C ₆ -alkoxycarbonyl and Ci- -alkylaminocarbonyl,

and

wherein aryl may be optionally substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, _Cι-C6 alkoxy, amino, Ci-Ce-alkylamino, Ci-C _θ alkylcarbonyl amino, hydroxycarbonyl, C -C _ö alkoxycarbonyl, Ci-C _ö alkylaminocarbonyl and Ci-Ce-alkyl, or

R ¹ and R ⁴ together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl ring, where the cycloalkyl ring can optionally be substituted with up to three substituents independently selected from the group consisting of Halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, amino, C ₁ -C ₆ -alkylamino, Ci- -alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl and Ci-Ce-alkylaminocarbonyl,

R represents C ₃ -Cs-cycloalkyl or C _δ -cio-aryl, where aryl can optionally be substituted with up to three substituents selected independently of one another from the group consisting of halogen, hydroxy, nitro, cyano, Ci-C _ö alkoxy , Hydroxycarbonyl, -CC ₆ alkoxycarbonyl, amino, -CC _. -C ₆ - alkylamino, -C-C ₆ alkylaminocarbonyl and Ci-C ₆ alkyl,

R ^{3 represents} hydrogen or -CC ₆ alkyl, where alkyl can optionally be substituted with up to two substituents independently of one another selected from the group consisting of -C ₆ alkoxy, hydroxycarbonyl and Ci-Ce-alkoxycarbonyl,

R ^{4 represents} Ci-Cβ-alkyl, where alkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxy, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkoxy, amino, C 1 - C ₆ alkyl amino, C _ö alkylcarbonylamino, hydroxy-carbonyl, Cι-C ₆ alkoxycarbonyl and Cι-C ₆ -AlkylarrrinocarbonyL

or

R represents C _ö -C ^ aryl, where aryl may optionally be substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, -CC ₆ alkoxy, amino, -C ₆ alkyl alkyl, Ci- alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl, CrC ₆ - AJJςylarninocarbonyl and Ci-C ₆ alkyl,

R ⁵ for hydrogen, halogen, hydroxy, Ci-C ₆ -alkoxy, amino, Ci-C ₆ -

Alkylamino or C ₁ -C ₆ -alkyl,

R ^{6 stands} for C _ö -Cio-aryl, C ₃ -C ₈ cycloalkyl or Cι-C ₆ alkyl, where alkyl can optionally be substituted with up to two substituents independently selected from the group consisting of hydroxy, C ₆ - C ₁₀ aryl,

C ₁ -C ₆ -alkoxy, amino, C ₁ -C ₆ -alkylamino, hydroxycarbonyl and Ci-Ce alkoxycarbonyl,

and

where cycloalkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxy, Ci-C ₆ alkyl, C ₆ -Cιo-aryl, Ci-C ₆ alkoxy, amino, Ci-Cβ- alkylamino, Hydroxycarbonyl and Ci-C ₆ alkoxycarbonyl.

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

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

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

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

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

Physiologically acceptable salts of the compounds (I) 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 C atoms, such as, by way of example and by way of preference, ethylamine, diemylamine, triemylamine, ethyldiisopropylamine, monoemanolairiin, diethanolamine, trie anolamine, dicyclo-hexylamine, dimemylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dihydroabginylamine amine, amine methylpiperidine.

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

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

Alkyl per se and "alk" and "alkyl" in alkoxy, alkylamino, alkylaminocarbonyl 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, playful 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) all yl substituents, for example and preferably for memylarnino, e ylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, NN-dimethylamino, NN -Diethylamino, N-EÜiyl-N-methylamino, N-

Methyl-N-n-propylamino, N-isopropyl-N-n-propylarnino, N-tert. -Butyl-N-methylamino, N-E yl-N-n-pentylamino and N-n-Hexyl-N-memylamino.

Alkylaminocarbonyl represents an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, for example and preferably for methylaminocarbonyl, ethylaminocarbonyl, n-propylarninocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylamino-carbon -Dimemylaminocarbonyl, NN-diethylaminocarbonyl, N-ethyl-N-methyl-aminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylamino-carbonyl, Nt-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylamino -carbonyl and

N-n-hexyl-N-methylaminocarbonyl.

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 8, preferably 5 to 7 carbon atoms, by way of example and preferably for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl. Aryl is an example of a mono- to tricyclic aromatic, carbocyclic radical with generally 6 to 14 colile atoms and preferably phenyl, naphthyl and phenanthrenyl.

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

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

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

Compounds of the formula (I) are preferred

in which

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

X for -N (R ⁶ ) - or a group

stands,

D stands for oxygen, R ¹ represents C ¹ -C ₆ -alkyl, where alkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxy, Ci-Ce-alkoxy, amino, C ₁ -C ₆ -alkylamino, Ci-Ce -

Alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl and C ₁ -C ₆ - alkylaminocarbonyl,

or

R ¹ and R ⁴ together with the carbon atom to which they are attached form a C ₅ -C ₆ cycloalkyl ring, it being possible for the cycloalkyl ring to be optionally substituted with up to three substituents selected independently of one another from the group consisting of halogen, hydroxy, _Ci-C6 alkyl, Ci- _C6 alkoxy, amino, Cι-C ₆ - alkylamino, _Ci-C6 alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl, and Ci-C ₆ alkylaminocarbonyl,

R ^{2 stands} for C ₆ -Cιo-aryl, where aryl may optionally be substituted with up to three substituents independently selected from the group consisting of halogen or C ₁ -C ₆ -alkyl,

R ^{3 represents} hydrogen or C ₁ -C ₆ -alkyl, where alkyl can optionally be substituted with up to two substituents independently of one another selected from the group consisting of C ₁ -C ₆ -alkoxy, hydroxycarbonyl and C ₁ -C ₆ -alkoxycarbonyl,

R ^{4 represents} Ci-Ce-alkyl, where alkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxyl, phenyl, -CC ₆ - alkoxy, amino, Ci-Ce alkylamino, Ci Ce-alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl and Ci-Ce-alkylaminocarbonyl, R ^{5 represents} hydrogen, halogen, hydroxyl, C ₁ -C ₆ -alkoxy, amino, C ₁ -C ₆ -alkylamino or C ₁ -C ₆ -alkyl,

R represents C ₃ -C ₈ cycloalkyl or -CC ₆ alkyl, where alkyl may optionally be substituted with up to two substituents independently selected from the group consisting of hydroxy, Ce-Cio-aryl, Ci-Ce alkoxy , Amino, Ci-C ₆ - alkylamino, hydroxycarbonyl and Ci-Ce-alkoxycarbonyl,

and

where cycloalkyl can be optionally substituted with up to three substituents independently selected from the group consisting of Ci-C ₆ alkyl and Ci-C ₆ alkoxy.

Compounds of the formula (I) are also preferred,

in which

the rest -NHC (D) NHR> 2. is bound to the aromatics via position 3,

X for -N (R) - or a group

stands,

D stands for oxygen,

R ^{1 represents} Ci-C ₆ alkyl, or

R and R together with the carbon atom to which they are attached form a C ₅ -C ₆ cycloalkyl ring,

R represents Ce-Cio-aryl, where aryl may optionally be substituted with up to two substituents independently selected from the

Group consisting of fluorine, chlorine or C ₁ -C ₆ -alkyl,

R ^{3 represents} hydrogen,

R ^{4 represents} d-Ce-alkyl,

R ^{5 represents} hydrogen or fluorine,

R ^{6 stands} for C ₅ -C ₇ cycloalkyl or Ci-Ce-alkyl, where alkyl can be optionally substituted with up to two substituents phenyl.

In a further preferred embodiment, the radical -NHC (D) NHR ² in the compounds of the formula (I) is bonded to the aromatics via position 3.

In a further preferred embodiment, X in the compounds of the formula (I) is a group

In a further preferred embodiment is in the compounds of the formula

(I) X for -N (R ⁶ ) -. In a further preferred embodiment, the compounds of the formula (I) have oxygen for D.

In a further preferred embodiment, R ^{1 is} methyl, or R ¹ and R ⁴ together with the carbon atom to which they are attached form a cyclohexyl ring. Methyl is preferred for R ¹ .

In a further preferred embodiment, the compounds of the formula (I) for R are phenyl, where phenyl can optionally be substituted with up to two substituents independently selected from the group consisting of fluorine, chlorine or methyl.

In a further preferred embodiment, R ^{3 is} hydrogen.

In a further preferred embodiment, R ⁴ stands for methyl.

In a further preferred embodiment, R ^{5 represents} hydrogen.

In a further preferred embodiment, R ^{6 is} isopropyl, cyclohexyl or 1-phenylethyl.

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

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

The invention further relates to processes for the preparation of the compounds of

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

in which

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

X, R and R have the meaning given above,

with compounds of the formula (ILT)

DCN - R "(),

in which R and D have the meaning given above, are implemented.

The reaction takes place in inert solvents, optionally in the 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, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, di- methylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or pyridine, tetrahydrofuran or methylene chloride 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.

The compounds of formula (Ha), which are compounds of formula (II), wherein X is

can be prepared by using compounds of the formula (IV)

in which

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

R ¹ , R ³ , R ⁴ and R ^{5 have} the meaning given above, can be reduced, for example with tin (IJ) chloride or hydrogen with palladium on carbon.

The reaction takes place in moderate solvents, preferably in a temperature range from room temperature to the reflux of the solvents at normal pressure up to 3 bar.

Inert solvents are, for example, ethers such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, 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 or pyridine, preferably ethanol, isopropanol or, in the case of tin dichloride, in dimethylformamide.

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

in which

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

R, R and R ^{5 have} the meaning given above, with hydrazine or a compound of the general formula (VI),

H ₂ N - NR ³ (VI)

H in which

R ^{3 has} the meaning given above, are implemented.

The reaction takes place in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at normal pressure.

Inert solvents are, for example, 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 or pyridine, ethanol or isopropanol are preferred.

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

Synthesize processes from the corresponding starting materials.

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

in which

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

R ^{5 has} the meaning given above,

with compounds of the formula (VHI)

where R and R have the meaning given above,

be implemented in the presence of boron trifluoroetherate.

The reaction takes place in inert solvents, preferably in a temperature range from room temperature to the reflux of the solvents at normal pressure.

Inert solvents are, for example, ethers such as diethylene 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 dimethylacetamide, acetonitrile or pyridine, diethyl ether is preferred.

The compounds of the formula (Vif) are known or can be prepared analogously to known processes.

The compounds of formula (VIII) are known or can be analogous to C. Ainsworth, F. Chen, Y.-N. Kuo, J Organomet. Chem. 1972, 46, 59-71 can be produced. The compounds of the formula (üb) which stand for compounds of the formula (II) in which X represents NR ⁶ can be prepared by compounds of the formula

OK)

in which

NHC (O) CH ₃ is bonded to the aromatics via one of the positions 2, 3, 5 or 6, and

R, R and R have the meaning given above,

in water in the presence of a base, preferably at 60 ° C. until the water refluxes under normal pressure.

Bases are, for example, alkali metal hydroxides such as sodium, lithium or potassium hydroxide, alkali metal carbonates such as cesium carbonate, sodium or potassium carbonate, sodium hydroxide is preferred.

The compounds of formula (LX) can be prepared by compounds of formula (X)

in which

NHC (O) CH ₃ is bonded to the aromatics via one of the positions 2, 3, 5 or 6, and

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

with compounds of the formula (XI)

OCN - R

(XI)

in which R ^{6 has} the meaning given above,

implemented by the process described for the preparation of the compounds of the formula (I).

The compounds of the formula (XI) are known or can be prepared analogously to known processes.

The compounds of formula (X) can be prepared by compounds of formula (XH)

in which

NHC (O) CH ₃ is bonded to the aromatics via one of the positions 2, 3, 5 or 6, and

R ^{5 has} the meaning given above,

with compounds of the formula (Xffl)

are implemented in a reductive amination according to processes known to those skilled in the art for reductive aminations.

The compounds of the formulas (XII) and (XIII) are known or can be prepared analogously to known processes.

Compounds of formula (II)

in which

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

X, R ³ and R ^{5 have} the meaning given above, thus represent valuable intermediates and are therefore also an object of the present invention.

The preparation of the compounds of the invention can be carried out by the following

Synthesis schemes 1-8 are clarified.

Synthetic schemes:

R ³ = H, Br R ^b = H, Br

Scheme 1

Scheme 2

Scheme 3: Alkylations of the pyrazolones

R ¹ = H, CHXOOEt

Scheme 4: Reactions to aniline

Scheme 5: Urea synthesis

Scheme 6: Synthesis of hydrazine carboxamides

Scheme 7: Synthesis of 3-aminotriazolones

Scheme 8: Urea synthesis

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

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

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

1) Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).

2) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients 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 new active ingredients can be used alone and, if necessary, in combination with other antiviral active ingredients such as Gancyclovir or Acyclovir.

The present invention further relates to medicaments which contain at least one compound according to the invention, preferably together with one or more pharmacologically acceptable auxiliaries or excipients, and to their use for the purposes mentioned above.

The active substance can act systemically and / or locally. For this purpose it can be applied in a suitable way, e.g. oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, transdermal, cojunctival, otic or as an implant.

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

Known application forms which release the active ingredient quickly and / or modified, such as tablets (tablets that are not coated and coated, for example, provided with enteric coatings) are suitable for oral administration Tablets or film-coated tablets), capsules, dragees, granules, pellets, powders, emulsions, suspensions, solutions and aerosols.

Parenteral administration can be done by bypassing a resorption step (intravenous, intraarterial, intracardial, intraspinal or intralumbal) or by switching on absorption (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 and sterile powders.

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

Implants.

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

In general, it has proven to be advantageous to administer amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg 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 25 mg / kg, preferably 0.1 to 10 mg kg

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

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

A. Examples

Abbreviations:

TLC thin layer chromatography

DCI direct chemical ionization (for MS)

DCM dichloromethane

DIEA N, N-diisopropylethylamine

DMSO dimethyl sulfoxide

DMF dimethylformamide d. Th. Of theory

EE ethyl acetate (ethyl acetate)

ESI electrospray ionization (for MS)

Mp melting point h hour

HPLC high pressure, high performance liquid chromatography

LC-MS liquid chromatography-coupled mass spectroscopy

MS mass spectroscopy

NMR nuclear magnetic resonance spectroscopy

RP-HPLC reverse phase HPLC

RT room temperature

Rt retention time (with HPLC)

THF tetrahydrofuran

General methods LC-MS and HPLC:

HPLC parameters

Method 1: Column: Kromasil C18, LR temperature: 30 ° C, flow = 0.75 nilmin ^"1 ,

Eluent: A = 0.01 M HClO ₄ , B = CH ₃ CΝ, gradient: → 0.5 min 98% A → 4.5 min 10% A → 6.5 min 10% A Method 3: Column: Kromasil C18 60 * 2, LR temperature: 30 ° C, flow = 0.75 min ^" eluent: A = 0.005 M HClO ₄ , B = CH ₃ CN, gradient: -» 0.5 min 98% A → 4.5 min 10% A → 6.5 min 10% A

Method 10: LCMS = column: Symmetry C18 2.1x150 mm, column oven: 70 ° C, flow = 0.9 mlmin ^"1 , eluent: A = CH ₃ CN, B = 0.23 g 30% HC1 / 1 water, gradient: 0.0 min 2% A -> 2.5 min 95% A → 5.0 min 95% A

starting compounds

General working instructions 1:

Synthesis of β-keto esters (analogous to the instructions by M.H. Stefaniak, F. Tinardon, J.D. Wallis, Synlett 1997, 677-678).

Under an argon atmosphere, 1 equivalent of the correspondingly substituted 3-nitrobenzoic acid chloride is dissolved in absolute diethyl ether (0.25 M solution) in a heated 500 ml three-necked flask and mixed with 1 equivalent of l-methoxy-2-methyl-1-trimethylsiloxypropene (C. Ainsworth, F. Chen, Y.-N. Kuo, J. Organomet.

Chem. 1972, 46, 59-71). After adding one equivalent (possibly 3 equivalents) of boron trifluoride-diethyl ether complex, the mixture is heated under reflux for 24 hours. After the reaction mixture has cooled, it is washed once with 1N sodium hydroxide solution, water and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate. After filtration and removal of the solvent, the crude product is purified by column chromatography (silica gel: cyclohexane / ethyl acetate 9: 1).

Example 1A 2,2-Dimethyl-3- (3-nitrophenyl) -3-oxopropanoic acid, methyl ester

Starting from 10 g (53.9 mmol) of 3-nitrobenzoic acid chloride, 9.40 g (53.9 mmol) of l-memoxy-2-memyl-l-trimefhylsiloxypropene and 7.65 g (53.9 mmol)

Boron trifluoride-diethyl ether complex 4.93 g (25% of theory) product obtained. HPLC (method 3): R _t = 4.49 min MS (DCI): m / z - 269 (M + NH ₄ ) ^"1"

Example 2A

3- (3-bromo-5-nitrophenyl) -2,2-dimethyl-3-oxopropansäuremethylester

Starting from 5 g (18.9 mmol) of 3-bromo-5-nitrobenzoic acid chloride, 3.30 g (18.9 mmol) of l-methoxy-2-methyl-l-trimethylsiloxypropene and 2.68 g (18.9 mmol ) Boron trifluoride-diethyl ether complex 3.62 g (58%. Th.) Product obtained.

HPLC (method 3): R _t = 4.86 min MS (DCI): m / z = 347 (M + NH ₄ ) ⁺

Example 3A 1- (3-nitrobenzoyl) cyclohexane carboxylic acid methyl ester

Starting from 1.84 g (9.92 mmol) of 3-bromo-5-nitrobenzoic acid chloride with

2.13 g (9.92 mmol) [cyclohexylidene (methoxy) methoxy] trimethylsilane (C.

Ainsworth, F. Chen, Y.-N. Kuo, J. Organomet. Chem. 1972, 46, 59-71) and 4.22 g (29.8 mmol) boron trifluoride-diethyl ether complex 0.81 g (28% of theory) of product.

HPLC (method 3): R _t = 4.90 min MS (DCI): m / z = 309 (M + NH ₄ ) ⁺

General working instruction 2:

Pyrazolonsynthesen

1 equivalent of the β-keto ester is heated together with 5 equivalents of hydrazine hydrate in ethanol (0.23 M solution) for 4 hours at reflux. The reaction product either precipitates from the reaction mixture or is precipitated with water and cyclohexane after removal of part of the solvent. The precipitate is filtered off, washed with diethyl ether and then dried in vacuo.

Example 4A

4,4-dimethyl-5- (3-nitrophenyl) -2,4-dihydro-3H-pyrazol-3 -one

Starting from 8.53 g (34 mmol) of 2,2-dimethyl-3- (3-nitrophenyl) -3-oxopropanoic acid mefethyl ester, 6.63 g (83% of theory) are mixed with 8.50 g (170 mmol) of hydrazine hydrate .) Product received. Mp: 164.6 ° C

HPLC (method 3): R _t = 3.99 min MS (DCI): m / z = 251 (M + NHι) ⁺ Example 5A

5- (3-bromo-5-nitrophenyl) -4,4-dimethyl-2,4-dihydro-3H-pyrazol-3 -one

Starting from 3.80 g (11.5 mmol) of 3- (3-bromo-5-nitrophenyl) -2,2-dimethyl-3-oxo propanoic acid methyl ester, 2.88 g (57.6 mmol) of hydrazine hydrate 3, 12 g (87% of theory) of product were obtained.

Mp: 214.9 ° C

HPLC (method 3): R _t = 4.26 min

MS (ESIpos): m / z = 312 (M + H) ⁺

General working instruction 3:

Alkylation of pyrazolone nitrogen

1 equivalent of the corresponding pyrazolone is dissolved in a heated flask under an argon atmosphere in absolute THF (0.1-0.25 M solution). After cooling to 0 ° C, 1.2-1.5 equivalents of sodium hydride are added in portions. Then allowed to stir for 30 min at room temperature and then give

1.2-2.5 equivalents of the alkylating agent. The reaction mixture is stirred at room temperature overnight, then water is carefully added and the mixture is extracted three times with diethyl ether. The combined organic phases are dried over magnesium sulfate, then filtered and concentrated. The residue is purified by column chromatography. Example 6A

[4,4-Dimethyl-3 - (3 -nitrophenyl) -5-oxo-4,5-dihydro-1H-pyrazol-1-yl] ethyl acetate

Starting from 1.85 g (7.9 mmol) of 4,4-dimethyl-5- (3-nitrophenyl) -2,4-dihydro-3H ^r - pyrazol-3-one, after deprotonation with 0.46 g ( 11.9 mmol) sodium liydride (60% dispersion in mineral oil), with 1.59 g (9.5 mmol) ethyl bromoacetate 0.82 g (32% of theory) of product.

Mp .: 120.2 ° C

HPLC (method 3): R _t = 4.46 min MS (DCI): m / z = 320 (M + NH ₄ ) ⁺

Example 7A

4- (3-aminophenyl) -2,3 -diazaspiro [4.5] dec-3 -en- 1 -one

803 mg (2.76 mmol) of methyl l- (3-nitrobenzoyl) cyclohexanecarboxylate are dissolved in 15 ml of ethanol, and 1.38 g (27.6 mmol) of hydrazine hydrate and 140 mg of palladium on carbon (10%) are added. It is stirred at reflux overnight. The desired product can be precipitated by adding cyclohexane. 278 mg (41% of theory) of product are obtained. HPLC (method 3): R _t = 3.31 min MS (ESIpos): m / z = 244 (M + H) ⁺

General working instruction 4:

Catalytic hydrogenation of the nitro group on the aromatic

20 mmol of the substance to be hydrogenated are dissolved in 100 ml of degassed methanol and then 250 mg of palladium on activated carbon are added under argon. Hydrogenation is carried out under a hydrogen atmosphere (normal pressure) until TLC control indicates complete conversion. It is then suctioned off through kieselguhr, the filtrate is concentrated, the residue is dried in vacuo and processed without further purification.

Example 8A 4,4-Dimethyl-5- (3-aminophenyl) -2,4-dihydro-3H-pyrazol-3-one

Starting from 4.60 g (19.2 mmol) of 4,4-dimethyl-5- (3-nitrophenyl) -2,4-dihydro-3H-pyrazol-3-one, 3.66 g (91% of theory) Received product.

HPLC (method 3): R _t = 3.04 min MS (ESIpos): m / z = 204 (M + Hf

Alternative synthesis of 4,4-dimethyl-5- (3-aninophenyl) -2,4-dihydro-3H-pyrazol-3 - one:

772 mg (2.49 mmol) of 2,2-dimefhyl-3- (3-nitrophenyl) -3-oxopropanoic acid,

1.87 g (37.4 mmol) hydrazine hydrate are dissolved in 80 ml ethanol, with 100 mg

Palladium added to activated carbon and heated to reflux for 20 hours. It is filtered hot over kieselguhr and washed with ethanol. After removing a large part of the ethanol, cyclohexane and a little water are added and placed in the refrigerator. After crystallization has ended, the product is filtered off with suction, washed with diethyl ether and dried in vacuo. There are 413 mg (82% of theory)

Received product.

HPLC (method 3): R _t = 3.03 min

MS (DCI): m / z = 204 (M + H) ⁺

Example 9A

[3- (3-aminophenyl) -4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl] ethyl acetate

Starting from 500 mg (1.57 mmol) of ethyl [4,4-dimethyl-3- (3-nitrophenyl) -5-oxo-4,5-di-hydro-lH-pyrazol-l-yl], 449 mg ( 85% of theory) product received. HPLC (method 3): R _t = 3.37 min MS (ESIpos): m / z = 290 (M + H) ⁺

General working instruction 5:

Reduction of the nitro group in bromine-containing aromatics

0.8 mmol of the bromine-containing nitroaromatics are dissolved in 10 ml of dioxane, 4 mmol of tin chloride dihydrate and a few drops of hydrochloric acid are added, and the mixture is then heated to 70 ° C. for 2 hours. After cooling to room temperature, the mixture is diluted with ethyl acetate and washed 3 times with 1N sodium hydroxide solution. The organic phase is dried over magnesium sulfate and concentrated after filtration. If necessary, this is followed by column chromatographic purification. With appropriate purity, the crude product that has not been further purified can also be processed.

Example 10A

4,4-dimethyl-5- (5-amino-3-bromophenyl) -2,4-dihydro-3H-pyrazol-3-one

Starting from 1 g (3.2 mmol) of 5- (3-bromo-5-nitrophenyl) -4,4-dimethyl-2,4-dihydro-

3iJ-pyrazol-3-one are obtained with 3.61 g (16 mmol) of tin dichloride dihydrate and 758 mg (84% of theory) of product.

HPLC (method 3): R _t = 3.31 min

MS (ESIpos): m / z = 282 (M + H) ⁺ Example 11A tert -butyl 2- [3- (acetylamino) benzoyl] hydrazine carboxylate

25.00 g (139.53 mmol) 3-aminoacetylbenzoic acid are dissolved in 300 ml THF (0.47 M

Solution) solved. The solution is mixed with 20.74 g (153.48 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 18.03 g (139.53 mmol) of NN-diisopropylethylamine and 26.75 g (139.53 mmol) of Ν'- (3-Dimethylaminopropyl) -N-ethylcarbodiimide x HC1 added. Then 18.44 g (139.53 mmol) of tert-butyl hydrazine formate are added and the mixture is stirred for 16 hours at room temperature.

The solvent is removed and the residue is partitioned between equal parts of ethyl acetate and 1N hydrochloric acid. The organic phase is washed twice with 1Ν hydrochloric acid and twice with saturated sodium hydrogen carbonate solution, part of the product already precipitating as a solid, which is filtered off with suction, washed with ethyl acetate and dried in vacuo. The organic phase is dried over sodium sulfate, then filtered and concentrated. The residue is taken up in ethyl acetate, the suspension obtained is mixed with the same volume of diethyl ether and stirred at room temperature. After crystallization has ended, the product is filtered off with suction, washed with diethyl ether and dried in vacuo. Both product fractions are combined, 31.47 g (77% of theory) of product are obtained.

1H-NMR (200 MHz, DMSO): δ = 1.43 (s, 9H), 2.06 (s, 3H), 7.28-7.58 (m, 2H), 7.69- 7.85 (m, 1H), 8.02 (s, 1H) , 8.90 (s, 1H), 9.98-10.27 (m, 2H). Example 12A

2- [3 - (Acetylamino) benzoyl] hycfrazinium chloride

30.97 g (105.58 mmol) of tert-butyl 2- [3- (acetylamino) benzoyl] hydrazine carboxylate are dissolved in 200 ml of dioxane (0.53 M solution) and with 200 ml of 4 M hydrochloric acid in dioxane (800 mmol ) offset. The mixture is stirred for four days at room temperature. The precipitated crystals are filtered off, washed with diethyl ether and dried in vacuo. 28.80 g (119% of theory) of product are obtained. HPLC (method 10): R _t = 1.92 min

General procedure 6: Synthesis of hydrazine carboxamides

1 equivalent of 2- [3- (acetylamino) benzoyl] hydrazinium chloride is placed in dichloromethane (0.15 M solution) and stirred together with 2 equivalents of diisopropylethylamine and 1 equivalent of the corresponding isocyanate at room temperature for 16 hours. The resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo. The raw product is then directly implemented. Example 13A

2- [3 - (Acetylamino) benzoyl] -N-isopropylhydrazinecarboxamide

7.00 g (30.48 mmol) of 2- [3- (acetylamino) benzoyl] hydrazinium chloride are reacted with 7.88 g (60.96 mmol) of diisopropylethylamine and 2.59 g (30.48 mmol) of isopropyl isocyanate. The raw product is then directly implemented. HPLC (method 3): R _t = 2.95 min

Example 14A

2- [3 - (Acetylamino) benzoyl] -N-cyclohexylhydrazinecarboxamide

7.00 g (30.48 mmol) of 2- [3- (acetylamino) benzoyl] hydrazinium chloride are reacted with 7.88 g (60.96 mmol) of diisopropylethylamine and 3.82 g (30.48 mmol) of cyclohexyl isocyanate. The raw product is then directly implemented. HPLC (method 3): R _t = 3.46 min Example 15A

2- [3 - (Acetylamino) benzoyl] -N- (1 -phenylethyl) hydrazine carboxamide

7.00 g (30.48 mmol) of 2- [3- (acetylamino) benzoyl] hydrazinium chloride are combined with 7.88 g (60.96 mmol) of diisopropylethylamine and 4.49 g (30.48 mmol) of 1-phenylethyl isocyanate implemented. The raw product is then directly implemented. HPLC (method 3): Rt - 3.53 min

General working instruction 7:

Synthesis of 3-aminotriazolones

1 equivalent of the corresponding hydrazine carboxamide is dissolved in 1 N sodium hydroxide solution (0.16 M solution) and 6.15 equivalents of sodium hydroxide are added. Allow to stir at 100 ° C for 48 hours. The reaction solution is adjusted to pH 7 with hydrochloric acid, the resulting precipitate is filtered off, washed with water and dried in vacuo.

Example 16A

5- (3-aminophenyl) -4-isopropyl-2,4-dihydro-3H-1, 2,4-triazol-3 -one

Starting from 6.06 g (32.55 mmol) of 2- [3- (acetylamino) benzoyl] -N-isopropyl-hydrazine carboxamide (crude) and 8.00 g (200.02 mmol) of sodium hydroxide in 200 ml of 1 N Sodium hydroxide solution gives 2.81 g (40% of theory) of product. HPLC (method 3): R _t = 2.76 min

Example 17A

5- (3-aminophenyl) -4-cyclohexyl-2,4-dihydro-3H-1, 2,4-triazol-3 -one

Starting from 7.43 g (32.55 mmol) of 2- [3- (acetylamino) benzoyl] -N-cyclohexyl-hydrazine carboxamide (crude) and 8.00 g (200.02 mmol) of sodium hydroxide in 200 ml of 1N

Sodium hydroxide solution gives 5.59 g (66% of theory) of product. HPLC (method 3): R _t = 3.31 min Example 18 A

5- (3-Arninoρhenyl) -4- (l-phenylethyl) -2,4-dihydro-3H-l, 2,4-triazol-3-one

Starting from 8.83 g (32.55 mmol) of 2- [3- (acetylamino) benzoyl] -N- (l-phenylethyι) - hydrazine carboxamide (crude) and 8.00 g (200.02 mmol) of sodium hydroxide in 200 ml 1 N sodium hydroxide solution gives 4.52 g (50% of theory) of product. HPLC (method 3): R _t = 3.35 min

Preparation Examples

General working procedure 8: synthesis of ureas

0.24 mmol of the corresponding isocyanate are dissolved in 1 ml of ethyl acetate (0.2 ml of THF are optionally added) and 0.2 mmol of the respective aniline are added. The mixture is left to stir at room temperature overnight. The solvent is then removed, the residue is taken up in DMSO or DMF and purified by RP-HPLC.

example 1

N- (4-Chloro-2-methylphenyl) -N '- [3- (4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl) phenyl] urea

46.2 mg (0.28 mmol) of 4-chloro-2-methylphenyl isocyanate are mixed with a solution of 40 mg of 5- (3-aminophenyl) -4,4-dimethyl-2,4-dihydro-3H-pyrazole-3- on in 1 ml of ethyl acetate and 0.2 ml of tetrahydrofuran and stirred overnight at room temperature. The formation of a white precipitate is observed.

Work-up: The reaction mixture is concentrated and the residue obtained is purified by RP-HPLC after being taken up in DMSO. 42 mg (58% of theory) of product are thus obtained as a white solid. Mp: 226.8 ° C

HPLC (method 3): R _t = 4.33 min MS (ESIpos): m / z = 371 (M + H) ⁺

1H-NMR (200 MHz, DMSO): δ = 1.37 (s, 6H), 2.25 (s, 3H), 7.21 (dd, 1H), 7.28 (d, 1H), 7.35-7.46 (m, 3H), 7.88 (d, 1H), 8.02 (s br, 1H), 8.11 (s br, 1H), 9.23 (s br, 1H),

11.54 (s br, 1H)

Example 2

N- (3,4-difluorophenyl) -N '- [3- (4,4-dimethyl-5-oxo-4,5-dihydro-lH-pyrazol-3-yl) phenyl urea

42.7 mg (0.28 mmol) of 3,4-difluorophenyl isocyanate are mixed in with a solution of 40 mg of 5- (3-aminophenyl) -4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one 1 ml of ethyl acetate and 0.2 ml of tetrahydrofuran were added and the mixture was stirred at room temperature overnight. The formation of a white precipitate is observed.

Work-up: The reaction mixture is concentrated and the residue obtained is purified by RP-HPLC after being taken up in DMSO. This gives 41.4 mg (59% of theory) of product as a white solid. Mp: 226.7 ° C

HPLC (method 3): R _t = 4.23 min MS (ESIpos): m / z = 359 (M + H) ⁺ 1H-NMR (200 MHz, DMSO): δ = 1.38 (s, 6H), 7.13-7.17 (m, 1H), 7.28-7.46 (m, 4 H), 7.66 (ddd, 1H), 8.06 (s br, 1H), 8.96 (s br, 2H), 11.54 (s br, 1H)

Example 3

N- (3-Bromophenyl) -N '- [3- (4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl) phenyl] urea

54.6 mg (0.28 mmol) of 3-bromophenyl isocyanate are mixed with a solution of 40 mg of 5- (3-aminophenyl) -4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one in 1 ml Ethyl acetate and 0.2 ml of tetrahydrofuran were added and the mixture was stirred at room temperature overnight. The formation of a white precipitate is observed.

Work-up: The reaction mixture is concentrated and the residue obtained is purified by RP-HPLC after being taken up in DMSO. This gives 65 mg (82% of theory) of product as a white solid.

Mp: 236.9 ° C

HPLC (method 3): R _t = 4.34 min

MS (ESIpos): m / z = 401 (M + H) ⁺

1H-NMR (200 MHz, DMSO): δ = 1.38 (s, 6H), 7.15 (m, 1H), 7.25 (t, 1H), 7.32-7.46

(m, 4 H), 7.84 (s br, 1H), 8.06 (s br, 1H), 8.96 (s br, 2H), 11.55 (s, br 1H) Example 4

N- (3-C or-4-fluoro-phenyl) -N '- [3- (4,4-dimethyl-5-oxo-4,5-dihydro-1H-ρyrazol-3-yl) phenyl] urea

47.3 mg (0.28 mmol) of 4-chloro-3-fluorophenyl isocyanate are mixed with a solution of 40 mg of 5- (3-aminophenyl) -4,4-dimethyl-2,4-dihydro-3H-pyrazole-3- on in 1 ml of ethyl acetate and 0.2 ml of tetraliydrofuran and stirred overnight at room temperature. The formation of a white precipitate is observed.

Work-up: The reaction mixture is concentrated and the residue obtained is purified by RP-HPLC after being taken up in DMSO. This gives 66.1 mg (90% of theory) of product as a white solid.

Mp: 257.5 ° C

HPLC (method 3): R _t = 4.38 min

MS (ESIpos): m / z = 375 (M + H) ⁺

1H-NMR (200 MHz, DMSO): δ = 1.38 (s, 6H), 7.31-7.47 (m, 5H), 7.79 (m, 1H),

8.06 (m, 1H), 8.94 (s br, 1H), 8.97 (s br, 1H), 10.99 (s br, 1H) 48

Example 5

N- (2,4-dichlorophenyl) -N '- [3- (4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl) phenyl urea

51.8 mg (0.28 mmol) of 2,4-dichlorophenyl isocyanate are mixed with a solution of 40 mg of 5- (3-aminophenyl) -4,4-dimethyl-2,4-dihydro-3H-pyrazol-3-one in 1 ml of acetic acid hylester and 0.2 ml of tetrahydrofuran were added and the mixture was stirred at room temperature overnight. The formation of a white precipitate is observed.

Work-up: The reaction mixture is concentrated and the residue obtained is purified by RP-HPLC after being taken up in DMSO. This gives 28.9 mg (38% of theory) of product as a white solid.

Mp: 242 ° C

HPLC (method 3): R _t = 4.56 min

MS (EI): m / z - 390 (M) ⁺

1H-NMR (200 MHz, DMSO): δ = 1.48 (s, 6H), 7.22 (dd, 1H), 7.28-7.48 (m, 4H),

8.09 (m, 1H), 8.14 (s br, 1H), 8.27 (d, 1H), 9.32 (s br, 1H), 11.10 (s br, 1H)

Example 6

{3 - [3 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) phenyl] -4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl }acetic acid

100 mg (0.22 mmol) {3- [3 - ({[(4-chloro-2-methylphenyl) amino] carbonyl} amino) - phenyl] -4,4-dimethyl-5-oxo-4,5- dihydro-lH-pyrazol-l-yl} ethyl acetate are dissolved in 2 ml of methanol and 1 ml of THF, mixed with 1.7 ml of 1N sodium hydroxide solution and stirred at 50 ° C. for 1 hour. Then water is added and the mixture is shaken out with ethyl acetate. The aqueous phase is acidified with hydrochloric acid and then extracted 3 times with ethyl acetate. The combined organic extracts are dried over magnesium sulfate. After filtration and removal of the solvent, the crude product is dried in vacuo and does not need to be further purified. 97 mg (quantitative) of product are obtained. HPLC (method 3): R _t = 4.35 min MS (ESIpos): m / z = 429 (M + H) ⁺

General Working Instructions 9; ureas

1 equivalent of the aniline is placed in THF (0.14 M solution) and mixed with 1 equivalent of the corresponding isocyanate. The solution is shaken at room temperature for 1 hour. The solvent is removed in vacuo and the product is purified by preparative HPLC (CromSil C 18, 250x30, flow: 50 ml / min, running time: 38 min, detection at 210 nm, gradient: 10% acetonitrile (3 min) -> 90% Acetonitrile (31 min) -> 90% acetonitrile (34 min) -> 10% acetonitrile (34.01 min)).

Example 17

N- (3-Chlorophenyl) -N '- [3- (4-isopropyl-5-oxo-4,5-dihydro-1H-l, 2,4-triazol-3-yl) phenyl urea

Starting from 60.00 mg (0.27 mmol) 5- (3-aminophenyl) -4-isopropyl-2,4-dihydro-

3H-l, 2,4-triazol-3-one with 42.22 mg (0.27 mmol) of 3-chlorophenyl isocyanate

67.60 mg (66% of theory) of product obtained.

HPLC (method 3): R _t = 4.22 min

1H-NMR (200 MHz, d ₆ -DMSO): δ = 11.80 (s, 1H); 9.00 (d, 2H); 7.70 (s, 2H); 7.57-

7.36 (m, 2H); 7.32-7.29 (m, 2H); 7.14-7.00 (m, 2H) 4.17-4.10 (m, 1H); 1.41 (d, 6H). Example 18

N- (3-Chloro-4-fluorophenyl) -N '- [3- (4-isopropyl-5-oxo-4,5-dihydro-1H-l, 2,4-triazol-3-yι) phenyι] urea

Starting from 150.0 mg (0.69 mmol) of 5- (3-aminophenyl) -4-isopropyl-2,4-dihydro-

3H-1,2,4-triazol-3-one are obtained with 94.2 mg (0.69 mmol) of 3-chloro-4-fluorophenyl isocyanate and 57 mg (33% of theory) of product.

HPLC (method 3): R _t = 4.12 min

1H NMR (200 MHz, D ₆ -DMSO): δ - 11.80 (s, IH); 9.31 (d, 2H); 7.86-7.09 (m, 8H);

4.17-4.10 (m, IH); 1.41 (d, 6H).

B. Assessment of physiological effectiveness

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

Anti-HCMV (Anti-Human Cytomegaly Virus) cytopathogenicity tests

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

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

Formalin and Giemsa's dye fixed and colored (30 minutes), with aqua bidest. washed and dried in a drying cabinet at 50 ° C. Then the plates are visually evaluated with an overhead microscope (plaque multiplier from Technomara).

The following data can be obtained from the test plates:

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

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

Table A

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

HCMV Xenograft-Gelfoam model animals:

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

Virus cultivation: Human cytomegalovirus (HCMV), DavisSmith strain, is grown in vitro on human embryonic foreskin fibroblasts (NHDF cells). After infection of the NHDF cells with a multiplicity of infection (MOI) of 0.01, the virus-infected cells are harvested 5-7 days later and in the presence of Minimal Essential Medium (MEM), 10% fetal calf serum (FKS) with 10% DMSO stored 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 ^® ; Peasel & Lorey, order no.

407,534; KT Chong et al., Abstracts of 39 ^th Interscience Conference on Anti-microbial Agents and Chemotherapy, 1999, p. 439) are first wetted with phosphate-buffered saline (PBS), the trapped air bubbles are removed by degassing and then in MEM + 10% FCS kept. 1 × 10 ⁶ virus-infected NHDF cells (infection with HCMV-Davis MOI = 0.01) are detached 3 hours after infection and dropped onto a moist sponge in 20 μl MEM, 10% FCS. 12-13 hours later, the infected sponges are incubated with 25 μl PBS / 0.1% BSA / 1 mM DTT with 5 ng / μl basic fibroblast growth factor (bFGF). For transplantation, the immunodeficient mice are anesthetized with avertine, the dorsal coat removed with the help of a dry razor, the epidermis opened 1-2 cm, relieved and the moist sponges transplanted under the dorsal skin. The surgical wound is closed with tissue glue. 24 hours after the transplant, the mice were treated orally with substance three times a day (7 a.m. and 2 p.m. and 7 p.m.) over a period of 8 days. The dose is 7 or 15 or 30 or 60 mg / kg body weight, the application volume 10 ml / kg body weight.

The substances are formulated in the form of a 0.5% tylose suspension with 2% DMSO. 9 days after the transplant and 16 hours after the last substance application, the animals are killed painlessly and the sponge is removed. The virus-infected cells are released from the sponge by 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 takes place after serial dilution of the virus-infected cells in steps of ten by titer determination on 24-well plates of confluent NHDF cells after vital staining with neutral red. The number of infectious virus particles after substance treatment compared to the placebo-treated control group is determined.

C. Examples of pharmaceutical compositions

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

Tablet:

Composition:

100 mg of the compound from Example 1, 50 mg 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 compressed with a conventional tablet press (tablet format see above). A pressure force of 15 kN is used as a guideline for the pressing.

Oral suspension:

Composition:

1000 mg of the compound from Example 1, 1000 mg of ethanol (96%), 400 mg of Rhodigel (xanthan gum from FMC, Pennsylvania, USA) and 99 g of water. A single dose of 100 mg of the 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

Compounds of the formula

in which

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

X for -N (R ⁶ ) - or a group

stands,

D represents oxygen or sulfur,

R ^{1 stands} for Cö-Cio-Arvl or Cj.-C ₆ -alkyl, where alkyl can optionally be substituted with up to three substituents independently selected from the group consisting of hydroxyl, C _\ - C ₆ -alkoxy, amino, Ci -C _ö alkylamino, Ci-C ₆ -alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl and -CC ₆ -alkylamino carbonyl,

and where aryl may optionally be substituted with up to three substituents independently of one another selected from the group consisting of halogen, hydroxy, Ci-C ₆ alkoxy, amino, -C-C ₆ - alkylamino, Ci-Cβ-alkylcarbonylamino, hydroxycarbonyl, Ci -Ce alkoxycarbonyl, Ci-C _ö -A kylaminocarbonyl and Ci-C _ö -AlkyL

or

R ¹ and R together with the carbon atom to which they are attached form a C ₃ -C ₆ cycloalkyl ring, it being possible for the cycloalkyl ring to be optionally substituted with up to three substituents selected independently of one another from the group from halogen, hydroxy, Ci-Cβ-alkyl, Ci-Ce-alkoxy, amino, Cι-C ₆ alkylamino, Ci-Ce-alkylcarbonylamino, hydroxycarbonyl, Cι-C ₆ -alkoxycarbonyl and Ci-Ce-alkylaminocarbonyl .

R ^{2 represents} C -C ₈ cycloalkyl or C ₆ -C ₁₀ aryl, where aryl can optionally be substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, nitro, cyano, Ci-Ce Alkoxy, hydroxycarbonyl,

Ci-Ce-alkoxycarbonyl, amino, Ci-Ce-alkylamino, -CC ₆ -alkylamino-carbonyl and Ci-C ₆ -alkyl,

R ^{3 represents} hydrogen or C ₁ -C ₆ -alkyl, where alkyl can optionally be substituted with up to two substituents independently of one another selected from the group consisting of C ₁ -C ₆ -alkoxy, hydroxycarbonyl and C ₁ -C ₆ -alkoxycarbonyl,

R ^{4 represents} Ci-Ce-alkyl, where alkyl can optionally be substituted with up to three substituents independently selected from the group consisting of hydroxy, C ₆ -Cιo-aryl, Ci-Cβ- Alkoxy, amino, Ci-Ce-alkylamino, Ci-Ce-alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl and Ci-Ce-alkylaminocarbonyl,

or

R ^{4 represents} C ₆ -Cio-aryl, where aryl can optionally be substituted with up to three substituents independently selected from the group consisting of halogen, hydroxy, C ₁ -C ₆ -alkoxy, amino,

Cι-C ₆ - alkylamino, Ci-Ce-alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl, Ci-C ₆ - ylaminocarbonyl and Ci-C ₆ - alkyl,

R ^{5 represents} hydrogen, halogen, hydroxyl, Ci-C ₆ -alkoxy, amino, Ci-Ce- alkylamino or Ci-Ce-alkyl,

R ^{6 stands} for C ₆ -Cιo-aryl, C ₃ -C ₈ cycloalkyl or dC ₆ - alkyl, wherein

Alkyl can optionally be substituted with up to two substituents independently of one another selected from the group consisting of hydroxy, C ₆ -C ₁₀ aryl, Ci-C ₆ alkoxy, amino, Ci-Ce alkylamino, hydroxycarbonyl and Cι-C ₆ - alkoxycarbonyl,

and

wherein cycloalkyl may be optionally substituted with up to three substituents independently selected from the group consisting of hydroxy, Ci-Ce-alkyl, C ₆ -C _0-aryl, Ci-C ₆ alkoxy, amino, Ci-Ce-alkylamino, Hydroxycarbonyl and Ci-C ₆ alkoxycarbonyl.

2. Compounds according to claim 1, wherein

the rest -NHC (D) NHR ² via one of the positions 2,

3, 5 or 6 to the

Aromatics is bound X for -N (R ⁶ ) - or a group

stands,

D stands for oxygen,

R ¹ represents C ¹ -C ₆ -alkyl, where alkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxy, C ₁ -C ₆ -alkoxy, amino, Ci-Ce-alkylamino, Ci-Ce -Alkylcarbonylamino, hydroxycarbonyl, ci-

Ce-alkoxycarbonyl and Ci-Ce-alkylaminocarbonyl,

or

R ¹ and R ⁴ together with the carbon atom to which they are attached form a C ₅ -C ₆ cycloalkyl ring, it being possible for the cycloalkyl ring to be optionally substituted with up to three substituents selected independently of one another from the group consisting of Halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, amino, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkylcarbonylamino, hydroxycarbonyl, Ci-Ce-alkoxycarbonyl and Ci-Ce-alkylaminocarbonyl,

R ^{2 represents} Ce-Cio-aryl, where aryl may optionally be substituted with up to three substituents independently selected from the group consisting of halogen or Ci-Ce-alkyl,

R ^{3 represents} hydrogen or -CC ₆ alkyl, where alkyl can be optionally substituted with up to two substituents independently of selected from the group consisting of -CC ₆ alkoxy, hydroxycarbonyl and Ci-Ce-alkoxycarbonyl,

R ^{4 represents} Ci-Ce-alkyl, where alkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxyl, phenyl, -CC ₆ -alkoxy, amino, Ci-Cβ- alkylamino, Ci Ce-alkylcarbonylamino, hydroxycarbonyl, Ci-C ₆ -alkoxycarbonyl and Ci-Ce-alkylaminocarbonyl,

R ⁵ for hydrogen, halogen, hydroxy, Ci-C ₆ -alkoxy, amino, Ci-C ₆ -

Alkylamino or Ci-Cβ-alkyl,

R ^{6 stands} for C ₃ -C ₈ cycloalkyl or Ci-C ₆ alkyl, where alkyl can optionally be substituted with up to two substituents independently selected from the group consisting of hydroxy, C ₆ -

Cio-aryl, Ci-C ₆ -alkoxy, amino, Ci-Ce-alkylamino, hydroxycarbonyl and Ci-Ce-alkoxycarbonyl,

and

where cycloalkyl can be optionally substituted with up to three substituents independently selected from the group consisting of Ci-C ₆ alkyl and Ci-C ₆ alkoxy.

Compounds according to claim 1, wherein

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

X for -N (R) - or a group stands,

D stands for oxygen,

R ^{1 represents} Ci-C ₆ alkyl,

or

R ¹ and R ⁴ together with the carbon atom to which they are attached form a C ₅ -C ₆ cycloalkyl ring,

R represents C ₆ -Cio-aryl, where aryl can optionally be substituted with up to two substituents independently selected from the group consisting of fluorine, chlorine or Ci-Ce-alkyl,

R represents hydrogen,

R ⁴ represents C ₁ -C ₆ -alkyl,

R ^{5 represents} hydrogen or fluorine,

R ^{6 represents} C ₅ -C ₇ cycloalkyl or -CC ₆ alkyl, where alkyl can be optionally substituted with up to two substituents phenyl.

4. Compounds according to claim 1, 2 or 3, wherein the radical -NHC (D) NHR ² is bonded via the 3 position to the aromatics.

5. Compounds according to claim 1, 2 or 3, wherein X is a group

stands.

6. Compounds according to claim 1, 2 or 3, wherein X is -N (R ⁶ ) -.

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

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

9. Compounds according to claim 1, 2 or 3, wherein R ^{2 is} phenyl, where phenyl may optionally be substituted with up to two substituents independently selected from the group consisting of fluorine, chlorine or methyl.

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

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

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

13. Compounds according to claim 1, 2 or 3, wherein R is isopropyl, cyclohexyl or 1-phenylethyl.

14. A method for producing compounds according to claim 1, characterized in that

Compounds of formula (II)

in which

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

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

with compounds of the formula (III)

DCN - R (πi),

in which R ² and D have the meaning given above,

be implemented.

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

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

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

18. Medicament according to claim 16 for the treatment and / or prophylaxis of viral diseases.

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

20. Compounds of formula (II)

in which

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

X, R ³ and R ^{5 have} the meaning given in claim 1.