DE10203086A1 - 5-ring heterocycles - 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

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

EP-A-8391 describes benzimidazole substituted pyridazinones for cardiovascular Diseases and with antiviral effects.

There are structurally different antiviral agents on the market present, but resistance development can occur regularly. New Means for better and more effective therapy are therefore desirable.

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

Surprisingly, it has been found that in the present invention described 5-ring heterocycles are highly effective antiviral.

The present invention relates to compounds of the formula


in which
the rest -NHC (D) NHR ² is bound to the aromatic system via one of the positions 2, 3, 5 or 6,
X for -N (R ⁶ ) - or a group


stands,
D represents oxygen or sulfur,
R ^{1 represents} C ₆ -C ₁₀ aryl or C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to three substituents independently selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, amino , C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
and
where aryl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of halogen, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl , C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylaminocarbonyl and C ₁ -C ₆ 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, 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, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
R ^{2 represents} C ₃ -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, C ₁ - C ₆ alkoxy, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, amino, C ₁ -C ₆ - alkylamino, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ alkyl,
R ^{3 represents} hydrogen or C ₁ -C ₆ alkyl, where alkyl can 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} C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to three 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, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
or
R ^{4 represents} 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, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ - alkylaminocarbonyl, and C ₁ -C ₆ alkyl,
R ^{5 represents} hydrogen, halogen, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkyl,
R ^{6 represents} C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to two substituents selected independently of one another from the group consisting of hydroxy, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, hydroxycarbonyl and C ₁ -C ₆ alkoxycarbonyl,
and
where cycloalkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxy, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkoxy, amino, C ₁ - C ₆ alkylamino, hydroxycarbonyl and C ₁ -C ₆ alkoxycarbonyl.

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

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

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

In the context of the invention, salts which are physiologically acceptable are the salts Compounds of the invention preferred.

Physiologically acceptable salts of the compounds (I) include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. B. salts of Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, Ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, Acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, Fumaric acid, maleic acid and benzoic acid.

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

Such forms of the compounds are considered as solvates in the context of the invention referred to, which in the solid or liquid state by coordination with Solvent molecules form a complex. Hydrates are a special form of solvate, where coordination takes place with water.

In the context of the present invention, unless otherwise specified, the substituents have the following meaning:
Alkyl per se and "alk" and "alkyl" in alkoxy, alkylamino, alkylaminocarbonyl and alkoxycarbonyl stand for a linear or branched alkyl radical with generally 1 to 6, preferably 1 to 4, particularly preferably 1 to 3 carbon atoms, by way of example and preferably for Methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
Alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.
Alkylamino stands for an alkylamino radical with one or two (independently selected) alkyl substituents, for example and preferably for methylamino, ethylamino, n-propylamino, isopropylamino, tert.-butylamino, n-pentylamino, n-hexylamino, N, N-dimethylamino, N , N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N-tert-butyl-N-methylamino, N-ethyl-Nn-pentylamino and Nn- hexyl-N-methylamino.
Alkylaminocarbonyl stands for an alkylaminocarbonyl radical with one or two (independently selected) alkyl substituents, for example and preferably for methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert.-butylaminocarbonyl, n-pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-N-N-N-N-N-N-N-N-N-N-N-N-Dim- , N-diethylaminocarbonyl, N ethyl-N-methylaminocarbonyl, N-methyl-Nn-propylaminocarbonyl, N-isopropyl-Nn-propylaminocarbonyl, Nt-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N- methylaminocarbonyl.
Alkoxycarbonyl is exemplified and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.
Cycloalkyl stands for a cycloalkyl group with generally 3 to 8, preferably 5 to 7 carbon atoms, by way of example and preferably for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.
Aryl stands for a mono- to tricyclic aromatic, carbocyclic radical with usually 6 to 14 carbon atoms; exemplary and preferably for phenyl, naphthyl and phenanthrenyl.
Heterocyclyl stands for a mono- or polycyclic, preferably mono- or bicyclic, non-aromatic heterocyclic radical with generally 4 to 10, preferably 5 to 8 ring atoms and up to 3, preferably up to 2 heteroatoms and / or hetero groups from the series N, O, S, SO, SO ₂ . The heterocyclyl residues can be saturated or partially unsaturated. Preference is given to 5- to 8-membered, monocyclic saturated heterocyclyl radicals having up to two heteroatoms from the O, N and S series, such as, for example and preferably, tetrahydrofuran-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolinyl, Piperidinyl, morpholinyl, perhydroazepinyl.
Halogen stands for fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

Compounds of the formula (I) are preferred
in which
the rest -NHC (D) NHR ² is bound to the aromatic system 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 stands} for C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to three substituents independently selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino , C ₁ -C ₆ -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, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
R ^{2 represents} C ₆ -C ₁₀ 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 stands} for 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, phenyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ Alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
R ^{5 represents} hydrogen, halogen, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkyl,
R ^{6 represents} C ₃ -C ₈ cycloalkyl or C ₁ -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 C ₁ -C ₆ alkoxycarbonyl,
and
where cycloalkyl can be optionally substituted with up to three substituents independently selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy.

Also preferred are compounds of formula (I)
in which
the remainder -NHC (D) NHR ² is bound to the aromatic system via position 3,
X for -N (R ⁶ ) - or a group


stands,
D stands for oxygen,
R ^{1 represents} C ₁ -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 ^{2 represents} C ₆ -C ₁₀ 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} C ₁ -C ₆ alkyl,
R ^{5 represents} hydrogen or fluorine,
R ^{6 represents} C ₅ -C ₇ cycloalkyl or C ₁ -C ₆ alkyl, where alkyl can optionally be 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 aromatic system via position 3.

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

In a further preferred embodiment, X in the compounds of the formula (I) is -N (R ⁶ ) -.

In a further preferred embodiment, the compounds of the formula (I) for D oxygen.

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 ^{2 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 is} methyl.

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

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

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

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

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

DCN-R ² (III),

in which R ² 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 Solvent reflux at normal pressure.

Inert solvents are, for example, halogenated hydrocarbons such as Methylene chloride, trichloromethane, carbon tetrachloride, trichloroethane, carbon tetrachloride, 1,2-dichloroethane or trichlorethylene, ethers such as diethyl ether, methyl tert-butyl ether, 1,2- Dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, hydrocarbons such as benzene, xylene, toluene, hexane, Cyclohexane or petroleum fractions, or other solvents such as ethyl acetate, acetone, Dimethylformamide, dimethylacetamide, 2-butanone, dimethyl sulfoxide, acetonitrile or Pyridine, tetrahydrofuran 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 are preferred Diisopropylethylamine and triethylamine.

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

The compounds of formula (IIa), 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,
be reduced, e.g. B. with tin (II) chloride or hydrogen with palladium on carbon.

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

Inert solvents are, for example, ethers such as diethyl ether, Methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or Diethylene glycol dimethyl ether, alcohols such as methanol, ethanol, n-propanol, iso- Propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as Dimethylformamide, dimethylacetamide, acetonitrile or pyridine are preferred Ethanol, iso-propanol 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 ¹ , R ⁴ and R ^{5 have} the meaning given above,
with hydrazine or a compound of the general formula (VI),


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

The reaction takes place in inert solvents, preferably in one Temperature range from room temperature to the reflux of 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, iso- Propanol, n-butanol or tert-butanol, hydrocarbons such as benzene, xylene, Toluene, hexane, cyclohexane or petroleum fractions, or other solvents such as Dimethylformamide, dimethylacetamide, acetonitrile or pyridine are preferred Ethanol or iso-propanol.

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 ₂ 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 formula (VIII)


wherein R ¹ and R ^{4 have} the meaning given above,
be implemented in the presence of boron trifluoroetherate.

The reaction takes place in inert solvents, preferably in one Temperature range from room temperature to the reflux of 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, 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 (VII) are known or can be known analogously Processes are made.

The compounds of the 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 (IIb) which stand for compounds of the formula (II) in which X represents NR ⁶ can be prepared by compounds of the formula (IX)


in which
NHC (O) CH ₃ is bonded to the aromatics via one of the positions 2, 3, 5 or 6, and
R ³ , R ⁵ and R ^{6 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 hydroxides such as sodium, lithium or Potassium hydroxide, alkali carbonates such as cesium carbonate, sodium or potassium carbonate, sodium hydroxide is preferred.

The compounds of formula (IX) 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 ⁶ (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 known analogously Processes are made.

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


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 (XIII)

OHC-R ³ (XIII)

are implemented in a reductive amination by methods known to those skilled in the art of reductive aminations.

The compounds of the formulas (XII) and (XIII) are known or can be used analogously known methods can be produced.

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 according to the invention can be illustrated by the following synthesis schemes 1-8. Synthesis schemes Scheme 1

Scheme 2

Scheme 3 Alkylations of the pyrazolones

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 do not show one predictable surprising spectrum of action. They have an antiviral effect to representatives of the group of herpes viridae, especially to the human cytomegalovirus (HCMV). They are therefore for treatment and Prophylaxis of diseases caused by herpes viridae, especially of Diseases caused by human cytomegaloviruses are suitable.

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

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

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

• 1. Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).
• 2. Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients who often suffer from life-threatening HCMV pneumonitis, encephalitis and gastrointestinal and systemic HCMV infections.
• 3. Treatment and prophylaxis of HCMV infections in newborns and young children.
• 4. Treatment of acute HCMV infection in pregnant women.
• 5. Treatment of HCMV infection in immunosuppressed patients with cancer and cancer therapy.

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

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

The active substance can act systemically and / or locally. For this purpose, he can be applied in a suitable manner, such as. B. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, transdermal, conjunctival, otic or as Implant.

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

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

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

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

The active substances can be incorporated into the listed substances in a manner known per se Application forms are transferred. This is done using inert ones non-toxic, pharmaceutically suitable excipients. These include u. a. Carriers (e.g. microcrystalline cellulose), solvents (e.g. liquid Polyethylene glycols), emulsifiers (e.g. sodium dodecyl sulfate), dispersants (e.g. Polyvinylpyrrolidone), synthetic and natural biopolymers (e.g. albumin), stabilizers (e.g. antioxidants such as ascorbic acid), dyes (e.g. inorganic pigments such as Iron oxides) or taste and / or smell.

In general, it has proven to be advantageous for intravenous administration Amounts of about 0.001 to 10 mg / kg, preferably about 0.01 to 5 mg / kg Body weight for effective results, and oral Application is about 0.01 to 25 mg / kg, preferably 0.1 to 10 mg / kg Body weight.

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

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

A. Examples Abbreviations

TLC: thin layer chromatography

DCI: direct chemical ionization (for MS)

DCM: dichloromethane

DIEA: N, N-diisopropylethylamine

DMSO: dimethyl sulfoxide

DMF: dimethylformamide

d. Th .: the 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

R

_t

: Retention time (with HPLC)

THF: tetrahydrofuran

General methods LC-MS and HPLC HPLC parameters Method 1

Column: Kromasil C18, L-R temperature: 30 ° C, flow = 0.75 mlmin

^-1

. Eluent: A = 0.01 M HClO

₄

, B = CH

₃

CN, gradient: → 0.5 min 98% A → 4.5 min 10% A → 6.5 min 10% A

Method 3

Column: Kromasil C18 60.2, L-R temperature: 30 ° C, flow = 0.75 mlmin

^-1

. Eluent: A = 0.005 M HClO

₄

, B = CH

₃

CN, gradient: → 0.5 min 98% A → 4.5 min 10% A → 6.5 min 10% A

Method 10

LCMS = column: Symmetry C18 2.1 × 150 mm, column oven: 70 ° C, flow = 0.9 mlmin

^-1

, Eluent: A = CH

₃

CN, B = 0.23 g 30% HCl / l 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 1-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 1 N 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 1-methoxy-2-methyl-1-trimethylsiloxypropene and 7.65 g (53.9 mmol) of boron trifluoride diethyl ether are used -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 ) ⁺ Example 2A methyl 3- (3-bromo-5-nitrophenyl) -2,2-dimethyl-3-oxopropanoate

Starting from 5 g (18.9 mmol) of 3-bromo-5-nitrobenzoic acid chloride, 3.30 g (18.9 mmol) of 1-methoxy-2-methyl-1-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, 2.13 g (9.92 mmol) of [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) of 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 instructions 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 out of 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 methyl ester, 6.63 g (83% of theory) are obtained with 8.50 g (170 mmol) of hydrazine hydrate. Received product.
Mp: 164.6 ° C
HPLC (method 3): R _t = 3.99 min
MS (DCI): m / z = 251 (M + NH ₄ ) ⁺ 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-oxopropanoic acid methyl ester, 2.88 g (57.6 mmol) of hydrazine hydrate are 3.12 g (87% of theory) Product received.
Mp: 214.9 ° C
HPLC (method 3): R _t = 4.26 min
MS (ESIpos): m / z = 312 (M + H) ⁺

General working instructions 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. The mixture is then allowed to stir at room temperature for 30 minutes and then 1.2-2.5 equivalents of the alkylating agent are added. 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-pyrazol-3-one, after deprotonation with 0.46 g (11 , 9 mmol) sodium hydride (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 1- (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. This gives 278 mg (41% of theory) of product.
HPLC (method 3): R _t = 3.31 min
MS (ESIpos): m / z = 244 (M + H) ⁺

General working instructions 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 diatomaceous earth, 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 + H) ⁺

Alternative synthesis of 4,4-dimethyl-5- (3-aminophenyl) -2,4-dihydro-3H-pyrazol-3- on

772 mg (2.49 mmol) of 2,2-dimethyl-3- (3-nitrophenyl) -3-oxopropanoic acid, methyl ester, 1.87 g (37.4 mmol) of hydrazine hydrate are dissolved in 80 ml of ethanol, with 100 mg of palladium on activated carbon added 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. 413 mg (82% of theory) of product are obtained.
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 ] acetate

Starting from 500 mg (1.57 mmol) [4,4-dimethyl-3- (3-nitrophenyl) -5-oxo-4,5-dihydro-1H-pyrazol-1-yl] ethyl acetate, 449 mg (85% d. Th.) Product received.
HPLC (method 3): R _t = 3.37 min
MS (ESIpos): m / z = 290 (M + H) ⁺

General working instructions 5 Reduction of the nitro group in bromine-containing aromatics

0.8 mmol of the bromo-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 1 N 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 further. 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-3H-pyrazol-3-one, 3.61 g (16 mmol ) Tin dichloride dihydrate 758 mg (84% of theory) Product obtained.
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) N, N-diisopropylethylamine and 26.75 g (139.53 mmol) N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl added. Then 18.44 g (139.53 mmol) of tert-butyl hydrazine formate added and allowed to stir 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 1 N hydrochloric acid and twice with saturated sodium bicarbonate solution, part of the product already precipitating out 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.
¹ H-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] hydrazinium 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 working instructions 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-cyclohexylhydrazine carboxamide

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 reacted with 7.88 g (60.96 mmol) of diisopropylethylamine and 4.49 g (30.48 mmol) of 1-phenylethyl isocyanate. The raw product is then directly implemented.
HPLC (method 3): Rt = 3.53 min

General working instructions 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. The mixture is stirred at 100 ° C. for 48 hours. The reaction solution is adjusted to pH 7 with hydrochloric acid, the precipitate formed is suction filtered, 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-isopropylhydrazinecarboxamide (crude) and 8.00 g (200.02 mmol) of sodium hydroxide in 200 ml of 1 N sodium hydroxide solution 2.81 g (40% of theory) of product obtained.
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 1 N sodium hydroxide solution 5.59 g (66% of theory) of product were obtained.
HPLC (method 3): R _t = 3.31 min Example 18A 5- (3-aminophenyl) -4- (1-phenylethyl) -2,4-dihydro-3H-1,2,4-triazol-3-one

Starting from 8.83 g (32.55 mmol) of 2- [3- (acetylamino) benzoyl] -N- (1-phenylethyl) 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 instructions 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-pyrazol-3-one in 1 ml Ethyl acetate and 0.2 ml of tetrahydrofuran and added overnight Room temperature stirred. The formation of a white precipitate is observed.

workup

The reaction mixture is concentrated and the residue obtained after taking up in DMSO is purified by RP-HPLC. This gives 42 mg (58% of theory) of product as a white solid.
Mp: 226.8 ° C
HPLC (method 3): R _t = 4.33 min
MS (ESIpos): m / z = 371 (M + H) ^+
1 H-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-1H-pyrazol-3-yl) phenyl] urea

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

workup

The reaction mixture is concentrated and the residue obtained after taking up in DMSO is purified by RP-HPLC. 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) ^+
1 H-NMR (200 MHz, DMSO): δ = 1.38 (s, 6H), 7.13-7.17 (m, 1H), 7.28-7.46 (m, 4H), 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) 3-bromophenyl isocyanate are mixed with a solution of 40 mg 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 overnight at room temperature touched. The formation of a white precipitate is observed.

workup

The reaction mixture is concentrated and the residue obtained after taking up in DMSO is purified by RP-HPLC. 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) ^+
1 H-NMR (200 MHz, DMSO): δ = 1.38 (s, 6H), 7.15 (m, 1H), 7.25 (t, 1H), 7.32-7.46 (m, 4H), 7.84 (s br, 1H) , 8.06 (s br, 1H), 8.96 (s br, 2H), 11.55 (s, br 1H) Example 4 N- (3-chloro-4-fluorophenyl) -N '- [3- (4,4-dimethyl -5-oxo-4,5-dihydro-1H-pyrazol-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-pyrazol-3-one in 1 ml Ethyl acetate and 0.2 ml of tetrahydrofuran and added overnight Room temperature stirred. The formation of a white precipitate is observed.

workup

The reaction mixture is concentrated and the residue obtained after taking up in DMSO is purified by RP-HPLC. 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) ^+
1 H-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) 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 Ethyl acetate and 0.2 ml of tetrahydrofuran and added overnight Room temperature stirred. The formation of a white precipitate is observed.

workup

The reaction mixture is concentrated and the residue obtained after taking up in DMSO is purified by RP-HPLC. 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) ^+
1 H-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-1H-pyrazol-1-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 × 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 1 equivalent of the corresponding isocyanate is added. 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, 250 × 30, 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-1,2,4-triazol-3-yl) phenyl] urea

Starting from 60.00 mg (0.27 mmol) of 5- (3-aminophenyl) -4-isopropyl-2,4-dihydro-3H-1,2,4-triazol-3-one, 42.22 mg ( 0.27 mmol) 3-chlorophenyl isocyanate 67.60 mg (66% of theory) of product.
HPLC (method 3): R _t = 4.22 min
¹ H 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-1,2,4-triazol-3-yl) phenyl ]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, 94.2 mg ( 0.69 mmol) 3-chloro-4-fluorophenyl isocyanate 57 mg (33% of theory) of product.
HPLC (method 3): R _t = 4.12 min
¹ H NMR (200 MHz, D ₆ -DMSO): δ = 11.80 (s, 1H); 9.31 (d, 2H); 7.86-7.09 (m, 8H); 4.17-4.10 (m, 1H); 1.41 (d, 6H).

B. Assessment of physiological effectiveness

The in vitro activity of the compounds according to the invention can be seen in the following Assays are shown:

Anti-HCMV (Anti-Human Cytomegalovirus) cytopathogenicity tests

The test compounds are used as 50 millimolar (mM) solutions in dimethysulfoxide (DMSO). Ganciclovir, foscarnet and cidofovir serve as reference compounds. After adding 2 µl of the 50, 5, 0.5 and 0.05 mM DMSO stock solutions to 98 µl cell culture medium in the 2 AH series in duplicate, 1: 2 dilutions with 50 µl medium are carried out up to the 11 series the 96-well plate. The wells in rows 1 and 12 each contain 50 µl medium. 150 μl of a suspension of 1 × 10 ⁴ cells (human foreskin fibroblasts [NHDF]) are then pipetted into the wells (row 1 = cell control) or a mixture of HCMV-infected and non-infected NHDF cells ( MOI = 0.001-0.002), ie 1-2 infected cells per 1000 uninfected cells. Row 12 (without substance) serves as a virus control. The final test concentrations are 250-0.0005 µM. The plates are incubated for 6 days at 37 ° C / 5% CO ₂ , ie until all cells in the virus controls are infected (100% cytopathogenic effect [CPE]). The wells are then fixed by adding a mixture of formalin and Giemsa's dye and colored (30 minutes), with aqua bidest. washed and dried in a drying cabinet at 50 ° C. The plates are then visually evaluated using an overhead microscope (plaque multiplier from Technomara).

The following data can be obtained from the test plates:
CC ₅₀ (NHDF) = substance concentration in µM, at which no visible cytostatic effects on the cells can be seen in comparison to the untreated cell control;
EC ₅₀ (HCMV) = substance concentration in µM 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 SCID-NOD or SCID-beige are used by commercial breeders (Bomholtgaard, Jackson). The animals are under sterile conditions (including litter and feed) kept in isolators.

virus growing

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

Preparation of the sponges, transplantation, treatment and evaluation

1 × 1 × 1 cm collagen sponges (Gelfoam®; Peasel & Lorey, Order No. 407534; KT Chong et al., Abstracts of 39 ^th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1999, p. 439) first wetted with phosphate buffered saline (PBS), the enclosed air bubbles removed by degassing and then stored in MEM + 10% FCS. 1 × 10 ⁶ virus-infected NHDF cells (infection with HCMV-Davis MOI = 0.01) are detached 3 hours after infection and dropped onto a moist sponge in 20 μl MEM, 10% FCS. 12-13 hours later, the infected sponges are incubated with 25 μl PBS / 0.1% BSA / 1 mM DTT with 5 ng / μl basic fibroblast growth factor (bFGF). For the transplantation, the immunodeficient mice are anesthetized with avertine, the dorsal coat removed with the help of a dry razor, the epidermis opened 1-2 cm, relieved and the moist sponges transplanted under the dorsal skin. The surgical wound is closed with tissue glue. 24 hours after the transplant, the mice are treated orally with substance three times a day for 8 days (7 a.m. and 2 p.m. and 7 p.m.). The dose is 7 or 15 or 30 or 60 mg / kg body weight, the application volume 10 ml / kg body weight. The substances are formulated in the form of a 0.5% tylose suspension with 2% DMSO. 9 days after the transplant and 16 hours after the last substance application, the animals are killed painlessly and the sponge is removed. The virus-infected cells are released from the sponge by collagenase digestion (330 U / 1.5 ml) and stored in the presence of MEM, 10% fetal calf serum, 10% DMSO at -140 ° C. The evaluation is carried out after serial dilution of the virus-infected cells in steps of ten by titer determination on 24-well plates of confluent NHDF cells after vital staining with neutral red. The number of infectious virus particles after substance treatment is determined in comparison to the placebo-treated control group.

C. Embodiments of pharmaceutical compositions

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

tablet composition

100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg Corn starch (native), 10 mg polyvinyl pyrolidone (PVP 25) (from BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.

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

manufacturing

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

Oral suspension composition

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

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

manufacturing

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

Claims (20)

1. Compounds of the formula


in which
the rest -NHC (D) NHR ² is bound to the aromatic system via one of the positions 2, 3, 5 or 6,
X for -N (R ⁶ ) - or a group


stands,
D represents oxygen or sulfur,
R ^{1 represents} C ₆ -C ₁₀ aryl or C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to three substituents independently selected from the group consisting of hydroxy, C ₁ - C ₆ alkoxy, amino , C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
and
where aryl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of halogen, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl , C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylaminocarbonyl and C ₁ -C ₆ 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, 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, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
R ^{2 represents} C ₃ -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, C ₁ - C ₆ -alkoxy, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, amino, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkyl,
R ^{3 represents} hydrogen or C ₁ -C ₆ alkyl, where alkyl can 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} C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to three 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, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
or
R ^{4 represents} 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, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ -Alkylamino, C ₁ -C ₆ -alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ -alkoxycarbonyl, C ₁ -C ₆ -alkylaminocarbonyl and C ₁ -C ₆ -alkyl,
R ^{5 represents} hydrogen, halogen, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkyl,
R ^{6 represents} C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to two substituents selected independently of one another from the group consisting of hydroxy, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, hydroxycarbonyl and C ₁ -C ₆ alkoxycarbonyl,
and
where cycloalkyl can optionally be substituted with up to three substituents independently of one another selected from the group consisting of hydroxy, C ₁ -C ₆ alkyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkoxy, amino, C ₁ - C ₆ alkylamino, hydroxycarbonyl and C ₁ -C ₆ alkoxycarbonyl. 2. Compounds according to claim 1, wherein
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 stands} for C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to three substituents independently selected from the group consisting of hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino , C ₁ -C ₆ 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, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
R ^{2 represents} C ₆ -C ₁₀ 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 stands} for 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, phenyl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ Alkylamino, C ₁ -C ₆ alkylcarbonylamino, hydroxycarbonyl, C ₁ -C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
R ^{5 represents} hydrogen, halogen, hydroxy, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino or C ₁ -C ₆ alkyl,
R ^{6 represents} C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ alkyl, where alkyl can optionally be substituted with up to two substituents selected independently of one another from the group consisting of hydroxy, C ₆ -C ₁₀ aryl, C ₁ -C ₆ alkoxy, amino, C ₁ -C ₆ alkylamino, hydroxycarbonyl and C ₁ -C ₆ alkoxycarbonyl,
and
where cycloalkyl can be optionally substituted with up to three substituents independently selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy. 3. Compounds according to claim 1, wherein
the remainder -NHC (D) NHR ² is bound to the aromatic system via position 3,
X for -N (R ⁶ ) - or a group


stands,
D stands for oxygen,
R ^{1 represents} C ₁ -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 ^{2 represents} C ₆ -C ₁₀ 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} C ₁ -C ₆ alkyl,
R ^{5 represents} hydrogen or fluorine,
R ^{6 represents} C ₅ -C ₇ cycloalkyl or C ₁ -C ₆ alkyl, where alkyl can optionally be 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 position 3 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 ^{3 is} hydrogen. 11. Compounds according to claim 1, 2 or 3, wherein R ^{4 is} methyl. 12. Compounds according to claim 1, 2 or 3, wherein R ^{5 is} hydrogen. 13. Compounds according to claim 1, 2 or 3, wherein R ^{6 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 formula (III)

DCN-R ² (III),

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 treatment and / or Prophylaxis of viral diseases. 16. Medicament containing at least one compound according to one of the Claims 1 to 3 in combination with at least one pharmaceutical compatible, pharmaceutically acceptable carrier or excipient. 17. Use of compounds according to one of claims 1 to 3 for Manufacture of a medicament for the treatment and / or prophylaxis of viral Diseases. 18. Medicament according to claim 16 for the treatment and / or prophylaxis of viral diseases. 19. Methods for combating viral diseases in humans and Animals by administration of an antivirally effective amount at least a connection according to one of claims 1 to 3. 20. 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 in claim 1.