DE102005021963A1 - New substituted dihydropyrazolotriazinone compounds, useful for treating bacterial diseases/infections - Google Patents

Abstract

Substituted dihydropyrazolotriazinone compounds (I) and their salts and solvates are new. Substituted dihydropyrazolotriazinone compound of formula (I) and their salts and solvates are new. R1>6-10C-aryl or 5-6 membered heteroaryl (both substituted by 1-3 T); R2>H, 1-4C-alkyl (optionally substituted by 1-2 substituents of OH or 1-4C alkoxylcarbonyl), 1-4C-alkoxycarbonyl or phenyl (optionally substituted by 1-3 T); or CR1>R2>1,2,3,4-tetrahydronaphthalene compound of formula (1), optionally substituted by 1-2 T; T : halo, trifluoromethyl, trifluoromethoxy, OH, NH3, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkylthio, 1-6C-alkylamino, CN, NO2, hydroxycarbonyl, aminocarbonyl, 1-4C-alkoxycarbonyl or 1-6C-alkylaminocarbonyl; a : carbon atom to which R1> and R2> are bound; R3>H, halo, 1-6C-alkyl, 3-6C-cycloalkyl or b-Ctriple boundC-R4>; b : attachment to the pyrazolotriazinone; and R4>H, trimethylsilyl, hydroxymethyl, 1-6C-alkylaminomethyl, phenyl or 3-6C-cycloalkyl, where phenyl and cycloalkyl are substituted by 1-3 T; and provided that 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-one is excluded. Independent claims are also included for the following: (1) use of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-one for treating and/or preventing bacterial infections; and (2) preparation of (I). [Image] ACTIVITY : Antibacterial. MECHANISM OF ACTION : None given.

Description

The The invention relates to substituted dihydropyrazolotriazinones and processes for their preparation, their use for treatment and / or prophylaxis of diseases as well as their use for the production of medicines for the treatment and / or prophylaxis of diseases, in particular from bacterial infections.

In P.G. Baraldi, et al., Synthesis, 1994, 1437-1440 describes the preparation of pyrazolotriazinones. In P.G. Baraldi, et al., Synthesis, 1988, 78-81 and S. Manfredini, et al., Journal of Medicinal Chemistry, 1992, 917-924, the production of Pyrazolotriazinonen, as z. 3-Benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one described. P.G. Baraldi, et al., Arzneimittel-Forschung, 1996, 365-368 describe 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one as Adenosine A1 and A2a antagonists.

the Although many physicians are structurally more different in their treatment antibacterial agent available, but one finds increasingly Germs that are already against the antibiotics used in the clinic become resistant. About that It also comes out regularly Development of further, especially multiple resistances, so that the available antibacterial agents are increasingly losing usefulness. New Funds for a good and more effective therapy is therefore desirable.

A Object of the present invention is therefore, new and alternative Compounds with the same or improved antibacterial activity for the treatment of bacterial diseases in humans and animals to disposal to deliver.

Surprisingly it was found that certain dihydropyrazolotriazinone derivatives are antibacterial and therefore for treatment and / or Prophylaxis of bacterial infections are suitable.

in welcher
R¹ für C₆-C₁₀-Aryl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Aryl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Hydroxy, Amino, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Alkylthio, C₁-C₆-Alkylamino, Cyano, Nitro, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
R² für Wasserstoff, C₁-C₄-Alkyl, C₁-C₄-Alkoxycarbonyl oder Phenyl steht,
wobei Alkyl substituiert sein kann mit 1 bis 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Hydroxy und C₁-C₄-Alkoxycarbonyl,
und
wobei Phenyl substituiert sein kann mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Hydroxy, Amino, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Alkylthio, C₁-C₆-Alkylamino, Cyano, Nitro, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
oder
R¹ und R² zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, für eine Gruppe der Formel

stehen und damit ein 1,2,3,4-Tetrahydronaphthalen bilden,
wobei
# für das Kohlenstoffatom steht, an das R¹ und R² gebunden sind,
und
wobei das 1,2,3,4-Tetrahydronaphthalen substituiert sein kann mit 1 bis 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Hydroxy, Amino, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄- Alkylthio, C₁-C₆-Alkylamino, Cyano, Nitro, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
R³ für Wasserstoff, Halogen, C₁-C₆-Alkyl, C₃-C₆-Cycloalkyl oder *-C≡C-R⁴ steht,
wobei
* die Anknüpfstelle an das Pyrazolotriazinon ist,
und
R⁴ für Wasserstoff, Trimethylsilyl, Hydroxymethyl, C₁-C₆-Alkylaminomethyl, Phenyl oder C₃-C₆-Cycloalkyl steht,
worin Phenyl und Cycloalkyl substituiert sein können mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Hydroxy, Amino, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Alkylthio, C₁-C₆-Alkylamino, Cyano, Nitro, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze,
mit Ausnahme von 3-Benzyl-7-methyl-3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-on.The invention relates to compounds of the formula

in which
R ^{1 is} C ₆ -C ₁₀ -aryl or 5- or 6-membered heteroaryl,
wherein aryl and heteroaryl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _4- alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
R ^{2 is} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxycarbonyl or phenyl,
wherein alkyl may be substituted with 1 to 2 substituents independently selected from the group consisting of hydroxy and C ₁ -C ₄ alkoxycarbonyl,
and
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - Alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
or
R ¹ and R ² together with the carbon atom to which they are attached represent a group of the formula

and thus form a 1,2,3,4-tetrahydronaphthalene,
in which
# represents the carbon atom to which R ¹ and R ^{2 are} bonded,
and
wherein the 1,2,3,4-tetrahydronaphthalene may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
R ^{3 is} hydrogen, halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl or * -C≡CR ⁴ ,
in which
* is the point of attachment to the pyrazolotriazinone,
and
R ^{4 is} hydrogen, trimethylsilyl, hydroxymethyl, C ₁ -C ₆ -alkylaminomethyl, phenyl or C ₃ -C ₆ -cycloalkyl,
wherein phenyl and cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _4- alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
and their salts, their solvates and the solvates of their salts,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates the salts as well as those of formula (I), hereinafter referred to as embodiment (e) mentioned compounds and their salts, solvates and solvates of Salts, as far as those of formula (I), hereinafter not already mentioned salts, solvates and solvates salts.

The Compounds of the invention can dependent on of their structure in stereoisomeric forms (enantiomers, diastereomers) exist. The invention therefore relates to the enantiomers or Diastereomers and their respective mixtures. From such mixtures Enantiomers and / or diastereomers can be prepared by known Methods such as chromatography on chiral phase or crystallization with chiral amines or chiral acids the stereoisomerically uniform Isolate ingredients in a known manner.

The Invention relates in dependence from the structure of the compounds also tautomers of the compounds.

When Salts are physiologically acceptable salts in the context of the invention the compounds of the invention prefers.

physiological Safe 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, trifluoroacetic acid and Benzoic acid.

physiological Safe salts of the compounds (I) also include salts of more common Bases, such as by way of example and preferably alkali metal salts (e.g. Sodium and potassium salts), alkaline earth 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, dicyclohexylamine, dimethylaminoethanol, Prokain, dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine, Lysine, ethylenediamine and methylpiperidine.

When Solvates are in the context of the invention, such forms of compounds designated, which in solid or liquid state by coordination with solvent molecules one Complex form. Hydrates are a special form of solvate, at which is coordinated with water.

In the context of the present invention, unless otherwise specified, the substituents have the the following meaning:
Alkyl per se and "Alk" and "alkyl" in alkoxy, alkylamino, alkoxycarbonyl and alkylaminocarbonyl are a linear or branched alkyl radical having usually 1 to 6, preferably 1 to 4 carbon atoms, by way of example and preferably methyl, ethyl, n- Propyl, isopropyl, n-butyl, tert-butyl, n-pentyl and n-hexyl.

alkoxy is exemplary and preferably methoxy, ethoxy, n-propoxy, Isopropoxy and tert-butoxy.

alkylthio is exemplary and preferably methylthio, ethylthio, n-propylthio, Isopropylthio and tert-butylthio.

Alkylamino represents an alkylamino radical having one or two (independently selected) alkyl substituents, by way of example and by way of preference 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. C ₁ -C ₃ -alkylamino is, for example, a monoalkylamino radical having 1 to 3 carbon atoms or a dialkylamino radical having in each case 1 to 3 carbon atoms per alkyl substituent.

alkoxycarbonyl is exemplary and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylaminocarbonyl is an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, the alkyl substituents independently of one another generally having 1 to 6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms, by way of example and preferably methylaminocarbonyl, ethylaminocarbonyl, n Propylaminocarbonyl, isopropylaminocarbonyl, tert -butylaminocarbonyl, n -pentylaminocarbonyl, n-hexylaminocarbonyl, N, N-dimethylaminocarbonyl, N, N -diethylaminocarbonyl, N -ethyl-N-methylaminocarbonyl, N -methyl-Nn-propylaminocarbonyl, N-isopropyl Nn-propylaminocarbonyl, N-tert-butyl-N-methylaminocarbonyl, N-ethyl-Nn-pentylaminocarbonyl and Nn-hexyl-N-methylaminocarbonyl. C ₁ -C ₃ -alkylaminocarbonyl is, for example, a monoalkylaminocarbonyl radical having 1 to 3 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 3 carbon atoms per alkyl substituent.

cycloalkyl stands for a cycloalkyl group of usually 3 to 6 carbon atoms, by way of example and preferably for Cycloalkyl are called cyclopropyl, cyclobutyl, cyclopentyl and Cyclohexyl.

aryl stands for a mono- or bicyclic aromatic radical, as a rule 6 to 10 carbon atoms, by way of example and preferably aryl called phenyl and naphthyl.

heteroaryl stands for an aromatic, monocyclic radical of usually 5 to 6 Ring atoms and up to 4 heteroatoms from the series S, O and N, where a nitrogen atom can also form an N-oxide, by way of example and preferably for Thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, Imidazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl.

halogen stands for Fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

If Residues in the compounds of the invention may be substituted the radicals, unless otherwise specified, one or more times be substituted identically or differently. A substitution with up to three identical or different substituents are preferred. Very particular preference is given to the substitution with a substituent.

stehen und damit ein 1,2,3,4-Tetrahydronaphthalen bilden,
wobei
# für das Kohlenstoffatom steht, an das R¹ und R² gebunden sind,
und
wobei das 1,2,3,4-Tetrahydronaphthalen substituiert sein kann mit 1 bis 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Hydroxy, Amino, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Alkylthio, C₁-C₆-Alkylamino, Cyano, Nitro, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
R³ für Wasserstoff, C₁-C₄-Alkyl oder *-C≡C-R⁴ steht,
wobei
* die Anknüpfstelle an das Pyrazolotriazinon ist,
und
R⁴ für Wasserstoff, Trimethylsilyl, Hydroxymethyl, C₁-C₆-Alkylaminomethyl, Phenyl oder C₃-C₆-Cycloalkyl steht,
worin Phenyl und Cycloalkyl substituiert sein können mit 1 bis 3 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Hydroxy, Amino, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Alkylthio, C₁-C₆-Alkylamino, Cyano, Nitro, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze,
mit Ausnahme von 3-Benzyl-7-methyl-3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-on.Preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 is} phenyl,
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - Alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
R ^{2 is} hydrogen, methyl, hydroxymethyl, methoxycarbonyl or phenyl,
where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
or
R ¹ and R ² together with the carbon atom to which they are attached represent a group of the formula

and thus form a 1,2,3,4-tetrahydronaphthalene,
in which
# represents the carbon atom to which R ¹ and R ^{2 are} bonded,
and
wherein the 1,2,3,4-tetrahydronaphthalene may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
R ^{3 is} hydrogen, C ₁ -C ₄ -alkyl or * -C≡CR ⁴ ,
in which
* is the point of attachment to the pyrazolotriazinone,
and
R ^{4 is} hydrogen, trimethylsilyl, hydroxymethyl, C ₁ -C ₆ -alkylaminomethyl, phenyl or C ₃ -C ₆ -cycloalkyl,
wherein phenyl and cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _4- alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
and their salts, their solvates and the solvates of their salts,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 is} phenyl,
wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl and cyano,
R ^{2 is} hydrogen or methyl,
R ^{3 is} hydrogen, methyl or C 1 -C ⁴ CR ⁴ ,
in which
* is the point of attachment to the pyrazolotriazinone,
and
R ^{4 is} hydroxymethyl, phenyl or C ₃ -C ₆ -cycloalkyl,
wherein phenyl and cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _4- alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
and their salts, their solvates and the solvates of their salts,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 is} phenyl,
wherein phenyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen and trifluoromethyl,
R ^{2 is} hydrogen or methyl,
R ^{3 is} hydrogen, methyl or C 1 -C ⁴ CR ⁴ ,
in which
* is the point of attachment to the pyrazolotriazinone,
and
R ^{4 is} hydroxymethyl, phenyl or cyclohexyl,
in which phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, C ₁ -C ₄ -alkoxy, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
and
in which cyclohexyl may be substituted by a substituent selected from the group consisting of C ₁ -C ₄ -alkoxy, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
and their salts, their solvates and the solvates of their salts,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

stehen und damit ein 1,2,3,4-Tetrahydronaphthalen bilden,
wobei
# für das Kohlenstoffatom steht, an das R¹ und R² gebunden sind,
und
wobei das 1,2,3,4-Tetrahydronaphthalen substituiert sein kann mit 1 bis 2 Substituenten unabhängig voneinander ausgewählt aus der Gruppe bestehend aus Halogen, Trifluormethyl, Trifluormethoxy, Hydroxy, Amino, C₁-C₄-Alkyl, C₁-C₄-Alkoxy, C₁-C₄-Alkylthio, C₁-C₆-Alkylamino, Cyano, Nitro, Hydroxycarbonyl, Aminocarbonyl, C₁-C₄-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
mit Ausnahme von 3-Benzyl-7-methyl-3,5-dihydro-4H-pyrazolo[4,3-d][1,2,3]triazin-4-on.Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 is} phenyl,
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ - Alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
R ^{2 is} hydrogen, methyl, hydroxymethyl, methoxycarbonyl or phenyl, where phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
or
R ¹ and R ² together with the carbon atom to which they are attached represent a group of the formula

and thus form a 1,2,3,4-tetrahydronaphthalene,
in which
# represents the carbon atom to which R ¹ and R ^{2 are} bonded,
and
wherein the 1,2,3,4-tetrahydronaphthalene may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ Alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 is} phenyl,
wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl and cyano,
R ^{2 is} hydrogen or methyl,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 is} phenyl,
wherein phenyl may be substituted by 1 to 3 substituents independently selected from the group consisting of halogen and trifluoromethyl,
R ^{2 is} hydrogen or methyl,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{3 is} hydrogen, C ₁ -C ₄ -alkyl or * -C≡CR ⁴ ,
in which
* is the point of attachment to the pyrazolotriazinone,
and
R ^{4 is} hydrogen, trimethylsilyl, hydroxymethyl, C ₁ -C ₆ -alkylaminomethyl, phenyl or C ₃ -C ₆ -cycloalkyl,
wherein phenyl and cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _4- alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{3 is} hydrogen, methyl or C 1 -C ⁴ CR ⁴ ,
in which
* is the point of attachment to the pyrazolotriazinone,
and
R ^{4 is} hydroxymethyl, phenyl or C ₃ -C ₆ -cycloalkyl,
wherein phenyl and cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, C ₁ -C _4- alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

Also preferred in the context of the present invention are compounds of the formula (I) in which
R ^{3 is} hydrogen, methyl or C 1 -C ⁴ CR ⁴ ,
in which
* is the point of attachment to the pyrazolotriazinone,
and
R ^{4 is} hydroxymethyl, phenyl or cyclohexyl,
in which phenyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, C ₁ -C ₄ -alkoxy, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
and
in which cyclohexyl may be substituted by a substituent selected from the group consisting of C ₁ -C ₄ -alkoxy, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one.

zur Behandlung und/oder Prophylaxe von bakteriellen Infektionen.3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one

for the treatment and / or prophylaxis of bacterial infections.

in welcher R¹, R² und R³ die oben angegebene Bedeutung haben,
mit Natriumnitrit zu Verbindungen der Formel (I) zyklisiert werden,
oder
[A2] Verbindungen der Formel

in welcher R³ die oben angegebene Bedeutung hat,
mit Verbindungen der Formel

in welcher R¹ und R² die oben angegebene Bedeutung haben,
in Gegenwart von Dehydratisierungsreagenzien zu Verbindungen der Formel (I) zyklisiert werden,
oder
[A3] Verbindungen der Formel

in welcher R¹ und R² die oben angegebene Bedeutung haben,
mit einem Halogenierungsreagenz zu Verbindungen der Formel

in welcher R¹ und R² die oben angegebene Bedeutung haben, und
R³ für Halogen steht, umgesetzt werden,
oder
[A4] Verbindungen der Formel (Ib) in Gegenwart eines Palladiumkatalysators zu Verbindungen der Formel

in welcher R¹ und R² die oben angegebene Bedeutung haben, und
R³ für *-C≡C-R⁴ steht, worin R⁴ die oben angegebene Bedeutung hat, umgesetzt werden.The invention further provides a process for the preparation of the compounds of the formula (I) or their salts, their solvates or the solvates of their salts, wherein
[A1] Compounds of the formula

in which R ¹ , R ² and R ^{3 have} the abovementioned meaning,
be cyclized with sodium nitrite to compounds of formula (I),
or
[A2] Compounds of the formula

in which R ^{3 has} the meaning given above,
with compounds of the formula

in which R ¹ and R ^{2 have} the abovementioned meaning,
be cyclized in the presence of dehydrating reagents to compounds of formula (I),
or
[A3] Compounds of the formula

in which R ¹ and R ^{2 have} the abovementioned meaning,
with a halogenating reagent to compounds of the formula

in which R ¹ and R ^{2 have} the abovementioned meaning, and
R ^{3 is} halogen, to be reacted
or
[A4] Compounds of the formula (Ib) in the presence of a palladium catalyst to give compounds of the formula

in which R ¹ and R ^{2 have} the abovementioned meaning, and
R ^{3 is} * -C≡CR ⁴ , wherein R ^{4 has} the meaning given above, are reacted.

The Compounds of formula (Ia) can according to method [A1] or [A2].

The Implementation according to procedure [A1] is generally carried out in a mixture of water with a solvent and acetic acid or hydrochloric acid, preferably in a temperature range from 0 ° C to 40 ° C at atmospheric pressure.

solvent are, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, Dioxane, tetrahydrofuran or acetonitrile, preferred is dimethylformamide.

The Implementation according to procedure [A2] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range of 0 ° C to 40 ° C at Normal pressure.

Examples of suitable dehydrating reagents are carbodiimides, such as N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N ' ethylcarbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phe nyl-1,2-oxazolium-3-sulfate or 2-tert-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis- (2-oxo-3-oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU) , 2- (2-Oxo-1- (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N 'tetramethyluronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro-phosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or mixtures of this, or mixture of these together with bases.

bases For example, alkali metal carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preferably the condensation with PyBOP in the presence of a base, in particular Diisopropylethylamine, performed.

inert solvent For example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbon, such as benzene, or nitromethane, Dioxane, dimethylformamide or acetonitrile. It is also possible to mix the solvent use. Particularly preferred is dimethylformamide.

The Implementation according to procedure [A3] is generally carried out in inert solvents, in the presence of N-iodosuccinimide, N-bromosuccinimide or N-chlorosuccinimide in a temperature range from room temperature to reflux the solvent at normal pressure.

inert solvent are, for example, acetonitrile, dimethylformamide or carbon tetrachloride preferred is acetonitrile.

at the implementation according to the procedure [A4] becomes the free N atom with a protecting group known to those skilled in the art, such as B. [2- (trimethylsilyl) ethoxy] methyl, protected and the protecting group will become known to the skilled person after the Sonogashira reaction split off again known conditions.

The Implementation according to procedure [A4] is generally carried out under Sonogashira reaction conditions under argon in inert and degassed solvents, in the presence of a catalyst, optionally in the presence of a Zusatzreagenzes, in the presence of a base and triphenylphosphine, preferably in a temperature range from room temperature to backflow of the solvent at normal pressure (R. R. Tykwinski, Angew Chem, Int Ed 2003, 42, 1566-1568, K. Sonogashira in Handbook of Organopalladium Chemistry for organic synthesis (Ed E.I. Negishi), 1133-1178 Wiley-Interscience, New York (2002)).

catalysts are for example Sonogashira reaction conditions conventional palladium catalysts, preferred For example, catalysts such as e.g. Tri (dibenzylideneacetone) dipalladium, Dichlorobis (triphenylphosphine) palladium, tetrakistriphenylphosphine palladium (0), Palladium (II) acetate, 1,1'-bis [(diphenylphosphino) ferrocene] palladium II chloride (1: 1) complex with dichloromethane.

additional reagents are, for example, copper (I) iodide and triphenylphosphine.

bases For example, amine bases such as triethylamine.

inert solvent For example, ethers such as dioxane, tetrahydrofuran or 1,2-dimethoxyethane, hydrocarbons such as benzene, xylene or toluene, or other solvents such as nitrobenzene, dimethylformamide, dimethylacetamide, Dimethylsulfoxide or N-methylpyrrolidone, preferred are solvents such as. Dimethylformamide, dimethylacetamide, dimethyl sulfoxide or 1,2-dimethoxyethane.

The Compounds of the formula (IV) are known or can be prepared analogously to known processes getting produced.

in welcher R¹, R² und R³ die oben angegebene Bedeutung haben,
mit einem Reduktionsmittel umgesetzt werden.The compounds of the formula (II) are known or can be prepared by reacting the compounds of the formula

in which R ¹ , R ² and R ^{3 have} the abovementioned meaning,
be reacted with a reducing agent.

The Reaction is generally carried out in inert solvents, preferably in a temperature range from room temperature to reflux the solvent at normal pressure up to 3 bar.

reducing agent are, for example, palladium on activated carbon and hydrogen, palladium on activated carbon and sodium borohydride, tin dichloride or titanium trichloride, preferred is palladium on activated carbon and sodium borohydride.

inert solvent 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, or mixtures of the solvents with water, as a solvent are preferably methanol, ethanol, isopropanol or mixtures of Alcohols with water or in the case of tin dichloride in dimethylformamide.

in welcher R³ die oben angegebene Bedeutung hat,
[B1] mit Thionylchlorid und anschließend mit Verbindungen der Formel

in welcher R¹ und R² die oben angegebene Bedeutung haben,
oder
[B2] mit Verbindungen der Formel (VII) in Gegenwart von Dehydratisierungsreagenzien umgesetzt werden.The compounds of the formula (V) are known or can be prepared by reacting the compounds of the formula

in which R ^{3 has} the meaning given above,
[B1] with thionyl chloride and then with compounds of the formula

in which R ¹ and R ^{2 have} the abovementioned meaning,
or
[B2] are reacted with compounds of formula (VII) in the presence of dehydrating reagents.

The Reaction according to process [B1] is generally carried out in inert solvents preferably in a temperature range from room temperature to backflow the solvent at normal pressure.

inert solvent are, for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, Acetonitrile, chloroform, dichloromethane, toluene or pyridine, or Mixtures of solvents, preferred is chloroform.

The Implementation according to procedure [B2] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range of 0 ° C to 40 ° C at Normal pressure.

Examples of suitable dehydrating reagents are carbodiimides, such as N, N'-diethyl, N, N'-dipropyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N ' ethyl carbodiimide hydrochloride (EDC), N-cyclohexylcarbodiimide-N'-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3 sulphate or 2-tert.-butyl-5-methylisoxazolium perchlorate, or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutylchloroformate, or bis (2-oxo-3- oxazolidinyl) -phosphoryl chloride or benzotriazolyloxy-tri (dimethylamino) phosphonium hexafluorophosphate, or O- (benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium hexafluorophosphate (HBTU), 2- (2-oxo-1 (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU) or O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU), or 1- Hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluoro-phosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or mixtures n from these, or mixtures of these together with bases.

bases For example, alkali metal carbonates, e.g. Sodium or potassium carbonate, or bicarbonate, or organic bases such as trialkylamines e.g. Triethylamine, N-methylmorpholine, N-methylpiperidine, 4-dimethylaminopyridine or diisopropylethylamine.

Preferably the condensation is carried out with HOBt and EDC.

inert solvent For example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbon, such as benzene, or nitromethane, Dioxane, dimethylformamide or acetonitrile. It is also possible to mix the solvent use. Particularly preferred is dimethylformamide.

The Compounds of the formulas (VI) and (VII) are known or can be analogous known methods are produced.

in welcher R³ die oben angegebene Bedeutung hat,
mit äquimolaren Mengen Kalium-tert.-butylat und Wasser in Tetrahydrofuran in einem Temperaturbereich von 0°C bis 40°C bei Normaldruck umgesetzt werden.The compounds of the formula (III) are known or can be prepared by reacting the compounds of the formula

in which R ^{3 has} the meaning given above,
be reacted with equimolar amounts of potassium tert-butoxide and water in tetrahydrofuran in a temperature range of 0 ° C to 40 ° C at atmospheric pressure.

in welcher R³ die oben angegebene Bedeutung hat,
mit Natriumnitrit und einem Überschuss Dimethylamin in verdünnter Salzsäure in einem Temperaturbereich von 0°C bis 40°C bei Normaldruck umgesetzt werden.The compounds of the formula (VIII) are known or can be prepared by reacting the compounds of the formula

in which R ^{3 has} the meaning given above,
be reacted with sodium nitrite and an excess of dimethylamine in dilute hydrochloric acid in a temperature range of 0 ° C to 40 ° C at atmospheric pressure.

The Compounds of the formula (IX) are known or can be prepared analogously to known processes getting produced.

The Preparation of the compounds of the invention can be illustrated by the following synthesis schemes.

Synthetic Scheme 1:

Synthesis Scheme 2:

Synthesis Scheme 3:

The Compounds of the invention show unpredictable, valuable antibacterial properties.

she are therefore suitable for use as a medicament for treatment and / or prophylaxis of diseases in humans and animals.

The Compounds of the invention can due to their pharmacological properties alone or in combination with other active ingredients for the treatment and / or prophylaxis of infectious diseases, especially of bacterial infections.

For example, local and / or systemic diseases caused and / or prevented by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:
Gram-positive cocci, eg staphylococci (S. aureus, S. epidermidis), streptococci (S. agalactiae, S. pneumoniae, S. pyogenes) and enterococci (E. faecalis, E. faecium); Gram-negative cocci (Neisseria gonorrhoeae) and Gram-negative rods such as Enterobacteriaceae, eg Escherichia coli, Hemophilus influenzae, Citrobacter (C. freundii, C. divernis), Salmonella and Shigella; Klebsiella (K. pneumoniae, K. oxytocy), Enterobacter (E. aerogenes, E. agglomerans), Hafnia, Serratia (S. marcescens), Proteus (P. mirabilis, P. rettgeri, P. vulgaris), Providencia, Yersinia , as well as the genus Acinetobacter. In addition, the antibacterial spectrum includes the genus Pseudomonas (P. aeruginosa, P. maltophilia) and strictly anaerobic bacteria such as Bacteroides fragilis, members of the genus Peptococcus, Peptostreptococcus and the genus Clostridium; also mycoplasma (M. pneumoniae, M. hominis, M. urealyticum) as well as mycobacteria, eg Mycobacterium tuberculosis.

The above list of pathogens is merely exemplary and by no means limiting.

Examples of diseases which are caused by the mentioned pathogens or mixed infections and which can be prevented, ameliorated or cured by the applicable preparations according to the invention include:
Infectious diseases in humans such. As septic infections, bone and joint infections, skin infections, postoperative wound infections, abscesses, phlegmon, wound infections, infected burns, burns, infections in the mouth, infections after dental surgery, septic arthritis, mastitis, tonsillitis, genital infections and eye infections.

Except when People can bacterial infections are also treated in other species.

Examples include:
Pig: coli-diarrhea, enterotoxemia, sepsis, dysentery, salmonellosis, metritis-mastitis-agalactiae syndrome, mastitis;
Ruminants (cattle, sheep, goats): diarrhea, sepsis, bronchopneumonia, salmonellosis, pasteurellosis, mycoplasmosis, genital infections;
Horse: bronchopneumonia, foal disease, puerperal and postpuerperal infections, salmonellosis;
Dog and cat: bronchopneumonia, diarrhea, dermatitis, otitis, urinary tract infections, prostatitis;
Poultry (chicken, turkey, quail, pigeon, ornamental birds and others): mycoplasmosis, E. coli infections, chronic respiratory diseases, salmonellosis, pasteurellosis, psittacosis.

Likewise, bacterial diseases in the rearing and keeping of farmed and ornamental fish can be treated, the antibacterial spectrum on the aforementioned pathogens on other pathogens such as Pasteurella, Brucella, Campylobacter, Listeria, Erysipelothris, Corynebacteria, Borellia, Tre ponema, Nocardia, Rikettsie, Yersinia, expanded.

Another The present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, preferably of bacterial diseases, especially of bacterial infections.

Another The present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another The present invention is the use of the compounds of the invention for the manufacture of a medicament for the treatment and / or prophylaxis of diseases, in particular the aforementioned diseases.

Another The subject of the present invention is a method of treatment and / or prophylaxis of diseases, in particular those mentioned above Diseases using an antibacterially effective amount the compounds of the invention.

The Compounds of the invention can act systemically and / or locally. For this purpose they can be applied in a suitable manner, e.g. oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For this Application routes can the compounds of the invention be administered in suitable administration forms.

For the oral Application are functioning according to the prior art rapidly and / or modifies the compounds according to the invention donating Application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, e.g. Tablets (uncoated or coated Tablets, for example, with enteric or delayed dissolving or insoluble coatings that control the release of the compound of the invention), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, Capsules (for example hard or soft gelatine capsules), dragees, Granules, pellets, powders, emulsions, suspensions, aerosols or Solutions.

The Parenteral administration can bypass a resorption step happen (e.g., intravenously, intraarterial, intracardiac, intraspinal or intralumbar) or involving absorption (e.g., intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). For parenteral administration are suitable as application forms u.a. Injection and infusion preparations in the form of solutions, Suspensions, emulsions, lyophilisates or sterile powders.

For the others Application routes are suitable, e.g. Inhalation medicines (i.a. Powder inhalers, nebulizers), nasal drops, solutions, sprays; lingual, sublingual or buccally applied tablets, films / wafers or capsules, Suppositories, ear or eye preparations, vaginal capsules, aqueous Suspensions (lotions, shake mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic Systems (such as patches), milk, pastes, foams, Implants or stents.

The Compounds of the invention can in the cited Application forms are transferred. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. Among these adjuvants include et al excipients (for example, microcrystalline cellulose, lactose, mannitol), solvent (e.g., liquid Polyethylene glycols), emulsifiers and dispersing or wetting agents (For example, sodium dodecyl sulfate, Polyoxysorbitanoleat), binder (For example, polyvinylpyrrolidone), synthetic and natural polymers (for example, albumin), stabilizers (e.g., antioxidants such as for example ascorbic acid), Dyes (e.g., inorganic pigments such as iron oxides) and flavor and / or scent remedies.

Another The present invention relates to medicaments which are at least a compound of the invention, usually together with one or more inert, non-toxic, pharmaceutical contain suitable excipients, as well as their use to the previously mentioned purposes.

In general, it has proven to be advantageous for parenteral administration amounts of about 5 up to 250 mg / kg body weight per 24 h to achieve effective results. When administered orally, the amount is about 5 to 100 mg / kg body weight per 24 h.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on of body weight, Route of administration, individual behavior towards the active substance, type of Preparation and time or interval to which the application he follows. So it can in some cases be sufficient, with less than the aforementioned minimum quantity to get along while in other cases exceeded the mentioned upper limit must become. In case of application of larger quantities it may be recommended be to distribute these in several single doses throughout the day.

The Percentages in the following tests and examples are provided not stated otherwise, weight percentages; Parts are parts by weight. Solvent ratios, dilution ratios and concentration data of liquid / liquid solutions each on the volume.

Used abbreviations:

• Section.

  absolutely

  aq.

  aqueous

  CDCl ₃

  chloroform

  CH

  cyclohexane

  d

  doublet (in ¹ H-NMR)

  dd

  doublet of doublet (in ¹ H-NMR)

  DC

  TLC

  DCC

  dicyclohexylcarbodiimide

  DIC

  diisopropylcarbodiimide

  DIEA

  diisopropylethylamine (Hünig's base)

  DMS

  O dimethyl sulfoxide

  DMAP

  4-N, N-dimethylaminopyridine

  DMF

  dimethylformamide

  d. Th.

  the theory

  EDC

  N '- (3-dimethylaminopropyl) -N-ethylcarbodiimide × HCl

  EE

  Ethyl acetate (ethyl acetate)

  IT I

  Electrospray ionization (in MS)

  ges.

  saturated

  HATU

  O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

  HBTU

  O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate

  HOBt

  1-hydroxy-1H-benzotriazole × H ₂ O

  H

  Hour (s)

  HPLC

  High pressure, high performance liquid chromatography

  LC-MS

  Liquid chromatography-coupled mass spectroscopy

  m

  multiplet (in ¹ H-NMR)

  min

  minute

  MS

  mass spectroscopy

  NMR

  Nuclear Magnetic Resonance Spectroscopy

  proc.

  percent

  q

  quartet (in ¹ H-NMR)

  R _f

  Retention index (at DC)

  RP

  Reverse phase (at HPLC)

  RT

  room temperature

  R _t

  Retention time (at HPLC)

  s

  singlet (in ¹ H-NMR)

  t

  triplet (in ¹ H-NMR)

  THF

  tetrahydrofuran

  TPTU

  2- (2-oxo-1 (2H) -pyridyl) -1,1,3,3-tetramethyluronium tetrafluoroborate

LC-MS and HPLC methods:

• Method 1 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2.1 mm, 3.5 microns; Eluent A: 5 ml perchloric acid (70%) / l water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 9.0 min 90% B, 9.2 min 2% B, 10 min 2% B; Flow: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
• Method 2 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2.1 mm, 3.5 μm; Eluent A: 5 ml perchloric acid (70%) / L water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B, 6.7 min 2% B, 7.5 min 2% B; River: 0.75 ml / min; Oven: 30 ° C; UV detection: 210 nm.
• Method 3 (HPLC): Instrument: HP 1100 with DAD detection; Column: Kromasil RP-18, 60 mm × 2.1 mm, 3.5 μm; Eluent A: 5 ml perchloric acid (70%) / L water, eluent B: acetonitrile; Gradient: 0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 15 min 90% B, 15.2 min 2% B, 16 min 2% B; River: 0.75ml / min; Oven: 30 ° C ;, UV detection: 210 nm.
• Method 4 (LC-MS): Device Type MS: Micromass ZQ; device type HPLC: HP 1100 Series; UV DAD; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min. 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
• Method 5 (LC-MS): Instrument: Micromass Quattro LCZ with HPLC Agilent 1100 series; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 208-400 nm.
• Method 6 (LC-MS): Instrument MS: Waters ZQ 2000; instrument HPLC: Agilent 1100, 2-column circuit, autosampler: HTC PAL; Pillar: YMC-ODS-AQ, 50 mm × 4.6 mm, 3.0 μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; Gradient: 0.0 min 100% A → 0.2 min 95% A → 1.8 min 25% A → 1.9 min 10% A → 2.0 min 5% A → 3.2 min 5% A → 3.21 min 100% A → 3.35 min 100% A; Oven: 40 ° C; River: 3.0 ml / min; UV detection: 210 nm.
• Method 7 (LC-MS): Device Type MS: Micromass ZQ; device type HPLC: Waters Alliance 2795; Pillar: Phenomenex Synergi 2μ Hydro-RP Mercury 20 mm × 4 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 90% A → 2.5 min 30% A → 3.0 min 5% A → 4.5 min 5% A; Flow: 0.0 min 1 ml / min, 2.5 min / 3.0 min / 4.5 min 2 ml / min; Oven: 50 ° C; UV detection: 210 nm.
• Method 8 (LC-MS): Instrument: Micromass Platform LCZ with HPLC Agilent 1100 series; Pillar: Thermo HyPURITY Aquastar 3μ 50 mm × 2.1 mm; Eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter acetonitrile + 0.5 ml 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Oven: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.
• Method 9 (Preparative HPLC): Instrument: Abimed Gilson Pump 305/306, Manometric Module 806; Column: Grom-Sil120 ODS-4HE 10 microns, 250 mm × 30 mm; Eluent: A = water, B = acetonitrile; Gradient: 0.0 min 30% B, 3 minutes 30% B, 31 minutes 95% B, 44 minutes 95% B, 45 minutes 30% B; Flow: 50 ml / min Säulentemp .: Room temperature; UV detection: 210 nm.

starting compounds

Example 1A N- (2,3-dichlorobenzyl) -4-nitro-1H-pyrazole-5-carboxylic acid amide

200 mg (1.27 mmol) of 4-nitropyrazole-5-carboxylic acid, 204 mg (1.16 mmol, 0.15 ml) of 2,3-dichlorobenzylamine and 188 mg (1.39 mmol) of HOBt are dissolved in 7.60 ml of anhydrous DMF and then treated with 288 mg (1.50 mmol) mmol) EDC. It is allowed to stir at RT overnight, quenched with water and diluted with ethyl acetate. The organic phase is separated, washed with saturated sodium chloride solution, separated and concentrated in vacuo. Chromatographic purification (Method 9) yields 276 mg (76% of theory) of the target compound.
HPLC (Method 2): R _t = 4.11 min.
MS (CIPOS): m / z = 349 (M + NH ₄₎ ^+, 332 (M + H) ^+.
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 4.55 (d, 2H), 7.40 (t, 1H), 7.45 (td, 1H), 7.59 (dd, 1H), 8.83 (s, br, 1H), 9.30 (t, br, 1H).

In Analogous to Example 1A or as for N-benzyl-3-methyl-4-nitro-1H-pyrazole-5-carboxylic acid amide (Example 17A in P.G. Baraldi, et al., Arzneimittel-Forschung, 1996, 365-368 described, Examples 2A to 17A of the following table produced.

Example 19A 4-Amino-N- (2,3-dichlorobenzyl) -1H-pyrazole-5-carboxylic acid amide

To a suspension of 19 mg Pd / C in 1.4 ml of water is added at 0 ° C, a suspension of 64 mg (1.69 mmol) of sodium borohydride in water (1.4 ml) / methanol (1.4 ml). Portions of 266 mg (0.84 mmol) of N- (2,3-dichlorobenzyl) -4-nitro-1H-pyrazole-5-carboxamide (Example 1A) are added over a period of 10 min. Allow to come to RT and stir for two hours, taking care that the temperature does not exceed 30 ° C. Thereafter, to complete the conversion, another equivalent of sodium borohydride is again added at 0 ° C. and the mixture is stirred at RT for a further hour. The resulting suspension is filtered through Celite, this eluted with methanol, the combined filtrate concentrated in vacuo and the remaining residue washed with water. This gives 180 mg (75% of theory) of the target compound, which is reacted further without further purification.
LC-MS (Method 2): R _t = 1.61 min;
MS (ESIpos): m / z = 285 (M + H) ⁺ .

In Analogous to Example 19A, Examples 20A to 36A become the following Table made.

Example 37A 7-Bromo-3- (2,3-dichlorobenzyl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2 , 3] triazin-4-one

1.00 g (2.67 mmol) of 7-bromo-3- (2,3-dichlorobenzyl) -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazine-4 are dissolved in an argon atmosphere -on (Example 19) and 1.39 g (8.36 mmol) of [2- (chloromethoxy) ethyl] (trimethyl) silane in 8.40 ml of anhydrous DMF and are added portionwise at 0 ° C 304 mg (7.60 mmol) of sodium hydride (60%) , let rise to RT and stir for 30 minutes. For work-up, it is quenched at 0 ° C. with saturated sodium bicarbonate solution and diluted with ethyl acetate. The organic phase is washed after separation with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. Chromatographic purification (Method 9) in two portions yields 904 mg (67% of theory) of the target compound.
HPLC (Method 3): R _t = 6.19 min.
MS (CIPOS): m / z = 521 (M + NH ₄₎ ^+.
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = -0.11 (s, 9H), 0.82 (t, 2H), 3.60 (t, 2H), 5.71 (s, 2H), 5.80 (s , 2H), 7.22 (dd, 1H), 7.30 (t, 1H), 7.62 (dd, 1H).

When By-product becomes a smaller amount of the isomer in the purification 7-bromo-3- (2,3-dichlorobenzyl) -6 - {[2- (trimethylsilyl) ethoxy] methyl} -3,6-dihydro-4H-pyrazolo [4,3-d] [1,2,3 ] triazin-4-one separated.

In Analogous to Example 37A, Examples 38A and 39A become the following Table made.

Example 40A 7- (3 - {[tert -Butyl (dimethyl) silyl] oxy} prop-1-yn-1-yl) -3- (2,3-dichlorobenzyl) -5 - {[2 (trimethylsilyl) ethoxy] methyl} -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one

500 mg (0.99 mmol) of 7-bromo-3- (2,3-dichlorobenzyl) -5 - {[2- (trimethylsilyl) ethoxy] methyl} -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one are suspended with 75 mg (0.40 mmol) of copper (I) iodide in 6.20 ml of anhydrous DMF and treated sequentially with 1.69 g (9.90 mmol, 2.01 ml) of tert-butyl (dimethyl) ( propan-2-yn-1-yloxy) silane, 200 mg (1.98 mmol, 0.28 ml) of triethylamine and 229 mg (0.20 mmol) of tetrakis (triphenylphosphine) palladium (0). Then stir for six days at RT. For workup, it is quenched with water and diluted with ethyl acetate. The organic phase is separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification (Method 9) in two portions gives 301 mg (51% of theory) of the target compound.
HPLC (Method 3): R _t = 6.76 min.
MS (ESIpos): m / z = 594 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = -0.13 (s, 9H), 0.15 (s, 6H), 0.81 (t, 2H), 0.89 (s, 9H), 3.60 (t, 2H ), 4.69 (s, 2H), 5.71 (s, 2H), 5.81 (s, 2H), 7.20 (dd, 1H), 7.30 (t, 1H), 7.62 (dd, 1H).

Example 41A Methyl 4- [3,3-dimethyltriaz-1-en-1-yl] -3-methyl-1H-pyrazole-5-carboxylate

Methyl 3-methyl-4-nitro-1H-pyrazole-5-carboxylate (13.10 g, 71 mmol) (P.Hrelia et al., Mutation Research 397 (1998) 293-301) is dissolved in methanol (150 ml) and two Hours hydrogenated at 4 bar hydrogen pressure over palladium (1.00 g, 10% on charcoal). The resulting solution is filtered through celite and concentrated, the remaining residue redissolved by the addition of water (40 ml) and concentrated hydrochloric acid (18 ml). The solution is cooled to 0 ° C and sodium nitrite (4.90 g, 71 mmol) dissolved in water (10 ml) is added dropwise. After 10 minutes at 0 ° C, a 40 percent aqueous solution of dimethylamine is added dropwise until a pH of 9 is reached, the ice bath is removed and the reaction mixture weiterge 10 minutes stir. The product is filtered off, washed with water and dried overnight at 60 ° C. in vacuo. This gives 7.32 g (48% of theory) of the target compound as a solid.
LC-MS (Method 5): R _t = 1.34 min;
MS (ESIpos): m / z = 212 (M + H) ⁺ .
¹ H-NMR (300 MHz, DMSO-d ₆ ): 2 signal sets for tautomeric or double-bond isomer pairs in the ratio of about 1.5: 1 Signal set 1: δ = 2.23 (s, 3H), 3.0-3.4 (s, br, 6H) , 3.72 (s, 3H), 13.03 (s, br, 1H). Signal set 2: δ = 2.20 (s, 3H), 3.0-3.4 (s, br, 6H), 3.78 (s, 3H), 13.24 (s, br, 1H).

Example 42A Methyl 4- [3,3-dimethyltriaz-1-en-1-yl] -1H-pyrazole-5-carboxylate

The Production is carried out in analogy to Example 41A.

Example 43A 4- [3,3-Dimethyltriaz-1-en-1-yl] -3-methyl-1H-pyrazol-1-yl-5-carboxylate

water (330 μl) is added to a suspension of potassium tert-butoxide (2.06 g, 18 mmol). in dry THF (20 ml) and 10 minutes at room temperature touched. 4- [3,3-Dimethyltriaz-1-en-1-yl] -3-methyl-1H-pyrazol-5-carbonsäuremethylester (1.29 g, 6.0 mmol) is added and the reaction mixture becomes 10 Stirred for another minute, after which it is concentrated. The resulting product is a non-stoichiometric salt, which will be implemented directly.

Example 44A 4- [3,3-Dimethyltriaz-1-en-1-yl] -1H-pyrazol-1-yl-5-carboxylate

The Preparation is analogous to Example 43A. The resulting Product is a non-stoichiometric Salt, which is directly further reacted.

embodiments

Example 1 3- (2,3-Dichlorobenzyl) -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one

179 mg (0.63 mmol) of 4-amino-N- (2,3-dichlorobenzyl) -1H-pyrazole-5-carboxamide (Example 18A) are dissolved in 4 ml of a 1: 1: 2 mixture of water / DMF / acetic acid and at 0 ° C with 54 mg (0.78 mmol) of sodium nitrite. Then stir overnight at RT. The precipitate formed is filtered off and washed with water. This gives 111 mg (60% of theory) of the target compound.
HPLC (Method 2): R _t = 4.31 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.69 (s, 2H), 7.12 (d, 1H), 7.32 (t, 1H), 7.62 (d, 1H), 8.85 (s, br, 1H), 15.06 (s, br, 1H).

In Analogous to Example 1, Examples 2 to 18 of the following Table made.

Example 19 7-Bromo-3- (2,3-dichlorobenzyl) -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one

9.00 g (30.4 mmol) of 3- (2,3-dichlorobenzyl) -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one (Example 1), and 5.95 g (33.4 mmol) of N-bromosuccinimide are suspended in 115 ml of anhydrous acetonitrile and the reaction mixture is stirred at 60 ° C. for two hours. To stop the reaction, add 57 ml of water and allow to cool to RT. The acetonitrile is then removed as far as possible in vacuo, the resulting solid is filtered off with suction and washed with water. This gives 10.4 g (91% of theory) of the target compound.
HPLC (Method 2): R _t = 4.75 min.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 5.70 (s, 2H), 7.17 (d, 1H), 7.31 (t, 1H), 7.63 (d, 1H), 15.46 (s, br, 1H).

In Analogously to Example 19, Examples 20 to 22 of the following Table made.

Example 23 3- (2,3-Dichlorobenzyl) -7- (3-hydroxyprop-1-yn-1-yl) -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3 ] triazine-4-one

Dissolve 293 mg (0.49 mmol) of 7- (3 - {[tert-butyl (dimethyl) silyl] oxy} prop-1-yn-1-yl) -3- (2,3-dichlorobenzyl) -5 - {[ 2 (trimethylsilyl) ethoxy] methyl} -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one at 0 ° C in 4.10 ml dichloromethane and 4.10 ml trifluoroacetic acid, Let it rise to RT and stir overnight. Then, the reaction mixture is concentrated in vacuo and the residue with a solution of 202 mg (2.46 mmol) of sodium acetate in 0.75 ml of water and 7.50 ml Ethanol added. The mixture is again stirred overnight, concentrated, and the remaining crude product is purified by chromatography (Method 9) to obtain 95 mg (55% of theory) of the target compound.
HPLC (Method 1): R _t = 4.21 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 4.44 (d, 2H), 5.59 (t, 1H), 5.70 (s, 2H), 7.14 (d, 1H), 7.31 (t, 1H) , 7.62 (d, 1H).

In Analogous to Example 40A and Example 23, Examples 24 to 31 of the following table.

Example 32 3-Benzyl-7-ethynyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one

69.0 mg (0.21 mmol) of 3-benzyl-7 - [(trimethylsilyl) ethynyl] -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one (Example 25 ) are introduced at 0 ° C in 5.2 ml of THF and treated with 0.23 ml of a 1M solution of tetra-n-butylammonium fluoride in THF. It is allowed to warm to RT and then the reaction mixture is concentrated in vacuo. Purification by preparative HPLC (Method 9). Dissolve the product thus obtained in dichloromethane and wash the solution with water and saturated sodium chloride solution, dry and concentrate the organic phase, followed by further preparative HPLC (Method 9) and silica gel chromatography in cyclohexane / ethyl acetate 2: 1 as eluent. This gives 20 mg (37% of theory) of the target compound.
HPLC (Method 2): R _t = 4.10 min
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 4.87 (s, br, 1H), 5.60 (s, 2H), 7.23-7.41 (m, 5H), 15.39 (s, br, 1H ).

Example 33 3- (4-Chlorobenzyl) -3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one

The crude product of the preparation of dipotassium 4- [3,3-dimethyltriaz-1-en-1-yl] -1H-pyrazol-1-yl-5-carboxylate (32 mg, 0.1 mmol) is treated with triethylammonium chloride (41 mg, 3.0 mmol)) in DMF (0.8 ml) for 15 minutes. PyBOP (62 mg, 0.12 mmol) is added, followed by p-chlorobenzylamine (42 mg, 0.3 mmol), and the solution is stirred for two hours at room temperature. Acetic acid (0.5 ml) is added and the reaction solution is stirred at room temperature for a further 16 hours. It is diluted with DMF, filtered and purified by preparative HPLC chromatography. The target compound is obtained as a solid: 7.8 mg (30% of theory).
LC-MS (Method 1): R _t = 2.06 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 5.58 (s, 2H), 7.36, 7.39 (AA 'part) 7.40, 7.43 (BB' part of an AA'BB 'system), 8.81 (s, br, 1H), 15.01 (s, br, 1H).

In Analogous to Example 33, Examples 34 and 35 become the following Table made.

In Analogous to Example 33, Examples 36 to 147 become the following Table made.

B. Assessment of physiological effectiveness

Used abbreviations:

• BHI

  Medium brain heart infusion medium

  DMSO

  dimethyl sulfoxide

  HTM

  Haemophilus test medium

  i.p.

  intraperitoneally

  iv

  intravenous

  MHK

  Minimal inhibitory concentration

  MTP

  microtiter plate

  PBS

  Phosphate Buffered saltworks

  PEG

  polyethylene glycol

The In vitro and in vivo action of the compounds of the invention can be seen in the following Assays are shown:

Determination of the minimum Inhibitory concentration (MIC)

The minimum inhibitory concentration (MIC) is the minimum concentration of antibiotic used to inhibit a test bacterium in its growth for 18-24 h. The inhibitor concentration can be determined according to standard microbiological procedures (see, for example, The National Committee for Clinical Laboratory Standards, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobic, approved standard-fifth edition, NCCLS document M7-A5 [ISBN 1-56238-394 NCCLS, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-98 USA, 2000). The MIC of the compounds of the invention is determined in the liquid dilution assay in 96-well microtiter plate scale. Fresh bacterial smears on Columbia blood agar plates with 5% sheep blood (Becton Dickinson) [Chocolate agar plates (Becton Dickinson) for Haemophilus influenzae] are adjusted to OD ₅₇₈ of 0.1 in normal saline. The test substances dissolved at 10 mM in DMSO are further diluted in 1: 2 dilution steps with DMSO. 1 μl each of the diluted test substances is placed in a 96-well microtiter plate and mixed with 100 μl of the 1: 300 in Mu eller-Hinton broth (HTM for Haemophilus influenzae) diluted germ suspension. For S. pneumoniae and S. pyogenes, the germ dilution is 1: 100 in Mueller-Hinton broth supplemented with 2% lysed horse blood. The microtiter plates are aerobically incubated for 18-24 h at 37 ° C; Streptococci and Haemophilus influenzae are incubated microaerophilically in the presence of 5% CO ₂ .

The lowest substance concentration, no visible Bacterial growth occurs more often, is defined as MIC.

Table A

• Concentration data: MIC in μM.

Systemic infection with S. aureus 133

The Suitability of the compounds of the invention for the treatment of bacterial infections can be found in various Animal models are shown. In addition, the animals in general infected with a suitable virulent germ and then with the compound to be tested, which in one to the respective therapy model adapted formulation is treated. Specifically, the Suitability of the compounds of the invention for the treatment of bacterial infections in a sepsis model on mice after infection with S. aureus.

For this purpose, S. aureus 133 cells are grown overnight in BH broth (Oxoid, Germany). The overnight culture was diluted 1: 100 in fresh BH broth and incubated for 3 hours. The bacteria in the logarithmic growth phase are centrifuged off and washed twice with buffered, physiological saline. Thereafter, a cell suspension in saline solution with an extinction of 50 units is set on the photometer (Dr. Lange LP 2W). After a dilution step (1:15), this suspension is mixed 1: 1 with a 10% mucin suspension. 0.2 ml / 20 g mouse ip is administered from this infectious solution. This corresponds to a cell count of about 1-2 x 10 ⁶ organisms / mouse. IV therapy is given 30 minutes after infection. For the infection trial female CFW1 mice are used. The survival of the animals is recorded over 5 days. The animal model is adjusted so that untreated animals die within 24 hours of infection. The ED ₁₀₀ corresponds to the minimum dose at which all animals survive the infection during the observation period.

C. Embodiments for pharmaceutical compositions

The Compounds of the invention can as follows be converted into pharmaceutical preparations:

Tablet:

Composition:

• 100 mg of the compound of Example 1, 50 mg lactose (monohydrate), 50 mg of corn starch (native), 10 mg polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg magnesium stearate.
• Tablet weight 212 mg. Diameter 8 mm, radius of curvature 12 mm.

production:

The Mixture of compound according to the invention, Lactose and starch is with a 5% solution (m / m) of the PVP in water granulated. The granules will dry after drying with the magnesium stearate for 5 minute mixed. This mixture is compressed with a conventional tablet press (Format of the tablet see above). As a guide for the compression a pressing force of 15 kN is used.

Orally apilicizable suspension:

Composition:

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

one Single dose of 100 mg of the compound of the invention correspond 10 ml oral suspension.

production:

The Rhodigel is suspended in ethanol, the compound of the invention is added to the suspension. While stirring the addition of the water takes place. Until the completion of the swelling of the Rhodigels is stirred about 61.

Intravenously administrable Solution:

Composition:

• 1 mg of the compound of Example 1, 15 g of polyethylene glycol 400 and 250 g of water for Injections.

production:

The inventive compound is dissolved together with polyethylene glycol 400 in the water with stirring. The solution is sterile filtered (pore diameter 0.22 microns) and under aseptic conditions in heat-sterilized infusion bottles filled. These are with infusion stoppers and crimp caps locked.

Claims (12)

Compound of the formula

in which R ^{1 is} C ₆ -C ₁₀ -aryl or 5- or 6-membered heteroaryl, where aryl and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, Amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alko xycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, R ^{2 is} hydrogen, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxycarbonyl or phenyl, wherein alkyl may be substituted by 1 to 2 substituents independently selected from the group consisting of hydroxy and C ₁ -C ₄ alkoxycarbonyl, and wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or R ¹ and R ² together with the carbon atom to which they are attached represent a group of the formula

and thus form a 1,2,3,4-tetrahydronaphthalene, wherein # is the carbon atom to which R ¹ and R ^{2 are} bonded, and wherein the 1,2,3,4-tetrahydronaphthalene may be substituted with 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ - Alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, R ^{3 is} hydrogen, halogen, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl or * -C≡CR ⁴ wherein * is the point of attachment to the pyrazolotriazinone and R ^{4 is} hydrogen, trimethylsilyl, hydroxymethyl, C ₁ -C ₆ alkylaminomethyl, phenyl or C ₃ -C ₆ cycloalkyl, in which phenyl and cycloalkyl are substituted may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, Amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or one of its salts, its solvates or the solvates of its salts, with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1 , 2,3] triazin-4-one. A compound according to claim 1, characterized in that R ^{1 is} phenyl, wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl , C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, R ^{2 is} hydrogen, methyl, hydroxymethyl, methoxycarbonyl or phenyl, wherein phenyl may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxy, amino, C ₁ -C ₄ alkyl, C C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or R ¹ and R ² together with the carbon atom to which they are attached represent a group of the formula

and thus form a 1,2,3,4-tetrahydronaphthalene, wherein # is the carbon atom to which R ¹ and R ^{2 are} bonded, and wherein the 1,2,3,4-tetrahydronaphthalene may be substituted with 1 to 2 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ - Alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, R ^{3 is} hydrogen, C ₁ -C ₄ -alkyl or * -C≡CR ⁴ , where * is the point of attachment to the pyrazolotriazinone, and R ^{4 is} Is hydrogen, trimethylsilyl, hydroxymethyl, C ₁ -C ₆ alkylaminomethyl, phenyl or C ₃ -C ₆ cycloalkyl, wherein phenyl and cycloalkyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy , Hydroxy, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ -alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ Alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or one of their salts, their solvates or the solvates of their salts, with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d ] [1,2,3] triazine-4-one. A compound according to claim 1 or 2, characterized in that R ^{1 is} phenyl, wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen, trifluoromethyl and cyano, R ^{2 is} hydrogen or methyl, R ^{3 is} hydrogen, methyl or * -C≡CR ⁴ wherein * is the point of attachment to the pyrazolotriazinone, and R ^{4 is} hydroxymethyl, phenyl or C ₃ -C ₆ cycloalkyl, wherein phenyl and cycloalkyl may be substituted with 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, amino, C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy, C ₁ -C ₄ -alkylthio, C ₁ -C ₆ - Alkylamino, cyano, nitro, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or one of their salts, their solvates or the solvates of their salts, with the exception of 3-benzyl-7-methyl- 3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazine 4-one. A compound according to any one of claims 1 to 3, characterized in that R ^{1 is} phenyl, wherein phenyl may be substituted with 1 to 3 substituents independently selected from the group consisting of halogen and trifluoromethyl, R ^{2 is} hydrogen or methyl, R ^{3 is} hydrogen, methyl or * -C≡CR ⁴ , wherein * is the point of attachment to the pyrazolotriazinone, and R ^{4 is} hydroxymethyl, phenyl or cyclohexyl, wherein phenyl may be substituted with 1 to 2 substituents independently selected from the group consisting of halogen, trifluoromethyl, C ₁ -C ₄ alkoxy, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl, and wherein cyclohexyl may be substituted with a substituent selected from the group consisting of C C ₁ -C ₄ -alkoxy, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or one of their salts, their solvates or the solvates thereof Salts, with the exception of 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one. 3-benzyl-7-methyl-3,5-dihydro-4H-pyrazolo [4,3-d] [1,2,3] triazin-4-one

for the treatment and / or prophylaxis of bacterial infections. Process for the preparation of a compound of formula (I) according to claim 1 or one of its salts, solvates or solvates of its salts, characterized in that [A1] is a compound of formula

in which R ¹ , R ² and R ^{3 have} the meaning given in claim 1, is cyclized with sodium nitrite to a compound of formula (I), or [A2] a compound of formula

in which R ^{3 has} the meaning given in claim 1, with a compound of the formula

in which R ¹ and R ^{2 have} the meaning given in claim 1, is cyclized in the presence of dehydrating reagents to give a compound of formula (I), or [A3] a compound of formula

in which R ¹ and R ^{2 have} the meaning given in claim 1, with a halogenating reagent to give a compound of the formula

in which R ¹ and R ^{2 have} the meaning given in claim 1, and R ^{3 is} halogen, or [A4] a compound of formula (Ib) in the presence of a palladium catalyst to give a compound of formula

in which R ¹ and R ^{2 have} the meaning given in claim 1, and R ^{3 is} * -C≡CR ⁴ , wherein R ^{4 has} the meaning indicated above, is reacted. A compound according to any one of claims 1 to 4 for the treatment and / or prophylaxis of diseases. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and / or prophylaxis of bacterial diseases. Medicaments containing at least one compound according to one of the claims 1 to 4 in combination with at least one inert, non-toxic, pharmaceutically suitable excipient. Medicament according to claim 10 for the treatment and / or Prophylaxis of bacterial infections. Method of combating bacterial infections in humans and animals by administering an antibacterial effective amount of at least one compound according to any one of claims 1 to 4 or a medicament according to claim 10 or 11.