DE102005031580A1 - Substituted sulfolanylpyrazoles and their use - Google Patents

Abstract

The present invention relates to new substituted sulfolanylpyrazoles, processes for their preparation, their use for the treatment and / or prophylaxis of diseases and their use for the preparation of medicaments for the treatment and / or prophylaxis of diseases, in particular retroviral diseases, in humans and / or animals .

Description

The present invention relates to novel substituted sulfolanylpyrazoles, Process for their preparation, their use for treatment and / or Prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, in particular of retroviral diseases, in humans and / or Animals.

HIV (Human immunodeficiency virus) causes a chronic-persistent, progressive infection. The disease runs through various stages of from asymptomatic infection to the clinical picture AIDS (Acquired Immunodeficiency syndrome). AIDS is the final stage of the through Infection-induced disease. Characteristic of HIV / AIDS disease is the long clinical latency with persistent viremia that in the final stage leads to failure of the immune system.

By the introduction the anti-HIV combination therapy then succeeded in the 90's to slow the disease progression sustainably and thus the Substantially prolong life expectancy of HIV-infected patients (Palella et al., N. Engl. J. Med. 1998, 238, 853-860).

The currently on the market anti-HIV substances inhibit the Replication of the HI virus by Inhibition of the essential viral enzyme reverse transcriptase (RT), the protease, or the HIV fusion (reviewed in Richman, Nature 2001, 410, 995-1001). There are two classes of RT inhibitors: nucleoside RT inhibitors (NRTI) contribute by competitive inhibition or chain termination the DNA polymerization. Non-nucleoside RT Inhibitors (NNRTI) bind allosterically to a hydrophobic pocket near the active Center of RT and convey a conformational change of the enzyme. The currently available Protease inhibitors (PI), however, block the active site the viral protease and thus prevent the maturation of emerging Particles too infectious Virions.

There the monotherapy with currently available anti-HIV drugs within a very short time to therapy failure by selection resistant viruses, usually takes place a combination therapy with several anti-HIV substances from different Classes (highly active antiretroviral therapy = HAART; Carpenter et al., J. Am. Med. Assoc. 2000, 283, 381-390).

In spite of Advances in antiretroviral chemotherapy show newer ones Investigations that with the available drugs an eradication of HIV and associated a cure of HIV infection is not expected: latent virus remains in resting lymphocytes and provides a reservoir for a reactivation and thus for a renewed virus spread (Finzi et al., Nature Med. 1999, 5, 512-517; Ramratnam et al., Nature Med. 2000, 6, 82-85). HIV-infected patients Therefore, they depend on an efficient antiviral therapy throughout their lifetime. Despite combination therapy, it comes after some time for selection resistant virus is coming. Therefore every therapeutic class characteristic resistance mutations accumulate, the failure of a therapy often means a loss of effect the complete substance class. This cross-resistance problem is in the class of NNRTIs most pronounced, since here already one single point mutation in the RT may be sufficient to cause a loss of efficacy all NNRTIs (overview in Kavlick & Mitsuya, Antiretroviral Chemotherapy (Ed. De Clercq E.), 2001, ASM Press, 279-312).

Is favored the emergence of resistance mostly due to poor compliance of the patients by an unfavorable Side effect profile and complicated dosing schedule of anti-HIV drugs is caused.

Consequently There is an urgent need for new therapeutic options for fighting of HIV infection. This is the identification of new chemical Leading structures important and an urgent goal of therapy research to HIV, which is either a new target in the propagation of HIV address and / or against the growing number of resistant clinical HIV isolates are effective are.

in welcher
R¹ für Phenyl oder 5- oder 6-gliedriges Heteroaryl steht, wobei Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Hydroxy, Amino, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy und C₁-C₆-Alkylamino,
R² für Phenyl oder 5- oder 6-gliedriges Heteroaryl steht,
wobei Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Hydroxy, Amino, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy und C₁-C₆-Alkylamino,
R³ für Phenyl oder 5- bis 10-gliedriges Heteroaryl steht,
wobei Phenyl und Heteroaryl substituiert sein können mit 1 bis 3 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Halogen, Hydroxy, Amino, Hydroxycarbonyl, Aminocarbonyl, Cyano, Nitro, Trifluormethyl, Trifluormethoxy, C₁-C₆-Alkyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₁-C₆-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
worin Alkyl substituiert sein kann mit 1 bis 2 Substituenten, wobei die Substituenten unabhängig voneinander ausgewählt werden aus der Gruppe bestehend aus Hydroxy, Amino, Hydroxycarbonyl, Aminocarbonyl, C₁-C₆-Alkoxy, C₁-C₆-Alkylamino, C₁-C₆-Alkoxycarbonyl und C₁-C₆-Alkylaminocarbonyl,
und ihre Salze, ihre Solvate und die Solvate ihrer Salze.The invention relates to compounds of the formula

in which
R ^{1 is} phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl , Trifluoromethoxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy and C ₁ -C ₆ -alkylamino,
R ^{2 is} phenyl or 5- or 6-membered heteroaryl,
wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, whereby the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₁ - C ₆ alkoxy and C ₁ -C ₆ alkylamino,
R ^{3 is} phenyl or 5- to 10-membered heteroaryl,
wherein phenyl and heteroaryl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl , C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl,
in which alkyl may be substituted by 1 to 2 substituents, the substituents being independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ - C ₆ alkoxycarbonyl and C ₁ -C ₆ alkylaminocarbonyl,
and their salts, their solvates, and the solvates of their salts.

Compounds of the invention are the compounds of formula (I) and their salts, solvates and solvates salts; the compounds encompassed by formula (I) below formulas and their salts, solvates and solvates of the salts as well as those of formula (I), hereinafter referred to as exemplary embodiments 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 includes the enantiomers or Diastereomers and their respective mixtures. From such mixtures enantiomers and / or diastereomers can be the stereoisomer isolate uniform components in a known manner.

Provided the compounds of the invention can occur in tautomeric forms, For example, the present invention encompasses all tautomeric forms.

When Salts are physiologically acceptable in the context of the present invention Salts of the compounds of the invention prefers. Also included are salts that are suitable for pharmaceutical applications themselves are not suitable but for example for insulation or cleaning the compounds of the invention can be used.

physiological Safe salts of the compounds of the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, e.g. Salts of hydrochloric acid, hydrobromic, Sulfuric acid, Phosphoric acid, methane, ethanesulfonic, toluene sulfonic acid, benzenesulfonic, naphthalenedisulfonic, Acetic acid, trifluoroacetic, propionic acid, Lactic acid, Tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and Benzoic acid.

physiological acceptable salts of the compounds of the invention also include Salts more usual 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, procaine, Dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

As solvates are in the context of the invention, such forms of the compounds of the invention denotes which form a complex in the solid or liquid state by coordination with solvent molecules. Hydrates are a special form of solvates that coordinate with water.

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
Alkyl and the alkyl moieties in alkoxy, alkylamino, alkoxycarbonyl and alkylaminocarbonyl are straight-chain or branched alkyl and, unless stated otherwise, comprises C ₁ -C ₆ -alkyl, in particular C ₁ -C ₄ -alkyl, such as, for example, methyl, ethyl, propyl , Isopropyl, butyl, isobutyl.

alkoxy is in the context of the invention preferably for a straight-chain or branched alkoxy, in particular with 1 to 6, 1 to 4 or 1 up to 3 carbon atoms. Preference is given to a straight-chain or branched one Alkoxy radical having 1 to 3 carbon atoms. Exemplary and preferably may be mentioned: methoxy, ethoxy, n-propoxy, isopropoxy, t-butoxy, n-pentoxy and n-hexoxy.

Alkylamino in the context of the invention represents an amino group having one or two (independently selected) straight-chain or branched alkyl substituents, which preferably have 1 to 6, 1 to 4 or 1 to 2 carbon atoms. Exemplary and preferably 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, t-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl.

Alkylaminocarbonyl in the context of the invention represents an aminocarbonyl group having one or two (independently selected) straight-chain or branched alkyl substituents, which preferably have 1 to 6, 1 to 4 or 1 to 2 carbon atoms. Exemplary 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.

heteroaryl stands for a 5- to 10-membered aromatic mono- or bicyclic Heterocycle, preferred for a 5- or 6-membered aromatic monocyclic heterocycle with up to 3 heteroatoms from the series S, O and / or N, where the Heterocycle may also be in the form of the N-oxide, for example for indolyl, 1H-indazolyl, 1H-1,2,3-benzotriazolyl, 1H-benzimidazolyl, pyridyl, Pyrimidyl, thienyl, furyl, pyrrolyl, thiazolyl, pyrazolyl, thiadiazolyl, N-triazolyl, isoxazolyl, oxazolyl or imidazolyl. Preferred are Pyridyl, thienyl, furyl and thiazolyl.

halogen stands for Fluorine, chlorine, bromine or iodine, with fluorine and chlorine being preferred, unless otherwise stated.

The listed above general or preferred ranges given Restedefnitionen apply to both the end products of formula (I) as well as corresponding to each required for the preparation of starting materials or intermediates.

The in the respective combinations or preferred combinations of Remains in the specified remainder definitions are independent of the respective indicated combinations of the radicals optionally also Remaining definitions of other combinations replaced.

The invention also relates to compounds of the formula (I) in which
R ^{1 is} phenyl, pyridyl, thienyl or furyl,
wherein phenyl may be pyridyl, thienyl and furyl substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy,
R ^{2 is} phenyl, pyridyl, thienyl or furyl,
wherein phenyl may be pyridyl, thienyl and furyl substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy,
R ^{3 is} phenyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, indolyl, 1H-indazolyl, 1H-1,2,3-benzotriazolyl or 1H-benzimidazolyl,
wherein phenyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, indolyl, 1H-indazolyl, 1H-1,2,3-benzotriazolyl and 1H-benzimidazolyl may be substituted with 1 to 3 substituents, wherein the substituents independently are selected from the group consisting of halogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ -alkyl and C ₁ -C ₄ -alkoxy,
wherein alkyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of hydroxy and C ₁ -C ₄ alkoxy,
and their salts, their solvates, and the solvates of their salts.

in welcher
R¹ und R² die oben angegebene Bedeutung aufweisen,
mit Verbindungen der Formel R₃-NH₂ (III),in welcher
R³ die oben angegebene Bedeutung aufweist,
umgesetzt werden.The invention further provides a process for the preparation of the compounds of the formula (I), where compounds of the formula

in which
R ¹ and R ^{2 have} the abovementioned meaning,
with compounds of the formula R ₃ -NH ₂ (III), in which
R ^{3 has} the meaning indicated above,
be implemented.

The Reaction is generally carried out in inert solvents, in the presence a dehydration reagent, optionally in the presence of a Base, preferably in a temperature range from -30 ° C to 50 ° C at atmospheric pressure.

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

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.

When Dehydrating reagents are suitable here, for example, 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-phenyl-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 isobutyl chloroformate, or bis (2-oxo-3-oxazolidinyl) phosphoryl chloride, 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'-tetramethyl-uronium hexafluorophosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), or benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate (PyBOP), or N-hydroxysuccinimide, or mixtures thereof, with Bases.

Preferably, the condensation with HATU, benzotriazol-1-yloxytris (pyrrolidino) -phosphoniumhe xafluorophosphate (PyBOP) or with EDC in the presence of HOBt.

The Compounds of formula (III) are known or can be after synthesize known methods from the corresponding starting materials.

in welcher
R¹ und R² die oben angegebene Bedeutung aufweisen, und
R⁴ für C₁-C₄-Alkyl, bevorzugt Methyl, Ethyl oder tert-Butyl, steht,
der Ester mit einer Base oder einer Säure verseift wird.The compounds of the formula (Π) are known or can be prepared by reacting in compounds of the formula

in which
R ¹ and R ^{2 have} the abovementioned meaning, and
R ^{4 is} C ₁ -C ₄ -alkyl, preferably methyl, ethyl or tert-butyl,
the ester is saponified with a base or an acid.

The Saponification of the ester with a base is generally carried out in inert Solvent, preferably in a temperature range from room temperature to backflow of the solvent at normal pressure.

bases For example, alkali hydroxides such as sodium, lithium or Potassium hydroxide, or alkali metal carbonates such as cesium carbonate, sodium or Potassium carbonate, preferably lithium or sodium hydroxide.

inert solvent are, for example, halogenated hydrocarbons, such as methylene chloride, Trichloromethane, tetrachloromethane, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichlorethylene, ethers, such as diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, 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, dimethyl sulfoxide, acetonitrile or pyridine, or water, or mixtures of solvents, as a solvent are preferably tetrahydrofuran and / or methanol.

Prefers is sodium hydroxide in tetrahydrofuran.

The Saponification of the ester with an acid generally occurs in a solvent optionally in the presence of water, in a temperature range from room temperature to reflux of the solvent at normal pressure.

Acids in a solvent are, for example, trifluoroacetic acid, hydrochloric acid, sulfuric acid or phosphoric acid in dioxane, Methylene chloride or tetrahydrofuran.

Prefers is trifluoroacetic acid in methylene chloride.

in welcher
R¹, R² und R⁴ die oben angegebene Bedeutung aufweisen,
mit 3-Sulfolanhydrazin in Essigsäure unter Rückfluss bei Normaldruck umgesetzt werden.The compounds of the formula (IV) are known or can be prepared by reacting compounds of the formula

in which
R ¹ , R ² and R ^{4 have} the abovementioned meaning,
be reacted with 3-sulfolane hydrazine in acetic acid under reflux at atmospheric pressure.

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

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

Synthesis scheme:

The Compounds of the invention show an unpredictable, valuable pharmacological activity spectrum.

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

The In particular, compounds of the present invention are characterized by an advantageous anti-retroviral spectrum of action.

Another The present invention is the use of the compounds of the invention for the treatment and / or prophylaxis of diseases caused by retroviruses caused, in particular of HI viruses.

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 a therapeutically effective amount the compounds of the invention.

• 1.) Die Behandlung und Prophylaxe von menschlichen Retrovirusinfektionen
• 2.) Für die Behandlung und Prophylaxe von HIV I (Virus der humanen Immundefizienz; früher HTLV III/LAV genannt) und HIV II verursachten Infektionen und Erkrankungen (AIDS) und den damit assoziierten Stadien wie ARC (AIDS related complex) und LAS (Lymphadenophathie-Syndrom) sowie der durch dieses Virus verursachten Immunschwäche und Enzephalopathie.
• 3.) Für die Behandlung von HIV-Infektionen hervorgerufen durch Einfach-, Mehrfach- oder Multi-resistente HIV Viren. Resistente HI-Viren bedeutet z.B. Viren mit Resistenzen gegen nukleosidische Inhibitoren (RTI), nicht nukleosidische Inhibitoren (NNRTI) oder Proteaseinhibitoren (PI) oder Viren mit Resistenzen gegen andere Wirksprinzipien z.B. T20 (Fusionsinhibitoren).
• 4.) Für die Behandlung oder die Prophylaxe des AIDS-carrier Zustandes (AIDS-Überträger-Zustand).
• 5.) Für die Behandlung oder die Prophylaxe einer HTLV-I oder HTLV-II Infektion

Examples of indications in human medicine include:

• 1.) The treatment and prophylaxis of human retrovirus infections
• 2.) For the treatment and prophylaxis of HIV I (human immunodeficiency virus, previously HTLV III / LAV and HIV II caused infections and diseases (AIDS) and the associated stages such as ARC (AIDS related complex) and LAS (lymphadenopathy syndrome) as well as the immunodeficiency and encephalopathy caused by this virus.
• 3.) For the treatment of HIV infections caused by single, multiple or multi-resistant HIV viruses. Resistant HI viruses means, for example, viruses with resistance to nucleoside inhibitors (RTI), non-nucleoside inhibitors (NNRTIs) or protease inhibitors (PI) or viruses with resistance to other principles of action, eg T20 (fusion inhibitors).
• 4.) For the treatment or prophylaxis of AIDS carrier condition (AIDS carrier state).
• 5.) For the treatment or prophylaxis of HTLV-I or HTLV-II infection

• a) Maedivisna (bei Schafen und Ziegen)
• b) progressivem Pneumonievirus (PPV) (bei Schafen und Ziegen)
• c) caprine arthirtis encephalitis Virus (bei Schafen und Ziegen)
• d) Zwoegerziekte Virus (bei Schafen)
• e) infektiösem Virus der Anämie (des Pferdes)
• f) Infektionen verursacht durch das Katzenleukämievirus
• g) Infektionen verursacht durch das Virus der Katzen-Immundefizienz (FIV)
• h) Infektionen verursacht durch das Virus der Affen-Immundefizienz (SIV)

Examples of indications in veterinary medicine include:
Infections with

• a) Maedivisna (in sheep and goats)
• b) progressive pneumonia virus (PPV) (in sheep and goats)
• c) caprine arthirtis encephalitis virus (in sheep and goats)
• d) Zwoegerziekte virus (in sheep)
• e) infectious anemia (horse) virus
• f) infections caused by the feline leukemia virus
• g) Infections caused by the Feline Immunodeficiency Virus (FIV)
• h) Infections caused by the Monkey Immunodeficiency Virus (SIV)

Prefers become from the indication area in the human medicine the above-mentioned Punke 2, 3 and 4.

Another The present invention relates to medicaments containing at least one compound of the invention and at least one or more further active ingredients, in particular for the treatment and / or prophylaxis of the aforementioned diseases.

The compounds according to the invention can also be used advantageously, in particular in the abovementioned points 2, 3 and 4, as components of a combination therapy with one or more other compounds active in these areas of application. By way of example, these compounds can be used in combination with effective doses of antivirally active substances based on the principles of action listed below:
Inhibitors of the HIV protease; Examples include: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, tipranavir;
Nucleosic and non-nucleosidic inhibitors of HIV reverse transcriptase; Examples include: zidovudine, lamivudine, didanosine, citalitabine, stavudine, abacavir, tenofovir, adefovir, nevirapine, delavirdine, efavirenz;
Inhibitors of HIV integrase, may be mentioned by way of example: 51360, L870810;
Inhibitors of HIV fusion; may be mentioned by way of example: Pentafuside, T1249.

These Selection should clarify the possible combinations, not for limitation on the listed here Serve examples; in principle, any combination of the compounds of the invention with antivirally active substances than in the context of the invention consider.

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, cermal, 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 oral administration are according to the prior art functioning rapidly and / or modified compounds of the invention donating application forms containing the compounds of the invention in crystalline and / or amorphous and / or dissolved form, such as tablets (uncoated or coated tablets, for example with enteric or delayed-dissolving or insoluble coatings controlling the release of the compound of the invention), rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (eg hard or soft gelatin capsules), dragees, granules, pellets, powders , Emulsions, suspensio NEN, 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 the Generally, it has been used in both human and veterinary medicine proved to be advantageous, the or the active compounds according to the invention in total amounts of 0.1 to 200 mg / kg, preferably 1 to 100 mg / kg body weight every 24 hours, possibly in the form of several individual doses, for Achieving the desired To give results. A single gift contains the or the active ingredients preferably in amounts of 1 to 80 mg / kg, in particular 1 to 30 mg / kg body weight.

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. The term "w / v" means "weight / volume". For example, "10 % w / v ": 100 ml solution or Suspension contain 10 g of substance.

A) Examples

Abbreviations:

• aq.

  aqueous, aqueous solution

  DCI

  direct chemical Ionization (in MS)

  DMA

  N, N-dimethylacetamide

  DMF

  N, N-dimethylformamide

  DMS

  O dimethyl sulfoxide

  d. Th.

  the theory (at yield)

  EDC

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

  eq.

  Equivalent (s)

  IT I

  Electrospray ionization (in MS)

  H

  Hour (s)

  HATU

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

  HPLC

  High pressure, high performance liquid chromatography

  conc.

  concentrated

  LC-MS

  Liquid chromatography-coupled mass spectroscopy

  min

  Minute (s)

  MS

  mass spectroscopy

  NMR

  Nuclear Magnetic Resonance Spectroscopy

  PyBOP

  Benzotriazol-1-yloxy-tris (pyrrolidino) phosphonium hexafluorophosphate

  R _t

  Retention time (at HPLC)

  RT

  room temperature

  TBTU

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

  TFA

  trifluoroacetic

  THF

  tetrahydrofuran

  TMOF

  trimethylorthoformate

LC / MS methods:

Method 1:

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 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 2:

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 3:

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; Flow: 3.0 ml / min; UV detection: 210 nm.

Method 4:

instrument MS: Micromass TOF (LCT); Instrument HPLC: 2-column circuit, Waters 2690; Column: 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; Oven: 40 ° C; Flow: 3.0 ml / min; UV detection: 210 nm.

Method 5:

Instrument: Micromass TOF-MUX interface 4-fold parallel injection with HPLC Waters 600; Column: Grom-SIL 120, 50 mm × 2.0 mm, 3.0 μm; Eluent A: 1 l of water + 1 ml of 50% formic acid, eluent B: 1 l of acetonitrile + 1 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 4.5 min 10% A → 4.6 min 100% A → 6.5 min 100% A; Oven: room temperature; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 6:

Instrument: Micromass Quattro LCZ with HPLC Agilent Series 1100; Column: 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: 208-400 nm.

HPLC Methods:

Method 1:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (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; Flow: 0.75 ml / min; Temperature: 30 ° C; UV detection: 210 nm.

Method 2:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; Eluent A: 5 ml HClO ₄ (70%) / L water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 9 min 90% B → 9.2 min 2% B → 10 min 2% B; Flow: 0.75 ml / min; Temperature: 30 ° C; UV detection: 210 nm.

Starting Compounds:

Example 1A 1-Phenyl-3-pyridin-2-yl-propane-1,3-dione

The Title compound is after W.R. Thiel, J. Eppinger, Chem. Europ. J. 1997, 3, 696-705 available.

Example 2A 1- (2-Furyl) -3-pyridin-2-ylpropane-1,3-dione

38 g (3.4 mol) of potassium tert-butoxide are initially charged in 200 ml of THF and admixed with 1057 g (4 mmol) of 18-crown-6. 24 g (2 mol) of 2-acetylpyridine and 50 g (4 mol) of methyl 2-furoate are added dropwise simultaneously and the mixture is stirred under reflux for 2 h. The precipitated solid is filtered off with suction and dissolved in ethyl acetate and 10% hydrochloric acid. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue obtained is crystallized from petroleum ether and recrystallized from methanol. There are obtained 8.9 g (19% of theory) of the title compound.
LC-MS (Method 6): R _t = 2.29 min
MS (ESIpos): m / z = 216 (M + H) ⁺ .

Example 3A 1- (5-Chloro-2-thienyl) -3-pyridin-2-yl-propane-1,3-dione

Starting from 54 g (4 mol) of methyl picolinate and 32 g (2 mol) of 2-acetyl-5-chlorothiophene, 36 g (68% of theory) of the title compound are obtained by the method described in Example 2A and after crystallization from diisopropyl ether.
LC-MS (Method 6): R _t = 2.97 min
MS (ESIpos): m / z = 266 (M + H) ⁺ .

Example 4A Methyl 3- (2-benzoyl-3-oxo-3-pyridin-2-yl-propyl) benzoate

3.0 g (13.3 mmol) of the compound from Example 1A and 3.2 g (13.3 mmol) of methyl 3- (bromomethyl) benzoate are dissolved in 70 ml of a 4: 1 mixture of dioxane and 2-propanol and then with 4.2 g (40.0 mmol) Sodium carbonate and 1.8 g (6.7 mmol) of 18-crown-6 added. The mixture is stirred at 85 ° C. for 18 h, allowed to cool to room temperature and 50 ml of water and ethyl acetate are added. The organic phase is separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is reacted further without purification.
Yield: 6.3 g (83% purity, 100% of theory)
LC-MS (Method 1): R _t = 2.73 min
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.53 (dd, 1H); 7.99-7.91 (m, 4H); 7.82-7.81 (m, 1H); 7.67 (dd, 1H); 7.62-7.40 (m, 5H); 7.31 (dd, 1H); 6.23 (t, 1H); 3.82 (s, 3H); 3.41-3.20 (m, 2H).

Example 5A 3- (2-Benzoyl-3-oxo-3-pyridin-2-yl-propyl) -benzoic acid tert-butyl ester

Starting from 4.4 g (19.55 mmol) of 1-phenyl-3-pyridin-2-ylpropane-1,3-dione from Example 1A and 4.77 g (17.6 mmol) of 3- (bromomethyl) benzoic acid tert-butyl ester are prepared according to the in Example 4A and after chromatographic purification over silica gel (eluent: dichloromethane / THF 95: 5) 6.67 g (82% of theory) of the title compound.
¹ H-NMR (300 MHz, CDCl ₃ ): δ = 8.54-8.48 (m, 1H), 8.07-7.96 (m, 3H), 7.88 (s, 1H), 7.82-7.7 (m, 2H), 7.55- 7.35 (m, 5H), 7.24-7.19 (m, 1H), 6.18 (t, 1H), 3.53-3.42 (m, 1H), 3.35-3.25 (m, 1H).

Example 6A 3- [2- (2-Furoyl) -3-oxo-3-pyridin-2-yl-propyl] benzoic acid methyl ester

Starting from 4 g (18.6 mmol) of the compound from Example 2A and 4.3 g (18.6 mmol) 3- (bromomethyl) benzoic acid methyl ester according to the method described in Example 4A and after chromatographic purification over silica gel (mobile phase: cyclohexane / ethyl acetate 6: 1 to 4: 1) 4.45 g (63% of theory) of the title compound were obtained.
HPLC (Method 2): R _t = 4.62 min
MS (ESIpos): m / z = 364 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.59 (d, 1H), 8.05-7.94 (m, 2H), 7.9 (s, 1H), 7.83 (s, 1H), 7.72 (dd, 1H), 7.68-7.6 (m, 1H), 7.55 (d, 1H), 7.4-7.3 (m, 2H), 6.7-6.62 (m, 1H), 5.95 (t, 1H), 3.83 (s, 3H) , 3.45-3.18 (m, 2H).

Example 7A 3- [3- (5-Chloro-2-thienyl) -3-oxo-2- (pyridin-2-ylcarbonyl) propyl] benzoic acid methyl ester

Starting from 6.6 g (24.8 mmol) of the compound from Example 3A and 5.69 g (24.8 mmol) of methyl 3- (bromomethyl) benzoate according to the method described in Example 4A and after chromatographic purification over silica gel (mobile phase: cyclohexane / ethyl acetate 6: 1). 8.36 g (79% of theory) of the title compound were obtained.
HPLC (Method 2): R _t = 5.21 min
MS (ESIpos): m / z = 414 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.58 (d, 1H), 8.05-7.95 (m, 1H), 7.82 (s, 1H), 7.79 (d, 1H), 7.72 (d, 1H), 7.67-7.6 (m, 1H), 7.5 5 (d, 1H), 7.3 6 (t, 1H), 7.22 (d, 1H), 6.03 (t, 1H), 3.83 (s, 3H), 3.4 -3.2 (m, 2H).

Example 8A 3 - {(1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} benzoic acid methyl ester

3.0 g (8.0 mmol) of the compound from Example 4A and 1.5 g (9.6 mmol) of 3-sulfolane-hydrazine [preparation according to CS Argyle et al., J. Chem. Soc. (Sect. C), 21, 2156-2170 (1967)] are mixed with 18 ml of acetic acid and stirred under reflux for 4 h. After cooling to room temperature, 300 ml of ethyl acetate are added and carefully neutralized with saturated aqueous sodium bicarbonate solution. The organic phase is separated, washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1). The title compound is separated from the regioisomer, which is obtained in a ratio of 1: 4 in favor of the desired compound.
Yield: 1.3 g (33% of theory)
LC-MS (Method 2): R _t = 2.37 min
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.56 (d, 1H); 8.01 (d, 1H); 7.86 (ddd, 1H); 7.61 (d, 1H); 7.55-7.53 (m, 4H); 7.40-7.37 (m, 2H); 7.31 (ddd, 1H); 7.25-7.17 (m, 2H); 5.01 (tt, 1H); 4.27 (dd, 2H); 3.77 (s, 3H); 3.67 (dd, 1H); 3.58-3.48 (m, 2H); 3.29-3.21 (m, 1H); 2.69-2.59 (m, 1H); 2.56-2.50 (m, 1H).

Example 9A 3- {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] -methyl} -benzoic acid tert -butyl ester

Starting from 2.77 g (6.67 mmol) of 3- (2-benzoyl-3-oxo-3-pyridin-2-yl-propyl) -benzoic acid tert-butyl ester from Example 5A and 1.2 g (8 mmol) of 3-sulfolane hydrazine are prepared according to the in Example 8A and after chromatographic purification over silica gel (mobile phase: cyclohexane / ethyl acetate 1: 1) 1.35 g (38% of theory) of the title compound.
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 8.57 (d, 1H), 8.01 (d, 1H), 7.85 (ddd, 1H), 7.61-7.47 (m, 5H), 7.44-7.35 ( m, 2H), 7.35-7.27 (m, 1H), 7.23-7.07 (m, 2H), 5.08-4.93 (m, 1H), 4.27 (d, 2H), 3.71-3.59 (m, 1H), 3.59- 3.44 (m, 2H), 3.3-3.17 (m, 1H), 2.71-2.5 (m, 2H), 1.47 (s, 9H).

Example 10A 3 - {[5- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } benzoate

Starting from 8.3 g (20.05 mmol) of methyl 3- [3- (5-chloro-2-thienyl) -3-oxo-2- (pyridin-2-ylcarbonyl) propyl] benzoate from Example 7A and 3.63 g (24.07 mmol) of 3 Sulfolane hydrazine are obtained according to the procedure described in Example 8A and after chromatographic purification over silica gel (eluent: cyclohexane / ethyl acetate 4: 1 to 1: 2) 4.13 g (39% of th.) Of the title compound.
HPLC (method 2): R _t = 4.42 min
MS (ESIpos): m / z = 528 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.58 (d, 1H), 8.0 (d, 1H), 7.88 (ddd, 1H), 7.7-7.64 (m, 1H), 7.62 (s, 1H), 7.37-7.25 (m, 4H), 7.18 (d, 1H), 5.29-5.18 (m, 1H), 4.36 (q, 2H), 3.7 (s, 3H), 3.73-3.64 (m, 1H) , 3.59-3.45 (m, 2H), 3.35-3.24 (m, 1H), 2.7-2.53 (m, 2H).

Example 11A 3 - {[3- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } benzoate

The title compound is obtained as a by-product (regioisomer) in the preparation of Example 10A.
Yield: 707 mg (7% of theory)
HPLC (Method 2): R _t = 4.97 min
MS (ESIpos): m / z = 528 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.78 (d, 1H), 7.94 (t, 1H), 7.75 (d, 1H), 7.68 (s, 1H), 7.53-7.3 (m, 4H), 7.05 (d, 1H), 6.94 (d, 1H), 5.49-5.3 5 (m, 1H), 4.1 (s, 2H), 3.8 (s, 3H), 3.75-3.68 (m, 1H), 3.56-3.46 (m, 2H), 3.3-3.2 (m, 1H), 2.72-2.56 (m, 2H).

Example 12A 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -3- (2-furyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -benzoic acid methyl ester

Starting from 4.73 g (13 mmol) of methyl 3- [2- (2-furoyl) -3-oxo-3-pyridin-2-yl-propyl] benzoate from Example 6A and 3.33 g (22 mmol) of 3-sulfolane hydrazine are prepared by the method described in Example 8A and after chromatographic purification over silica gel (mobile phase: cyclohexane / ethyl acetate 3: 1 to 1: 2) 2.29 g (37% of theory) of the title compound.
HPLC (Method 2): R ^t = 4.07 min
MS (ESIpos): m / z = 478 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 8.57 (d, 1H), 8.0 (d, 1H), 7.94 (s, 1H), 7.87 (ddd, 1H), 7.72-7.64 (m, 2H), 7.36-7.28 (m, 3H), 6.72 (dd, 2H), 5.45-5.35 (m, 1H), 4.45 (s, 2H), 3.8-3.7 (m, 4H), 3.6-3.49 (m, 2H), 3.4-3.3 (m, 1H), 2.65 (q, 2H).

Example 13A 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} benzoic acid

1.3 g (2.7 mmol) of the compound from Example 8A and 0.2 g (5.3 mmol) of lithium hydroxide monohydrate are stirred in 26 ml of 7HF and 5.2 ml of water for 20 h at room temperature. Thereafter, 0.1 g (2.7 mmol) of lithium hydroxide monohydrate in 2.6 ml of water are added again. After 5 h, 80 ml of water and 80 ml Ethyl acetate added. It is acidified with 5.3 ml of 1 N hydrochloric acid, the organic phase is then separated off, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is reacted without further purification.
Yield: 1.1 g (90% of theory)
LC-MS (Method 1): R _t = 2.08 min
¹ H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.65 (s, 1H); 8.53 (dd, 1H); 8.01 (d, 1H); 7.85 (ddd, 1H); 7.61-7.50 (m, 5H); 7.38-7.35 (m, 2H); 7.28 (ddd, 1H); 7.20-7.11 (m, 2H); 5.01 (tt, 1H); 4.27 (s, 2H); 3.66 (dd, 1H); 3.58-3.47 (m, 2H); 3.27-3.19 (m, 1H); 2.68-2.53 (m, 2H).

Example 14A 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} benzoic acid trifluoroacetate

A solution of 1.3 g (2.45 mmol) of 3 - {[1- (1,1-dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} benzoic acid tert-butyl ester from Example 9A in 20 ml of dichloromethane is treated with 8 ml of trifluoroacetic acid and 1.33 g (12.27 mmol) of anisole and stirred for 1 h at room temperature. The reaction mixture is extracted by shaking with sodium bicarbonate solution. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue obtained is purified over a silica gel column (mobile phase: cyclohexane / ethyl acetate 1: 1). 702 mg (60% of theory) of the title compound are obtained.
LC-MS (Method 1): R _t = 2.1 min
MS (ESIpos): m / z = 474 (M + H) ⁺ .

Example 15A 3 - {[5- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } benzoic acid

A solution of 4.1 g (7.7 mmol) of 3 - {[5- (5-chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazole -4-yl] methyl} benzoic acid methyl ester from Example 10A in 90 ml of THF is mixed with 58.2 ml of 10% sodium hydroxide solution and stirred at 50 ° C for 12 h. After cooling, the batch is diluted with water, adjusted to pH 5 with 1 M hydrochloric acid and extracted by shaking with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is crystallized from dichloromethane, the crystals are filtered off with suction and dried. There are obtained 1.55 g (51% of theory) of the title compound.
HPLC (Method 2): R _t = 4.06 min
MS (ESIpos): m / z = 514 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 12.76 (br.s, 1H), 8.55 (d, 1H), 8.0 (d, 1H), 7.87 (t, 1H), 7.65 (d, 1H), 7.62 (s, 1H), 7.35-7.2 (m, 4H), 5.28-5.18 (m, 1H), 4.3 5 (t, 2H), 3.7 (q, 1H), 3.6-3.46 (m, 2H ), 3.4-3.2 (m, 1H), 2.7-2.53 (m, 2H).

Example 16A 3 - {[3- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } benzoic acid

Starting from 663.3 mg (1.26 mmol) of 3 - {[3- (5-chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -5-pyridin-2-yl-1H-pyrazole] 4-yl] methyl} benzoic acid methyl ester from Example 11A and 9.5 ml of 10% Na Aqueous solution is obtained by the method described in Example 15A and, after crystallization from diethyl ether, 557 mg (85% of theory) of the title compound.
HPLC (Method 2): R _t = 4.44 min
MS (ESIpos): m / z = 514 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.9 (br.s, 1H), 8.78 (d, 1H), 7.95 (t, 1H), 7.72 (d, 1H), 7.68 (d, 1H), 7.52-7.25 (m, 4H), 7.05 (d, 1H), 6.92 (d, 1H), 5.49-5.3 5 (m, 1H), 4.1 (s, 2H), 3.72 (q, 1H), 3.58-3.45 (m, 2H), 3.4-3.2 (m, 1H), 2.75-2.55 (m, 2H).

Example 17A 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5- (2-furyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} benzoic acid

Starting from 2.44 g (5.1 mmol) of 3 - {[1- (1,1-dioxotetrahydro-3-thienyl) -3- (2-furyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] methyl methyl benzoate from Example 12A and 38.5 ml 10% sodium hydroxide solution are obtained according to the procedure described in Example 15A and after crystallization from dichloromethane 248 mg (11% of theory) of the title compound.
HPLC (Method 1): R _t = 3.72 min
MS (ESIpos): m / z = 464 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 12.8 (br.s, 1H), 8.56 (d, 1H), 8.01 (d, 1H), 7.94 (s, 1H), 7.88 (t, 1H), 7.7-7.6 (m, 2H), 7.37-7.21 (m, 3H), 6.74-6.66 (m, 2H), 5.48-5.35 (m, 1H), 4.45 (s, 2H), 3.78 (q, 1H), 3.62-3.49 (m, 2H), 3.4-3.2 (m, 1H), 2.55 (q, 2H).

EXAMPLES

Example 1 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N-pyridin-4-yl-benzamide

750 mg (1.6 mmol) of the compound from Example 13A are dissolved in 15 ml of DMF. 164 mg (1.7 mmol) of 4-aminopyridine, 1.2 g (3.2 mmol) of HATU and 0.4 ml (321 mg, 3.2 mmol) of triethylamine are added and the mixture is stirred for 2 h at room temperature. Then 25 ml of water and 25 ml of ethyl acetate are added, the organic phase separated, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is purified by column chromatography on silica gel (eluent: dichloromethane / methanol 9: 1).
Yield: 433 mg (46% of theory)
HPLC (Method 1): R _t = 3.78 min
MS (ESIpos): m / z = 550 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.39 (s, 1H); 8.56 (dd, 1H); 8.45 (d, 2H); 8.01 (d, 1H); 7.84 (ddd, 1H); 7.73 (dd, 2H); 7.61 (d, 1H); 7.54-7.50 (m, 4H); 7.42-7.38 (m, 2H); 7.30-7.22 (m, 2H); 7.13 (d, 1H); 5.01 (tt, 1H); 4.31 (dd, 2H); 3.66 (dd, 1H); 3.58-3.47 (m, 2H); 3.28-3.20 (m, 1H); 2.68-2.51 (m, 2H).

Example 2 N- (2-Chlorophenyl) -3 - {[1- (1,1-dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} benzamide

The preparation of the title compound is carried out starting from Example 14A in an analogous manner to Example 1 (amide coupling by EDC instead of HATU).
LC-MS (Method 1): R _t = 2.72 min
MS (ESIpos): m / z = 583 (M + H) ^+
1 H-NMR (200 MHz, CDCl ₃ ): δ = 8.62 (d, 1H), 8.17-7.9 (m, 4H), 7.86 (s, 1H), 7.75 (ddd, 1H), 7.6-7.3 (m, 10H), 5.05-4.85 (m, 1H), 4.3 8 (s, 2H), 3.9-3.7 (m, 1H), 3.7-3.5 (m, 1H), 3.5-3.3 (m, 1H), 3.2-3.0 (m, 1H), 2.9-2.7 (m, 1H), 2.7-2.45 (m, 1H).

Example 3 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N- (3-methylphenyl) benzamide

The preparation of the title compound is carried out starting from Example 14A in an analogous manner to Example 1 (amide coupling by EDC instead of HATU).
LC-MS (Method 2): R _t = 2.46 min
MS (ESIpos): m / z = 563 (M + H) ^+
1 H-NMR (300 MHz, CDCl _3): δ = 8.6 (d, 1H), 8.0 (d, 1H), 7.75 (ddd, 1H), 7:58 (d, 1H), 7.54-7.4 (m, 6H) , 7.38-7.1 (m, 6H), 5.0-4.87 (m, 1H), 4.32 (s, 2H), 3.85-3.75 (m, 1H), 3.68-3.55 (m, 1H), 3.45-3.35 (m, 1H), 3.18-3.03 (m, 1H), 2.9-2.7 (m, 1H), 2.61-2.5 (m, 1H), 2.38 (s, 3H).

Example 4 N- (3-Chlorophenyl) -3 - {[1- (1,1-dioxydotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} benzamide

The preparation of the title compound is carried out starting from Example 14A in an analogous manner to Example 1 (amide coupling by EDC instead of HATU).
LC-MS (Method 2): R _t = 2.58 min
MS (ESIpos): m / z = 583 (M + H) ⁺ .

Example 5 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N-pyridin-2-yl-benzamide

The preparation of the title compound is carried out starting from Example 13A in an analogous manner to Example 1.
LC-MS (Method 6): R _t = 2.37 min
MS (ESIpos): m / z = 550 (M + H) ^+
1 H-NMR (300 MHz, CDCl _3): δ = 8.72 (d, 1H), 8.61 (d, 1H), 8:47 (d, 1H), 8.0 (t, 2H), 7.87 (s, 1H), 7.75 (ddd, 1H), 7.56-7.38 (m, 5H), 7.38-7.2 (m, 4H), 5.02-4.9 (m, 1H), 4.38 (s, 2H), 3.8 (q, 1H), 3.7-3.55 (m, 1H), 3.4 (q, 1H), 3.18-3.02 (m, 1H), 2.9-2.73 (m, 1H), 2.63-2.5 (m, 1H).

Example 6 (+) - 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N-phenylbenzamide

The preparation of the racemic title compound is carried out starting from Example 14A in an analogous manner to Example 1 (amide coupling by EDC instead of HATU).
LC-MS (Method 6): R _t = 2.53 min
MS (ESIpos): m / z = 549 (M + H) ^+
1 H-NMR (300 MHz, CDCl _3): δ = 8.62 (d, 1H), 8.0 (d, 1H), 7.75 (ddd, 1H), 7.65-7.42 (m, 9H), 7:36 (t, 2H) , 7.3-7.08 (m, 4H), 5.0-4.85 (m, 1H), 4.35 (s, 2H), 3.8 (dd, 1H), 3.7-3.5 (m, 1H), 3.4 (dd, 1H), 3.2 -3.0 (m, 1H), 2.9-2.7 (m, 1H), 2.55-2.43 (m, 1H).

The Racemat is subsequently analyzed by HPLC on a chiral phase (column: Daicel Chiralpak AD, 250 mm × 20 mm; Eluent: isohexane / ethanol 5: 1) to the enantiomers.

(+) - enantiomer:

• [α] ²⁰ _D = + 10 ° (c = 0.008, methanol)
• LC-MS (Method 2): R _t = 2.34 min
• MS (ESIpos): m / z = 549 (M + H) ⁺
• ¹ H-NMR (200 MHz, CDCl _3): δ = 8.62 (d, 1H), 8.0 (d, 1H), 7.75 (ddd, 1H), 7.65-7.42 (m, 9H), 7:36 (t, 2H) , 7.3-7.08 (m, 4H), 5.03-4.82 (m, 1H), 4.31 (s, 2H), 3.8 (q, 1H), 3.7-3.5 (m, 1H), 3.4 (q, 1H), 3.2 -3.0 (m, 1H), 2.9-2.7 (m, 1H), 2.55-2.43 (m, 1H).

Example 7 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N-pyridin-3-yl-benzamide

The title compound is prepared starting from Example 13A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (method 2): R _t = 3.69 min
MS (ESIpos): m / z = 550 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.3 (s, 1H), 8.87 (d, 1H), 8.57 (d, 1H), 8.3 (d, 1H), 8.15 (d, 1H) , 8.03 (d, 1H), 7.85 (ddd, 1H), 7.65 (d, 1H), 7.58-7.47 (m, 4H), 7.47-7.35 (m, 3H), 7.32-7.2 (m, 2H), 7.12 (d, 1H), 5.1-4.98 (m, 1H), 4.32 (q, 2H), 3.7 (q, 1H), 3.62-3.45 (m, 2H), 3.4-3.2 (m, 1H), 2.75-2.55 (m, 2H).

Example 8 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5-phenyl-3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N- (2-methylpyridine) 4-yl) benzamide

The title compound is prepared starting from Example 13A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): R _t = 3.81 min
MS (ESIpos): m / z = 564 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.35 (s, 1H), 8.55 (d, 1H), 8.32 (d, 1H), 8.02 (d, 1H), 7.85 (ddd, 1H) , 7.6 (s, 2H), 7.58-7.48 (m, 5H), 7.48-7.33 (m, 2H), 7.33-7.2 (m, 2H), 7.12 (d, 1H), 5.1-4.97 (m, 1H) , 4.3 (q, 2H), 3.7 (q, 1H), 3.6-3.45 (m, 2H), 3.4-3.2 (m, 1H), 2.75-2.53 (m, 2H), 2.43 (s, 3H).

Example 9 3 - {[5- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N-pyridin-2-yl benzamide

The title compound is prepared starting from Example 15A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (method 2): R _t = 3.9 min
MS (ESIpos): m / z = 590 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.6 (s, 1H), 8.6 (d, 1H), 8.39 (d, 1H), 8.13 (d, 1H), 8.0 (d, 1H) , 7.9-7.72 (m, 3H), 7.7 (s, 1H), 7.35-7.22 (m, 3H), 7.22-7.1 (m, 3H), 5.3-5.18 (m, 1H), 4.38 (t, 2H) , 3.7 (q, 1H), 3.6-3.45 (m, 2H), 3.4-3.25 (m, 1H), 2.7-2.53 (m, 2H).

Example 10 3 - {[5- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N-pyridin-3-ylbenzamide

The title compound is prepared starting from Example 15A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): R _t = 3.84 min
MS (ESIpos): m / z = 590 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.35 (s, 1H), 8.9 (d, 1H), 8.57 (d, 1H), 8.3 (d, 1H), 8.17 (d, 1H) , 8.0 (d, 1H), 7.86 (ddd, 1H), 7.7 (d, 1H), 7.63 (s, 1H), 7.42-7.25 (m, 4H), 7.24-7.15 (m, 2H), 5.3-5.19 (m, 1H), 4.4 (t, 2H), 3.72 (q, 1H), 3.6-3.45 (m, 2H), 3.4-3.3 (m, 1H), 2.7-2.52 (m, 2H).

Example 11 3 - {[5- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N-pyridin-4-ylbenzamide

The title compound is prepared starting from Example 15A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): R _t = 3.88 min
MS (ESIpos): m / z = 590 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.5 (s, 1H), 8.58 (d, 1H), 8.47 (d, 2H), 8.0 (d, 1H), 7.86 (ddd, 1H) , 7.75 (d, 2H), 7.69 (d, 1H), 7.66 (s, 1H), 7.38-7.27 (m, 3H), 7.27-7.17 (m, 2H), 5.32-5.19 (m, 1H), 4.4 (t, 2H), 3.7 (q, 1H), 3.6-3.45 (m, 2H), 3.4-3.3 (m, 1H), 2.7-2.55 (m, 2H).

Example 12 3 - {(5- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazol-4-yl) -methyl } -N- (2-methyl-pyridin-4-yl) benzamide

The title compound is prepared starting from Example 15A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): _Rt = 3.93 min
MS (ESIpos): m / z = 604 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.4 (s, 1H), 8.58 (d, 1H), 8.32 (d, 1H), 8.0 (d, 1H), 7.86 (ddd, 1H) , 7.7-7.58 (m, 3H), 7.53 (d, 1H), 7.36-7.26 (m, 3H), 7.26-7.15 (m, 2H), 5.3-5.2 (m, 1H), 4.4 (t, 2H) , 3.7 (q, 1H), 3.6-3.47 (m, 2H), 3.4-3.3 (m, 1H), 2.7-2.55 (m, 2H), 2.43 (s, 3H).

Example 13 3 - {[5- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N- (2,6-dimethyl-pyridin-4-yl) benzamide

The title compound is prepared starting from Example 15A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (method 2): R _t = 3.99 min
MS (ESIpos): m / z = 618 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.3 (s, 1H), 8.56 (d, 1H), 8.0 (d, 1H), 7.88 (ddd, 1H), 7.7-7.58 (m, 2H), 7.43 (s, 2H), 7.38-7.28 (m, 3H), 7.28-7.15 (m, 2H), 5.3-5.19 (m, 1H), 4.4 (t, 2H), 3.72 (q, 1H) , 3.62-3.47 (m, 2H), 3.4-3.25 (m, 1H), 2.7-2.55 (m, 2H), 2.38 (s, 6H).

Example 14 3 - {[1- (1,1-Diozidotetrahydro-3-thienyl) -5- (2-furyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N-pyridine -2-yl benzamide

The preparation of the title compound is carried out starting from Example 17A in an analogous manner to Example 1 (amide coupling using PyBOP instead of HATU).
HPLC (Method 2): R _t = 3.61 min
MS (ESIpos): m / z = 540 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.6 (s, 1H), 8.57 (d, 1H), 3.38 (d, 1H), 8.13 (d, 1H), 8.02 (d, 1H) , 7.93 (s, 1H), 7.9-7.7 (m, 4H), 7.37-7.1 (m, 4H), 6.72 (dd, 2H), 5.5-5.35 (m, 1H), 4.5 (t, 2H), 3.78 (q, 1H), 3.65-3.42 (m, 2H), 3.4-3.3 (m, 1H), 2.67 (q, 2H).

Example 15 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5- (2-furyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N-pyridine -3-yl benzamide

The preparation of the title compound is carried out starting from Example 17A in an analogous manner to Example 1 (amide coupling using PyBOP instead of HATU).
HPLC (method 2): R _t = 3.56 min
MS (ESIpos): m / z = 540 (M + H) ^+
1 H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.35 (s, 1H), 8.88 (d, 1H), 8.56 (d, 1H), 8.3 (d, 1H), 8.15 (d, 1H) , 8.02 (d, 1H), 7.93 (s, 1H), 7.86 (ddd, 1H), 7.7 (d, 2H), 7.4-7.28 (m, 3H), 7.23 (d, 1H), 6.72 (dd, 2H ), 5.48-5.35 (m, 1H), 4.5 (s, 2H), 3.78 (q, 1H), 3.63-3.5 (m, 2H), 3.4-3.3 (m, 1H), 2.68 (q, 2H).

Example 16 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5- (2-furyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N-pyridine -4-yl benzamide

The preparation of the title compound is carried out starting from Example 17A in an analogous manner to Example 1 (amide coupling using PyBOP instead of HATU).
HPLC (Method 2): R _t = 3.61 min
MS (ESIpos): m / z = 540 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.5 (s, 1H), 8.58 (d, 1H), 8.45 (d, 2H), 8.02 (d, 1H), 7.93 (s, 1H) , 7.86 (ddd, 1H), 7.72 (d, 2H), 7.69 (d, 2H), 7.88-7.2 (m, 3H), 6.72 (dd, 2H), 5.48-5.35 (m, 1H), 4.5 (s , 2H), 3.78 (q, 1H), 3.65-3.48 (m, 2H), 3.45-3.3 (m, 1H), 2.67 (q, 2H).

Example 17 3 - {[1- (1,1-Dioxotetrahydro-3-thienyl) -5- (2-furyl) -3-pyridin-2-yl-1H-pyrazol-4-yl] methyl} -N- ( 2-methyl-pyridin-4-yl) benzamide

The preparation of the title compound is carried out starting from Example 17A in an analogous manner to Example 1 (amide coupling using PyBOP instead of HATU).
HPLC (Method 2): R _t = 3.67 min
MS (ESIpos): m / z = 554 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.4 (s, 1H), 8.58 (d, 1H), 8.32 (d, 1H), 8.02 (d, 1H), 7.92 (s, 1H) , 7.86 (ddd, 1H), 7.7-7.6 (m, 3H), 7.55 (d, 1H), 7.38-7.28 (m, 2H), 7.24 (d, 1H), 6.72 (dd, 2H), 5.5-5.35 (m, 1H), 4.5 (s, 2H), 3.78 (q, 1H), 3.65-3.45 (m, 2H), 3.4-3.25 (m, 1H), 2.66 (q, 2H), 2.42 (s, 3H ).

Example 18 3 - {[3- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N-pyridin-2-yl benzamide

The title compound is prepared starting from Example 16A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): R _t = 4.31 min
MS (ESIpos): m / z = 590 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.7 (s, 1H), 8.79 (d, 1H), 8.39 (d, 1H), 8.15 (d, 1H), 7.95 (ddd, 1H) , 7.9-7.75 (m, 3H), 7.53-7.42 (m, 2H), 7.38 (t, 1H), 7.27-7.12 (m, 2H), 7.06 (d, 1H), 6.92 (d, 1H), 5.5 -5.35 (m, 1H), 4.12 (s, 2H), 3.73 (q, 1H), 3.59-3.45 (m, 2H), 3.3-3.2 (m, 1H), 2.7-2.57 (m, 2H).

Example 19 3 - {[3- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N-pyridin-3-ylbenzamide

The title compound is prepared starting from Example 16A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): _Rt = 4.22 min
MS (ESIpos): m / z = 590 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.4 (s, 1H), 8.9 (d, 1H), 8.78 (d, 1H), 8.3 (d, 1H), 8.18 (d, 1H) , 7.95 (ddd, 1H), 7.79 (d, 1H, 7.72 (s, 1H), 7.54-7.35 (m, 4H), 7.26 (d, 1H), 7.07 (d, 1H), 6.93 (d, 1H) , 5.5-5.35 (m, 1H), 4.14 (s, 2H), 3.72 (q, 1H), 3.5 8-3.44 (m, 2H), 3.3-3.2 (m, 1H), 2.72-2.58 (m, 2H ).

Example 20 3 - {[3- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N-pyridin-4-ylbenzamide

The title compound is prepared starting from Example 16A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): R _t = 4.29 min
MS (ESIpos): m / z = 590 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.54 (s, 1H), 8.78 (d, 1H), 8.47 (d, 2H), 7.95 (ddd, 1H), 7.8-7.7 (m, 3H), 7.68 (s, 1H), 7.53-7.38 (m, 3H), 7.27 (d, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 5.5-5.35 (m, 1H), 4.13 (s, 1H), 3.72 (q, 1H), 3.58-3.43 (m, 2H), 3.3-3.18 (m, 1H), 2.7-2.55 (m, 2H).

Example 21 3 - {[3- (5-Chloro-2-thienyl) -1- (1,1-dioxotetrahydro-3-thienyl) -5-pyridin-2-yl-1H-pyrazol-4-yl] -methyl } -N- (2-methyl-pyridin-4-yl) benzamide

The title compound is prepared starting from Example 16A in a manner analogous to Example 1 (amide coupling by means of PyBOP instead of HATU).
HPLC (Method 2): R _t = 4.36 min
MS (ESIpos): m / z = 604 (M + H) ^+
1 H-NMR (300 MHz, DMSO-d ₆ ): δ = 10.44 (s, 1H), 8.78 (d, 1H), 8.33 (d, 1H), 7.93 (ddd, 1H), 7.77 (d, 1H) , 7.65 (d, 2H), 7.58-7.36 (m, 4H), 7.27 (d, 1H), 7.06 (d, 1H), 6.94 (d, 1H), 5.5-5.35 (m, 1H), 4.14 (s , 2H), 3.78-3.67 (m, 1H), 3.58-3.45 (m, 2H), 3.3-3.2 (m, 1H), 2.72-2.55 (m, 2H), 2.44 (s, 3H).

Examples 22-55

Starting from 100 μmol of compound 13A, the compounds listed in Table 1 are prepared in analogy to Example 1 (amide coupling by means of TBTU instead of HATU, purification of the crude product by preparative HPLC, detection of the respective molar mass as [M + H] ⁺ ):

Table 1

Examples 56-58

The compounds listed below in Table 2 are by solid phase synthesis, by conducted in IRORI-Kans.

General rule:

1 eq each. 4- (4-Formyl-3-methoxyphenoxy) butyrylamide resin (Polymer Labs) are initially charged in 10 ml / g resin of a mixture of DMF / TMOF (1: 1) and mixed with 4.5 eq. of the corresponding aniline added. After shaking for 20 h, the supernatant is aspirated from the resin, washed twice with DMF and then with 4 eq. Added tetrabutylammonium borohydride. After 15 min, it is cooled to -40 ° C and washed with 16 eq. Glacial acetic acid. After warming to RT over 4 h, the supernatant is filtered off with suction and the resin is washed with DMF, methanol and dichloromethane. The resulting aniline-loaded resins are slurried in dichloromethane / DMF (65:35) and filled into the IRORI kans. 10 eq each. of the corresponding aniline resin are filled into the kans with dichloromethane / DMF (65:35). It will be 10 eq. N, N-diisopropylethylamine and 3-chloromethylbenzoyl chloride were added and shaken for 2 h. It is decanted off and washed with DMF, methanol and dichloromethane. After drying, the kans are presented in dioxane / 2-propanol (4: 1), with 5 eq. Sodium iodide added and shaken at 90 ° C for 5 h. It is decanted off again and washed with dioxane / 2-propanol. The kans are presented in dioxane / 2-propanol, with 5 eq. 1-phenyl-3-pyridin-2-yl-propane-1,3-dione (Example 1A), 3 eq. Sodium carbonate and 0.5 eq. 18-crown-6 and shaken at 85 ° C for 18 h. The solvent is decanted off and washed with DMF, methanol and dichloromethane. The dried kans are presented in DMA / acetic acid (4: 1), with 5 eq. 3-sulfolane hydrazine and shaken at 85 ° C for 12 h. It is decanted, washed with DMF, methanol and dichloromethane and then dried in vacuo. The products are cleaved from the resin with dichloromethane / trifluoroacetic acid (1: 1) and evaporated in the vacuum centrifuge. The residues are purified by preparative HPLC (silica gel, RP 18 material). By MS coupling, all peaks with the expected mass (detected as [M + H] ⁺ ) are collected and pooled. The compounds listed in Table 2 correspond in each case to the excess isomer obtained in the ratio of about 4: 1.

Table 2

B) Assessment of physiological effectiveness

Abbreviations:

• RPMI 1640 medium

  from Gibco, Invitrogen Corporation, Karlsruhe, Germany

  FCS

  Fetal Calf Serum

The Suitability of the compounds of the invention for the treatment of retrovirus-induced diseases can be shown in the following assay systems:

In vitro assays

HIV infection in cell culture

Of the HIV test is carried out with modifications according to the method of Pauswels et al. [see. Journal of Virological Methods 1988, 20, 309-321].

Primary human Blood lymphocytes (PBLs) be over Ficoll-Hypaque enriched and in RPMI 1640 medium, 20% fetal calf serum with phytagemagglutinin (90 μg / ml) and Interleukin-2 (40 U / ml). Infection with infectious HIV PBLs are pelleted and then the cell pellet in 1 ml of a suitably diluted HIV virus adsorption and suspended for 1 hour at 37 ° C incubated (pellet infection). Unabsorbed virus is then used by Zentifugation removed, and the infected cells are transferred to test plates (z. B. 96-well microtiter plates) containing the test substances in a suitable dilution.

alternative are used e.g. HIV-susceptible, permanent H9 cells (ATCC or NIAID, USA) instead of normal human blood lymphocytes for testing the antiviral effects of the compounds of the invention used. Infected H9 cells are used for Test purposes in RPMI 1640 medium, 2% and / or 20% fetal calf serum, bred.

The virus adsorption solution is centrifuged and the infected cell pellet is taken up in growth medium so that 1 × 10 ⁵ cells per ml are set. The cells infected in this way are pipetted approximately 1 × 10 4 cells / well into the wells of 96-well microtiter plates (pellet infection). Alternatively, the HIV is pipetted separately after preparation of the substance dilutions in the microtiter plates and after addition of the cells (supernatant infection).

The first vertical row of the microtiter plate contains only growth medium and cells that are not infected but otherwise treated the same way as described above (cell control). The second vertical row of the microtiter plate receives only HIV-infected cells (virus control) in growth medium. The remaining wells contain compounds of the invention in different concentrations, starting from the wells of the 3rd vertical row of the microtiter plate, from which the test substances are diluted in steps of 2. 2 ¹⁰ -fold.

alternative become supernatant infections carried out (see above), in which the cells are seeded in 96-well plates. The HIV virus is then added in a volume of 50 μl.

The assays be so long at 37 ° C incubated until untreated virus control for HIV typical syncytia formation occurs (between day 3 and 6 after infection), then either microscopically or via p24 ELISA detection method (Vironostika, BioMerieux, The Netherlands) or Alamar Blue Indicator dye evaluated photometrically or fluorometrically becomes. In the untreated virus control result among these Test conditions about 20-100 Syncytia while the untreated cell control has no syncytia. Corresponding The ELISA test shows values less than 0.1 for the cell controls and values between 0.1 and 2.9 for the virus controls on. The photometric evaluation of Alamar Blue treated cells shows for the cell controls extinctions less than 0.1, while the Virus controls have values between 0.1 and 3 at appropriate wavelengths.

The IC ₅₀ values are determined as the concentration of the treated and infected cells in which 50% (about 20-100 syncytia) of the virus-induced syncytia are suppressed by the treatment with the compound according to the invention. Accordingly, the cut-off values are set in the ELISA test and in the photometric or fluorometric determination using Alamar Blue. In addition to the determination of antiviral effects, the treated cell cultures are also examined microscopically for cytotoxic, cytostatic or cytological changes as well as for solubility. Active compounds which show cell-altering, cytotoxic findings in the concentration range of action are not evaluated in their antiviral activity.

It it is found that the compounds of the invention infected HIV Protect cells from virus-induced cell destruction. Experimental data are summarized in Table A.

Table A:

C) exemplary 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 of lactose (monohydrate), 50 mg of corn starch (native), 10 mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Germany) and 2 mg of 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 mixed with the magnesium stearate for 5 minutes. This mixture will with a usual Pressed tablet press (format of the tablet see above). When Guideline for the compression is used a pressing force of 15 kN.

Orally administrable solution:

composition

500 mg of the compound of Example 1, 2.5 g of polysorbate and 97 g of polyethylene glycol 400. A single dose of 100 mg of the compound of the invention correspond to 20 g of oral solution.

manufacturing

The inventive compound is suspended in the mixture of polyethylene glycol and polysorbate with stirring. The stirring process will be up to the full resolution the compound of the invention continued.

iv Solution:

The inventive compound becomes in a concentration below the saturation solubility in a physiological acceptable solvent (e.g., isotonic saline, Glucose solution 5%, PEG 400 solution 30%) solved. The solution is sterile filtered and placed in sterile and pyrogen-free injection containers bottled.

Claims (8)

Compound of the formula

in which R ^{1 is} phenyl or 5- or 6-membered heteroaryl, wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro , Trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₁ -C ₆ alkylamino, R ^{2 is} phenyl or 5- or 6-membered heteroaryl, where phenyl and heteroaryl may be substituted having 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₁ C ₆ alkylamino, R ^{3 is} phenyl or 5- to 10-membered heteroaryl, wherein phenyl and heteroaryl may be substituted by 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydro xy, amino, hydroxycarbonyl, aminocarbonyl, cyano, nitro, trifluoromethyl, trifluoromethoxy, C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, C ₁ -C ₆ -alkylamino, C ₁ -C ₆ -alkoxycarbonyl and C ₁ C ₆ alkylaminocarbonyl, wherein alkyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ -Alkylamino, C ₁ -C ₆ -alkoxycarbonyl and C ₁ -C ₆ -alkylaminocarbonyl, or one of their salts, their solvates or the solvates of their salts. A compound according to claim 1, characterized in that R ^{1 is} phenyl, pyridyl, thienyl or furyl, wherein phenyl pyridyl, thienyl and furyl may be substituted with 1 to 3 substituents, wherein the substituents are independently selected from the group consisting of halogen , C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, R ^{2 is} phenyl, pyridyl, thienyl or furyl, wherein phenyl pyridyl, thienyl and furyl may be substituted with 1 to 3 substituents, wherein the substituents independently are selected from the group consisting of halogen, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, R ³ is phenyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, indolyl, 1H-indazolyl, 1H-1,2,3-benzotriazolyl or 1H-benzimidazolyl, wherein phenyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, indolyl, 1H-indazolyl, 1H-1,2,3-benzotriazolyl and 1H- Benzimidazolyl may be substituted with 1 bi s 3 substituents, wherein the substituents are independently selected from the group consisting of halogen, hydroxy, amino, hydroxycarbonyl, aminocarbonyl, C ₁ -C ₄ alkyl and C ₁ -C ₄ alkoxy, wherein alkyl may be substituted with 1 to 2 substituents, wherein the substituents are independently selected from the group consisting of hydroxy and C ₁ -C ₄ alkoxy, or one of their salts, their solvates or the solvates of their salts. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that a compound of formula

in which R ¹ and R ² have the meaning indicated in claim 1, with a compound of formula R ₃ -NH ₂ (III), in which R ^{3 has} the meaning given in claim 1, is reacted. A compound according to any one of claims 1 or 2 for the treatment and / or prophylaxis of diseases. Medicaments containing at least one compound according to one of the claims 1 or 2 in combination with at least one inert, non-toxic, pharmaceutically suitable excipient. Use of a compound according to any one of claims 1 or 2 for the manufacture of a medicament for the treatment and / or prophylaxis of diseases. Medicament according to claim 5 for the treatment and / or Prophylaxis of viral diseases. Method of control of viral diseases in humans and animals by administration an antivirally effective amount of at least one compound one of the claims 1 or 2, a medicament according to claim 5 or 7 or one according to claim 6 obtained drug.