HK1122803B - 4-(pyridin-3-yl)-2-(pyridin-2-yl)-1,2-dihydro-3h-pyrazol-3-one derivatives as specific hif-prolyl-4-hydroxylase inhibitors for treating cardiovascular and haematological diseases - Google Patents

Description

4- (pyridin-3-yl) -2- (pyridin-2-yl) -1, 2-dihydro-3H-pyrazolin-3-one derivatives as specific inhibitors of the transcription factor-prolyl-4-hydroxylase for the treatment of cardiovascular and hematological diseases

The invention relates to novel dipyridyl-dihydropyrazolones, to methods for the production thereof, to the use thereof for the treatment and/or prophylaxis of diseases and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular and hematological diseases, kidney diseases and for promoting wound healing.

The lack of oxygen supply to a human organ or part thereof, which either impairs the normal operation of the organ or part thereof due to its time and/or its extent, or causes its operation to come to a complete halt, is called hypoxia (Hypoxie). Hypoxia may be due to a reduction in the oxygen available in the breathing air (e.g. staying at higher altitudes), external respiratory disturbances (e.g. due to lung dysfunction or airway obstruction), a reduction in cardiac output (e.g. in heart failure, acute right heart overload at pulmonary embolism), hypoxemia of the blood's oxygen delivery capacity (e.g. due to anemia or poisoning such as carbon monoxide poisoning), local restriction due to insufficient blood supply caused by vascular occlusion (typically such as states of anemia in the heart, lower limbs or brain, diabetic macroangiopathy and microangiopathy) or an increase in the oxygen demand of the tissue (e.g. due to increased muscle labor capacity or local fatigue) [ Eder, Gedigk (Hrsg.), algemeine Pathologie und pathologiste, 33 rd edition, springer verlag, Berlin, 1990 ].

Human organs can be acutely or chronically regulated in response to reduced oxygen supply. In addition to the immediate response (which includes, inter alia, increased cardiac output by autonomic nervous mechanisms and local dilation of blood vessels), hypoxia causes countless eventsAlteration of gene transcription. Here, the function of the gene product is to compensate for hypoxia. Thus, expression of various glycolytic and glucose transporter 1 enzymes is enhanced, thereby increasing anaerobic ATP access and allowing survival under hypoxic conditions [ Schmidt, Thews (Hrsg.), Physiologie des Menschen, 27 th edition, Springer Verlag, Berlin, 1997; l isffler, Petrides (Hrsg.), Biochemie und pathochemie, 7 th edition, springer verlag, Berlin, 2003]。

In addition, hypoxia leads to enhanced expression of Vascular Endothelial Growth Factor (VEGF), thereby stimulating neovascularization in hypoxic tissues (angiogenesis). Thereby effectively improving the blood supply to the anemic tissue for a long period of time. This counter-regulation is apparently far from sufficient in various diseases of the cardiac circulation and vascular occlusion [ reviewed by Simons and Ware, Therapeutic angiogenisis in cardiovascular disease, nat. rev. drug. discov.2(11), 863-71(2003) ].

Furthermore, peptide hormones formed primarily in the interstitial fibroblasts of the kidney enhance erythropoietin expression under systemic hypoxia. Thereby stimulating the formation of red blood cells in the bone marrow and thereby increasing the oxygen transport capacity of the blood. This effect is used in so-called high intensity training for competitive sports. For example, a decrease in the oxygen transport capacity of the blood due to insufficient blood supply often results in an increase in erythropoietin production in the kidney. Certain forms of anemia can interfere with this autoregulation mechanism or adjust below its desired value. Thus, for example, in the case of patients with renal failure, the relative oxygen transport capacity to the blood is a significantly reduced amount despite the production of erythropoietin in the renal parenchyma, which results in so-called renal ischemia. In particular renal ischemia but also ischemia caused by tumors and HIV infection is usually treated by parenteral administration of recombinant human erythropoietin (rhEPO). There is currently no alternative to this expensive therapy using orally available drugs [ reviewed in Eckardt, The potential of erythropoetin and related strategies to mucolaterythroides, curr. opin. investig. drugs 2(8), 1081-5 (2001); berns, shell the target hemoglobin for properties with a chromatographic kit isolated with an iterative reconstruction of thermal be changed? Semin. dial.18(1), 22-9(2005) ]. Recent studies have shown that erythropoietin has a protective (anti-apoptotic) effect on hypoxic tissues, particularly the heart and brain, independently of its erythropoiesis-enhancing effect. Furthermore, according to recent studies, treatment with erythropoietin reduced the average severity of the condition in patients with heart failure [ reviewed by Caiola and Cheng, Useof erythropoetin heart failure management, Ann. Pharmacother.38(12), 2145-9 (2004); katz, mechanics and transaction of emission in viral health, Congest.Heart.Fail.10(5), 243-7 (2004).

It is common for the above-mentioned genes induced by hypoxia that their increased expression under hypoxic conditions is due to the so-called hypoxia-induced transcription factor (HIF). HIF is involved in heterodimeric transcription factors, which are composed of an alpha-subunit and a beta-subunit. Three HIF- α -isoforms are described, of which HIF-1 α and HIF-2 α are highly homologous and of significance for hypoxia-induced gene expression. While the substantial expression of the beta-subunit (2 isomers are described) called ARNT (arene receptor nuclear translocation molecule) depends on the expression of the alpha-subunit of oxygen content in the cell. Under normoxic conditions, HIF- α -proteins are polyubiquitinated (poly-ubiquitin) and then degraded by proteases. Under hypoxic conditions, this degradation is inhibited, allowing HIF- α to dimerize with ARNT and activate its target gene. Thus, HIF-dimers are linked to so-called hypoxia response units (HREs) in the regulator sequences of their target genes. HREs are defined by consensus sequences. Functionalized HREs have been demonstrated in the regulatory unit of many Hypoxia-inducible genes [ reviewed by Semenza, Hypoxia-inducer factor 1: oxygenated hormone and disease pathology, Trends mol. Med.7(8), 345-50 (2001); wenger und Gassmann, Oxygen (es) and the hypoxia-indicle factor-1, biol. chem.378(7), 609-16 (1997).

The molecular mechanisms underlying this HIF- α regulation are explained by the work of several independent research groups. This mechanism is maintained via material bridging: HIF- α is hydroxylated to two specific prolyl residues (P402 and P564 of the human HIF-1- α -subunit) by a subclass of aerobic prolyl-4-hydroxylase called PHD or EGLN. HIF-prolyl-4-hydroxylase is related to the iron-containing dioxygenase enzyme converting 2-oxoglutarate [ Epstein et al, C.elegans EGL-9 and dmammalian homology of enzymes and of dioxygenases that are present in Cell 107(1), 43-54 (2001); bruick and McKnight, Aconserved family of prolyl-4-hydroxyesas that modify HIF, Science 294(5545), 1337-40 (2001); ivan et al, Biochemical purification and pharmacological inhibition of a macromolecular hydrolysis reaction

The pfhl tumor suppressor protein is linked to the prolyl-hydroxylated HIF- α -subunit, which together with the extensins B and C is linked to the so-called VBC complex which is adapted to the HIF- α -subunit at the E3 ubiquitin-ligase. Because prolyl-4-hydroxylation and subsequent degradation of the HIF- α -subunit is dependent on intracellular oxygen concentration, HIF-prolyl-4-hydroxylase is also referred to as a cellular oxygen sensor. Three isoforms of this enzyme have been identified: EGLNl/PHD2, EGLN2/PHD1 and EGLN3/PHD 3. Two of these enzymes (EGLN2/PHD1 and EGLN3/PHD3) themselves induce transcription under hypoxic conditions and may have an effect on the reduced HIF-. alpha. -levels observed under chronic hypoxic conditions [ reviewed by Schofield and Ratcliffe, Oxygen sensing by HIF hydrolxylases, nat. Rev. mol. cell. biol.5(5), 343-54(2004) ].

Selective pharmacological inhibition of HIF-prolyl-4-hydroxylase results in enhanced gene expression of HIF-associated target genes, and thus is useful in the treatment of a number of conditions. In particular in the case of diseases of the cardio-blood circulatory system, recovery from the disease process is expected by inducing new blood vessels and switching the metabolic status of the ischemic organ from aerobic to anaerobic ATP uptake. The improvement in vascularization of chronic wounds promotes the healing process, particularly of difficult-to-heal ulcers and other chronic skin wounds. In the case of patients with specific conditions, in particular renal ischemia, the induction of erythropoietin itself is also an attractive therapeutic target.

To date, HIF-prolyl-4-hydroxylase inhibitors described in the scientific literature have not been able to be delivered in pharmaceutical formulations. In which either competitive ketoglutarate analogs (e.g.oxalylglycine) are involved, which are characterized by a very low activity intensity and thus have hitherto not acted upon in vivo models in the context of the induction of HIF target genes. Alternatively, this involves an iron-complex forming agent (chelator) such as deferoxamide (Desferroamin) which acts as a non-specific inhibitor of the iron-containing dioxygenase which, despite inducing a target gene such as erythropoietin in vivo, apparently inhibits erythropoiesis due to the iron available for complexation.

The object of the present invention is to provide novel compounds which can be used for the treatment of diseases, in particular cardiovascular and haematological diseases.

Within the scope of the present invention, compounds are described which act as specific inhibitors of the HIF-prolyl-4-hydroxylase and, owing to this in vivo specific mechanism of action after parenteral or oral administration, lead to the induction of HIF-target genes, such as erythropoietin, and to the biological processes caused thereby, such as erythropoiesis.

EP 165448 and EP 212281 disclose that 2-heteroaryl-4-aryl-1, 2-dihydrobutanones have a fungicidal and/or fungicidal action. EP 183159 claims the use of 2-heteroaryl-4-aryl-1, 2-dihydrobutanones as lipoxygenase inhibitors for the treatment of diseases of the respiratory tract, the cardiac-blood circulation and inflammation. DE 2651008 describes 2, 4-diphenyl-1, 2-dihydrobutazone as having herbicidal activity. The preparation and pharmacological properties of specific 2-pyridyl-1, 2-dihydrobutanones are described in Heiv. Chim. acta 49(1), 272-280 (1966). Compounds having a dihydrobupropion partial structure for the treatment of various diseases are claimed in WO 96/12706, WO00/51989 and WO 03/074550.

The subject of the present invention is a compound of general formula (I) and the salts, solvates and solvates of the salts thereof:

wherein

A represents CH or N, and the compound is represented by,

R¹represents a substituent selected from: (C)₁-C₆) Alkyl, trifluoromethyl, halogen, cyano, nitro, hydroxy, (C)₁-C₆) Alkoxy, amino, (C)₁-C₆) Alkoxycarbonyl, hydroxycarbonyl and-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₆) Alkyl, it may be substituted by hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino or of the formula-NH-C (═ O) -R⁵、-NH-C(＝O)-NH-R⁶or-NH-SO₂-R⁷Is substituted by a group of (1), wherein

R⁵Is represented by (C)₁-C₆) Alkyl, which may be substituted by hydroxy, (C)₁-C₄) Alkoxy, phenyl or 5-or 6-membered heteroaryl, or represents phenyl,

wherein, in the case of phenyl and heteroaryl, they are each identically or differently substituted by halogen, cyano, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethyl or trifluoromethoxy mono-to trisubstituted,

R⁶is represented by (C)₁-C₆) Alkyl, which may be substituted by hydroxy or (C)₁-C₄) Alkoxy substituted, and

R⁷is represented by (C)₁-C₆) Alkyl, and

R⁴represents hydrogen or (C)₁-C₆) Alkyl, the latter possibly being substituted by hydroxy, (C)₁-C₄) Alkoxy or phenyl is substituted by the group consisting of,

wherein, as for phenyl, it may be substituted by halogen, cyano, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or trifluoromethoxy,

R²represents a substituent selected from: halogen, cyano, nitro, (C)₁-C₆) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₆) Alkoxy, trifluoromethoxy, amino, hydroxycarbonyl and-C (═ O) -NH-R⁸Wherein

Then (C)₁-C₆) Alkyl and (C)₁-C₆) In the case of alkoxy groups, they may be substituted by hydroxyl groups, and

R⁸represents hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

m represents the number 0, 1 or 2,

n represents the number 0, 1,2 or 3,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group.

The compounds of the invention are compounds of formula (I) and salts, solvates and solvates of salts thereof, the compounds covered by formula (I) of the following formula and the salts, solvates and solvates of salts thereof, and the compounds covered by formula (I) mentioned below as examples and the salts, solvates and solvates of salts thereof; as far as the compounds mentioned below are covered by formula (I), this does not relate to salts, solvates and solvates of salts.

Depending on the structure of the compounds of the invention, the compounds of the invention may exist in stereoisomeric forms (enantiomers, diastereomers). Accordingly, the present invention includes enantiomers or diastereomers, as well as various mixtures thereof. Mixtures of these enantiomers and/or diastereomers can be separated in a known manner into stereoisomerically identical components.

If a compound of the invention can exist in tautomeric forms, the invention includes all tautomeric forms.

Within the scope of the present invention, salts which are not physiologically feared by the compounds according to the invention are preferred as salts. Salts also include salts which are not themselves suitable for pharmaceutical use, but which may be used, for example, in the isolation or purification of the compounds of the invention.

Physiologically non-feared salts of the compounds of the invention include acid addition salts of inorganic acids, carboxylic and sulfonic acids, for example salts of hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, toluenesulfonic, benzenesulfonic, naphthalenedisulfonic, acetic, trifluoroacetic, propionic, lactic, tartaric, malic, citric, fumaric, maleic and benzoic acids.

Physiologically non-feared salts of the compounds of the invention also include salts of the usual bases, such as, and preferably, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonium or amines of 1 to 16 carbon atoms, such as, and preferably, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, prokai in, dibenzylamine, N-methyl-morpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.

Within the scope of the present invention, by solvate is meant the form of the compound of the invention which forms a complex in a solid or liquid environment by coordination with solvent molecules. Hydrates are a special form of solvates in which coordination occurs with water. Solvates are preferably hydrates within the scope of the present invention.

In addition, the compounds of the present invention also include prodrugs of the compounds of the present invention. The term "prodrug" includes compounds that may be biologically active or inactive by themselves, but which are converted (e.g., metabolized or hydrolyzed) to the compounds of the invention during the residence time in the body.

Within the scope of the present invention, unless otherwise specified, substituents have the following meanings:

within the scope of the present invention, (C)₁-C₆) Alkyl and (C)₁-C₄) Alkyl represents a straight-chain or branched alkyl group having 1 to 6 or 1 to 4 carbon atoms. Preferred are straight-chain or branched alkyl groups having 1 to 4 carbon atoms. For example and preferably, mention is made of: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

Within the scope of the present invention, (C)₃-C₇) Cycloalkyl and (C)₃-C₆) Cycloalkyl means a saturated monocyclic cycloalkyl of 3 to 7 or 3 to 6 carbon atoms. Cycloalkyl groups of 3 to 6 carbon atoms are preferred. For example and preferably, mention is made of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Within the scope of the present invention, (C)₁-C₆) Alkoxy and (C)₁-C₄) Alkoxy represents a straight-chain or branched alkoxy group of 1 to 6 carbon atoms or 1 to 4 carbon atoms. Preferred are linear or branched alkoxy groups of 1 to 4 carbon atoms. By way of example and preferably, mention may be made of: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.

Within the scope of the present invention, (C)₁-C₆) Alkoxycarbonyl and (C)₁-C₄) Alkoxycarbonyl denotes a straight-chain or branched alkoxy group of 1 to 6 carbon atoms or 1 to 4 carbon atoms, which is linked via a carbonyl group. Preference is given to linear or branched alkoxycarbonyl groups having from 1 to 4 carbon atoms in the alkoxy radical. By way of example and preferably, mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl.

Within the scope of the invention, mono (C)₁-C₄) Alkylamino represents an amino group having a straight-chain or branched alkyl substituent having 1 to 4 carbon atoms. By way of example and preferably, mention may be made of: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino and tert-butylamino.

Within the scope of the invention, bis (C)₁-C₄) Alkylamino denotes an amino group having two identical or different, straight-chain or branched alkyl substituents which each contain 1 to 4 carbon atoms. By way of example and preferably, mention may be made of: n, N-dimethylamino, N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-N-propylamino, N-isopropyl-N-methylamino, N-diisopropylamino, N-N-butyl-N-methylamino, N-tert-butyl-N-methylamino.

In the context of the present invention, a 5-or 6-membered heteroaryl group denotes an aromatic heterocycle having a total of 5 or 6 ring atoms (heteroaromatic compound) which is bonded via a ring carbon atom or, if appropriate, via a ring nitrogen atom and has up to 3 identical or different ring heteroatoms from the group N, O and/or S. Mention is made by way of example of: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,Azolyl radical, isoAzolyl, isothiazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinesPyridazinyl, pyrazinyl, triazinyl. Preference is given to 5-membered heteroaryl having up to two ring heteroatoms from N, O and/or S, for example furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,Azolyl radical, isoAzolyl, isothiazolyl.

In the context of the present invention, halogen includes fluorine, chlorine, bromine and iodine. Fluorine, chlorine or bromine are preferred.

If a group of a compound of the present invention is substituted, it may be mono-or polysubstituted, as long as it is not otherwise specified. Within the scope of the present invention, all radicals are suitable in which the meaning of the radicals, when polysubstituted, is identical to or different from one another. Preference is given to substitution with one, two or three identical or different substituents. Very particular preference is given to substitution with one substituent.

Preferred are compounds of formula (I) and salts, solvates and solvates of salts thereof, wherein:

a represents CH or N, and the compound is represented by,

R¹represents a substituent selected from: (C)₁-C₆) Alkyl, trifluoromethyl, cyano, nitro, hydroxy, (C)₁-C₆) Alkoxy, amino, (C)₁-C₆) An alkoxycarbonyl group and a hydroxycarbonyl group,

R²represents a substituent selected from: halogen, cyano, nitro, (C)₁-C₆) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₆) Alkoxy, trifluoromethoxy, amino and hydroxycarbonyl, wherein (C)₁-C₆) Alkyl and (C)₁-C₆) Alkoxy groups, which may be substituted by hydroxy groups,

m represents the number 0, 1 or 2,

n represents the number 0, 1,2 or 3,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group.

Also preferred are compounds of formula (I) and salts, solvates and solvates of salts thereof, wherein:

a represents a group represented by the formula (I),

R¹represents a substituent selected from: (C)₁-C₆) Alkyl, fluoro, chloro, bromo and-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₆) Alkyl, it may be substituted by hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino or of the formula-NH-C (═ O) -R⁵、-NH-C(＝O)-NH-R⁶or-NH-SO₂-R⁷Is substituted by a group of (1), wherein

R⁵Is represented by (C)₁-C₆) Alkyl which may be substituted by hydroxy, methoxy, ethoxy, phenyl or 5-membered heteroaryl, or represents phenyl,

wherein for phenyl and heteroaryl, they are each mono-to trisubstituted, identically or differently, by fluorine, chlorine, bromine, cyano, methyl, hydroxy, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy, and

R⁶and R⁷Independently of one another represent (C)₁-C₆) Alkyl, and

R⁴is represented by (C)₁-C₆) Alkyl radical of (C)₁-C₆) The alkyl group may be substituted with hydroxy, methoxy, ethoxy or phenyl,

wherein, in the case of phenyl, it may be substituted by fluorine, chlorine, bromine, cyano, methyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy,

R²represents a substituent selected from: fluorine, chlorine, bromine, cyano, (C)₁-C₆) Alkyl, trifluoromethyl, hydroxycarbonyl and-C (═ O) -NH-R⁸Wherein

Then (C)₁-C₆) In the case of alkyl groups, they may be substituted by hydroxy groups, and

R⁸is represented by (C)₁-C₄) An alkyl group, a carboxyl group,

m represents the number 0, 1 or 2,

n represents the number 0, 1 or 2,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen.

Particular preference is given to compounds of the formula (I) and salts, solvates and solvates of the salts, where

A represents a group represented by the formula (I),

R¹represents a substituent selected from: (C)₁-C₄) Alkyl, trifluoromethyl, nitro, (C)₁-C₄) Alkoxy, amino and (C)₁-C₄) An alkoxycarbonyl group, a carbonyl group,

R²represents a substituent selected from: chlorine, bromine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethoxy and amino, wherein₁-C₄) Alkyl and (C)₁-C₄) Alkoxy groups, which may be substituted by hydroxy groups,

m represents the number 0 or 1,

n represents the number 0, 1,2 or 3,

wherein for multiple occurrences R²In the case where they are the same or different, and

R³represents hydrogen or methyl.

Also particularly preferred are compounds of formula (I) and salts, solvates and solvates of salts thereof, wherein:

a represents a group represented by the formula (I),

R¹represents a substituent selected from: (C)₁-C₄) Alkyl, fluoro, chloro, bromo and-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₄) Alkyl may be substituted by hydroxy, amino or by a group of formula-NH-C (═ O) -R⁵or-NH-C (═ O) -NH-R⁶Is substituted by a group of (1), wherein

R⁵Is represented by (C)₁-C₄) Alkyl, which may be substituted by phenyl or pyrazolyl, or represents phenyl,

wherein in the case of phenyl and pyrazolyl, they are each identically or differently mono-to trisubstituted by fluorine, chlorine, methyl or trifluoromethyl, and

R⁶is represented by (C)₁-C₄) Alkyl, and

R⁴is represented by (C)₁-C₄) Alkyl radical of (C)₁-C₄) The alkyl group may be substituted with a phenyl group,

R²represents a substituent selected from: chlorine, bromine, cyano, (C)₁-C₄) Alkyl and trifluoromethyl, wherein₁-C₄) In the case of alkyl, it may be substituted by hydroxy

m represents the number 0, 1 or 2,

n represents the number 0, 1 or 2,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen.

Of particular interest are compounds of formula (I-A) and salts, solvates and solvates of salts thereof:

wherein:

R^1Arepresents hydrogen, methyl or trifluoromethyl, and

R^2A、R^2Band R^2CAre identical or different and, independently of one another, represent hydrogen, chlorine, bromine, cyano, methyl, hydroxymethyl, methoxy or ethoxy.

Also of particular interest are compounds of formula (I-B) and salts, solvates and solvates of salts thereof:

wherein:

R^1Aand R^1BAre the same or different and independently represent hydrogen, fluorine, chlorine, (C)₁-C₄) Alkyl or-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₄) Alkyl may be substituted by hydroxy, amino or by a group of formula-NH-C (═ O) -R⁵Is substituted by a group of (1), wherein

R⁵Is represented by (C)₁-C₄) Alkyl, which may be substituted by phenyl or pyrazolyl, or represents phenyl,

wherein in the case of phenyl and pyrazolyl, they are each identically or differently mono-to trisubstituted by fluorine, chlorine, methyl or trifluoromethyl, and

R⁴is represented by (C)₁-C₄) Alkyl radical of (C)₁-C₄) The alkyl group may be substituted with a phenyl group,

R²represents a substituent selected from: chlorine, bromine, cyano, methyl, hydroxymethyl or trifluoromethyl, and

n represents the number 0, 1 or 2,

wherein for multiple occurrences R²Its meaning may be the same or different.

Independent of the individual combinations of radicals indicated, the radical definitions given separately in the individual and preferred combinations of radicals are also arbitrarily replaced by radical definitions of other combinations.

Very particular preference is given to combinations of two or more of the abovementioned preferred ranges.

The 1, 2-dihydropyrazolin-3-one derivatives of formula (I) according to the invention can also be present in the form of the tautomeric 1H-pyrazol-5-ol (I') (cf. scheme 1 below); the present invention expressly encompasses both tautomeric forms.

Scheme 1

Another subject of the invention is a process for preparing the compounds of the formula (I) according to the invention, which process is characterized in that a compound of the formula (II)

Wherein R is²、R³And n has the above-mentioned meaning, and

Z¹represents a methyl group or an ethyl group,

with a compound of formula (III) in an inert solvent optionally in the presence of an acid,

a, R therein¹And m has the meaning given above,

to obtain the compound of the formula (IV),

wherein Z¹、A、R¹、R²、R³M and n have the above-mentioned meanings,

then cyclizing the compound of formula (IV) in the presence of a base in an inert solvent, and

the compounds of formula (I) are optionally converted with a suitable (I) solvent and/or (ii) base or acid to their solvates, salts and/or solvates of the salts.

The compounds of the invention of formula (I) wherein R³Representing hydrogen, can also be prepared in a manner in which a compound of formula (V):

wherein Z¹、R²And n has the meaning given above,

with compounds of the formula (VI)

Wherein Z²Represents a methyl group or an ethyl group,

condensed to a compound of formula (VII),

wherein Z¹、R²And n has the meaning given above,

then reacting with a compound of formula (III) in the presence of an acid to obtain a compound of formula (IV-A)

Wherein Z¹、A、R¹、R²M and n have the above-mentioned meanings,

and cyclizing in an inert solvent in the presence of a base.

The compounds of the invention can optionally also be prepared by further converting the substituents, in particular in R, starting from the compounds of the formula (I) obtained according to the process described above¹And R²Described below). The conversion may be carried out according to conventional methods and includes, for example, nucleophilic or electrophilic substitution reactions, oxidation reactions, reduction reactions, hydrogenation reactions, esterification reactions, ester bond cleavage reactions, etherification reactions, ether bond cleavage reactions, urea formation (Carbonamide), sulfonamides and ureas, and the introduction and removal of temporary protecting groups.

As solvents for process steps (II) + (III) → (IV), (IV) → (I) and (IV-a) → (I), particularly suitable are alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol. Ethanol is preferably used.

Process steps (II) + (III) → (IV) can, if desired, advantageously be carried out with addition of acid. Suitable for this purpose are the customary inorganic or organic acids, for example hydrochloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid. Acetic acid is preferably used.

The reaction (II) + (III) → (IV) is usually carried out in a temperature range of from 0 ℃ to +100 ℃, preferably from +10 ℃ to +40 ℃.

As the base for the cyclization steps (IV) → (I) and (IV-a) → (I), a conventional inorganic or organic base is suitable. Particular of this class are alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal or alkaline earth metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate or cesium carbonate, alkali metal alkoxides such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide, or sodium tert-butoxide or potassium tert-butoxide, or alkali metal hydrides such as sodium hydride. Sodium ethoxide is preferably used.

Reactions (IV) → (I) and (IV-a) → (I) are usually carried out in a temperature range of 0 ℃ to +60 ℃, preferably 0 ℃ to +30 ℃.

The process sequence (II) + (III) → (IV) → (I) can be carried out in a two-stage reaction process or as a one-pot reaction without isolation of the intermediate product (IV).

Process steps (V) + (VI) → (VII) are preferably carried out without solvent in the presence of an excess of (VI) under microwave irradiation conditions. The reaction is usually carried out at a temperature in the range of +20 ℃ to +150 ℃, preferably +80 ℃ to +120 ℃ [ see also j.p. bazureau et al Synthesis 1998, 967; ibid2001(4), 581 ].

The process steps (VII) + (III) → (IV-a) are advantageously carried out with addition of acid. Suitable for this purpose are the customary inorganic or organic acids, for example hydrochloric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-toluenesulfonic acid. Acetic acid is preferably used. As inert solvents for this process step, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, can be used. Particularly preferably, the reaction is carried out in acetic acid without addition of further solvents.

The reaction (VII) + (III) → (IV-A) is usually carried out in a temperature range of from 0 ℃ to +60 ℃, preferably from +10 ℃ to +30 ℃.

All process steps can be carried out at atmospheric pressure, at elevated pressure or at reduced pressure (for example from 0.5 to 5 bar). Usually at atmospheric pressure.

The compounds of formula (II) can be prepared according to literature-known methods from the carboacylation of carboxylic acid esters of compounds of formula (V). The compounds of the formulae (III), (V) and (VI) are commercially available, known from the literature or can be prepared analogously to methods known from the literature.

The preparation of the compounds of the invention can be illustrated by the following synthesis schemes 2-4:

scheme 2

[ a): NaH, 18-Krone-6, toluene, 1h RT → 1h 90 ℃; b) the method comprises the following steps 1. Ethanol, 16h RT; NaOEt, ethanol, 30min RT; c) the method comprises the following steps Ethanol, 1d RT; d) (ii) a NaOEt, ethanol, 1h RT ].

Scheme 3

[ a); LiHDMS, THF, -78 ℃→ 1h 0 ℃; 2. acetic anhydride, at-78 ℃; 3.36h RT; b) (ii) a Glacial acetic acid, ethanol, 16h RT; NaOEt, ethanol, 30min RT ].

Scheme 4

[ a): microwave irradiation is carried out for 1h 100 ℃; b) the method comprises the following steps 1. Glacial acetic acid, 2h RT; 2. application of NaHCO₃An aqueous solution; 3, NaOEt, ethanol, 30min 5 ℃; or b): cat, camphor-10-sulfonic acid, ethanol, 78 deg.C, 12-18h]。

The compounds of the present invention exhibit an unpredictable and meaningful spectrum of pharmacological effects. The compounds are therefore suitable as medicaments for the treatment and/or prophylaxis of diseases in humans and animals.

The compounds of the present invention are excellent as specific inhibitors of HIF-prolyl-4-hydroxylase.

Due to the pharmacological properties of the compounds of the invention, the compounds of the invention can be used for the treatment and/or prophylaxis of cardiovascular diseases, in particular heart failure, coronary heart disease, angina pectoris, myocardial infarction, stroke, arteriosclerosis, primary, pulmonary and malignant hypertension and peripheral arterial occlusive diseases. Furthermore, the compounds are suitable for the treatment and/or prophylaxis of hematopoietic disorders, such as essential anemia, renal ischemia, anemia associated with tumor diseases, infections or other inflammatory diseases, such as rheumatoid arthritis.

In addition, the compounds are suitable for increasing the hematocrit (H)matokrit) to obtain blood for self-feeding prior to surgery.

Furthermore, the compounds of the invention can be used for the treatment and/or prevention of surgery-induced states of ischemia (Isch)miezustnd) and its secondary symptoms after surgery, in particular heart surgery with the use of heart-lung machines (e.g. bypass surgery, heart valve transplantation), carotid surgery, aortic surgery, surgery with instrumental dissection or craniotomy (Sch)delkalotte) surgery. Furthermore, the compounds are suitable for general therapy and/or prophylaxis with the aim of accelerating wound healing and shortening recovery time.

Furthermore, the compounds may be used for the treatment and/or prevention of cancer and for the treatment and/or prevention of health state damage that occurs during the treatment of cancer, in particular after treatment with cytostatics, antibiotics and irradiation.

Furthermore, the compounds are suitable for the treatment and/or prophylaxis of rheumatic diseases and other diseases which are autoimmune diseases and in particular for the treatment and/or prophylaxis of impairment of the health state which occurs during the course of pharmacological treatment of such diseases.

Furthermore, the compounds of the invention can be used for the treatment and/or prevention of diseases of the eye (e.g. glaucoma), of the brain (e.g. parkinson's disease, alzheimer's disease, dementia, chronic pain), of chronic kidney diseases, of renal insufficiency and of acute renal failure and for promoting wound healing.

Furthermore, the compounds are suitable for the treatment and/or prophylaxis of the general debility to cachexia which often occurs, in particular at higher ages.

Furthermore, the compounds are suitable for the treatment and/or prevention of sexual dysfunction.

Furthermore, the compounds are suitable for the treatment and/or prophylaxis of true diabetes mellitus and its secondary symptoms, such as diabetic macroangiopathy and microangiopathy, diabetic nephropathy and neuropathy.

Furthermore, the compounds of the invention are suitable for the treatment and/or prophylaxis of fibrotic diseases, for example of the heart, lungs and liver.

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

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

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

The compounds of the present invention may be used alone or in combination with other active ingredients as desired. The invention further relates to medicaments containing at least one compound according to the invention and one or more other active ingredients, in particular for the treatment and/or prophylaxis of the abovementioned diseases. Mention may be made, as examples and preferred, of suitable combined active ingredients: ACE-inhibitors, angiotensin II-receptor antagonists, beta-receptor blockers, mineralocorticoid receptor antagonists, aspirin, diuretics, iron supplements, vitamin B12 and folic acid supplements, calcium antagonists, statins and digitalis (digoxin) derivatives.

Another subject of the invention are pharmaceutical agents containing at least one compound according to the invention, usually together with one or more inert, non-toxic, pharmacologically suitable auxiliary ingredients, and their use for the above-mentioned purposes.

The compounds of the invention may act systemically and/or locally. For this purpose, the compounds can be administered in a suitable manner, for example orally, parenterally, pulmonarily, nasally, sublingually, glossally, buccally, rectally, dermally, transdermally, conjunctivally, otically or as implants or implants.

For these routes of administration, the compounds of the invention can be administered in a suitable administration form.

For oral administration, suitable are functionalized administration forms with rapid and/or modified release of the compounds according to the invention in crystalline and/or amorphous and/or dissolved form, such as tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed-dissolving or insoluble coatings which control the release of the compounds according to the invention), tablets which disintegrate rapidly in the oral cavity or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatin capsules), lozenges, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

Parenteral administration can be carried out under conditions that bypass the absorption step (e.g., intravenous, intraarterial, intracardial, intraspinal, intralumbar) or under conditions that switch on absorption (e.g., intramuscular, subcutaneous, intradermal, percutan, intraperitoneal). Suitable administration forms for parenteral administration are, in particular, injections and infusions in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For other administration routes, suitable are, for example, inhalation medicaments (in particular powder inhalers, nebulizers), nasal drops or sprays, tablets for sublingual, sublingual or buccal administration, films/oblate tablets or capsules, suppositories, otic or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), creams, pastes, foams, spray powders, implants or implants.

Oral or parenteral administration, in particular oral administration, is preferred.

The compounds of the invention may be applied in the administration forms described above. It can be carried out in a known manner by means of inert, non-toxic, pharmacologically suitable auxiliaries. Mention may in particular be made, with regard to these auxiliaries, of carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (for example sodium lauryl sulfate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants such as ascorbic acid), colorants (for example inorganic pigments such as iron oxide) and flavoring and/or odor-improving agents.

In general, it has proven advantageous to administer the compound parenterally in an amount of about 0.001 to 1mg, preferably about 0.01 to 0.5mg, per kg of body weight in order to achieve effective results. In the case of oral administration, the dosage is about 0.01 to 100mg, preferably about 0.01 to 20mg, very particularly preferably 0.1 to 10mg, per kg of body weight.

Nevertheless, the above amounts can be deviated from as desired, depending, inter alia, on the body weight, the route of administration, the individual's performance with respect to the active ingredient, the type and point of formulation and the interval, to whom the administration is to be carried out. Thus, in some cases, it may be sufficient to lower the minimum amount, while in other cases the upper limit must be exceeded. In the case of administration of larger amounts, it may be recommended to administer the drug in divided doses throughout the day.

The invention is illustrated in the following examples. The invention is not limited to the embodiments described.

The percentages given in the following tests and examples, if not otherwise specified, are percentages by weight; the parts are weight parts. The solvent ratio, dilution ratio, and concentration data for the liquid/liquid solution are all based on volume.

A. Examples of the embodiments

Abbreviations and acronyms

aq. aqueous solution

cat catalyst

d days

DCI direct chemical ionization (by MS)

DMF dimethyl formamide

DMSO dimethyl sulfoxide

Th.theory (yield)

EI Electron Collision ionization (by MS)

ESI electrospray ionization (by MS)

Et Ethyl group

GC-MS and gas chromatography coupled mass spectrometry

h hours

HPLC high pressure-, high performance-liquid chromatography

Concentrated by konz

LC-MS and liquid chromatography coupled mass spectrum

LiHMDS lithium hexamethyldisilazide

min for

MS Mass Spectrometry

MTBE methyl tert-butyl ether

NMR nuclear magnetic resonance spectrum

R_tResidence time (HPLC)

RT Room temperature

TFA trifluoroacetic acid

THF tetrahydrofuran

LC-MS-, HPLC-and GC-MS-methods:

the method comprises the following steps:

the instrument comprises the following steps: micromass Platform LCZ with HPLC Agilent series 1100; column: thermo Hypersil GOLD 3 μ, 20mm × 4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 5.5min 10% A; furnace: 50 ℃; flow rate: 0.8 ml/min; UV detector: 210 nm.

The method 2 comprises the following steps:

the instrument comprises the following steps: micromass Platform LCZ with HPLC Agilent series 1100; column: thermo Hypurity Aquastar 3 μ, 50mm × 2.1 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 100% A → 0.2min 100% A → 2.9min 30% A → 3.1min 10% A → 5.5min 10% A; furnace: 50 ℃; flow rate: 0.8 ml/min; and (4) UV detection: 210 nm.

The method 3 comprises the following steps:

an instrument; micromass Quattro LCZ with HPLC Agilent series 1100; column: phenomenex Synergi 2. mu. Hydro-RP Mercury 20 mm. times.4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min 2 ml/min; furnace: 50 ℃; and (4) UV detection: 208-400 nm.

The method 4 comprises the following steps:

MS instrument type: micromass ZQ; PLC instrument type: waters Alliance 2795; column: phenomenex Synergi 2. mu. Hydro-RP Mercury 20 mm. times.4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min 2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

The method 5 comprises the following steps:

MS instrument type: micromass ZQ; HPLC instrument type: HP1100 Series; UVDAD; column: phenomenex Synergi 2. mu. Hydro-RP Mercury 20 mm. times.4 mm; eluent A: 11 water +0.5ml 50% formic acid, eluent B: 11 acetonitrile +0.5ml 50% formic acid; gradient: 0.0min 90% A → 2.5min 30% A → 3.0min 5% A → 4.5min 5% A; flow rate: 0.0min 1ml/min → 2.5min/3.0min/4.5min 2 ml/min; furnace: 50 ℃; and (4) UV detection: 210 nm.

The method 6 comprises the following steps:

the instrument comprises the following steps: HP1100 with DAD-detector; column: kromasil 00 RP-18, 60mm × 2.1mm, 3.5 μm; eluent A: 5ml HClO₄(70%)/1 water, eluent B: acetonitrile; gradient: 0min 2% B → 0.5min 2% B → 4.5min 90% B → 6.5min 90% B → 6.7min 2% B → 7.5min 2% B; flow rate: 0.75 ml/min; column temperature: 30 ℃; and (4) UV detection: 210 nm.

The method 7 comprises the following steps:

the instrument comprises the following steps: micromass GCT, GC 6890; column: restek RTX-35MS, 30 m.times.250. mu.m.times.0.25. mu.m; constant flow rate of helium: 0.88 ml/min; furnace: 60 ℃; an inlet: 250 ℃; gradient: 60 deg.C (0.30 min hold), 50 deg.C/min → 120 deg.C, 16 deg.C/min → 250 deg.C, 30 deg.C/min → 300 deg.C (1.7 min hold).

The method 8 comprises the following steps:

and (4) an instrument MS: waters ZQ 2000; HPLC (high Performance liquid chromatography) of an instrument: agilent 1100, 2-column junction; automatic sampling instrument: HTC PAL; column: YMC-ODS-AQ, 50 mm. times.4.6 mm, 3.0 μm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile + 0.1% formic acid; gradient: 0.0min 100% A → 0.2min 95% A → 1.8min 25% A → 1.9min 10% A → 2.0min 5% A → 3.2min 5% A → 3.21min 100% A → 3.35min 100% A; furnace: 40 ℃; flow rate: 3.0 ml/min; and (4) UV detection: 210 nm.

Starting compounds and intermediates

Example 1A

2-hydrazino-4-methylpyridine

3.33g (30.0mmol) of 2-fluoro-4-methylpyridine are initially taken in 40ml of 2-ethoxyethanol, the solution is mixed with 14.6ml (15.0g, 300mmol) of hydrazine hydrate, and the batch is stirred for 16 hours at the boiling temperature (bath temperature of 150 ℃). The reaction solution was concentrated in a rotary evaporator, the residue was added to 100ml of water, and extraction was performed with ethyl acetate (100 ml each, three times). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The resulting residue was dried in vacuo.

Yield: 1.90g (51% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.83(d，1H)，7.22(s，1H)，6.5 1(s，1H)，6.38(d，1H)，4.04(s，2H)，2.17(s，3H)

LC-MS (method 1): r_t＝0.80min；MS(ESIpos)：m/z＝124[M+H]⁺。

Example 2A

3-hydroxy-2-pyridin-3-yl-acrylic acid ethyl ester

1.65g (10.0mmol) of ethyl 3-pyridylacetate are initially taken under argon into 20ml of anhydrous toluene. The solution was mixed with 410mg (10.3mmol) of sodium hydride suspension (60% suspension in paraffin oil) and 130mg (0.50mmol) of 18-crown-6, and the batch was stirred at room temperature for 30 minutes and then at 85 deg.C (bath temperature) for 30 minutes. Then, it was cooled, and 1.48g (20.0mol) of ethyl formate was added dropwise at about 20 ℃. The mixture was stirred at room temperature for 60 minutes and then at 90 deg.C (bath temperature) for 60 minutes. After cooling, the reaction solution was poured into about 50ml of a saturated ammonium chloride solution and extracted with ethyl acetate (40 ml each five times). The combined organic phases are washed with 50ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The resulting solid was washed with pentane and dried in vacuo.

Yield: 1.3g (67% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.38(br.s，1H)，8.50(d，1H)，8.39(dd，1H)，7.97(s，1H)，7.71(d，1H)，7.35(dd，1H)，4.12(q，2H)，1.97(t，3H)。

MS(DCI)：m/z＝194[M+H]⁺。

Example 3A

2-pyridin-3-yl-3- (pyridin-2-Ylhydrazono) propionic acid Ethyl ester

2.90g (15.0mmol) of the compound from example 2A and 1.72g (15.8mmol) of 2-pyridylhydrazine are dissolved in 75ml of ethanol and the batch is stirred at room temperature for 4 days. The solvent of the reaction mixture is removed in a rotary evaporator and the residue is chromatographed over silica gel 60 (flow agent (laufmitel): dichloromethane → dichloromethane/methanol 10: 1 → dichloromethane/methanol 2: 1). The product fractions were combined and freed from solvent on a rotary evaporator. Drying in vacuo gives 3.95g (93% of theory) of the title compound.

LC-MS (method 2): r_t＝2.10min；MS(ESIpos)：m/z＝285[M+H]⁺。

Example 4A

(6-Bromopyridin-3-yl) methanol

1.34ml (1.34mmol) of a 1M solution of lithium aluminum hydride in THF was placed in 5ml of dry THF in advance under argon, and a solution of 500mg (2.69mmol) of 6-bromo-3-pyridylaldehyde in 3ml of dry THF was added dropwise thereto at 0 ℃. After stirring at room temperature for 1 hour, the batch was mixed with 25ml of ethyl acetate under ice-bath cooling and slowly hydrolyzed with 50ml of saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (20ml each, three times). The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated in a rotary evaporator. After removal of the residual solvent in vacuo, 375mg (74% of theory) of the title compound are obtained.

LC-MS (method 3): r_t＝1.02min；MS(ESlpos)：m/z＝189[M+H]⁺。

Example 5A

(6-chloro-5-methylpyridin-3-yl) methanol

The title compound was obtained as follows: 3.11g (20.0mmol) of 6-chloro-5-methylnicotinaldehyde [ preparation described in DE 4429465-A1, example 7] were reacted with 1.51g (40.0mmol) of sodium borohydride in 30ml of water and the aqueous phase was extracted with dichloromethane. The product obtained after removal of the solvent in a rotary evaporator is dried in vacuo and used as such.

Example 6A

2-bromo-5- (chloromethyl) pyridine

3.69g (19.7mmol) of the compound from example 4A were placed in advance under argon and mixed dropwise at-60 ℃ with 25ml of thionyl chloride. The batch was stirred at-60 ℃ for 1 hour. Concentrated at room temperature in a rotary evaporator and the residue is mixed with 50ml of saturated sodium bicarbonate solution and 50ml of ethyl acetate. The aqueous phase was extracted with ethyl acetate (25 ml each four times). The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed in a rotary evaporator and the residue is dried in vacuo.

Yield: 3.71g (91% of theory).

LC-MS (method 1): r_t＝3.28min；MS(ESIpos)：m/z＝208[M+H]⁺。

Example 7A

2-chloro-5- (chloromethyl) -3-methylpyridine

Preparation is carried out in analogy to example 6A from 1.00g (6.35mmol) of (6-chloro-5-methylpyridin-3-yl) methanol and 5ml of thionyl chloride. 1.26g of the title compound are obtained, which are used without further purification in the reaction.

LC-MS (method 4): r_t＝1.92min；MS(ESIpos)：m/z＝176[M]⁺。

Example 8A

(6-Bromopyridin-3-yl) acetonitrile

3.75g (18.2mmol) of the compound from example 6A were placed in advance in 20ml of DMF, 979mg (20.0mmol) of sodium cyanide were added to it and the batch was stirred at room temperature for 2 hours. The reaction mixture was poured into a mixture consisting of 250ml of saturated ammonium chloride solution and 200ml of ethyl acetate, and the aqueous phase was extracted with ethyl acetate (100 ml each, three times). The combined organic phases were dried over sodium sulfate, filtered, concentrated and the residue was dried in vacuo. The resulting product was used in the reaction without further purification.

Yield: 3.23g (90% of theory)

LC-MS (method 3): r_t＝1.46min；MS(ESIpos)：m/z＝197[M+H]⁺。

Example 9A

(6-chloro-5-methylpyridin-3-yl) acetonitrile

The synthesis is carried out in analogy to example 8A from 1.26g (7.14mmol) of the compound from example 7A. The crude product obtained is purified by chromatography on silica gel 60 (flow agent: dichloromethane → dichloromethane/methanol 50: 1).

Yield: 215mg (18% of theory)

LC-MS (method 1): r_t＝2.95min；MS(ESIpos)：m/z＝167[M+H]⁺。

Example 10A

(2-Chloropyridin-3-yl) acetic acid ethyl ester

To a mixture consisting of 270g of ethanol and 101ml of concentrated sulfuric acid, 22.0g (144mmol) of (6-chloropyridin-3-yl) acetonitrile were added and the batch was stirred under reflux for 24 hours. The reaction mixture was slowly added dropwise with stirring to a mixture consisting of 350g of sodium bicarbonate and 1 liter of water. The liquid phase is extracted with dichloromethane (400 ml each time, five times). The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed in a rotary evaporator. 23.1g (80% of theory) of the expected product are obtained, which is used in the reaction without further purification.

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.32(d，1H)，7.78(dd，1H)，7.49(d，1H)，4.10(q，2H)，3.77(s，2H)，1.19(t，3H)。

LC-MS (method 3): r_t＝1.91min；MS(ESIpos)：m/z＝200[M+H]⁺。

The compounds listed in table 1 were obtained in analogy to example 10A from the corresponding feeds:

TABLE 1

Example 13A

(5-Bromopyridin-3-yl) acetic acid ethyl ester

1.00g (4.63mmol) of (5-bromopyridin-3-yl) acetic acid are initially taken up in 20ml of ethanol, mixed with 2ml of concentrated sulfuric acid and the batch is stirred under reflux overnight. The reaction solution was added to a mixture consisting of 100ml of saturated sodium bicarbonate solution and 100ml of ethyl acetate with stirring, and the aqueous phase was extracted with ethyl acetate (three times with 50ml each). The combined organic phases were dried over sodium sulfate, filtered, concentrated and the residue was freed from residual solvent under vacuum overnight.

Yield: 1.06g (94% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.61(d，1H)，8.48(d，1H)，8.01(dd，1H)，4.10(q，2H)，3.78(s，2H)，1.20(t，3H)。

LC-MS (method 5): r_t＝2.06min；MS(ESIpos)：m/z＝246[M+H]⁺。

Example 14A

2- (6-Bromopyridin-3-yl) -3- (dimethylamino) acrylic acid ethyl ester

1.30g (2.98mmol) of the compound from example 11A are dissolved in 6ml of dimethylformamide-diethylacetal and the batch is stirred under microwave irradiation at 100 ℃ for 60 minutes. The batch is concentrated in a rotary evaporator and the residue is chromatographed over silica gel 60 (flow agent: cyclohexane → cyclohexane/ethyl acetate 1: 3).

Yield: 854mg (96% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.11(d，1H)，7.61(s，1H)，7.54(d，1H)，7.48(dd，1H)，4.01(q，2H)，2.70(br.s，6H)，1.12(t，3H)。

MS(DCI，NH₃)：m/z＝316[M+NH₄]⁺

LC-MS (method 4): r_t＝1.88min；MS(ESIpos)：m/z＝299[M+H]⁺。

In analogy to example 14A, the compounds listed in table 2 were prepared from the corresponding feeds:

TABLE 2

Example 18A

3-oxo-2-pyridin-3-yl-butyric acid ethyl ester

500mg (3.0mmol) of ethyl-pyridine-3-acetate are placed in 5ml of anhydrous THF in advance under argon and a solution of lithium hexamethyldisilazide (6.7ml, 1M in THF) is added dropwise thereto at-78 ℃. After 15 minutes the mixture was warmed to 0 ℃ and stirred for 1 hour and then cooled to-78 ℃. After addition of 340mg (3.3mmol) of acetic anhydride, the batch is stirred at room temperature for 36 hours. It was mixed with aqueous ammonium chloride, extracted with dichloromethane, and the organic phase was dried over magnesium sulfate and concentrated in vacuo. 488mg of the title compound with a purity of 70% was obtained and used in the reaction without further purification.

LC-MS (method 1): r_t＝2.24min；MS(ESIpos)：m/z＝208[M+H]⁺。

Example 19A

(5-methylpyridin-3-yl) acetonitrile

The preparation of the title compound is described in DE 2854210-C2 (Table 2, example 37).

Example 20A

5- (cyanomethyl) pyridine-2-carboxylic acid ethyl ester

10.5g (52.6mmol) of ethyl 5- (chloromethyl) pyridine-2-carboxylate [ prepared in accordance with H.Barth et al, Liebigs Ann. chem.1981, 2164-2179 ] were placed in advance in 75ml of anhydrous DMF and 2.58g (52.6mmol) of sodium cyanide were admixed in portions thereto at room temperature within 3 hours. The batch is then added to 500ml of saturated ammonium chloride solution and extracted with dichloromethane (four times 100ml each). The combined organic phases are dried over sodium sulfate, concentrated and the residue is purified by chromatography on silica gel (flow agent: cyclohexane → cyclohexane/ethyl acetate 1: 4). 3.80g (38% of theory) of the title product are obtained.

¹H-NMR(300MHz，DMSO-d₆)：δ＝8.69(d，1H)，8.10(d，1H)，7.99(dd，1H)，4.36(q，2H)，4.24(s，2H)，1.34(t，3H)。

LC-MS (method 3): r_t＝1.45min；MS(ESIpos)：m/z＝191[M+H]⁺。

In a similar manner to example 10A, the compounds listed in table 3 were obtained from the corresponding feeds:

TABLE 3

Example 23A

(4-methylpyridin-3-yl) acetic acid ethyl ester

The synthesis of the title compound is carried out in analogy to example 13A from 200mg (1.32mmol) of (4-methylpyridin-3-yl) acetic acid.

Yield: 235mg (99% of theory)

¹H-NMR(300MHz，DMSO-d₆)：δ＝8.32(d，1H)，7.56(dd，1H)，7.20(dd，1H)，4.08(q，2H)，3.67(s，2H)，2.44(s，3H)，1.18(t，3H)。

LC-MS (method 1): r_t＝1.86min；MS(ESIpos)：m/z＝180[M+H]⁺。

Example 24A

(6-methylpyridin-3-yl) acetic acid ethyl ester

The synthesis of the title compound was carried out in analogy to the preparation of example 13A from 493mg (3.26mmol) (6-methylpyridin-3-yl) acetic acid [ preparation: n.specber et al, j.am.chem.soc.81，704-709(1959)]。

Yield: 580mg (99% of theory)

¹H-NMR(300MHz，DMSO-d₆)：δ＝8.32(d，1H)，7.57(dd，1H)，7.20(d，1H)，4.08(q，2H)，3.67(s，2H)，2.44(s，3H)，1.18(t，3H)。

LC-MS (method 1): r_t＝1.85min；MS(ESIpos)：m/z＝180[M+H]⁺。

The compounds listed in table 4 were prepared in analogy to example 14A from the corresponding feed:

TABLE 4

The compounds listed in table 5 were obtained in analogy to example 1A from the corresponding 2-chloropyridine. Instead of the work-up described in example 1A, the reaction solution was concentrated here and the residue and the mixture consisting of diethyl ether and dichloromethane were stirred. The excess crystalline hydrazine hydrochloride was filtered off, the filtrate was concentrated, dried in vacuo and the product was reacted without further purification.

TABLE 5

Example 33A

2-hydrazino-isonicotinic acid nitrilesurenitril)

20.0g (144mmol) of 2-chloroisonicotinic acid nitrile are initially taken in 150ml of 1-butanol, admixed with 303ml (303mmol) of a 1M solution of hydrazine hydrate in THF and heated for 16 hours (110 ℃ bath temperature). The mixture is concentrated and the residue is purified by flash chromatography on silica gel (flow agent: dichloromethane/methanol 10: 1).

Yield: 9.48g (49% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.15(d，1H)，8.05(s，1H)，7.01(s，1H)，6.83(dd， 1H)，4.30(s，2H)。

LC-MS (method 1): r_t＝0.52min；MS(ESIpos)：m/z＝135[M+H]⁺。

Example 34A

(6-hydrazinopyridin-3-yl) methanol

20.0g (139mmol) of (6-chloropyridin-3-yl) methanol are heated at reflux overnight in 400ml of 35% aqueous hydrazine hydrate solution. The mixture was concentrated, mixed with toluene, reconcentrated and the residue stirred with a mixture consisting of dichloromethane, methanol and diethyl ether. The crystalline residue (hydrazine hydrochloride) was filtered off, the filtrate was concentrated and dried in vacuo.

Yield: 19.3g (99% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.91(d，1H)，7.40(dd，1H)，7.29(s，1H)，6.66(d，1H)，4.93(s，1H)，4.31(s，2H)，4.14(s，2H)。

LC-MS (method 1): r_t＝0.50min；MS(ESIpos)：m/z＝140[M+H]⁺。

Example 35A

Benzophenone- (4-methoxypyridin-2-yl) hydrazone

500mg (3.48mmol) 2-chloro-4-methoxypyridine, 752mg (3.83mmol) benzophenone hydrazone, 469mg (4.88mmol) sodium tert-butoxide, 15.6mg (0.07mmol) palladium (II) acetate, 21.2mg (0.17mmol) phenylboronic acid and 43.4mg (0.07mmol) racemic 2, 2 '-bis (diphenylphosphino) -1, 1' -binaphthyl are heated in degassed toluene at 90 ℃ overnight under argon. After cooling, the reaction mixture was poured into water, the aqueous phase was extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is purified by means of preparative HPLC (RP18 column, flow agent: acetonitrile/water gradient).

Yield: 872mg (83% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝10.8(s，1H)，8.07(d，1H)，7.70-7.64(m，5H)，7.50-7.38(m，5H)，6.94(d，1H)，6.78(dd，1H)，3.92(s，3H)。

LC-MS (method 3): r_t＝1.70min；MS(ESIpos)：m/z＝304[M+H]⁺。

Example 36A

2-hydrazino-4-methoxypyridine

850mg (2.80mmol) of the compound from example 35A are heated in concentrated hydrochloric acid at 65 ℃ overnight. After cooling, the reaction mixture was washed with dichloromethane and concentrated. 470mg of the crude product are obtained as hydrochloride. 250mg of polymer-bound tris (2-aminoethyl) amine were stirred in dichloromethane at room temperature overnight. It was filtered, the filtrate was concentrated and dried under high vacuum.

Yield: 170mg (39% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝7.78(d，1H)，7.26(s，1H)，6.25(d，1H)，6.15(dd，1H)，4.09(s，2H)，3.73(s，3H)。

LC-MS (method 1): r_t＝0.89min；MS(ESIpos)：m/z＝140[M+H]⁺。

Example 37A

3- (chloromethyl) -2-methylpyridine

1.00g (8.12mmol) of 3- (hydroxymethyl) -2-methylpyridine are placed in advance and 5.9ml (81.2mmol) of thionyl chloride are slowly added thereto at 0 ℃. The batch was heated under reflux conditions for 3 hours. It was concentrated, the residue and saturated sodium bicarbonate solution were mixed and extracted several times with diethyl ether. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated.

Yield: 0.98g (85% of theory)

GC-MS (method 7): r_t＝4.85min；MS(EIpos)：m/z＝141[M]⁺。

Example 38A

(2-methylpyridin-3-yl) acetonitrile

970mg (6.85mmol) of the compound from example 37A are initially taken in 10ml of DMF, admixed with 336mg (6.85mmol) of sodium cyanide and the batch is stirred at 45 ℃ overnight. The reaction mixture was added to 75ml of a saturated ammonium chloride solution and extracted several times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (flow agent: dichloromethane/methanol 20: 1).

Yield: 795mg (88% of theory)

GC-MS (method 7): r_t＝6.14min；MS(EIpos)：m/z＝132[M]⁺。

Example 39A

(2-methylpyridin-3-yl) acetic acid ethyl ester

790mg (5.98mmol) of the compound from example 38A are initially taken in 10ml of ethanol, slowly mixed with 4ml of concentrated sulfuric acid and heated under reflux for 6 hours. After cooling, it was neutralized with 6.00g of sodium bicarbonate and a saturated sodium bicarbonate solution. The aqueous phase was extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was reacted without further purification.

Yield: 614mg (57% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.34(dd，1H)，7.57(dd，1H)，7.18(dd，1H)，4.10(q，2H)，3.73(s，2H)，2.40(s，3H)，1.18(t，3H)。

LC-MS (method 1): r_t＝1.84 min；MS(ESIpos)：m/z＝180[M+H]⁺。

Example 40A

(6-Trifluoromethylpyridin-3-yl) acetic acid ethyl ester

4.23g (20.6mmol) of (6-trifluoromethylpyridin-3-yl) acetic acid [ obtainable from [6- (trifluoromethyl) -pyridin-3-yl ] methanol in analogy to the reaction sequence of examples 37A, 38A and 41 ] were placed in 200ml of ethanol in advance under argon, mixed with 0.2ml of concentrated sulfuric acid and heated under reflux for 5 hours. After cooling, the reaction solution was concentrated, and the residue was introduced into ethyl acetate and washed with a saturated sodium bicarbonate solution. The aqueous phase was back-extracted several times with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (flow agent: gradient cyclohexane → cyclohexane/ethyl acetate 1: 1).

Yield: 3.24g (67% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.69(s，1H)，8.02(d，1H)，7.89(d，1H)，4.13(q，2H)，3.91(s，2H)，1.21(t，3H)。

LC-MS (method 3): r_t＝2.12min；MS(ESIpos)：m/z＝234[M+H]⁺。

Example 41A

3-hydroxy-2- (6-trifluoromethylpyridin-3-yl) acrylic acid ethyl ester

3.46g (14.8mmol) of the compound from example 40A are initially taken in 50ml of anhydrous toluene under argon, mixed in portions with 712mg (17.8mmol) of sodium hydride suspension (60% in paraffin oil) and stirred at room temperature for 1 hour and then at 80 ℃ for 20 minutes. After cooling, 392mg (1.48mmol) of 18-crown-6 were added thereto, and then 2.20g (29.7mmol) of ethyl formate was added dropwise under cooling in an ice bath. First stirred at 0 ℃ for 1 hour, then at room temperature for 1 hour. To this mixture was then added a mixture consisting of 100ml of ethyl acetate and 150ml of 0.1M hydrochloric acid, the phases were separated, the aqueous phase was extracted several times with ethyl acetate, and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography on silica gel (flow agent: cyclohexane/ethyl acetate gradient).

Yield: 3.9g (100% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝11.8(s，1H)，8.70(d，1H)，8.03(s，1H)，8.00(d，1H)，7.87(d，1H)，4.15(q，2H)，1.21(t，3H).

Example 42A

3- (dimethylamino) -2-pyridin-3-yl-acrylic acid ethyl ester

37.4g (226mmol) of ethyl pyridin-3-ylacetate are stirred in 100g (679mmol) of dimethylformamide-diethylacetal at 100 ℃ overnight. After cooling, concentration is carried out and the residue is purified by flash chromatography on silica gel (flow agent: cyclohexane/ethyl acetate 1: 1 → ethyl acetate/ethanol 9: 1 gradient). The product obtained is purified finely by vacuum distillation (1 mbar, bath temperature 200 ℃).

Yield: 35.0g (70% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.37(dd，1H)，8.31(dd，1H)，7.59(s，1H)，7.51(dt，1H)，7.29(ddd，1H)，4.00(q，2H)，2.67(s，6H)，1.11(t，3H)。

LC-MS (method 1): r_t＝2.38min；MS(ESIpos)：m/z＝221[M+H]⁺。

Example 43A

3- (dimethylamino) -2- (2-methylpyridin-3-yl) acrylic acid ethyl ester

600mg (3.35mmol) of the compound from example 39A are heated overnight at 100 ℃ in 1.7ml (10.0mmol) of dimethylformamide diethylacetal. After cooling, it is concentrated and the residue is purified by means of preparative HPLC (RP18 column; flow agent: acetonitrile/water gradient).

Yield: 619mg (79% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝8.30(dd，1H)，7.54(s，1H)，7.38(dd，1H)，7.13(dd，1H)，4.05-3.92(m，2H)，2.62(s，6H)，2.30(s，3H)，1.08(t，3H)。

LC-MS (method 1): r_t＝2.19min；MS(ESIpos)：m/z＝235 [M+H]⁺。

Examples

Example 1

4-pyridin-3-yl-2-pyrimidin-2-yl-1, 2-dihydro-3H-pyrazolin-3-one

193mg (1mmol) of the compound from example 2A and 116mg (1.05mmol) of 2-hydrazinopyrimidine are introduced into 2ml of absolute ethanol under argon and the batch is stirred at room temperature for 20 hours. Then, 40mg (1mmol) of sodium hydride suspension (in paraffin oil, 60%) were added thereto in portions, wherein a significant turbidity of the reaction solution was generated. Stirring was continued at room temperature for 10 minutes. The black reaction mixture was then mixed with 1ml of 1M hydrochloric acid, thereby producing a precipitate. The product was aspirated, the residue washed with water (2X 1ml) and dried in vacuo. 173mg (72% of theory) of the target compound are obtained.

¹H-NMR(300MHz，DMSO-d₆)：δ＝12.8(br.s，1H)，9.04(d，1H)，8.92(d，2H)，8.38(m，2H)，8.19(d，1H)，7.50(dd，1H)，7.42(dd，1H)。

LC-MS (method 5): r_t＝0.59min；MS(ESIpos)：m/z＝240[M+H]⁺。

Example 2

2- (4-methylpyridin-2-yl) -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

1.53g (7.90mmol) of the compound from example 2A and 2.92g (23.7mmol) of the compound from example 1A are dissolved in 2ml of absolute ethanol under argon and the batch is stirred at room temperature for 16 hours. 537mg (7.90mmol) of sodium ethoxide was added thereto, and the reaction solution became dark red. Stirring was continued for 30 minutes at room temperature and then mixed with 7.9ml of 1M hydrochloric acid. The solution was partially concentrated, wherein a precipitate was generated. The precipitate was filtered, washed with water (5ml each, twice) and MTBE (5ml), and dried in vacuo. 435mg (22% of theory) of the target compound are obtained.

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.06(d，1H)，8.35(m，3H)，8.20(d，1H)，8.08(s，1H)，7.37(dd，1H)，7.21(d，1H)，2.45(s，3H)。

LC-MS (method 5): r_t＝1.42min；MS(ESIpos)：m/z＝253[M+H]⁺。

Example 3

4-pyridin-3-yl-2- [5- (trifluoromethyl) pyridin-2-yl ] -1, 2-dihydro-3H-pyrazolin-3-one

The above compound is prepared in analogy to example 2 from 580mg (3.00mmol) of the compound from example 2A and 558mg (3.00mmol) of 2-hydrazino-5- (trifluoromethyl) pyridine.

Yield: 55mg (6% of theory)

HPLC (method 6): r_t＝3.7min。

MS(ESIpos)：m/z＝307[M+H]⁺

¹H-NMR (ethanol adduct) (300MHz, DMSO-d)₆)：δ＝13.3(s，1H)，9.14(d，1H)，8.86(d，1H)，8.66(d，1H)，8.60(s，1H)，8.31-8.41(m，3H)，7.40(dd，1H)，4.36(s，1H)，3.45(q，2H)，1.05t，3H)。

Example 4

2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) isonicotinic acid tert-butyl ester

The above compound is prepared in analogy to example 2 from 500mg (2.59mmol) of the compound from example 2A and 662mg (2.85mmol) of 2-hydrazino-isonicotinic acid tert-butyl ester. 288mg (33% of theory) of the title compound are obtained as a yellow solid.

¹H-NMR(300MHz，CDCl₃)：δ＝12.7 (br.s，1H)，8.97(d，1H)，8.47-8.41(m，3H)，8.03(dt，1H)，7.91(s，1H)，7.76(dd，1H)，7.32(dd，1H)，1.64(s，9H)。

LC-MS (method 5): r_t＝1.75min；MS(ESIpos)：m/z＝339[M+H]⁺。

Example 5

4-pyridin-3-yl-2- [4- (trifluoromethyl) pyridin-2-yl ] -1, 2-dihydro-3H-pyrazolin-3-one

The above compound was prepared in analogy to example 2, from 18mg (0.09mmol) of the compound from example 2A and 18mg (0.10mmol) of 2-hydrazino-4- (trifluoromethyl) pyridine [ R.A.Evans, C.Wentrup, J.chem.Soc.chem.Commun.15, 1062-1064(1992) ]. 11.7mg (41% of theory) of the title compound are obtained as a yellow solid.

¹H-NMR(400MHz，CDCl₃)：δ＝12.6(br.s，1H)，8.97(s，1H)，8.53(d，1H)，8.46(d，1H)，8.25(s，1H)，8.01(d，1H)，7.92(s，1H)，7.45(d，1H)，7.32(dd，1H)。

LC-MS (method 5): r_t＝1.50min；MS(ESIpos)：m/z＝307[M+H]⁺。

Example 6

2-pyridin-2-yl-4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

3.95g (13.9mmol) of the compound from example 3A are initially taken under argon into 80ml of absolute ethanol and admixed portionwise at room temperature with 945mg (13.9mmol) of sodium ethoxide. After stirring for 30 minutes, 13.9ml of 1M hydrochloric acid was added dropwise thereto. The resulting precipitate was filtered off with suction, washed with cold ethanol (20ml) and water (20ml each, twice) and dried in vacuo. 2.80g (85% of theory) of the title compound are obtained.

¹H-NMR(400MHz，CDCl₃)：δ＝13.5(br.s，1H)，8.97(d，1H)，8.44(dd， 1H)，8.34((d，1H)，8.05-7.91(m，3H)，7.87(s，1H)，7.31(dd，1H)，7.25(m，1H)。

HPLC (method 6): r_t＝3.00min。

MS(DCI)：m/z＝239[M+H]⁺。

Example 7

4- (6-chloropyridin-3-yl) -2-pyridin-2-yl-1, 2-dihydro-3H-pyrazolin-3-one

5.06g (19.9mmol) of the compound from example 16A and 4.34g (39.7mmol) of 2-hydrazinopyridine are stirred in 100ml of glacial acetic acid for 2 hours at room temperature. The batch is concentrated, the residue is taken up in 300ml of ethyl acetate and washed twice with saturated sodium bicarbonate solution (100 ml each). The organic phase was dried over sodium sulfate, filtered and concentrated. The residue obtained is taken up in 100ml of ethanol, 1.49g (21.9mmol) of sodium ethoxide are added in portions with ice-bath cooling, and the batch is stirred for a further 30 minutes at 0 ℃. The reaction solution and 22ml of 1M hydrochloric acid were mixed at 0 ℃ and stirring was continued at this temperature for 30 minutes. The precipitate obtained is filtered off with suction and washed with cold ethanol. Drying in vacuo gave 3.18g (59% of theory) of the title compound.

¹H-NMR(300MHz，DMSO-d₆)：δ＝8.93(s，1H)，8.50(d，2H)，8.34(d，2H)，8.05(dd，1H)，7.51(d，1H)，7.36(dd，1H)。

LC-MS (method 3): r_t＝2.27min；MS(ESIpos)：m/z＝273[M+H]⁺。

In analogy to example 7, the examples listed in table 6 were prepared from the corresponding feeds:

TABLE 6

Example 11

5- [2- (4-methylpyridin-2-yl) -3-oxo-2, 3-dihydro-1H-pyrazol-4-yl ] pyridine-2-carbonitrile

100mg (0.35mmol) of the compound from example 8, 81.9mg (0.70mmol) of zinc cyanide and 40.3mg (0.03mmol) of tetrakis (triphenylphosphine) palladium (0) are initially taken in 4ml of anhydrous DMF under argon and the reaction mixture is stirred for 90 minutes at 190 ℃ under microwave irradiation (single mode instrument probe from CEM (Explorer)). The reaction mixture was filtered with suction through silica gel, the residue was washed further with DMF, and the filtrate was concentrated in a rotary evaporator. The residue thus obtained was subjected to preparative HPLC chromatography (column: YMC GEL ODS-AQ S-5/15 μm; gradient: acetonitrile/water + 0.2% TFA 10: 90 → 95: 5). The solid obtained from the combined product fractions was washed with 6ml of dichloromethane, filtered off with suction and dried in vacuo.

Yield: 7mg (7% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.23(d，1H)，8.55(s，1H)，8.43(dd，1H)，8.35(d，1H)，8.15(s，1H)，7.94(d，1H)，7.25(d，1H)，2.47(s，3H)。

LC-MS (method 3): r_t＝2.01min；MS(ESIpos)：m/z＝278 [M+H]⁺。

Example 12

5- (3-oxo-2-pyridin-2-yl-2, 3-dihydro-1H-pyrazol-4-yl) pyridine-2-carbonitrile

Preparation is carried out in analogy to example 11 from 100mg (0.37mmol) of the compound from example 7.

Yield: 12mg (12% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.27(s，1H)，8.66(s，1H)，8.50(m，2H)，8.35(d，1H)，8.08(dd，1H)，7.97(d，1H)，7.38(dd，1H)。

LC-MS (method 3): r_t＝1.70min；MS(ESIpos)：m/z＝264[M+H]⁺。

Example 13

4- (5-bromopyridin-3-yl) -2-pyridin-2-yl-1, 2-dihydro-3H-pyrazolin-3-one

The synthesis of the title compound was carried out in analogy to example 7 from 1.40g (3.50mmol) of the compound from example 17A.

Yield: 345mg (31% of theory)

LC-MS (method 5): r_t＝2.24min；MS(ESIpos)：m/z＝319[M+H]⁺。

Example 14

5- (3-Oxo-2-pyridin-2-yl-2, 3-dihydro-1H-pyrazol-4-yl) nicotinonitrile (5- (3-Oxo-2-pyridine-2-y 1-2, 3-dihydro-1H-pyrazole-4-y 1) nicotinonitril)

Preparation is carried out in analogy to example 11 from 50mg (0.16mmol) of the compound from example 13.

Yield: 20mg (48% of theory)

¹H-NMR(300MHz，DMSO-d₆)：δ＝9.40(d，1H)，8.76(d，1H)，8.72(m，1H)，8.61(s，1H)，8.51(d，1H)，8.36(d，1H)，8.07(dd，1H)，7.37(dd，1H)。

LC-MS (method 3): r_t＝1.65min；MS(ESIpos)：m/z＝264[M+H]⁺。

Example 15

5-methyl-2-pyridin-2-yl-4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

To a solution of 58mg (0.28mmol) of the compound from example 18A and 34mg (0.31mmol) of 2-hydrazinopyridine in 0.4ml of absolute ethanol was added 22. mu.l of glacial acetic acid and the mixture was stirred at room temperature overnight. This was mixed with 19mg of sodium ethoxide, stirred at room temperature for a further 30 minutes and then neutralized with 1N hydrochloric acid. After addition of water, extraction with dichloromethane was carried out, the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was stirred in diisopropyl ether and the solid was filtered off with suction. After drying, 13.5mg (19% of theory) of the title compound are obtained.

¹H-NMR(400MHz，CDCl₃)：δ＝13.28(br.s，1H)，8.83(s，1H)，8.47(d，1H)，8.30(d，1H)，7.957，86(m，3H)，7.33(dd，1H)，7.18(t，1H)，2.44(s，3H)。

LC-MS (method 1): r_t＝2.11min；MS(ESIpos)：m/z＝253[M+H]⁺。

Example 16

4- (6-hydroxypyridin-3-yl) -2-pyridin-2-yl-1, 2-dihydro-3H-pyrazolin-3-one

50.0mg (0.18mmol) of the compound from example 7 and 600mg (7.74mmol) of ammonium acetate as a suspension in 3ml of glacial acetic acid are heated at 180 ℃ for 2 hours in a monomodal microwave (probe from CEM). After completion of the reaction as detected by analytical HPLC, toluene was added and the volatile components were distilled off azeotropically. The residue was introduced into water and the remaining solid was filtered off. The light brown powder was then washed with water followed by MTBE. After drying, 39mg (84% of theory) of the title compound are obtained.

¹H-NMR(300MHz，DMSO-d₆)：δ＝12.7(br.s，1H)，11.58(br.s，1H)，8.47(d，1H)，8.32(m，1H)，8.21(s，1H)，8.01(m，2H)，7.87(dd，1H)，7.32(dd，1H)，6.39(d，1H)。

LC-MS (method 3): r_t＝1.31min；MS(ESIpos)：m/z＝255[M+H]⁺。

Analogously to example 7, the examples listed in Table 7 were prepared from the corresponding feedstocks

TABLE 7

[^*The crude product was purified by preparative HPLC (column: YMC Gel ODS-AQ S-5/15 μm; gradient: acetonitrile/water + 0.2% trifluoroacetic acid 10: 90 → 95: 5)]。

Example 21

4- [6- (hydroxymethyl) pyridin-3-yl ] -2-pyridin-2-yl-1, 2-dihydro-3H-pyrazolin-3-one

73mg (1.93mmol) of sodium borohydride are initially taken in 20ml of ethanol and 115mg (1.03mmol) of calcium chloride are added at 0 ℃. The compound from example 20(400mg, 1.29mmol) was added portionwise thereto and the batch was stirred at 0 ℃ for 1 hour and then at room temperature for 4 hours. To allow the reaction to proceed to completion, 73mg (1.93mmol) of sodium borohydride was supplemented, and the batch was stirred at room temperature for 20 hours. Hydrolysis was carried out with the aid of 5ml of water and slight acidification with 1N hydrochloric acid. Then, the mixture was stirred at room temperature for 1 hour. It was concentrated and the residue introduced into approximately 16ml of a DMSO/water mixture (1: 1) and purified batchwise by preparative HPLC (column: YMC Gel ODS-AQ S-5/15 μm; gradient: acetonitrile/water + 0.2% trifluoroacetic acid 10: 90 → 95: 5).

Yield: 332mg (96% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.19(s，1H)，8.71(d，1H)，8.64(s，1H)，8.51(d，1H)，8.37(d，1H)，8.09(dd，1H)，7.81(d，1H)，7.38(dd，1H)，4.77(s，2H)。

LC-MS (method 3): r_t＝0.65 min；MS(ESIpos)：m/z＝269[M+H]⁺。

Example 22

2-pyridin-2-yl-4- (6-trifluoromethylpyridin-3-yl) -1, 2-dihydro-3H-pyrazolin-3-one

261mg (1.00mmol) of the compound from example 41A and 115mg (1.05mmol) of 2-hydrazinopyridine are dissolved in 5ml of absolute ethanol under argon and the batch is stirred at room temperature for 20 hours. To this was added 68mg (1.00mmol) of sodium ethoxide, stirred at room temperature for 30 minutes, and then 1ml of 1M hydrochloric acid and a little ethanol were added, whereby a precipitate was precipitated. The precipitate was filtered off, washed with a little ethanol and dried in vacuo.

Yield: 180mg (59% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.26(s，1H)，8.63(s，1H)，8.55(d，1H)，8.51(d，1H)，8.35(d，1H)，8.05(t，1H)，7.87(d，1H)，7.37(dd，1H)。

LC-MS (method 4): r_t＝2.15min；MS(ESIpos)：m/z＝307[M+H]⁺。

Example 23

2- (5-hydroxymethyl-pyridin-2-yl) -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one-hydrochloride

4.00g (18.2mmol) of the compound from example 42A, 2.70g (19.4mmol) of the compound from example 34A and 450mg (1.94mmol) of camphor-10-sulfonic acid are dissolved in 120ml of absolute ethanol and the batch is heated under reflux overnight. After cooling, the precipitate formed is filtered off with suction, washed with ethanol and diethyl ether, suspended in methanol and reacted with excess 4N hydrogen chloride in the presence of 1, 4-bisThe solution in the alkane was mixed and re-concentrated. The residue is stirred into a mixture consisting of methanol and dichloromethane, filtered off with suction and dried.

Yield: 3.23g (66% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.36(s，1H)，8.91(d，1H)，8.72(s，1H)，8.61(d，1H)，8.45-8.43(m，1H)，8.36(d，1H)，8.04(dd，1H)，7.98(dd，1H)，4.58(s，2H)。

LC-MS (method 1): r_t＝2.12min；MS(ESIpos)：m/z＝269 [M+H]⁺。

The compounds listed in table 8 were prepared from the corresponding feeds in analogy to example 23. Purification of the various precipitates can alternatively be carried out by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with or without addition of 0.1% strength hydrochloric acid).

TABLE 8

[^*Ethyl 6-hydrazinonicotinate can be obtained in analogy to example 42, by esterification of 6-hydrazinonicotinic acid in ethanol]。

Example 29

2- (4-cyanopyridin-2-yl) -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

545mg (4.06mmol) of the compound from example 33A and 1.07g (4.88mmol) of the compound from example 42A are stirred in 15ml of glacial acetic acid for 2 hours at room temperature. The batch is concentrated, the residue is taken up in 300ml of ethyl acetate and washed several times with saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The residue is taken up in 30ml of ethanol, mixed at room temperature with 1.33g (4.88mmol) of a 25% solution of sodium ethoxide in ethanol and stirred for 30 minutes. The pH was adjusted to 5 by addition of 1M hydrochloric acid, the resulting solid was filtered off with suction and washed with diethyl ether and dried under high vacuum.

Yield: 890mg (83% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.01-8.98(m，2H)，8.54(dd，1H)，8.18(dt，1H)，8.01(dd，1H)，7.85(s，1H)，7.39(dd，1H)，7.14(dd，1H)。

LC-MS (method 5): r_t＝1.13min；MS(ESIpos)：m/z＝264[M+H]⁺。

Example 30

2- (5-Chloropyridin-2-yl) -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

250mg (1.74mmol) of the compound from example 30A and 460mg (2.09mmol) of the compound from example 42A are stirred in 4ml of glacial acetic acid for 0.5 h at room temperature. The batch is concentrated, the residue is taken up in ethyl acetate and washed several times with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was taken up in 9ml of ethanol, mixed at room temperature with 664mg (2.44mmol) of a 25% solution of sodium ethoxide in ethanol and stirred for 1 hour. The pH was adjusted to 5 by addition of 1M hydrochloric acid, stirred overnight at room temperature, the resulting solid was filtered off with suction, washed with water and dried under high vacuum.

Yield: 239mg (50% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.04(d，1H)，8.51(d，1H)，8.39(d，1H)，8.22(dt，1H)，8.10(dd，1H)，8.00(s，1H)，7.92(dd，1H)，7.20(dd，1H)。

LC-MS (method 5): r_t＝1.33min；MS(ESIpos)：m/z＝273[M+H]⁺。

Example 31

2- (5-iodopyridin-2-yl) -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

The synthesis of the title compound is carried out in analogy to example 30 from 250mg (1.06mmol) of the compound from example 32A and 281mg (1.28mmol) of the compound from example 42A.

Yield: 80mg (21% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.12(s，1H)，8.70(s，1H)，8.54-8.46(m，1H)，8.40-8.25(m，4H)，7.43-7.36(m，1H)。

LC-MS (method 3): r_t＝1.44min；MS(ESIpos)：m/z＝365[M+H]⁺。

Example 32

2- (5-bromopyridin-2-yl) -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

The synthesis of the title compound was carried out in analogy to example 30, from 250mg (1.33mmol) of the compound from example 31A and 351mg (1.60mmol) of the compound from example 42A.

Yield: 166mg (39% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.06(d，1H)，8.50(d，1H)，8.46(s，1H)，8.24(d，1H)，8.16(d，1H)，8.13(s，1H)，8.08(dd，1H)，7.24(dd，1H)。

LC-MS (method 5): r_t＝1.40min；MS(ESIpos)：m/z＝318[M+H]⁺。

Example 33

2- (5-bromo-4-methylpyridin-2-yl) -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one

300mg (1.49mmol) of the compound from example 29A and 392mg (1.78mmol) of the compound from example 42A are stirred in 7ml of glacial acetic acid for 36 hours at room temperature. The batch is concentrated, the residue is taken up in ethyl acetate and washed several times with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was taken up in 13ml of ethanol, mixed at room temperature with 566mg (2.08mmol) of a 25% solution of sodium ethoxide in ethanol and stirred for 1 hour. The pH is adjusted to 5 by addition of 1M hydrochloric acid, concentrated and the residue is purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with addition of 0.1% strength hydrochloric acid).

Yield: 55mg (11% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.41(s，1H)，8.99(d，1H)，8.86(s，1H)，8.67(d，1H)，8.60(s，1H)，8.45(s，1H)，8.03(dd，1H)，2.47(s，3H)。

LC-MS (method 3): r_t＝1.53min；MS(ESIpos)：m/z＝331[M+H]⁺。

Example 34

4- (6-cyanopyridin-3-yl) -2- (4-methylpyridin-2-yl) -1, 2-dihydro-3H-pyrazolin-3-one-hydrochloride

50mg (136. mu. mol) of the compound from example 24 were dissolved in 0.6ml of 1-methyl-2-pyrrolidone, 31.9mg (272. mu. mol) of zinc cyanide and 15.7mg (14. mu. mol) of tetrakis (triphenylphosphine) palladium (0) were mixed therein, and heated in a microwave at 200 ℃ for 30 minutes. The reaction mixture was filtered through silica gel and eluted through methanol. The filtrate is adjusted to a slightly acidic pH by addition of 1M hydrochloric acid, the precipitate is filtered off and purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with addition of 0.1% strength hydrochloric acid).

Yield: 13mg (31% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.25(s，1H)，8.57(s，1H)，8.44(d，1H)，8.36(d，1H)，8.15(s，1H)，7.95(d，1H)，7.25(d，1H)，2.47(s，3H)。

LC-MS (method 4): r_t＝2.20min；MS(ESIpos)：m/z＝278[M+H]⁺。

Example 35

2- [4- (aminomethyl) pyridin-2-yl ] -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one-dihydrochloride

100mg (380. mu. mol) of the compound from example 29 were dissolved in 10ml of acetic acid, and 50.0mg of a catalyst (10% palladium on carbon) was mixed thereto and stirred under a hydrogen atmosphere at normal pressure and room temperature overnight. The reaction mixture is then filtered, concentrated and the residue is purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient, addition of 0.1% strength hydrochloric acid).

Yield: 64mg (49% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.38(s，1H)，8.93(d，1H)，8.79(s，1H)，8.75(s，3H)，8.64(d，1H)，8.56(d，1H)，8.48(s，1H)，7.99(dd，1H)，7.54(d，1H)，4.21(q，2H)。

LC-MS (method 1): r_t＝1.39min；MS(ESIpos)：m/z＝268[M+H]⁺。

Example 36

N- { [2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) pyridin-4-yl ] methyl } butanamide-hydrochloride

80.0mg (235. mu. mol) of the compound from example 35 and 22.8mg (259. mu. mol) of butyric acid are dissolved in 5ml of DMF and combined with 119mg (1.18mmol) of triethylamine and 90.2mg (470. mu. mol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloride with cooling in an ice bath and stirred at room temperature overnight. The reaction mixture is then purified directly by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient, with addition of 0.1% strength hydrochloric acid).

Yield: 7mg (7% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.33-9.31(m，1H)，8.87(d，1H)，8.66(s，1H)，8.61-8.56(m，2H)，8.43(d，1H)，8.25(s，1H)，7.96(dd，1H)，7.26(d，1H)，4.41(d，1H)，2.19(t，2H)，1.58(sext，2H)，0.90(t，3H)。

LC-MS (method 1): r_t＝2.26min；MS(ESIpos)：m/z＝338[M+H]⁺。

Example 37

N-isopropyl-N' - { [2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) pyridin-4-yl ] methyl } urea-hydrochloride

40.0mg (470. mu. mol) of isopropyl isocyanate were dissolved in 5ml of DMF under argon, mixed with 80.0mg (235. mu. mol) of the compound from example 35 and 71.4mg (705. mu. mol) of triethylamine and stirred at room temperature overnight. It is then concentrated and the residue is purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with addition of 0.1% strength hydrochloric acid).

Yield: 80mg (85% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.35(s，1H)，8.95(d，1H)，8.66(s，1H)，8.59(d，1H)，8.42(d，1H)，8.24(s，1H)，8.02(dd，1H)，7.27(d，1H)，6.55(s，1H)，4.35(s，2H)，3.76-3.63(m，1H)，2.75(s，1H)，1.08-1.03(m，6H)。

LC-MS (method 1): r_t＝2.81min；MS(ESIpos)：m/z＝353[M+H]⁺。

Example 38

N- { [2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) pyridin-4-yl ] methyl } methanesulfonamide-hydrochloride

80.0mg (235. mu. mol) of the compound from example 35 and 53.9mg (470. mu. mol) of methanesulfonyl chloride are dissolved in 5ml of DMF under cooling with argon and an ice bath, mixed with 152mg (1.18mmol) of N, N-diisopropylethylamine and stirred at room temperature overnight. The reaction mixture is then purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient, with addition of 0.1% strength hydrochloric acid).

Yield: 31mg (34% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.34(s，1H)，8.88(d，1H)，8.69(s，1H)，8.59(d，1H)，8.47(d，1H)，8.40(s，1H)，7.95(dd，1H)，7.89(t，1H)，7.36(d，1H)，4.36(d，2H)，2.99(s，3H)。

LC-MS (method 1): r_t＝2.35min；MS(ESIpos)：m/z＝346[M+H]⁺。

Example 39

6- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) nicotinic acid

1.49g (4.81mmol) of the compound from example 25 are dissolved in 60ml of 4-bisAlkane, to which 40ml of 1M lithium hydroxide solution was mixed, and heated under reflux for 1 hour. The reaction mixture was then cooled to 0 ℃, adjusted to a weakly acidic pH with 40ml of 1M hydrochloric acid and stirred at 0 ℃ for 2 hours. The resulting precipitate was filtered off with suction, washed with water and diethyl ether and dried under high vacuum.

Yield: 1.20g (88% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.40(s，1H)，9.00-8.94(m，2H)，8.90(s，1H)，8.66(d，1H)，8.60-8.54(m，1H)，8.49(dd，1H)，8.02(dd，1H)。

LC-MS (method 3): r_t＝0.63 min；MS(ESIpos)：m/z＝283[M+H]⁺。

Example 40

N-benzyl-6- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) nicotinamide-hydrochloride

50mg (177. mu. mol) of the compound from example 39 are dissolved in 2ml of DMF, to which are admixed 1.9mg (16. mu. mol) of 4-N, N-dimethylaminopyridine, 71.0mg (549. mu. mol) of N, N-diisopropylethylamine and 98.0mg (188. mu. mol) of (benzotriazol-1-yloxy) -tripyrrolidineHexafluorophosphate salt, and stirred at room temperature for 15 minutes. To this was added 25.2mg (235. mu. mol) of benzylamine, and stirring was continued at room temperature for 5 hours. To allow the reaction to complete, an additional 25mg (235. mu. mol) of benzylamine was added and stirred at room temperature overnight. The reaction mixture is purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with addition of 0.1% strength hydrochloric acid), followed by flash chromatography on silica gel (flow agent: dichloromethane/methanol gradient) to precipitate the crude product from methanol and the precipitate is purified again by preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with addition of 0.1% strength hydrochloric acid).

Yield: 21mg (30% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.41(s，1H)，9.38-9.33(m，1H)，9.01(s，1H)，8.95(d，1H)，8.87(s，1H)，8.64(d，1H)，8.56-8.49(m，2H)，7.99(dd， 1H)，7.38-7.32(m，4H)，7.30-7.24(m，1H)，4.53(d，2H)。

LC-MS (method 5): r_t＝1.50min；MS(ESIpos)：m/z＝372[M+H]⁺。

EXAMPLE 41

2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) isonicotinic acid

200mg (760. mu. mol) of the compound from example 29 are suspended in a mixture of 6ml of ethanol and 4ml of water, 0.6ml of 50% aqueous sodium hydroxide solution are admixed and heated under reflux for 1 hour. After cooling, the weakly acidic pH is adjusted with 1M hydrochloric acid and the precipitate is filtered off with suction, washed with water and dried.

Yield: 180mg (84% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.11(d，1H)，8.86(s，1H)，8.62(d，1H)，8.46(s，1H)，8.32(dd，1H)，8.28(dt，1H)，7.69(dd，1H)，7.36(dd，1H)。

LC-MS (method 1): r_t＝2.19min；MS(ESIpos)：m/z＝283[M+H]⁺。

Example 42

2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) isonicotinic acid methyl ester

150mg (531. mu. mol) of the compound from example 41 were dissolved in 20ml of methanol, 1ml of concentrated sulfuric acid was admixed thereto and stirred under reflux overnight. After cooling, the resulting precipitate was filtered off with suction, washed with methanol and dried.

Yield: 117mg (74% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.41(d，1H)，8.99-8.94(m，2H)，8.86(s，1H)，8.71(d，1H)，8.66(d，1H)，8.01(dd，1H)，7.78(dd，1H)，3.96(s，3H)。

LC-MS (method 4): r_t＝1.03min；MS(ESIpos)：m/z＝297[M+H]⁺。

Example 43

2- [4- (hydroxymethyl) pyridin-2-yl ] -4-pyridin-3-yl-1, 2-dihydro-3H-pyrazolin-3-one-hydrochloride

197mg (1.77mmol) of calcium chloride and 319mg (8.44mmol) of sodium borohydride are initially taken in 26ml of ethanol, 50mg (169. mu. mol) of the compound from example 42 are admixed in portions at 0 ℃ and stirred at room temperature overnight. The reaction mixture is brought to a weakly acidic pH by addition of 1M hydrochloric acid, concentrated and the residue is purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with addition of 0.1% strength hydrochloric acid).

Yield: 32mg (63% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.34(s，1H)，8.93(d，1H)，8.66(s，1H)，8.58(d，1H)，8.42(d，1H)，8.36(s，m)，8.00(dd，1H)，7.34(d，1H)，4.68(s，2H)。

LC-MS (method 1): r_t＝2.14min；MS(ESIpos)：m/z＝269[M+H]⁺。

Example 44

5- (3-oxo-2-pyridin-2-yl-2, 3-dihydro-1H-pyrazol-4-yl) nicotinic acid

100mg (380. mu. mol) of the compound from example 14 are suspended in a mixture of 3ml of ethanol and 2ml of water, 0.3ml of 50% aqueous sodium hydroxide solution are admixed and heated under reflux for 2 hours. After cooling, the precipitate is filtered off with suction, washed with diethyl ether and dried.

Yield: 50mg (47% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.04(d，1H)，8.47-8.42(m，2H)，8.36-8.33(m，2H)，7.75-7.70(m，1H)，7.68(s，1H)，7.01-6.97(m，1H)。

LC-MS (method 5): r_t＝1.28min；MS(ESIpos)：m/z＝283[M+H]⁺。

Example 45

N-methyl-5- (3-oxo-2-pyridin-2-yl-2, 3-dihydro-1H-pyrazol-1-yl) nicotinamide

45.0mg (159. mu. mol) of the compound from example 44 are dissolved in 1ml of DMF, to which are admixed 1.9mg (16. mu. mol) of 4-N, N-dimethylaminopyridine, 24.7mg (191. mu. mol) of N, N-diisopropylethylamine and 100mg (191. mu. mol) (benzotriazol-1-yloxy) -tripyrrolidineHexafluorophosphate salt and stirred at room temperature for 15 minutes. To this was added 120. mu.l (239. mu. mol) of methylamineA 2M solution in THF and stirred at rt overnight. To allow the reaction to complete, a further 120 μ l (239 μmol) of a 2M solution of methylamine in THF was added and stirring continued overnight at room temperature. The reaction mixture was purified directly by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient).

Yield: 23mg (49% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.18(s，1H)，8.74(d，1H)，8.64-8.57(m，2H)，8.53-8.44(m，2H)，8.40-8.25(m，1H)，8.09-8.03(m，1H)，7.40-7.34(m，1H)，2.83(d，3H)。

LC-MS (method 3): r_t＝1.21min；MS(ESIpos)：m/z＝296[M+H]⁺。

Example 46

N- { [2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) pyridin-4-yl ] methyl } -2-phenylacetamide hydrochloride

80.0mg (235. mu. mol) of the compound from example 35 and 35.2mg (259. mu. mol) of phenylacetic acid are dissolved in 5ml of DMF, to which 119mg (1.18mmol) of triethylamine, 90.2mg (470. mu. mol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide-hydrochloride and 127mg (941. mu. mol) of 1-hydroxy-1H-benzotriazole hydrate are admixed under cooling in an ice bath and stirred at room temperature overnight. The precipitate is filtered off and the filtrate is purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient, with addition of 0.1% strength hydrochloric acid).

Yield: 58mg (57% of theory)

¹H-NMR(400 MHz，DMSO-d₆)：δ＝9.38(d，1H)，8.97(dt，1H)，8.88(t，1H)，8.72(s，1H)，8.62(d，1H)，8.41(d，1H)，8.29(s，1H)，8.04(dd，1H)，7.36-7.29(m，4H)，7.26-7.21(m，2H)，4.42(d，2H)，3.56(s，2H)。

LC-MS (method 3): r_t＝1.30min；MS(ESIpos)：m/z＝386[M+H]⁺。

Example 47

N- { [2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) pyridin-4-yl ] methyl } acetamide-hydrochloride

80.0mg (235. mu. mol) of the compound from example 35 was dissolved in 5ml of DMF, and 71.4mg (705. mu. mol) of triethylamine and 20.3mg (259. mu. mol) of acetyl chloride were mixed thereto under cooling in an ice bath and stirred at room temperature overnight. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; flow agent: acetonitrile/water gradient with addition of 0.1% strength hydrochloric acid).

Yield: 33mg (41% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.37(s，1H)，8.97(d，1H)，8.71(s，1H)，8.68(t，1H)，8.61(d，1H)，8.43(d，1H)，8.26(s，1H)，8.03(dd，1H)，7.28(d，1H)，4.40(d，2H)，1.95(s，3H)。

LC-MS (method 1): r_t＝2.09min；MS(ESIpos)：m/z＝310[M+H]⁺。

Example 48

N- { [2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) pyridin-4-yl ] methyl } benzamide-hydrochloride

60.0mg (176. mu. mol) of the compound from example 35 were dissolved in 4ml of DMF, and 53.5mg (529. mu. mol) of triethylamine and 27.3mg (194. mu. mol) of benzoyl chloride were mixed thereto under cooling in an ice bath and stirred at room temperature overnight. The reaction mixture is purified directly by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient, with addition of 0.1% strength hydrochloric acid).

Yield: 36mg (50% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.35-9.29(m，2H)，8.91(d，1H)，8.68(s，1H)，8.59(d，1H)，8.44(d，1H)，8.34(s，1H)，8.01-7.92(m，3H)，7.62-7.48(m，3H)，7.35(d，1H)，4.62(d，2H)。

LC-MS (method 4): r_t＝1.07min；MS(ESIpos)：m/z＝372[M+H]⁺。

Example 49

N-benzyl-2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) isonicotinamide

60.0mg (213. mu. mol) of the compound from example 41 are dissolved in 24ml of DMF, to which are admixed 2.6mg (21. mu. mol) of 4-N, N-dimethylaminopyridine, 65.9mg (510. mu. mol) of N, N-diisopropylethylamine and 265mg (510. mu. mol) (benzotriazol-1-yloxy) -tripyrrolidineHexafluorophosphate salt and stirring at room temperature for 45 minutes. To this was added 68.3mg (638. mu. mol) of benzylamine and stirred at room temperature overnight. To allow the reaction to complete, 65.9mg (510. mu. mol) of N, N-diisopropylethylamine and 265mg (510. mu. mol) (benzotriazol-1-yloxy) -tripyrrolidine were further addedHexafluorophosphate, stirred at room temperature for 45 minutes, supplemented with a further 68.3mg (638. mu. mol) of benzylamine, then stirred at room temperature overnight. It is concentrated and the residue is purified by means of preparative HPLC (RP 18-column; flow agent: acetonitrile/water gradient with addition of 0.1% strength formic acid).

Yield: 35mg (44% of theory)

¹H-NMR(400MHz，DMSO-d₆)：δ＝9.49(t，1H)，9.26(s，1H)，8.79(s，1H)，8.70-8.62(m，3H)，8.52(d，1H)，7.76-7.70(m，2H)，7.37-7.34(m，4H)，7.31-7.24(m，1H)，4.52(d，2H)。

LC-MS (method 5): r_t＝1.57 min；MS(ESIpos)：m/z＝372[M+H]⁺。

Example 50

3- (4-chloro-1H-pyrazol-1-yl) -N- { [2- (5-oxo-4-pyridin-3-yl-2, 5-dihydro-1H-pyrazol-1-yl) pyridin-4-yl ] methyl } propionamide

17.5mg (100. mu. mol) of 3- (4-chloro-1H-pyrazol-1-yl) propionic acid, 41.7mg (130. mu. mol) of O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate and 20.2mg (200. mu. mol) of triethylamine were dissolved in 0.2ml of DMSO. To this was added 33.9mg (100. mu. mol) of the compound from example 35 in 0.2ml DMSO and the reaction mixture was stirred at room temperature overnight. The resulting precipitate was filtered off and the filtrate was purified by means of HPLC (method 8).

Yield: 5.8mg (14% of theory)

LC-MS (method 8): r_t＝1.20min；MS(ESIpos)：m/z＝424[M+[Eta]]⁺。

The compounds listed in table 9 were prepared in analogy to example 50 from example 35 and the corresponding carboxylic acids:

TABLE 9

[ for example 55: the synthesis of the starting material 3- (4-hydroxy-3, 5-dimethylphenyl) propionic acid is described in J.Med.chem.1995, 38, 695-one 707 ].

B.Evaluation of pharmacological effectiveness

The pharmacological profile of the compounds of the invention may be shown in the following assays:

abbreviations:

DMEM Dulbecco's modified eagle's medium

FCS fetal serum

TMB 3, 3 ', 5, 5' -Tetramethylbenzidine

Tris Tris (hydroxymethyl) aminomethane

1.In vitro assay for determining the activity and selectivity of HIF-prolyl-4-hydroxylase inhibitors Test (experiment)

A) inhibitory Activity of HIF-prolyl hydroxylase

Hydroxylated HIF is specifically linked to the Hippel-Lindau protein-extensin B-extensin C complex (VBC complex). This interaction occurs when HIF is hydroxylated on preserved prolyl residues. This is the basis for biochemical determination of HIF-prolyl hydroxylase activity. The assay was performed as described [ Oehme f., JonghaUS w., Narouz-Ott l., hueter j., Flamme i., anal. biochem.330(1), 74-80(2004) ]:

clean 96-well microtiter plates (Pierce Corp.) coated with NeutrAvidin HBC were incubated with blocker-casein for 30 minutes. The plate was then washed with 200. mu.l each time of wash buffer (50mM Tris, pH7.5, 100mM NaCl, 10% (v/v) blocker-casein, 0.05% (v/v) Tween 20) per well. The peptide biotin-DLDLDLDLEMLAPYIPMDDDFQL (Eurogentec, 4102Seraing, Belgien) was added at a concentration of 400nM to 100. mu.l of wash buffer. This peptide serves as a substrate for prolinamidation hydroxylation and is bound to a microtiter plate. After 60 minutes of incubation, the plates were washed three times with wash buffer, incubated for 30 minutes with 1mM biotin in blocker-casein, and washed three more times with wash buffer.

To perform the prolyl hydroxylase reaction, the plate-bound peptide substrate is incubated with a cell lysate containing prolyl hydroxylase for 1-60 minutes. The reaction was carried out in 100. mu.l of reaction buffer (20mM Tris, pH7.5, 5mM KCl, 1.5mM MgCl)₂1. mu.M-1 mM 2-oxoglutarate, 10. mu.M FeSO₄2mM vitamin C) at room temperature. The reaction mixture additionally contained various concentrations of the prolyl hydroxylase enzyme inhibiting substance to be tested. The test substance is preferably, but not exclusively, used at a concentration of 1nM to 100. mu.M. The reaction was stopped by washing the plate three times with wash buffer.

For quantitative determination of prolyl hydroxylation, fusion proteins containing both thioredoxin from E.coli and VBC-complex were added to 80. mu.l of binding buffer (50mM Tris, pH7.5, 120mM NaCl). After 15 minutes, 10. mu.l of polyclonal anti-thioredoxin antibody from rabbit was added to the binding buffer. After a further 30 minutes, 10. mu.l of a solution of anti-rabbit immunoglobulin conjugated to horseradish (Meerrettich) peroxidase was added to the binding buffer. After incubation for 30 minutes at room temperature, three washes with wash solution are performed to remove unbound VBC complexes and antibodies. To determine the amount of VBC antibody bound, incubation with TMB was performed for 15 minutes. The coloration reaction was completed by adding 100. mu.l of 1M sulfuric acid. The amount of bound VBC complex is determined by measuring the absorbance at 450 nm. Which is proportional to the amount of hydroxylated proline in the peptide substrate.

Alternatively, for detection of prolyl hydroxylation, VBC complex in combination with europium (Perkin Elmer) can be used. In this case, the amount of bound VBC complex is resolved by time (zeitaufgel)st) fluorescence. Further, the compound may be used in the form of [, ]³⁵S]Methionine VBC complex labeling. For this purpose, radiolabeled VBC complexes can be prepared by in vitro transcription translation in reticulocyte lysates.

In these tests, the compounds of the invention have an IC of ≦ 10. mu.M₅₀Values inhibit HIF-prolyl hydroxylase activity. The comparative results are given in table 10:

watch 10

Example numbering	IC50[μM]
		6	0.43
23	0.86
		26	0.76
34	0.18
		35	2.3
43	1.5
		46	0.70
47	2.2
		48	1.9
50	1.9

B) cytological, functional in vitro tests

The quantitative determination of the effectiveness of the compounds of the invention is carried out with the aid of recombinant cell lines. The cells were derived from a human lung cancer cell line (A549, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell line was stably migrated by means of a vector containing a reporter gene of North American firefly (Photinus pyralis) luciferase (hereinafter referred to as luciferase) to control an artificial minimal promoter. The lowest promoter consists ofTwo hypoxia response units of the upstream region of TATA-BOX [ Oehme F., Ellinghaus P., Kolkhof P., Smith T.J., Ramakrisihnan S., Hutter J., Schramm M., Flamme I., biochem. Biophys. Res. Commun.296(2), 343-9(2002)]. The test cell line produces luciferase either under the effect of hypoxia (e.g.incubation for 24 hours in the presence of 1% oxygen) or under the effect of a non-selective dioxygenase inhibitor (e.g.deferoxamide at a concentration of 100. mu.M, cobalt chloride at a concentration of 100. mu.M or diethyl N-oxalylglycinate at a concentration of 1 mM), which may be assisted by a suitable bioluminescent reactant (e.g.Steady-Glo)LuciferaseAssay System, Promega Corporation, Madison, WI 53711, USA) and a suitable luminometer.

Test procedure: the cells were plated in 384 or 1536 well microtiter plates in precisely measured amounts of medium (DMEM, 10% FCS, 2mM glutaminase) the day before testing and contained in cell culture vessels (96% air flow, 5% v/v CO)₂37 ℃ C.). The test shows that the test substance is added to the culture medium in a step-like concentration. In the batch used as a negative control, no test substance was added to the cells. As a positive control for determining the sensitivity of the cells to the inhibitor, deferoxamide is added, for example, at a final concentration of 100 μ M. After transfer of the test substances into the wells of the microtiter plate for 6 to 24 hours, the resulting light signal is measured in a luminometer. From the measured values, a dose-effect relationship is given, which is used to determine the half-maximal effective concentration (hereinafter referred to as EC)₅₀Value).

Compounds of the invention have a test EC of ≦ 30 μ M as described herein₅₀The value is obtained. Representative results are listed in table 11.

TABLE 11

Example numbering	EC50[μm]
		6	4.9
23	13.4
		26	6.0
34	4.7
		35	17.2
43	7.6
		46	7.4
47	12.4

48	18.9
		50	7.1

1, c) cytological, functional in vitro tests for modifying gene expression:

to study the expression of specific mRNA in human cell lines after treatment with test substances, the following cell lines were incubated on 6-well or 24-well plates: human hepatoma cells (HUH, JCRBCell Bank, Japan), human embryonic kidney fibroblasts (HEK/293, ATCC, Manassas, VA 20108, USA), human cervical cancer cells (HeLa, ATCC, Manassas, VA 20108, USA), human umbilical vein endothelial cells (HUVEC, Cambrex, East Rutherford, New Jersey 07073, USA). 24 hours after addition of the test substance, the cells are washed with phosphate buffered saline and total RNA therefrom (e.g., Trizol) is obtained using a suitable method-Reagenz，Invitrogen GmbH，76131 Karlsruhe，Deutschland)。

For a typical assay, total RNA thus obtained is digested with DNase I per 1. mu.g and converted to complementary DNA (cDNA) using a suitable reverse transcriptase reaction (ImProm-II reverse transcription System, Promega corporation, Madison, Wis 53711, USA). 2.5% of the cDNA batches thus obtained were used in the polymerase chain reaction. The mRNA expression level of the investigated gene was determined by means of real-time quantitative polymerase chain reaction [ TaqMan-PCR; heid CA., Stevens J., Livak K.J., Williams P.M., Genome Res.6(10), 986-94(1996) was studied using an ABI Prism 7700 sequencer (Applied Biosystems, Inc.). The Primer-probe combinations used for this were generated by means of Primer Express 1.5 software (Applied Biosystems, inc.). The mRNAs for erythropoietin, carbonic anhydrase IX, lactate dehydrogenase A, and vascular endothelial growth factor were studied separately.

The substances according to the invention lead to a significant dose-related increase of the mRNA hypoxia inducible gene in human cells.

2. In vivo test for confirming the action of cardiovascular systems

A) in vivo test for altering Gene expression

Test compounds dissolved in a suitable solvent are administered to mice or rats orally, intraperitoneally, or intravenously via a swallow probe. Typical doses are 0.1, 0.5, 1, 5, 10, 20, 50, 100 and 300mg substance per kg body weight and are administered. The control animals were dosed with solvent only. After 4, 8 or 24 hours of administration of the test substance, animals were killed with an overdose of isoflurane and subsequently twisted off the neck and the organ to be tested was removed. Part of the organ was snap frozen in liquid nitrogen. The total RNA described in B.1.a) was obtained from a part of the organs and converted into cDNA. The expression level of the mRNA of the gene to be investigated is determined by means of the real-time quantitative polymerase chain reaction [ TaqMan-PCR; heid CA., Stevens J., Livak K.J., Williams P.M., Genome Res.6(10), 986-94(1996) was studied using an ABI Prism 7700 sequencer (Applied Biosystems, Inc.).

The substance according to the invention results in a significant dose-related increase of erythropoietin mRNA in the kidney after oral or parenteral administration compared to placebo control.

B) determination of erythropoietin in serum

Mice or rats are administered a test compound dissolved in a suitable solvent, either intraperitoneally or orally, once or twice daily. Typical doses are 0.1, 0.5, 1, 5, 10, 20, 50, 100 and 300mg substance per kg body weight and are administered. The control animals were dosed with solvent only. Short-term unconsciousness from the retroorbital vascular network or the caudal vasculature before administration and 4 hours after the last administration of the substanceThe naive animals draw 50. mu.l of blood. Blood was rendered non-coagulable by the addition of lithium heparin. Plasma was obtained by centrifugation. In plasma by means of Erythropoetin-ELISA (Quantikine)mouse Epo Immunoassay，R&D Systems, inc., Minneapolis, USA) the content of erythropoietin was determined according to the manufacturer's guidelines. The measurements were converted to pg/ml according to the comparative test proposed for rat-erythropoietin.

The substance according to the invention leads to a significant, dose-related increase of plasma erythropoietin after oral and parenteral administration compared to the initial value and placebo control.

C) determination of the cellular composition of peripheral blood vessels:

test compounds dissolved in a suitable solvent are administered to mice or rats, either intraperitoneally or orally, once or twice daily. Typical doses are 0.1, 0.5, 1, 5, 10, 20, 50, 100 and 300mg substance per kg body weight and are administered. The control animals were dosed with solvent only. After the test was completed, blood was drawn from the retro-orbital vascular network or tail vessels to briefly unconscious animals and rendered non-coagulable by the addition of sodium citrate. The red blood cell, white blood cell and platelet concentrations in a blood sample are determined in a suitable electronic meter. The reticulocyte concentration is determined by microscopic scrutiny of each 1000 erythrocytes according to a blood smear of a staining solution suitable therefor (KABE Labortechnik, Inc., Tumbrecht). For the determination of the hematocrit, the blood from the retroorbital blood network is taken off by means of a hematocrit capillary and the hematocrit value is read manually after centrifuging the capillary in a centrifuge suitable therefor.

The substances according to the invention lead to a significant, dose-related increase in hematocrit, red blood cell count and reticulocytes after oral and parenteral administration compared to the initial values and placebo controls.

C. Examples for pharmaceutical compositions

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

And (3) tablet preparation:

consists of the following components:

100mg of a compound according to the invention, 50mg of lactose (monohydrate), 50mg of maize starch (native), 10mg of polyvinylpyrrolidone (PVP 25) (BASF, Ludwigshafen, Deutschland) and 2mg of magnesium stearate.

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

Preparation:

the mixture consisting of the compound of the invention, lactose and starch is granulated together with a 5% aqueous solution of PVP (m/m). After drying, the granules were mixed with magnesium stearate for 5 minutes. The mixture was compressed with a conventional tablet press (tablet formation as above). A pressure of 15kN was used as a standard value for pressing.

Orally administrable suspending agents:

consists of the following components:

1000mg of a compound according to the invention, 1000mg of ethanol (96%), 400mg of Rhodigel(Xanthomonas campestris, Pennsylvania, USA, FMC) and 99g of water.

A unit dose of 100mg of a compound of the invention corresponds to 10ml of an oral suspension.

Preparation:

rhodigel is suspended in ethanol and the compound of the invention is added to this suspension. Water was added with stirring. Stirring for about 6 hours until the Rhodigel stops swelling.

Orally administrable solutions:

consists of the following components:

500mg of a compound of the invention, 2.5g polysorbate 80 and 97g polyethylene glycol 400. A unit dose of 100mg of a compound of the invention corresponds to 20g of oral solution.

Preparation:

the compounds of the present invention are suspended in a mixture consisting of polyethylene glycol and polysorbate 80 under stirring. The stirring process is continued until the compound of the present invention is completely dissolved.

Intravenous solution:

the compounds of the invention are dissolved in a physiologically acceptable solvent (e.g., isotonic saline solution, 5% glucose solution and/or 30% PEG 400 solution) at a concentration above the saturation solubility. The solution was sterile filtered and filled into injection containers aseptically and pyrogen-free in situ.

Claims (12)

1. Compounds of formula (I) and physiologically non-worrying salts, hydrates and hydrates of the salts,

wherein

A represents CH or N, and the compound is represented by,

R¹represents a substituent selected from: (C)₁-C₆) Alkyl, trifluoromethyl, haloElement, cyano, nitro, hydroxy, (C)₁-C₆) Alkoxy, amino, (C)₁-C₆) Alkoxycarbonyl, hydroxycarbonyl and-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₆) Alkyl, it may be substituted by hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino or of the formula-NH-C (═ O) -R⁵、-NH-C(＝O)-NH-R⁶or-NH-SO₂-R⁷Is substituted by a group of (1), wherein

R⁵Is represented by (C)₁-C₆) Alkyl, which may be substituted by hydroxy, (C)₁-C₄) Alkoxy, phenyl or 5-or 6-membered heteroaryl, or represents phenyl,

wherein, in the case of phenyl and heteroaryl, they are each identically or differently substituted by halogen, cyano, (C)₁-C₄) Alkyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethyl or trifluoromethoxy mono-to trisubstituted,

R⁶is represented by (C)₁-C₆) Alkyl, which may be substituted by hydroxy or (C)₁-C₄) Alkoxy substituted, and

R⁷is represented by (C)₁-C₆) Alkyl, and

R⁴represents hydrogen or (C)₁-C₆) Alkyl, the latter possibly being substituted by hydroxy, (C)₁-C₄) Alkoxy or phenyl is substituted by the group consisting of,

wherein, as for phenyl, it may be substituted by halogen, cyano, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, trifluoromethyl or trifluoromethoxy,

R²represents a substituent selected from: halogen, cyano, nitro, (C)₁-C₆) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₆) Alkoxy, trifluoromethoxy, amino, hydroxycarbonyl and-C (═ O) -NH-R⁸Wherein

Then (C)₁-C₆) Alkyl and (C)₁-C₆) In the case of alkoxy groups, they may be substituted by hydroxyl groups, and

R⁸represents hydrogen or (C)₁-C₄) An alkyl group, a carboxyl group,

m represents the number 0, 1 or 2,

n represents the number 0, 1,2 or 3,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group.

2.A compound of formula (I) as claimed in claim 1 and physiologically non-worrying salts, hydrates and hydrates of said salts thereof, wherein

A represents CH or N, and the compound is represented by,

R¹represents a substituent selected from: (C)₁-C₆) Alkyl, trifluoromethyl, cyano, nitro, hydroxy, (C)₁-C₆) Alkoxy, amino, (C)₁-C₆) An alkoxycarbonyl group and a hydroxycarbonyl group,

R²represents a substituent selected from: halogen, cyano, nitro, (C)₁-C₆) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₆) Alkoxy, trifluoromethoxy, amino and hydroxycarbonyl, wherein (C)₁-C₆) Alkyl and (C)₁-C₆) Alkoxy groups as such may be substituted by hydroxy,

m represents the number 0, 1 or 2,

n represents the number 0, 1,2 or 3,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen, (C)₁-C₆) Alkyl or (C)₃-C₇) A cycloalkyl group.

3. A compound of formula (I) according to claim 1, wherein:

a represents a group represented by the formula (I),

R¹represents a substituent selected from: (C)₁-C₆) Alkyl, fluoro, chloro, bromo and-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₆) Alkyl, it may be substituted by hydroxy, (C)₁-C₄) Alkoxy, amino, mono- (C)₁-C₄) Alkylamino radical, di (C)₁-C₄) Alkylamino or of the formula-NH-C (═ O) -R⁵、-NH-C(＝O)-NH-R⁶or-NH-SO₂-R⁷Is substituted by a group of (1), wherein

R⁵Is represented by (C)₁-C₆) Alkyl which may be substituted by hydroxy, methoxy, ethoxy, phenyl or 5-membered heteroaryl, or represents phenyl,

wherein for phenyl and heteroaryl, they are each mono-to trisubstituted, identically or differently, by fluorine, chlorine, bromine, cyano, methyl, hydroxy, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy, and

R⁶and R⁷Independently of one another represent (C)₁-C₆) Alkyl, and

R⁴is represented by (C)₁-C₆) Alkyl radical of (C)₁-C₆) The alkyl group may be substituted with hydroxy, methoxy, ethoxy or phenyl,

wherein, in the case of phenyl, it may be substituted by fluorine, chlorine, bromine, cyano, methyl, methoxy, ethoxy, trifluoromethyl or trifluoromethoxy,

R²represents a substituent selected from: fluorine, chlorine, bromine, cyano, (C)₁-C₆) Alkyl, trifluoromethyl, hydroxycarbonyl and-C (═ O) -NH-R⁸Wherein

Then (C)₁-C₆) In the case of alkyl groups, they may be substituted by hydroxy groups, and

R⁸is represented by (C)₁-C₄) An alkyl group, a carboxyl group,

m represents the number 0, 1 or 2,

n represents the number 0, 1 or 2,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen.

4. A compound of formula (I) according to claim 1 or 2 and physiologically non-worrying salts, hydrates and hydrates of said salts thereof, wherein

A represents a group represented by the formula (I),

R¹represents a substituent selected from: (C)₁-C₄) Alkyl, trifluoromethyl, nitro, (C)₁-C₄) Alkoxy, amino and (C)₁-C₄) An alkoxycarbonyl group, a carbonyl group,

R²represents a substituent selected from: chlorine, bromine, cyano, (C)₁-C₄) Alkyl, trifluoromethyl, hydroxy, (C)₁-C₄) Alkoxy, trifluoromethoxy and amino, wherein₁-C₄) Alkyl and (C)₁-C₄) Alkoxy groups, which may be substituted by hydroxy groups,

m represents the number 0 or 1,

n represents the number 0, 1,2 or 3,

wherein for multiple occurrences R²In the case where they are the same or different, and

R³represents hydrogen or methyl.

5. A compound of formula (I) as claimed in claim 1 or 3 and physiologically non-worrying salts, hydrates and hydrates of said salts thereof, wherein

A represents a group represented by the formula (I),

R¹represents a substituent selected from: (C)₁-C₄) Alkyl, fluoro, chloro, bromo and-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₄) Alkyl may be substituted by hydroxy, amino or by a group of formula-NH-C (═ O) -R⁵or-NH-C (═ O) -NH-R⁶Is substituted by a group of (1), wherein

R⁵To represent(C₁-C₄) Alkyl, which may be substituted by phenyl or pyrazolyl, or represents phenyl,

wherein in the case of phenyl and pyrazolyl, they are each identically or differently mono-to trisubstituted by fluorine, chlorine, methyl or trifluoromethyl, and

R⁶is represented by (C)₁-C₄) Alkyl, and

R⁴is represented by (C)₁-C₄) Alkyl radical of (C)₁-C₄) The alkyl group may be substituted with a phenyl group,

R²represents a substituent selected from: chlorine, bromine, cyano, (C)₁-C₄) Alkyl and trifluoromethyl, wherein₁-C₄) Alkyl groups which may be substituted by hydroxy groups,

m represents the number 0, 1 or 2,

n represents the number 0, 1 or 2,

wherein for multiple occurrences R¹Or R²In the case where they are the same or different, and

R³represents hydrogen.

6. Compounds of formula (I-A) and physiologically non-worrying salts, hydrates and hydrates of the salts,

wherein, wherein:

R^1Arepresents hydrogen, methyl or trifluoromethyl, and

R^2A、R^2Band R^2CAre identical or different and, independently of one another, represent hydrogen, chlorine, bromine, cyano, methyl, hydroxymethyl, methoxy or ethoxy.

7. A compound of formula (I-B) and physiologically non-worrying salts, hydrates and hydrates of said salts:

wherein:

R^1Aand R^1BAre the same or different and independently represent hydrogen, fluorine, chlorine, (C)₁-C₄) Alkyl or-C (═ O) -NH-R⁴Wherein

Then (C)₁-C₄) Alkyl may be substituted by hydroxy, amino or by a group of formula-NH-C (═ O) -R⁵Is substituted by a group of (1), wherein

R⁵Is represented by (C)₁-C₄) Alkyl, which may be substituted by phenyl or pyrazolyl, or represents phenyl,

wherein in the case of phenyl and pyrazolyl, they are each identically or differently mono-to trisubstituted by fluorine, chlorine, methyl or trifluoromethyl, and

R⁴is represented by (C)₁-C₄) Alkyl radical of (C)₁-C₄) The alkyl group may be substituted with a phenyl group,

R²represents a substituent selected from: chlorine, bromine, cyano, methyl, hydroxymethyl or trifluoromethyl, and

n represents the number 0, 1 or 2,

wherein for multiple occurrences R²Its meaning may be the same or different.

8. Process for the preparation of compounds of formula (I), (I-A) and/or (I-B) as defined in claims 1 to 7,

reacting a compound of formula (II)

Wherein R is²、R³And n has the meaning given in claims 1 to 7, and

Z¹represents a methyl group or an ethyl group,

with a compound of formula (III) in an inert solvent in the optional presence of an acid,

a, R therein¹And m has the meaning given in claims 1 to 7,

to obtain the compound of the formula (IV),

wherein Z¹、A、R¹、R²、R³M and n have the above-mentioned meanings,

then cyclizing the compound of formula (IV) in the presence of a base in an inert solvent, and

the compounds of formula (I), (I-A) or (I-B) are optionally converted with suitable (I) solvents and/or (ii) bases or acids into their physiologically unimportant salts, hydrates and/or hydrates of the salts.

9. Process for the preparation of a compound of formula (I), (I-A) and/or (I-B) as defined in claims 1 to 7, wherein R³Representing hydrogen, which process is characterized in that,

wherein a compound of formula (V):

wherein R is²And n has the meaning given in claims 1 to 7,

Z¹represents a methyl group or an ethyl group,

with compounds of the formula (VI)

Wherein Z²Represents a methyl group or an ethyl group,

condensed to a compound of formula (VII),

wherein Z¹、R²And n has the meaning given above,

then reacting with a compound of formula (III) in the presence of an acid,

a, R therein¹And m has the meaning given in claims 1 to 7,

to obtain the compound of formula (IV-A)

Wherein Z¹、A、R¹、R²M and n have the above-mentioned meanings,

it is then cyclized in an inert solvent in the presence of a base.

10. Use of a compound as defined in any of claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of diseases of the cardio-blood circulation, heart failure, anemia, chronic kidney diseases and renal failure.

11. A medicament comprising a combination of a compound as defined in any one of claims 1 to 7 and inert, non-toxic, pharmacologically suitable auxiliaries.

12. The medicament according to claim 11 for the treatment and/or prophylaxis of cardio-blood circulation disorders, heart failure, anemia, chronic kidney disease and renal failure.