DE102007048447A1 - New substituted dihydropyrazole-3-thione compounds are hypoxia inducible factor-prolyl-4-hydroxylase inhibitor, useful for preparing medicament to treat and/or prevent e.g. cardiovascular diseases, wound healing and anemia - Google Patents

Abstract

Substituted 1,2-dihydro-pyrazole-3-thione compounds (I), and their salts, solvates or solvates of the salts, where (I) excludes 3-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyridin-2-yl-1H-pyrazol-5-thiol, are new. Substituted 1,2-dihydro-pyrazole-3-thione compounds of formula (I) and their salts, solvates or solvates of the salts, where (I) excludes 3-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyridin-2-yl-1H-pyrazol-5-thiol, are new. R 1>a heteroaryl-group of formula (a), (b), (c), (d), (e) or (f); A : CR 4>or N, where at most two A are N; D 1>O, S or NR 5>; E : CR 6>or N, where at most two E are N; R 2>heteroaryl of formula (i)-(xiii); G : CR 7>or N, where at most two G are N; J : O, S or NR 8>; L : CR 9>or N, where at most two L are N; R 4>, R 7>, R 9>H, halo, CN, NO 2, (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl or L 1>; R 5>, R 8>H, (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl (where in R 4>, R 5>, R 7>-R 9>: (1-6C)-alkyl is 1-3 times substituted by halo, CN, oxo, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl, 5-6-membered heteroaryl, or L 1>, where cycloalkyl-, heterocycloalkyl-, phenyl- or heteroaryl are 1-3 times substituted by L 2>, and (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl are 1-3 times substituted by (1-6C)-alkyl, halo, CN, oxo or L 1>where the alkyl is 1-3 times substituted by L 3>); R 10>, R 11>H, (1-6C)-alkyl, (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl, where (3-7C)-cycloalkyl, 4-7-membered heterocycloalkyl, phenyl or 5-6-membered heteroaryl are 1-3 times substituted by L 2>, and (1-6C)-alkyl is 1-3 times substituted by L 3>; R 12>, R 14>, R 15>, R 18>, R 20>, R 22>, R 25>-R 27>, R 29>-R 31>R 10>; and R 13>, R 16>, R 17>, R 19>, R 21>, R 23>, R 24>, R 28>, R 32>H or (1-6C)-alkyl 1-3 times substituted by halo, CN, OH, CF 3, (1-4C)-alkoxy, NH 2, (1-4C)-alkylamino, di-(1-4C)-alkylamino, COOH and/or (1-4C)-alkoxycarbonyl; or R 12>R 13>, R 15>R 16>, R 17>R 18>, R 19>R 20>, R 21>R 22>, R 22>R 23>, R 24>R 25>, R 27>R 28>, R 31>R 32>5-6-membered heterocycloalkyl ring (1-3 times substituted by L 2>); L 1>C(O)R 10>, C(O)OR 11>, C(O)NR 12>R 13>, OC(O)R 14>, OC(O)NR 15>R 16>, NR 17>C(O)R 18>, NR 19>C(O)OR 20>, NR 21>C(O)NR 22>R 23>, NR 24>SO 2R 25>, SO 2R 26>, SO 2NR 27>R 28>,-OR 29>, SR 30>or NR 31>R 32>; L 2>halo, CN, (1-4C)-alkyl, CF 3, OH, (1-4C)-alkoxy, CF 3O, oxo, NH 2, (1-4C)-alkylamino, di-(1-4C)alkylamino, COOH and/or (1-4C)-alkoxycarbonyl; L 3>halo, CN, OH, CF 3O, (1-4C)-alkoxy, NH 2, (1-4C)-alkylamino, di-(1-4C)-alkylamino, COOH, (1-4C)-alkoxycarbonyl, (3-7C)-cycloalkyl, 4-7-memebred heterocycloalkyl, phenyl and/or 5-6-membered heteroaryl; R 6>H, halo, CN, NO 2, (1-6C)-alkyl, CF 3, OH, (1-6C)-alkoxy, CF 3O, NH 2, (1-6C)-alkylamino, di-(1-6C)alkylamino, COOH or (1-6C)-alkoxycarbonyl; and R 3>H, 1-6C alkyl or (3-7C)-cycloalkyl. Independent claims are included for: (1) preparations of (I); and (2) a medicament comprising (I) in combination with an inert, non-toxic, auxiliary material and one or more active substances from angiotensin-converting enzyme or phosphodiesterase inhibitor, angiotensin II-receptor antagonist, beta-blocker, calcium-antagonist, mineralocorticoid receptor antagonist, diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, statin, digitalis (digoxin)-derivative, tumor chemotherapeutics or antibiotics. [Image] [Image] [Image] [Image] [Image] ACTIVITY : Cardiovascular-Gen.; Cardiant; Antianemic; Nephrotropic; Vulnerary; Antimicrobial; Anti-HIV; Antiinflammatory; Antiarthritic; Antirheumatic; Metabolic; Cytostatic; Ophthalmological; Cerebroprotective; Antiparkinsonian; Neuroprotective; Nootropic; Analgesic; Endocrine-Gen.; Antidiabetic; Vasotropic; Antianginal; Antiarteriosclerotic. MECHANISM OF ACTION : Hypoxia inducible factor-prolyl-4-hydroxylase inhibitor. The ability of (I) to inhibit hypoxia inducible factor-prolyl-4-hydroxylase was tested using in-vitro test by inhibiting prolylhydroxylase containing cell lysate with (I) for 60 minutes. The results showed that 2-pyridin-2-yl-4-pyridin-3-yl-1,2-dihydro-3H-pyrazol-3-thion-hydrochloride exhibited an IC 50value = 30.

Description

The present application relates to novel, substituted 1,2-dihydropyrazole-3-thione derivatives, Process for their preparation, their use for treatment and / or Prophylaxis of diseases and their use for the production of medicaments for the treatment and / or prophylaxis of diseases, especially of cardiovascular and hematological Diseases, kidney disease as well as promoting the Wound healing.

Inadequate supply of the human organism or its parts with oxygen, which either by its duration and / or extent interferes with a proper function of the organism or its parts, or completely stops its function, is called hypoxia. Hypoxia can be caused by a decrease in available oxygen in the breath (eg when staying at high altitude), by disturbances of external breathing (eg due to impaired lung function or airway obstruction), by a reduction of the cardiac output (eg in heart failure, acute right-sided overload in pulmonary embolism), by a too low oxygen transport capacity of the blood (eg as a result of anemia (anemia) or intoxication eg with carbon monoxide), localized due to reduced perfusion due to vascular obstruction (ischemic conditions typically eg of the heart, lower extremities or brain, diabetic macro- and microangiopathy) or due to increased oxygen demand of the tissue (eg due to increased muscle work or local inflammation) [ Eder, Gedigk (ed.), General Pathologist and pathological anatomy, 33rd ed., Springer Verlag, Berlin, 1990 ].

The human organism is conditionally able to adapt acutely and chronically to situations of diminished oxygenation. In addition to an immediate response, which includes an increase in cardiac output and respiratory time, as well as a local dilation of blood vessels by means of autonomic control mechanisms, hypoxia causes a change in the transcription of numerous genes. The function of the gene products serves to compensate for the lack of oxygen. Thus, several enzymes of glycolysis and glucose transporter 1 are expressed more intensely, which increases the anaerobic production of ATP and allows survival of the oxygen deficiency [ Schmidt, Thews (ed.), Physiology of Man, 27th ed., Springer Verlag, Berlin, 1997 ; Löffler, Petrides (ed.), Biochemistry and Pathobiochemistry, 7th ed., Springer Verlag, Berlin, 2003 ].

Furthermore, hypoxia leads to increased expression of the vascular endothelial cell growth factor, VEGF, which stimulates blood vessel neoplasms (angiogenesis) in hypoxic tissues. As a result, the circulation of ischemic tissue is improved in the long term. In various cardiovascular diseases and vascular occlusive diseases, this counter-regulation appears to be very inadequate [review in: Simons and Ware, Therapeutic angiogenesis in cardiovascular disease, Nat. Rev. Drug. Discov. 2 (11), 863-71 (2003) ].

Further, in systemic hypoxia, the peptide hormone erythropoietin formed predominantly in the kidney interstitial fibroblasts is amplified. This stimulates the formation of red blood cells in the bone marrow and thus increases the oxygen transport capacity of the blood. This effect was and is used by competitive athletes in the so-called altitude training. A decrease in the oxygen transport capacity of the blood z. Due to bleeding anemia normally causes an increase in erythropoietin production in the kidney. In certain forms of anemia, this regulatory mechanism may be disturbed or its setpoint may be set lower. So z. For example, in patients suffering from renal insufficiency, erythropoietin is produced in the renal parenchyma, but in significantly reduced amounts relative to the oxygen transport capacity of the blood, resulting in so-called renal anemia. In particular, renal anemia, but also tumor and HIV infection-related anemias are usually treated by parenteral administration of recombinant human erythropoietin (rhEPO). Currently there is no alternative therapy with an orally available drug for this expensive therapy [reviews in: Eckardt, The potential of erythropoietin and related strategies to stimulate erythropoiesis, Curr. Opin. Investig. Drugs 2 (8), 1081-5 (2001) ; Berns, Should the target hemoglobin for patients with chronic kidney disease treated with erythropoietic replacement therapy be changed ?, Semin. Dial. 18 (1), 22-9 (2005) ]. Recent research has shown that erythropoietin, in addition to its erythropoietin-enhancing effect, also exerts an independent, protective (anti-apoptotic) effect on hypoxic tissues, especially the heart and brain. Furthermore, erythropoietin therapy according to recent studies reduces the mean morbidity severity of heart failure patients [reviews in: Caiola and Cheng, Use of erythropoietin in heart failure management, Ann. Pharmacother. 38 (12), 2145-9 (2004) ; Katz, Mechanisms and treatment of anemia in chronic heart failure, congestion. Heart. Fail. 10 (5), 243-7 (2004) ].

The hypoxia-induced genes described above have in common that the increase in their expression under hypoxia is caused by the so-called hypoxia-inducible transcription factor (HIF). HIF is a heterodimeric transcription factor consisting of an alpha and a beta subunit. Three HIF alpha isoforms were described, of which HIF-1 alpha and HIF-2 alpha are highly homologous and of importance for hypoxia-induced gene expression. While the beta subunit (also known as aryl hydrocarbon receptor nuclear translocator) (constituted by 2 isoforms) is constitutively expressed, the expression of the alpha subunit depends on the oxygen content in the cell. Under normoxia, the HIF alpha protein is poly-ubiquitinated and subsequently degraded proteasomally. Under hypoxia, this degradation is inhibited, allowing HIF-alpha to dimerize with ARNT and activate its target genes. The HIF dimer binds to so-called hypoxia-responsible elements (HRE) in the regulatory sequences of its target genes. The HRE are defined by a consensus sequence. Functional HRE have been demonstrated in the regulatory elements of numerous hypoxia-induced genes [reviews in: Semenza, Hypoxia-inducible factor 1: Oxygen homeostasis and disease pathophysiology, Trends Mol. Med. 7 (8), 345-50 (2001) ; Wenger and Gassmann, Oxygen (es) and the hypoxia-inducible factor-1, Biol. Chem. 378 (7), 609-16 (1997). ].

The molecular mechanism underlying this regulation of HIF-alpha has been elucidated through the work of several independent research groups. The mechanism is conserved across species: HIF-alpha is hydroxylated by a subclass of oxygen-dependent prolyl 4-hydroxylases called PHD or EGLN at two specific prolyl residues (P402 and P564 of the human HIF-1 alpha subunit). , The HIF prolyl 4-hydroxylases are iron-dependent, 2-oxoglutarate-converting dioxygenases [ Epstein et al., C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation, Cell 107 (1), 43-54 (2001) ; Bruick and McKnight, A conserved family of prolyl-4-hydroxylases that modify HIF, Science 294 (5545), 1337-40 (2001). ; Ivan et al., Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor, Proc. Natl. Acad. Sci. USA 99 (21), 13459-64 (2002) ]. The enzymes were first annotated as prolyl hydroxylases in 2001 [ Aravind and Koonin, the DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate and iron-dependent dioxygenases, genomes biol. 2 (3), research 0007.1-0007.8, Epub 2001 Feb 19 ].

The pVHL tumor suppressor protein binds to the prolyl-hydroxylated HIF-alpha subunit, forming together with Elongin B and C the so-called VBC complex, which adapts the HIF-alpha subunit to an E3 ubiquitin ligase. Since prolyl 4-hydroxylation of the HIF-alpha subunit and its subsequent degradation occur as a function of the intracellular concentration of oxygen, HIF prolyl 4-hydroxylases have also been termed a cellular oxygen sensor. Three isoforms of these enzymes were identified: EGLN1 / PHD2, EGLN2 / PHD1 and EGLN3 / PHD3. Two of these enzymes (EGLN2 / PHD1 and EGLN3 / PHD3) are transcriptionally induced even under hypoxia and may be responsible for the decrease in HIF-alpha levels observed in chronic hypoxia [reviewed in: Schofield and Ratcliffe, Oxygen sensing by HIF hydroxylases, Nat. Rev. Mol. Cell. Biol. 5 (5), 343-54 (2004) ].

A selective pharmacological inhibition of HIF prolyl 4-hydroxylases prefers to increase the gene expression of HIF-dependent target genes and is thus for the therapy of numerous diseases of Use. Especially in diseases of the cardiovascular system is due to the induction of new blood vessels as well as the change the metabolic situation of ischemic organs of aerobic towards anaerobic ATP recovery an improvement of the disease process expected. An improvement in the vascularization of chronic Wounds promotes the healing process, especially in hard healing ulcers cruris and other chronic skin wounds. The Induction of endogenous erythropoietin in certain Forms of disease, especially in patients with renal anemia, is also a desirable therapeutic target.

The HIF prolyl 4-hydroxylase inhibitors previously described in the scientific literature do not meet the requirements for a medicinal product. These are either competitive oxoglutarate analogues (such as N-oxalylglycine), due to their very low potency are characterized and therefore in in vivo models so far none Have shown an effect in the sense of induction of HIF target genes. Or they are iron complexing agents (chelators) such as desferroxamine, which act as unspecific inhibitors of iron-containing dioxygenases and, despite induction of the target genes such. B. erythropoietin in vivo, by complexing the available Iron apparently counteract erythropoiesis.

task the present invention provides new compounds, used for the treatment of diseases, especially cardiovascular and hematological diseases.

in the Within the scope of the present invention, compounds will now be described. which act as specific inhibitors of HIF prolyl 4-hydroxylases and due to this specific mechanism of action in vivo after parenteral orally, the induction of HIF target genes, such as. As erythropoietin, and the resulting biological processes, such as As erythropoiesis cause.

2-Heteroaryl-4-aryl-1,2-dihydropyrazolone with bactericidal and / or fungicidal action are in EP 165 448 and EP 212 281 disclosed. The use of 2-heteroaryl-4-aryl-1,2-dihydropyrazolones as lipoxygenase inhibitors for the treatment of respiratory, cardiovascular and inflammatory diseases is described in US Pat EP 183 159 claimed. 2,4-diphenyl-1,2-dihydropyrazolones with herbicidal activity are in DE 2 651 008 described. The preparation and pharmacological properties of certain 2-pyridyl-1,2-dihydropyrazolones are described in Helv. Chim. Acta 49 (1), 272-280 (1966) reported. In WO 96/12706 . WO 00/51989 and WO 03/074550 For example, compounds having dihydropyrazolone partial structure are claimed for the treatment of various diseases. Substituted pyrazolylpyrimidines and their use as pesticides are described in U.S. Pat WO 02/068413 described, and in WO 2006/101903 For example, hydroxy- or alkoxy-substituted bipyrazoles are disclosed for the treatment of neuropsychiatric disorders. Meanwhile, in WO 2006/114213 2,4-dipyridyl-1,2-dihydropyrazolones have been disclosed as inhibitors of HIF prolyl 4-hydroxylases.

The compound 3-methyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) -1-pyridin-2-yl-1H-pyrazole-5-thiol and its use as an intermediate for the preparation of herbicides is in JP 63 146 878-A2 [Chem. Abstr. 1989: 95227].

in welcher
R¹ für eine Heteroaryl-Gruppe der Formel

steht, worin
* die Verknüpfungsstelle mit dem Dihydropyrazolthion-Ring bedeutet,
A bei jedem einzelnen Auftreten C-R⁴ oder N bedeutet, wobei maximal zwei Ringglieder A zugleich für N stehen,
D O, S oder N-R⁵ bedeutet
und
E bei jedem einzelnen Auftreten C-R⁶ oder N bedeutet, wobei maximal zwei Ringglieder E zugleich für N stehen,
R² für eine Heteroaryl-Gruppe der Formel

steht, worin
# die Verknüpfungsstelle mit dem Dihydropyrazolthion-Ring bedeutet,
G bei jedem einzelnen Auftreten C-R⁷ oder N bedeutet, wobei maximal zwei Ringglieder G zugleich für N stehen,
J O, S oder N-R⁸ bedeutet
und
L bei jedem einzelnen Auftreten C-R⁹ oder N bedeutet, wobei maximal zwei Ringglieder L zugleich für N stehen,
worin
R⁴, R⁷ und R⁹ gleich oder verschieden sind und in jedem einzelnen Fall, unabhängig voneinander, für Wasserstoff oder einen Substituenten ausgewählt aus der Reihe Halogen, Cyano, Nitro, (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl, 5- oder 6-gliedriges Heteroaryl, -C(=O)-R¹⁰, -C(=O)-OR¹¹, -C(=O)-NR¹²R¹³, -O-C(=O)-R¹⁴, -O-C(=O)-NR¹⁵R¹⁶, -NR¹⁷-C(=O)-R¹⁸, -NR¹⁹-C(=O)-OR²⁰, -NR²¹-C(=O)-NR²²R²³, -NR²⁴-SO₂-R²⁵, -SO₂-R²⁶, -SO₂-NR²⁷R²⁸, -OR²⁹, -SR³⁰ und -NR³¹R³² stehen, worin

• (i) (C₁-C₆)-Alkyl seinerseits ein- bis dreifach, gleich oder verschieden, mit Resten ausgewählt aus der Reihe Halogen, Cyano, Oxo, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl, 5- oder 6-gliedriges Heteroaryl, -C(=O)-R¹⁰, -C(=O)-OR¹¹, -C(=O)-NR¹²R¹³, -O-C(=O)-R¹⁴, -O-C(=O)-NR¹⁵R¹⁶, -NR¹⁷-C(=O)-R¹⁸, -NR¹⁹-C(=O)-OR²⁰, -NR²¹-C(=O)-NR²²R²³, -NR²⁴-SO₂-R²⁵, -SO₂-R²⁶, -SO₂-NR²⁷R²⁸, -OR²⁹, -SR³⁰ und -NR³¹R³² substituiert sein kann, wobei die letztgenannten Cycloalkyl-, Heterocycloalkyl-, Phenyl- und Heteroaryl-Reste ihrerseits jeweils bis zu dreifach, gleich oder verschieden, mit Halogen, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamio, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein können,
• (ii) (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl ihrerseits jeweils ein- bis dreifach, gleich oder verschieden, mit Resten ausgewählt aus der Reihe (C₁-C₆)-Alkyl, Halogen, Cyano, Oxo, -C(=O)-R¹⁰, -C(=O)-OR¹¹, -C(=O)-NR¹²R¹³, -O-C(=O)-R¹⁴, -O-C(=O)-NR¹⁵R¹⁶, -NR¹⁷-C(=O)-R¹⁸, -NR¹⁹-C(=O)-OR²⁰, -NR²¹-C(=O)-NR²²R²³, -NR²⁴-SO₂-R²⁵, -SO₂-R²⁶, -SO₂-NR²⁷R²⁸, -OR²⁹, -SR³⁰ und -NR³¹R³² substituiert sein können, wobei der letztgenannte Alkyl-Rest seinerseits bis zu dreifach, gleich oder verschieden, mit Halogen, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₇)-Cyclo alkyl, 4- bis 7-gliedrigem Heterocycloalkyl, Phenyl und/oder 5- oder 6-gliedrigem Heteroaryl substituiert sein kann,
• (iii) R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁸, R²⁰, R²², R²⁵, R²⁶, R²⁷, R²⁹, R³⁰ und R³¹ unabhängig voneinander bei jedem einzelnen Auftreten für einen Rest ausgewählt aus der Reihe Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl stehen, wobei (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl ihrerseits jeweils bis zu dreifach, gleich oder verschieden, mit Halogen, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein können und (C₁-C₆)-Alkyl ein- bis dreifach, gleich oder verschieden, mit Halogen, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedrigem Heterocycloalkyl, Phenyl und/oder 5- oder 6-gliedrigem Heteroaryl substituiert sein kann,
• (iv) R¹³, R¹⁶, R¹⁷, R¹⁹, R²¹, R²³, R²⁴, R²⁸ und R³² unabhängig voneinander bei jedem einzelnen Auftreten für einen Rest ausgewählt aus der Reihe Wasserstoff und (C₁-C₆)-Alkyl stehen, wobei (C₁-C₆)-Alkyl ein- bis dreifach, gleich oder verschieden, mit Halogen, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann, und/oder worin
• (v) R¹² und R¹³, R¹⁵ und R¹⁶, R¹⁷ und R¹⁸, R¹⁹ und R²⁰, R²¹ und R²², R²² und R²³, R²⁴ und R²⁵, R²⁷ und R²⁸ sowie R³¹ und R³² jeweils paarweise zusammen mit den Atomen, an die sie gebunden sind, einen 5- oder 6- gliedrigen Heterocycloalkyl-Ring bilden können, welcher ein- bis dreifach, gleich oder verschieden, mit Halogen, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann,

R⁵ und R⁸ gleich oder verschieden sind und unabhängig voneinander für Wasserstoff oder einen Substituenten ausgewählt aus der Reihe (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl stehen, worin

• (i) (C₁-C₆)-Alkyl seinerseits ein- bis dreifach, gleich oder verschieden, mit Resten ausgewählt aus der Reihe Halogen, Cyano, Oxo, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl, 5- oder 6-gliedriges Heteroaryl, -C(=O)-R¹⁰, -C(=O)-OR¹¹, -C(=O)-NR¹²R¹³, -O-C(=O)-R¹⁴, -O-C(=O)-NR¹⁵R¹⁶, -NR¹⁷-C(=O)-R¹⁸, -NR¹⁹-C(=O)-OR²⁰, -NR²¹-C(=O)-NR²²R²³, -NR²⁴-SO₂-R²⁵, -SO₂-R²⁶, -SO₂-NR²⁷R²⁸, -OR²⁹, -SR³⁰ und -NR³¹R³² substituiert sein kann, wobei die letztgenannten Cycloalkyl-, Heterocycloalkyl-, Phenyl- und Heteroaryl-Reste ihrerseits jeweils bis zu dreifach, gleich oder verschieden, mit Halogen, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein können, und
• (ii) (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl ihrerseits jeweils ein- bis dreifach, gleich oder verschieden, mit Resten ausgewählt aus der Reihe (C₁-C₆)-Alkyl, Halogen, Cyano, Oxo, -C(=O)-R¹⁰, -C(=O)-OR¹¹, -C(=O)-NR¹²R¹³, -O-C(=O)-R¹⁴, -O-C(=O)-NR¹⁵R¹⁶, -NR¹⁷-C(=O)-R¹⁸, -NR¹⁹-C(=O)-OR²⁰, NR²¹-C(=O)-NR²²R²³, -NR²⁴-SO₂-R²⁵, -SO₂-R²⁶, -SO₂-NR²⁷R²⁸, -OR²⁹, -SR³⁰ und -NR³¹R³² substituiert sein können, wobei der letztgenannte Alkyl-Rest seinerseits bis zu dreifach, gleich oder verschieden, mit Halogen, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedrigem Heterocycloalkyl, Phenyl und/oder 5- oder 6-gliedrigem Heteroaryl substituiert sein kann, worin (a) R¹⁰, R¹¹, R¹², R¹⁴, R¹⁵, R¹⁸, R²⁰, R²², R²⁵, R²⁶, R²⁷, R²⁹, R³⁰ und R³¹ unabhängig voneinander bei jedem einzelnen Auftreten für einen Rest ausgewählt aus der Reihe Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl stehen, wobei (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl ihrerseits jeweils bis zu dreifach, gleich oder verschieden, mit Halogen, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein können und (C₁-C₆)-Alkyl ein- bis dreifach, gleich oder verschieden, mit Halogen, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₇)-Cycloalkyl, 4- bis 7-gliedrigem Heterocycloalkyl, Phenyl und/oder 5- oder 6-gliedrigem Heteroaryl substituiert sein kann, (b) R¹³, R¹⁶, R¹⁷, R¹⁹, R²¹, R²³, R²⁴, R²⁸ und R³² unabhängig voneinander bei jedem einzelnen Auftreten für einen Rest ausgewählt aus der Reihe Wasserstoff und (C₁-C₆)-Alkyl stehen, wobei (C₁-C₆)-Alkyl ein- bis dreifach, gleich oder verschieden, mit Halogen, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann, und/oder (c) R¹² und R¹³, R¹⁵ und R¹⁶, R¹⁷ und R¹⁸, R¹⁹ und R²⁰, R²¹ und R²², R²² und R²³, R²⁴ und R²⁵, R²⁷ und R²⁸ sowie R³¹ und R³² jeweils paarweise zusammen mit den Atomen, an die sie gebunden sind, einen 5- oder 6-gliedrigen Heterocycloalkyl-Ring bilden können, welcher ein- bis dreifach, gleich oder verschieden, mit Halogen, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann, und R⁶ in jedem einzelnen Fall, unabhängig voneinander, für Wasserstoff oder einen Substituenten ausgewählt aus der Reihe Halogen, Cyano, Nitro, (C₁-C₆)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₆)-Alkoxy, Trifluormethoxy, Amino, Mono-(C₁-C₆)-alkylamino, Di-(C₁-C₆)-alkylamino, Hydroxycarbonyl und (C₁-C₆)-Alkoxycarbonyl steht,

und
R³ für Wasserstoff, (C₁-C₆)-Alkyl oder (C₃-C₇)-Cycloalkyl steht,
sowie ihre Salze, Solvate und Solvate der Salze,
mit Ausnahme der Verbindung 3-Methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)-1-pyridin-2-yl-1H-pyrazol-5-thiol.The present invention relates to compounds of the general formula (I)

in which
R ^{1 represents} a heteroaryl group of the formula

stands in which
* means the point of attachment to the dihydropyrazolethione ring,
A means each occurrence CR ⁴ or N, wherein a maximum of two ring members A are N at the same time,
DO, S or NR ⁵ means
and
E at each individual occurrence means CR ⁶ or N, with a maximum of two ring members E being N at the same time,
R ^{2 is} a heteroaryl group of the formula

stands in which
# means the point of attachment to the dihydropyrazolethione ring,
G means at each occurrence CR ⁷ or N, with a maximum of two ring members G being N at the same time,
JO, S or NR ⁸ means
and
L at each individual occurrence means CR ⁹ or N, with a maximum of two ring members L being N at the same time,
wherein
R ⁴ , R ⁷ and R ^{9 are the} same or different and in each case, independently of one another, represent hydrogen or a substituent selected from the group halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl, (C ₃ - C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , - SR ³⁰ and -NR ³¹ R ³² are in which

• (i) (C ₁ -C ₆ ) -alkyl, in turn, one to three, same or different, with radicals selected from the group halogen, cyano, oxo, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered Heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O ) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² may be substituted, wherein the latter cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals in turn each up to three times, identically or differently, with halogen, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) Alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamio, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl .
• (ii) (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each one to three times, identically or differently, with radicals selected from the series (C ₁ -C ₆ ) alkyl, halogen, cyano, oxo, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O ) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² may be substituted, wherein the latter alkyl radical in turn up to three times, identically or differently, with halogen, cyano, hydroxy, trifluoromethoxy, (C ₁ -C ₄ ) alkoxy, amino, mono - (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₇ ) -cycloalkyl, 4 to 7 substituted heterocycloalkyl, phenyl and / or 5- or 6-membered heteroaryl may be substituted,
• (iii) R ^10, R ^11, R ^12, R ^14, R ^15, R ^18, R ^20, R ^22, R ^25, R ^26, R ^27, R ^29, R ³⁰ and R ³¹ are independently at each occurrence is a radical selected from among hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where ( C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn in each case up to three times, identically or differently, with halogen, cyano, (C ₁ -C ₄ ) -alkyl , Trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or ( C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₆ ) -alkyl may be mono- to trisubstituted, identically or differently, by halogen, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino , Mono (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbon yl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and / or 5- or 6-membered heteroaryl may be substituted,
• (iv) R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ , R ²⁸ and R ³² independently of one another each occurrence are selected from the group consisting of hydrogen and (C ₁ -C ₆ ) Alkyl, where (C ₁ -C ₆ ) alkyl is mono- to trisubstituted, identically or differently, by halogen, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono (C ₁ C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and / or wherein
• (v) R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² , R ²² and R ²³ , R ²⁴ and R ²⁵ , R ²⁷ and R ²⁸ and R ³¹ and R ³² in pairs together with the atoms to which they are attached can form a 5- or 6-membered heterocycloalkyl ring which is monosubstituted to trisubstituted, identical or different, with halogen, cyano, (C ₁ C ₄ ) alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino , Hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl,

R ⁵ and R ^{8 are the} same or different and are independently hydrogen or a substituent selected from the group consisting of (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl wherein

• (i) (C ₁ -C ₆ ) -alkyl, in turn, one to three, same or different, with radicals selected from the group halogen, cyano, oxo, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered Heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O ) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² may be substituted, wherein the latter cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals in turn each up to three times, identically or differently, with halogen, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -Alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl , and
• (ii) (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each one to three times, identically or differently, with radicals selected from the series (C ₁ -C ₆ ) alkyl, halogen, cyano, oxo, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O ) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , NR ²¹ -C (= O ) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² may be substituted, the last-mentioned alkyl radical being in turn up to three times, identical or different, with halogen, cyano, hydroxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di-, (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and / or 5- or 6-membered Heteroaryl may be substituted, wherein (a) R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁸ , R ²⁰ , R ²² , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁹ , R ³⁰ and R ³¹ independently of one another each occurrence represent a radical selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, and 4- to 7-membered Heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each up to three times, same or different with halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di-, (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl may be substituted and (C ₁ -C ₆ ) -alkyl mono- to trisubstituted, identical or different, with halogen, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino , Di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and / or 5- or (B) R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ , R ²⁸ and R ^{32 are} independently each occurrence of a radical selected from the series Hydrogen and (C ₁ -C ₆ ) alkyl, wherein (C ₁ -C ₆ ) alkyl, one to three times, same or different, with halogen, cyano, hydroxy, trifluoromethoxy, (C ₁ -C ₄ ) alkoxy , Amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and / or (c) R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² , R ²² and R ²³ , R ²⁴ and R ²⁵ , R ²⁷ and R ²⁸ and R ³¹ U.N d R ³² in pairs, together with the atoms to which they are attached, can form a 5- or 6-membered heterocycloalkyl ring which is mono- to trisubstituted, identical or different, with halogen, cyano, (C ₁ -C ₄ ) Alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, hydroxycarbonyl and and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and R ⁶ in each case, independently of one another, represents hydrogen or a substituent selected from the group halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl , Trifluoromethyl, hydroxy, (C ₁ -C ₆ ) alkoxy, trifluoromethoxy, amino, mono (C ₁ -C ₆ ) alkylamino, di (C ₁ -C ₆ ) alkylamino, hydroxycarbonyl and (C ₁ -C ₆ ) alkoxycarbonyl,

and
R ^{3 is} hydrogen, (C ₁ -C ₆ ) -alkyl or (C ₃ -C ₇ ) -cycloalkyl,
and their salts, solvates and solvates of the salts,
with the exception of the compound 3-methyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) -1-pyridin-2-yl-1H-pyrazole-5-thiol.

invention Compounds are the compounds of the formula (I) and their salts, Solvates and solvates of the salts, the compounds encompassed by formula (I) the following formulas and their salts, solvates and solvates the salts as well as those of formula (I), hereinafter referred to as exemplary embodiments mentioned compounds and their salts, solvates and solvates of Salts, as far as those of formula (I), hereinafter not already mentioned salts, solvates and solvates salts.

The Compounds according to the invention can depending on their structure in stereoisomeric forms (Enantiomers, diastereomers) exist. The invention therefore comprises the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and / or diastereomers can the stereoisomerically uniform constituents in known Isolate way.

Provided the compounds of the invention in tautomers Forms may include the present invention all tautomeric forms.

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

physiological acceptable salts of the compounds of the invention include acid addition salts of mineral acids, Carboxylic acids and sulfonic acids, e.g. B. salts of Hydrochloric acid, hydrobromic acid, sulfuric acid, Phosphoric acid, methanesulfonic acid, ethanesulfonic acid, Toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, Acetic acid, trifluoroacetic acid, propionic acid, Lactic acid, tartaric acid, malic acid, citric acid, Fumaric acid, maleic acid and benzoic acid.

physiological acceptable salts of the compounds of the invention Also include salts of conventional bases, such as by way of example and preferably alkali metal salts (eg sodium and potassium salts), Alkaline earth salts (eg calcium and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 C atoms, as exemplified and preferably ethylamine, diethylamine, triethylamine, Ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, Dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, Arginine, lysine, ethylenediamine and N-methylpiperidine.

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

Furthermore For example, the present invention also encompasses prodrugs of the invention Links. The term "prodrugs" includes compounds which themselves may be biologically active or inactive, but during their residence time in the body to inventive Compounds are reacted (for example, metabolically or hydrolytically).

Unless otherwise specified, in the context of the present invention, the substituents have the following meaning:
(C ₁ -C ₆ ) -Alkyl and (C ₁ -C ₄ ) -alkyl are in the context of the invention a straight-chain or branched alkyl radical having 1 to 6 or 1 to 4 carbon atoms. Preferred is a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.

In the context of the invention, (C ₁ -C ₆ ) -alkoxy and (C ₁ -C ₄ ) -alkoxy represent a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Mono- (C ₁ -C ₆ ) -alkylamino and mono- (C ₁ -C ₄ ) -alkylamino in the context of the invention are an amino group having a straight-chain or branched alkyl substituent having 1 to 6 or 1 to 4 carbon atoms having. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, tert-butylamino, n-pentylamino and n-hexylamino.

Di (C ₁ -C ₆ ) -alkylamino and di (C ₁ -C ₄ ) -alkylamino are in the context of the invention an amino group having two identical or different straight-chain or branched alkyl substituents, each of which is 1 to 6 or Have 1 to 4 carbon atoms. Preference is given to straight-chain or branched dialkylamino radicals each having 1 to 4 carbon atoms. Examples which may be mentioned by way of example and with preference: N, N-dimethylamino, N, N-diethylamino, N-ethyl-N-methylamino, N-methyl-Nn-propylamino, N-isopropyl-Nn-propylamino, N, N-diisopropylamino, Nn Butyl-N-methylamino, N-tert-butyl-N-methylamino, N-methyl-Nn-pentylamino and Nn-hexyl-N-methylamino.

(C ₁ -C ₆ ) -Alkoxycarbonyl and (C ₁ -C ₄ ) -alkoxycarbonyl are in the context of the invention a straight-chain or branched alkoxy radical having 1 to 6 or 1 to 4 carbon atoms which is linked via a carbonyl group. Preferred is a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms in the alkoxy group. By way of example and preferably mention may be made of: methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

In the context of the invention, (C ₃ -C ₇ ) -cycloalkyl and (C ₃ -C ₆ ) -cycloalkyl represent a monocyclic, saturated carbocycle having 3 to 7 or 3 to 6 ring carbon atoms. Examples which may be mentioned by way of example include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

4 to 7-membered heterocycloalkyl is within the scope of the invention for a monocyclic, saturated heterocycle with a total of 4 to 7 ring atoms containing one or two ring heteroatoms from the series N, O and / or S contains and over a ring carbon atom or optionally a ring nitrogen atom is linked. Examples include: azetidinyl, Oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, Thiolanyl, 1,3-oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, Tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, morpholinyl, Thiomorpholinyl, hexahydroazepinyl, hexahydro-1,4-diazepinyl. Is preferred a 4- to 6-membered heterocycloalkyl radical having a total of 4 to 6 ring atoms containing one or two ring heteroatoms from the series N and / or O, such as, for example, pyrrolidinyl, tetrahydrofuranyl, Piperidinyl, piperazinyl, tetrahydropyranyl and morpholinyl.

5- or 6-membered heteroaryl is in the context of the invention for an aromatic heterocycle (heteroaromatic) with a total of 5 or 6 ring atoms, which contains up to four identical or different ring heteroatoms from the series N, O and / or S. a ring carbon atom or optionally linked via a ring nitrogen atom. Examples which may be mentioned are: furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thazolyl, oxazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, Pyridazinyl, pyrazinyl, triazinyl. Preferred are 5- or 6-membered heteroaryl radicals having up to three ring heteroatoms from the series N, O and / or S, such as furyl, thienyl, thazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyazolyl, imidazolyl, triazolyl, oxadiazolyl , Thiadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl.

halogen in the context of the invention includes fluorine, chlorine, bromine and Iodine. Preference is given to fluorine, chlorine and bromine, particularly preferred Fluorine and chlorine.

If Residues substituted in the compounds of the invention Unless otherwise specified, the radicals may be be mono- or polysubstituted. In the context of the present Invention is that for all residues that occur several times, whose meaning is independent of each other. A substitution with one, two or three identical or different substituents is preferred. Particularly preferred is the substitution with a or two identical or different substituents.

steht, worin
* die Verknüpfungsstelle mit dem Dihydropyrazolthion-Ring bedeutet,
A bei jedem einzelnen Auftreten C-R⁴ oder N bedeutet, wobei maximal zwei Ringglieder A zugleich für N stehen,
R⁴ in jedem einzelnen Fall, unabhängig voneinander, Wasserstoff oder einen Substituenten ausgewählt aus der Reihe Fluor, Chlor, Brom, Cyano, (C₁-C₆)-Alkyl, Hydroxy, (C₁-C₆)-Alkoxy, Trifluormethoxy, Amino, Mono-(C₁-C₆)-alkylamino, Di-(C₁-C₆)-allylamino, Hydroxycarbonyl und (C₁-C₆)-Alkoxycarbonyl bedeutet,
wobei der genannte (C₁-C₆)-Alkylrest seinerseits bis zu dreifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann,
und
D O, S oder N-R⁵ bedeutet, worin
R⁵ für Wasserstoff oder (C₁-C₆)-Alkyl steht,
R² für eine Heteroaryl-Gruppe der Formel

steht, worin
# die Verknüpfungsstelle mit dem Dihydropyrazolthion-Ring bedeutet,
G jeweils C-R⁷ oder N bedeutet, wobei nicht mehr als eines der beiden Ringglieder G für N steht, worin
R⁷ in jedem einzelnen Fall, unabhängig voneinander, für Wasserstoff oder einen Substituenten ausgewählt aus der Reihe Fluor, Chlor, Brom, Cyano, (C₁-C₆)-Alkyl, (C₃-C₆)-Cycloalkyl, 4- bis 6-gliedriges Heterocycloalkyl, Phenyl, 5- oder 6-gliedriges Heteroaryl, -C(=O)-OR¹¹, -C(=O)-NR¹²R¹³, -O-C(=O)-R¹⁴, -O-C(=O)-NR¹⁵R¹⁶, -NR¹⁷-C(=O)-R¹⁸, -NR¹⁹-C(=O)-OR²⁰, -NR²¹-C(=O)-NR²²R²³, -NR²⁴-SO₂-R²⁵, -OR²⁹ und -NR³¹R³² steht, worin

• (i) (C₁-C₆)-Alkyl seinerseits ein- bis dreifach, gleich oder verschieden, mit Resten ausgewählt aus der Reihe Fluor, Chlor, Brom, Cyano, (C₃-C₆)-Cycloalkyl, 4- bis 6-gliedriges Heterocycloalkyl, Phenyl, 5- oder 6-gliedriges Heteroaryl, -C(=O)-OR¹¹, -C(=O)-NR¹²R¹³, -O-C(=O)-R¹⁴, -O-C(=O)-NR¹⁵R¹⁶, -NR¹⁷-C(=O)-R¹⁸, -NR¹⁹-C(=O)-OR²⁰, -NR²¹-C(=O)-NR²²R²³, -NR²⁴-SO₂-R²⁵, -OR²⁹ und -NR³¹R³² substituiert sein kann, wobei die letztgenannten Cycloalkyl-, Heterocycloalkyl-, Phenyl- und Heteroaryl-Reste ihrerseits jeweils bis zu zweifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein können,
• (ii) (C₃-C₆)-Cycloalkyl, 4- bis 6-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl ihrerseits jeweils ein- oder zweifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein können,
• (iii) R¹¹, R¹², R¹⁴, R¹⁵, R¹⁸, R²⁰, R²², R²⁵, R²⁹ und R³¹ unabhängig voneinander bei jedem einzelnen Auftreten für einen Rest ausgewählt aus der Reihe Wasserstoff, (C₁-C₆)-Alkyl, (C₃-C₆)-Cycloalkyl, 4- bis 6-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl stehen, wobei (C₃-C₆)-Cycloalkyl, 4- bis 6-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl ihrerseits jeweils bis zu dreifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein können und (C₁-C₆)-Alkyl ein- bis dreifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl, (C₃-C₆)-Cycloalkyl, 4- bis 6-gliedrigem Heterocycloalkyl, Phenyl und/oder 5- oder 6-gliedrigem Heteroaryl substituiert sein kann,
• (iv) R¹³, R¹⁶, R¹⁷, R¹⁹, R²¹, R²³, R²⁴ und R³² unabhängig voneinander bei jedem einzelnen Auftreten für einen Rest ausgewählt aus der Reihe Wasserstoff und (C₁-C₆)-Alkyl stehen, wobei ( C₁-C₆)-Alkyl ein- oder zweifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, Hydroxy, Trifluormethoxy, (C₁-C₄)-Alkoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann, und/oder worin
• (v) R¹² und R¹³, R¹⁵ und R¹⁶, R¹⁷ und R¹⁸, R¹⁹ und R²⁰, R²¹ und R²², R²² und R²³, R²⁴ und R²⁵ sowie R³¹ und R³² jeweils paarweise zusammen mit den Atomen, an die sie gebunden sind, einen 5- oder 6-gliedrigen Heterocycloalkyl-Ring bilden können, welcher ein- oder zweifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl substituiert sein kann,

und
J O oder S bedeutet,
und
R³ für Wasserstoff oder Methyl steht,
sowie ihre Salze, Solvate und Solvate der Salze.
Besonders bevorzugt im Rahmen der vorliegenden Erfindung sind Verbindungen der Formel (1), in welcher
R¹ für eine Heteroaryl-Gruppe der Formel

steht, worin
* die Verknüpfungsstelle mit dem Dihydropyrazolthion-Ring
und
R⁴ Wasserstoff, Fluor, Cyano, Methyl, Ethyl, Trifluormethyl, Hydroxymethyl, Methoxy, Trifluormethoxy, Hydroxycarbonyl, Methoxycarbonyl oder Ethoxycarbonyl bedeutet,
R² für eine Heteroaryl-Gruppe der Formel

steht, worin
# die Verknüpfungsstelle mit dem Dihydropyrazolthion-Ring bedeutet
und
R⁷, R^7A und R^7B gleich oder verschieden sind und unabhängig voneinander Wasserstoff oder einen Substituenten ausgewählt aus der Reihe Fluor, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl, (C₁-C₄)-Alkoxycarbonyl, 4- bis 6-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl bedeuten, wobei
(C₁-C₄)-Alkyl seinerseits mit Hydroxy, (C₁-C₄)-Alkoxy oder Amino
und
4- bis 6-gliedriges Heterocycloalkyl, Phenyl und 5- oder 6-gliedriges Heteroaryl ihrerseits jeweils ein- oder zweifach, gleich oder verschieden, mit Fluor, Chlor, Brom, Cyano, (C₁-C₄)-Alkyl, Trifluormethyl, Hydroxy, (C₁-C₄)-Alkoxy, Trifluormethoxy, Oxo, Amino, Mono-(C₁-C₄)-alkylamino, Di-(C₁-C₄)-alkylamino, Hydroxycarbonyl und/oder (C₁-C₄)-Alkoxycarbonyl
substituiert sein können,
und
R³ für Wasserstoff steht,
sowie ihre Salze, Solvate und Solvate der Salze.Preferred in the context of the present invention are compounds of the formula (I) in which
R ^{1 represents} a heteroaryl group of the formula

stands in which
* means the point of attachment to the dihydropyrazolethione ring,
A means each occurrence CR ⁴ or N, wherein a maximum of two ring members A are N at the same time,
R ⁴ in each case, independently of one another, denotes hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C ₁ -C ₆ ) -alkyl, hydroxyl, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, Amino, mono- (C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -allylamino, hydroxycarbonyl and (C ₁ -C ₆ ) -alkoxycarbonyl,
wherein said (C ₁ -C ₆ ) alkyl radical, in turn, is up to three times, identically or differently, substituted with fluorine, chlorine, bromine, cyano, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, amino, mono (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl,
and
DO, S or NR ⁵ means in which
R ^{5 is} hydrogen or (C ₁ -C ₆ ) -alkyl,
R ^{2 is} a heteroaryl group of the formula

stands in which
# means the point of attachment to the dihydropyrazolethione ring,
G each represents CR ⁷ or N, wherein not more than one of the two ring members G is N, wherein
R ⁷ in each case, independently of one another, is hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 4 to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC ( = O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -OR ²⁹ and -NR ³¹ R ³² in which

• (i) (C ₁ -C ₆ ) -alkyl in turn one to three, same or different, with radicals selected from the group fluorine, chlorine, bromine, cyano, (C ₃ -C ₆ ) -cycloalkyl, 4-6 heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , - NR ²⁴ -SO ₂ -R ²⁵ , -OR ²⁹ and -NR ³¹ R ³² may be substituted, wherein the latter cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals in turn each up to two times, identically or differently, with fluorine, Chlorine, bromine, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di-, (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl may be substituted,
• (ii) (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, in each case one or two times, identically or differently, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl,
• (iii) R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁸ , R ²⁰ , R ²² , R ²⁵ , R ²⁹ and R ³¹ independently of one another at each occurrence represent a radical selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each up to three times, identically or differently, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) alkoxycarbonyl and (C ₁ -C ₆ ) -alkyl may be mono- to trisubstituted, identically or differently, with fluorine, chlorine, bromine, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkyl. C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and / or 5- or 6-membered heteroaryl may be substituted,
• (iv) R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ and R ³² independently of each occurrence are each hydrogen selected from (C ₁ -C ₆ ) alkyl where (C ₁ -C ₆ ) -alkyl is monosubstituted or disubstituted, identical or different, with fluorine, chlorine, bromine, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and / or in which
• (v) R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² , R ²² and R ²³ , R ²⁴ and R ²⁵ and R ³¹ and R ³² in pairs, together with the atoms to which they are attached, can form a 5- or 6-membered heterocycloalkyl ring which is monosubstituted or disubstituted, identical or different, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl,

and
JO or S means
and
R ^{3 is} hydrogen or methyl,
and their salts, solvates and solvates of the salts.
Particularly preferred in the context of the present invention are compounds of the formula (1) in which
R ^{1 represents} a heteroaryl group of the formula

stands in which
* the point of attachment with the dihydropyrazolethione ring
and
R ^{4 is} hydrogen, fluorine, cyano, methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl,
R ^{2 is} a heteroaryl group of the formula

stands in which
# means the point of attachment to the dihydropyrazolethione ring
and
R ⁷ , R ^7A and R ^{7B are the} same or different and are independently hydrogen or a substituent selected from fluorine, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy , Trifluoromethoxy, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) alkoxycarbonyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein
(C ₁ -C ₄ ) -alkyl in turn with hydroxy, (C ₁ -C ₄ ) -alkoxy or amino
and
4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each one or two times, same or different, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy , (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) alkoxycarbonyl
can be substituted
and
R ^{3 is} hydrogen,
and their salts, solvates and solvates of the salts.

The in the respective combinations or preferred combinations of Residues in the specified radical definitions become independent of the respective specified combinations of the radicals as desired also replaced by residue definitions of other combinations.

All Particularly preferred are combinations of two or more of above preferred ranges.

The 1,2-dihydro-3H-pyrazole-3-thione derivatives of the formula (I) according to the invention can also be present in the tautomeric 1H-pyrazole-5-thiol form (I ') (see Scheme 1 below); both tautomeric forms are expressly encompassed by the present invention. Scheme 1

in welcher R¹, R² und R³ die oben angegebenen Bedeutungen aufweisen,
in einem inerten Lösungsmittel mit einem Phosphorsulfid, wie z. B. Phosphorpentasulfid oder 2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfid (Lawesson-Reagens), behandelt
und die resultierenden Verbindungen der Formel (I) gegebenenfalls mit den entsprechenden (i) Lösungsmitteln und/oder (ii) Basen oder Säuren in ihre Solvate, Salze und/oder Solvate der Salze überführt.The invention further provides a process for the preparation of the compounds of the formula (I) according to the invention, which comprises reacting compounds of the formula (I)

in which R ¹ , R ² and R ^{3 have} the meanings given above,
in an inert solvent with a phosphorus sulfide, such as. For example, phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's reagent) treated
and optionally converting the resulting compounds of the formula (I) with the corresponding (i) solvents and / or (ii) bases or acids into their solvates, salts and / or solvates of the salts.

When inert solvents are suitable for this process Hydrocarbons such as hexane, cyclohexane, benzene, toluene or xylene; toluene is preferably used. The reactions take place generally in a temperature range from + 50 ° C to + 150 ° C, preferably at + 80 ° C to + 120 ° C. The reactions can be normal, elevated or at low pressure (eg from 0.5 up to 5 bar); generally one works at normal pressure.

in welcher R¹ und R³ die oben angegebenen Bedeutungen aufweisen und
Z¹ für Methyl oder Ethyl steht,
in einem inerten Lösungsmittel gegebenenfalls in Gegenwart einer Säure mit einer Verbindung der Formel (IV)

in welcher R² die oben angegebene Bedeutung aufweist,
zu Verbindungen der Formel (V)

in welcher Z¹, R¹, R² und R³ die oben angegebenen Bedeutungen aufweisen,
umsetzt, welche bereits unter diesen Reaktionsbedingungen oder in einem nachfolgenden Reaktionsschritt unter dem Einfluss einer Base zu den Verbindungen der Formel (II) cyclisieren.The compounds of the formula (II) can be prepared by reacting a compound of the formula (III)

in which R ¹ and R ^{3 have} the meanings given above and
Z ^{1 is} methyl or ethyl,
in an inert solvent, if appropriate in the presence of an acid, with a compound of the formula (IV)

in which R ^{2 has} the abovementioned meaning,
to compounds of the formula (V)

in which Z ¹ , R ¹ , R ² and R ^{3 have} the meanings given above,
which already under these reaction conditions or in a subsequent reaction step cyclize under the influence of a base to the compounds of formula (II).

in welcher R¹ die oben angegebene Bedeutung aufweist und
Z¹ für Methyl oder Ethyl steht,
mit einer Verbindung der Formel (VII)

in welcher
Z² für Methyl oder Ethyl steht,
zu Verbindungen der Formel (VIII)

in welcher Z¹ und R¹ die oben angegebenen Bedeutungen aufweisen,
kondensiert und anschließend in Gegenwart einer Säure mit einer Verbindung der Formel (IV) zu Verbindungen der Formel (V-A)

in welcher Z¹, R¹ und R² die oben angegebenen Bedeutungen aufweisen,
umsetzt, welche bereits unter diesen Reaktionsbedingungen oder in einem nachfolgenden Reaktionsschritt unter dem Einfluss einer Base zu den Verbindungen der Formel (II), worin R³ für Wasserstoff steht, cyclisieren.Compounds of the formula (II) in which R ^{3 is} hydrogen can also be prepared by initially preparing a compound of the formula (VI)

in which R ^{1 has} the abovementioned meaning and
Z ^{1 is} methyl or ethyl,
with a compound of the formula (VII)

in which
Z ^{2 is} methyl or ethyl,
to compounds of the formula (VIII)

in which Z ¹ and R ^{1 have} the meanings given above,
condensed and then in the presence of an acid with a compound of formula (IV) to give compounds of formula (VA)

in which Z ¹ , R ¹ and R ^{2 have} the meanings given above,
which already under these reaction conditions or in a subsequent reaction step under the influence of a base to the compounds of formula (II), wherein R ^{3 is} hydrogen, cyclize.

If appropriate, further compounds of the formula (II) can also be prepared by conversions of functional groups of individual substituents, in particular those listed under R ¹ and R ² , starting from the compounds of the formula (II) obtained by the above processes. These transformations are carried out by customary methods known to those skilled in the art and include, for example, reactions such as nucleophilic or electrophilic substitution, oxidation, reduction, hydrogenation, transition metal-catalyzed coupling reactions, alkylation, acylation, amination, esterification, ester cleavage, etherification, ether cleavage, formation of carbonamides, Sulfonamides, carbamates and ureas, as well as the introduction and removal of temporary protecting groups.

When inert solvent for the process steps (III) + (IV) → (V), (V) → (II), (VIII) + (IV) → (V-A) and (V-A) → (II) are particularly suitable alcohols such as Methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol. Preferably, methanol or ethanol are used.

The process step (VI) + (VII) → (VIII) is preferably carried out in dimethylformamide as a solvent or else in the presence of an excess of (VI) without further solvent. Optionally, the reaction can also be advantageously carried out under microwave irradiation. The reaction is generally carried out in a temperature range from + 20 ° C to + 150 ° C, preferably at + 80 ° C to + 120 ° C [see. also JP Bazureau et al., Synthesis 1998, 967; ibid. 2001 (4), 581 ].

The Process steps (III) + (IV) → (V) and (VIII) + (IV) (V-A) may optionally be advantageous with the addition of a Acid are carried out. Suitable for this purpose usual inorganic or organic acids like for example, hydrogen chloride, acetic acid, trifluoroacetic acid, Methanesulfonic acid, p-toluenesulfonic acid or camphor-10-sulfonic acid. Preferably acetic acid or in particular camphor-10-sulfonic acid are used.

The Reaction (III) + (IV) → (V) is generally carried out in a temperature range from 0 ° C to + 100 ° C, preferred at + 10 ° C to + 50 ° C. The reaction (VIII) + (IV) → (V-A) is generally in a temperature range of + 20 ° C to + 120 ° C, preferably at + 50 ° C to + 100 ° C. carried out.

The Process Sequences (III) + (IV) → (V) → (II) and (VIII) + (IV) → (V-A) → (II) under two-stage reaction or as a one-pot reaction, without isolation of the intermediate (V) or (V-A) performed become. In part, a ring closure to (II) already at the preparation of (V) or (V-A); the cyclization can then optionally by in situ treatment of the reaction mixture with to complete a base.

When Base for such a separate cyclization step (V) → (II) or (V-A) → (II) are customary inorganic or organic bases. These include in particular alkali metal hydroxides such as sodium or potassium hydroxide, alkali or alkaline earth metal carbonates such as sodium, potassium, calcium or cesium carbonate, alkali alcoholates such as sodium or potassium methoxide, sodium or potassium ethanolate or sodium or potassium tert-butoxide, or alkali hydrides such as Sodium hydride. Preference is given to sodium methoxide or ethanolate used.

The Reaction (V) → (II) or (V-A) → (II) takes place generally in a temperature range from 0 ° C to + 60 ° C, preferably at 0 ° C to + 30 ° C.

All Process steps may be normal, increased or at a reduced pressure (e.g. from 0.5 to 5 bar). Generally, one works at normal pressure.

The Compounds of the formula (III) can be obtained according to customary literature Methods for the C-Acylation of Carboxylic Esters from Compounds of the formula (VI). The compounds of the formulas (IV), (VI) and (VII) are commercially available, known from the literature or may be analogous to those described in the literature Process are produced.

[a): DMF, 16 h, +100°C; b): Ethanol, cat. Campher-10-sulfonsäure, +78°C; c): NaOEt, Ethanol, 1 h, RT]. Schema 3

[d): Lawesson-Reagens, Toluol, +110°C].The preparation of the compounds of this invention can be illustrated by the following Reaction Schemes 2 and 3: Scheme 2

[a): DMF, 16h, + 100 ° C; b): ethanol, cat. Camphor-10-sulfonic acid, + 78 ° C; c): NaOEt, ethanol, 1 h, RT]. Scheme 3

[d): Lawesson's reagent, toluene, + 110 ° C].

in welcher R¹ die oben angegebene Bedeutung aufweist und
Z¹ für Methyl oder Ethyl steht,
in einem inerten Lösungsmittel mit einem Phosphorsulfid, wie z. B. Phosphorpentasulfid oder 2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetan-2,4-disulfid (Lawesson-Reagens), in die entsprechenden Thio-Verbindungen der Formel (VIII-A)

in welcher Z¹ und R¹ die oben angegebenen Bedeutungen aufweisen,
überführt und diese dann analog zum zuvor beschriebenen Verfahren in Gegenwart einer Säure mit einer Verbindung der Formel (IV)

in welcher R² die oben angegebene Bedeutung aufweist,
zu Verbindungen der Formel (V-B)

in welcher Z¹, R¹ und R² die oben angegebenen Bedeutungen aufweisen,
umsetzt, welche bereits unter diesen Reaktionsbedingungen oder in einem nachfolgenden Reaktionsschritt unter dem Einfluss einer Base zu den Verbindungen der Formel (I), worin R³ für Wasserstoff steht, cyclisieren.According to a further aspect of the present invention, compounds of the formula (I) according to the invention in which R ^{3 is} hydrogen can also be prepared by reacting the above-described compounds of the formula (VIII)

in which R ^{1 has} the abovementioned meaning and
Z ^{1 is} methyl or ethyl,
in an inert solvent with a phosphorus sulfide, such as. As phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide (Lawesson's reagent), in the corresponding thio compounds of the formula (VIII- A)

in which Z ¹ and R ^{1 have} the meanings given above,
and then converted analogously to the method described above in the presence of an acid with a compound of formula (IV)

in which R ^{2 has} the abovementioned meaning,
to compounds of the formula (VB)

in which Z ¹ , R ¹ and R ^{2 have} the meanings given above,
which already under these reaction conditions or in a subsequent reaction step under the influence of a base to the compounds of formula (I), wherein R ^{3 is} hydrogen, cyclize.

For the process sequence (VIII) → (VIII-A), (VIII-A) + (IV) → (V-B) and (V-B) → (I) find the above for the reactions (II) (I), (VIII) + (IV) → (V-A) and (V-A) → (II) described reaction parameters such as solvents, acids or bases and reaction temperatures in an analogous manner application.

[e): Lawesson-Reagens, Toluol, +110°C; f): Ethanol, cat. Campher-l0-sulfonsäure, +78°C; g): NaOEt, Ethanol, 1 h, RT].
[Abkürzungen: cat. = katalytisch; DMF = Dimethylformamid; Et = Ethyl; h = Stunden; RT = Raumtemperatur].This preparation variant can be illustrated by the following Reaction Scheme 4: Scheme 4

[e]: Lawesson's reagent, toluene, + 110 ° C; f): ethanol, cat. Camphor-10-sulfonic acid, + 78 ° C; g): NaOEt, ethanol, 1 h, RT].
[Abbreviations: cat. = catalytic; DMF = dimethylformamide; Et = ethyl; h = hours; RT = room temperature].

The Compounds of the invention do not show a predictable, valuable pharmacological spectrum of action. They are suitable Therefore, for use as a medicament for the treatment and / or Prophylaxis of diseases in humans and animals.

The Compounds of the invention are characterized as specific inhibitors of HIF-prolyl-4-hydroxylases.

The Compounds according to the invention can due to their pharmacological properties for treatment and / or Prophylaxis of cardiovascular diseases, in particular heart failure, coronary artery disease, angina pectoris, Myocardial infarction, stroke, arteriosclerosis, more essential, pulmonary and malignant hypertension and peripheral arterial disease be used.

The Compounds according to the invention are also suitable for the treatment and / or prophylaxis of disorders of blood formation, such as Idiopathic anemia, renal anemia and anemias accompanied by a tumor disease (in particular chemotherapy-induced anemia), an infection (especially HIV infection) or another inflammatory Illness such as Rheumatoid arthritis. The invention Compounds are also suitable for supporting Treatment of anemia due to blood loss, iron deficiency anemia, Vitamin deficiency anemia (eg as a result of vitamin B12 deficiency or due to folic acid deficiency), hypoplastic and aplastic Anemia, hemolytic anemia or to supporting treatment of anemias in succession of iron utilization disorders (sideroachestische anämie) or anemia due to other endocrine disorders (eg hypothyroidism).

The Compounds are also useful for increasing hematocrit with the aim of obtaining blood for autologous blood donation before surgery.

The compounds of the invention may also be used for the treatment and / or prophylaxis of surgical ischemic conditions and their sequelae after surgical procedures, in particular heart surgery using a heart-lung machine (eg bypass surgery, heart valve implantation), carotid artery interventions, Interventions on the body artery (aorta) and procedures with instrumental opening or penetration of the calvarium can be used. The Ver Furthermore, compounds are suitable for general treatment and / or prophylaxis in surgical interventions with the aim of accelerating wound healing and shortening the convalescence time.

The In addition, compounds are for treatment and prophylaxis of sequelae of acute and protracted ischemic conditions of the brain (eg, stroke, birth asphyxia).

The Compounds may also be used for treatment and / or prophylaxis of cancer and for the treatment and / or prophylaxis of one in the course of Treatment of cancer occurring impairment of the State of health especially after treatment with cytostatics, Antibiotics and radiation are used.

The Compounds are also suitable for treatment and / or prophylaxis of diseases of the rheumatic type and other den Autoimmune diseases attributable to diseases and in particular for the treatment and / or prophylaxis of a drug Treatment of such disorders occurring impairment of health status.

Farther can the compounds of the invention used for the treatment and / or prophylaxis of diseases of the eye (eg glaucoma), of the brain (eg Parkin son's disease, Alzheimer's disease, dementia, chronic pain sensation), of chronic Kidney disease, renal insufficiency and acute renal failure and to promote wound healing.

Farther the compounds are suitable for treatment and / or prophylaxis especially in old age occurring general physical weakness to cachexia.

Further the compounds are suitable for treatment and / or prophylaxis sexual dysfunction.

Furthermore are the compounds for the treatment and / or prophylaxis of diabetes mellitus and its sequelae, such. B. diabetic macro and microangiopathy, diabetic nephropathy and neuropathy, suitable.

Farther the compounds of the invention are suitable for the treatment and / or prophylaxis of fibrotic diseases z. The heart, lungs and liver.

Especially the compounds according to the invention are also for Prophylaxis and treatment of retinopathy of prematurity (Retinopathia praematurorum) suitable.

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

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

Another The subject of the present invention is a method of treatment and / or disease prevention, in particular the aforementioned diseases, using an effective amount of at least one of the compounds of the invention.

The Compounds according to the invention can Used alone or as needed in combination with other drugs become. Another object of the present invention are pharmaceuticals, containing at least one of the invention Compounds and one or more other active ingredients, in particular for the treatment and / or prevention of the aforementioned Diseases. As suitable combination active ingredients are exemplary and preferably named: ACE inhibitors, angiotensin II receptor antagonists, Beta-receptor blockers, calcium antagonists, PDE inhibitors, mineralocorticoid receptor antagonists, Diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, Statins, digitalis (digoxin) derivatives, tumor chemotherapeutics as well Antibiotics.

at a preferred embodiment of the invention the compounds of the invention in combination with an ACE inhibitor, such as by way of example and preferably enalapril, Captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, Perindopril or trandopril.

at a preferred embodiment of the invention the compounds of the invention in combination with an angiotensin AII antagonist, as exemplified and preferably Losartan, candesartan, valsartan, telmisartan or embusartan.

at a preferred embodiment of the invention the compounds of the invention in combination with a beta-receptor blocker, as exemplified and preferably Propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, Penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, Metoprolol, Betaxolol, Celiprolol, Bisoprolol, Carteolol, Esmolol, Labetalol, Carvedilol, Adaprolol, Landiolol, Nebivolol, Epanolol or bucindolol.

at a preferred embodiment of the invention the compounds of the invention in combination with a calcium antagonist, as exemplified and preferably Nifedipine, amlodipine, verapamil or diltiazem.

at a preferred embodiment of the invention the compounds of the invention in combination with a phosphodiesterase (PDE) inhibitor as exemplified and preferably milrinone, amrinone, pimobendan, cilostazol, sildenafil, Vardenafil or tadalafil.

at a preferred embodiment of the invention the compounds of the invention in combination with a mineralocorticoid receptor antagonist, as exemplified and preferably spironolactone, eplerenone, canrenone or potassium canrenoate, administered.

at a preferred embodiment of the invention the compounds of the invention in combination with a diuretic, such as by way of example and preferably furosemide, Bumetanide, Torsemid, Bendroflumethiazide, Chlorothiazide, Hydrochlorothiazide, Hydroflumethiazide, methyclothiazide, polythiazide, trichloromethiazide, Chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, Dichlorophenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene.

at a preferred embodiment of the invention the compounds of the invention in combination with a HMG-CoA reductase inhibitor from the class of statins, as exemplary and preferably lovastatin, simvastatin, pravastatin, Fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin, administered.

at a preferred embodiment of the invention the compounds of the invention in combination administered with a tumor chemotherapeutic, by way of example and preferably from the group of platinum complexes, such as. Cisplatin and carboplatin, the alkylating agents, such as. B. cyclophosphamide and Chlorambucil, the antimetabolites, such as. 5-fluorouracil and methotrexate, the topoisomerase inhibitor, such as. Etoposide and camptothecin, the Antibiotics, such as. , Doxorubicin and daunorubicin, or the kinase inhibitors, such as Sorafenib and sunitinib.

at a preferred embodiment of the invention the compounds of the invention in combination administered with an antibiotic, by way of example and preferably from the group of penicillins, cephalosporins or quinolones, such as z. Ciprofloxacin and moxifloxacin.

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

The Compounds according to the invention can act systemically and / or locally. For this purpose can they are applied in a suitable manner, such as. Oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival, otic or as an implant or stent.

For These routes of administration can be the inventive Compounds are administered in suitable administration forms.

For oral administration are according to the prior art working, the compounds of the invention rapidly and / or modified donating application forms containing the compounds of the invention in crystalline and / or amorphized and / or dissolved form, such. As tablets (uncoated or coated tablets, for example, with enteric or delayed dissolving or insoluble coatings, which control the release of the compound of the invention ren), in the oral cavity rapidly disintegrating tablets or films / wafers, films / lyophilisates, capsules (for example, hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

The Parenteral administration can bypass a resorption step happen (eg intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or with involvement of absorption (eg, intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Suitable for parenteral administration themselves as application forms u. a. Injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other routes of administration are suitable for. B. Inhalation medicines (including powder inhalers, nebulizers), nasal drops, solutions or -sprays, lingual, sublingual or buccal tablets to be applied, films / wafers or capsules, suppositories, ear or eye preparations, Vaginal capsules, aqueous suspensions (lotions, Shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (eg patches), milk, pastes, Foams, scattering powders, implants or stents.

Prefers are the oral or parenteral administration, especially oral and intravenous administration.

The Compounds according to the invention can converted into the mentioned application forms become. This can be done in a conventional manner by mixing with inert, Non-toxic, pharmaceutically suitable excipients happen. These adjuvants include u. a. excipients (for example, microcrystalline cellulose, lactose, mannitol), Solvents (eg liquid polyethylene glycols), Emulsifiers and dispersing or wetting agents (for example sodium dodecylsulphate, Polyoxysorbitanoleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), Stabilizers (eg antioxidants such as ascorbic acid), Dyes (eg inorganic pigments such as iron oxides) and flavor and / or scent remedies.

in the In general, it has proven to be beneficial in parenteral Application amounts of about 0.001 to 1 mg / kg, preferably about 0.01 to 0.5 mg / kg body weight to achieve effective To give results. For oral administration is the dosage about 0.01 to 100 mg / kg, preferably about 0.01 to 20 mg / kg and most preferably 0.1 to 10 mg / kg of body weight.

Nevertheless it may be necessary, if necessary, of the quantities mentioned to deviate, depending on body weight, Application route, individual behavior towards the Active substance, method of preparation and time or interval, too which the application takes place. So it can in some cases be sufficient, with less than the aforementioned minimum quantity while in other cases the said upper limit must be exceeded. In case of application larger quantities may be recommended, this one in several single doses to distribute over the day.

The The following embodiments illustrate the Invention. The invention is not limited to the examples.

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

A. Embodiments

Abbreviations and acronyms:

• aq.

  aqueous solution

  cat.

  catalytic

  d

  Day (s)

  DCI

  direct chemical Ionization (in MS)

  DMF

  dimethylformamide

  DMSO

  dimethyl sulfoxide

  d. Th.

  the theory (at yield)

  EGG

  Electron impact ionization (in MS)

  IT I

  Electrospray ionization (in MS)

  et

  ethyl

  H

  Hour (s)

  HPLC

  High pressure, high performance liquid chromatography

  conc.

  concentrated

  LC-MS

  Liquid chromatography-coupled mass spectroscopy

  Meth.

  method

  min

  Minute (s)

  MS

  mass spectroscopy

  NMR

  Nuclear Magnetic Resonance Spectroscopy

  R _t

  Retention time (at HPLC)

  RT

  room temperature

  TFA

  trifluoroacetic

  THF

  tetrahydrofuran

  LC-MS

  and HPLC methods:

Method 1:

Instrument: Micromass Platform LCZ with HPLC Agilent Series 1100; Pillar: Thermo Hypersil GOLD 3 μ, 20 mm × 4 mm; eluent A: 1 l of water + 0.5 ml of 50% formic acid, eluent B: 1 liter of acetonitrile + 0.5 ml of 50% formic acid; Gradient: 0.0 min 100% A → 0.2 min 100% A → 2.9 min 30% A → 3.1 min 10% A → 5.5 min 10% A; Oven: 50 ° C; Flow: 0.8 ml / min; UV detection: 210 nm.

Method 2:

Instrument: HP 1100 with DAD detection; Column: Kromasil 100 RP-18, 60 mm × 2.1 mm, 3.5 μm; Eluent A: 5 ml perchloric acid (70%) / liter water, eluent B: acetonitrile; Gradient: 0 min 2% B → 0.5 min 2% B → 4.5 min 90% B → 6.5 min 90% B → 6.7 min 2% B → 7.5 min 2% B; Flow: 0.75 ml / min; Column temperature: 30 ° C; UV detection: 210 nm. Starting compounds and intermediates: Example 1A Ethyl 3- (dimethylamino) -2-pyridin-3-ylacrylate

37.4 g (226 mmol) of pyridin-3-yl-ethyl acetate are heated to 100 ° C. in 100 g (679 mmol) of dimethylformamide diethyl acetal overnight. After cooling, the mixture is concentrated and the residue is first purified by flash chromatography on silica gel (mobile phase: gradient cyclohexane / ethyl acetate 1: 1 → ethyl acetate / ethanol 9: 1). The product thus obtained is then finely purified by vacuum distillation (1 mbar, 200 ° C bath temperature).
Yield: 35.0 g (70% of theory)
LC-MS (Method 1): R _t = 2.38 min; MS (ESIpos): m / z = 221 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): 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). Example 2A O-Ethyl-3- (dimethylamino) -2-pyridin-3-yl-prop-2-enthioate

10.0 g (45.4 mmol) of the compound from Example 1A are mixed with 300 ml of toluene and 20.2 g (49.9 mmol) of 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4 disulfide (Lawesson's reagent). The reaction mixture is refluxed for 4 hours and then concentrated in vacuo. The residue is taken up in 100 ml of ethyl acetate and 100 ml of saturated sodium bicarbonate solution. The organic phase is separated and washed twice with 50 ml of saturated sodium bicarbonate solution, then dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by double column chromatography on silica gel (eluent dichloromethane / methanol 95: 5).
Yield: 1.8 g (17% of theory)
LC-MS (Method 1): R _t = 2.43 min; MS (ESIpos): m / z = 237 [M + H] ⁺ . Example 3A 2-Hydrazino-4-methylpyridine

3.3 g (30.0 mmol) of 2-fluoro-4-methylpyridine are initially charged in 40 ml of ethylene glycol monoethyl ether, the solution is combined with 14.6 ml (15.0 g, 300 mmol) of hydrazine hydrate and the batch is stirred at boiling temperature (150 ° C. bath temperature) for 16 h , The reaction solution is then concentrated on a rotary evaporator, the residue is added to 100 ml of water and extracted with ethyl acetate (three times per 100 ml). The combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue obtained is dried in vacuo.
Yield: 1.90 g (51% of theory)
LC-MS (Method 1): R _t = 0.80 min; MS (ESIpos): m / z = 124 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 7.83 (d, 1H), 7.22 (s, 1H), 6.51 (s, 1H), 6.38 (d, 1H), 4.04 (s, 2H) , 2.17 (s, 3H). Exemplary embodiments: Example 1 2-Pyridin-2-yl-4-pyridin-3-yl-1,2-dihydro-3H-pyrazole-3-thione hydrochloride

400 mg (1.7 mmol) of the compound from Example 2A and 185 mg (1.7 mmol) of 2-pyridylhydrazine are dissolved in 4 ml of ethanol and admixed with 79 mg (0.3 mmol) of camphor-10-sulfonic acid. It is refluxed for 24 h, then cooled to RT and purified directly by preparative HPLC (RP18 column, mobile phase: acetonitrile / water gradient with the addition of 0.1% formic acid in water). The product-containing fractions are concentrated in vacuo, the residue dissolved in 0.5 ml of methanol and treated with 0.5 ml of a 4 N solution of hydrogen chloride in dioxane. It is stirred for 30 min at RT. The resulting precipitate is filtered off, washed with diethyl ether and dried under high vacuum.
Yield: 21 mg (4% of theory)
LC-MS (Method 1): R _t = 2.06 min; MS (ESIpos): m / z = 255 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 10.03 (s, 1H), 9.35 (d, 1H), 8.76-8.65 (m, 3H), 8.58 (s, 1H), 8.37 (dd, 1H), 8.03 (dd, 1H), 7.65 (dd, 1H). Example 2 2- (4-Methylpyridin-2-yl) -4-pyridin-3-yl-1,2-dihydro-3H-pyrazole-3-thione hydrochloride

768 mg (3.2 mmol) of the compound from Example 2A and 400 mg (3.2 mmol) of the compound from Example 3A are dissolved in 4 ml of ethanol and admixed with 151 mg (0.7 mmol) of camphor-10-sulfonic acid. It is heated under reflux for 24 h, then cooled to RT and the resulting precipitate is filtered off. This is dissolved in 0.4 ml of methanol and treated with 0.2 ml of a 4 N solution of hydrogen chloride in dioxane. It is stirred for 30 min at RT. The precipitate is filtered off, then stirred in a 9: 1 mixture of acetonitrile and water, filtered off again and finally dried under high vacuum.
Yield: 22 mg (2% of theory)
HPLC (Method 2): R _t = 3.20 min; MS (ESIpos): m / z = 269 [M + H] ⁺ ;
¹ H-NMR (400 MHz, DMSO-d ₆ ): δ = 9.97 (s, 1H), 9.37 (d, 1H), 8.66 (d, 1H), 8.60-8.57 (m, 3H), 8.02 (dd, 1H), 7.57 (d, 1H), 2.60 (s, 3H).

Beispiel 4 2-[4-(Aminomethyl)pyridin-2-yl]-4-pyridin-3-yl-1,2-dihydro-3H-pyrazol-3-thion

Beispiel 5 2-Pyridin-2-yl-4-[5-(trifluormethyl)-1,3,4-thiadiazol-2-yl]-1,2-dihydro-3H-pyrazol-3-thion

Beispiel 6 2-[5-(Hydroxymethyl)pyridin-2-yl]-4-pyridin-3-yl-1,2-dihydro-3H-pyrazol-3-thion

Beispiel 7 2-(6-Piperidin-1-ylpyrimidin-4-yl)-4-pyridin-3-yl-1,2-dihydro-3H-pyrazol-3-thion

Beispiel 8 5-(2-Pyridin-2-yl-3-thioxo-2,3-dihydro-1H-pyrazol-4-yl)pyridin-2-carbonitril

Beispiel 9 2-(4-Methoxypyridin-2-yl)-4-pyridin-3-yl-1,2-dihydro-3H-pyrazol-3-thion

The following compounds according to the invention (in the form of their hydrochlorides or as free bases) can also be prepared by the processes described above: EXAMPLE 3 2- (6-morpholin-4-yl-pyrimidin-4-yl) -4-pyridin-3-yl 1,2-dihydro-3H-pyrazol-3-thione

Example 4 2- [4- (Aminomethyl) pyridin-2-yl] -4-pyridin-3-yl-1,2-dihydro-3H-pyrazole-3-thione

Example 5 2-Pyridin-2-yl-4- [5- (trifluoromethyl) -1,3,4-thiadiazol-2-yl] -1,2-dihydro-3H-pyrazole-3-thione

Example 6 2- [5- (Hydroxymethyl) pyridin-2-yl] -4-pyridin-3-yl-1,2-dihydro-3H-pyrazole-3-thione

Example 7 2- (6-piperidin-1-yl-pyrimidin-4-yl) -4-pyridin-3-yl-1,2-dihydro-3H-pyrazole-3-thione

Example 8 5- (2-Pyridin-2-yl-3-thioxo-2,3-dihydro-1H-pyrazol-4-yl) pyridine-2-carbonitrile

Example 9 2- (4-Methoxypyridin-2-yl) -4-pyridin-3-yl-1,2-dihydro-3H-pyrazole-3-thione

B. Evaluation of Pharmacological Activity

The pharmacological properties of the invention Compounds can be shown in the following assays:

Abbreviations:

• DMEM

  Dulbecco's Modified Eagle Medium

  FCS

  Fetal Calf Serum

  TMB

  3,3 ', 5,5'-tetramethylbenzidine

  Tris

  Tris (hydroxymethyl) aminomethane

1. In vitro tests to determine the activity and selectivity of HIF prolyl 4-hydroxylase inhibitors

1.a) inhibition of the activity of HIF prolyl hydroxylase:

Hydroxylated HIF binds specifically to von Hippel-Lindau protein Elongin B-Elongin C complex (VBC complex). This interaction only occurs when HIF is hydroxylated on a conserved prolyl residue. It is the basis for the biochemical determination of HIF-prolyl hydroxylase activity. The test is carried out as described [ Oehme F., Jonghaus W., Narouz-Ott L., Huetter J., Flame I., Anal. Biochem. 330 (1), 74-80 (2004) ]:
A clear, NeutrAvidin HBC coated 96-well microtiter plate (Pierce) is incubated for 30 minutes with blocker casein. The plate is then washed three times with 200 μl of wash buffer (50 mM Tris, pH 7.5, 100 mM NaCl, 10% (v / v) Blocker Casein, 0.05% (v / v) Tween 20) per well. The peptide biotin-DLDLEMLAPYIPMDDDFQL (Eurogentec, 4102 Seraing, Belgium) is added at a concentration of 400 nM in 100 μl washing buffer. This peptide serves as a substrate for prolyl hydroxylation and is bound to the microtiter plate. After incubation for 60 minutes, the plate is washed three times with washing buffer, incubated with 1 mM biotin in blocking casein for 30 minutes and then washed again three times with washing buffer.

To perform the prolyl hydroxylase reaction, the peptide substrate bound to the plate is incubated for 1 to 60 minutes with a prolyl hydroxylase-containing cell lysate. The reaction is carried out in 100 μl of reaction buffer (20 mM Tris, pH 7.5, 5 mM KCl, 1.5 mM MgCl ₂ , 1 μM-1 mM 2-oxoglutarate, 10 μM FeSO ₄ , 2 mM As corbat) at room temperature. The reaction mixture also contains the test inhibitor of prolyl hydroxylase in various concentrations.

The Test substance is preferred, but not exclusive used at concentrations between 1 nM and 100 uM. By washing the plate three times with wash buffer, the reaction becomes stopped.

to quantitative determination of prolyl hydroxylation becomes a fusion protein, containing both thioredoxin from E. coli and the VBC complex, in 80 μl of binding buffer (50 mM Tris, pH 7.5, 120 mM NaCl). After 15 minutes, 10 μl of a solution of rabbit polyclonal anti-thioredoxin antibody added in binding buffer. After another 30 minutes continues Add 10 μl of a solution of horseradish peroxidase coupled anti-rabbit immunoglobulin in binding buffer. After 30 minutes incubation at room temperature is repeated three times with washing buffer washed to unbound VBC complex and antibodies too remove. To determine the amount of bound VBC complex, is incubated with TMB for 15 minutes. The color reaction is by addition of 100 μl of 1 M sulfuric acid. By measurement the optical density at 450 nm becomes the amount of bound VBC complex certainly. It is proportional to the amount of hydroxylated proline in the peptide substrate.

Alternatively, a VBC complex coupled with Europium (Perkin Elmer) can be used to detect prolyl hydroxylation. In this case, the amount of bound VBC complex is determined by time-resolved fluorescence. In addition, the use of [ ³⁵ S] -methionine labeled VBC complex is possible. For this, the radioactively labeled VBC complex can be prepared by in vitro transcription translation into reticulocyte lysate.

The embodiments inhibit the activity of HIF prolyl hydroxylase in this assay with an IC ₅₀ of ≤30 μM.

1.b) Cellular, more functional in vitro test:

The quantification of the activity of the compounds according to the invention is carried out with the aid of a recombinant cell line. The cell is originally derived from a human lung carcinoma cell line (A549, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell line is stably transfected with a vector containing the reporter gene of Photinus pyralis luciferase (hereinafter called luciferase) under the control of a minimal artificial promoter. The minimal promoter consists of two hypoxia-responsive elements upstream of a TATA box [ Oehme F., Ellinghaus P., Kolkhof P., Smith TJ, Ramakrishnan S., Hütter J., Schramm M., Flamme I., Biochem. Biophys. Res. Commun. 296 (2), 343-9 (2002) ]. Under the influence of hypoxia (eg cultivation in the presence of 1% oxygen for 24 hours) or under the action of unselective dioxygenase inhibitors (eg desferroxamine in a concentration of 100 μM, cobalt chloride in a concentration of 100 μM or Oxalylglycindiethyl in a concentration of 1 mM) ester produces the test cell line luciferase (using appropriate bioluminescence reagents z. B. steady-Glo ^® luciferase assay system, Promega Corporation, Madison, WI 53711, USA) and a suitable luminometer detected and can be quantified.

Test sequence: The cells are plated in 384 or 1536 well microtiter plates in a precisely measured amount of culture medium (DMEM, 10% FCS, 2 mM glutamine) the day before the test and incubated in a cell incubator (96% humidity, 5% v / v CO ₂ , 37 ° C). On the test day, the test substances are added to the culture medium in graduated concentrations. In negative control approaches, no test substance is added to the cells. As a positive control for determining the sensitivity of the cell for inhibitors z. B. desferroxamine added in a final concentration of 100 uM. Six to 24 hours after transfer of the test substances into the wells of the microtiter plates, the resulting light signal is measured in the luminometer. On the basis of the measured values, a dose-response relationship is established which serves as the basis for determining the half-maximal effective concentration (referred to as EC ₅₀ value).

1.c) Cellular, more functional in vitro test for altering gene expression:

To study the change in the expression of specific mRNAs in human cell lines after treatment with test substances, the following cell lines are cultured on 6 or 24-well plates: human hepatoma cells (HUH, JCRB Cell Bank, Japan), human embryonic kidney fibroblasts (HEK / 293, ATCC , Manassas, VA 20108, USA), human cervical carcinoma 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 substances, the cells are washed with phosphate-buffered saline and extracted from ih NEN total RNA extracted using an appropriate method (eg. B. Trizol reagent ^®, Invitrogen GmbH, 76131 Karlsruhe, Germany).

For a typical analytical experiment, 1 μg each of the total RNA so obtained is digested with DNase I and into a complementary DNA using a suitable reverse transcriptase reaction (ImProm-II Reverse Transcription System, Promega Corporation, Madison, WI 53711, USA) (cDNA) translated. 2.5% of the cDNA mixture thus obtained are used in each case for the polymerase chain reaction. The expression level of the mRNA of the genes to be investigated is determined by means of the real time quantitative polymerase chain reaction [ TaqMan PCR; Heid CA, Stevens J., Livak KJ, Williams PM, Genome Res. 6 (10), 986-94 (1996) ] using an ABI Prism 7700 sequence detection instrument (Applied Biosystems, Inc.). The primer-probe combinations used here are generated by means of the Primer Express 1.5 software (Applied Biosystems, Inc.). Specifically, the mRNAs of erythropoietin, carbonic anhydrase IX, lactate dehydrogenase A, and vascular endothelial cell growth factor are examined.

substances lead in accordance with the present invention to a significant, dose-dependent increase in mRNA Hypoxia-induced genes in cells of human origin.

2. In vivo tests for detection the effect in the cardiovascular system

 2.a) In vivo test for change Gene expression:

Mice or rats are given the test compounds dissolved in suitable solvents either orally by gavage, intraperitoneally or intravenously. Typical dosages are 0.1, 0.5, 1, 5, 10, 20, 50, 100 and 300 mg substance per kg body weight and administration. Control animals receive only solvents. 4, 8 or 24 hours after administration of the test substance, the animals are killed with an overdose of isoflurane and subsequent cervical dislocation and the organs to be examined are removed. Parts of the organs are snap frozen in liquid nitrogen. From the organ parts as described under B.1.a) total RNA is recovered and this translated into a cDNA. The expression level of the mRNA of the genes to be investigated is determined by means of the real time quantitative polymerase chain reaction [ TaqMan PCR; Heid CA, Stevens J., Livak KJ, Williams PM, Genome Res. 6 (10), 986-94 (1996) ] using an ABI Prism 7700 sequence detection instrument (Applied Biosystems, Inc.).

substances lead in accordance with the present invention compared with placebo control after oral or parenteral Administration to a significant, dose-dependent increase mRNA of erythropoietin in kidney.

2.b) Determination of the erythropoietin level in serum:

Mice or rats are administered the test substance in a suitable solvent either intraperitoneally or orally once or twice daily. Typical dosages are 0.1, 0.5, 1, 5, 10, 20, 50, 100 and 300 mg substance per kg body weight and administration. Placebo control animals receive only solvents. Before the application and four hours after the last administration of the substance, 50 μl of blood are taken from the retroorbital venous plexus or the tail vein in short anesthesia. The blood is made impracticable by the addition of lithium heparin. By centrifuging, the blood plasma is recovered. In the blood plasma is by means of a Erythropoietin ELISA (Quantikine ^® mouse Epo Immunoassay, R & D Systems, Inc., Minneapolis, USA) according to the manufacturer's instructions, the content of erythropoietin. The measured values are converted into pg / ml using a reference measurement for mouse erythropoietin.

substances lead in accordance with the present invention after oral and parenteral administration to a significant, versus the dose-dependent increase in plasma erythropoietin baseline and placebo control.

2.c) Determination of the cellular Composition of the peripheral blood:

Mice or rats are given the test substance in a suitable solvent either intraperitoneally or orally once or twice daily for several days. Typical dosages are z. B. 0.1, 0.5, 1, 5, 10, 20, 50, 100 and 300 mg of substance per kg of body weight and administration. Control animals receive only solvents. At the end of the experiment, the animals are bled from the venous plexus of the corner of the eye or the tail vein under anesthesia and made unreachable by the addition of sodium citrate. In a suitable electronic measuring device in the blood samples, the concentrations of erythrocytes, leukocytes and platelets are determined. The concentration of the reticulocytes is determined by means of blood smears, which are stained with a suitable dye solution (KABE Labortechnik, Nümbrecht), by microscopic examination of 1000 erythrocytes. For the determination of the hematocrit blood is taken from the retroorbital venous plexus by means of a hematocrit capillary and the hematocrit value is read manually after centrifuging the capillary in a suitable centrifuge.

substances according to the present invention lead to oral and parenteral administration to a significant, dose-dependent Increase in hematocrit, erythrocyte count and reticulocytes baseline and placebo control.

C. Embodiments for pharmaceutical compositions

The Compounds according to the invention can converted into pharmaceutical preparations as follows become:

Tablet:

Composition:

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

production:

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

Orally administrable suspension:

Composition:

1000 mg of the compound of the invention, 1000 mg of ethanol (96%), 400 mg of Rhodigel ^® (xanthan gum of the Fa. FMC, Pennsylvania, USA) and 99 g of water.

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

production:

The Rhodigel is suspended in ethanol, the inventive Compound is added to the suspension. While stirring the addition of the water takes place. Until the completion of the swelling Rhodigels is stirred for about 6 h.

Orally administrable solution:

Composition:

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

production:

The Compound of the invention is in the mixture of polyethylene glycol and polysorbate suspended with stirring. The stirring process is until complete dissolution continued the compound of the invention.

iv solution:

The Compound of the invention is in a concentration below the saturation solubility in a physiological compatible solvents (eg isotonic Saline, glucose solution 5% and / or PEG 400 solution 30%). The solution will be filtered sterile and into sterile and pyrogen-free injection containers bottled.

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• - EP 165448 [0013]
• - EP 212281 [0013]
• - EP 183159 [0013]
• - DE 2651008 [0013]
• WO 96/12706 [0013]
• WO 00/51989 [0013]
• WO 03/074550 [0013]
• WO 02/068413 [0013]
• - WO 2006/101903 [0013]
• WO 2006/114213 [0013]
• JP 63146878 A2 [0014]

Cited non-patent literature

• - Eder, Gedigk (ed.), General Pathologist and Pathological Anatomy, 33. ed., Springer Verlag, Berlin, 1990 [0002]
• - Schmidt, Thews (ed.), Physiology of Man, 27th ed., Springer Verlag, Berlin, 1997 [0003]
• - Löffler, Petrides (ed.), Biochemistry and Pathobiochemistry, 7th ed., Springer Verlag, Berlin, 2003 [0003]
• - Simons and Ware, Therapeutic angiogenesis in cardiovascular disease, Nat. Rev. Drug. Discov. 2 (11), 863-71 (2003) [0004]
• - Eckardt, The potential of erythropoietin and related strategies to stimulate erythropoiesis, Curr. Opin. Investig. Drugs 2 (8), 1081-5 (2001) [0005]
• - Berns, Should the target hemoglobin for patients with chronic kidney disease treated with erythropoietic replacement therapy be changed ?, Semin. Dial. 18 (1), 22-9 (2005) [0005]
• - Caiola and Cheng, Use of erythropoietin in heart failure management, Ann. Pharmacother. 38 (12), 2145-9 (2004) [0005]
• - Katz, Mechanisms and treatment of anemia in chronic heart failure, congestion. Heart. Fail. 10 (5), 243-7 (2004) [0005]
• - Semenza, Hypoxia-inducible factor 1: Oxygen homeostasis and disease pathophysiology, Trends Mol. Med. 7 (8), 345-50 (2001) [0006]
• Wenger and Gassmann, Oxygen (es) and the hypoxia-inducible factor-1, Biol. Chem. 378 (7), 609-16 (1997) [0006]
• Epstein et al., C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation, Cell 107 (1), 43-54 (2001) [0007]
• Bruick and McKnight, A conserved family of prolyl-4-hydroxylases that modify HIF, Science 294 (5545), 1337-40 (2001) [0007]
• Ivan et al., Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor, Proc. Natl. Acad. Sci. USA 99 (21), 13459-64 (2002) [0007]
• - Aravind and Koonin, the DNA-repair protein AlkB, EGL-9, and leprecan define new families of 2-oxoglutarate and iron-dependent dioxygenases, genomes biol. 2 (3), research 0007.1-0007.8, Epub 2001 Feb 19 [0007]
• - Schofield and Ratcliffe, Oxygen sensing by HIF hydroxylases, Nat. Rev. Mol. Cell. Biol. 5 (5), 343-54 (2004) [0008]
• - Helv. Chim. Acta 49 (1), 272-280 (1966) [0013]
• JP Bazureau et al., Synthesis 1998, 967; ibid. 2001 (4), 581 [0044]
• Oehme F., Jonghaus W., Narouz-Ott L., Huetter J., Flamme I., Anal. Biochem. 330 (1), 74-80 (2004) [0106]
• Oehme F., Ellinghaus P., Kolkhof P., Smith TJ, Ramakrishnan S., Hütter J., Schramm M., Flamme I., Biochem. Biophys. Res. Commun. 296 (2), 343-9 (2002) [0112]
• TagMan PCR; Heid CA, Stevens J., Livak KJ, Williams PM, Genome Res. 6 (10), 986-94 (1996) [0115]
• TagMan PCR; Heid CA, Stevens J., Livak KJ, Williams PM, Genome Res. 6 (10), 986-94 (1996) [0117]

Claims (11)

Compound of the formula (I)

in which R ^{1 is} a heteroaryl group of the formula

where * is the point of attachment to the dihydropyrazolethione ring, A in each individual occurrence is CR ⁴ or N, with a maximum of two ring members A being N at the same time, DO, S or NR ⁵ and E being CR ⁶ or N means, wherein a maximum of two ring members E are both N, R ^{2 is} a heteroaryl group of the formula

where # is the point of attachment to the dihydropyrazolethione ring, G in each individual occurrence is CR ⁷ or N, with a maximum of two ring members G being N at the same time, JO, S or NR ⁸ and L being CR ⁹ at each occurrence N is where a maximum of two ring members L are simultaneously N, where R ⁴ , R ⁷ and R ^{9 are} identical or different and in each case, independently of one another, represent hydrogen or a substituent selected from the group halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O ) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² are in which (i) (C ₁ -C ₆ ) alkyl in turn one to three times, same or different, with residues au selected from the group halogen, cyano, oxo, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O ) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² PR ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² may be substituted, wherein the last-mentioned cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals in turn each up to three times, the same or various, with halogen, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) alkylamino, di - (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, (ii) (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each one to three times, same or different, with radicals selected from the group consisting of (C ₁ -C ₆ ) -alkyl, halogen, cyano, oxo, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and NR ³¹ R ³² in turn, the last-mentioned alkyl radical can be substituted up to three times, identically or differently, by halogen, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and / or 5 - or 6-membered heteroaryl may be substituted, (iii) R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁸ , R ²⁰ , R ²² , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁹ , R Each of R ³⁰ and R ³¹ independently represents a radical selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5 - or 6-membered heteroaryl, where (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each up to three times, same or different, with halogen, cyano , (C ₁ -C ₄ ) -alkyl, trifluoromethyl, H ydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ - C ₄ ) -alkoxycarbonyl and (C ₁ -C ₆ ) -alkyl may be mono- to trisubstituted, identically or differently, with halogen, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₇ ) -cycloalkyl, 4 to 7-membered Heterocycloalkyl, phenyl and / or 5- or 6-membered heteroaryl may be substituted, (iv) R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ , R ²⁸ and R ³² independently of each other individual occurrence is a radical selected from the group consisting of hydrogen and (C ₁ -C ₆ ) -alkyl, where (C ₁ -C ₆ ) -alkyl is mono- to trisubstituted, identical or different, with halogen, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -Alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) alkoxycarbonyl, and / or wherein (v) R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² , R ²² and R ²³ , R ²⁴ and R ²⁵ , R ²⁷ and R ²⁸ as well as R ³¹ and R ³² in pairs together with the atoms to which they are attached, can form a 5- or 6-membered heterocycloalkyl ring which is one to three times identical or different, with halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino , Di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, R ⁵ and R ^{8 are the} same or different and are independently selected from hydrogen or a substituent selected from (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, in which (i) (C ₁ -C ₆ ) Alkyl, in turn, one to three times, the same or different, with Res selected from the group halogen, cyano, oxo, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -R ¹⁰ , - C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² may be substituted, wherein the last-mentioned cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals in turn each up to three times, the same or differently, with halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, Di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and (ii) (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl , Phenyl and 5- or 6-membered heteroaryl in turn each one to three times, same or different, with R esters selected from the group consisting of (C ₁ -C ₆ ) -alkyl, halogen, cyano, oxo, -C (= O) -R ¹⁰ , -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -SO ₂ -R ²⁶ , -SO ₂ -NR ²⁷ R ²⁸ , -OR ²⁹ , -SR ³⁰ and -NR ³¹ R ³² may be substituted, the last-mentioned alkyl radical in turn having up to three, identical or different, with halogen, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- ( C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl , Phenyl and / or 5- or 6-membered heteroaryl, in which (a) R ¹⁰ , R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁸ , R ²⁰ , R ²² , R ²⁵ , R ²⁶ , R ²⁷ , R ²⁹ , R ³⁰ and R ³¹ independently of one another each occurrence represent a radical selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₇ ) -cycloalkyl , 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each up to three times, identically or differently, with halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₆ ) -alkyl may be mono- to trisubstituted, the same or different, with halogen, cyano, hydroxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₇ ) -cycloalkyl, 4- to 7-membered heterocycloalkyl, phenyl and / or 5- or 6-membered heteroaryl may be substituted, (b) R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ , R ²⁸ and R ³² independently of one another each occurrence represent a radical selected from the group consisting of hydrogen and (C ₁ -C ₆ ) -alkyl, where (C ₁ -C ₆ ) -alkyl is bis to triply, identically or differently, with halogen, cyano, hydroxy, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di (C ₁ -C ₄ ) -alkylamino , Hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and / or (c) R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² , R ²² and R ²³ , R ²⁴ and R ²⁵ , R ²⁷ and R ^28, and R ³¹ and R ³² each in pairs together with the atoms to which they are attached form a 5- or 6-membered het cycloalkyl ring, which is mono- to trisubstituted, identical or different, with halogen, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino , Mono- (C ₁ -C ₄ ) -alkylamino, di (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and R ⁶ in each case, independently of one another, represents hydrogen or a substituent selected from the group halogen, cyano, nitro, (C ₁ -C ₆ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, amino, mono- (C C ₁ -C ₆ ) -alkylamino, di- (C ₁ -C ₆ ) -alkylamino, hydroxycarbonyl and (C ₁ -C ₆ ) -alkoxycarbonyl, and R ^{3 is} hydrogen, (C ₁ -C ₆ ) -alkyl or ( C ₃ -C ₇ ) -cycloalkyl, and their salts, solvates and solvates of the salts, with the exception of the compound 3-methyl-4- (3-methyl-1,2,4-oxadiazol-5-yl) -1- pyridin-2-yl-1H-pyrazol-5-thiol. A compound of the formula (I) according to claim 1, in which R ^{1 is} a heteroaryl group of the formula

where * is the point of attachment to the dihydropyrazolethione ring, A in each individual occurrence is CR ⁴ or N, with a maximum of two ring members A being N at the same time, R ⁴ in each case independently of one another, hydrogen or a substituent selected from in the series fluorine, chlorine, bromine, cyano, (C ₁ -C ₆ ) -alkyl, hydroxy, (C ₁ -C ₆ ) -alkoxy, trifluoromethoxy, amino, mono- (C ₁ -C ₆ ) -alkylamino, di-, (C ₁ -C ₆ ) -Alkylamino, hydroxycarbonyl and (C ₁ -C ₆ ) alkoxycarbonyl, wherein said (C ₁ -C ₆ ) alkyl radical in turn up to three times, identically or differently, with fluorine, chlorine, bromine , Cyano, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) alkoxycarbonyl, and DO, S or NR ⁵ , wherein R ^{5 is} hydrogen or (C ₁ -C ₆ ) alkyl, R ^{2 is} a heteroaryl group of the formula

where # is the point of attachment to the dihydropyrazolethione ring, G is in each case CR ⁷ or N, where not more than one of the two ring members G is N, where R ⁷ in each case, independently of one another, represents hydrogen or a substituent selected from the group fluorine, chlorine, bromine, cyano, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered heteroaryl, -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ -C ( = O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -OR ²⁹ and NR ³¹ R ³² in which (i) (C ₁ -C ₆ ) -alkyl in turn is mono- to trisubstituted, identical or different, with radicals selected from the group consisting of fluorine, chlorine, bromine, cyano, (C ₃ -C ₆ ) Cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl, 5- or 6-membered Heteroaryl, -C (= O) -OR ¹¹ , -C (= O) -NR ¹² R ¹³ , -OC (= O) -R ¹⁴ , -OC (= O) -NR ¹⁵ R ¹⁶ , -NR ¹⁷ - C (= O) -R ¹⁸ , -NR ¹⁹ -C (= O) -OR ²⁰ , -NR ²¹ -C (= O) -NR ²² R ²³ , -NR ²⁴ -SO ₂ -R ²⁵ , -OR ²⁹ and -NR ³¹ R ³² may be substituted, wherein the last-mentioned cycloalkyl, heterocycloalkyl, phenyl and heteroaryl radicals in turn each up to two times, identically or differently, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, (ii) (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in each case in each case or doubly, identically or differently, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, (iii) R ¹¹ , R ¹² , R ¹⁴ , R ¹⁵ , R ¹⁸ , R ²⁰ , R ²² , R ²⁵ , R ²⁹ and R ³¹ independently of one another in each occurrence, a radical selected from the group consisting of hydrogen, (C ₁ -C ₆ ) -alkyl, (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl where (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in turn each up to three times, identically or differently, with fluorine, chlorine, bromine, cyano, ( C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, oxo, amino, mono- (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl and (C ₁ -C ₆ ) -alkyl may be mono- to trisubstituted, identically or differently, with fluorine, chlorine, bromine, cyano, hydroxy, trifluoromethoxy , (C ₁ -C ₄ ) -alkoxy, amino, mono (C ₁ -C ₄ ) -alkylamino, di (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl, (C ₃ -C ₆ ) -cycloalkyl, 4- to 6-membered heterocycloalkyl, phenyl and / or 5- or 6-membered heteroaryl may be substituted, (iv) R ¹³ , R ¹⁶ , R ¹⁷ , R ¹⁹ , R ²¹ , R ²³ , R ²⁴ and R ³² independently of each occurrence are each hydrogen selected from (C ₁ -C ₆ ) alkyl where (C ₁ -C ₆ ) -alkyl is monosubstituted or disubstituted, identical or different, with fluorine, chlorine, bromine, cyano, hydroxyl, trifluoromethoxy, (C ₁ -C ₄ ) -alkoxy, amino, mono- (C C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and / or wherein (v) R ¹² and R ¹³ , R ¹⁵ and R ¹⁶ , R ¹⁷ and R ¹⁸ , R ¹⁹ and R ²⁰ , R ²¹ and R ²² , R ²² and R ²³ , R ²⁴ and R ²⁵ and R ³¹ and R ³² in pairs together with the atoms to which they are bonded, can form a 5- or 6-membered heterocycloalkyl ring, which one or two times, the same or the like r different, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy, (C ₁ -C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) -alkylamino, di- (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) -alkoxycarbonyl, and JO or S, and R ^{3 is} hydrogen or methyl, and theirs Salts, solvates and solvates of salts. A compound of the formula (I) as claimed in claim 1 or 2, in which R ^{1 is} a heteroaryl group of the formula

in which * the point of attachment to the dihydropyrazolethione ring and R ^{4 is} hydrogen, fluorine, cyano, methyl, ethyl, trifluoromethyl, hydroxymethyl, methoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl or ethoxycarbonyl, R ^{2 is} a heteroaryl group of the formula

stands in which # is the point of attachment to the Dihydropyrazolthion ring and R ⁷ , R ^7A and R ^{7B are the} same or different and independently hydrogen or a substituent selected from the group fluorine, cyano, (C ₁ -C ₄ ) alkyl, trifluoromethyl, hydroxy , (C ₁ -C ₄ ) -alkoxy, trifluoromethoxy, amino, mono- (C ₁ -C ₄ ) -alkylamino, di (C ₁ -C ₄ ) -alkylamino, hydroxycarbonyl, (C ₁ -C ₄ ) -alkoxycarbonyl , 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, where (C ₁ -C ₄ ) -alkyl in turn with hydroxy, (C ₁ -C ₄ ) -alkoxy or amino and 4-6 heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, in each case one or two times, identically or differently, with fluorine, chlorine, bromine, cyano, (C ₁ -C ₄ ) -alkyl, trifluoromethyl, hydroxy, (C ₁ C ₄ ) alkoxy, trifluoromethoxy, oxo, amino, mono (C ₁ -C ₄ ) alkylamino, di (C ₁ -C ₄ ) alkylamino, hydroxycarbonyl and / or (C ₁ -C ₄ ) alkoxycarbonyl may be substituted, and R ³ is hydrogen, and their salts, solvates and solvates of the salts. Process for preparing a compound of the formula (I) as defined in claims 1 to 3, characterized in that compounds of the formula (II)

in which R ¹ , R ² and R ^{3 have} the meanings given in claims 1 to 3, are treated in an inert solvent with a phosphorus sulfide and the resulting compounds of the formula (I), if appropriate with the appropriate (i) solvents and / or ( ii) converting bases or acids into their solvates, salts and / or solvates of the salts. Process for the preparation of a compound of the formula (I) as defined in claims 1 to 3, in which R ^{3 is} hydrogen, characterized in that compounds of the formula (VIII)

in which R ^{1 has} the meaning given in claims 1 to 3 and Z ^{1 is} methyl or ethyl, in an inert solvent with a phosphorus sulfide in the corresponding thio compounds of the formula (VIII-A)

in which Z ¹ and R ^{1 have} the abovementioned meanings, and then converting these in the presence of an acid with a compound of the formula (IV)

in which R ^{2 has} the meaning given in claims 1 to 3, to compounds of formula (VB)

in which Z ¹ , R ¹ and R ^{2 have} the meanings given above, which already under these reaction conditions or in a subsequent reaction step under the influence of a base to the compounds of formula (I), wherein R ^{3 is} hydrogen, cyclize , and the resulting compounds of formula (I) optionally with the corresponding (i) solvents and / or (ii) bases or acids in their solvates, salts and / or solvates of the salts. A compound as claimed in any one of claims 1 to 3, for the treatment and / or prophylaxis of diseases. Use of a compound as in any of the claims 1 to 3 for the manufacture of a medicament for treatment and / or prophylaxis of cardiovascular diseases, heart failure, Anemia, chronic kidney disease and renal insufficiency. Medicaments containing a compound as in one of claims 1 to 3, in combination with a inert, non-toxic, pharmaceutically acceptable excipient. Medicaments containing a compound as in one of claims 1 to 3, in combination with a or more other active ingredients selected from the group consisting of ACE inhibitors, angiotensin II receptor antagonists, Beta-receptor blockers, calcium antagonists, PDE inhibitors, mineralocorticoid receptor antagonists, Diuretics, aspirin, iron supplements, vitamin B12 and folic acid supplements, Statins, digitalis (digoxin) derivatives, tumor chemotherapeutics and Antibiotics. Medicament according to claim 8 or 9 for the treatment and / or prophylaxis of cardiovascular diseases, heart failure, Anemia, chronic kidney disease and renal insufficiency. Method for the treatment and / or prophylaxis of Cardiovascular diseases, heart failure, anemia, chronic kidney disease and renal insufficiency in humans and animals using an effective amount of at least one A compound as defined in any one of claims 1 to 3, or a drug as in any one of claims 8 defined to 10.