WO2007065010A2 - Anti-angiogenesis compounds - Google Patents

Abstract

The present invention provides methods and pharmaceutical compositions for inhibiting expressions of HIF and HIF regulated genes, inhibiting angiogenesis, inducing cell cycle arrest in tumor cells, and treating cell proliferating diseases or conditions.

Description

ANΪΪ-ANGIOGENESIS COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of priority to UJS. Provisional Patent Application Serial NoI 60/741,742, filed December 2, 2005, the contents of which are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention:

The present invention relates to methods and pharmaceutical compositions for inhibiting tumor growth by arresting the cell cycle or by suppressing HIF-regutated gene expression, inhibiting angiogenesis in tumor cells or tissues, and for treating HIF mediated disorders or conditions.

2. Background of the Invention

Hypoxia, a reduction in tissue oxygen levels below physiologic levels, commonly develops within solid tumors because tumor cell proliferation is greater than the rate of blood vessel formation. Thus, the increase in tumor mass results in aberrant vasculature formation, which compromises the blood supply (Hockel et al., J Natl Cancer Inst 2001 93:266-276). Tumor hypoxia is one stimulus that leads to the increased expression of vascular endothelial growth factor (VEGF) and stimulates angiogenesis, which is essential for meeting the metabolic requirements of tumor growth (Dachs et al., Bur J Cancer 2000 36:1649-1660). In addition, hypoxia contributes to tumor progression to a more malignant phenotype because cells surviving under hypoxic conditions often become resistant to radiotherapy and chemotherapy (Brown, J. M. Cancer Res 1999 59:5863-5870). Thus, factors that regulate the hypoxic events may be good targets for anticancer therapy.

One such target is hypoxia-inducible factor 1 (HIF-I). HIF-I is a key transcription factor that regulates the blood supply through the expression of vascular endothelial growth factor (VEGF) (Forsythe et al., MoI Cell Biol 1996 16:4604-4613). The biologic activity of HIF-I, a heterqdimer composed of HIF-lα and HIF-lβ (Ψanget αl., J Biol Chem 1995 270:1230-1237), depends on the amount of HIF-lα, which is tightly regulated by oxygen tension. Under normoxic conditions, HIF-lα protein is unstable. The instability is^' mainly regulated by the binding to the von Hippel-Lindau tumor suppressor protein (pVHL) (Maxwell et αl, Nature 1999399:271-275). This binding occurs after the hydroxylation of the two HIF-I α proline residues by HIF-prolyl hyroxylases (Jaakkolae* αl., Science 2001 292:468-472; Ivan et ah, Science 2001 292:464-468; Masson et ah, EMBO J 2001 20:5197-5206). The von Hippel-Lindau protein is one of the components of the multiprotein ubiquitin-E3-ligase complex, which mediates the ubiquitylation of HIF-I α, targeting it for proteasomal proteolysis (Huang et ah, Proc Natl Acad Sci U S A 1998 95:7987-7992). However, under hypoxic conditions, proline hydroxylation is inhibited, binding between HIF-I and the von Hippel-Lindau protein is eliminated and HIF-I α becomes stable. HIF-2α (also known as endothelial PAS protein-1 or MOP2) is another member in HEF family. It was found by homology searches in ihe gene bank and by cloning experiments. HIF-2α is highly similar to HDF-lα in protein structure, but exhibits restricted tissue-specific expression. HIF-2α is also lightly regulated by oxygen tension and its complex with H-F-I β appears to be directly involved in hypoxic gene regulation,"as is HDF-lα. Since HIF-2α is expressed in a number of cancer cell lines and involved in hypoxic gene regulation, HIF-2α is also suggested to be associated with tumor promotion, but may not contribute to the growth of most tumors. In breast cancer cell lines mat express both HIF-lα and HEF-2α, HEF-Iα rather than HIF-2α appears to predominantly contribute to the transcriptional response to hypoxia. However, HIF-2α may take over the role of HIF-I α in tumors that express only HIF-2α. Indeed, in von Hippel-Lindau (VHL)-defective 786-O renal cell carcinoma cells, the transcriptional response to hypoxia depended on expression levels of HIF-2α. Moreover, the ectopic expression of HEF-2α led to enhanced growth of 786-O tumors grafted in nude mice. Therefore, HTJF-2α is also a good target for cancer treatment. See Semenza, G. L., Nature Reviews, Cancer, Vol.3, (2003), pp. 70-81.

As used herein, the term HIF means the combined effect of or total proteins of HIF-I plus EOGF-2. In addition the term HIF-I means the combined effect of or total proteins of HIF-I α plus HIF-I β. The term HEF-2 means the combined effect of or total proteins of HIF-2α plus HIF-2β.

While searching for anticancer agents mat inhibit HEF-I activity, we identified a novel pharmacologic action of YC-I and novel analogs thereof. YC-I, S-^'-hydroxymethyl^'- furyl)-l-benzylindazole, has been known to inhibit platelet aggregation and vascular contraction by activating soluble guanylyl cyclase, and was originally developed as a potential therapeutic agent for circulation disorders (Teng et ah, Eur J Pharmacol 1997 320:161-166; Galle et ah, Br J Pharmacol 1999 127:195-203). Recently, we have found two novel biological actions of YC-I and novel analogs thereof; one is the inhibitory effect on either HIF-I or HIF-2 activity, and the other is the antiproliferative effect on cancer cells by arresting the cell cycle and leading to cell apoptosis.

The inhibitory effects of compounds of the invention on the expression of HIF-lα and The inhibitory effects of compounds of the invention on the expression of HIP-loc and on the induction of VEGF, aldolase A, and enolase I in cancer cells cultured under hypoxic conditions are also exhibited in vivo, treatment by halting the growth of xenografted tumors originating from human cancers, such as hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma cells. Tumors from mice treated with the compounds showed fewer blood vessels and reduced expression of HϊF-lα protein and HIF-I -regulated genes than tumors from vehicle-treated mice. These results support that the compounds are inhibitors of HIF-I and HIF-2, and halt tumor growth by blocking tumor angiogenesis and tumor adaptation to hypoxia. The compounds are also useful against tumors that overexpress HIF proteins.

The eukaryotic cell cycle is divided into four stages: Gl, S, G2, and M. Gl is the gap phase during which cells prepare for the process of DNA replication. During this phase, cells integrate mitogenic and growth-inhibitory signals and make the decision to proceed, pause, or exit cell cycle. The S Phase is defined as the stage in which DNA synthesis occurs. G2 is the second gap phase during which the cell prepares for the process of division. The M phase is defined as the stage in which the replicated chromosomes are segregated into separate nuclei and other cellular components are divided to make two daughter cells. In addition to Gl, S, G% and M, GO is defined as the cell stage in which cells exit cell cycle and become .quiescent. Cells have evolved signaling pathways to coordinate cell cycle transitions and ensure faithful replication of the genome before cell division. Cell cycle progression is stimulated by protein kinase complexes, each of which consists of a cyclin and a cyclin-dependent kinase (CDK). The CDK's are expressed constitutively through cell cycle, whereas cyclin levels are restricted by transcriptional regulation of the cyclin genes and by ubiquitin-mediated degradation. The CDK activation requires the binding of a cyclin partner in addition to site-specific phosphorylation. To ■ carry on error-free cell cycle, eukaryotic cells have developed control mechanisms that restrain cell cycle.transitions in response to stress. These regulatory pathways are termed cell cycle checkpoints, which can be divided into three points, i.e., Gϊ-S, G2, and M phase checkpoint.

U.S. Patent No. 6,387,940 Bl describes various analogs of YC-I, The contents of this document are incorporated by reference herein in their entirety, especially as they relate to the process for making the compounds that are described herein. WO 2005/030121 A2 discloses anti-cancer and antϊ-HIF disorder related uses of YC-I analogs. The contents of this document are incorporated by reference herein in their entirety, especially as they relate to the process for testing and using YC-I analogs for anticancer, anti-cell proliferation and anti-HIF related disorder effects.

SUMMARY OF THE INVENTION

In one aspect, the invention is directed to using compound to treat a HIF-related disease or disorder by administering without limitation any of the compounds described below. Further, the compounds indicated below may be used as an anti-proliferative agent of cancer cells.

1. A 3-FϊeterocycIyl-substituted pyrazole derivative of the formula (III-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S₃ N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴\ wherein R^4S denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula CB₃ en,,

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R^S2 denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times m an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula ~S(O)_c3 NR⁵⁰R^S1', wherein c3, R^50' and R^5t' have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl. hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (— CO)^ -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

2. A compound according to 1 above of formula (HI-I), wherein R⁴² represents pyranyl or morpholinyl, which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amin'o, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms, or by a radical of the formula --OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula — SiR⁴⁶R⁴⁷ R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms, and/or are substituted by a radical of the formula

wherein a3 denotes the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, R⁴³ and R⁴⁴, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, A³ represents tetrahydropyranyl, tetrahydrofuranyϊ, thienyl, pyrimidyl, phenyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkyϊthϊo, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having, in each case up to 4 carbon atoms, and/or are substituted by a group of the formula — (CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight- chain or branched alkyl or acyl having in each case up to 4 carbon atoms, or an isomer or salt thereof.

3. A compound according to 1 above wherein in formula (IH-I), R⁴² represents imidazolyl, oxazolyl, oxadiazolyl or thiazolyl, which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, fluorine, chlorine, trifluoromethyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms or by the radical of the formula -O-CO--CH3, and/or are substituted by a radical of the formula

/ r . "11

wherein a3 denotes the number 0, 1 or 2, Jl⁴⁹ denotes hydrogen or methyl, R⁴³ and R⁴⁴, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain, or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyanσ, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or allcoxycarbonyl having in each case up to 3 carbon atoms, A3 represents tetrahydropyranyl, phenyl, thienyl, pyrimidyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydmxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, and/or are substituted by a group of the formula -(CO)^ -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1 , R⁵³ and R⁵⁴ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms, or an isomer or salt thereof.

Thus, in one aspect, the invention is directed to the invention is directed to a method of inhibiting HIF expression in tumor cells or tissues in a subject, comprising administering to the subject a composition comprising a compound or mixture of compounds of a 3- heterocyclyl-substituted pyrazole derivative of the formula (HI-I) described herein at an effective amount for inhibiting HIF expression. The effective amount may be effective to inhibit HlF- lα expression. The effective amount may be effective to inhibit HIF-2α expression. The tumor cells or tissue may include tumors that overexpress HlF proteins. The tumor may be selected without limitation from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma and neuroblastoma, and prostate carcinoma.

In another aspect, the invention is directed to a method of inhibiting HIF-regulated gene expression in tumor cells or tissues in a subject, including administering to the subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl- substϊtuted pyrazole derivative of the formula (IH-I) described herein at an effective amount for inhibiting HIF-regulated gene expression. The HIF-regulated gene . may be selected without limitaion from the group consisting of erythropoietin, transferrin, transferrin receptor, ceruloplasmϊn, vascular endothelial . growth factor (VBGF), VEGF receptor FLT-I, transforming growth factor β3, plasminogen activator inhibitor 1, αlB adrenergic receptor, adrenomedullin, endothelin 1, nitric oxide synthase 2, heme oxygenase 1, glucose transporter 1 and 3, hexokinase 1 and 2, enolase 1, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase 1, phosphoglucokinase L, pyruvate kinase M, aldolase A and C, rios phosphate isomerase, lactate dehydrogenase A, carbonic anhydrase 9, adenylate kinase 3, ρropyl-4-hydroxylase al, insulin-like growth factor (IGF) 2, IGP-binding protein 1, 2 and 3, P21, Nip3, cyclin G2 and differentiated embryo chondrocyte 1. In particular, the HIF-regulated gene may be selected from the group consisting of VEGF, aldolase A and enolase l.The effective amount may be effective to inhibit HIF- lα expression. The effective amount may be effective to inhibit HIF-2α expression. The tumor cells or tissue may include tumors that overexpress HIF proteins. The tumor may be selected from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

In yet another aspect, the invention is directed to a method of inhibiting angiogenesis in tumor cells or tissues in a subject, comprising administering to the subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (HI-I) described Herein at an effective amount for inhibiting angiogenesis. The tumor cells or tissue may include tumors that overexpress HIF proteins. The tumor may be selected from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

In another aspect, the invention is directed to a method of inhibiting tumor growth in animal tissues in a subject, comprising administering to the subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (IH-I) described herein at an effective amount for inhibiting tumor growth. The tumor may overexpress HIF proteins. The tumor may be selected without limitation from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

In yet another aspect, the invention is directed to a method of inhibiting tumor progression and metastasis in tissues in a subject, comprising administering to the subject a composition comprising a compound or a mixture of compounds of a 3-heterocyclyl- substituted pyrazole derivative of the formula (IH-I) described herein at an effective amount for inhibiting tumor progression and metastasis. The tumor may overexpress HIF proteins. The tumor may be selected without limitation from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

In still another aspect, the invention is directed to a method of treating a HIF-mediated and/or VEGF-mediated disorder or condition in a subject comprising administering to the subject a composition, comprising a therapeutically effective amount of a compound or a mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (IH-O described herein. Overepression of HIF proteins may be an indication of the disorders or condition. The HIF-mediated disorder or condition may be selected without limitation from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

In another aspect, the invention is directed to a method of enhancing the inhibitory effect on tumor growth in a subject in combination with another antitumor therapy comprising administering to said subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (HI-I) described herein at an effective amount for synergistically enhancing the combined tumor- inhibiting effect of the therapy and the composition in the subject.

In yet another aspect, the invention is directed to a method for arresting the cell cycle in proliferating cells in a subject comprising administering to said subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (HI-I) described herein at an effective amount to inhibit progression of cell proliferation. The proliferating cells may include tumors. The proliferating cells may include cells symptomatic of a hyper-proliferafcive skin disorder.

These and other objects of the invention will be more fully understood from the following description of the invention, the referenced drawings attached hereto and the claims appended hereto.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present application, "a" and "an" are used to refer to both single and a plurality of objects.

Formula I

The present invention relates to using for treating HIF-related disorders and symptoms of cancer heterocyclylmethyl-substituted pyrazole derivatives, in the embodiment designated I (roman one), of the general formula (I-I)

in which

R¹ represents a 5-membered aromatic heterocyclic ring having one heteroatotn from the series consisting of S, N and/or O, or represents phenyl, which are optionally substituted up 'to 3 times in an identical or different manner by formyl, carboxyl, mercaptyl, hydroxyl, straight-chain or branched acyl, alkylthio, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight- chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —OR⁴, wherein R⁴ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula --SiR⁵R⁶R⁷, wherein R⁵, R⁶ and R⁷ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or are substituted by a radical of the formula

P — J P — <c8&t — CH,

O— (CH₂),!, O (CH_W— C^j,

N^ or S(O)₀₁)MR=R¹'

wherein bl and bl' are identical or different and denote the number 0, 1, 2 or 3, al denotes the number 1, 2 or 3, R⁸ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, cl denotes the number 1 or 2 and R⁹ and R¹⁰ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁹ and R¹⁰, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical — NP¹ ' , wherein R¹ ' denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R² and R³. including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of S, N and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, wherein the alkyl in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a radical of the formula --S(O)₀I-, NR⁹ R¹⁰, wherein Cr, R⁹ and R¹⁰ have the abovementioned meaning of C\>, R⁹ and R¹⁰ and are identical to or different from these, A¹ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, which is optionally substituted up to 3 times in an identical or different manner by mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula --(CO)di -NR¹² R¹³, wherein dl denotes the number 0 or 1, R¹² and R¹³ are identical or different and denote hydrogen, phenyl, benzyl or straight- chain or branched alkyl or acyl having in each case up to 5 carbon atoms, and their isomeric forms, salts and their N-oxides.

The compounds of the general formula (I-l) according to the invention can also be present in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here.

In the context of embodiment I of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the heterocyclylmethyl-substituted pyrazole derivatives can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, Citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocyclic ring in the context of embodiment I of the invention, and depending on the abovementioned substituents, in general represents a 5- to 6-membered heterocyclic ring which can contain 1 heteroatom in the 5-membered ring in the case of R¹ and up to 3 heteroatoms from the series consisting of S; N and/or O in the case of A. Examples which may be mentioned are: pyridazinyl, pyridyl, pyrimidyl, thienyl, furyli morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofuranyl. Fiiryl, pyridyl, thienyl, pyrrolyl, pyrimidyl, pyrϊdazinyl, morpholinyl, tetrahydropyranyl or tetrahydrofiiranyl are preferred.

Preferred compounds of the general formula (I-I) according to the invention are those in which R¹ represents fiiryl, pyrrolyl, thienyl or phenyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl. amino, carboxyi, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms or by a radical of the formula -OR⁴, wherein R⁴ denotes straight-chain or branched acyl having up to 4 carbon atoms, and/or are substituted by a radical of the formula

wherein al denotes the number 1, 2 or 3, R^{8 '}denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, R² and R³, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxy!, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, A¹ represents tetrahydropyranyl, thienyl, furyl, tetrahydrofuranyl, pyrazinyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carbox^l, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, and/or are substituted by a group of the formula — (CO)di -NR¹² R¹³, wherein dl denotes the number 0 or 1, R¹² and R¹³ are identical or different and denote hydrogen, phenyl, benzyl or straight- chain or branched alkyl or acyl having in each case up to 4 carbon atoms, and their isomeric forms and salts and their N-oxides.

Particularly preferred compounds of the general formula (H) according to the invention are those in which R¹ represents furyl, pyrryl, thienyl or phenyl, which are optionally substituted up to twice in an identical or different manner by fbrmyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms, and/or are substituted by a radical of the formula

O-OOHøu N^ ₈ wherein al denotes the number 1 or 2, R⁸ denotes hydrogen or methyl, R² and R³, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, A¹ represents tetrahydropyranyl, tetrahydroftiranyl, thienyl, pyrimidyl, pyrazinyl. pyridazinyl, furyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydrexyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, and/or are substituted by a group of the formula ~(CO)di -NR¹² R¹³, wherein dl denotes the number 0 or 1, R¹² and R¹³ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms, and their isomeric forms and salts and their N- oxides.

Especially preferred compounds of the general formula (I-ϊ) according to the invention are those in which R¹ represents .furyl, which is optionally substituted by formyl or by radical of the formula -CEb —OH or

R² and R³, including the double bond, form a phenyl ring which is substituted by phenyl, fluorine or nitro, A¹ represents fiiryl, pyridyl, pyrimidyl, pyridazinyl, thienyl, tetrahydrofiiranyl or tetrahydropyranyl, which are optionally substituted by chlorine, bromine, methoxy, methoxycarboπyl or carboxyl. and their salts, isomeric forms and N-oxides.

The invention furthermore relates to processes for the preparation of the compounds of the general formula (H) according to_.theinvention, characterized in that [Al] compounds of the general formula (T-II)

in which R¹, R² and R³ have the abovementioned meaning, are reacted with compounds of the general foπnula (I-III)

D¹ -CH₂ -A¹ (MII)

in which A¹ has the abovementioned meaning and D¹ represents triflate or halogen, preferably bromine, in inert solvents, if appropriate in the presence of a base, or [Bl] compounds of the general formula (I-IV)

in which A', R² and R³ have the abovementioned meaning and L¹ represents a radical of the formula -SnR¹⁴R¹⁵R¹⁶, ZnR¹⁷, iodine or triflate, wherein R¹⁴, R¹⁵ and R¹⁶ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and R¹⁷ denotes halogen, are reacted with compounds of the general formula (I-V)

R¹ -T¹ (1-V) in which R¹ has the abovementioned meaning and in the case where L¹ =SnR¹⁴R¹⁵R¹⁶ or ZnR¹⁷, T¹ represents triflate or represents halogen, preferably bromine, and in the case where L¹ =iodine or triflate, T¹ represents a radical of the formula SnR¹⁴¹R¹⁵R¹⁶', ZnR¹⁷' OrBR¹⁸R¹⁹, wherein R^14', R^15', R^16' and R¹⁷' have the abovementioned meaning of R¹⁴, R¹⁵ _? R¹⁶ and R¹⁷ and are identical to or different from these, RΪ.⁸ and R¹⁹ are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring, in a palladium-catalysed reaction in inert solvents, and, in the case of the radicals — S(O)ci NR⁹ R¹⁰ and -S(O)₀I-NR^9' R^10', starting from the unsubstituted compounds of the general formula (I-I), these are first reacted with thionyl chloride, and finally the amine component is employed, and, if appropriate, the substituents listed under R¹, R², R³ and/or A¹ are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.

The processes according to the invention can be illustrated by way of example by the following equations.

Suitable solvents here for the individual steps of process [Al] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran; hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dϊmethylformramide are particularly preferred. Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trialkyl-(Ci - Cβ)amines), such as triethylamine, or heterocyclic compounds, such as 1,4- diazabicyclo[2.2.2]octane. (DABCO), l,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyrϊdine, methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (I-II).

The reaction is in general carried out in a temperature range from O⁰C. to 150⁰C, preferably from +20⁰C. to +110⁰C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable solvents here for process [Bl] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane,.halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0⁰C. to 150⁰C, preferably from +20⁰C to +110⁰C

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂ (P(Cδ 1*5)3)₂, palladium bis-dibenzylideneacetone (Pd(dba)₂), [l,l'-bis-(diphenyl- phosphino)ferrocene]-palladium(II) chloride (Pd(dpρf)Cl₂) or Pd(P(C₆Hs)₃).*. Pd(P(C₆H₅)₃)₄ is preferred. The compounds of the general formulae (TL-III) and (I-V) are known per se or can be prepared by customary methods.

The compounds of the general formula (I-II) are known in some cases or are new, and can then be prepared by a process in which compounds of the general formula (I-VI)

in which R² and R³ have the abovementϊoned meaning and L^1' has the abovementioned meaning of L¹ and is identical to or different from this, are reacted with compounds of the general formula (I-V) analogously to the abovementioned process [Bl].

The compounds of the general formula (HV) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which the compounds of the general formula (I-IVa)

in which R², R³ and A¹ have the abovementioned meaning, and L¹ represents triflate or halogen, preferably iodine, are reacted with compounds of the general formula (I- VII)

(SnR¹⁴R^lsR^l6)₂(I-VIΪ) in which R¹⁴, R¹⁵ and R¹⁶ have the abovementioned meaning, under palladium catalysis, as described above.

The compounds of the general formulae (I-IVa) and (I- VII) are known per se or can be prepared by customary methods.

The reductions are in general carried out witii reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metaJ hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkyihydridoboranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

^• The reduction in general proceeds in a temperature range from -78°C. to +5.0⁰C.., preferably from -78°C. to 0⁰C, in the case of DIBAH, 0⁰C, room temperature in the case of NaBH₄, particularly preferably at-78°C, in each case depending on the choice of reducing agent and solvents.

The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

The protective group is in general split off in one of the abovementioned alcohols and/or THF or acetone, preferably methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonϊc acid in a temperature range from 0°C to 70⁰C, preferably at room temperature under normal pressure.

In the case where the radicals of the formulae ~S(O)_ci (NfR⁹R¹⁰ and — S(O)_0I ¹NR⁹R¹⁰ are present, the corresponding unsubstituted compounds are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a second step. In the case where cl=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0⁰C. to 70⁰C. under normal pressure.

The invention moreover relates to the combination of the compounds of the general formula (I-I) according to the invention with organic nitrates and NO donors.

Organic nitrates and NO donors in the context of the invention are in general substances which display their therapeutic action via the liberation of NO or NO species. Sodium nitroprusside (SNP), nitroglycerol, isosorbide dinitrate, isosorbide mononitrate, molsidomine and SIN-I and similar substances are preferred.'

The invention also relates to the combination with compounds which inhibit tiie breakdown of cyclic guanosine monophosphate (cGMP). These are, in particular, inhibitors of phosphodiesterases I₉2 and 5; nomenclature according to Beavo and Reifsnyder (1990) TIPS 11 pages 150-155. The action of the compounds according to the invention is potentiated and the desired pharmacological effect increased by these inhibitors.

The compounds of the general formula (I-I) according to the invention show an unforeseeable, valuable pharmacological action spectrum. Formula π

The present invention relates to using for treating HIF-related disorders and symptoms of cancer 1-heterocyclyl-methyl-substituted pyrazoles, in the embodiment designated II (roman two), of the general formula (II-I),

in which

R²⁰ represents a 6-membered aromatic heterocyclic ring having up to 3 nitrogen atoms, which is optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, mercaptyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, sizido, halogen, phenyl and/or by a group of the formula

--NR²³R²⁴

wherein R²³ and R²⁴ are identical or different and denote hydrogen or straight-chain or branched acyl having up to 6 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl, amino or by straight-chain or branched alkoxy, acyl or alkoxycarbonyl having in each case up to 5 carbon atoms, or R²³ and R²⁴, together with the nitrogen atom, form a 3- to 7-membered saturated or partly unsaturated heterocyclic ring, which can optionally additionally contain an oxygen or sulphur atom or a radical of the formula -NR²⁵, wherein R²⁵ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, and/or is substituted by straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, halogen, carboxyl, straight-chain branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —OR²⁶, wherein R²⁶ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR²⁷R²⁸R²⁹, wherein R²⁷, R²⁸ and R²⁹ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or is optionally substituted by a radical of the formula

wherein b2 and b2' are identical or different and denote the number O₃ 1, 2 or 3, a2 denotes the number 1, 2 or 3, R³⁰ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c2 denotes the number 1 or 2 and R³¹ and R³² are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R³¹ and R³², together with the nitrogen atom, form a 5 to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical — NR³³, wherein R³³ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R2¹ and R²², including the double bond, form a 5-membered aromatic heterocyclic ring having a heteroatom from the series consisting of S, N and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, mercaptyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkylthio, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, or are optionally substituted by a group of the formula — S(O)_c2NR³¹R³² wherein cy, R^31' and R³² have the abovementioned meaning of c2, R^3t and R³² and are Identical to or different from these, A² represents phenyl or a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, which are optionally substituted up to 3 times in an identical or different manner by mercapiyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or^'branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula — (CO)_d2 -NR³⁴R³⁵, wherein d2 denotes the number 0 or 1, R³⁴ and R³⁵ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, their isomeric forms and salts and their N-oxides.

In the context of embodiment II of the present invention, physiologically acceptable salts with organic or inorganic bases or acids are preferred. Physiologically acceptable salts of the l-heterocyclyl-methyl-substituted pyrazoles can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fiimaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

The compounds according to the invention according to embodiment II can exist in stereoisomeric forms which either behave as mirror images (enantϊomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or dϊastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocyclic ring in the context of the invention according to embodiment II represents a 6-membered aromatic heterocyclic ring in the case of R²⁰, a 5-membered aromatic heterocyclic ring having 1 heteroatom in the case OfR²¹ZR²², and a 5- to 6- membered aromatic or saturated heterocyclic ring in the case of A², and a saturated or partly unsaturated 3- to 7-membered heterocyclic ring in the case of the group NR²³R²⁴. Examples which may be mentioned are: pyridazinyl, quinolyl, isoquinolyl, pyrazinyl, pyridyL, pyrimidyl, thienyl, furyl, morpholinyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, tetrahydropyranyl or tetrahydrofiiranyl.

Preferred compounds of the general formula (II-I) according to the invention are those in which R²⁰ represents a radical of the formula

which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl and/or by a group of the formula --NR²³R²⁴, wherein JR²³ and R²⁴ are identical or different and denote hydrogen or straight-chain or branched acyl having up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by hydroxyl, amino or by straight-chain or branched alkoxy having up to 3 carbon atoms, or

R²³ and R²⁴, together with the nitrogen atom, form a morpholine ring or a radical of the formula

r\

and/or are substituted by straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino_?flour, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms or by a radical of the formula —OR²⁶, wherein R²⁶ denotes straight-chain or branched acyl having up to 4 carbon atoms, and/or are optionally substituted by a radical of the formula

wherein b2 and b2" are identical or different and denote the number 0, 1, 2 or 3, a2 denotes the number 1, 2 or 3, R³⁰ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R²¹ and R²², including the double bond, form a furyl, thϊenyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, A² represents phenyl, or represents tetrahydropyranyl, furyl, tetrahydrofuranyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl. alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, and/or are substituted by a group of the formula ~(CO)_d2 --NR³⁴R^3S wherein d2 denotes the number 0 or 1, R³⁴ and R³⁵ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 4 carbon atoms, their isomeric forms and salts and their N-oxϊdes.

Particularly preferred compounds of the general formula Ql-T) according to the invention are those in which R²⁰ represents a radical of the formula

wherein the ring systems are optionally substituted up to 3 times in an identical or different manner by formyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, methylamino, amino, fluorine, chlorine, bromine, cyano, azido or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms, and/or are optionally substituted by a radical of the formula..

9 P-CaPs

■N CHa CHj* °H ■ o* \

R²¹ and R²², including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, A² represents phenyl, tetrahydropyranyl, tetrahydrofuranyl, furyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or represents straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, and/or are substituted by a group of the formula — (CO)d2 -NR³⁴R³⁵, wherein d2 denotes the number 0 or 1, R³⁴ and R³⁵ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms, their isomeric forms, salts and N- oxides.

Especially preferred compounds of the general formula (H-I) according to the invention are those in which R²⁰ represents a radical of the formula

wherein the abovementioned heterocyclic ring systems are optionally substituted up to 3 times in an identical or different manner by methyl, fluorine, forrnyl, amino, cyano, methoxy, methoxycarbonvL rnethylamino, chlorine or by a radical of the formula

O-~Ctf-5 NH- — (ps&s — OH. (^

R²¹ and R²². including the double bond, together form a phenyl ring and A² represents phenyl, which is optionally substituted by fluorine or cyano, and their isomeric forms, salts and N- oxides.

The invention furthermore relates to processes for the preparation of compounds of the general formula (II-I), characterized in that

[A2] compounds of the^" general formula (II-II)

in which R²⁰, R²¹ and R²²IIaVe the abovementioned meaning, are reacted with compounds of the general formula (TI-III)

D² --CH₂ -A² CII-HI)

in which A² has the abovementioned meaning, and D² represents trifiate or halogen, preferably bromine, in inert solvents, if appropriate in the presence of a base, or

[B2] compounds of the general formula (ΪI-IV)

iri which A², R²¹ and R²² have the abovementioned meaning and L² represents a radical of the formula -SnR³⁶R³⁷R³⁸, ZnR³⁹, iodine^'or inflate, wherein R³⁶, R³⁷ and R³⁸ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and R³⁹ denotes halogen, are reacted with compounds of the general formula (II-V)

in which R²⁰ has the abovementioned meaning and in the case where L² =SnR³⁶R³⁷R^3S or ZnR³⁹, T² represents triflate or represents halogen, preferably bromine, and in the case where L² =iodine or triflate, T² represents a radical of the formula SnR³⁶R³⁷R^38', ZnR³⁹' or BR⁴⁰R⁴¹, wherein R^36', R^37', R^38' and R^39' have the abovementioned meaning of R³⁶, R³⁷, R³⁸ and R³⁹ and are identical to or different from these and R⁴⁰ and R⁴¹ are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring, in a palladium-catalysed reaction in inert solvents, and, in the case of the radicals — S(O)₀₂NR³¹R³² and -S(O)C₂NR³¹R^32', starting from the unsubstituted compounds of the general formula (TI-I), these are first reacted with thϊonyl chloride and finally the amine component is employed, and, if appropriate, the substituents listed under R²⁰, R²¹, R²² and/or A² are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.

The processes according to the invention for the preparation of the compounds according to embodiment II can be illustrated by way of example by the following equations:

NaH/PiCHjBr

Suitable solvents here for the individual steps of process [A2] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be employed for the process according to the invention according to embodiment II are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (trϊalkyHp_! -examines), such as triethyl amine, or heterocyclic compounds, such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is employed in an amount of 1 mol to 5^'mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (II-II).

The reaction is in general carried out in a temperature range from 0⁰C. to 150⁰C, preferably from +20⁰C. to +110⁰C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable solvents here for process [B2] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachlofoethane, 1,2-dIchloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0⁰C. to 150° C., preferably from +20⁰C. to +110⁰C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂ ((C₆H₅)₃)2, palladium bis-dibenzylideneacetone (Pd(dba)₂), [l,l'-bis- (diphenylρhosphino)ferrocene]-ρalladium(II) chloride (Pd(dppf)Cl2) or Pd(P(CeHs)3)4. Pd(P(C₆Hs)3)4 is preferred.

The compounds of the general formulae (II-III) and (II-V) are known or can be prepared by customary methods.

The compounds of the general forjtnula (II-II) are known in some cases and can be prepared by a process in which compounds of the general formula (II-VI)

in which R²¹ and R²² have the abovementioned meaning and L² has the abovementioned meaning of L² and is identical to or different from this, are reacted with compounds of the general formula (II- V) analogously to the abovementioned process [B2].

The compounds of the general formula (II-IV) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which compounds of the general formula (I-IVa)

in which R²¹, R²² and A² have the abovementioned meaning, and L²' represents triflate or halogen, preferably iodine, are reacted with compounds of the general formula (II- VII)

(SnR^R^R³⁸^ (H-VII)

in which R³⁶, R³⁷ and R³⁸ have the abovementioned meaning, under palladium catalysis, as described above.

The compounds of the general formula (II-VII) are known or can be prepared by customary methods.

The compounds of the general formula (U-IVa) are new in most cases and can be prepared by a process in which compounds of the general formula (II-VIII)

in which R²¹ and R²² have the abovementioned meaning, are reacted with the abovementioned compounds of the general formula (II-V) R²⁰ -T² (H-V)

wherein R²⁰ and T² have the abovementioned meaning, in one of the abovementioned- solvents, preferably tetrahydrofuran, and in the presence of sodium hydride in a temperature range from 0⁰C. to 4O⁰C, preferably at room temperature and under an inert gas atmosphere.

The compounds of the general formula (II-VΪII) are known in most cases or can be prepared by customary methods.

The reductions are in general earned out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol. preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

The reduction in general proceeds in a temperature range from -78°C. to +50⁰C, preferably from -78°C. to 0⁰C, in the case of DIBAH, 0⁰C, room temperature in the case of NaBH₄, particularly preferably at -78°C, in each case depending on the choice of reducing agent and solvents.

The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

In the case where the radicals of the formulae -S(O)^NR³¹R³² and — S(O)_c2'NR³¹ R³² are substituted, the corresponding unsubstituted compounds are first reacted with thionyl chloride and reacted with the amines in the presence of the abovementioned ethers, preferably dioxane, in a second step and in the case where c2=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in general in a temperature range from 0°C. to 70° C. under normal pressure.

The protective group is in general split off in one of the abovementioned alcohols and/or THF or acetone, preferably methanol/THF, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonig acid in a temperature range from 0⁰C to 70⁰C, preferably at room temperature under normal pressure. The compounds of the general formula (11-1) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

Abbreviations:

Me=methyl

OMe=methoxy

E*=efhyl

OEt=ethoxy

Ph=phenyl

Formula WL

The present invention relates to using for treating HIF-related disorders and symptoms of cancer 3-heterocyclyl-substituted pyrazole derivatives, in the embodiment designated III (roman three) of the general formula (IH-I)

in which

R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthϊo or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula — OR45, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote^* aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R^S1 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical — NR⁵², wherein R⁵² denotes hydrogen, straight-chain or branched . alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, foirm a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula ~S(O)_c3' NR^S0' R^sl', wherein c3', R⁵⁰ and R^51' have the abovementioned meaning of c3, R⁵⁰ and R⁵¹, and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O, or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, rπercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its' turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula -(CO)d3 -NR⁵³ R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight- chain or branched alkyl or acyl having in each case up to 5 carbon atoms, and their isomeric forms and salts.

The compounds of the general formula (EGH) according to the invention can also be present in the form of their salts with organic or inorganic bases or acids.

In the context of embodiment III of the present invention, physiologically acceptable salts are preferred. Physiologically acceptable salts of the compounds according to the invention can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, salts with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic^'acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention which have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

• The compounds according to the invention can exist in stereoisomeric forms which either behave as mirror images (enantiomers) or do not behave as mirror images (diastereomers). The invention relates both to the enantiomers or diastereomers or their particular mixtures. The racemic forms, like the diastereomers, can be separated into the stereoisomerically uniform constituents in a known manner.

Heterocyclic ring in the context of embodiment III of the invention in general, depending on the abovementioned substituents, represents a saturated or aromatic 5- or 6-membered heterocyclic ring, which can contain 1, 2 or 3 heteroatoms from the series consisting of S, N and/or O and, in the case of a nitrogen atom, can also be bonded via this. Examples which may be mentioned are: oxadiazolyl, thiadϊazolyl, pyrazolyl, pyrimid pyridyl, thienyl, furyl, pyrrolyl, tetrahydropyranyl, tetrahydrofuranyl, 1,2,3-triazolyl, thiazolyi, oxazoiyl, imϊdazolyl, morpholinyl or piperidyl. Oxazolyl, thiazolyi, pyrazolyl, pyrimid ,pyridyl or tetrahydropyranyl are preferred.

Preferred compounds of the general formula (UI-I) according to the invention are those in which R⁴² represents imidazolyl, oxazolyl, thiazolyi, 1,2,3-trϊazolyl, pyrazolyl, oxadiazolyl. thiadiazolyl, isoxazolyl, isothiazolyl, pyranyl or morpholinyl. which are optionally substituted up to twice in an identical or different manner by forrnyl, trifluoromethyl, phenyl, carboxyl, hydroxy., straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms, or by a radical of the formula — OR^4S, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms, and/or are substituted by a radical of the formula

wherein a3 denotes the number 0, 1₅ 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, R⁴³ and R⁴⁴, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, A³ represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, phenyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner byhydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, and/or are substituted by a group of the formula ~(CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight- chain or branched alkyl or acyl having in each case up to 4 carbon atoms, and their isomeric forms and salts.

Particularly preferred compounds of the general formula (HI-I) according to the invention are those in which R⁴² represents imidazolyl, oxazolyl, oxadiazolyl or thiazolyL which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyi having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, fluorine, chlorine, trifluoromethyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms or by the radical of the formula --O—CO--CH₃, and/or are substituted by a radical of the formula

wherein a3 denotes the number 0, 1 or 2, R⁴⁹ denotes hydrogen or metihyl, R⁴³ and R⁴⁴, including the double bond, form a fiiryl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxy., amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, A³ represents tetrahydropyranyl, phenyl, thienyl, pyrimidyl or pyridyl, which are option substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacy), alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, ilitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, and/or are substituted by a group of the formula — (CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms, and their isomeric forms and salts.

Especially preferred compounds of the general formula (HI-I) according to the invention are those in which R⁴² represents imidazolyl, oxazolyl, thiazolyl or oxadiazolyl, which are optionally substituted up to twice in an identical or different manner by ethoxycarbonyl, phenyl or by methyl or ethyl, wherein the alkyl radicals in their turn can be substituted by hydroxyl, chlorine, ethoxycarbonyl, oxycarbonylmethyl or methoxy, R⁴³ and R⁴⁴ together, in changing the double bond, represent phenyl, which is optionally substituted by nitro, A³ represents phenyl or phenyl which is substituted by fluorine, or pyrimidyl and their isomers and salts.

The invention furthermore relates to processes for the preparation of the compounds of the general formula (III-I) according to the invention, characterized in that [A3] compounds of the general formula (III-II)

in which R⁴², R⁴³ and R⁴⁴ have the abovementioned meaning, are reacted with compounds of the general formula (III-III) JJ- -CH₂ ~A^J (HI-III)

in which A³ has the abovementioned meaning and D³ represents triflate or halogen, preferably bromine, in inert solvents, if appropriate in the presence of a base, or.

[B3] compounds of the general formula (IU-IV)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning and L³ represents a radical of the formula -SnR⁵⁵R^s6R⁵⁷, ZnR⁵⁸, iodine, bromine or triflate, wherein R⁵⁵, R⁵⁶ and R⁵⁷ are identical or different and denote straight-chain or branched aϊkyl having up to 4 carbon atoms and R^S8 denotes halogen, are reacted with compounds of the general formula (IH-V)

R⁴² -T³ (H-V)₅

in which R⁴² has the abovementioned meaning and in the case where L³ =SnR^ssR^s6R⁵⁷ or ZnR⁵⁸, T³ represents triflate or represents halogen, preferably bromine, and in the case where L³ =iodine, bromine or triflate, T³ represents a radical of the formula SnR⁵⁵R⁵⁶¹R^57'', ZhR^ss'or BR⁵⁹R⁶⁰, wherein R^5y, R^56', R^57' and R^58' have the abovementioned meaning of R⁵⁵, R⁵⁶, R⁵⁷ and R⁵⁸ and are identical to or different from these, and R⁵⁹ and R⁶⁰ are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring, in a palladium-catalysed reaction in inert solvents, or [C3] in the case where

in which R⁶¹ represents straight-chain or branched alkyl having up to 4 carbon atoms, compounds of the general formula 011- VI)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are reacted with diazo compounds of the general formula (II- VII)

in which R⁶² represents straight-chain or branched alkyl having up to 4 carbon atoms, in the presence of copper salts or rhodium salts to give compounds of the general formula (Ill-la)

in

the abovementioned meaning,

[D3] in the case where

compounds of the general formula (III-VIII)

in which A³, R⁴³ and R⁴⁴IIaVe the abovementioned meaning, are either converted directly by reaction with the compound of the formula (III-IX)

in the system NaOCO-CHs/N-methylpyrrolidine into the compounds of the general formula (HI-Ib)

in which R⁴³, R⁴⁴ and A³ have the abovementioned meaning, and the acetyl group is then split off by the action of potassium hydroxide in methanol, or by reaction of the compounds of the general formula (III-VHI) with the compound of the formula (III-IX), the compounds of the general formula (Ul-X)

in which R⁴³, R⁴⁴ and A³ have the abovementioned meaning, are first prepared, and the hydroxymethyl compounds are prepared in a further step by the action of potassium hydroxide, and, if appropriate, are converted into the corresponding alkoxy compounds by an alkylation by customary methods, or [E3] compounds of the general formula (III-XI)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, by reaction with the compound of the formula (III-XII)

the compounds of the general formula (HI-XIII)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are prepared, and are then reacted in the context of a retro-Diels-AΪder reaction (cf. J. Org. Chem, 1988, 58, 3387-90), or

[F3] compounds of the general formula (HI-XIV)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are reacted with compounds of the general formula (IH-XV) Br-CH₂ -CO--R 6"3 (III-XV),

in which R⁶³ denotes straight-chain or branched alkyl or alkoxycarbonyl having in each case up to 4 carbon atoms, in inert solvents to give the compounds of the general formula (III-Ic)

in which A³, R⁴³, R⁴⁴ and R⁶³ have the abovementioried meaning (cf. Oxazoles, J. Wiley/New York, 1986, page 11/12), and, in the case of the esters (R⁶³ =CO₂-~(C_t -C₄ -alkyl), a reduction is carried out by customary methods to give the corresponding hydroxymethyl compounds, or ^' [G3] in the case where

o^^csi— OH

carboxylic acids of the general formula (IH-XVI)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are first converted with hydrazine hydrate into the compounds of the general formula (III-XVΪI)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, in a further step, with the compound of the formula (HI-XVIII)

Cl-CO-CH₂ -Cl (III-XVIH)

the compounds of the general formula (IH-XIX)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are prepared then under the action of phosphorus oxytrichloride, cyclϊzation is carried out to give the compounds of the general formula (HI-Id)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, and, as already described above, the — CH₂ — OH-substituted compounds are prepared via the stage of the corresponding —CEfe -0--CO-CH₃ -substituted compounds (cf. Aran. Forsch.45 (1995) 10, 1074-1078), or [H3] in the case where R⁴² represents a radical of the formula

wherein R⁶⁴ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and R⁶⁵ has the scope of meaning of the secondary substituents listed above under the heterocyclic radical R⁴², compounds of the general formula (U-XX.)

in which A³, R⁴³, R⁴⁴, R⁶⁴ and R^6S have the abovementioned meaning, are reacted in the system PPha Ih. in the presence of a base, preferably with triethylamine, or [13] in the case where R42 represents a radical of the formula

wherein a3 has the abovementioned meaning,

compounds of the general formula (III-XXI)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning and R⁶⁶ has the abovementioned meaning of R⁶⁴ and is identical to or different from this, either are first converted by reduction by customary methods into the compounds of the general formula (III-XXII)

in which A³, R⁴³ and R⁴⁴ have the aboveraβntioned meaning, and the compounds of the general formula (III-XXIII)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning, are then prepared by oxidation, or the compounds of the general formula (IH-XXI) are converted directly by reduction into the compounds of the general formula (III-XXIII), and, finally, these are reacted with 1,2- or 1,3-dihydroxy compounds by conventional methods, or [J3] in the case where R⁴² represents the radical of the formula

wherein R⁶⁷ has the abovementioned meaning of R⁶⁵ and is identical to or different from this, either compounds of the general formula (III-XXIV)

in which R⁴³ and R⁴⁴ have the abovementioned meaning and Q represents hydrogen or represents the --CH₂ —A³ radical and R⁶⁸ represents halogen or straight-chain or branched alkoxy having up to 4 carbon atoms, preferably chlorine, methoxy or ethoxy, are reacted with compounds of the general formula (III-XXV)

in which R⁶⁷ has the abovementioned meaning, if appropriate in the presence of a base, and, in the case where Q=H, the products are then reacted with compounds of the general formula A³ --CH2 —Br (III-XXVI), in which A has the abovementioned meaning, or compounds of the general formula (III-XXVII)

in which A³, R⁴³ and R⁴⁴ have the abovementioned meaning are reacted with compounds of the general formula (III-XXVIII)

(III-XXVIII)

in which R^6r has the abovementioned meaning of R⁶⁷ and is identical to or different from this and R⁶⁸ has the abovementioned meaning of R⁶⁸ and is identical to or different from this, if appropriate in the presence of a base, and, in the case of the radicals ~S(O)_c3NR⁵⁰R⁵¹ and — S(O)_CS-NR⁵⁰R^51' starting from the unsubstituted compounds of the general formula (IH-I)₃ a reaction first wilh. thionyl chloride and finally with the amine component is carried out, and, if appropriate, the substituents listed under R⁴², R⁴³, R⁴⁴ and/or A³ are varied or introduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution. The processes according to the invention described above can be explained by way of example by the following equations:

[∞l

Suitable solvents here for the individual steps of process [A3] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane. dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (triaIkyl-(Ci - examines), such as triethylarnine, or heterocyclic compounds, such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, N-methylpyrrolidone methylpiperidine or morpholine. It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine, sodium hydride and N- methylpyrrolidone are preferred.

The base is employed in an amount of 1 mol to 5 mol, preferably 1 mol to 3 mol, per mole of the compound of the general formula (HI-I). ' .

The reaction is in general carried out in a temperature range from 0° C. to 150° C, preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable solvents here for process [B3] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuiran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane, or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformrnamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0° C. to 150° C, preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂ (P(C₆ H₅)3)2, palladium bis-dibenzylideneacetone (Pd(dba)₂), [1,1'- bϊs(diphenylphosphino)ferrocene]palladium(ll) chloride (Pd(dppf)Cl2) or Pd(P(Ce 1*₅)₃)₄. Pd(P(C₆ Hs)₃)4 is preferred.

Suitable solvents for process [C3] are some of the abovementioned solvents, benzene being particularly preferred.

Suitable metal salts in the context of the invention are copper salts or rhodium(II) salts, such as, for example, CuOTf, Cu(acac)2 and Rh(OAc)2. Copper acetylacetonate is preferred.

The salts are employed in catalytic amounts.

The reaction is in general carried out in a temperature range from 0° C. to 150° C, preferably +20° C. to +110.° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Process [D3] according to the invention is carried out with one of the abovementioned cyclic amine bases, preferably with N-methylpyrrolidone, in a temperature range from 100° C. to 200° C, preferably at 150° C.

Process [E3J according to the invention is carried out in a temperature range from 150° C. to 210° C, preferably at 195° C.

Process [F3] according to the invention is in general carried out in one of the abovementioned ethers, preferably in tetrahydrofuran at the reflux temperature.

The reaction of the free methylhydroxy group to give the corresponding methylalkoxy compounds is carried out by customary methods by alkylation with alkyl halides, preferably alkyl iodides, in the presence of one of the abovementioned bases, preferably sodium hydride.

The compounds of the general formulae (III-III), (IH-V)₃ (IH-VI), (IH-VII), (III-VIII), (III-IX), OH-XI)₅ (IH-XII), (HI-XIV), OH-XVI) and (HI-XVIII) are known per se or can be prepared by customary methods.

The compounds of the general formula (IH-II) are known in some cases and can be prepared by a process in which compounds of the general formula (III-XXXIX)

in which R⁴³ and R⁴⁴ have the abovementioned meaning and L^3' has the abovementioned meaning of L³ and is identical to or different from this, are reacted with compounds of the general formula (HI-V) analogously to the abovementioned process {B3].~

^■ The compounds of the general formula (IH-W) are known in some cases or, in the case of the stannyls, are new and can be prepared, for example, by a process in which the compounds of the general formula (Ill-IVa)

in which R⁴³, R⁴⁴ and A³ have the abovementioned meaning, and L³' represents triflate or halogen, preferably iodine, are reacted with compounds of the general formula (HI-XXX)

(SnR^S5R^s6R⁵⁷)₂ (III-XXX),

wherein R⁵⁵, R⁵⁶ and R⁵⁷ have the abovementioned meaning under palladium catalysis as described above.

The compounds of the general formulae (Ill-IVa) and (III-XXX) are known or can be prepared by customary methods.

The compounds of the general formulae (Ul-X), (IH-XIII), (III-XVII) and (III-XIX) are new in some cases and can be prepared, for example, as described above.

Process [H3] proceeds by customary methods in the context of the invention, in particular in accordance with the descriptions from the publications P. Wipf, C P. Miller, J. Org. Chem. 1993, 58, 3604, C. S. Moody et al., Synlett 1966, page 825.

The compounds of the general formula (III-XX) are known in some cases or can be prepared from the corresponding amides by reaction with α-diazo-β-keto esters under rhodium salt catalysis (in this context, cf. C. J. Moody et al., Synlett 1996, 825).

Process [13] is carried out by the customary methods for the preparation of acetals. The reduction steps are described in detail below.

The compounds of the general formulae (HI-XXI)₃ (III-XXH) and (III-XXIII) are known in some cases or are new as a species, and can then be prepared as described above.

Process [13] is carried out analogously to the publications S. Chirα and H. J. Shirie, J. Heterocycl. Chem. 1989, 26, 125 and J. Med. Chem. 1990, 33, 113.

The compounds of the general formulae (M-XXIV) and (III-XXV) are known in some cases or can be prepared by customary-methods.

The compounds of the general formula (HI-XXVI) are known in some cases or are new, and can then be prepared from the corresponding cyano-substituted compounds and hydroxylamine hydrochloride. If appropriate, a base, preferably sodium methanolate in methanol, can be added for this reaction.

The compounds of the general formula (III-XXVII) are known per se or can be prepared by customary methods.

Processes [H3] to [J3] in general proceed in a temperature range from 0° C. up to the particular reflux temperature under normal pressure.

The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable .WUUV.UWU Here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate. zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

The reduction in general proceeds in a temperature range from -78° C. to +50° C, preferably from -78° C. to 0° C, in the case of DB3AH, 0° C₉ room temperature in the case of NaBH_t, particularly preferably at -78° C, in each case depending on the choice of reducing agent and solvents.

The reduction hi general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

The protective group is in general split off in one of the abovementioned alcohols and/or tetrahydrofuran or acetone, preferably methanol/tetrahydrofiiran, in the presence of hydrochloric acid or trifluoroaqetic acid or toluenesulphonic acid in a temperature range from 0° C. to 70° C, preferably at room temperature under normal pressure.

In the case where the radicals of the formulae -S(O)_C3NR⁵⁰R⁵¹ and -S(O)_C3-NR⁵⁰R⁵¹' are present, the corresponding unsubstituted compounds are first reacted with thionyl chloride. The reaction witihi the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a further step. In the case where c3=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0° C. to 70° C. under normal pressure.

Compounds according to the invention according to embodiment IH in which R⁴² represents an oxazolyl radical of the formula (IH-XXVIII)

wherein Y and Z have the meaning given below can preferably be prepared by the new process described below, which can be used generally for the preparation of oxazolyl compounds of this type.

The invention thus furthermore relates to a process for the preparation of oxazolyl compounds of the general formula (III-XXIX)

in which X and Y are identical or different and can represent optionally substituted aliphatic, cycloaliphatic, araliphatic, aromatic and heterocyclic radicals, including saturated, unsaturated or aromatic, heteromono- or heteropolycyclic radicals, carboxyl, acyl, alkoxy, alkoxycarbonyl or cyano or can represent hydrogen, wherein the aromatic and heterocyclic radicals can be substituted by one or more substituents which are chosen from the group which consists of: halogen, formyl, acyl, carboxyl, hydroxyl, alkoxy. aroxy, acyloxy, optionally alkyl-substituted amino, acylamϊno, aminocarbonyl, alkoxycarbonyl, nitro, cyano, phenyl and alkyl, which can be substituted by one or more substituents which are chosen from the group which consists of: halogen, hydroxyl, amino, carboxyl, acyl, alkoxy, alkoxycarbonyl and heterocyclyl and phenyl, which can be substituted by one or more substituents chosen from: amino, mercaptyl, hydroxyl, formyl, carboxyl, acyl, alkylthio, alkyloxyacyl, alkoxy, alkoxycarbonyl, nitro, cyano, trifluoromethyl, azido, halogen, phenyl and alkyl which is optionally substituted by hydroxyl, carboxyl, acyl, alkoxy or alkoxycarbonyl, and wherein the aliphatic, cycloaliphatic and araliphatic radicals can be substituted by one or more substituents which are chosen from the group which consists of: . fluorine, hydroxyl, alkoxy, aroxy, acyloxy, alkyl-substituted amino, acylamino, aminocarbonyl, alkoxycarbonyl and acyl, Z is chosen from the group which consists of:

hydroxyl, alkoxy, optionally alkyl- and/or halogen-substituted arylalkoxy, optionally alkyl- and/or halogen-substituted aroxy, aroyloxy, acyloxy, alkylthio, optionally alkyl- and/or halogen-substituted arylthio, diacylimido or a group of the formula (HI-XXX)

in which Y and X have the abovementioned meaning, characterized in that amides of the formula (III-XXXI)

in which Y and X have the abovementioned meaning and Hal represents chlorine or bromine, are reacted with compounds of the formula Ml⁺ Z^" or M2²⁺ (ZTtøj in which Ml is an alkali metal, M2 is an alkaline earth metal and Zi) as defined above.

In respect of concrete examples which contain the above definitions of the substituents in their scope, reference is made to the corresponding meanings in the explanations given above on the compounds of embodiment HI of the present invention.

In a preferred embodiment of this process, oxazolyl compounds of the present invention in which X in the above general formula (III-XXIX) is

wherein R⁴³, R⁴⁴ and A³ are as defined above and Y is alkyl or optionally alkyl- or halogen- substituted phenyl, are prepared.

Examples which may be mentioned of oxazoles which are obtained by the preparation process are: 2,4-dimethyl-5-methoxymethyl-oxazole, 2-ethyl-5-methoxymethyl-oxazole, 2- isoρropyi-4-ethyl-5-ethoxymethyl-oxazole, 2-cyclopropyl-4-hexyl-5-isopropoxymethyl- oxazole, 2-phenyl-4-methyl-5-methoxymethyl-oxazole, 2-(m-trifluoromethylphenyl)-4- ineuiyi-4-butoxymethyl-oxazole, 4-methyl-5-methoxymethyl-2-(m-trifluorophenyl)-oxazole₃

2-phenyl-4-metfayI-5-phenoxymethyl-oxazole, 2-(2-chloro-6-fluoroρhβnyl)-4methyl-5-ρ-tert- butylphenoxyraethyl<>xazoIe, 2,4-dimethyl-5^ heptylcarbonyloxy)methyl-oxazole, 2-phenyl-4-methyI-5-acetoxymethyl-oxazole, 2-( 1 - benzylmdazol-3-yl)-54iydroxymethyMHmfit%loxazole, 5^^^ ben2ylmdazol-3~yl)-4-memyl-oxazole, 2-(f-benzylmdazol-3-yl)^^ oxazole, 2-[l-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyI-4-methyl-oxazole» 2-[l-(2- fluoroben-^l)-indazol-3-yl]-5-methoxymethyI-4-methyl-oxazoIe_} 2-[l -(2- fluoroben-^l)inda2ol-3-yl]^-raethyl-5-(N-phthalimidomethyl)-oxazol e, 4-ethyl-2-[l -(2- fluorobenzyl)-indazol~3-yl]-5-hydroxymethyl-oxazoIe, 2-phenyl-4-ethyl-5- benzoyloxymethyl-oxazole, 2-phenyl-4-methyl-5-methylmercaptomethyl-oxazole, bϊs[(2- phenyI-4-methyl-oxazole-5-yl)methyl] disulphide and 2-phenyl-4-methyl-5-N- phthalimidomethyl-oxazole.

The process according to the invention for the preparation of the oxazole compounds is carried out, for example, by a process in which amides are reacted, according to equation (a), with compounds of the formula M I⁺ Z^" or M2²⁺ (ZT)₂ :

*

+ ZB

Ml in the compound Ml⁺ ZT is an alkali metal chosen from, for example, lithium (Li), sodium (Na) or potassium (K)₅ preferably sodium or potassium. Examples which may be mentioned of compounds of the formula Ml⁺ Z^" are alcoholates, such as Na methylate, Na butylate or K tert-butylate, phenolates, such as Na phenolate and Na 4-tert-bύtyl-ρhenolate, carboxylic acid salts, such as Na acetate or K acetate, Li butyrate, Na benzoate and Na 2,6- difluorobenzoate, phthalimide salts, such as K phthalimides and Na phthalimides, hydroxides, such as KOH, NaOH and LiOH, mercaptidejs, such as the sodium salts of methylmercaptan or thiophenol, and Na₂$₂, which leads to the disulphide of the formula

M2 in the compound M2²⁺ (Z^")2 is an alkaline earth metal chosen from, for example, magnesium or calcium.

The reaction according to the invention in accordance with equation (a) is carried out in solvents at temperatures from about 20° C. to 200° C. Suitable solvents are polar compounds, such as, for example, dimethylformamide, dϊmethylacetamide, N- methylpyrrolidone, N-methyl-.epsilon.-caprolactam and dimethyl sulphoxide, and compounds of the formula Z-H are furthermore also possible as solvents, for example the reaction of the amides with Na methylate can be carried out successfully in methanol. Addition of basic auxiliaries, such as, for example, K2CO3 or CS2CO3, may be advantageous. The resulting oxazoles are isolated, after removal of insoluble salts by filtration and, if appropriate, removal of solvents by distillation, by extraction of the oxazoles with suitable solvents, such as, for example, hydrocarbons, such as cyclohexane or toluene, or chlorohydrocarbons, such as, for example, methylene chloride or chlorobenzene, or esters, such as ethyl acetate or ethers, from the crude product, to which water has been added to remove water-soluble products. The crude product can be purified by customary processes, such as, for example, distillation or crystallization or by chromatography.

The amides as starting compounds are obtained by known processes, for example starting from compounds of the formula a, b or c.

V^X^∞

C = OH

Bi; L" B Cl Ot Br

Starting from amines of the formula a, amines of the formula (III-XXXI) are obtained in a known manner by reaction with corresponding acylating agents, such as, for example, acid halides, esters or acids. Matting from compounds of the formula b or c, amides are obtained in a known manner by reaction with nitrites in the presence of strong acids.

Amides corresponding to the formula a are accessible, for example, by hydrolysis under acid conditions from amides, which are obtained in a known manner by a Ritter reaction from alkyl halides or allyl alcohols of the formula b and c. Finally, such amines can also be obtained via allylic nucleophilic substitution with, for example, phthalimide salts from the corresponding allyl halides of the formula c via the stage of the corresponding substituted phthalimides and subsequent solvolysis.

Compounds of the formula b are readily accessible according to equation (b) and (c) in two reaction steps from simple starting materials in a known manner: β>>

Y COHaI +■ CHp=CHaIa

V-^O-CHiCH* ^- V-CO-CE=CBaI

CHoIj "*"

Y CSOSI CHS=CHhI

Compounds of me formula c are obtained in a known manner, for example by addition, initiated by free radicals, of carbon tetrachloride or tetrabromide onto corresponding olefmic compounds and subsequent elimination of hydrogen halide in accordance with equation (d):

Y CBS=CSs + CHaI₂ ~

The compounds of the general formulae (HI-I)/(III-Id) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations. If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight, of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention.

In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

Formula IV

According to embodiment IV, the present invention relates to using for treating HIF-related disorders and symptoms of cancer l-benzyl-3-(substxtuted heteroaryl)-fiised pyrazole derivatives of the general formula (IV-I)

in which A⁴ represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by halogen, hydroxyl, cyano, carboxyl, nitro, trifluoromethyi, trifluoromethoxy, azido, straight-chain, or branched alky I, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, R⁶⁹ represents a radical of the formula

wherein R⁷² denotes a radical of the formula -CH(OH)-CHb or straight-chain or branched alkyl having 2 to 6 carbon atoms, which is substituted once to twice by hydroxyl or straight- chain or branched alkoxy having up to 4 carbon atoms, or denotes foπnyl, straight-chain or branched acyl having up to 6 carbon atoms, nitro or straight-chain or branched alkyl having up to 6 carbon atoms, which is substituted by amino, azido or by a radical of the formula — OR⁷³, wherein R⁷³ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁷⁴R⁷⁵R⁷⁶,

wherein R⁷⁴R⁷⁵ and R⁷⁶ are identical or different and denote aryl having 6 to 10 carbon atoms or straight-chain or branched alkyl having up to 6 carbon atoms, R⁷⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and R⁷⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4. carbon atoms, or R⁷² denotes a group of the formula

o— CCHsU

O CCHUM CHj

0-(CHi)Mi CBj or SCcDbiNR∞R¹⁰ wherein R⁸⁰ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, R⁸¹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms and a4 denotes the number 1, 2 or 3, b4 and b4' are identical or different and denote the number 0, 1, 2 or 3, c4 denotes the number 1 or 2 and R⁸² and R⁸³ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁸² and R⁸³, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical — NR⁸⁴, wherein R⁸⁴ denotes hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, or R⁷² denotes a group of the formula --CHfe —OR⁸⁵, wherein R^8S denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, R⁷⁰ and R⁷¹ together form a radical of the formula

wherein R⁸⁶ denotes hydrogen, halogen, hydroxyl, nitro, amino, trifluoromethyl or straight- chain or branched alkyl or alkoxy having in each case up to 4 carbon atoms, or a group of the formula — S(O)c4_'NR⁸²R^83', wherein c4', R⁸² and R⁸³ have the abovementioned meaning of c4, R⁸² and R⁸³ and are identical to or different from these, and their isomeric forms and salts, with the proviso that R⁷², in the case of the phenyl ring and in the position directly adjacent to the heterpatom, may represent the group of the formula --CH2 -OR⁸⁵OnIy if A⁴ either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or is substituted at ^' least twice by the radicals listed above, or R⁸⁶ represents nitro, amino, trifluoromethyl or represents the group of the formula -S(O)₀₄NR⁸²¹R^83'.

The compounds of the general formula (FV-I) according to the invention can also be present in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here. Physiologically acceptable salts are preferred in the context of embodiment IV of the present invention. Physiologically acceptable salts can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, • phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention if they have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine or ethylenediamine.

Preferred compounds of the general formula (IV-I) according to the invention are those in which A⁴ represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by fluorine, chlorine, bromine, hydroxyl, cyano, carboxyl, nitro, trifluoromethyl, trifluoromethoxy, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, R⁶⁹ represents a radical of the formula

wherein R⁷² denotes a radical of the formula — CH(OH)~CH3 or straight-chain or branched alkyl having 2 to 4 carbon atoms, which is substituted once to twice by hydroxyl or straight- chain or branched alkoxy having up to 3 carbon atoms, or denotes formyl, straight-chain or branched acyl having up to 4 carbon atoms, nitro or straight-chain or branched alkyl having up to 4 carbon atoms, which is substituted by amino, azido or by a radical of the formula — OR⁷³, wherein R⁷³ denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula

or

-CH₂ -OR 79

wherein R⁷⁸ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and R⁷⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or R⁷² denotes a group of the formula

wherein R⁸⁰ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, R⁸¹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms and a4 denotes the number 1 or 2, or R⁷² denotes a group of the formula --CH₂ —OR⁸⁵, wherein R⁸⁵ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, R⁷⁰ and R⁷¹ together form a radical of the formula

*⁶

wherein R⁸⁶ denotes hydrogen, fluorine, chlorine, bromine, hydroxyl, nitro, amino, trifluoromethyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, and their isomeric forms and salts, with the proviso that R⁷², in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula -CH₂ —OR⁸⁵ only if A⁴ either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or is substituted at least twice by the radicals listed above, or R ,, 88⁸6 represents nitro, amino or trifluoromethyl.

Particularly preferred compounds of the general formula (TV-I) according to the invention are those in which A⁴ represents phenyl, which is optionally substituted up to 3 times in an identical or different manner by fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy, cyano, nitro, carboxyl, azido, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, R⁶⁹ represents a radical of the formula

wherein R⁷² denotes a radical of the formula ~CH(OH)--CH3 or straight-chain or branched alkyl having 2 to 4 carbon atoms, which is substituted once to twice by hydroxy!, methyl or methoxy, or denotes formyl, straight-chain or branched acyl having up to 3 carbon atoms, nitro or straight-chain or branched alkyl having up to 3 carbon atoms, which is substituted by amino, azido or by a radical of the formula —OR⁷³, wherein R⁷³ denotes straight-chain or branched acyl having up to 3 carbon atoms or a group of the formula

~Si(CH₃)₂C(CH)₃,

or

-CH₂ -OR⁷⁹

wherein R⁷⁸ denotes hydrogen or methyl and R⁷⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, or R⁷² denotes a group of the formula

wherein R^so denotes hydrogen or straight-chain, or branched alkyl having up to 3 carbon atoms, R⁸¹ denotes hydrogen or methyl and a4 denotes the number 1 or 2, or R⁷² denotes the group of the formula -CH₂-OR⁸⁵, wherein R⁸⁵ denotes hydrogen or methyl, R⁷⁰ and R⁷¹ together form a radical of the formula

wherein R⁸⁶ denotes hydrogen, fluorine, chlorine, bromine, nitro, trifluoromethyl, amino, hydroxyl or straight-chain or branched alkyl or alkoxy having in each case up to 3 carbon atoms, and their isomeric forms and salts.

Especially preferred compounds of the general formula (TV-T) according to the invention are those in which A⁴ represents phenyl, which is optionally substituted up to twice in an identical or different manner by fluorine, chlorine, methyl, rnethoxy, cyano, nϊtro, trifluoromethyl or trifluoromethoxy and R⁷⁰ and R⁷¹ together, including the double bond, form a phenyl ring_* which is optionally substituted by nitro, fluorine, amino or methoxy, with the proviso that R⁷², in the case of the phenyl ring and in the position directly adjacent to the heteroatom, may represent the group of the formula -CHz OR⁸⁵ only if A⁴ either represents phenyl, which is substituted by cyano, nitro, trifluoromethyl, azido, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms, or is substituted at least twice by the radicals listed above, or R⁸⁶ represents nitro, amino or trifluoromethyl.

The invention furthermore relates to processes for the preparation of the compounds of the general formula (TV-I) according to the invention, characterized in that

[A4] compounds of the general formula (IV-II)

H₂N-NH-CH₂ -A⁴ (IV-II)

in which A⁴ has the abovementioned meaning, are converted by reaction with compounds of the general formula (TV-III)

in which R⁶⁹, R⁷⁰ and R⁷¹ have the abovementioned meaning, into the compounds of the general formula (IV-IV)

in which A⁴, R⁶⁹, R⁷⁰ and R⁷¹ have the abovementioned meaning, in inert solvents, if appropriate in the presence of an acid, and the products are finally oxidized and cyclϊzed with lead tetraacetate/BF3xether, or [B4] compounds of the general formula (IV-V)

in which R⁶⁹, R⁷⁰ and R⁷¹ have the abovementioned meaning, are reacted with compounds of the general formula (IV-VI) D⁴ -CH₂ -A⁴ (IV-VI) in which A⁴ has the abovementioned meaning and D⁴ represents triflate or halogen, preferably bromine, in inert solvents, if appropriate in the presence of a base, or [C4] compounds of the general formula (TV-VII)

in which A⁴, R⁷⁰ and R⁷¹ have the abovementioned meaning and L⁴ represents a radical of the formula -SnR⁸⁷R⁸⁸R⁸⁹, ZnR⁹⁰, iodine or triflate wherein R⁸⁷, R⁸⁸ and R⁸⁹ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms and R⁹⁰ denotes halogen, are reacted with compounds of the general formula (JV-VIH)

R⁶⁹ -T⁴ (IV-VIII)

in which R⁶⁹ has the abovementioned meaning and in the case where L⁴ =SnR⁸⁷R⁸⁸R⁸⁹ or ZnR⁹⁰, T⁴ represents triflate or represents halogen, preferably bromine, and in the case where L⁴ =iodine or triflate, T⁴ represents a radical of the formula SnR^8TR^88'R^89', ZnR⁹⁰Or BR⁹¹R⁹² wherein R^87', R^88', R⁸⁹' and R^90' have the abovementioned meaning of R⁸⁷, R⁸⁸, R⁸⁹ and R⁹⁰ and are identical to or different from these and R⁹¹ and R⁹² are identical or different and denote hydroxyl, aryloxy having 6 to 10 carbon atoms or straight-chain or branched alkyl or alkoxy having in each case up to 5 carbon atoms, or together form a 5- or 6-membered carbocyclic ring in a palladium-catalysed reaction in inert solvents, or

[D4] in the case where R⁷² represents an alkyl having 2 to 6 carbon atoms, which is substituted twice by hydroxyl, compounds of the general formula (IV-Ia)

in which A⁴, R⁷⁰ and R⁷¹ have the abovementioned meaning, are first converted by a Wittig reaction in the system

-CHb^" into the compounds of the general formula (IV-EX)

in which R⁷⁰, R⁷¹ and A⁴ have the abovementioned meaning, and finally the hydroxyl functions are introduced with osmium tetroxide, and, if appropriate, the substituents listed under R⁶⁹, R⁷⁰, R⁷¹ and/or A⁴ are varied orintroduced by customary methods, preferably by reduction, oxidation, splitting off of protective groups and/or nucleophilic substitution.

The processes according to the invention can be illustrated by way of example by the following equations:

. [M]

Suitable solvents for the individual steps of process [A4] are in general inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether, dimerahydrofuran, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, alcohols, such as methanol, ethanol or propanol, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Ethanol and THF are preferred for the first step of process [A4], and methylene chloride is preferred for the cyclization. The reaction is in general carried out in a temperature range from 0° C. to 150° C, preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable acids are in general carboxylic acids, such as, for example, acetic acid, toluenesulphonic acid, sulphuric acid or hydrogen chloride. Acetic acid is preferred.

Suitable solvents here for the individual steps of process [B4] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonitrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, toluene or dimethylformamide are particularly preferred.

Bases which can be employed for the process according to the invention are in general inorganic or organic bases. These include, preferably, alkali metal hydroxides, such as, for example, sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides, such as, for example, barium hydroxide, alkali metal carbonates, such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates, such as calcium carbonate, or alkali metal or alkaline earth metal alcoholates, such as sodium or potassium methanolate, sodium or potassium ethanolate or potassium tert-butylate, or organic amines (triaIkyl-(Ci - C₆)amines), such as triethylamine, or heterocyclic compounds, such as 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo-[5.4.0]undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine.

It is also possible to employ as the bases alkali metals, such as sodium, and hydrides thereof, such as sodium hydride. Sodium carbonate and potassium carbonate, triethylamine and sodium hydride are preferred.

The base is employed in an amount of 1 mol to5 mol, preferably 1 mol to 3 mol, per 5 mole of the compound of the general formula (IV-II).

The reaction is in general carried out in a temperature range from 0° C. to 150° C, preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is hi general carried out under normal pressure.

Suitable solvents here for processes [C4] and [D4] are inert organic solvents which do not change under the reaction conditions. These include ethers, such as diethyl ether or tetrahydrofuran, DME or dioxane, halogenohydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or petroleum fractions, nitromethane, dimethylformamide, acetone, acetonϊtrile or hexamethylphosphoric acid triamide. It is also possible to employ mixtures of the solvents. Tetrahydrofuran, dimethylformamide, toluene, dioxane or dimethoxyethane are particularly preferred.

The reaction is in general carried out in a temperature range from 0° C. to 150° C, preferably from +20° C. to +110° C.

The reaction can be carried out under normal, increased or reduced pressure (for example 0.5 to 5 bar). It is in general carried out under normal pressure.

Suitable palladium compounds in the context of the present invention are in general PdCl₂ ((C_O 1*5)3)2, palladium bϊs-dibenzylideneacetone (Pd(dba)2), [l,l'-bis- (diphenylphosphino)ferrocene]-palladium(II) chloride (Pd(dppf)Cl₂) or Pd(P(C₆Hs)₃)₄. Pd(P(C₆H₅)₃)4 is preferred.

The compounds of the general formulae (IV-II), (TV-III), (IV-VI) and (IV-VIII) are known per se or can be prepared by customary methods.

The compounds of the general formula (IV-IV) are known in some cases or can be prepared as described above.

The compounds of the general formula (IV-V) are known in some cases and can be prepared by a process in which compounds of the general formula (IV-IX)

in which R⁷⁰ and R⁷¹ have the abovementioned meaning and L^4' has the abovementioned meaning of L⁴ and is identical to or different from this, are reacted with compounds of the general formula (IV-VIII) analogously to the abovementioned process [C4].

The compounds of the general formula (IV-VII) are known in some cases or, in the case of the stannyls, are new and can then be prepared, for example, by a process in which the compounds of the general formula (IV-VIIa)

in which R⁷⁰, R⁷¹ and A have the abovementioned meaning, and L⁴ represents triflate or halogen, preferably iodine, are reacted with compounds of the general formula (IV-X)

(SnR⁸⁷R⁸⁸R⁸⁹)₂ (TV-X)

in which R⁸⁷, R⁸⁸ and R⁸⁹ have the abovementioned meaning, under palladium catalysis as described above.

The compounds of the general formulae (TV-Vila), (IV-IX) and (IV-X) are known or can be prepared by customary methods.

The compounds of the general formula (TV-IX) are new and can be prepared as described above.

The reductions are in general carried out with reducing agents, preferably with those which are suitable for reduction of carbonyl to hydroxy compounds. A particularly suitable reduction here is reduction with metal hydrides or complex metal hydrides in inert solvents, if appropriate in the presence of a trialkylborane. The reduction is preferably carried out with complex metal hydrides, such as, for example, lithium boranate, sodium boranate, potassium boranate, zinc boranate, lithium trialkylhydridoboranate, diisobutylaluminium hydride or lithium aluminium hydride. The reduction is especially preferably carried out with diisobutylaluminium hydride and sodium borohydride.

The reducing agent is in general employed in an amount of 1 mol to 6 mol, preferably 1 mol to 4 mol, per mole of the compounds to be reduced.

The reduction in general proceeds in a temperature range from -78° C. to +50° C, preferably from -78° C. to 0° C, in the case of DIBAH, 0° C, room temperature in the case of NaBH_t, particularly preferably at -78° C, in each case depending on the choice of reducing agent and solvents.

The reduction in general proceeds under normal pressure, but it is also possible to carry it out under increased or reduced pressure.

In the case of the radicals -S(O)C₄R⁸¹R⁸² and ~S(O)c4_'R^8rR^82', the corresponding unsubstituted compounds of the general formula (TV-I) are first reacted with thionyl chloride. The reaction with the amines in one of the abovementioned ethers, preferably dioxane, is carried out in a further step. In the case where c4=2, oxidation by customary methods is subsequently carried out. The reactions are carried out in a temperature range from 0° C. to 70° G. under normal pressure. The protective group is in general split off in one of the abovementioned alcohols and/or tetrahydrofuran or acetone, preferably methanol/tetrahydrofuran, in the presence of hydrochloric acid or trifluoroacetic acid or toluenesulphonic acid in a temperature range from 0° C. to 70° C, preferably at room temperature under normal pressure.

The compounds of the general formula (TV-Ic) are new and can be prepared as described under processes [A4] to [C4].

The compounds of the general formula (TV-I) and (TV-Ia) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention. In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every ^"24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

Formula V

According to embodiment V, the present invention relates to using for treating HTF-related disorders and symptoms of cancer,

, which is described in Nature (Stasch et α/.,^*Nature (2001), 410: 212-215).

The compounds of the general formula (V) according to the invention can also be present in the form of their salts. Salts with organic or inorganic bases or acids may be mentioned in general here.

Physiologically acceptable salts are preferred in the context of embodiment V of the present invention. Physiologically acceptable salts can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. Particularly preferred salts are, for example, those with hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonie acid, toluenesulphonic acid, benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleϊc acid or benzoic acid.

Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention if they have a free carboxyl group. Particularly preferred salts are, for example, sodium, potassium, magnesium or calcium salts, and ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylarniπe, di- or triethylamine, di- or triethanolamine, dϊcyclohexylamine, dimethylamϊnoethanol, arginine, lysine or ethylenediamine.

The compounds of the general formula (V) according to the invention show an unforeseeable, valuable pharmacological action spectrum.

The present invention includes pharmaceutical formulations which comprise, in addition to non-toxic, inert pharmaceutically suitable carriers, one or more compounds according to the invention, or which consist of one or more active compounds according to the invention, and processes for the preparation of these formulations.

If appropriate, the active compound or compounds can also be present in microencapsulated form in one or more of the abovementioned carriers.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical formulations in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95% by weight of the total mixture.

The abovementioned pharmaceutical formulations can also comprise further pharmaceutical active compounds in addition to the compounds according to the invention. In general, it has proved advantageous both in human and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of about 0.5 to about 500, preferably 5 to 100 mg/kg of body weight every 24 hours, if appropriate in the form of several individual doses, to achieve the desired results. An individual dose preferably comprises the active compound or compounds according to the • invention in amounts of about 1 to about 80, in particular 3 to 30 mg/kg of body weight.

UTILITY, TESTING AND ADMINISTRATION UTILITY

The present invention is based on the surprising discovery that described compounds herein exhibit an antitumor effect in vivo either by inhibiting HIF activity or by arresting the cell cycle essential for tumor growth and metastasis.

Accordingly, one aspect of the present invention provides a method of inhibiting HIF- 1 ot or HIF-2α expression in tumor cells or tissues, and to induce cell cycle arrest leading to apoptosis, comprising contacting the tumor cells or tissues with a composition comprising the compounds described herein at an effective amount for inducing cell cycle arrest.

Another aspect of the present invention provides a method of inhibiting HIF- regulated gene expression in tumor cells or tissues, comprising contacting the tumor cells or tissues with a composition comprising the compounds described herein at an effective amount for inhibiting HIF- regulated gene expression.

A further aspect of the present invention provides a method of inhibiting tumor growth in animal tissues, comprising contacting the animal tissues with a composition comprising the compounds described herein at an effective amount for inhibiting tumor growth.

Yet another aspect of the present invention provides a method of inhibiting tumor progression and metastasis in animal tissues, comprising contacting the animal tissues with a composition comprising the compounds described herein at an effective amount for inhibiting tumor progression and metastasis.

The present invention is broadly applicable to a variety of uses which include single agent or a component in combination therapy to treat HIF-mediated disorders or conditions with accompanying undesired angiogenesis, such as solid and blood-borne tumors including but not limited to melanomas, carcinomas, sarcomas, rhabdomyosarcoma, retinoblastoma, Ewϊng sarcoma, neuroblastoma, osteosarcoma, and leukemia. TESTING

Compounds of the invention have an inhibitory effect on the expression of HIF- lα and HIF-2α and on the induction of VEGF, aldolase A, and enolase 1 in cancer cells cultured under hypoxic conditions. In vivo, treatment halts the growth of xenografted tumors originating from hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, and neuroblastoma cells. Tumors from treated mice show fewer blood vessels and reduced expression of HIF-I α and HIF-2α proteins and HIF-regulated genes than tumors from vehicle-treated mice.

The compounds induce cell cycle arrest in Hep3B liver tumor cells. After application of 1 μM into cultures of Hep3B cells, typically in 48 hours, about 28% of the cells are in the G0/G1 phases, 15% in the G2/M phases, 57% in the S phase, and a small percentage are characterized as being in the sub-Gl phase. In the control, typically 60% of the cells are in the G0/G1 phases, 16% in the G2/M phases, and 30% in the S-phase. Substantial arrest of the cell cycle such that almost double the percentage of cells are in the S-phase.

The described compounds can be evaluated for efficacy using the methods described above. In addition, compounds of the invention have efficacy in in a cell viability assay using human cancer cells. The cells are treated with the described compound (at concentrations ranging from 0.5-2 μM) and buffer. Cellular viability is measured at 24, 48, and 72 hours. Treatment with the compound results in a notable decrease in cell viability.

ADMINISTRATION

The described compounds are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. While human dosage levels have yet to be optimized for the compounds of the invention, generally, a daily dose is from about 0.05 to 100 mg/kg of body weight, preferably about 0.10 to 10.0 mg/kg of body weight, and most preferably about 0.15 to 1.0 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be about 3.5 to 7000 mg per day, preferably about 7.0 to 700.0 mg per day, and most preferably about 10.5 to 70 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician; for example, a likely dose range for oral administration would be about 700 to 7000 mg per day, whereas for intravenous administration a likely dose range would be about 70 to 700 mg per day, the active agents being selected for longer or shorter plasma half-lives, respectively.

The nonspecific cytotoxicity of the compounds according to the invention is generally greater than 90% survival tested in vitro by MTT assay at a concentration of 5 μg/ml. In the assay cells are plated in culture plates at a density of 2x10⁴ cells per well. After stabilizing for 24 hr., Hep3B cells are treated with test ^"compound at a concentration of 5 μg/ml, then assayed after 24-hr, for viability. MTT-labeling reagent (final cone. 0.5 mg/ml) is added to each well and 4 hours later the cells are lysed with i-propyl alcohol. Absorbance is measured at 570 nm.

Administration of the compounds of the invention or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administration are customary in treating the indications that are the subject of the present invention.

Pharmaceutically acceptable compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The compounds can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. Preferably, the compositions are provided in unit dosage forms suitable for single administration of a precise dose.

The compounds can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamϊne acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, the pharmaceutical formulation will contain about 0.005% to 95%, preferably about 0.5% to 50% by weight of a compound of the invention. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania. In addition, the compounds of the invention can be co-administered with other active medicinal agents and/or administered in conjunction with other anticancer, antitumor, or antiproliferative disease therapies. Such therapies include, but are not limited to, radiation therapy, chemotherapy, immunotherapy, laser/microwave thermotherapy, and gene therapy using antisense DNA and RNA. See Moeller et al., Cancer Cell 2004 5:429-441. Suitable additional active agents include, for example: with aϊfa interferons such as Interferon alfa-2b; alkylators such as asaley, AZQ, BCNU, busulfan, carboxyphthalatoplatinum, CBDCA, CCNU, CHIP, chlorambucil, chlorozotocin, clomesone, cyclodisone, cyclophosphamide, dacarbazine, dianhydrogalactitol, fluorodopan, hepsulfam, hycanthone, L-TAM, melphalan, methyl CCNU, mitomycin C, mitozolamide, nitrogen mustard, PCNU, pϊperazine alkylator, piperazinedione, pipobroman, porfiromycin, spirohydantoin mustard, temozolomide, teroxirone, tetraplatin, thio-tepa, triethylenemelamine, uracil nitrogen mustard, and Yoshi-864; anthracyclines such as doxorubicin, cyanomorpholinodoxorubicin, mitoxantrone, idarubicin, doxorubicin liposomal, valrubicin, epirubϊcin, daunomycin, and daunorubicin liposomal; antibiotics such as dactinomycϊn, actinomycin D, bleomycin, and daunorubicin; aromatases inhibitor such as anastrozole and letrozole; covalent conjugate of recombinant methionyl human GCSF and monomethoxypolyethylene glycol; cyclo-oxygenase inhibitors such as celecoxib; diluents such as Elliott's B Solution; enzymes such as Asparaginase; erythropoiesis stimulating proteins such as Epoetin alfa and Darbepoetin alfa; estrogen receptor modulators such as tamoxifen and fulvestrant; folate antagonists such as methotrexate; granulocyte colony stimulating factors such as Filgrastim; hormonals such as anastrozole; inorganic arsenates such as arsenic trioxide; microtubule inhibitors such as vincristine, vinblastine, paclitaxel, vinorelbine, and docetaxel; modifiers such as leucovorin and dexrazoxane; monoclonal antibodies such as anti- CD20 (Rituximab, ⁹⁰Y-ibrtumomab tiuexetan, and ¹³¹I-tositumomab), anti-CD22 (Epratuzumab and ⁹⁰Y-epratuzumab), anti-HLA-DR (Remitogen), anti-HER2/NEU (Trastuzumab), anti-CD33 (Gemtuzumab ozogamicin), anti-CD52 (Alemtuzumab), anti-carcinoembryonic antigen (⁹⁰Y-CEA-cide), anti-epithelial cellular-adhesion molecule (Edrecolomab), anti-epidermaj growth-factor receptor (Cetuximab, h-R3, and ABX-EGF), anti-VEGF (Bevacizumab), anti-VEGFR2 (IMC-ICl 1), anti-A33 (huA33), anti-G250/MN (G250), anti-Lewis Y antigen (SGN-15 and Hu3S193), and anti-GD3 (KW-2871); nitrosoureas such as procarbazine, lomustine, CCNU, carmustine, estramustine, and carmustine with Polifeprosan 20 Implant; nucleoside analogues such as mercaptopurine, 6-MP, fluorouracil, 5-FU, thioguanine, 6-TG, cytarabine, floxuridine (intraarterial), fludarabine, pentostatin, cladribine, pentostatin, gemcitabine, capecitabine, gemcitabine, and cytarabine liposomal; osteoclast inhibitors such as pamidronate; platinums such as carboplatin, cisplatin, and oxaliplatin; retinoids such as tretinoin, ATRA, alitretinoin, and bexarotene capsules gel; stem cell stimulators such as Oprelvekin; topoisomerase 1 inhibitors such as topotecan and irinotecan; topoisomerase 2 inhibitors such as etoposide, (VP- 16), teniposide, (VM -26), and etoposide phosphate; tyrosine kinase inhibitors such as imatinib mesylate; urate-oxidase enzymes such as Rasburicase; and hydroxyurea.

In one preferred embodiment, the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.

Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and will be higher if the composition is a solid that will be subsequently diluted to the above percentages. Preferably the composition will comprise 0.2-2% of the active agent in solution.

Formulations of the active compound or a salt may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.

The present invention is more specifically illustrated by the following examples. However, it should be understood that these examples are provided only for illustration of the present invention, but not intended to limit the present invention in any manner.

EXAMPLES

EXAMPLE I/I A - as set forth in U.S. Patent No. 6,387,940 5-(l ,3-Dioxan-2-yl)-2-tributylstannyl-furan .

200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) are added dropwise to a solution of 34.4 g of 2-(2-furyl)-l,3-dioxane (224 mmol, obtainable from furfural and propane- 1,3-diol) in 320 ml of THF at -70° C. in the course of 20 minutes. The solution is warmed at -20° C. for 30 minutes and then cooled again to -78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF is then added dropwise in the course of 30 minutes, after which the mixture is allowed to warm to room temperature. After 2.5 hours, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried with magnesium sulphate and concentrated and the residue is distilled (boiling pointo.g 180° C). 93 g are obtained.

EXAMPLE 1/2 A

3-(5_(l₅3-Dioxan-2-yl)furan-2-yl)indazole

10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1979, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PPh₃^ is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-l,3-dioxane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(l,3-dioxolan-2-yl)fury,)indazole are obtained. Rf(SiO₂, toluenetethyl acetate 4:1): 0.1; MS (ESI/POS): 271 (82, M+H), 213 (100), 157 (10).

EXAMPLE π/3 A

2-(l ,3-Dioxan-2-yl)-6-trimethylsta]mylpvridine

2 g (8.19 mmol) of 2-(l,3-dioxan-2-yl)-6-bromopyridine (R_f(SiO₂, ethyl acetate): 0.67), obtainable from 6-bromo-2-pyridinecarboxaldehyde (Inorg. Chem. 1971, 10, 2474) and 1,3- propanediol, are initially introduced into 50 ml of ether, and 3.6 ml of a 2.5N solution of n- BuLi in hexane are added at -80° C. The mixture is stirred at -80° C. for 30 minutes and 1.8 j of trimethyltin chloride in 5 ml of ether are added. The mixture is first stirred at -80° C. and then allowed to come to -30° C. It is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and the solvent is evaporated in vacuo. The product (1.1 g) can be employed for the next stage without further purification. R_f (SiO₂, ethyl acetate): 0.2; MS (CI): 330 (80, M+H), 166 (100).

EXAMPLE Π/4 A

3-(6-(l,3-Dioxan-2-yl)-2-pyridyl)indazole

60 mg of Pd(PPh₃)4 are added to 0.82 g (3.35 mmol) of 3-iodoindazole in 10 ml of DMF at room temperature under argon, and the mixture is stirred for 15 minutes. 1.1 g (3.35 mmol) of 2-(l,3-dioxan-2-yl)-6-trimethyIstannylpyriJine are added and the mixture is stirred at 100° C. for 4 hours. It is then evaporated in vacuo and the residue is chromatographed over silica gel. 300 mg (32% of theory) of an oil are obtained. MS (CI/NH₃): 283 (100, M+H).

EXAMPLE W5 A

3-Iodoindazole

58.1 g of iodine (229 mmol) are introduced in portions into a suspension of 25.6 g of indazole (217 mmol) in 625 ml of methanol and 625 ml of 2N sodium hydroxide solution in the course of 1 hour. The mixture is stirred at room temperature for 3 days and 75 ml of concentrated hydrochloric acid is then added, while cooling with ice, the mixture is rendered acid with 2N hydrochloric acid and 20% strength sodium thiosulphate pentahydrate solution is added until the iodine colour disappears. The precipitate which separates out is filtered off with suction, washed neutral with water and dried in a vacuum drying cabinet at 50° C. For purification, the solid is taken up in methanol. After undissolved constituents are filtered off, the filtrate is concentrated to dryness on a rotary evaporator, the product being obtained as an almost white solid.

Yield: 52.6 g (quantitative)

R_f value: 0.63 (silica gel; cyclohexane/ethyl acetate 1:1)

Melting point: 137° C. EXAMPLE ϊl/6 A

1 -Benzyl-3-iodoindazole

1.49 g of 95% pure sodium hydride (59.0 mmol) are added in portions to a solution of 12.0 g (49.2 mmol) of 3-iodoindazole in 100 ml of anhydrous tetrahydrofuran under argon. After the mixture is stirred at room temperature for 45 minutes, 7.02 ml (59.0 mmol) of benzyl bromide are added dropwise. The mixture is stirred overnight at room temperature, and diethyl ether and water are then added. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated to dryness on a rotary evaporator. The excess benzyl bromide, is separated off by bulb tube distillation. The distillation residue gives a product in the form of an oil which is gradually crystallized.

Yield: 15.4 g (94% of theory) R_f value: 0.78 (silica gel; cyclohexane/ethyl acetate 1:1) Melting point: 54° C.

EXAMPLE Π/7 A

1 -Benzyl-3-trimethylstannylindazole

800 g of 1 -benzyl-3-iodoindazole (24.0 mmol), 23.7 g of hexamethylditin (72.0 mmol) and 2.00 g of Pd(PPli₃)₄ (7.2 mol %) in 240 ml of anhydrous 1,4-dioxane are heated under reflux overnight in an argon atmosphere. The mixture is cooled to room temperature, 72 ml of IM potassium fluoride solution and 200 ml of -ethyl acetate are added and the mixture is stirred for 30 minutes. After the precipitate is filtered off over Celite, the organic phase of the filtrate is washed with saturated sodium chloride solution, dried over magnesium sulphate and freed from the solvent on a rotary evaporator. The residue is stirred in n-pentane and the precipitate is filtered off with suction and dried at 50° C. under a high vacuum, whereupon the product is obtained in the form of a white solid.

Yield: 6.05 g (68%; purity: 88% according to GC) R_f value: 0.47 (silica gel; cyclohexane/ethyl acetate 10:1) Melting point: 122° C. MS-EI: 372 (Sn, M+, 23), 357 (Sn, 56), 207 (100), 165 (Sn, 61),

91 (68).

Abbreviations:

Ph phenyl

Et ethyl

Me - = methyl

EE ethyl acetate

H hexane

PE petroleum ether

MeOH methanol

E ether

DMF dimethylformamide

Ac ^" = acetyl

KOH potassium hydroxide

NMP = N-methylpyrrolidone

EXAMPLE m/8 A l-Benzyl-3-iodoindazole

A solution of 2.99 g of iodoindazole (12.25 mmol) in 10 ml of THF is added dropwise to a suspension of 515 mg of NaH (60% in oil, 12.88 mmol) in 20 ml of THF. After 15 minutes, 1.55 ml of benzyl bromide is added. After 6 hours at room temperature and 3 hours at 40° C. water is added to the reaction mixture and the mixture is extracted with ether. The organic phases are dried with sodium sulphate and concentrated. After chromatography (Siθ₂ ; petroleum etheπethyl acetate 9:1), 3.351 g of a viscous oil which solidifies in vacuo are obtained. Melting point: 51.5-52.5° C. R_f =0^'38 (hexanelethyl acetate 3:1).

EXAMPLE UU9 A

1 -Benzyl-3-cyanoindazole

420 mg of NaH (60% in oil, 10.3 mmol) are added in portions to 1,0 g of 3-cyanoindazole (7.0 mmol) and 1.7 ml of benzyl bromide (14.0 mmol) in 6 ml of THF, and the mixture is stirred at room temperature for.15 hours. The reaction is quenched with 2 drops of water, the mixture is concentrated and the residue is chromatographed (S1O2 ; petroleum etheπethyl acetate 3:1). 1.3 g of a solid are obtained.

Melting point: 91° C.

EXAMPLE TWlO A

1 -Benzyl-3-trimethylstannyl-indazole

1.67 g of l-benzyl-3-iodoindazole (5.00 mmol), 4.95 g of hexamethylditin (15.0 mmol) and 530 mg of Pd(PPh3>4 (10 mol %) are heated under reflux in 50 ml of anhydrous 1,4-dioxane overnight. The mixture is cooled to room temperature, 15 ml of IM potassium fluoride solution and 50 ml of ethyl acetate are added and this mixture is stirred for 30 minutes. After the precipitate is filtered off, the organic phase of the filtrate is washed with water, dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Drying of the residue at 50° C. under a high vacuum gives the product in the form of a white solid, which could be employed in the subsequent Pd-catalysed couplings without further purification. Yield: 78%. R_f : 0.32 (silica gel; cyclohexane/ethyl acetate 16:1). MS-EI: 372 (Sn, M^.23), 357 (Sn, 56), 207 (100), 165 (Sn₅ 61), 91 (6S).

EXAMPLE ΓV/11 A

5-( 1 ,3-Dioxan-2-yl)-2-tributylstannyl-furan

200 ml of sec-butyllithium (1.3M solution in cyclohexane, 260 mmol) are added dropwise to a solution of 34.4 g of 2-(2-furyl)-l,3-dioxane (224 mmol, obtainable from furfural and propane-l,3-diol) in 320 ml of THF at -70° C. in the course of 20 minutes. The solution is warmed at -20° C. for 30 minutes and then cooled again to -78° C. A solution of 60.8 ml of tributylstannyl chloride in 160 ml of THF is then added dropwise in the course of 30 minutes, after which the mixture is allowed to warm to room temperature. After 2.5 hours, water is added and the mixture is extracted with ettfyl acetate. The organic phase is dried with magnesium sulphate and concentrated and the residue is distilled (boiling pointb.β 180° C). 93 g are obtained.

EXAMPLE TV/12 A 3-(5-(l₅3-Dioxolan-2-yl)furan-2-yl)indazole

10 g (41 mmol) of 3-iodoindazole (U. Wrzeciono et al., Pharmazie 1978, 34, 20) are dissolved in 125 ml of DMF under argon, 0.7 g of Pd(PP-Ia)₄ is added and the mixture is stirred for 15 minutes. 19.4 g (43.9 mmol) of 2-(5-tributylstannyl-2-furanyl)-l,3-dioxolane are added and the mixture is stirred at 100° C. for 2 hours. The solvent is evaporated off in vacuo and the residue is chromatographed over silica gel using toluene and toluene/ethyl acetate mixtures as the eluent. 10 g (90.3% of theory) of 3-(2-(5-(l,3-dioxolan-2- yl)furyl)indazole are obtained. Rf(SiO₂, toluene/ethyl acetate=4:l): 0.1.

PREPARATION EXAMPLES - as set forth in u.s. Patent No.6,387,940 EXAMPLE I/I

3-(5-(l ,3-Dioxan-2-yl)furan-2-yl)-l -(4-picβlyl)indazole

A solution of 2 g (7.41 mmol) of 3-(5-(l,3-dioxan-2-yl)furan-2-yl)indazole in 10 ml of DMF is added to a suspension of 355 mg of NaH (60 percent in paraffin) in 10 ml of DMF under argon, and the mixture is stirred at room temperature for 1 hour. 1.46 g of 4-picolyl chloride hydrochloride are then added, followed by 355 mg of NaH (60 percent in paraffin). The mixture is stirred at room temperature for 1 hour and then at 100° C. for 1 hour, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent. 1 g (37% of theory) of an oil is obtained. R_f (SiO₂, ethyl acetate): 0.25. EXAMPLE Ul 3KS-Formyl-2-fuiyl)-l-(4-picolyl)mdazole

1 g (2.77 mmol) of 3-(5<l,3^ioxan-2-yl)furan-2-yl)Λ-(4-picolyl)indazole is dissolved in 10 ml of acetone, and 20 ml of 50 percent strength acetic acid are added. The mixture is boiled for 1 hour, introduced into water and extracted with ethyl acetate and the organic phase is dried with sodium sulphate and evaporated in vacuo to give 0.8 g (95.3% of theory) of an oil. R_f(SiO₂, ethyl acetate): 0.25.

EXAMPLE 1/3 3-(2-(5-Hydroxymethylfuryl))-l-(4-picolyl)indazole

0.4 g (1.3 mmol) of 3-(5-formyl-2-furanyl)-l-(4-picolyI)indazole is suspended in 20 ml of propanol, and 0.4 g of NaBH, is slowly added at 0° C. After the mixture-has been stirred at room temperature for 1 hour, the clear solution is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent. 200 mg (50% of theory) of crystals are obtained. Melting point 183° C. R_f(SiO₂, ethyl acetate): 0.14.

The compounds listed in Tables I/I, 1/2 artd 1/3 are prepared analogously to the instructions of Examples I/I, 1/2 and 1/3:

TABLE I/I

Ex.

No. A¹ Rl R_f*/mp°C. Yield (% of theory)

1/5 0.52 (T4E1)/12O° C. 70

1/7 0.06 (T1E1)/1O3° C. 53

1/8 O.46(T4E1)/119°C. 71

/9 0.25 (T1E1)/1O5°C. 37

/10

/11 O.38(T4E1)/112°C. 69

/12 0.14(E4MeOHl)/oil 50

1/15 0.27 (TlEl)/oU 88.6

1/16

0.45 T1E1/132 47.5

I/I 7 0.65 T1E1/148 39.3

I/IS

1/19

/21

TABLE 1/2

Ex. Yield

No. R¹ R_f(TIzEl) (% of theory)

*E = ethyl acetate/MeOH = methanol/T = toluene numbers: parts

TABLE 1/3

E = ethyl acetate

H = hexane

Cy = cyclohexaπe

EXAMPLE Π/34

1 -Benzyl-3-(6-(l ,3-dioxan-2-yl)-2-pyridyl)indazole

580 mg of NaH (60 percent strength in paraffin) are slowly added to 3.7 g (13.1 mmol) of 3- (6-(l,3-dioxan-2-yl)-2-pyridyl)indazole in THF under argon. After the mixture has been stirred for 30 minutes, 1.71 ml of benzyl bromide are added and the mixture is stirred at room temperature for 1 hour. It is then introduced into water and extracted with ethyl acetate, the organic phase is dried with magnesium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel and eluted with ethyl acetate/toluene mixtures. 1.52 g (31 % of theory) of an oil are obtained. Rf (SiO₂, eϊhyl acetate): 0.3; MS 372 (100, M+l).

EXAMPLE π/35 l-Benzyl-3-(6-formyl-2-pyridyI)indazole

1.52 g (4.1 mmol) of l-benzyl-3-(6-(l,3-dioxan-2-yl)-2-pyridyl)indazole are dissolved in 10 ml of acetone, and 20 ml of 50 percent strength acetic acid are added. The mixture is stirred at 50° C. for 3 hours, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures to give 180 mg (14% of theory) of an oil. Rf(SiO₂, toluene/ethyl acetate): 0.7; MS (CI/NH₃): 314 (100, M-HH).

EXAMPLE Π/36 l-Benzyl-3-(6-hydroxymethyl-2-pyridyl)indazole

180 mg (0.57 mmol) of l-benzyl-3-(6-formyl-2-pyridyl)indazole are suspended in 20 ml of propanol, and 180 mg OfNaBH₄ are slowly added. After the mixture has been stirred at room temperature for 30 minutes, the clear solution is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent. 120 mg (66% of theory) of crystals are obtained. Melting point 75° C; R_f (Siθ₂, ethyl acetate): 0.15; MS (Cl, NH₃): 316 (100, M+H).

EXAMPLE 11/37 -pyrimidyl)indazole

200 mg of l-benzyl-3-trimethylstannylindazole (crude product, 70% according to GC), 35 mg of 2-chloropyrimidine (0.30 mmol) and 29 mg (0.025 mmol) of Pd(PPh₃)₄in 2.5 ml of toluene are heated under reflux overnight in an argon atmosphere. The mixture is cooled to room temperature, saturated ammonium chloride solution is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification is carried out by chromatography over aluminium oxide using cyclohexane/ethyl acetate as the eluent (gradient from 10:1 to 1:1).

Yield: 80 mg (93%)

R_f value: 0.67 (aluminum oxide; cyclohexane/ethyl acetate 10:1)

Melting point: 154° C.

MS-EI: 286 (M⁺, 100), 285 (64), 209 (40), 91 (71)

EXAMPLE Π/38 l-Benzyl-3-(4,5-dimethyl-2-pyrimidyl)indazole

640 mg of l-benzyl-3-trimethylstannylindazole (1.72 mmol), 212 mg of 2-chloro-4,5- dimethylpyrimidϊne* (1.49 mmol) and 72 mg (0.10 mmol) of Pd(PPh₃)₂ Cl₂ (5.8 mol %) in 20 ml of toluene are heated under reflux overnight in an argon atmosphere. The mixture is cooled to room temperature, saturated ammonium chloride solution is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and freed from the solvent on a rotary evaporator. Purification is carried out by chromatography over silica gel using cyclohexane/ethyϊ acetate as the eluent (gradient from 10:1 to 1:1).

Yield: 239 mg (51% of theory) Rf value: 0.33 (silica gel; cyclohexane/ethyl acetate 1:1) Melting point: 119° C.

* Sugasawa et al., Yakugaku Zasshi, 71, 1951, 1345, 1348, Chem. Abstr., 1952, 8034. The examples listed in Tables II/l, II/2 and II/3 are prepared analogously to the instructions of Examples 11/34-38:

TABLE II/l

TABLE II/2

Rf value Yield

EE: ethyl acetate Cy: cyclohexane

EXAMPLE m/69 l-Benzyl-3-(l-methyl-imidazol-2-yl)-indazole

2.50 g of l-benzyl-3-iodoindazole (7.48 mmol), 3.33 g of l-methyl-2-tributyl- stannylimidazole (8.98 mmol) (K. Gaare, K. Undheim et al, Acta Chem. Scand. 1993, 47, 57) and 432 mg of tetrakis-triphenylphosphinepalladium (0.37 mmol) in 10 ml of DMF are heated at 80° C. for 2 days under argon. After cooling, water is added to the mixture and the mixture is extracted with ethyl acetate. The organic phases are dried with sodium sulphate and concentrated. After chromatography (SiO₂ ; CH2CI2 :MeOH 100:1), 2.40 g of an oil are obtained. MS: (CI, NH₃): 289 (M+W, 100).

EXAMPLE IH/70

Ethyl 2-( 1 -benzyl-indazol-S-yO-oxazole-S-carboxylate

A solution of ethyl diazopyruvate (250 mg,~l .76 mmol) (T. Ohsumi & H. Neunhofer, Tetrahedron 1992, 48, 5227) in 4 ml of benzene is added dropwise to a refluxing solution of 600 mg of l-benzyl-3-cyanoindazole (2.57 mmol) and 0.8 mg of copper(II) acetylacetonate (3 mmol) in 1 ml of benzene in the course of 4 hours. Thereafter, the reaction mixture is heated under reflux for a further 15 minutes, cooled and evaporated in vacuo. The residue is chromatographed (Siθ2 ; cyclohexane:ethyl acetate 3:1). 67 mg of a yellow oil are obtained. R_f =0.11 (hexane/ethyl acetate 3:1).

EXAMPLE WJ71

1 -Benzyl-3 -(5 -hydroxymethyl-oxazol-2-yl)-indazole

18 mg of lithium aluminium hydride (0.47 mmol) are added to a solution of 67 mg of ethyl 2- (l-benzyl-indazoI-3-yl)-oxazole-5-carboxylate in 2 ml of ether at 0° C. After 3 hours at 0° C, the reaction mixture is stirred at room temperature for a further 24 hours, water is then added and the mixture is extracted 3 times with ether. The organic phases are dried with sodium sulphate and concentrated. After chromatography (SiO₂ ; cyclohexanerethyl acetate 2:1 to 3:2), 12 mg of a white solid are obtained. Rf =0.12 (hexane/ethyl acetate 1:1).

EXAMPLE m/72

Ethyl 2-( 1 _j-benzyl~imidazol-3-yl)-thiazole-4-carboxylate

148 mg of l-benzyl-3-trimethylstaϊinyl-indazole (0.399 mmol), 86 mg of ethyl 2- bromothiazole-4-carboxylate (0.364 mmol) (Erlenmeyer et al. HeIv. Chim. Acta 1942 (25) 1073) and 42 mg of Pd(PPh₃^ are stirred in 2 ml of DMF under argon at 80° C. for 2 days. After cooling, water is added to the mixture and the mixture is extracted with ethyl acetate. The organic phases are dried with sodium sulphate and concentrated. After chromatography (SiO₂ ; petroleum etheπethyl acetate 3:1), 75 mg of a white solid (52%) are obtained. R_f =0.31 (hexane:ethyl acetate 3:1). Melting point: 95-96° C.

The compounds listed in Table III/l are prepared analogously to the instructions given above:

TABLE πi/1

HI/74 0.25 (H:E 3:1) 37 Melting point 77° C.

H: hexane

E: ethyl acetate

The compounds listed in Table HI/2 are prepared either analogously to the instructions given above or obtained via the corresponding indazole derivatives

(identified in what follows by indazole-CO2 H, indazole-CO— Cl or indazole-CO—NH^) by the process variants described under [A3]-[G3].

TABLE III/2

Yield/

Ex. Preparation melting

No. Structure method point ° C. Rf

111/89 36%/ 0.24

*= build up from indazole

or indazole-COOH or indazole

[ ] = see process equation

TABLE HI/3

Yield/

Ex. Preparation melting

No. Structure method point ° C. Rf

HI/100 F3 11% 0.47 (?E/E 1 :1)

III/l 16

Al₂O

EXAMPLES OF THE PROCESS ACCORDING TO THE INVENTION FOR THE PREPARATION OF THE OXAZOLYL COMPOUNDS OF THE GENERAL FORMULA III-XXIX AND COMPOUNDS IN WHICH R⁴² REPRESENTS A RADICAL OF THE FORMULA III-XXVIII

In the following descriptions of experiments, the retention factors Rf are measured on silica gel TLC, unless stated otherwise. H=hexane, EE=ethyl acetate.

Process Example 1

A mixture of 10 g of 3-(m-trifluoromethylbenzoylamϊdo)-l,l-dichlorobut-l-ene, 5.1 g of sodium methylate and 35 ml of dimethylacetamide is stirred at 25° C. overnight, 50 ml of water are then added and the mixture is extracted several times with methylene chloride. The methylene chloride phase is separated off, dried with sodium sulphate and filtered and the solvent is removed in a vacuum rotary evaporator. Distillation of the resulting crude product gives 7.3 g of 4-memyl-5-methoxymethyl-2-(m-trifluorophenyl)-oxazole (boiling range 96- 100° C./0.2 mbar). Preparation of the l,l-dichloro-3-(m-trifluoromethylbenzoylamido)-but-l- ene

Employed:

1st stage

<Λ÷_ζ

A mixture of 615 g of 1,1,1,3-tetrachlorobutane, obtained by addition, initiated by free radicals, of carbon tetrachloride onto propene, 13.3 g of tetrabutylammonium bromide and a solution of 138.2 g of sodium hydroxide in 390 ml of water is mixed thoroughly by stirring at room temperature for 24 hours.21 of water are then added, the phases are separated and the organic phase is dried with sodium sulphate. A mixture of 1,1,3-trichloro- but-1-ene and l,l,l-trichloro-but-2-ene is obtained by distillation of the crude product (492 g of boiling range 45-50° C./20 mbar).

2nd stage •

210 g of a mixture of 1,1,3-trichloro-but-l-ene and l,l,l-trichloro-but-2-ene and 52 ml of anhydrous hydrocyanic acid are metered simultaneously into a solution, heated at 40° C₅ of 38 g of H₂O in 568 g of concentrated sulphuric acid in the course of 1 hour, while stirring. A further 78 ml of hydrocyanic acid are then added in the course of 2 hours. After a further reaction time of 2 hours, the excess hydrocyanic acid is distilled off. The reaction mixture is rendered alkaline with 20% strength sodium hydroxide solution and the crude product (195 g) is separated off by extraction with methylene chloride.

This crude product is mixed with 950 ml of half-concentrated hydrochloric acid, while stirring, the mixture being heated at the boiling point under reflux cooling. After 24 hours, the mixture is cooled and a small amount of by-product is removed by extraction with methylene chloride. The aqueous phase is concentrated to dryness in a rotary evaporator. Half-concentrated sodium hydroxide solution is then added and the mixture is stirred, the pH being adjusted to 9. The amine which separates out is isolated and distilled. 156 g of 3- amino-1, 1-dichloro-but-l-ene are obtained, boiling point 45-50° C./18 mbar.

3rd stage

A solution of 26.9 g of m-trifluoromethylbenzoyl chloride in 25 ml of methylene chloride is added dropwise to a mixture of 21.0 g of 3-amino-l, 1-dichloro-but-l-ene, 35 ml of methylene chloride and a solution of 15.9 g of sodium carbonate in 45 ml of water in the course of 30 minutes, while cooling with ice and stirring vigorously. After a reaction time of a further hour, the phases are separated. Concentration of the organic phase gives 39.0 g of 2,2-dichloro-3-(m-trifluoromethylbenzoylamido)-but-l-ene.

Process Example 2

A mixture of l,l-dichloro-(m-trifluoromethylbenzoylamϊdo)-but-l-ene, 4.2 g of sodium butylate and 35 ml of dimethylacetamide is heated at 100° C. for 7 hours, while stirring. After the reaction, the mixture is worked up analogously to Example 1. Vacuum distillation of the resulting crude product gives 6.4 g of 5-butoxymethyl-4-methyl-2-(m- trifluorophenyO-oxazole (boiling range 106-110° CJ0.2 mbar).

Process Example 3

A solution of 1.8 g of 3-acetamido-_l,l-dichlorobut-l-ene and l,0 g of sodium methylate in 20 ml of methanol is heated at the boiling point under reflux for 24 hours. Thereafter, the methanol is distilled off, the residue is taken up in 5 ml of water and 30 ml of methylene chloride and the organic phase isjseparated off and distilled in vacuo. 0.9 g of 2,4- dimethyl-5-methoxymethy!-oxazole is obtained, boiling point 54° C./120 mbar.

Process Example 4

A mixture of 7 g of 3-(2-chloro-6-fluorobenzoylamido)-l,l-dichloro-but-l-ene, 11.7 g of sodium 4-tert-butylphenolate and 100 ml of N-methylpyrrolidone is heated at 100° C. for 8 hours, while stirring. The solvent is then separated off by vacuum distillation, the residue is taken up in water and methylene chloride and the organic phase is separated off, dried with sodium sulphate and freed from the solvent in a vacuum rotary evaporator. The crude product is purified by chromatography. 5.1 g of 2-(2-chloro-6-fluorophenyl)-4-methyl-5-(4-tert- butylphenoxymethyl)-oxazole are obtained.

Process Example 5

A mixture of 5 g of 3-benzoylamido-l,l-dichloro-but-l-ene, 36 g of sodium acetate and 500 ml of N-methylpyrrolidone is heated at 150° C. for 36 hours, while stirring. The crude product is then isolated in a manner analogous to that described in Example 4. Vacuum distillation gives 35 g of 5-acetoxymethyl-4-methyl-2-phenyl-oxazole (boiling range 88-91° CJO.1 mbar).

Process Example 6

80 μl of NaOH, IM, are added to 15 mg of 3-(l-benzylindazole-3-carboxamido)-l,l- dichlorobut-1-ene (40 μmol) in 20 μl of N-methylpyrrolidone under argon and the mixture is heated at 55° C. for 1 hour. It is cooled and 0.8 ml of water and 8 ml of ethyl acetate are added. The organic phase is concentrated and the residue is purified by preparative TLC (SiO₂). 9.9 mg (77%) of 2-(l-benzylindazol-3-yl)-5-hydroxymethyl-4-methyl-oxazole are obtained (melting point 127-129° C). MS (DCI/NH₃): 320 (100, MH⁴). R_f : 0.17 (H:EE 1:1).

Process Example 7

(For this example, the amide intermediate stage was prepared in situ from the formula 3a and an acid chloride.)

500 mg of 1 -benzylindazole-3-carboxyl chloride (1.847 mmol), 260 mg of 3-amino- 1,1-dichlorύ-but-l-ene (1.847 mmol) and 318 mg of sodium acetate (3.88 mmol) were stirred in 4 ml of N-methylpyrrolidone at 150° C. under argon for 5 days. The crude mixture was cooled, water was added and the mixture was extracted several times with ethyl acetate. The organic phases were dried (over NazSCU) and concentrated and the residue was chromatographed (SiCh, petroleum ether/ethyl acetate 3:1). Two products were isolated: 1,1- dichloro-3-(l-benzylindazole-3-carboxamido)-but-l-ene (410 mg, 59%) R_f : 0.26 (H:EE 3:1) and 5-acetoxymethyl-2-(l-benzylindazol-3-yl)-4-methyloxazole (160 mg, 24%). MS (DCI/NH3): 362 (100, MH⁺). Rf : 0.17 (H:EE 3:1).

Process Example 8

100 mg of 3-(l-benzylindazole-3-carboxamido)-l,l-dichloro-but-l-ene (0.267 mmol) and 29 mg of sodium methylate are stirred in 0.5 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture is cooled and purified directly by column chromatography (SiO₂, cyclohexane:ethyl acetate 3:1). 35.9 mg (40%) of 2r(l-benzylindazol- 3-yl)-5-methoxymethyl-4-methyloxazole are isolated as a yellowish oil. MS (DCI/H₃): 334 . (100, MH⁺). Rf. 0.67 (CH₂Cl₂ :MeOH 100:5).

Process Example 9

730 mg of l,l-dichloro-3-[l-(2-fluorobenzyl)indazole-3-carboxamido]-but-l-ene (1.86 mmol) and 3,75 ml of NaOH, IN (3.75 mmol) are stirred in 7.4 ml of N- methylpyrrolidone at 50° C: under argon overnight. After cooling, the mixture is poured onto ice-water and the product which is precipitated out is filtered off and dried. Finally, it is, purified by column chromatography (S1O2, cyclohexanexthyl acetate 2:1). 375 mg (60%) of 2-[l-(2-fluorobenzyl)indazol-3-yl]-5-hydroxymethyl-4-methyl-oxazole are obtained as white crystals. Melting point 144° C; MS (ESI-POSITIVE): 338 (100, MH⁺). Rf. 0.20 (H:EE 1:1).

The l,l-dichloro-3-[l-(2-fluorobenzyl)indazole-3-carboxamido]-but-l-ene employed is prepared as follows: 120 μl of pyridine are added to 400 mg of l-(2-fluorobenzyl)- indazole-3-carboxyl chloride (1.385 mmol) and 200 mg of 3-amino-l,l-dichloro-but-l-ene in 1.5 ml of THF and the mixture is stirred at room temperature for 3 hours. Ethyl acetate and water are then added. The organic phase is dried over sodium sulphate and concentrated. The crude product l,l-dichloro-3-[l-(2-fluorobenzyl)indazole-3-carboxamido]-but-l-ene is pure enough, according to TLC, to be further reacted directly. R_f: 0.32 (H:EE 3:1).

Process Example 10

136 mg of l.l-dichloro-S-tl-Cl-fluorobenzyOindazole-S-carboxamidoJ-but-l-ene (0.267 mmol) and 47 mg of sodium methylate are stirred in 0.6 ml of N-methylpyrrolidone at 100° C. under argon overnight. The crude mixture is cooled and purified directly by column chromatography (SiO₂).24 mg (20%) of 2-[l-(2-fluorobenzyl)-indazol-3-yl]-5- methoxymethyl-4-methyl-oxazole are isolated as yellowish crystals. Melting point 86-88° C. MS (ESI-POSITIVE): 374 (65, M-I-Na⁺), 352 (100, MH⁺). R_f: 0.18 (CH₂Cl₂ :MeOH 100:1).

Process Example 11

136 mg of l,l-dichloro-3-[l-(2-fluorobenzyl)indazole-3-carboxamido]-but-l-ene (0.267 mmol) and 164 mg of potassium phthalimide are stirred in 0.6 ml of N- methylpyrrolidone at 150° C. under argon overnight. The N-methylpyrrolidone is then stripped off under a high vacuum at 60° C. and the residue is chromatographed (SiO₂, cyclohexane/ethyl acetate 2:1) to give 48.5 mg (36%) of 2-[l-(2-fluorobenzyl)-indazole-3- yl]-4-methyl-5-(N-phthalimidomethyl)-oxaz ole. Yellowish crystals. Melting point 175-177° C. MS (ESI-POSITIVE): 467 (100, MH⁺). R_f: 0.64 (CH₂Cl₂ :MeOH 100:1).

Process Example 12

1.05 g of l,l-dichloro-3-[l-(2-fluofobenzyl)indazole-3-carboxamido]-pent-l-ene (2.58 mmol) and 5.20 ml of NaOH, IN (5.20 mmol) are stirred in 15 ml of N- methylpyrrolidone at 50° C. under argon for 2 days. After cooling, the mixture is poured onto ice-water and extracted several times with ethyl acetate. The organic phase is dried (sodium sulphate) and concentrated (N-methylpyrrolidone stripped off under a high vacuum). The residue is purified by column chromatography (aluminium oxide, cyclohexane/ethyl acetate 2:1). 470 mg (52%) of 5-ethyl-2-[l-(2-fluorobenzyl)-indazol-3-yI]-5-hydroxymethyl-oxazole are obtained as white crystals. Melting point 137-139° C. MS (ESI-POSITIVE): 352 (100, MH⁺). Rf: 0.08 (aluminium oxide, cyclohexane:EE 2:1).

PREPARATION EXAMPLES FOR EMBODIMENT IV

EXAMPLE IV/134

1 -(2-Cyanobenzyl)-3-(5-(l ,3-dioxolan-2-yl)fiiran-2-yl)-indazole

A solution of 2 g (7.41 mmol) of 3-(5-(l,3-dioxolan-2-yl)-furan-2-yl)indazole in 10 ml of DMF is added to a suspension of 355 mg of NaH (60 percent in paraffin) in 10 ml of DMF under argon and the mixture is stirred at room temperature for 1 hour. 1.5 g of 2- cyanobenzyl bromide are then added. The mixture is stirred at 100° C. for 30 minutes, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent.2.1 g (73.5% of theory) of an oil are obtained. R_f (SiO₂, toluene/ethyl acetate 1:1): 0.63

EXAMPLE IV/135 l-(2-Cyanobenzyl)-3-(5-formyl-2-furanyl)-indazole

2.1 g (5.5 mmol) of l-(2-cyanobenzyl)-3-(5-(l,3-dioxolan-2-yI)furan-2-yl)-indazole are dissolved in 20 ml of acetone, and 40 ml of 50% strength acetic acid are added. The mixture is boiled for 1 hour, introduced into water and extracted with ethyl acetate and the organic phase is washed with NaHCO3 solution, dried with sodium sulphate and evaporated in vacuo to give 1.61 g (89% of theory) of a solid. Melting point: 137° C; R_f (SiO₂, toluene/ethyl acetate 4:1): 0.4.

EXAMPLE IV/136

1 -(2-C yanobenzy l)-3 -(5-hydroxymethylfuran-2-yl)-indazole

0.8 g (2.44 mmol) of l-(2-cyanobenzyl)-3-(5-formyl-2-furanyl)-_:indazole is suspended in 50 ml of propanol, and 0.8 g OfNaBH₄ is slowly added at 0° C. After the mixture has been stirred at room temperature for 1 hour, the clear solution is introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluenelethyl acetate mixtures as the eluent. 600 mg (75% of theory) of crystals are obtained. Melting point 147° C; R_f (SiO₂, toluene/ethyl acetate 1:1): 0.52.

EXAMPLE IV/137 l-Beπzyl-3-[5-(l,3-dioxolan-2-yl)-furan-2-yl]-indazole

661 mgof 5-(l,3-dioxolan-2-yl)-2-tributylstannyl-furan (1.54 mmol) (M. Yamamoto, H. Izukawa, M. Saiki, K. Yamada, J. Chem. Soc. Chem. Comra. 1988, 560), 431.5 tng of 1- benzyl-3-iodoindazole (1.29 mmol) and 90 mg of tetrakistriphenylphosphinepalladium (0.078 mmol) in 2.5 ml of DMF are heated at 80° C. under argon for 10 hours. After cooling, water is added to the mixture and the mixture is extracted with ethyl acetate. The organic phases are dried with sodium sulphate and concentrated. Chromatography (Siθ₂ ; petroleum etheπethyl acetate 9:1) gives 381.3 mg of a viscous oil. R_f : 0.16 (hexane/ethyl acetate 3:1).

EXAMPLE IV/138 l-Benzyl-3-(5-foiτnylfuran-2~yl)-indazole

336 mgof l-benzyl-3-[5-(l,3-dioxolan-2-yl)-furan-2-yl]-indazoIe (0.97 mmol) are heated under reflux with a pair of crystals of p-toluenesulphonic acid in 5 ml of acetone and 0.3 ml of water for 20 hours. Thereafter, 40 ml of ether are added to the reaction mixture. The organic phase is washed with a little sodium chloride solution, dried over sodium sulphate and concentrated. The residue is crystallized slowly. The crystals are washed with a little ether and dried in vacuo: 210.4 mg. Rf : 0.24 (hexanelethyl acetate 3:1); Melting point: 97- 99° C.

EXAMPLE IV/139

1 -[5-(I -Benzylindazol-3-yl)-furan-2-yl]-ethanol

300 1 of an MeLi solution (1.6 M in ether; 0.480 mmol) are added dropwise to a solution, cooled to -78° C, of l-benzyl-3-(5-formylfiιran-2-yl)-indazole (134.1 mg; 0.44 mmol) in 3 ml THF. After 10 minutes, aqueous NH₄Cl is added to the mixture and the mixture is extracted with ether. The organic phase is washed with a sodium chloride solution, dried over sodium sulphate and concentrated. Chromatography (Siθ₂ ; petroleum ether: ethyl acetate 2:1) gives 133 mg of a viscous oil. R_f : 0.11 (hexane/ethyl acetate 3:1); MS (Cl, NH₃): 319 (M-I-H⁺, 100).

EXAMPLE IV/140

3 -(5-Acetylfuran-2-yl)- 1 -benzyl-indazole

A mixture of l-[5-(l-benzyIindazol-3-yl)-furan-2-yl]-ethanol (51.2 mg; 0.160 mmol) and 250 mg OfMnO₂ (2.9 mmol) in 2 ml OfCHCl₃ is heated under reflux. After 12 hours, a further 250 mg OfMnO₂ are added. After a further 12 hours, the mixture is filtered through Celite, the filtrate is concentrated and the residue is chromatographed (Siθ2 ; petroleum ether: ethyl acetate 3:1). 29.8 mg of a pale yellow solid are obtained. Rf: 0.21 (hexane/ethyl acetate 3:1); Melting point: 99-100° C.

EXAMPLE lV/141

3-(5-Azidomethylfuran-2-yl)-l-benzyl-indazole

195.1 mg of l-benzyl-3-(5-hydroxymethylfuran-2-yl)-indazole (0.64 mmol) (Kuo S.- C, Yu Lee F., Teng C-M. EP 0 667345 Al), 252 mg of triphenylphosphine (0.96 mmol) and 60.3 mg of sodium azide (0.93 mmol) are dissolved in 2.5 ml of DMF. 308.4 mg of carbon tetrabromide are added and the resulting mixture is stirred at room temperature for 20 hours. After addition of 5 ml of water, it is extracted with ethyl acetate. The organic phase is washed with a sodium chloride solution, dried over sodium sulphate and concentrated. Chromatography (S1O2; cyclohexane: ethyl acetate 2:1) gives 206.7 mg of a viscous oil, which slowly solidifies. R^ 0.63 (hexane/ethyl acetate 1:1); Melting point 51-52° C.

EXAMPLE TV/142

3-(5-Aminomethylfiiran-2-yl)-l-ben2yl-indazole

121.5 mg of 3-(5-azidomethylfuran-2-yl)-l-benzyl-indazole (0,369 mmol) and 102 mg of triphenylphosphine (0.389 mmol) are stirred in 1 ml of TEDF for 3.5 hours. 10 μl of water are then added. After 24 hours, ether and aqueous HCI, 0.3M, are added to the reaction mixture. The solid which is filtered off and the aqueous phase are combined, rendered alkaline with NaOH, 2M, and extracted with ether. The organic phase is washed with a little water and then with a sodium chloride solution, dried over sodium sulphate and concentrated. 79.9 mg of a yellow oil are obtained.

EXAMPLE ΓV/143

1 -Benzyl-3-(5 -nitrofiιran-2-yl)-indazole

800 mg of 5-nitrofuran~2-yl phenyl ketone benzylhydrazones (mixture of E+Z, 2.49 mmol) are dissolved in 35 ml of methylene chloride. 1.99 g of lead tetraacetate (4.49 mmol) and 15.6 ml of BF₃ etherate (50% in ether, 62 mmol) are added and the mixture is heated under reflux for 1 hour. After cooling, the reaction mixture is poured onto ice and the organic phase is separated off, washed with 0.2M NaOH and then water, dried over sodium sulphate and concentrated. Chromatography gives 140 mg of yellow crystals. R_f : 0.20 (petroleum ether/ethyl acetate 10:1); Melting point: 148-151° C. (decomposition). The compounds summarized in Tables IV/1, IV/2, IV/3, IV/4 and IV/5 are prepared analogously to the instructions of the examples given above.

TABLE IV/1

Rf*/ Yield

IV/145 0.28(H3El)/77 98

IV/146 0.64(TlEl)/oil 87

IV/147 0.49(T4El)/oil 82

IV/148 0.68(TlEl)/oil 58

IV/149 O.76(T1E1)/146 54

IV/150 O.63(T1E1)/11O 13

IV/151 O.6O(T1E1)/14O 92

IV/154 O.24(T4E1)/215 76

IV/155 O.62(T1E1)/215 71

IV/156 O.58(T4E1)/132 56

IV/157 0.45(T4El)/80 57

IV/158 0.44(T4El)/oil 12

IV/159 0.39(T4El)/oil 47

IV/160 O.68(T2E1)/125 85

IV/161 O.63(T1E1)/151 87

IV/162 0.72(TlEiyi20 65

IV/163

IV/164

IV/165

IV/166

0.35 (ToI: EE)

IV/167

TABLE IV/2

Yield Melting

Ex. No. A⁴ (% of theory) point ° C.

IV/168 42 126° C.

TABLE IV/3

Yield Melting

Ex. No. A⁴ (% of theory) point ° C.

IV/175 117

IV/176 84

IV/177 56 106

IV/178 22

TABLE IV/4

Yield Melting

Ex. No. Structure (% of theory) point ⁰ C/ R_f

TABLE IV/5

Ex. No. Structure Yield/ melting point R_f

*EE = ethyl acetate H = hexane P = petroleum ether T — toluene

* * * *

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention specifically described herein.

Claims

Claims

1. A method of inhibiting HIF expression in tumor cells or tissues in a subject, comprising administering to said subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (III-I) at an effective amount for inhibiting HIF expression: 3-Heterocyclyl-substituted pyrazole derivative of the formula (III-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to S carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R⁵² denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

atfxdur — CH₃,

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula ~S(O)_c3 NR⁵⁰R⁵¹', wherein c3, R^s0 and R^sr have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or. is substituted by a group of the formula (~CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

2. The method according to claim 1, wherein in formula (IU-I), R⁴² represents pyranyl or morpholinyl, which are optionally substituted up to twice in an identical or different manner by formyl, trifluoromethyl, phenyl, carboxyl, hydroxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyano, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 4 carbon atoms, or by a radical of the formula —OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 4 carbon atoms or a group of the formula — SiR⁴⁶R⁴⁷ R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms, and/or are substituted by a radical of the formula

wherein a3 denotes the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 3 carbon atoms, R⁴³ and R⁴⁴, including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, nitro, cyanό, azido, fluorine, chlorine, bromine, phenyl or straight-chain or branched alkyl having up to 5 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, A³ represents tetrahydropyranyl, tetrahydrofuranyl, thienyl, pyritnidyl, phenyl, morpholinyl, pyrimidyl, pyridazinyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkyithio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, fluorine, chlorine, bromine, πitro. cyano, trifluoromethyl or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having, in each case up to 4 carbon atoms, and/or are substituted by a group of the formula — (CO)d3 --NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight- chain or branched alkyl or acyl having in each case up to 4 carbon atoms, or an isomer or salt thereof.

3. The method according to claim 1, wherein in formula (M-I), R⁴² represents imidazolyl, oxazolyl, oxadiazolyl or thiazolyl, which are optionally substituted up to twice, in an identical or different manner by formyl, trifluoromethyl, phenyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms or straight-chain or branched alkyl having up to 4 carbon atoms, which in its turn can be substituted by hydroxyl, fluorine, chlorine, trifluoromethyl, carboxyl, amino, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 3 carbon atoms or by the radical of the formula — O--CO— CH3, and/or are substituted by a radical of the formula

wherein a3 denotes the number 0, 1 or 2, R⁴⁹ denotes hydrogen or methyl, R⁴³ and R⁴⁴, .including the double bond, form a furyl, thienyl or phenyl ring, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 4 carbon atoms, nitro, cyano, fluorine, chlorine, phenyl or. straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, A3 represents tetrahydropyranyl, phenyl, thienyl, pyrimidyl or pyridyl, which are optionally substituted up to twice in an identical or different manner by formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, fluorine, chlorine, bromine, nitro, cyano, trifluoromethyl, or straight-chain or branched alkyl having up to 3 carbon atoms, which in its turn can be substituted by hydroxy!, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 3 carbon atoms, and/or are substituted by a group of the formula --(CO)^ -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen or straight-chain or branched alkyl or acyl having in each case up to 3 carbon atoms, or an isomer or salt thereof.

4. The method according to claim 1, wherein in the formula (HI-I), R⁴² represents imidazolyl, oxazolyl, thiazolyl or oxadiazolyl, which are optionally substituted up to twice in an identical or different manner by ethoxycarbonyl, phenyl or by methyl or ethyl, wherein the alkyl radicals in their turn can be substituted by hydroxyl, chlorine; ethoxycarbonyl, oxycarbonylmethyl or methoxy, R⁴³ and R⁴⁴ together, including the double bond, represent phenyl, which is optionally substituted by nitro, A³ represents phenyl or phenyl which is substituted by fluorine, or pyrimidyl or an isomer or salt thereof.

5. The method according to claim 1 wherein said effective amount is effective to inhibit HIF- lα. expression.

6. The method according to claim 1 wherein said effective amount is effective to inhibit HIF-2α expression.

7. The method according to claim 1 wherein said tumor cells or tissue comprise tumors that overexpress HIF proteins.

8. The method according to claim 1, wherein said tumor is selected from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma and neuroblastoma, and prostate carcinoma.

9. A method of inhibiting HIF-regulated gene expression in tumor cells or tissues in a subject, comprising administering to said subject a composition comprising a compound or mixture of a 3-heterocyclyl-substituted pyrazole derivative of the formula (III-I) at an effective amount for inhibiting HIF-regulated gene expression: 3-Heterocyclyl-substituted pyrazole derivative of the formula (III-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms jrom the series consisting of S₅ N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R^soand R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R^soand R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R⁵² denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or atkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula — S(O)_c3 NR⁵⁰R^51', wherein c3, R^s0' and R^sr have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series "consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (— CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an . isomer or salt thereof.

10. The method of claim 9 wherein said HIF-regulated gene is selected from the group consisting of erythropoietin, transferrin, transferrin receptor, ceruloplasmϊn, vascular endothelial growth factor (VEGF), VEGF receptor FLT-I, transforming growth factor β3, plasminogen activator inhibitor 1, αlB adrenergic receptor, adrenomedullin, endothelin I, nitric oxide synthase 2, heme oxygenase 1, glucose transporter 1 and 3, hexokinase 1 and 2, enolase 1, glyceraldehyde-3-phosphate dehydrogenase, phosphoglycerate kinase 1, phosphόglucokinase L, pyruvate kinase M, aldolase A and C, rios phosphate isomerase, lactate dehydrogenase A, carbonic anhydrase 9, adenylate kinase 3, ρropyl-4-hydroxyIase al, insulin-like growth factor (IGF) 2, IGP-binding protein 1, 2 and 3, P21, Nip3, cyclin G2 and differentiated embryo chondrocyte 1.

11. The method of claim 10, wherein said HIF-regulated gene is selected from the group consisting of VEGF, aldolase A and enolase 1.

12. The method according to claim 9, wherein said effective amount is effective to inhibit HIF- 1 α expression.

13. The method according to claim 9, wherein said effective amount is effective to inhibit HIF-2α expression.

14. The method according to claim 9, wherein said tumor cells or tissue comprise tumors that overexpress HIF proteins.

15. The method according to claim 9, wherein said tumor is selected from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

16. A method of inhibiting angϊogenesis in tumor cells or tissues in subject, comprising administering to said subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (IH-I) at an effective amount for inhibiting angiogenesis:

3-Heterocyclyl-substituted pyrazole derivative of the formula (HI-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or Oτ>r represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N. and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl. halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷. and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R⁵² denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula — S(O)_c3 NR⁵⁰R⁵¹', wherein c3, R^s0 and R⁵¹ have the abovementioned meaning of c3, R⁵⁰ and R^S1 and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (~CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

17. The method according to claim 16, wherein said tumor cells or tissue comprise tumors that overexpress HIF proteins.

18. The method of claim 16, wherein said tumor is selected from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma,, neuroblastoma, and prostate carcinoma.

19. A method of inhibiting tumor growth in animal tissues in a subject, comprising administering to said subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (HI-I) at an effective amount for inhibiting tumor growth: 3-Heterocyclyl-substituted pyrazole derivative of the formula (III-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifiuoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifiuoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R⁵² denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula ~S(O)c3 NR⁵⁰R^51', wherein c3, R^5σ and R⁵¹' have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (~CO)_d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R^S3 and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

20. A method according to claim 19 wherein said tumor overexpresses HIF proteins.

21. The method of claim 19, wherein said tumor is selected from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

22. A method of inhibiting tumor progression and metastasis in tissues in a subject, comprising administering to said subject a composition comprising a compound or a mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (HI-I) at an effective amount for inhibiting tumor progression and metastasis: 3-Heterocyclyl-substituted pyrazole derivative of the formula (III-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group-of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote- aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3^r denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl' having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R⁵² denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

PtCBώa: CSj ojcaitø — CH₃,

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula — S(O)c3 NR⁵⁰R⁵¹ , wherein c3, R^sυ and R⁵¹ have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight_rchain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (~CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

23. A method according to claim 1 wherein said tumor overexpresses HIF proteins.

24. The method of claim 22, wherein said tumor is selected from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

25. A method of treating a HDF-mediated and/or VEGF-mediated disorder or condition in a subject comprising administering to said subject a composition comprising a therapeutically effective amount of a compound or a mixture of compounds of a 3-heterocyclyl-substituted pyrazole derivative of the formula (III-I):

3-Heterocyclyl-substituted pyrazole derivative of the formula (111-1)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated Heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to ό carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R^S2 denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula — S(O)_c3 NR⁵⁰R^{5 v}, wherein c3, R⁵⁰ and R^51' have the abovementioned meaning of c3, R⁵⁰ and R^SI and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (— CO)^ -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

26. A method according to claim 25 wherein overepression of HBF proteins is an indication of said disorders or condition.

27. The method of claim 25, wherein said HEF-mediated disorder or condition is selected . from the group consisting of hepatoma, stomach carcinoma, renal carcinoma, cervical carcinoma, neuroblastoma, and prostate carcinoma.

28. A method of enhancing the inhibitory effect on tumor growth in a subject in combination with another antitumor therapy comprising administering to said subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyl- substituted pyrazole derivative of the formula (IXI-I) at an effective amount for synergistically enhancing the combined tumor-inhibiting effect of said therapy and said composition in said subject:

3-Heterocyclyl-substituted pyrazole derivative of the formula (III-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro. cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula —OR⁴⁵, wherein R^4S denotes straight-chain or branched acyl having up to 5 carbon atoms or a group of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number 0, 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and

R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical -NR⁵², wherein R⁵² denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula — S(O)_c3 NR⁵⁰R⁵¹ , wherein c3, R⁵⁰ and R⁵¹' have the abovementioned meaning of c3, R⁵⁰ and R⁵¹ and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyi, hydroxyl, formyl, carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (~CO)d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

29. A method for arresting the cell cycle in proliferating cells in a subject comprising administering to said subject a composition comprising a compound or mixture of compounds of a 3-heterocyclyI-substituted pyrazole derivative of the formula (HI-I) at an effective amount to inhibit progression of cell proliferation: 3-Heterocyclyl-substituted pyrazole derivative of the formula (HI-I)

in which R⁴² represents a saturated 6-membered heterocyclic ring having up to 2 heteroatoms from the series consisting of S, N and/or O or represents a 5-membered aromatic or saturated heterocyclic ring having 2 to 3 heteroatoms from the series consisting of S, N and/or O, which can also be bonded via a nitrogen atom and which are optionally substituted up to 3 times in an identical or different manner by formyl, phenyl, mercaptyl, carboxyl, trifluoromethyl, hydroxyl, straight-chain or branched acyl, alkoxy, alkylthio or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, halogen, trifluoromethyl, amino, carboxyl, straight-chain or branched acyl, alkoxy, alkoxycarbonyl or acylamino having in each case up to 5 carbon atoms or by a radical of the formula -OR⁴⁵, wherein R⁴⁵ denotes straight-chain or branched acyl having up to 5 carbon atoms or a group^*of the formula -SiR⁴⁶R⁴⁷R⁴⁸, wherein R⁴⁶, R⁴⁷ and R⁴⁸ are identical or different and denote aryl having 6 to 10 carbon atoms or alkyl having up to 6 carbon atoms, and/or can be substituted by a radical of the formula

wherein a3, b3 and b3' denote the number O^ 1, 2 or 3, R⁴⁹ denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, c3 denotes the number 1 or 2 and R⁵⁰ and R⁵¹ are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 carbon atoms, which in its turn can be substituted by halogen, or denote aryl having 6 to 10 carbon atoms, which is optionally substituted by halogen, or denote cycloalkyl having 3 to 7 carbon atoms, or R⁵⁰ and R⁵¹, together with the nitrogen atom, form a 5- to 7-membered saturated heterocyclic ring, which can optionally contain a further oxygen atom or a radical —MR⁵², wherein R⁵² denotes hydrogen, straight- chain or branched alkyl having up to 4 carbon atoms or a radical of the formula

or denotes benzyl or phenyl, wherein the ring systems are optionally substituted by halogen, R⁴³ and R⁴⁴, including the double bond, form a 5-membered aromatic heterocyclic ring having one heteroatom from the series consisting of N, S and/or O, or a phenyl ring, which are optionally substituted up to 3 times in an identical or different manner by formyl, carboxyl, hydroxyl, amino, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, amino, carboxyl, straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or are optionally substituted by a group of the formula —S(O)c3 NR⁵⁰R⁵¹ , wherein c3, R^5ff and R⁵¹ have the abovementioned meaning of c3, R^s0 and R^S1 and are identical to or different from these, A³ represents a 5- to 6-membered aromatic or saturated heterocyclic ring having up to 3 heteroatoms from the series consisting of S, N and/or O or phenyl, which are optionally substituted up to 3 times in an identical or different manner by amino, mercaptyl, hydroxyl, formyl. carboxyl, straight-chain or branched acyl, alkylthio, alkyloxyacyl, alkoxy or alkoxycarbonyl having in each case up to 6 carbon atoms, nitro, cyano, trifluoromethyl, azido, halogen, phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, which in its turn can be substituted by hydroxyl, carboxyl. straight-chain or branched acyl, alkoxy or alkoxycarbonyl having in each case up to 5 carbon atoms, and/or is substituted by a group of the formula (--CO)_d3 -NR⁵³R⁵⁴, wherein d3 denotes the number 0 or 1, R⁵³ and R⁵⁴ are identical or different and denote hydrogen, phenyl, benzyl or straight-chain or branched alkyl or acyl having in each case up to 5 carbon atoms, or an isomer or salt thereof.

30. A method according to claim 29 wherein said proliferating cells comprise tumors.

31. A method according to claim 29 wherein said proliferating cells comprise cells symptomatic of a hyper-proliferative skin disorder.