HK1105961A - 1,5-diphenylpyrazoles - Google Patents

Description

1, 5-diphenylpyrazoles

no marking

Background

The object on which the present invention is based is to find new compounds having valuable properties, in particular those which can be used for the preparation of medicaments.

The present invention relates to compounds in which the inhibition, regulation and/or modulation of HSP90 plays a role, to pharmaceutical compositions comprising these compounds and to the use of said compounds for the treatment of diseases in which HSP90 plays a role.

The correct folding and conformation of proteins in cells is ensured by molecular chaperones and is crucial for the regulation of the balance between synthesis and degradation of proteins. These chaperones are important for many important functions of the cell such as, for example, the regulation of cell proliferation and apoptosis (Jolly and Morimoto, 2000; Smith et al, 1998; Smith, 2001).

Heat Shock Proteins (HSP)

Cells of a tissue respond to external stress such as, for example, heat, hypoxia, oxidative stress, or toxic substances such as heavy metals or alcohols, with activation of a number of chaperones known as "heat shock proteins" (HSPs).

Activation of HSPs protects cells from damage caused by such stressors, accelerates recovery from physiological states and leads to stress-tolerant states of cells.

In addition to this initially discovered protective mechanism against external stress caused by HSPs, other important chaperone functions of individual HSPs under normal stress-free conditions were finally described. Thus, various HSPs regulate the proper folding, intracellular localization and function or controlled degradation of, for example, many biologically important proteins of a cell.

HSPs form a gene family, with cellular expression, function and localization of individual gene products varying among different cells. Within this family, naming and classification is based on their molecular weight, e.g., HSP27, HSP70, and HSP 90.

The basis of some human diseases is incorrect protein folding (see reviews such as Tytell et al, 2001; Smith et al, 1998). Thus, it may be useful in such circumstances to develop therapies that are involved in chaperonin-dependent protein folding mechanisms. For example, in the case of alzheimer's disease, prion disease, or huntington's disease, incorrectly folded proteins lead to protein aggregation and progression of neurodegeneration. Incorrect protein folding can also lead to loss of wild type function, which may have the consequence of incorrectly regulated molecular and physiological functions.

HSPs are also of great importance in tumor diseases. For example, expression of certain HSPs has been shown to be associated with the stage of tumor progression (Martin et al, 2000; Conroy et al, 1996; Kawanishi et al, 1999; Jameel et al, 1992; Honng et al, 2000; Lebeau et al, 1991).

The fact that HSP90 plays a role in many important oncogenic signaling pathways in cells and certain natural products with cancer inhibitory activity are targeted to HSP90 has created the concept that inhibition of HSP90 function would be useful in the treatment of neoplastic diseases. 17-allylamino-17-demethoxygeldanamycin (17AAG), a geldanamycin derivative, an HSP90 inhibitor is currently undergoing clinical trials.

HSP90

HSP90 represents approximately 1-2% of the total cellular protein mass. It is usually in dimeric form in the cell and is associated with complex proteins, so-called co-chaperones (co-chaperonen) (see e.g. Pratt, 1997). HSP90 is essential for cell viability (Young et al, 2001) and plays a key role in the response to cellular stress by interacting with many proteins whose natural folding has been altered by external stress such as, for example, heat shock, in order to restore the original folding or to prevent aggregation of the protein (Smith et al, 1998).

HSP90 has also been shown to be important as a buffer against the effects of mutations, presumably by correcting for incorrect protein folding caused by mutations (Rutherford and Lindquist, 1998).

In addition, HSP90 also has important regulatory roles. Under physiological conditions, HSP90 plays a role in ensuring conformational stability and cellular balance for maturation of various key client proteins (client proteins) together with its homolog GRP94 in the endoplasmic reticulum. It can be divided into three groups: a collection of steroid hormone receptors, Ser/Thr or tyrosine kinases (e.g., ERBB2, RAF-1, CDK4, and LCK) and various proteins such as, for example, mutated p53 or the catalytic subunit of telomerase hTERT. Each of these proteins plays a key role in the regulation of physiological and biochemical processes of the cell.

The conserved HSP90 family in humans consists of four genes, namely the cytoplasmic HSP90 α, the inducible HSP90 β isoform (Hickey et al, 1989), GRP94 in the endoplasmic reticulum (Argon et al, 1999), and HSP75/TRAP1 in the mitochondrial matrix (Felts et al, 2000). All members of the family are thought to have similar modes of action, but bind to different client proteins, depending on their localization in the cell. For example, ERBB2 is a specific client protein of GRP94(Argon et al, 1999), while type 1 tumor necrosis factor receptor (TNFR1) or retinoblastoma protein (Rb) has been found to be a client protein of TRAP1 (Song et al, 1995; Chen et al, 1996).

HSP90 is involved in many complex interactions with a large number of client proteins and regulatory proteins (Smith, 2001). Although precise molecular details remain to be elucidated, biochemical experiments and studies performed with the aid of X-ray crystallography have in recent years become increasingly able to explain the details of the function of HSP90 chaperone proteins (Prodromou et al, 1997; Stebbins et al, 1997). Thus, HSP90 is an ATP-dependent chaperone (Prodromou et al, 1997), and dimerization is important for the hydrolysis of ATP. Binding of ATP results in the formation of a cyclic dimeric structure in which the two N-terminal domains are in close contact with each other and serve as switches of conformation (Prodromou and Pearl, 2000).

Known HSP90 inhibitors

The first class of HSP90 inhibitors discovered were benzoquinone ansamycins, which included the compounds herbimycin (herbimycin) a and geldanamycin. Initially, they were used to detect reversal of the malignant phenotype in fibroblasts induced by transformation with the v-Src oncogene (Uehara et al, 1985). Later, strong antitumor activity was demonstrated in vitro (Schulte et al, 1998) and in vivo in animal models (Supko et al, 1995).

Immunoprecipitation and studies on affinity matrices then showed that the major mechanism of action of geldanamycin involved binding to HSP90 (Whitesell et al, 1994; Schulte and Neckers, 1998). In addition, X-ray crystallography studies have shown that geldanamycin competes for the ATP binding site and inhibits the intrinsic ATPase activity of HSP90 (Prodromou et al, 1997; Panaretou et al, 1998). This prevents the formation of multimeric HSP90 complexes that function as chaperones for the client proteins. Thus, the client proteins are degraded via the ubiquitin-proteasome pathway.

The geldanamycin derivative 17-allylamino-17-demethoxygeldanamycin (17AAG) showed no change in the properties of inhibition of HSP90, degradation of client proteins and antitumor activity in cell culture and xenograft models (Schulte et al, 1998; Kelland et al, 1999), but had significantly less hepatotoxicity than geldanamycin (Page et al, 1997). 17AAG is currently undergoing phase I/II clinical trials.

Radicicol, a macrocyclic antibiotic, also exhibits a modification of the malignant phenotype of v-Src and v-Ha-Ras-induced fibroblasts (Kwon et al, 1992; Zhao et al, 1995). Radicicol degrades many signaling proteins as a result of HSP90 inhibition (Schulte et al, 1998). X-ray crystallography studies have shown that radicicol binds also to the N-terminal domain of HSP90 and inhibits intrinsic ATPase activity (Roe et al, 1998).

As is known, coumarins bind to the ATP binding site of the HSP90 homolog DNA gyrase in bacteria. The coumarin antibiotics neomycin bound to the carboxyl terminus of HSP90, i.e., the different HSP90 site from benzoquinone-ansamycin and radicicol, and the benzoquinone-ansamycin and radicicol bound to the N-terminus of HSP90 (Marcu et al, 2000 b).

Inhibition of HSP90 by novobiocin results in massive HSP 90-dependent signal protein degradation (Marcu et al, 2000 a).

Degradation of signaling proteins such as ERBB2 was demonstrated with PU3, a purine-derived HSP90 inhibitor. PU3 causes cell cycle arrest and differentiation in breast cancer cell lines (Chiosis et al, 2001)

HSP90 as therapeutic target

Since HSP90 is involved in the regulation of many signaling pathways important in the phenotype of tumors and certain natural products were found to exert their biological effects by inhibiting the activity of HSP90, HSP90 is currently being investigated as a new target for the development of tumor therapeutics (Neckers et al, 1999).

The main mechanisms of action of geldanamycin, 17AAG and radicicol include inhibition of binding of ATP to the ATP binding site at the N-terminus of the protein and inhibition of the intrinsic ATPase activity of the resulting HSP90 (see, e.g., Prodromou et al, 1997; Stebbins et al, 1997Panaretou et al, 1998). Inhibition of the ATPase activity of HSP90 prevents recruitment of co-chaperones and contributes to the formation of HSP90 heterocomplexes, which lead to degradation of client proteins via the ubiquitin-proteasome pathway (see, e.g., Neckers et al, 1999; Kelland et al, 1999). Treatment of tumor cells with HSP90 inhibitors results in the selective degradation of important proteins that are important for processes such as the regulation of cell proliferation, cell cycle and apoptosis. These processes are often uncontrolled in tumors (see e.g. Hostein et al, 2001). An attractive principle for the development of HSP90 inhibitors is that strong tumor therapeutic effects can be achieved by simultaneously degrading multiple proteins associated with the transformed phenotype.

In particular, the present invention relates to compounds that inhibit, modulate and/or modulate HSP90, compositions comprising these compounds, and methods of use thereof for treating HSP 90-induced diseases, such as neoplastic diseases, viral diseases such as hepatitis b (Waxman, 2002); immunosuppression in transplantation (Bijlmakers, 2000 and Yorgin, 2000); inflammation-induced diseases (Bucci, 2000), such as rheumatoid arthritis, asthma, multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis, and inflammatory bowel disease; cystic fibrosis (Fuller, 2000); diseases associated with angiogenesis (Hur, 2002 and Kurebayashi, 2001), such as diabetic retinopathy, hemangiomas, endometriosis and tumor angiogenesis; infectious diseases; (ii) an autoimmune disease; ischemia; promoting nerve regeneration (Rosen et al, WO 02/09696; Degranco et al, WO 99/51223; Gold, US 6,210,974B 1); fibrotic diseases (fibroschtereerkrankungen), such as scleroderma, polymyositis, systemic lupus erythematosus, cirrhosis of the liver, keloid formation, interstitial nephritis and pulmonary fibrosis (Strehlow, WO 02/02123).

The invention also relates to the use of the compounds of the invention for protecting normal cells from chemotherapy-induced toxicity and in diseases in which incorrect protein folding or aggregation is the main causative factor, such as scrapie, creutzfeldt-jakob disease, huntington's chorea or alzheimer's disease (Sittler, hum. mol. gene., 10, 1307, 2001; Tratzelt et al, proc. nat. acad. sci., 92, 2944, 1995; Winklhofer et al, j.biol. chem., 276, 45160, 2001). WO 01/72779 describes purine compounds and their use for the treatment of GRP94 (homolog or paralog of HSP90) -induced diseases, such as neoplastic diseases, wherein the cancerous tissue comprises a sarcoma or carcinoma selected from the group consisting of: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, ewing's tumor, leiosarcoma (leiosarkom), rhabdomyosarcoma, colon carcinoma, pancreatic carcinoma, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma (taldrsen karzinom), papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, myeloid cancer, bronchial cancer, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma (embryonalem karzinom), wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, and angiosarcoma, Hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, and heavy chain disease.

WO 01/72779 also discloses the use of the compounds mentioned therein for the treatment of viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis a virus, hepatitis b virus, hepatitis c virus, influenza virus, varicella virus, adenovirus, herpes simplex virus type I (HSV-I), herpes simplex virus type II (HSV-II), rinderpest virus, rhinovirus, echovirus, rotavirus, Respiratory Syncytial Virus (RSV), papilloma virus, papova virus, cytomegalovirus, echinovirus (echinovirus), arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II). WO 01/72779 also describes the use of the compounds mentioned therein for the modulation of GRP94, wherein the modulated biological GRP94 activity causes an immune response, protein transport from the endoplasmic reticulum, recovery from hypoxic/anoxic stress, recovery from malnutrition, recovery from thermal stress or a combination thereof in an individual and/or wherein the disorder is cancer, an infectious disease, a disorder associated with disrupted protein transport from the endoplasmic reticulum, a disorder associated with ischemia/reperfusion or a combination thereof, wherein the disorder associated with ischemia/reperfusion is cardiac arrest, cardiac arrest and delayed ventricular arrhythmias (verz ö gertententrikul < renn > arrhythmien), cardiac surgery (herzopertation), cardiopulmonary bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, thromboembolic stroke (thrombo schlem schlagranfalaganfall), hemorrhagic stroke (hemmorbigischemgaherthur), cerebral vascular stroke, hypotonia, hypoglycemia, status epilepticus, epileptic seizures (einem epihepetischem anfall), anxiety, schizophrenia, neurodegenerative disorders, alzheimer's disease, huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), or a consequence of neonatal stress (stresbeim neugeberenen).

Finally, WO 01/72779 describes the use of an effective amount of a GRP94 protein modulator in the manufacture of a medicament for modifying the response of subsequent cells to an ischemic state at a tissue site in an individual by treating cells at the tissue site with a GRP94 protein modulator so as to increase GRP94 activity in the cells to a degree that modifies the response of subsequent cells to the ischemic state, wherein the subsequent ischemic state is preferably cardiac arrest, asystole and delayed ventricular arrhythmia, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotonia, hypoglycemia, status epilepticus, epileptic seizure, anxiety, schizophrenia, neurodegenerative disorders, huntington's disease, chorea, Amyotrophic Lateral Sclerosis (ALS) or neonatal stress, or wherein said tissue site is transplanted donor tissue.

Therapeutic and diagnostic applications of HSP90 activation, particularly for the treatment of central nervous system and cardiovascular diseases, are described by kamal et al in Trends in Molecular Medicine, volume 10, stage 6, month 6 2004.

Thus, the identification of small molecule compounds that specifically inhibit, modulate and/or modulate HSP90 is desirable and an object of the present invention.

It has been found that the compounds of the invention and their salts have very valuable pharmacological properties while being well tolerated.

They exhibit in particular the property of inhibiting HSP 90.

The present invention therefore relates to the compounds of the invention as medicaments and/or pharmaceutically active compounds for the treatment and/or prophylaxis of said diseases and to the use of the compounds of the invention for the preparation of medicaments for the treatment and/or prophylaxis of said diseases, and also to methods for the treatment of said diseases, which comprise the administration of one or more compounds of the invention to a patient in need of such administration.

The subject or patient may belong to any mammalian species, e.g., primates, particularly humans; rodents, including mice, rats and rats; a rabbit; horses, cattle, dogs, cats, etc. For experimental studies, several animal models are of interest, in which case they provide a model for the treatment of human diseases.

Prior Art

WO 00/53169 describes the inhibition of HSP90 with coumarin or coumarin derivatives.

WO 03/041643 a2 discloses zeranol derivatives that inhibit HSP 90.

Other pyrazole derivatives inhibiting HSP90 substituted at the 3-or 5-position with aromatic residues are disclosed in WO 2004/050087 a1 and WO 2004/056782 a 1.

WO 03/055860 a1 describes 3, 4-diaryl pyrazoles as HSP90 inhibitors.

Purine derivatives having HSP 90-inhibiting properties are disclosed in WO 02/36075 a 2.

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Summary of The Invention

The present invention relates to compounds of formula (I),

wherein

R¹Represents OH, OCH₃、OCF₃、OCHF₂OBzl, OAc, p-methoxy-benzyloxy, SH, S (O)_mCH₃、SO₂NH₂、Hal、CF₃Or CH₃，

R²，R³Each independently of the others represents H, Hal, CN, NO₂、A、Alk、(CH₂)_nAr、(CH₂)_nHet、(CH₂)_nCOOH、(CH₂)_nCOOA、COOAr、COOHet、CONH₂、CONHA、CONAA′、CONHAr、CONAAr、CON(Ar)₂、CONHHet、CON(Het)₂、NH₂、NHA、NHAr、NHHet、NAA′、NHCOA、NACOA′、NHCOAr、NHCOHet、NHCOOA、NHCOOAr、NHCOOHet、NHCONHA、NHCONHAr、NHCONHHet、OH、OA、OAr、OHet、SH、S(O)_mA、S(O)_mAr、S(O)_mHet、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、SO₂N(Ar)₂、SO₂N(Het)₂、CONH(CH₂)_oHet、NH(CH₂)_oHet、O(CH₂)_oAr、S(O)_m(CH₂)_oHet、S(O)_m(CH₂)_oAr、(CH₂)_oCH(Ar)CH₃、CONAR¹²、SO₂NA(CH₂CONAA′)、SO₂NH(CH₂Ar)、SO₂NA[(CH₂)_oCN]、SO₂NA(CH₂Ar)、(CH₂)_oNHAr、(CH₂)_oNAAr、(CH₂)_oOAr、(CH₂)_oS(O)_mAr, CH ═ CH-Ar, CHO, COA, or R¹²，

R⁴，R⁵，R⁶Each independently of the others represents H, Hal, CN, NO₂、A、Alk、(CH₂)_nAr、(CH₂)_nHet、COOH、COOA、COOAr、COOHet、CONH₂、CONHA、CONAA′、CONHAr、CONAAr、CON(Ar)₂、CONHHet、CON(Het)₂、NH₂、NHA、NHAr、NHHet、NAA′、NHCOA、NACOA′、NHCOAr、NHCOHet、NHCOOA、NHCOOAr、NHCOOHet、NHCONHA、NHCONHAr、NHCONHHet、OH、OA、OAr、OHet、SH、S(O)_mA、S(O)_mAr、S(O)_mHet、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、SO₂N(Ar)₂、SO₂N(Het)₂、CONH(CH₂)_oAr、NHCO(CH₂)_oAr、NHCO(CH₂)_oOA or O (CH)₂)_oHet，

R⁴And R⁵And together also represents OCH₂O or OCH₂CH₂O，

A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 10 carbon atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂、NH、NR⁸And/or by-CH ═ CH-groups and/or, in addition, 1 to 5 hydrogen atoms may be replaced by F, Cl, Br and/or R⁷Instead, Alk or cycloalkyl having 3 to 7 carbon atoms,

a and A' together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by CH₂OH、CH₂Br、CH₂NEt₂Substituted, and/or wherein CH₂The radicals being selected from the group consisting of O, S, SO₂、N、NH、NR⁸、NCOR⁸Or NCOOR⁸Instead of this, the user can,

alk represents an alkenyl group having 2 to 6 carbon atoms,

R⁷represents COOR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR⁹、NHCOOR⁹OR OR⁹，

R⁸Denotes cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkylene having 4 to 10 carbon atoms, Alk or unbranched or branched alkyl having 1 to 6 carbon atoms, in which one, two or three CH₂The radicals being selected from the group consisting of O, S, SO₂NH and/or, in addition, 1 to 5 hydrogen atoms can be replaced by F and/or Cl,

R⁹，R¹⁰each independently of the other represents H or an alkyl radical having 1 to 5 carbon atoms, in which 1 to 3 CH groups₂The radicals being selected from the group consisting of O, S, SO₂NH, NMe or NEt and/or, in addition, 1 to 5 hydrogen atoms can be replaced by F and/or Cl,

R⁹and R¹⁰Together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, wherein CH₂The radicals being selected from the group consisting of O, S, SO₂、NH、NR⁸、NCOR⁸Or NCOOR⁸Instead of this, the user can,

ar represents phenyl, naphthyl OR biphenyl, each of which is unsubstituted OR substituted by Hal, A, OR¹¹、N(R¹¹)₂、NO₂CN, phenyl, CON (R)¹¹)₂、NR¹¹COA、NR¹¹CON(R¹¹)₂、NR¹¹SO₂A、COR¹¹、NR¹¹CO(CH₂)_oR¹¹、SO₂N(R¹¹)₂、S(O)_mA、-[C(R¹¹)₂]_n-COOR¹¹and/or-O [ C (R)¹¹)₂]_o-COOR¹¹Mono-, di-or tri-substituted,

het represents a monocyclic OR bicyclic, saturated, unsaturated OR aromatic heterocycle having 1 to 4N, O and/OR S atoms which may be substituted by Hal, A, OR¹¹、N(R¹¹)₂、NO₂、CN、COOR¹¹、CON(R¹¹)₂、NR¹¹COA、NR¹¹SO₂A、COR¹¹、SO₂NR¹¹、S(O)_mA、＝S、＝NR¹¹And/or mono-, di-or tri-substituted ═ O (carbonyl oxygen),

R¹¹represents a group of a compound represented by the formula H or A,

R¹²represents cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkylene having 4 to 12 carbon atoms,

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 0, 1, 2, 3 or 4,

o represents 1, 2 or 3,

and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

The invention relates to compounds of formula I and salts thereof and to a process for the preparation of compounds of formula I as claimed in claims 1 to 16 and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, characterized in that a) R is substituted¹、R²And R³A compound of the formula II having the meaning indicated in claim 1 and X represents H or methyl

And wherein R⁴、R⁵And R⁶A compound of the formula III having the meaning indicated in claim 1,

subsequently, if desired, converting the resulting compound in which X represents methyl into a compound of the formula I in which X represents H by ether cleavage,

and/or by reacting one or more radicals R in the compounds of the formula I, for example by¹、R²、R³、R⁴And/or R⁵Conversion into one or more radicals R¹、R²、R³、R⁴And/or R⁵：

i) The nitro group is reduced into amino group,

ii) hydrolysis of the ester group to a carboxyl group,

iii) converting the amino group to an alkylated amine by reductive amination,

iv) converting the carboxyl group into a sulfonamidocarbonyl group,

v) converting the acid chloride into an amide,

and/or

Converting a base or acid of formula I into one of its salts.

The invention also relates to stereoisomers (E, Z isomers) as well as hydrates and solvates of these compounds. Solvates of these compounds refer to adducts of inert solvent molecules to the compounds formed due to their mutual attraction. Solvates are, for example, mono-or di-hydrates or alcoholates.

Pharmaceutically acceptable derivatives refer, for example, to salts of the compounds of the invention as well as to so-called prodrug compounds.

Prodrug derivatives refer to compounds of formula I which have been modified, for example, by alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the organism to yield the active compounds of the invention.

These also include biodegradable polymer derivatives of the compounds of the invention, such as, for example, int.j.pharm.11561-67 (1995).

The expression "effective amount" refers to an amount of a drug or pharmaceutically active compound that produces a sought or desired biological or medical response in a tissue, system, animal or human, e.g., a sought or desired biological or medical response by a researcher or physician.

Furthermore, the expression "therapeutically effective amount" refers to an amount which has the following result compared to a corresponding individual not receiving the amount: improved healing treatment, healing, prevention or elimination of the disease, disease manifestation, disease state, discomfort, disorder or side effect or also reduced progression of the disease, discomfort or disorder.

The term "therapeutically effective amount" also includes an amount effective to enhance normal physiological function.

The invention furthermore relates to mixtures of the compounds of the formula I according to the invention, for example mixtures of two diastereomers in a ratio of 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1: 10, 1: 100 or 1: 1000. Mixtures of stereoisomeric compounds are particularly preferred.

For all groups which occur more than once, their meanings are independent of one another.

In this context, the radicals and the parameter R¹、R²、R³、R⁴And R⁵Have the meanings indicated in formula I, unless explicitly stated otherwise.

A or a' preferably represents alkyl, is unbranched (linear) or branched, and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A or A' particularly preferably represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1-, 1, 2-or 2, 2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 2-or 1, 2, 2-trimethylpropyl.

A or A' very particularly preferably represents alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl or 1, 1, 1-trifluoroethyl.

A or A' also represents cycloalkyl. Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A or A' also represents Alk. Alk represents an alkenyl group having 2 to 6 carbon atoms, such as, for example, ethenyl or propenyl.

Cycloalkylalkylene represents, for example, cyclopropylmethyl or cyclopentylmethyl.

Ac represents acetyl, Bzl represents benzyl, Ms represents-SO₂CH₃。

Selectfluor/F-TEDA-BF4/1 (1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate)) ═

PdCl₂(dppf) represents [1, 1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride:

R¹preferably OH, OCH₃Or SH, particularly preferably OH or OCH₃And further represents OCF₃、OCHF₂。

R²、R³Preferably each, independently of one another, represents H, Hal, A, (CH)₂)_nAr、(CH₂)_nHet、(CH₂)_nCOOH、(CH₂)_nCOOA、CONH₂、CONHA、CONAA′、CONHAr、CONHHet、NH₂、NHA、NHAr、NHHet、NAA′、S(O)_mA、S(O)_mAr、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、CONH(CH₂)_oHet、NH(CH₂)_oHet、O(CH₂)_oAr、S(O)_m(CH₂)_oHet、S(O)_m(CH₂)_oAr、(CH₂)_oCH(Ar)CH₃、CONAR¹²、SO₂NA(CH₂CONAA′)、SO₂NH(CH₂Ar)、SO₂NA[(CH₂)_oCN]、SO₂NA(CH₂Ar)、(CH₂)_oNHAr、(CH₂)_oNAAr、(CH₂)_oOAr、(CH₂)_oS(O)_mAr, CH-Ar or R¹²Wherein R is³Particularly preferably represents H.

R²Particularly preferably represents H; hal, such as, for example, Cl, Br or I; a, such as for example methyl or ethyl; SO (SO)₂NAA′、CONAA′、SO₂NHA in which A, A' each, independently of one another, denote an unbranched or branched alkyl radical having 1 to 6 carbon atoms, in addition in which 1 to 5 hydrogen atoms can be replaced by F, Cl and/or Br,

or a cycloalkyl group having 3 to 7 carbon atoms,

and wherein A and A' together also represent an alkylene chain having 3, 4, 5 or 6 carbon atoms, which may be substituted by CH₂OH、CH₂Br or CH₂NEt₂Substituted, and/or wherein CH₂The group may be replaced by O, N, NH or NA;

R²also particularly preferably represents SO₂NH₂Fluorophenyl aminosulfonyl, phenylaminosulfonyl, benzylaminosulfonyl, pyridylaminosulfonyl, phenylthio, benzyl, phenylsulfonyl, phenyl, 2-phenylethyl, 2- (pyridyl) ethyl, fluorophenyl, 2-phenylvinyl, 2-carboxyethyl, 2- (methoxycarbonyl) ethyl, 2- (fluorophenyl) ethyl, SO₂N(CH₂CH₂OH，CH₂CH₂Br)、SO₂NA(CH₂CH₂CN)、SO₂NA(CH₂CH₂Br)、SO₂NA(CH₂CONAA') or SO₂NA(CH₂Phenyl).

R⁴、R⁵、R⁶Preferably each independently of the others represents H, Hal, CN, NO₂、A、(CH₂)_nAr、COOH、COOA、CONH₂、CONHA、CONAA′、CONHAr、NH₂、NHA、NAA′、NHCOA、NHCOAr、NHCOHet、OH、OA、SO₂NH₂、SO₂NHA、SO₂NAA′、CONH(CH₂)_oAr、NHCO(CH₂)_oAr、NHCO(CH₂)_oOA or O (CH)₂)_oHet。

R⁴Particularly preferably represents H.

R⁵Particularly preferably represents H, F, Cl, CN or A, such as, for example, methyl, ethyl or trifluoromethyl.

R⁶Particularly preferably H, NHCOA, NH₂、NO₂、COOH、Fl、Cl、Br、A、OA、OH、CN、SO₂NH₂COOA, 4- [2- (4-methylpiperazin-1-yl) ethoxy]Phenyl, benzyl, benzoylamino, benzylcarbonylamino,Pyridylcarbonylamino or methoxyethylcarbonylamino, wherein A preferably represents an unbranched or branched alkyl group having 1 to 6 carbon atoms in which 1 to 5 hydrogen atoms may be replaced by F, Cl and/or Br.

R⁷Preferably represents COOR⁹Such as for example COOH or COOCH₃；CONR⁹R¹⁰Such as, for example, CONH₂；NR⁹R¹⁰Such as, for example, amino, methylamino or dimethylamino; NHCOR⁹、NHCOOR⁹OR OR⁹Such as, for example, hydroxy or methoxy;

R⁸preferably cyclopentyl, cyclohexyl, methyl, ethyl, propyl or butyl.

R⁹、R¹⁰Preferably each, independently of one another, represents H or an alkyl radical having 1 to 5 carbon atoms, where 1 to 5 hydrogen atoms may be replaced by F and/or Cl.

Ar denotes, for example, phenyl, o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butylphenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) phenyl, o-, m-or p- (N-methylaminocarbonyl) phenyl, o-, m-or p-acetylaminophenyl, o-, m-or p-methoxyphenyl, O-, m-or p-ethoxyphenyl, o-, m-or p-ethoxycarbonylphenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) phenyl, o-, m-or p- (N-ethylamino) phenyl, o-, m-or p- (N, N-diethylamino) phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p- (methylsulfonylamino) phenyl, o-, m-or p- (methylsulfonyl) phenyl, o-, m-or p- (N, N-dimethylamino) phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl, O-, m-or p-cyanophenyl, o-, m-or p-ureidophenyl, o-, m-or p-formylphenyl, o-, m-or p-acetylphenyl, o-, m-or p-aminosulfonylphenyl, o-, m-or p-carboxyphenyl, o-, m-or p-carboxymethylphenyl, o-, m-or p-carboxymethoxyphenyl and preferably also 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-difluorophenyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dichlorophenyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2, 5-di-nitrophenyl, 2, 5-dimethoxyphenyl, 3-nitro-4-N, N-chlorophenyl, 2-amino-4-chloro-or 2-amino-6-chlorophenyl, 2, 3, 4-, 2, 3, 5-, 2, 3, 6-, 2, 4, 6-or 3, 4, 5-trichlorophenyl, 2, 4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetylaminophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar preferably represents, for example, unsubstituted OR substituted by Hal, A, OR¹¹、N(R¹¹)₂、NR¹¹COA、NR¹¹CO(CH₂)_oR¹¹And/or- [ C (R)¹¹)₂]_n-COOR¹¹Mono-, di-or tri-substituted phenyl, wherein R¹¹Represents H or A, such as, for example, methyl. Ar very particularly preferably represents phenyl which is unsubstituted or mono-, di-or trisubstituted by Hal and/or A.

Het, whether further substituted or not, represents for example 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2-, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, and preferably also 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or 5-yl, 1-or 5-tetrazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4-or 5-isoindolyl, 1-, (a) amino acid or a salt thereof, 2-, 4-or 5-benzimidazolyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl, 4-, 5-, 6-or 7-benzo-2, 1, 3-oxadiazolyl, 2-, or 5-indazolyl, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo-1, 4-oxazinyl, preferably also 1, 3-benzodioxol-5-yl, 1, 4-benzodioxan-6-yl, 2, 1, 3-benzothiadiazol-4-or-5-yl or 2, 1, 3-benzooxadiazol-5-yl.

The heterocyclic group may also be partially or fully hydrogenated.

Het may therefore also represent, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or 5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3-thienyl, 2, 3-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 1-, 2-or 3-pyrrolidinyl, tetrahydro-1-, -2-or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-or 5-pyrazolyl, tetrahydro-1-, -3-or 4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3-or 4-pyridyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-or 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxan-2-, -4-or-5-yl, hexahydro-1-, -3-or-4-pyridazinyl, hexahydro-1-, -2-, -4-or-5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-quinolinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo-1, 4-oxazinyl, preferably also 2, 3-methylenedioxyphenyl, 3, 4-methylenedioxyphenyl, 2, 3-ethylenedioxyphenyl, 3, 4- (difluoromethylenedioxy) phenyl, 2, 3-dihydrobenzofuran-5-or-6-yl, 2, 3- (2-oxomethylenedioxy) phenyl or 3, 4-dihydro-2H-1, 5-benzodioxin * (benzodioxins) -6-or-7-yl, and preferably also 2, 3-dihydrobenzofuranyl or 2, 3-dihydro-2-oxofuranyl.

Het preferably represents a monocyclic, saturated, unsaturated or aromatic heterocycle having 1 to 2N and/or O atoms, which may be unsubstituted or mono-, di-or trisubstituted by a, Hal, OH and/or OA.

Het particularly preferably represents a monocyclic saturated heterocycle having 1 to 2N and/or O atoms, which may be unsubstituted or mono-or disubstituted by A.

In another embodiment, Het very particularly preferably represents pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl.

In another embodiment Het particularly preferably denotes furyl, thienyl, pyrrolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, indolyl, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl, each of which is unsubstituted or mono-, di-or tri-substituted by a, Hal, OH and/or OA.

In a very particularly preferred embodiment, Het represents pyridyl, piperidyl or piperazinyl.

The compounds of formula I may have one or more chiral centers and may therefore exist in the form of various stereoisomers. Formula I includes all of these forms.

Particularly preferred are compounds of formula I selected from the group consisting of

5- [5- (N-propyl-N '-methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole, 5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N-propyl-N '-methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole, 5- [5- (N-isopropyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (2-fluorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, 5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxy-5-chlorophenyl) -1- (2-fluorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-ethylphenyl) -1H-pyrazole,

5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- {4- [2- (4-methylpiperazin-1-yl) -ethoxy ] phenyl } -1H-pyrazole,

and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios.

The present invention therefore relates in particular to compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the following sub-formulae Ia to Il, which correspond to formula I and in which the radicals not specified in more detail have the meanings indicated in formula I, but wherein

In Ia R¹Represents OH, OCH₃Or SH;

in Ib R²，R³Each independently of the others represents H, Hal, A, (CH)₂)_nAr、(CH₂)_nHet、(CH₂)_nCOOH、(CH₂)_nCOOA、CONH₂、CONHA、CONAA′、CONHAr、CONHHet、NH₂、NHA、NHAr、NHHet、NAA′、S(O)_mA、S(O)_mAr、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、CONH(CH₂)_oHet、NH(CH₂)_oHet、O(CH₂)_oAr、S(O)_m(CH₂)_oHet、S(O)_m(CH₂)_oAr、(CH₂)_oCH(Ar)CH₃、CONAR¹²、SO₂NA(CH₂CONAA′)、SO₂NH(CH₂Ar)、SO₂NA[(CH₂)_oCN]、SO₂NA(CH₂Ar)、(CH₂)_oNHAr、(CH₂)_oNAAr、(CH₂)_oOAr、(CH₂)_oS(O)_mAr or R¹²；

In Ic R⁴，R⁵，R⁶Each independently of the others represents H, Hal, CN, NO₂、A、(CH₂)_nAr、COOH、COOA、CONH₂、CONHA、CONAA′、CONHAr、NH₂、NHA、NAA′、NHCOA、NHCOAr、NHCOHet、OH、OA、SO₂NH₂、SO₂NHA、SO₂NAA′、CONH(CH₂)_oAr、NHCO(CH₂)_oAr、NHCO(CH₂)_oOA or O (CH)₂)_oHet；

In Id A, A' each independently of the others denote an unbranched or branched alkyl radical having 1 to 10C atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂、NH、NR⁸And/or by-CH ═ CH-groups and/or, in addition, 1 to 5 hydrogen atoms may be replaced by F, Cl, Br and/or R⁷Instead, Alk or cycloalkyl having 3 to 7 carbon atoms,

a and A' together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by CH₂OH、CH₂Br or CH₂NEt₂Substituted, and/or wherein CH₂The radicals may be O, N, NH or NR⁸Replacing;

in Ie A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 6 carbon atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂NH and/or by a-CH ═ CH-group and/or, in addition, 1 to 5 hydrogen atoms can be replaced by F, Cl and/or Br, Alk or cycloalkyl having 3 to 7 carbon atoms;

in If R⁷Represents COOR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR⁹、NHCOOR⁹OR OR⁹；

In Ig R⁸Represents an unbranched or branched alkyl group having 1 to 6 carbon atoms;

in Ih R⁹，R¹⁰Each independently of the other represents H or an alkyl radical having 1 to 5 carbon atoms, wherein 1 to 5 hydrogen atoms may be replaced by F and/or Cl;

in Ii A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 6 carbon atoms, in which 1 to 5 hydrogen atoms can be replaced by F, Cl and/or Br, or a cycloalkyl radical having 3 to 7 carbon atoms;

in Ij Ar represents unsubstituted OR substituted by Hal, A, OR¹¹、N(R¹¹)₂、NR¹¹COA、NR¹¹CO(CH₂)_oR¹¹And/or- [ C (R)¹¹)₂]_n-COOR¹¹Mono-, di-or tri-substituted phenyl;

het in Ik represents a monocyclic or bicyclic, saturated or aromatic heterocycle having 1 to 2N and/or O atoms, which may be mono-or di-substituted by a;

in Il R¹Represents OH, OCH₃Or the presence of an SH group or an SH group,

R²，R³each being independent of each otherThe vertical place represents H, Hal, A, (CH)₂)_nAr、(CH₂)_nHet、(CH₂)_nCOOH、(CH₂)_nCOOA、CONH₂、CONHA、CONAA′、CONHAr、CONHHet、NH₂、NHA、NHAr、NHHet、NAA′、S(O)_mA、S(O)_mAr、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、CONH(CH₂)_oHet、NH(CH₂)_oHet、O(CH₂)_oAr、S(O)_m(CH₂)_oHet、S(O)_m(CH₂)_oAr、(CH₂)_oCH(Ar)CH₃、CONAR¹²、SO₂NA(CH₂CONAA′)、SO₂NH(CH₂Ar)、SO₂NA[(CH₂)_oCN]、SO₂NA(CH₂Ar)、(CH₂)_oNHAr、(CH₂)_oNAAr、(CH₂)_oOAr、(CH₂)_oS(O)_mAr or R¹²，

R⁴，R⁵，R⁶Each independently of the others represents H, Hal, CN, NO₂、A、(CH₂)_nAr、COOH、COOA、CONH₂、CONHA、CONAA′、CONHAr、NH₂、NHA、NAA′、NHCOA、NHCOAr、NHCOHet、OH、OA、SO₂NH₂、SO₂NHA、SO₂NAA′、CONH(CH₂)_oAr、NHCO(CH₂)_oAr、NHCO(CH₂)_oOA or O (CH)₂)_oHet，

R⁴And R⁵And together also represents OCH₂O or OCH₂CH₂O，

A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 10 carbon atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂、NH、NR⁸And/or substituted by-CH ═ CH-groups andor, in addition, 1 to 5 hydrogen atoms may be replaced by F, Cl, Br and/or R⁷Instead, Alk or cycloalkyl having 3 to 7 carbon atoms,

a and A' together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by CH₂OH、CH₂Br or CH₂NEt₂Substituted, and/or wherein CH₂The radicals may be O, N, NH or NR⁸Instead of this, the user can,

R⁷represents COOR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR⁹、NHCOOR⁹OR OR⁹，

R⁸Represents an unbranched or branched alkyl group having 1 to 6 carbon atoms,

R⁹，R¹⁰each independently of the other, H or alkyl having 1 to 5 carbon atoms, where 1 to 5 hydrogen atoms may be replaced by F and/or Cl,

ar represents unsubstituted OR substituted by Hal, A, OR¹¹、N(R¹¹)₂、NR¹¹COA、NR¹¹CO(CH₂)_oR¹¹And/or- [ C (R)¹¹)₂]_n-COOR¹¹Mono-, di-or tri-substituted phenyl,

het represents a monocyclic or bicyclic, saturated or aromatic heterocycle having 1 to 2N and/or O atoms which may be mono-or di-substituted by A,

R¹¹represents a group of a compound represented by the formula H or A,

R¹²represents cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkylene having 4 to 12 carbon atoms,

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 0, 1, 2, 3 or 4,

o represents 1, 2 or 3;

and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, including mixtures thereof in all ratios.

In addition, the compounds of the invention and the starting materials for their preparation are prepared in a manner known per se, in particular under reaction conditions which are known and suitable for the reaction, as described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [ methods of organic chemistry ], Georg-Thieme-Verlag, Stuttgart). Variants of the method known per se, which are not mentioned here in more detail, can also be used.

If desired, the starting materials may also be formed in situ, without isolation from the reaction mixture, but immediately converted further to the compounds of the invention.

The starting compounds are generally known. If they are new, they can be prepared by methods known per se.

The compounds of formula I can preferably be obtained by reacting a compound of formula II with a hydrazide of formula III. This reaction generally produces a1, 5-diphenylpyrazole derivative. 1, 3-diphenyl derivatives may be formed as by-products.

The reaction is carried out by methods known to the person skilled in the art.

The reaction is first carried out in a suitable solvent.

Examples of suitable inert solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether, ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of said solvents.

Particularly preferred solvents are alcohols, such as, for example, isopropanol or ethanol.

Depending on the conditions used, the reaction time is from a few minutes to 14 days and the reaction temperature is from about-30 ℃ to 140 ℃, usually from-10 ℃ to 110 ℃ and in particular from about 20 ℃ to about 100 ℃.

In the resulting compounds of formula I wherein X represents H or methyl,

ether cleavage is optionally carried out using methods known to those skilled in the art.

The reaction is carried out in a suitable solvent as described above, preferably by adding boron tribromide.

The reaction is particularly preferably carried out in methylene chloride at a reaction temperature of from about-30 ° to 50 °, usually from-20 ° to 20 °, in particular from about-15 ° to about 0 °.

This gives compounds of the formula I in which X represents H.

It is also possible to use by reacting one or more radicals R¹、R²、R³、R⁴And/or R⁵Into one or more other radicals R¹、R²、R³、R⁴And/or R⁵While converting a compound of formula I to another compound of formula I, e.g. reducing the nitro group to an amino group, e.g. by hydrogenation over Raney nickel or Pd/carbon in an inert solvent such as methanol or ethanol; and/or

Converting an ester group to a carboxyl group and/or an amino group to an alkylated amine by reductive amination and/or a carboxyl group by esterification with an alcohol and/or an acid chloride to an amide by reaction with an amine.

Furthermore, the free amino group can be acylated with an acid chloride or anhydride or alkylated with an unsubstituted or substituted alkyl halide in a conventional manner, advantageously in an inert solvent such as dichloromethane or THF and/or in the presence of a base such as triethylamine or pyridine at a temperature of-60 to +30 °.

The invention also relates to intermediate compounds of formula I-I

Wherein

R¹Represents OCH₃OBzl, OAc, p-methoxybenzyloxy or I,

R²，R³the expression "H" is used to indicate the formula,

R⁴，R⁵，R⁶each independently of the others represents H, Hal, CN, NO₂、A、COOH、COOA、NH₂OH, OA or SO₂NH₂，

X represents CH₃Bzl, Ac or p-methoxybenzyl,

a represents an unbranched or branched alkyl radical having 1 to 6 carbon atoms in which 1 to 5 hydrogen atoms may be replaced by F and/or Cl, or a cycloalkyl radical having 3 to 7 carbon atoms, and salts thereof.

An alternative process for the preparation of compounds of formula I:

1. arylation of pyrazoles with substituted phenyliodides

The literature:

demande, 2840303, 12 months and 5 days 2003;

U.S. patent application publication 2003236413, 12 months and 25 days 2003;

2.

3. other processes for preparing 1, 5-diaryl pyrazoles are described in the following documents:

a)Zhu，Jiuxiang；Song，Xueqin；Lin，Ho-Pi；Young，Donn C.；Yan，Shunqi；Marquez，Victor E.；Chen，Ching-Shih.College of Pharmacy，Division of Medicinal Chemistry and Pharmacognosy，The Ohio StateUniversity，Columbus，OH，USA.Journal of the National Cancer Institute(2002)，94(23)，1745-1757。

b)Pal，Manojit；Madan，Manjula；Padakanti，Srinivas；Pattabiraman，Vijaya R.；Kalleda，Srinivas；Vanguri，Akhila；Mullangi，Ramesh；Mamidi，N.V.S.Rao；Casturi，Seshagiri R.；Malde，Alpeshku mar；Gopalakrishnan，B.；Yeleswarapu，Koteswar R.Discovery-Chemistry and Discovery-Biology，Dr Reddy′s LaboratoriesLtd.，Hyderabad，India.Journal of Medicinal Chemistry(2003)，46(19)。

pharmaceutically acceptable salts and other forms

The compounds of the present invention may be used in their final non-salt form. In another aspect, the invention also includes the use of these compounds in the form of their pharmaceutically acceptable salts, which can be derived from various organic and inorganic acids and bases using methods known in the art. The pharmaceutically acceptable salt forms of the compounds of formula I are mostly prepared by conventional methods. If a compound of formula I contains a carboxyl group, one of its suitable salts may be formed by reacting the compound with a suitable base to form the corresponding base addition salt. Such bases are, for example, alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides such as barium hydroxide and calcium hydroxide; alkali metal alkoxides such as potassium ethoxide and sodium propoxide; and various organic bases such as piperidine, diethanolamine and N-methylglutamine. Also included are aluminum salts of the compounds of formula I. In the case of certain compounds of formula I, acid addition salts may be formed by treating these compounds with pharmaceutically acceptable organic and inorganic acids, for example hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, other inorganic acids and their corresponding salts such as sulfates, nitrates or phosphates and the like, alkyl-and monoaryl-sulfonates such as ethanesulfonate, toluenesulfonate and benzenesulfonate, and other organic acids and their corresponding salts such as acetates, trifluoroacetates, tartrates, maleates, succinates, citrates, benzoates, salicylates, ascorbates and the like. Thus, pharmaceutically acceptable acid addition salts of the compounds of formula I include the following salts: acetate, adipate, alginate, arginate (alginat), aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galactarate (from mucic acid), galacturonate, glucoheptonate (glucoheptonate), gluconate, glutamate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate, lactobionate, malate, and so forth, Maleate, malonate, mandelate, metaphosphate, methanesulfonate, methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, phenylacetate, 3-phenylpropanesulfonate, phosphate, phosphonate, phthalate, but this is not a limiting example.

Further, base salts of the compounds of the present invention include aluminum, ammonium, calcium, copper, iron (III), iron (II), lithium, magnesium, manganese (III), manganese (II), potassium, sodium and zinc salts, but this is not a limiting example. Among the above salts, ammonium salts are preferred; alkali metal salt sodium and potassium salts, and alkaline earth metal salt calcium and magnesium salts. Salts of compounds of formula I derived from pharmaceutically acceptable organic non-toxic bases include salts of: primary, secondary and tertiary amines, substituted amines, and also naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, chloroprocaine, choline, N' -dibenzylethylenediamine (benzathine), dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine (hydrabamin), isopropylamine, lidocaine, lysine, meglumine, N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamine resins (polyaminoharze), procaine, purines, theobromine, triethanolamine, triethylamine, trimethylamine, tripropylamine, and tris (hydroxymethyl) methylamine (tromethamine), this is not a limiting example.

Compounds of the invention containing basic nitrogen-containing groups may be quaternized with substances such as (C)₁-C₄) Alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chloride, bromine and iodine; sulfuric acid di (C)₁-C₄) Alkyl esters such as dimethyl, diethyl and diamyl sulfate; (C)₁₀-C₁₈) Alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl (C)₁-C₄) Alkyl halides, such as benzyl chloride and phenethyl bromide. Such salts can be used to prepare water-soluble and oil-soluble compounds of the invention.

Preferred such pharmaceutically acceptable salts include acetate, trifluoroacetate, benzenesulfonate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate and tromethamine, but are not limiting examples.

The acid addition salts of the basic compounds of formula I are prepared by contacting the free base form with a sufficient amount of the desired acid to form the salt in a conventional manner. The free base can be regenerated by contacting the salt form with a base and isolating the free base in a conventional manner. The free base form differs from its corresponding salt form in certain respects, for example in certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, salts are comparable to their respective free base forms.

As mentioned above, pharmaceutically acceptable base addition salts of the compounds of formula I are salts formed with metals or amines, such as alkali metals and alkaline earth metals or organic amines. Preferred metals are sodium, potassium, magnesium and calcium. Preferred organic amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

Base addition salts of the acidic compounds of the present invention are prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt in a conventional manner. The free acid may be regenerated by contacting the salt form with an acid and isolating the free acid in a conventional manner. The free acid form differs from its corresponding salt form in certain respects, for example in certain physical properties such as solubility in polar solvents; however, for the purposes of the present invention, the salts are comparable to their respective free acid forms.

If the compounds of the present invention contain more than one group capable of forming such pharmaceutically acceptable salts, the present invention also includes multiple salts. Typical multiple salt forms include, for example, bitartrat, diacetate, difumartat, meglumine, diphosphate, disodium salt, and trihydrochloride.

In the light of the above, it can be seen that the expression "pharmaceutically acceptable salt" in this context refers to an active compound comprising a compound of formula I in the form of one of its salts, in particular if this salt form confers improved pharmacokinetic properties on the active compound compared to the free form of the active compound or any other salt form of the active compound used earlier. The pharmaceutically acceptable salt forms of the active compounds may also provide for the first time the active activity with desirable pharmacokinetic properties not previously possessed by the active compounds, and may even have a positive effect on the pharmacodynamics of the active compounds with respect to their in vivo therapeutic effect.

Due to their molecular structure, the compounds of formula I according to the invention can be chiral and can therefore exist in various enantiomeric forms. Thus, they may exist in racemic or optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers of the compounds of the present invention may differ, it may be desirable to use the enantiomers thereof. In these cases, the end products or intermediates can be separated into enantiomeric compounds by chemical or physical measures known to the person skilled in the art or even used as such in syntheses.

In the case of racemic amines, diastereomers are formed from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as tartaric acid in the R and S form, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, amino acids protected by a suitable N-protection (e.g.N-benzoylproline or N-phenylsulphonylproline) or various optically active camphorsulphonic acids. Also advantageous is the chromatographic enantiomeric resolution by means of optically active resolving agents, such as dinitrobenzoylphenylglycine, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers immobilized on silica gel. Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as, for example, hexane/isopropanol/acetonitrile, for example in the ratio 82: 15: 3.

The invention also relates to the use of said compounds and/or their physiologically acceptable salts for producing medicaments (pharmaceutical compositions), in particular non-chemically produced medicaments (pharmaceutical compositions). They can be converted into the dosage forms suitable here, together with at least one solid, liquid and/or semisolid excipient or adjuvant, and, if desired, in combination with one or more further active compounds.

The invention also relates to medicaments comprising at least one compound according to the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

Pharmaceutical preparations may be administered in the form of dosage units, each containing a predetermined amount of the active compound. Such units may comprise, for example, from 0.1mg to 3g, preferably from 1mg to 700mg, particularly preferably from 5mg to 100mg, of a compound according to the invention, depending on the disease state to be treated, the method of administration and the age, weight and condition of the patient, or the pharmaceutical preparations may be administered in the form of dosage units, each containing a predetermined amount of active compound. Preferred dosage unit formulations are those containing the active compound in the above-mentioned daily dose or partial dose or fractions thereof. In addition, such pharmaceutical preparations may be prepared by methods widely known in the pharmaceutical field.

The pharmaceutical formulations may be adapted for administration by any desired suitable method, for example, oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) methods. Such formulations may be prepared by all methods known in the art of pharmacy, for example by combining the active compound with excipients or auxiliaries.

Pharmaceutical preparations suitable for oral administration may be administered in the form of separate units such as, for example, capsules or tablets; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

Thus, for example, in the case of oral administration in the form of tablets or capsules, the active ingredient component can be combined with non-toxic pharmaceutically acceptable oral inert excipients such as, for example, ethanol, glycerol, water and the like. Powders may be prepared by comminuting the compound to a suitably fine size and mixing it with a similarly comminuted pharmaceutical excipient such as, for example, an edible carbohydrate such as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agents may also be present.

Capsules are prepared by preparing a powder mixture as described above and filling into shaped gelatin capsule shells. Glidants and lubricants, such as, for example, highly disperse silicic acid, talc, magnesium stearate, calcium stearate or polyethylene glycol in solid form, can be added to the powder mixture before the filling operation. Disintegrating or solubilizing agents such as, for example, agar-agar, calcium carbonate or sodium carbonate may also be added to enhance the availability of the drug after the capsule is used.

In addition, if desired or necessary, suitable binders, lubricants and disintegrants and also dyes can be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as, for example, glucose or beta-lactose, sweeteners made from corn, natural and synthetic rubbers such as, for example, acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include, without limitation, starch, methylcellulose, agar, bentonite, xanthan gum, and the like. Tablets are prepared, for example, by preparing a powder mixture, granulating or dry-compressing the mixture, adding a lubricant and a disintegrant, and compressing the entire mixture into a tablet. Powder mixtures are prepared by mixing the compounds comminuted in a suitable manner with the abovementioned diluents or bases and optionally with binders such as, for example, carboxymethylcellulose, alginates, gelatin or polyvinylpyrrolidone, dissolution retarders such as, for example, paraffin, absorption promoters such as, for example, quaternary salts and/or absorbents such as, for example, bentonite, kaolin or dicalcium phosphate. The powder mixture may be granulated by wetting with a binder such as, for example, syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and sieving. As an alternative to granulation, the powder mixture may be passed through a tablet press to obtain a non-uniformly shaped mass which is broken up to form granules. The granules may be lubricated to prevent sticking to the tablet mould by the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. It is also possible to combine the compounds of the present invention with free flowing inert excipients and then compress directly into tablets without a granulation or dry compression step. There may be a transparent or opaque protective layer consisting of a shellac barrier layer, a layer of sugar or polymer material and a glossy layer of wax. Dyes may be added to these coatings to enable differentiation between different dosage units.

Oral liquids such as, for example, solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution with a suitable flavoring agent, while elixirs are prepared with a non-toxic alcoholic vehicle. Suspensions may be prepared by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavoring additives such as, for example, peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like, may also be added.

Dosage unit formulations for oral administration may be encapsulated in microcapsules, if desired. The formulations may also be prepared in a form in which the release is prolonged or retarded, such as, for example, by coating the particulate material with or embedding it in a polymer, wax or the like.

The compounds of the invention, as well as salts, solvates and physiologically functional derivatives thereof, may also be administered in the form of liposome delivery systems such as, for example, unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as, for example, cholesterol, stearylamine, or phosphatidylcholines.

The compounds of the invention, as well as salts, solvates and physiologically functional derivatives thereof, may also be delivered using a monoclonal antibody as a separate carrier to which the compound molecule is coupled. The compounds may also be coupled to soluble polymers as targeted drug carriers. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidophenol (polyhydroxypropylmethacrylamidophenol), polyhydroxyethylaspartamidephenol (polyhydroxyethylaspartamidephenol), or polyethyleneoxide polylysine (substituted with palmitoyl). The compounds may also be coupled to a class of biodegradable polymers suitable for achieving controlled release of a drug, such as polylactic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydroxypyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymer hydrogels.

Pharmaceutical formulations adapted for transdermal administration may be administered in the form of a separate plaster for long-term intimate contact with the epidermis of the recipient. Thus, for example, iontophoresis may be used to deliver the active compound from a plaster, as described in general terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissues, such as the mouth and skin, the formulations are preferably applied in the form of a topical ointment or cream. In the case of formulating ointments, the active compound may be applied together with a paraffinic or water-miscible cream base. Alternatively, the active compound may be formulated as a cream in an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations suitable for topical application to the eye include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, particularly an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouth include lozenges, pastilles and mouthwashes.

Pharmaceutical preparations suitable for rectal administration may be administered in the form of suppositories or enemas.

Pharmaceutical preparations suitable for nasal administration, in which the carrier substance is a solid, comprise a coarse powder having a particle size of, for example, 20 to 500 μm, which can be administered in an olfactory manner, i.e. by rapid inhalation through the nasal passages from a powder-containing container close to the nose. Suitable formulations for administration in the form of nasal sprays or nasal drops comprise solutions of the active ingredients in water or oil, with liquids as carrier substances.

Pharmaceutical formulations adapted for administration by inhalation comprise a fine particulate powder or mist which may be produced by various types of aerosol-containing pressurised dispensers, nebulisers or insufflators.

Pharmaceutical formulations adapted for vaginal administration may be administered in the form of pessaries, tampons, creams, gels, pastes, foams or spray formulations.

Pharmaceutical formulations suitable for parenteral administration include: aqueous and non-aqueous sterile injection solutions containing antioxidants, buffers, bacteriostats and solutes that render the formulation isotonic with the blood of the recipient being treated; and aqueous and non-aqueous sterile suspensions which may contain a suspending medium and a thickening agent. The formulations may be administered in single-or multi-dose containers, for example sealed ampoules and vials, and stored in a freeze-dried (lyophilized) condition, so that only the addition of the sterile carrier liquid, for example water for injections, is required immediately prior to use.

Injection solutions and suspensions prepared according to the prescription can be prepared from sterile powders, granules, and tablets.

It is understood that the formulations may contain, in addition to the ingredients particularly mentioned above, other materials commonly used in the art for the particular type of formulation; thus, for example, formulations suitable for oral administration may contain flavouring agents.

The therapeutically effective amount of a compound of the present invention will depend upon a number of factors including, for example, the age and weight of the human or animal, the precise condition and severity of the condition requiring treatment, the nature of the formulation and the method of administration, and will ultimately be at the discretion of the attendant physician or veterinarian. However, an effective amount of a compound of the invention is generally from 0.1 to 100mg/kg of recipient (mammal) body weight per day, and in particular is usually from 1 to 10mg/kg of body weight per day. Thus, for an adult mammal weighing 70kg, the actual amount per day is typically 70 to 700mg, wherein the amount may be administered in the form of one individual dose per day or typically in the form of a series of partial doses per day (such as e.g. two, three, four, five or six partial doses) such that the total daily dose is the same. The effective amount of a salt or solvate or physiologically functional derivative thereof may be determined as a fraction of the effective amount of the compound of the invention itself. Similar dosages may be considered appropriate for the treatment of the other conditions mentioned above.

The invention also relates to medicaments comprising at least one compound according to the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active compound.

The further pharmaceutically active compounds are preferably chemotherapeutic agents, in particular those which inhibit angiogenesis and thus inhibit the growth and spread of tumor cells; VEGF receptor inhibitors are preferred herein, including ribozymes (robozymes) and antisense sequences directed against VEGF receptors, as well as angiosomatostatin and endostatin.

Examples of antineoplastic agents that may be used in combination with the compounds of the present invention generally include alkylating agents; an antimetabolite; epiphyllotoxin (epiphyllotoxin); an anti-tumor enzyme; a topoisomerase inhibitor; (ii) procarbazine; mitoxantrone or platinum coordination complexes.

The antineoplastic agent is preferably selected from the following classes: anthracyclines, vinca drugs, mitomycins, bleomycin, cytotoxic nucleosides, epothilones (epothilones), discodermolide, pteridines, enediynes, and podophyllotoxins.

Among the species, particular preference is given to, for example, nordaunorubicin, daunorubicin, aminopterin, methotrexate, methylfolic acid, dichloromethotrexate, mitomycin C, profomycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytarabine, podophyllotoxin or podophyllotoxin derivatives such as, for example, etoposide phosphate or teniposide, melphalan, vinblastine, vincristine, vinblastine, vindesine, vinblastine and taxol. Other preferred antineoplastic agents are selected from the group consisting of estramustine, carboplatin, cyclophosphamide, bleomycin, gemcitabine, ifosfamide (ifosamide), melphalan, hexamethylmelamine, thiotepa, cytarabine, idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin, CPT-11, topotecan, arabinocytosine, bicalutamide, flutamide, leuprolide, pyridobenzindole derivatives, interferons, and interleukins.

The invention also relates to a kit (kit) consisting of the following individual packages:

(a) an effective amount of a compound of the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios,

and

(b) an effective amount of another pharmaceutically active compound.

The kit comprises a suitable container, such as a box, a separate bottle, a bag or an ampoule. A kit may, for example, comprise separate ampoules, each containing an effective amount of a compound of the invention and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, in dissolved or freeze-dried form, and an effective amount of the other pharmaceutically active ingredient.

Use of

The compounds of the present invention are suitable as pharmaceutically active compounds for use in mammals, especially humans, for the treatment of diseases in which HSP90 plays a role.

The present invention therefore relates to the use of a compound according to claim 1 as well as pharmaceutically acceptable derivatives, solvates and stereoisomers thereof (including mixtures thereof in all ratios) for the preparation of a medicament for the treatment of diseases in which the inhibition, modulation and/or modulation of HPS90 plays a role.

SGK is preferred here.

The use of the compounds as claimed in claim 1, and the pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, for the production of medicaments for the treatment of tumor diseases, such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous cell carcinoma, papillary adenocarcinoma, cystadenocarcinoma, myeloid carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms's tumor, cervical carcinoma, neuroblastoma, neuro, Testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, and heavy chain disease; viral diseases, wherein the viral pathogen is selected from the group consisting of hepatitis A virus, hepatitis B virus, hepatitis C virus, influenza virus, varicella virus, adenovirus, herpes simplex virus type I (HSV-I), herpes simplex virus type II (HSV-II), rinderpest virus, rhinovirus, echovirus, rotavirus, Respiratory Syncytial Virus (RSV), papilloma virus, papova virus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II); for immunosuppression in transplantation; inflammation-induced diseases, such as rheumatoid arthritis, asthma, multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis, and inflammatory bowel disease; cystic fibrosis; diseases associated with angiogenesis, such as, for example, diabetic retinopathy, hemangiomas, endometriosis, tumor angiogenesis; infectious diseases; (ii) an autoimmune disease; ischemia; promoting nerve regeneration; fibrotic diseases, such as, for example, scleroderma, polymyositis, systemic lupus erythematosus, cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.

The compounds of the invention can inhibit, in particular, cancer, the growth of tumor cells and tumor metastases and are therefore suitable for tumor therapy.

The invention also comprises the use of a compound according to claim 1 of the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for protecting normal cells from toxicity caused by chemotherapy, for the treatment of diseases in which incorrect protein folding or aggregation is a major causative factor, such as for example pruritis, creutzfeldt-jakob disease, huntington's chorea or alzheimer's disease.

The invention also relates to the use of the compounds according to claim 1 of the invention and/or their physiologically acceptable salts and solvates for the production of medicaments for the treatment of diseases of the central nervous system, cardiovascular diseases and cachexia.

In another embodiment, the invention also relates to the use of a compound according to claim 1 of the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for HSP90 modulation, wherein the modulated biological HSP90 activity causes an immune response, protein transport from the endoplasmic reticulum, recovery from hypoxia/hypoxia stress, recovery from malnutrition, recovery from heat stress or a combination thereof in an individual and/or wherein the disorder is cancer, an infectious disease, a disorder associated with disrupted protein transport from the endoplasmic reticulum, a disorder associated with ischemia/reperfusion or a combination thereof, wherein the disorder associated with ischemia/reperfusion is cardiac arrest, cardiac arrest and delayed ventricular arrhythmia, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, cardiac surgery, heart and pulmonary bypass surgery, organ transplantation, spinal cord trauma, heart disease, Thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotonia, hypoglycemia, status epilepticus, epileptic seizures, anxiety, schizophrenia, neurodegenerative disorders, Alzheimer's disease, Huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), or a consequence of neonatal stress.

In another embodiment, the invention also relates to the use of a compound according to claim 1 of the invention and/or physiologically acceptable salts and solvates thereof for the preparation of a medicament for the treatment of ischemia due to cardiac arrest, asystole and delayed ventricular arrhythmias, cardiac surgery, cardiopulmonary bypass surgery, organ transplantation, spinal cord trauma, head trauma, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral vasospasm, hypotonia, hypoglycemia, status epilepticus, epileptic seizures, anxiety, schizophrenia, neurodegenerative disorders, alzheimer's disease, huntington's chorea, Amyotrophic Lateral Sclerosis (ALS), or neonatal stress.

Assay for measuring HSP90 inhibitors

The inhibitory activity of the compounds of the invention can be determined by the binding of geldanamycin or 17-allylamino-17-demethoxygeldanamycin (17AAG) to HSP90 and its competitive inhibition (Carreras et al 2003, Chiosis et al 2002).

In certain cases, radioligand filter binding assays were used. The radioligand used here was tritiated 17-allylaminogeldanamycin, [3H ]17 AAG. This filter binding assay allows for targeted searching for inhibitors that interfere with ATP binding sites.

Material

Recombinant human HSP90 α (expressed by e.coli, purity 95%);

[3H]17AAG (17-allylaminogeldanamycin, [ allylamino-2, 3-³H. Specific activity: 1.11X 10¹²Bq/mmol(Moravek，MT-1717)；

HEPES filter buffer (50mM HEPES, pH7.0, 5mM MgCl2, BSA 0.01%)

Multiscreen FB (1 μm) filter plates (Millipore, MAFBNOB 50).

Method

First, 96-well microtiter filter plates were rinsed and coated with 0.1% polyethyleneimine.

The test was carried out under the following conditions:

reaction temperature: 22 deg.C

Reaction time: shaking at 800rpm for 30 minutes

Test volume: 50 μ l

Final concentration:

50mM HEPES HCl，pH7.0，5mM MgCl2，0.01％(w/v)BSA

HSP 90: 1.5. mu.g/assay

[3H]17AAG：0.08μM。

At the end of the reaction, the supernatant in the filter plate was removed by suction with a vacuum manifold (Multiscreen Separation System, Millipore) and the filter plate was washed twice.

The filter plates were then measured in a beta counter (Microbeta, Wallac) with a scintillator (Microscint 20, Packard).

"percent of control" is determined from the "count/min" value from which the IC-50 value of the compound is calculated.

In this context, all temperatures are given in degrees Celsius. In the following examples, "conventional post-processing" refers to: if desired, water is added, the pH is adjusted, if desired, to 2 to 10, depending on the composition of the end product, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product is purified by chromatography on silica gel and/or by crystallization. Rf value on silica gel; eluent: ethyl acetate/methanol 9: 1.

LC-MS conditions

An HP 1100 series Hewlett Packard Syste having the following characteristics: an ion source: electrospray (positive ion mode); scanning: 100-1000 m/e; crushing voltage: 60V; gas temperature: 300 ℃, DAD: 220 nm.

Flow rate: 2.4 ml/min. After DND, the flow splitter used reduced the MS flow rate to 0.75 ml/min.

Column: chromolith SpeedROD RP-18e 50-4.6

Solvent: LiChrosolv mass from Merck KgaA

Solvent A: H2O (0.01% TFA)

Solvent B: CAN (0.008% TFA)

Gradient:

20% B → 100% B: 0 minute to 2.8 minutes

100% of B: 2.8 to 3.3 minutes

100% B → 20% B: 3.3 to 4 minutes

Retention time and M + H shown in the following examples⁺The data are measurements of LC-MS measurements.

Example 1

Preparation of 5- (2-hydroxy-4-methoxyphenyl) -1- (3-nitrophenyl) -1H-pyrazole ("a 1"):

1. reacting resorcinol with glacial acetic acid in the presence of boron trifluoride diethyl etherate to obtain 2, 4-dihydroxy acetophenone.

2. N, N-dimethylformamide dimethyl acetal (DMA) was added to a solution of 2, 4-dihydroxyacetophenone in Dimethylformamide (DMF) and the mixture was refluxed on a water separator for 24 hours. Removal of the solvent and conventional work-up to give ("1")

3.A solution of 500mg of "1" and 428.5mg of (3-nitrophenyl) hydrazine hydrochloride in 20ml of ethanol is refluxed for 16 hours. Removal of the solvent and conventional work-up to give "A1", retention time [ min. ]]Is 1.776, M + H⁺[m/e]312.30;

the following compounds were obtained in a similar manner:

5- (2-hydroxy-4-methyl-5-chlorophenyl) -1-phenyl-1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3, 5-dichlorophenyl) -1H-pyrazole, retention time [ min]Is 2.251, M + H⁺[m/e]324.15;

5- (2-hydroxy-4-fluorophenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazole, retention time [ min]Is 1.843, M + H⁺[m/e]324.15;

5- (2-hydroxy-4-fluorophenyl) -1- (2-chloro-5-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 2.068, M + H⁺[m/e]357.71;

5- (2-hydroxy-4-fluorophenyl) -1- (2-ethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.917, M + H⁺[m/e]283.32;

5- (2-hydroxy-4-fluorophenyl) -1- (3-methoxyphenyl) -1H-pyrazole, retention time [ min]Is 1.755, M + H⁺[m/e]285.29;

5- (2-hydroxy-4-fluorophenyl) -1- (3-cyanophenyl) -1H-pyrazole, Retention time [ min]Is 1.731, M + H⁺[m/e]280.27;

5- (2-hydroxy-4-fluorophenyl) -1- (3-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 2.067, M + H⁺[m/e]323.26;

5- (2-hydroxy-4-fluorophenyl) -1- (3-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.965, M + H⁺[m/e]289.71;

5- (2-hydroxy-4-fluorophenyl) -1- (3-fluorophenyl) -1H-pyrazole, Retention time [ min]Is 1.823, M + H⁺[m/e]273.25;

5- (2-hydroxy-4-fluorophenyl) -1-phenyl-1H-pyrazole, Retention time [ min]Is 1.729, M + H⁺[m/e]255.26;

5- (2-hydroxy-4-fluorophenyl) -1- (4-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 2.090, M + H⁺[m/e]323.26;

5- (2-hydroxy-4-fluorophenyl) -1- (4-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.962, M + H⁺[m/e]289.71;

5- (2-hydroxy-4-fluorophenyl) -1- (4-aminosulfonylphenyl) -1H-pyrazole, retention time [ min]Is 1.376, M + H⁺[m/e]334.34;

5- (2-hydroxy-4-fluorophenyl) -1- (4-carboxyphenyl) -1H-pyrazole, retention time [ min]Is 1.472, M + H⁺[m/e]299.27;

5- (2-hydroxy-4-fluorophenyl) -1- (4-cyanophenyl) -1H-pyrazole, safenerRetention time [ min ]]Is 1.758, M + H⁺[m/e]280.27;

5- (2-hydroxy-4-fluorophenyl) -1- (4-methoxyphenyl) -1H-pyrazole, retention time [ min]Is 1.734, M + H⁺[m/e]285.29;

5- (2-hydroxy-4-fluorophenyl) -1- (3-chloro-4-methylphenyl) -1H-pyrazole, Retention time [ min]Is 2.095, M + H⁺[m/e]303.74;

5- (2-hydroxy-4-fluorophenyl) -1- (4-methylphenyl) -1H-pyrazole, Retention time [ min]Is 1.865, M + H⁺[m/e]269.29;

5- (2-hydroxy-4-fluorophenyl) -1- (4-bromophenyl) -1H-pyrazole, Retention time [ min]Is 2.009, M + H⁺[m/e]334.16;

5- (2-hydroxy-4-fluorophenyl) -1- (2-methoxyphenyl) -1H-pyrazole, retention time [ min]Is 1.601, M + H⁺[m/e]285.29;

5- (2-hydroxy-4-fluorophenyl) -1- (2-fluorophenyl) -1H-pyrazole, Retention time [ min]Is 1.667, M + H⁺[m/e]273.25;

5- (2-hydroxy-4-fluorophenyl) -1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.753, M + H⁺[m/e]289.71;

5- (2-hydroxy-4-fluorophenyl) -1- (2, 6-difluorophenyl) -1H-pyrazole, retention time [ min]Is 1.702, M + H⁺[m/e]Is 291.24.

Example 2

Preparation of 5- (2, 4-dihydroxyphenyl) -1- (3-nitrophenyl) -1H-pyrazole ("A2"):

124mg of "A1" were dissolved in 3ml of dichloromethane and the solution was cooled to-10 ℃. Then, a solution of 0.475ml of boron tribromide in 2ml of dichloromethane was added dropwise, and the mixture was stirred for a further 16 hours. Conventional work-up was carried out to give 77mg of "A2", retention time [ min. ]]Is 1.418, M + H⁺[m/e]Is 298.27.

Example 3

The compound 5- (2-hydroxy-4-methoxyphenyl) -1- (4-nitrophenyl) -1H-pyrazole ("A3"), having a retention time of [ min ], was obtained in analogy to example 1]Is 1.789, M + H⁺[m/e]Is 312.30.

Reduction of the nitro group in "A3" with 5% Pd/C and hydrogen in tetrahydrofuran under standard conditions and removal of catalyst and solvent gave 5- (2-hydroxy-4-methoxyphenyl) -1- (4-aminophenyl) -1H-pyrazole ("A4"), retention time [ min. ]]Is 0.826, M + H⁺[m/e]Is 282.31.

Obtained by a similar method

5- (2-hydroxy-4-methoxyphenyl) -1- (2-nitrophenyl) -1H-pyrazole

Reducing it to obtain

5- (2-hydroxy-4-methoxyphenyl) -1- (2-aminophenyl) -1H-pyrazole, retention time [ min]Is 1.123, M + H⁺[m/e]Is 282.31.

Example 4

Analogously to example 2, 5- (2-hydroxy-4-methoxyphenyl) -1- (4-aminophenyl) -1H-pyrazole ("A4") was ethercleaved to give the compound 5- (2, 4-dihydroxyphenyl) -1- (4-aminophenyl) -1H-pyrazole ("A5"), a retention time of [ min. ]]Is 0.537, M + H⁺[m/e]Is 268.29.

Example 5

In analogy to example 1, 367.5mg of "1" was reacted with 500mg of (2-fluorophenyl) hydrazine hydrochloride to give the compound 5- (2-hydroxy-4-methoxyphenyl) -1- (2-fluorophenyl) -1H-pyrazole ("a 6").

"A6" was ethercleaved in analogy to example 2 to give the compound 5- (2, 4-dihydroxyphenyl) -1- (2-fluorophenyl) -1H-pyrazole ("A7"), retention time [ min]Is 1.191, M + H⁺[m/e]Is 271.26.

In a similar manner to example 1, the following compounds were obtained:

5- (2-hydroxy-4-methoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.725, M + H⁺[m/e]301.74;

5- (2-hydroxy-4-methoxyphenyl) -1- (2, 4-difluorophenyl) -1H-pyrazole, retention time [ min]Is 1.683, M + H⁺[m/e]303.28;

5- (2-hydroxy-4-methoxyphenyl) -1- (3, 5-dichlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-chloro-2-cyanophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazole, retention time [ min]Is 1.756, M + H⁺[m/e]336.19;

5- (2-hydroxy-4-methoxyphenyl) -1- (2-chloro-5-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.999, M + H⁺[m/e]369.74;

5- (2-hydroxy-4-methoxyphenyl) -1- (2-ethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.830, M + H⁺[m/e]295.35;

5- (2-hydroxy-4-methoxyphenyl) -1- (3-methoxyphenyl) -1H-pyrazole, retention time [ min ]]Is 1.680, M + H⁺[m/e]297.33;

5- (2-hydroxy-4-methoxyphenyl) -1- (3-cyanophenyl) -1H-pyrazole, retention time [ min]Is 1.650, M + H⁺[m/e]292.31;

5- (2-hydroxy-4-methoxyphenyl) -1- (3-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 2.002, M + H⁺[m/e]335.30;

5- (2-hydroxy-4-methoxyphenyl) -1- (3-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.852, M + H⁺[m/e]301.74;

5- (2-hydroxy-4-methoxyphenyl) -1- (3-carboxyphenyl) -1H-pyrazole, Retention time [ min ]]Is 1.371, M + H⁺[m/e]311.31;

5- (2-hydroxy-4-methoxyphenyl) -1- (3-fluorophenyl) -1H-pyrazole, retention time [ min]Is 1.725, M + H⁺[m/e]285.29;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-bromophenyl) -1H-pyrazole, Retention time [ min]Is 1.921, M + H⁺[m/e]346.20;

5- (2-hydroxy-4-methoxyphenyl) -1-phenyl-1H-pyrazole, retention time [ min]Is 1.601, M + H⁺[m/e]267.30;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.997, M + H⁺[m/e]335.30;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.887, M + H⁺[m/e]301.74;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-aminosulfonylphenyl) -1H-pyrazole, retention time [ min]Is 1.309, M + H⁺[m/e]346.38;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-carboxyphenyl) -1H-pyrazole, retention time [ min]Is 1.409, M + H⁺[m/e]311.31;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-cyanophenyl) -1H-pyrazole, retention time [ min]Is 1.661, M + H⁺[m/e]292.31;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-methoxyphenyl) -1H-pyrazole, retention time [ min]Is 1.600, M + H⁺[m/e]297.33;

5- (2-hydroxy-4-methoxyphenyl) -1- (3-chloro-4-methylphenyl) -1H-pyrazole, retention time [ min]Is 2.002, M + H⁺[m/e]315.77;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-methylphenyl) -1H-pyrazole, retention time [ min ]]Is 1.726, M + H⁺[m/e]281.33;

5- (2-hydroxy-4-methoxyphenyl) -1- (2, 6-difluorophenyl) -1H-pyrazole, retention time [ min]Is 1.540, M + H⁺[m/e]303.28;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-cyano-2-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-trifluoromethyl-2-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-nitrophenyl) -1H-pyrazole, retention time [ min]Is 1.509, M + H⁺[m/e]312.30;

5- (2-hydroxy-4-methoxyphenyl) -1- (4-ethoxycarbonylphenyl) -1H-pyrazole, retention time [ min]Is 1.899, M + H⁺[m/e]339.36;

5- (2-hydroxy-4-methoxyphenyl) -1- (2-aminophenyl) -1H-pyrazole,

subjecting it to ether cleavage to give the following compounds

5- (2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.548, M + H⁺[m/e]287.72;

5- (2, 4-dihydroxyphenyl) -1- (2, 4-difluorophenyl) -1H-pyrazole, Retention time [ min]Is 1-288, M + H⁺[m/e]289.25;

5- (2, 4-dihydroxyphenyl) -1- (3, 5-dichlorophenyl) -1H-pyrazole, retention time [ min]Is 1.807, M + H⁺[m/e]322.16;

5- (2, 4-dihydroxyphenyl) -1- (3-chloro-2-cyanophenyl) -1H-pyrazole, Retention time [ min]Is 1.726, M + H⁺[m/e]312.73;

5- (2, 4-dihydroxyphenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazole, retention time [ min]Is 1.356, M + H⁺[m/e]322.16;

5- (2, 4-dihydroxyphenyl) -1- (2-chloro-5-trifluoromethylphenyl) -1H-pyraneAzole, Retention time [ min ]]Is 1.641, M + H⁺[m/e]355.71;

5- (2, 4-dihydroxyphenyl) -1- (2-ethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.439, M + H⁺[m/e]281.33;

5- (2, 4-dihydroxyphenyl) -1- (3-hydroxyphenyl) -1H-pyrazole, Retention time [ min]Is 0.984, M + H⁺[m/e]269.27;

5- (2, 4-dihydroxyphenyl) -1- (3-cyanophenyl) -1H-pyrazole, Retention time [ min]Is 1.296, M + H⁺[m/e]278.28;

5- (2, 4-dihydroxyphenyl) -1- (3-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.665, M + H⁺[m/e]321.27;

5- (2, 4-dihydroxyphenyl) -1- (3-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.506, M + H⁺[m/e]287.72;

5- (2, 4-dihydroxyphenyl) -1- (3-carboxyphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-fluorophenyl) -1H-pyrazole, Retention time [ min]Is 1.360, M + H⁺[m/e]271.26;

5- (2, 4-dihydroxyphenyl) -1- (4-bromophenyl) -1H-pyrazole, Retention time [ min]Is 1.545, M + H⁺[m/e]332.17;

5- (2, 4-dihydroxyphenyl) -1-phenyl-1H-pyrazole, Retention time [ min]Is 1.217, M + H⁺[m/e]253.27;

5- (2, 4-dihydroxyphenyl) -1- (4-trifluoromethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.687, M + H⁺[m/e]321.27;

5- (2, 4-dihydroxyphenyl) -1- (4-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.506, M + H⁺[m/e]287.72;

5- (2, 4-dihydroxyphenyl) -1- (4-aminosulfonylphenyl) -1H-pyrazole, with retentionTime [ min ]]Is 0.936, M + H⁺[m/e]332.35;

5- (2, 4-dihydroxyphenyl) -1- (4-carboxyphenyl) -1H-pyrazole, retention time [ min]Is 1.051, M + H⁺[m/e]297.28;

5- (2, 4-dihydroxyphenyl) -1- (4-cyanophenyl) -1H-pyrazole, Retention time [ min]Is 1.325, M + H⁺[m/e]278.28;

5- (2, 4-dihydroxyphenyl) -1- (4-hydroxyphenyl) -1H-pyrazole, Retention time [ min]Is 0.907, M + H⁺[m/e]269.27;

5- (2, 4-dihydroxyphenyl) -1- (3-chloro-4-methylphenyl) -1H-pyrazole, Retention time [ min]Is 1.638, M + H⁺[m/e]301.74;

5- (2, 4-dihydroxyphenyl) -1- (4-methylphenyl) -1H-pyrazole, Retention time [ min]Is 1.384, M + H⁺[m/e]267.30;

5- (2, 4-dihydroxyphenyl) -1- (2, 6-difluorophenyl) -1H-pyrazole, Retention time [ min]Is 1.175, M + H⁺[m/e]289.25;

5- (2, 4-dihydroxyphenyl) -1- (4-cyano-2-nitrophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-trifluoromethyl-2-nitrophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2-nitrophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-ethoxycarbonylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2-aminophenyl) -1H-pyrazole, Retention time [ min]Is 0.903, M + H⁺[m/e]268.29;

5- (2, 4-dihydroxyphenyl) -1- (2-methylphenyl) -1H-pyrazole, Retention time [ min]Is 1.498, M + H⁺[m/e]267.30;

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-aminobenzene)Radical) -1H-pyrazole, retention time [ min]Is 1.478, M + H⁺[m/e]347.19;

5- (2, 4-dihydroxyphenyl) -1- (3-aminophenyl) -1H-pyrazole, Retention time [ min]Is 0.806, M + H⁺[m/e]268.29;

5- (2, 4-dihydroxy-5-bromophenyl) -1- (3-aminophenyl) -1H-pyrazole, M + H⁺[m/e]347.19;

5- (2, 4-dihydroxyphenyl) -1- (3-methylphenyl) -1H-pyrazole, Retention time [ min]Is 1.547, M + H⁺[m/e]267.30;

5- (2, 4-dihydroxyphenyl) -1- (2-carboxyphenyl) -1H-pyrazole, retention time [ min]0.95, M + H⁺[m/e]297.28;

5- (2, 4-dihydroxyphenyl) -1- (4-fluorophenyl) -1H-pyrazole, Retention time [ min]Is 1.437, M + H⁺[m/e]271.26;

5- (2, 4-dihydroxy-5-bromophenyl) -1- (4-fluorophenyl) -1H-pyrazole, Retention time [ min]Is 1.809, M + H⁺[m/e]350.16;

5- (2, 4-dihydroxy-5-bromophenyl) -1- (3-methylphenyl) -1H-pyrazole, M + H⁺[m/e]Is 346.20.

The following compounds were obtained in a similar manner

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.599, M + H⁺[m/e]366.62;

5- (2, 4-dihydroxy-5-chlorophenyl) -1- (2-fluorophenyl) -1H-pyrazole, Retention time [ min]Is 1.511, M + H⁺[m/e]305.71;

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-ethylphenyl) -1H-pyrazole, Retention time [ min]Is 1.659, M + H⁺[m/e]Is 360.23.

Example 6

1. N, N-dimethylformamide dimethyl acetal (DMA) was added to a solution of 2, 4-dimethoxyacetophenone in Dimethylformamide (DMF) and the mixture was refluxed on a water separator for 24 hours. Removal of the solvent and work-up to give ("1 a")

2. A solution of 7.0g of "1 a" and 4.68g of (4-nitrophenyl) hydrazine in 100ml of ethanol is refluxed for 16 hours. The solvent was removed and a conventional work-up was carried out to give 6.6g of 5- (2, 4-dimethoxyphenyl) -1- (4-nitrophenyl) -1H-pyrazole ("A8").

3. In analogy to example 3, this was reduced with hydrogen over Pd/C to give the compound 5- (2, 4-dimethoxyphenyl) -1- (4-aminophenyl) -1H-pyrazole ("A9").

4. The reaction of "a 9" was carried out with the following acid chlorides under standard acylation conditions:

the presence of a benzoyl chloride (I) in the composition,

the reaction solution is prepared by the reaction of acetyl chloride,

the propionyl chloride is used for the reaction of propionyl chloride,

the butyryl chloride is used as a raw material,

the presence of pyridine-4-carbonyl chloride,

phenylacetyl chloride

The following N-acyl compounds are obtained

5- (2, 4-dimethoxyphenyl) -1- (4-benzoylaminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- (4-acetylaminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- (4-propionylaminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- [4- (butyrylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- [4- (pyridin-4-ylcarbonylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- [4- (phenylacetylamino) phenyl ] -1H-pyrazole.

5. This was subjected to ether cleavage in analogy to example 2 to give the following compounds

5- (2, 4-dihydroxyphenyl) -1- (4-benzoylaminophenyl) -1H-pyrazole, Retention time [ min]Is 1.734, M + H⁺[m/e]372.40;

5- (2, 4-dihydroxyphenyl) -1- (4-acetylaminophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-propionylaminophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (butyrylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (pyridin-4-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.012, M + H⁺[m/e]373.38;

5- (2, 4-dihydroxyphenyl) -1- [4- (phenylacetylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.495, M + H⁺[m/e]Is 386.42

The following compounds were obtained in a similar manner

5- (2, 4-dihydroxyphenyl) -1- (3-benzoylaminophenyl) -1H-pyrazole, Retention time [ min]Is 1.427, M + H⁺[m/e]372.40;

5- (2, 4-dihydroxyphenyl) -1- [4- (pyridin-3-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.214, M + H⁺[m/e]373.38;

5- (2, 4-dihydroxyphenyl) -1- [3- (pyridin-2-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.683, M + H⁺[m/e]373.38;

5- (2, 4-dihydroxyphenyl) -1- [4- (pyridin-2-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.669, M + H⁺[m/e]373.38;

5- (2, 4-dihydroxyphenyl) -1- [3- (pyridin-3-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.205, M + H⁺[m/e]373.38;

5- (2, 4-dihydroxyphenyl) -1- [3- (pyridin-4-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.210, M + H⁺[m/e]373.38;

5- (2, 4-dihydroxyphenyl) -1- [4- (methoxyethylcarbonylamino) phenyl]-1H-pyrazole, M + H⁺[m/e]354.38;

5- (2, 4-dihydroxyphenyl) -1- [2- (pyridin-3-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.159, M + H⁺[m/e]373.38;

5- (2, 4-dihydroxyphenyl) -1- (2-benzoylaminophenyl) -1H-pyrazole, Retention time [ min]Is 1.875, M + H⁺[m/e]372.40;

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-benzoylaminophenyl) -1H-pyrazole, Retention time [ min]Is 2.120, M + H⁺[m/e]451.30;

5- (2, 4-dihydroxyphenyl) -1- [2- (benzylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.820, M + H⁺[m/e]386.42;

5- (2, 4-dihydroxy-5-bromophenyl) -1- [2- (benzylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 2.079, M + H⁺[m/e]465.32;

5- (2, 4-dihydroxyphenyl) -1- [2- (pyridin-4-ylcarbonylamino) phenyl]-1H-pyrazole, retention time [ min. ]]Is 1.148, M + H⁺[m/e]Is 373.38.

Example 7

It may also be advantageous to replace the methyl group in "1 a" with a benzyl group as the hydroxy-protecting group.

Alternatively, acetyl or p-methoxybenzyl may be used.

1. N, N-dimethylformamide dimethyl acetal (DMA) was added to a solution of 2, 4-dibenzyloxyacetophenone in Dimethylformamide (DMF) and the mixture was refluxed on a water separator for 24 hours. Removal of the solvent and work-up to give ("1 b")

2. A solution of "1 b" and (4-carboxyphenyl) hydrazine in ethanol was refluxed for 16 hours. The solvent was removed and conventional work-up was carried out to give 5- (2, 4-dibenzyloxyphenyl) -1- (4-carboxyphenyl) -1H-pyrazole ("A10").

This was reacted with thionyl chloride under standard conditions to give 5- (2, 4-dibenzyloxyphenyl) -1- (4-chlorocarbonylphenyl) -1H-pyrazole ("A11").

Reaction of "a 11" with the following amines under standard conditions:

a group of benzylamines which is capable of reacting with an amine,

the reaction product of a methylamine and a methylamine,

an ethylamine which is a mixture of at least two of ethylene amine,

the amino acid is a compound of propylamine,

the following N-acyl compounds are obtained

5- (2, 4-dibenzyloxyphenyl) -1- [4- (benzylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- [4- (methylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- [4- (ethylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- [4- (propylaminocarbonyl) phenyl ] -1H-pyrazole.

Analogously to example 3, the ether cleavage was carried out with hydrogen on Pd/C. The following compounds were obtained

5- (2, 4-dihydroxyphenyl) -1- [4- (benzylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (methylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (ethylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (propylaminocarbonyl) phenyl ] -1H-pyrazole.

Example 8

Synthetic schemes for the preparation of sulfonamide derivatives

Preparation of 5- (5-aminosulfonyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole ("C3

8.1. 18.0g of 5- (2, 4-dimethoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole ("B1"; obtainable in a similar manner to example 1) are added at-5 ℃ to 30ml of chlorosulfonic acid and the mixture is stirred at room temperature for a further 3 hours. The mixture was poured onto ice and the crystals precipitated were isolated and washed with water to give 23.6g of 5- (5-chlorosulfonyl-2, 4-dimethoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole ("B2").

8.2. 20ml of a 32% aqueous ammonia solution are added to a solution of 413.3mg of "B2" in 5ml of dry methanol at room temperature. The mixture was stirred overnight, about half of the solvent was removed, and the precipitated crystals were isolated and washed with water to give 230mg of 5- (5-aminosulfonyl-2, 4-dimethoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole ("C1"), and 5- (5-hydroxysulfonyl-2, 4-dimethoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole ("C2") as a by-product.

8.3. 450mg of "C1" were dissolved in 5ml of dichloromethane under a nitrogen atmosphere and the solution was cooled to-20 ℃ in a dry ice bath. Then, 1ml of boron tribromide was slowly added dropwise through the septum with a syringe, and the mixture was stirred at room temperature for another 16 hours.

The mixture was cooled to-20 °, methanol was added dropwise and finally a drop of water was added dropwise. The solvent was removed at room temperature and the residue was dissolved in 2ml of methanol.

Separating with a CombiFlash COMPANION instrument through 130g RP-18 column to obtain 122mg of "C3", and retaining time [ min ]]Is 0.837, M + H⁺[m/e]Is 366.79.

"B2" was subjected to a similar reaction with:

N-ethyl-N' -methyl amine is used,

n, N' -diethylamine is used as the solvent,

a piperidine compound,

the reaction mixture of aniline,

2-fluoroaniline, a compound of formula (I),

the 3-fluoroaniline compound is a compound of formula (I),

4-fluoroaniline, in the presence of a compound of formula (I),

3-amino-pyridine, and a pharmaceutically acceptable salt thereof,

3-hydroxy-methyl-piperidine, which is a compound of the formula,

N-benzyl-N' -methylamine,

n, N '-dimethylamine, which is a salt of N, N' -dimethylamine,

n- (2-hydroxyethyl) -N' -methylamine,

N-cyclohexyl-N' -methylamine,

3-methylamino-1, 2-propanediol,

N-butyl-N' -methylamine in the presence of a catalyst,

N-propyl-N' -methylamine is used,

n- (2-cyanoethyl) -N' -methylamine,

N-isopropyl-N' -methylamine,

n, N '-dimethyl-2-methylaminoacetamide (sarcosine-N, N' -dimethylamide),

2-hydroxy-methyl-piperidine which is a compound of the formula,

a morpholine,

2- (N, N' -diethylaminomethyl) piperidine,

1-methyl piperazine and a salt thereof,

the reaction product of a methylamine and a methylamine,

4-aminopyridines

To obtain the compound

5- [5- (N-ethyl-N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N, N' -diethylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (piperidine-1-sulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-phenylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (2-fluorophenyl) aminosulfonyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (3-fluorophenyl) aminosulfonyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (4-fluorophenyl) aminosulfonyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (pyridin-3-yl) aminosulfonyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (3-hydroxymethylpiperidine-1-sulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-benzyl-N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N, N' -dimethylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N- (2-hydroxyethyl) -N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-cyclohexyl-N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N- (2, 3-dihydroxypropyl) -N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-butyl-N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N- (2-cyanoethyl) -N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-isopropyl-N' -methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (dimethylaminocarbonylmethyl) -N' -methylaminosulfonyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (2-hydroxymethylpiperidine-1-sulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (morpholine-4-sulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (N, N' -diethylaminomethyl) piperidin-4-yl ] sulfonyl } -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (1-methylpiperazin-4-yl) sulfonyl ] -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-methylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (pyridin-4-yl) aminosulfonyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

subjecting it to ether cleavage to obtain a compound

5- [5- (N-Ethyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.367, M + H⁺[m/e]408.88;

5- [5- (N-N' -diethylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.468, M + H⁺[m/e]422.90;

5- [5- (piperidine-1-sulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.558, M + H⁺[m/e]434.91;

5- [5- (N-phenylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.620, M + H⁺[m/e]Is 442.89 and

5- [5- (N-phenylaminosulfonyl) -2-hydroxy-4-methoxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, M + H⁺[m/e]456.92;

5- {5- [ N- (2-fluorophenyl) aminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.475, M + H⁺[m/e]460.88;

5- {5- [ N- (3-fluorophenyl) aminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retentionTime [ min ]]Is 1.502, M + H⁺[m/e]460.88;

5- {5- [ N- (4-fluorophenyl) aminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.478, M + H⁺[m/e]460.88;

5- {5- [ N- (pyridin-3-yl) aminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 0.923, M + H⁺[m/e]443.99;

5- [5- (3-Hydroxymethylpiperidine-1-sulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.176, M + H⁺[m/e]Is 464.94 and

5- [5- (3-bromomethylpiperidine-1-sulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, M + H⁺[m/e]527.84;

5- [5- (N-benzyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.710, M + H⁺[m/e]Is 470.95 and

5- [5- (N-benzyl-N' -methylaminosulfonyl) -2-methoxy-4-hydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-N' -dimethylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.234, M + H⁺[m/e]394.85;

5- [5- (N- (2-bromoethyl) -N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.483, M + H⁺[m/e]487.78;

5- [5- (N-cyclohexyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.738, M + H⁺[m/e]462.97;

5- [5- (N- (2, 3-dibromopropyl) -N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.694, M + H⁺[m/e]580.70;

5- [5- (N-butyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.665, M + H⁺[m/e]436.93;

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.511, M + H⁺[m/e]422.90;

5- {5- [ N- (2-cyanoethyl) -N' -methylaminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.271, M + H⁺[m/e]433.89;

5- [5- (N-isopropyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.412, M + H⁺[m/e]422.90;

5- {5- [ N- (dimethylaminocarbonylmethyl) -N' -methylaminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.044, M + H⁺[m/e]465.93;

5- [5- (2-Hydroxymethylpiperidine-1-sulfonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.159, M + H⁺[m/e]464.94;

5- [5- (morpholine-4-sulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole and

5- {5- [ N- (2-hydroxyethyl) -N' - (2-bromoethyl) aminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.250, M + H⁺[m/e]Is 517.80 and

5- {5- [ N- (2-hydroxyethyl) -N' - (2-bromoethyl) aminosulfonyl ] -2-hydroxy-4-methoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole;

5- {5- [2- (N, N' -diethylaminomethyl) piperidin-4-yl]Sulfonyl } -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole,retention time [ min ]]Is 0.967, M + H⁺[m/e]520.06;

5- [5- (1-methylpiperazin-4-yl) sulfonyl group]-2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 0.848, M + H⁺[m/e]449.93;

5- [5- (N-methylaminosulfonyl) -2, 4-hydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.011, M + H⁺[m/e]380.82;

5- {5- [ N- (pyridin-4-yl) aminosulfonyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 0.784, M + H⁺[m/e]Is 443.88.

In a similar way, the compound is obtained

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.441, M + H⁺[m/e]402.48;

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-fluorophenyl) -1H-pyrazole, retention time [ min]Is 1.395, M + H⁺[m/e]Is 406.45.

Example 9

In analogy to example 8, 5- (5-chlorosulfonyl-2, 4-dimethoxyphenyl) -1- (2-methylphenyl) -1H-pyrazole ("D1") was reacted with the following substance:

the reaction mixture of aniline,

a group of benzylamines which is capable of reacting with an amine,

n, N' -diethylamine is used as the solvent,

an ethylamine which is a mixture of at least two of ethylene amine,

the amount of ammonia is such that the ammonia,

to obtain the compound

5- [5- (N-phenylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N-benzylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N, N' -diethylaminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (ethylamino sulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (aminosulfonyl) -2, 4-dimethoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

subjecting it to ether cleavage to obtain a compound

5- [5- (N-phenylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.438, M + H⁺[m/e]Is 422.47 and

5- [5- (N-phenylaminosulfonyl) -2-hydroxy-4-methoxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.662, M + H⁺[m/e]436.50;

5- [5- (N-benzylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.483, M + H⁺[m/e]Is 436.50 and

5- [5- (N-benzylaminosulfonyl) -2-hydroxy-4-methoxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.702, M + H⁺[m/e]436.50;

5- [5- (N, N' -diethylaminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.497, M + H⁺[m/e]Is 402.48 and

5- [5- (N, N' -diethylaminosulfonyl) -2-hydroxy-4-methoxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.790, M + H⁺[m/e]416.51;

5- [5- (ethylamino sulfonyl) -2, 4-dihydroxy phenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.423, M + H⁺[m/e]Is 374.43 and

5- [5- (ethylamino sulfonyl) -2-hydroxy-4-methoxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.156, M + H⁺[m/e]388.46;

5- [5- (aminosulfonyl) -2, 4-dihydroxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.573, M + H⁺[m/e]Is 346.38 and

5- [5- (aminosulfonyl) -2-hydroxy-4-methoxyphenyl]-1- (2-methylphenyl) -1H-pyrazole, retention time [ min]Is 1.864, M + H⁺[m/e]Is 360.40.

Example 10

General scheme for the preparation of iodine compounds of formula I

Preparation of 5- [ 5-iodo-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole:

10.1. to a solution of 90.1g of 2, 4-dimethoxyacetophenone in 2.5L of acetonitrile was added 63.45g of iodine at room temperature, followed by 88.57g of Selectfluor, and the mixture was stirred for a further 2.5 hours. Conventional work-up and crystallization from 400ml of methanol gave 166g of 2, 4-dimethoxy-5-iodoacetophenone ("E1").

10.2. A mixture of 18.3g of "E1" and 50ml of N, N-dimethylformamide dimethyl acetal was refluxed (170 ℃ C.) on a water separator for 16 hours. The solvent was separated off, 100ml of MTB ether was added, and the catalyst was separated off to give 15.5g of (E) -3-dimethylamino-1- (5-iodo-2, 4-dimethoxyphenyl) propenone ("E2").

10.3. A solution of 8.05g of "E2" and 4.0g of (2-chlorophenyl) hydrazine hydrochloride in 50ml of ethanol is refluxed for 16 hours. The reaction mixture was purified by chromatography (ISCO/330g column; petroleum ether/ethyl acetate: 10/90 to 1/1) to give 8.4g of 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E2 a").

The boron tribromide is used for ether cleavage to obtain 5- [ 5-iodine-2, 4-dihydroxyphenyl ] -1- (2-chlorphenyl) -1H-pyrazole.

A similar reaction between "E2" and (2-fluorophenyl) hydrazine gave the compound 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole ("E3 a"),

subjecting it to ether cleavage to obtain

5- [ 5-iodo-2, 4-dihydroxyphenyl]-1- (2-fluorophenyl) -1H-pyrazole ("E3"), M + H⁺[m/e]Is 397.16.

Example 11

General scheme for the preparation of Compounds of formula I by Heck reaction

11-A

Preparation of 5- [ 5-carboxyethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole and 5- [ 5-methoxycarbonylethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole:

a.1. a mixture of 1.061g "E3 a", 250.29mg ethyl acrylate, 0.7ml triethylamine, 22.45mg palladium (II) acetate (47% Pd), 30.74mg tri-o-tolylphosphine and 5ml acetonitrile was irradiated in a microwave at 160 ° for 30 minutes. Toluene was added to the reaction mixture, which was extracted with water several times. The organic phase was dried and evaporated. The product was purified by chromatography (ISCO/40g column; petroleum ether/ethyl acetate: 4/1 to 1/1) to yield 0.7g of 3- {5- [2- (2-fluorophenyl) -2H-pyrazol-3-yl ] -2, 4-dimethoxyphenyl } acrylic acid ethyl ester ("E4") as an isomer mixture (E/Z) in a proportion of 95/5;

11.A.2. A mixture of 383mg of "E4", 400mg of 5% Pd/C (56% water) and 10ml of THF was hydrogenated at 1.4 bar and room temperature for 16 h in a B * CHI apparatus. The catalyst was removed and the solvent was removed to give 398.4mg of 5- [5- (2-ethoxycarbonylethyl) -2, 4-dimethoxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole ("E5").

Ether cleavage in analogy to example 8.3 to yield 73mg of 5- [5- (2-carboxyethyl) -2, 4-dihydroxyphenyl]-1- (2-fluorophenyl) -1H-pyrazole, M + H⁺[m/e]Is 343.33

And

356mg of 5- [5- (2-methoxycarbonylethyl) -2, 4-dihydroxyphenyl]-1- (2-fluorophenyl) -1H-pyrazole, M + H⁺[m/e]Is 357.35

A mixture of (a).

11.B

Analogously to example 11.A.1, ` E2a ` was reacted with styrene to give the compound 5- [ 5-styryl-2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E6 `)

Hydrogenation of "E6" to give the compound 5- [5- (2-phenylethyl) -2, 4-dimethoxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, which is subjected to ether cleavage to give the compound 5- [5- (2-phenylethyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.872, M + H⁺[m/e]Is 391.87.

Carrying out a similar reaction to give a compound

5- [ 5-styryl-2, 4-dimethoxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

hydrogenating it to give 5- [5- (2-phenylethyl) -2, 4-dimethoxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole, and subjecting it to ethereal cleavage to give

5- [5- (2-phenylethyl) -2, 4-dihydroxyphenyl]-1- (2-fluorophenyl) -1H-pyrazole, M + H⁺[m/e]Is 375.41.

In the ether cleavage process, the compound 5- [5- (2-phenyl-2-methoxyethyl) -2, 4-dihydroxyphenyl group is formed as a by-product]-1- (2-fluorophenyl) -1H-pyrazole, M + H⁺[m/e]Is 405.44.

Reacting 5- [ 5-styryl-2, 4-dimethoxyphenyl]Subjecting the (E) -1- (2-fluorophenyl) -1H-pyrazole to ether cleavage to obtain 5- [ 5-styryl-2, 4-dihydroxyphenyl]-1- (2-fluorophenyl) -1H-pyrazole, M + H⁺[m/e]Is 373.40.

11.C

C.1. in analogy to example 11.a.1., "E2 a" was reacted with 4-vinylpyridine to give the compound 5- {5- [2- (pyridin-4-yl) vinyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole ("E7").

C.2 hydrogenation of "E7" with 5% Pt/C as catalyst gave the compound 5- {5- [2- (pyridin-4-yl) ethyl]-2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, which was subjected to ether cleavage to give the compound 5- {5- [2- (pyridin-4-yl) ethyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.397, M + H⁺[m/e]Is 392.86.

"E7" was subjected to ether cleavage to give the compound 5- {5- [2- (pyridin-4-yl) vinyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

11.D

A similar reaction was carried out with 2-vinylpyridine "E2 a" to give the compound 5- {5- [2- (pyridin-2-yl) vinyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole ("E8").

Hydrogenation thereof and subsequent ether cleavage gave the compound 5- {5- [2- (pyridin-2-yl) ethyl]-2, 4-bisHydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 0.702, M + H⁺[m/e]Is 392.86.

11.E

"E2 a" was reacted similarly with 4-fluorostyrene to give the compounds 5- [5- (4-fluorostyryl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E9") and 5- {5- [1- (4-fluorophenyl) vinyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

Hydrogenation of "E9" followed by ether cleavage gave the compound 5- {5- [2- (4-fluorophenyl) ethyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.882, M + H⁺[m/e]Is 409.86.

11.F

"E2 a" was reacted similarly with 3-fluorostyrene to give the compounds 5- [5- (3-fluorostyryl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E10") and 5- {5- [1- (3-fluorophenyl) vinyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

Hydrogenation of "E10" followed by ether cleavage gave the compound 5- {5- [2- (3-fluorophenyl) ethyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.895, M + H⁺[m/e]Is 409.86.

11.G

"E2 a" was reacted similarly with 2-fluorostyrene to give the compounds 5- [5- (2-fluorostyryl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E11") and 5- {5- [1- (2-fluorophenyl) vinyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

Hydrogenation of "E11" followed by ether cleavage gave the compound 5- {5- [2- (2-fluorophenyl) ethyl]-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole, retention time [ min]Is 1.866, M + H⁺[m/e]Is 409.86.

11.H

700mg of "E9" were hydrogenated in 1.8g of 5% Pt/C THF and after 30 hours, complete dechlorination was obtained in addition to the hydrogenation of the double bond. The catalyst was removed and the solvent was removed to give 470mg of 5- {5- [1- (4-fluorophenyl) ethyl ] -2, 4-dimethoxyphenyl } -1-phenyl-1H-pyrazole.

This was subjected to ether cleavage to give 5- {5- [1- (4-fluorophenyl) ethyl group]-2, 4-dihydroxyphenyl } -1-phenyl-1H-pyrazole, retention time [ min. ]]Is 1.874, M + H⁺[m/e]Is 375.41.

11.I

Similar reaction of "E2 a" with 3-nitrostyrene gave the compound 5- [5- (3-nitrostyrene) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E12").

Hydrogenation of "E12" affords the compound 5- {5- [2- (3-aminophenyl) ethyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole ("E13").

Acylation of "E13" with trifluoroacetyl chloride followed by ether cleavage gave the compound 5- {5- [2- (3-trifluoroacetylaminophenyl) ethyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

Reaction of "E13" with BOC-glycine followed by removal of its BOC group and also removal of the methyl ether gives

11.J

"E2 a" was subjected to a similar reaction with 3-carboxystyrene to give the compound 5- [5- (3-carboxystyrene) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole, which was hydrogenated to give 5- {5- [2- (3-carboxyphenyl) ethyl ] -2, 4-dimethoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole. Ether cleavage gave 5- {5- [2- (3-carboxyphenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

Example 12

12.1. The compound 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2, 3-dihydrobenzo-1, 4-dioxin-6-yl) -1H-pyrazole was obtained in a similar manner to example 10.

Analogously to example 11, this was reacted with 1-chloro-2-vinylbenzene, hydrogenated and subsequently ether-cleaved to give the compound 5- {5- [2- (2-chlorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2, 3-dihydrobenzo-1, 4-dioxin-6-yl) -1H-pyrazole

12.2. An analogous reaction of "2 a" with propylene, hydrogenation and ether cleavage gave the compound 5- { 5-propyl-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole

12.3. "E2 a" was reacted analogously with methylenecyclopropane, hydrogenated and ether cleaved to give the compound 5- { 5-cyclopropylmethyl-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

12.4. A similar reaction of 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (3-methylphenyl) -1H-pyrazole with 2-methyl-1-butene was carried out, hydrogenated and ether cleaved to give the compound 5- {5- (2-methylbutyl) -2, 4-dihydroxyphenyl } -1- (3-methylphenyl) -1H-pyrazole.

12.5. "E2 a" was reacted similarly with 2-fluoropropene, hydrogenated and ether cleaved to give the compound 5- {5- (2-fluoropropyl) -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

12.6. 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2, 3-dihydrobenzo-1, 4-dioxin-6-yl) -1H-pyrazole was subjected to a similar reaction with 4-vinyltoluene, hydrogenated and subjected to ether cleavage to give the compound 5- {5- [2- (4-methylphenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2, 3-dihydrobenzo-1, 4-dioxin-6-yl) -1H-pyrazole.

12.7. "E2 a" was reacted similarly with isopropenylbenzene, hydrogenated and ether cleaved to give the compound 5- {5- (2-phenylpropyl) -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole.

12.8. A similar reaction of 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2-nitrophenyl) -1H-pyrazole with isopropenylbenzene, hydrogenation and ether cleavage gave the compound 5- {5- (2-phenylpropyl) -2, 4-dihydroxyphenyl } -1- (2-aminophenyl) -1H-pyrazole.

Example 13

General reaction scheme for the preparation of compounds of formula I wherein the groups are defined as follows:

R²is represented by- (CH)₂)_r-X-(CH)_s-R，

R represents Ar or Het in the presence of a catalyst,

x represents NH, NA or O,

r represents a number of 1 s, and r represents a number of 1 s,

s represents 0 or 1:

13.A

a.1. A solution of 1g of "E2 a" in 10ml of THF was cooled to-70 ℃. 1.6ml of butyllithium (15% in n-hexane) are added dropwise, during which the temperature is maintained at-70 to-60 ℃. The mixture was stirred for an additional 30 minutes. Then, 0.25ml of N-formylpiperidine was added dropwise and the mixture was warmed to-15 ℃. Semi-concentrated (semi-concentrated) hydrochloric acid was added dropwise and the mixture was extracted with MTB ether. The organic phase was dried. The solvent was removed to give 5- [ 5-formyl-2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E2 b").

Use of BBr₃Subjecting "E2 b" to ether cleavage to obtain 5- [ 5-formyl-2, 4-dihydroxyphenyl ] compound]-1- (2-chlorophenyl) -1H-pyrazole ("E2 c").

Reaction of "E2 c" with aniline (Schiff base formation) to give the compound

Reduction of the double bond under standard conditions gives 5- [ 5-phenylaminomethyl-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole.

The compound 5- [ 5-phenylaminomethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole was obtained in a similar manner.

13.B

Etherification of "E2 c" with tert-butyldimethylsilyl chloride under standard conditions gave 5- [ 5-formyl-2, 4-di- (tert-butyldimethylsilyloxy) phenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("E2 d").

Using NaBH 13.B.2₄Reduction of the formyl group in "E2 d" under standard conditions gave 5- [ 5-hydroxymethyl-2, 4-di- (tert-butyldimethylsilyloxy) phenyl]-1- (2-chlorophenyl) -1H-pyrazole ("E2E").

B.3. A mixture of "E2E", phenol, triphenylphosphine and diethyl azodicarboxylate ("DEAD")The reaction is carried out in a Mitsunobu reaction to obtain the compound 5- [ 5-phenoxymethyl-2, 4-di- (tert-butyl dimethyl silicon alkoxy) phenyl]-1- (2-chlorophenyl) -1H-pyrazole.

This is ethercleaved with HCl in dioxane to give 5- [ 5-phenoxymethyl-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole.

The compound 5- [ 5-phenoxymethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole was obtained in a similar manner.

13.C

C.1. analogously to 13.B.3., "E2E" was mixed with thiophenol, PPh₃Reacting with DEAD to obtain 5- [ 5-phenylthiomethyl-2, 4-di- (tert-butyldimethylsilyloxy) phenyl]-1- (2-chlorophenyl) -1H-pyrazole, by ether cleavage to give 5- [ 5-phenylthiomethyl-2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole.

In a similar way, compounds are obtained

5- [ 5-phenylthiomethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (4-Methoxyphenylthiomethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole.

Simple oxidation of 5- [ 5-phenylthiomethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole and 5- [5- (4-methoxyphenylthiomethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole gave 5- [ 5-phenylsulfinylmethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole and 5- [5- (4-methoxyphenylsulfinylmethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole.

5- [ 5-phenylthiomethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole and 5- [5- (4-methoxyphenylthiomethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole are oxidized with sodium perborate in acetic acid under standard conditions, to obtain the compounds 5- [ 5-phenylsulfonylmethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole and 5- [5- (4-methoxyphenylsulfonylmethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole.

Example 14

14.A

A.1. A.A mixture of 440.6mg of "E2 a", 153. mu.l of thiophenol, 194.3mg of copper (I) iodide, 139.6mg of N, N-dimethylglycine hydrochloride, 651.6mg of cesium carbonate and 4ml of 1, 4-dioxane was stirred at 90 ℃ for 50 hours. Conventional work-up gave 510mg of 5- [ 5-phenylthio-2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("F1").

A.2. mixing "F1" with BBr₃Reaction in dichloromethane to obtain 5- [ 5-thiophenyl-2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.767, M + H⁺[m/e]Is 395.88

And

5- [ 5-phenylthio-2-hydroxy-4-methoxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 2.021, M + H⁺[m/e]Is 409.91

A mixture of (a).

A.3. treatment of 5- [ 5-phenylthio-2-hydroxy-4-methoxyphenyl ] with sodium perborate in glacial acetic acid]Oxidation of (E) -1- (2-chlorophenyl) -1H-pyrazole to give 5- [ 5-phenylsulfonyl-2-hydroxy-4-methoxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, by ether cleavage to give 5- [ 5-phenylsulfonyl-2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.403, M + H⁺[m/e]Is 427.88.

14.B

14.b.1. analogously to 14.a.1. reaction of "E2 a" with:

2-fluorobenzylamine, a process for the preparation of (I),

a benzyl alcohol,

(pyridin-4-yl) methanethiol,

the reaction mixture of aniline,

3-fluorophenyl methyl mercaptan is added into the reaction kettle,

(pyridin-2-yl) methylamine,

4-fluorobenzyl alcohol,

to obtain the compound

5- [5- (2-fluorobenzylamino) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-benzyloxy-2, 4-dimethoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (pyridin-4-ylmethylsulfanyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-phenylamino-2, 4-dimethoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (3-fluorophenylmethylthio) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

simply oxidizing it to obtain

5- [5- (3-fluorophenylmethylsulfinyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (pyridin-2-ylmethylamino) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (4-Fluorobenzyloxy) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole.

14.B.2. the compound obtained under 14.B.1. was subjected to ether cleavage to give the following dihydroxypyrazole derivative

5- [5- (2-fluorobenzylamino) -2, 4-bis-hydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-benzyloxy-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (pyridin-4-ylmethylthio) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-phenylamino-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (3-fluorophenylmethylsulfinyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (pyridin-2-ylmethylamino) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (4-Fluorobenzyloxy) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole.

14.C

The 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1-phenyl-1H-pyrazole was subjected to a similar reaction with 4-fluorophenylmethanethiol to give a compound

5- [5- (4-fluorophenylmethylthio) -2, 4-dimethoxyphenyl ] -1-phenyl-1H-pyrazole,

oxidizing it with perborate to give

5- [5- (4-fluorophenylmethylsulfonyl) -2, 4-dimethoxyphenyl ] -1-phenyl-1H-pyrazole.

This was subjected to ether cleavage to give 5- [5- (4-fluorophenylmethylsulfonyl) -2, 4-dihydroxyphenyl ] -1-phenyl-1H-pyrazole.

A similar reaction was carried out between 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (3-ethylphenyl) -1H-pyrazole and 3-fluorophenylthiol to give the compound 5- [5- (3-fluorophenylsulfonyl) -2, 4-dihydroxyphenyl ] -1- (3-ethylphenyl) -1H-pyrazole.

14.D

The 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (3-methylphenyl) -1H-pyrazole was subjected to a similar reaction with thiophenol to give a compound

5- [ 5-phenylthio-2, 4-dimethoxyphenyl ] -1- (3-methylphenyl) -1H-pyrazole,

cleaving the ether to obtain

5- [ 5-phenylthio-2, 4-dihydroxyphenyl ] -1- (3-methylphenyl) -1H-pyrazole.

14.E

The 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (4-nitrophenyl) -1H-pyrazole was subjected to a similar reaction with 2-fluorophenylthiol to give a compound

5- [5- (2-fluorophenylthio) -2, 4-dimethoxyphenyl ] -1- (4-nitrophenyl) -1H-pyrazole;

subjecting it to monoether cracking to obtain

5- [5- (2-fluorophenylthio) -2-hydroxy-4-methoxyphenyl ] -1- (4-nitrophenyl) -1H-pyrazole;

it is subjected to H by using Pd/C as a catalyst₂Reducing to obtain a compound

5- [5- (2-fluorophenylthio) -2-hydroxy-4-methoxyphenyl ] -1- (4-aminophenyl) -1H-pyrazole.

Example 15

For the preparation of compounds in which R²General reaction scheme for compounds of formula I representing an unsubstituted or substituted amide group

15.A

A.1. A.176.3 mg of "E2 a", 123.6. mu.l of diethylamine, 3mg of palladium (II) acetate (47% Pd), 179.1. mu.l of 1, 8-diazabicyclo [5.4.0] undec-7-ene, 2ml of THF and 105.6mg of molybdenum hexacarbonyl were irradiated in a microwave at 120 ℃ for 1 hour. Conventional work-up was carried out to give 5- [5- (N, N-diethylaminocarbonyl) -2, 4-dimethoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole ("G1").

Use of BBr₃Subjecting "G1" to ether cleavage to give the compound 5- [5- (N, N-diethylaminocarbonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole.

B. a similar reaction was performed with "E2 a" and the following:

the reaction mixture of aniline,

the reaction product of a methylamine and a methylamine,

a mixture of dimethylamine,

an ethylamine which is a mixture of at least two of ethylene amine,

N-propyl-N-methyl amine is used,

N-cyclopentyl-N-methylamine,

to obtain the compound

5- (5-phenylaminocarbonyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N, N-dimethylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-ethylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl]-1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.325, M + H⁺[m/e]Is 386.85;

5- [5- (N-cyclopentyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole.

C similar reaction of 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2-chloro-5-fluorophenyl) -1H-pyrazole with C-benzo-1, 3-dioxol-5-ylmethylamine gave compound

5- {5- { N- [ (benzo-1, 3-dioxol-5-yl) methyl ] aminocarbonyl } -2, 4-dihydroxyphenyl } -1- (2-chloro-5-fluorophenyl) -1H-pyrazole.

D analogous reaction of 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2-ethylphenyl) -1H-pyrazole and N-ethyl-N-methylamine to give the compound

5- [5- (N-ethyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-ethylphenyl) -1H-pyrazole.

E analogous reaction of 5- [ 5-iodo-2, 4-dimethoxyphenyl ] -1- (2, 3-dichlorophenyl) -1H-pyrazole with N-butyl-N-methylamine to give the compound

5- [5- (N-butyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2, 3-dichlorophenyl) -1H-pyrazole.

The preparation of the F compound 5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- {4- [2- (4-methylpiperazin-1-yl) ethoxy ] phenyl } -1H-pyrazole ("GG") was carried out in analogy to the following reaction scheme

"GG": retention time [ min ]]Is 0.97, M + H⁺[m/e]Is 494.61.

Example 16

For the preparation of compounds in which R²General reaction scheme for compounds of formula I representing unsubstituted or substituted benzyl

16.A

A.1. 41mg of PdCl₂(dPPf) was added to 2.5ml of benzylzinc bromide (0.5M in THF) and the mixture was stirred at room temperature for 5 minutes under an argon atmosphere. Subsequently, a solution of 440.6mg of "E2 a" in 3ml of THF was added dropwise, and the mixture was stirred at 45 ° for a further 30 minutes and then at 65 ° for 1 hour. The mixture was cooled and poured into saturated NH₄Cl solution and conventional work-up to give a mixture of 3 compounds which are separated by chromatography (ISCO/120g column; petroleum ether/ethyl acetate: 95/5 to 60/40) to give 185mg of "H1", 188mg of "H2" and 190mg of "H3"

Use of BBr in A.2₃Subjecting "H1" to ether cleavage to give the compound

5- (5-benzyl-2, 4-dihydroxyphenyl) -1- (2-benzylphenyl) -1H-pyrazole, M + H⁺[m/e]Is 433.52.

16.A.3. with BBr₃Subjecting "H3" to ether cleavage to give the compound

5- (5-benzyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole, Retention time [ min]Is 1.741, M + H⁺[m/e]Is 377.84.

Example 17

For the preparation of compounds in which R²General reaction scheme for compounds of formula I representing unsubstituted or substituted phenyl

17.A

A.1. A.A mixture of 170.7mg of phenylboronic acid, 616.9mg of "E2 a", 10ml of propanol, 1.79mg of palladium (II) acetate, 3.1mg of triphenylphosphine, 2ml of sodium carbonate solution and 1.2ml of water is stirred in N₂Reflux under atmosphere for 16 hours. The mixture was cooled and worked up conventionally to give 5- (5-phenyl-2, 4-dimethoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole ("K1").

Use of BBr₃Ether cleavage of "K1" gave the compound 5- (5-phenyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole with retention time [ min]Is 1.675, M + H⁺[m/e]Is 363.82.

The following examples relate to pharmaceutical compositions:

example A: injection vial

A solution of 100g of the active compound according to the invention and 5g of disodium hydrogenphosphate in 3L of bidistilled water is brought to pH6.5 with 2N hydrochloric acid, sterile-filtered, transferred into injection vials, freeze-dried under sterile conditions and sealed under sterile conditions. Each injection vial contained 5mg of active compound.

Example B: suppository

A mixture of 20g of the active compound according to the invention with 100g of soya lecithin and 1400g of cocoa butter is melted, poured into a mould and allowed to cool. Each suppository contains 20mg of active compound.

Example C: solution preparation

Preparation of 1g of active compound according to the invention, 9.38g of NaH₂PO₄·2H₂O、28.48gNa₂HPO₄·12H₂O and 0.1g benzalkonium chloride in 940ml double distilled water. The pH was adjusted to 6.8, the solution was brought to a constant volume of 1L and sterilized by irradiation. The solution may be used in the form of eye drops.

Example D: ointment formulation

500mg of the active compound according to the invention are mixed with 99.5g of vaseline under sterile conditions.

Example E: tablet formulation

A mixture of 1kg of the active compound according to the invention, 4kg of lactose, 1.2kg of potato starch, 0.2kg of talc and 0.1kg of magnesium stearate is compressed into tablets in a conventional manner, so that each tablet contains 10mg of active compound.

Example F: candy tablet

Tablets were compressed in a similar manner to example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsule preparation

2kg of active compound according to the invention are introduced into gelatin capsules in a conventional manner, so that each capsule contains 20mg of active compound.

Example H: ampoule agent

A solution of 1kg of the active compound according to the invention in 60L of bidistilled water is sterile-filtered, transferred into ampoules, freeze-dried under sterile conditions and sealed under sterile conditions. Each ampoule contains 10mg of active compound.

Claims (29)

1. Compounds of formula I and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios,

wherein

R¹Represents OH, OCH₃、OCF₃、OCHF₂OBzl, OAc, p-methoxy-benzyloxy, SH, S (O)_mCH₃、SO₂NH₂、Hal、CF₃Or CH₃，

R²，R³Each independently of the others represents H, Hal, CN, NO₂、A、Alk、(CH₂)_nAr、(CH₂)_nHet、(CH₂)_nCOOH、(CH₂)_nCOOA、COOAr、COOHet、CONH₂、CONHA、CONAA′、CONHAr、CONAAr、CON(Ar)₂、CONHHet、CON(Het)₂、NH₂、NHA、NHAr、NHHet、NAA′、NHCOA、NACOA′、NHCOAr、NHCOHet、NHCOOA、NHCOOAr、NHCOOHet、NHCONHA、NHCONHAr、NHCONHHet、OH、OA、OAr、OHet、SH、S(O)_mA、S(O)_mAr、S(O)_mHet、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、SO₂N(Ar)₂、SO₂N(Het)₂、CONH(CH₂)_oHet、NH(CH₂)_oHet、O(CH₂)_oAr、S(O)_m(CH₂)_oHet、S(O)_m(CH₂)_oAr、(CH₂)_oCH(Ar)CH₃、CONAR¹²、SO₂NA(CH₂CONAA′)、SO₂NH(CH₂Ar)、SO₂NA[(CH₂)_oCN]、SO₂NA(CH₂Ar)、(CH₂)_oNHAr、(CH₂)_oNAAr、(CH₂)_oOAr、(CH₂)_oS(O)_mAr, CH ═ CH-Ar, CHO, COA, or R¹²，

R⁴，R⁵，R⁶Each independently of the others represents H, Hal, CN, NO₂、A、Alk、(CH₂)_nAr、(CH₂)_nHet、COOH、COOA、COOAr、COOHet、CONH₂、CONHA、CONAA′、CONHAr、CONAAr、CON(Ar)₂、CONHHet、CON(Het)₂、NH₂、NHA、NHAr、NHHet、NAA′、NHCOA、NACOA′、NHCOAr、NHCOHet、NHCOOA、NHCOOAr、NHCOOHet、NHCONHA、NHCONHAr、NHCONHHet、OH、OA、OAr、OHet、SH、S(O)_mA、S(O)_mAr、S(O)_mHet、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、SO₂N(Ar)₂、SO₂N(Het)₂、CONH(CH₂)_oAr、NHCO(CH₂)_oAr、NHCO(CH₂)_oOA or O (CH)₂)_oHet，

R⁴And R⁵And together also represents OCH₂O or OCH₂CH₂O，

A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 10 carbon atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂、NH、NR⁸And/or by-CH ═ CH-groups and/or, in addition, 1 to 5 hydrogen atoms may be replaced by F, Cl, Br and/or R⁷Instead of this, the user can,

alk or cycloalkyl having 3 to 7 carbon atoms,

a and A' together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by CH₂OH、CH₂Br、CH₂NEt₂The substitution is carried out by the following steps,

and/or wherein CH₂The radicals being selected from the group consisting of O, S, SO₂、N、NH、NR⁸、NCOR⁸Or NCOOR⁸Instead of this, the user can,

alk represents an alkenyl group having 2 to 6 carbon atoms,

R⁷represents COOR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR⁹、NHCOOR⁹OR OR⁹，

R⁸Represents a cycloalkyl group having 3 to 7 carbon atoms,

cycloalkylalkylene having 4 to 10 carbon atoms,

alk or

Unbranched or branched alkyl having 1 to 6 carbon atoms, in which one, two or three CH₂The radicals being selected from the group consisting of O, S, SO₂NH and/or, in addition, 1 to 5 hydrogenAtoms may be replaced by F and/or Cl,

R⁹，R¹⁰each independently of the other represents H or an alkyl radical having 1 to 5 carbon atoms, in which 1 to 3 CH groups₂The radicals being selected from the group consisting of O, S, SO₂NH, NMe or NEt and/or, in addition, 1 to 5 hydrogen atoms can be replaced by F and/or Cl,

R⁹and R¹⁰Together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, wherein CH²The radicals being selected from the group consisting of O, S, SO²、NH、NR⁸、NCOR⁸Or NCOOR⁸Instead of this, the user can,

ar represents phenyl, naphthyl OR biphenyl, each of which is unsubstituted OR substituted by Hal, A, OR¹¹、N(R¹¹)₂、NO₂CN, phenyl, CON (R)¹¹)₂、NR¹¹COA、NR¹¹CON(R¹¹)₂、NR¹¹SO₂A、COR¹¹、NR¹¹CO(CH₂)_oR¹¹、SO₂N(R¹¹)₂、S(O)_mA、-[C(R¹¹)₂]_n-COOR¹¹and/or-O [ C (R)¹¹)₂]_o-COOR¹¹Mono-, di-or tri-substituted,

het represents a monocyclic OR bicyclic, saturated, unsaturated OR aromatic heterocycle having 1 to 4N, O and/OR S atoms which may be substituted by Hal, A, OR¹¹、N(R¹¹)₂、NO₂、CN、COOR¹¹、CON(R¹¹)₂、NR¹¹COA、NR¹¹SO₂A、COR¹¹、SO₂NR¹¹、S(O)_mA、＝S、＝NR¹¹And/or mono-, di-or tri-substituted ═ O (carbonyl oxygen),

R¹¹represents a group of a compound represented by the formula H or A,

R¹²represents cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkylene having 4 to 12 carbon atoms,

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 0, 1, 2, 3 or 4,

o represents 1, 2 or 3.

2. A compound according to claim 1, and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

R¹Represents OH, OCH₃Or SH.

3.A compound according to claim 1 or 2, and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

R²，R³Each independently of the others represents H, Hal, A, (CH)₂)_nAr、(CH₂)_nHet、(CH₂)_nCOOH、(CH₂)_nCOOA、CONH₂、CONHA、CONAA′、CONHAr、CONHHet、NH₂、NHA、NHAr、NHHet、NAA′、S(O)_mA、S(O)_mAr、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、CONH(CH₂)_oHet、NH(CH₂)_oHet、O(CH₂)₂Ar、S(O)_m(CH₂)_oHet、S(O)_m(CH₂)_oAr、(CH₂)_oCH(Ar)CH₃、CONAR¹²、SO₂NA(CH₂CONAA′)、SO₂NH(CH₂Ar)、SO₂NA[(CH₂)_oCN]、SO₂NA(CH₂Ar)、(CH₂)_oNHAr、(CH₂)_oNAAr、(CH₂)_oOAr、(CH₂)_oS(O)_mAr or R¹²。

4.A compound according to one or more of claims 1 to 3 and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, includingMixtures thereof in all proportions, wherein R⁴，R⁵，R⁶Each independently of the others represents H, Hal, CN, NO₂、A、(CH₂)_nAr、COOH、COOA、CONH₂、CONHA、CONAA′、CONHAr、NH₂、NHA、NAA′、NHCOA、NHCOAr、NHCOHet、OH、OA、SO₂NH₂、SO₂NHA、SO₂NAA′、CONH(CH₂)_oAr、NHCO(CH₂)_oAr、NHCO(CH₂)_oOA or O (CH)₂)_oHet。

5.A compound according to one or more of claims 1 to 4, and the pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 10 carbon atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂、NH、NR⁸And/or by-CH ═ CH-groups and/or, in addition, 1 to 5 hydrogen atoms may be replaced by F, Cl, Br and/or R⁷Instead of this, the user can,

alk or cycloalkyl having 3 to 7 carbon atoms,

a and A' together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by CH₂OH、CH₂Br or CH₂NEt₂The substitution is carried out by the following steps,

and/or wherein CH₂The radicals may be O, N, NH or NR⁸Instead.

6.A compound according to one or more of claims 1 to 5, and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 6 carbon atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂NH and/or by a-CH ═ CH-group and/or, in addition, 1 to 5 hydrogen atoms can be replaced by F, Cl and/or Br,

alk or cycloalkyl having 3 to 7 carbon atoms.

7. The compounds according to one or more of claims 1 to 6 and their pharmaceutically acceptable derivatives, salts, solvates and stereoisomers, including mixtures thereof in all ratios, wherein

R⁷Represents COOR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR⁹、NHCOOR⁹OR OR⁹。

8. The compounds according to one or more of claims 1 to 7 and the pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

R⁸Represents an unbranched or branched alkyl group having 1 to 6 carbon atoms.

9. A compound according to one or more of claims 1 to 8, and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

R⁹，R¹⁰Each independently of the other, H or an alkyl radical having 1 to 5 carbon atoms, where 1 to 5 hydrogen atoms may be replaced by F and/or Cl.

10. Compounds according to one or more of claims 1 to 9, and the pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

A, A' each, independently of one another, denote an unbranched or branched alkyl radical having 1 to 6 carbon atoms, in which 1 to 5 hydrogen atoms can be replaced by F, Cl and/or Br,

or a cycloalkyl group having 3 to 7 carbon atoms.

11. Compounds according to one or more of claims 1 to 10, and the pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

Ar represents unsubstituted OR substituted by Hal, A, OR¹¹、N(R¹¹)₂、NR¹¹COA、NR¹¹CO(CH₂)_oR¹¹And/or- [ C (R)¹¹)₂]_n-COOR¹¹Mono-, di-or tri-substituted phenyl.

12. Compounds according to one or more of claims 1 to 11, and the pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

Het represents a monocyclic or bicyclic, saturated or aromatic heterocycle having 1 to 2N and/or O atoms, which may be mono-or di-substituted by a.

13. Compounds according to one or more of claims 1 to 12, and the pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios, wherein

R¹Represents OH, OCH₃Or the presence of an SH group or an SH group,

R²，R³each independently of the others represents H, Hal, A, (CH)₂)_nAr、(CH₂)_nHet、(CH₂)_nCOOH、(CH₂)_nCOOA、CONH₂、CONHA、CONAA′、CONHAr、CONHHet、NH₂、NHA、NHAr、NHHet、NAA′、S(O)_mA、S(O)_mAr、SO₂NH₂、SO₂NHA、SO₂NAA′、SO₂NHAr、SO₂NAAr、SO₂NHHet、CONH(CH₂)_oHet、NH(CH₂)_oHet、O(CH₂)_oAr、S(O)_m(CH₂)_oHet、S(O)_m(CH₂)_oAr、(CH₂)_oCH(Ar)CH₃、CONAR¹²、SO₂NA(CH₂CONAA′)、SO₂NH(CH₂Ar)、SO₂NA[(CH₂)_oCN]、SO₂NA(CH₂Ar)、(CH₂)_oNHAr、(CH₂)_oNAAr、(CH₂)_oOAr、(CH₂)_oS(O)_mAr or R¹²，

R⁴，R⁵，R⁶Each independently of the others represents H, Hal, CN, NO₂、A、(CH₂)_nAr、COOH、COOA、CONH₂、CONHA、CONAA′、CONHAr、NH₂、NHA、NAA′、NHCOA、NHCOAr、NHCOHet、OH、OA、SO₂NH₂、SO₂NHA、SO₂NAA′、CONH(CH₂)_oAr、NHCO(CH₂)_oAr、NHCO(CH₂)_oOA or O (CH)₂)_oHet，

R⁴And R⁵And together also represents OCH₂O or OCH₂CH₂O，

A, A' each independently of one another denote an unbranched or branched alkyl radical having 1 to 10 carbon atoms in which one, two or three CH groups₂The radicals being selected from the group consisting of O, S, SO₂、NH、NR⁸And/or by-CH ═ CH-groups and/or, in addition, 1 to 5 hydrogen atoms may be replaced by F, Cl, Br and/or R⁷Instead of this, the user can,

alk or cycloalkyl having 3 to 7 carbon atoms,

a and A' together also represent an alkylene chain having 2, 3, 4, 5 or 6 carbon atoms, which may be substituted by CH₂OH、CH₂Br or CH₂NEt₂The substitution is carried out by the following steps,

and/or itMiddle CH₂The radicals may be O, N, NH or NR⁸Instead of this, the user can,

R⁷represents COOR⁹、CONR⁹R¹⁰、NR⁹R¹⁰、NHCOR⁹、NHCOOR⁹OR OR⁹，

R⁸Represents an unbranched or branched alkyl group having 1 to 6 carbon atoms,

R⁹，R¹⁰each independently of the other, H or alkyl having 1 to 5 carbon atoms, where 1 to 5 hydrogen atoms may be replaced by F and/or Cl,

ar represents unsubstituted OR substituted by Hal, A, OR¹¹、N(R¹¹)₂、NR¹¹COA、NR¹¹CO(CH₂)_oR¹¹And/or- [ C (R)¹¹)₂]_n-COOR¹¹Mono-, di-or tri-substituted phenyl,

het represents a monocyclic or bicyclic, saturated or aromatic heterocycle having 1 to 2N and/or O atoms which may be mono-or di-substituted by A,

R¹¹represents a group of a compound represented by the formula H or A,

R¹²represents cycloalkyl having 3 to 7 carbon atoms or cycloalkylalkylene having 4 to 12 carbon atoms,

hal represents F, Cl, Br or I,

m represents 0, 1 or 2,

n represents 0, 1, 2, 3 or 4,

o represents 1, 2 or 3.

14. The compound according to claim 1, selected from

5- (2-hydroxy-4-methoxyphenyl) -1- (3-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methyl-5-chlorophenyl) -1-phenyl-1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3, 5-dichlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (2-chloro-5-trifluoromethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (2-ethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3-methoxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3-cyanophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3-trifluoromethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3-chlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3-fluorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1-phenyl-1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-trifluoromethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-chlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-aminosulfonylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-carboxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-cyanophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-methoxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (3-chloro-4-methylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-methylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (4-bromophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (2-methoxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (2-fluorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-fluorophenyl) -1- (2, 6-difluorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-aminophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-nitrophenyl) -1H-pyrazole

5- (2-hydroxy-4-methoxyphenyl) -1- (2-aminophenyl) -1H-pyrazole,

5- (2, 4-bis-hydroxyphenyl) -1- (4-aminophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-fluorophenyl) -1H-pyrazole,

5- (2, 4-bis-hydroxyphenyl) -1- (2-fluorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2, 4-di-fluorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3, 5-dichlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-chloro-2-cyanophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-chloro-5-trifluoromethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-ethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-methoxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-cyanophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-trifluoromethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-chlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-carboxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-fluorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-bromophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1-phenyl-1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-trifluoromethylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-chlorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-aminosulfonylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-carboxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-cyanophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-methoxyphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (3-chloro-4-methylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-methylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2, 6-difluorophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-cyano-2-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-trifluoromethyl-2-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-nitrophenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (4-ethoxycarbonylphenyl) -1H-pyrazole,

5- (2-hydroxy-4-methoxyphenyl) -1- (2-aminophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2, 4-difluorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3, 5-dichlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-chloro-2-cyanophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2, 6-dichlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2-chloro-5-trifluoromethylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2-ethylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-hydroxyphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-cyanophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-trifluoromethylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-chlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-carboxyphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-fluorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-bromophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1-phenyl-1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-trifluoromethylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-chlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-aminosulfonylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-carboxyphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-cyanophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-hydroxyphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (3-chloro-4-methylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-methylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2, 6-difluorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-cyano-2-nitrophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-trifluoromethyl-2-nitrophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2-nitrophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-ethoxycarbonylphenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (2-aminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- (4-nitrophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- (4-aminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- (4-benzoylaminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- (4-acetylaminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- (4-propionylaminophenyl) -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- [4- (butyrylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- [4- (pyridin-4-ylcarbonylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dimethoxyphenyl) -1- [4- (phenylacetylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-benzoylaminophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-acetylaminophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- (4-propionylaminophenyl) -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (butyrylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (pyridin-4-ylcarbonylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (phenylacetylamino) phenyl ] -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- (4-carboxyphenyl) -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- [4- (benzylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- [4- (methylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- [4- (ethylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dibenzyloxyphenyl) -1- [4- (propylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (benzylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (methylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (ethylaminocarbonyl) phenyl ] -1H-pyrazole,

5- (2, 4-dihydroxyphenyl) -1- [4- (propylaminocarbonyl) phenyl ] -1H-pyrazole,

and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

15. The compound according to claim 1, selected from

5- (5-aminosulfonyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-ethyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-N' -diethylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (piperidine-1-sulfonyl) -2, 4-di-hydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-phenylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-phenylaminosulfonyl) -2-hydroxy-4-methoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (2-fluorophenyl) aminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (3-fluorophenyl) aminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (4-fluorophenyl) aminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (pyridin-3-yl) aminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (3-hydroxymethylpiperidine-1-sulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (3-bromomethylpiperidine-1-sulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-benzyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-benzyl-N' -methylaminosulfonyl) -2-methoxy-4-hydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-N' -dimethylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N- (2-bromoethyl) -N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-cyclohexyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N- (2, 3-dibromopropyl) -N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-butyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (2-cyanoethyl) -N' -methylaminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-isopropyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (dimethylaminocarbonylmethyl) -N' -methylaminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (2-hydroxymethylpiperidine-1-sulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (morpholine-4-sulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole and

5- {5- [ N- (2-hydroxyethyl) -N' - (2-bromoethyl) aminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (2-hydroxyethyl) -N' - (2-bromoethyl) aminosulfonyl ] -2-hydroxy-4-methoxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole;

5- {5- [2- (N, N' -diethylaminomethyl) piperidin-4-yl ] sulfonyl } -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (1-methylpiperazin-4-yl) sulfonyl ] -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-methylaminosulfonyl) -2, 4-hydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [ N- (pyridin-4-yl) aminosulfonyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (N-phenylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N-phenylaminosulfonyl) -2-hydroxy-4-methoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N-benzylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N-benzylaminosulfonyl) -2-hydroxy-4-methoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N, N' -diethylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N, N' -diethylaminosulfonyl) -2-hydroxy-4-methoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (ethylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (ethylamino sulfonyl) -2-hydroxy-4-methoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (aminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (aminosulfonyl) -2-hydroxy-4-methoxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [ 5-iodo-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [ 5-iodo-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-carboxyethyl-2, 4-di-hydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-methoxycarbonylethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (2-phenylethyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (2-phenylethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (2-phenyl-2-methoxyethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-styryl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- {5- [2- (pyridin-4-yl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (pyridin-4-yl) vinyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (pyridin-2-yl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (4-fluorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (3-fluorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (2-fluorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [1- (4-fluorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1-phenyl-1H-pyrazole,

5- {5- [2- (3- (aminomethylcarbonylamino) phenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole

5- {5- [2- (3-carboxyphenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (2-chlorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2, 3-dihydrobenzo-1, 4-dioxin-6-yl) -1H-pyrazole,

5- { 5-propyl-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole

5- { 5-Cyclopropylmethyl-2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- (2-methylbutyl) -2, 4-dihydroxyphenyl } -1- (3-methylphenyl) -1H-pyrazole,

5- {5- (2-fluoropropyl) -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (4-methylphenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2, 3-dihydrobenzo-1, 4-dioxin-6-yl) -1H-pyrazole,

5- {5- (2-phenylpropyl) -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- (2-phenylpropyl) -2, 4-dihydroxyphenyl } -1- (2-aminophenyl) -1H-pyrazole,

5- [ 5-phenylaminomethyl-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [ 5-phenylaminomethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-phenoxymethyl-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [ 5-phenoxymethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-phenylthiomethyl-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [ 5-phenylthiomethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (4-methoxyphenylthiomethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-phenylsulfinylmethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (4-methoxyphenylsulfinylmethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-phenylsulfonylmethyl-2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (4-methoxyphenylsulfonylmethyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [ 5-phenylthio-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [ 5-phenylthio-2-hydroxy-4-methoxyphenyl ] -1- (2-chloro-phenyl) -1H-pyrazole,

5- [ 5-phenylsulfonyl-2-hydroxy-4-methoxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [ 5-phenylsulfonyl-2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (2-fluorobenzylamino) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-benzyloxy-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (pyridin-4-ylmethylthio) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-phenylamino-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (3-fluorophenylmethylsulfinyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (pyridin-2-ylmethylamino) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (4-fluorobenzyloxy) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (4-fluorophenylmethylsulfonyl) -2, 4-dihydroxyphenyl ] -1-phenyl-1H-pyrazole,

5- [5- (3-fluorophenylsulfonyl) -2, 4-dihydroxyphenyl ] -1- (3-ethylphenyl) -1H-pyrazole,

5- [ 5-phenylthio-2, 4-dihydroxyphenyl ] -1- (3-methylphenyl) -1H-pyrazole,

5- [5- (2-fluorophenylthio) -2-hydroxy-4-methoxyphenyl ] -1- (4-nitrophenyl) -1H-pyrazole,

5- [5- (2-fluorophenylthio) -2-hydroxy-4-methoxyphenyl ] -1- (4-aminophenyl) -1H-pyrazole,

5- [5- (N, N-diethylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-phenylaminocarbonyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N, N-dimethylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-ethylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-cyclopentyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- { N- [ (benzo-1, 3-dioxol-5-yl) methyl ] aminocarbonyl } -2, 4-dihydroxyphenyl } -1- (2-chloro-5-fluorophenyl) -1H-pyrazole,

5- [5- (N-ethyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-ethylphenyl) -1H-pyrazole,

5- [5- (N-butyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2, 3-dichlorophenyl) -1H-pyrazole,

5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- {4- [2- (4-methylpiperazin-1-yl) ethoxy ] phenyl } -1H-pyrazole,

5- (5-benzyl-2, 4-dihydroxyphenyl) -1- (2-benzylphenyl) -1H-pyrazole,

5- (5-benzyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- (5-phenyl-2, 4-dihydroxyphenyl) -1- (2-chlorophenyl) -1H-pyrazole,

and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

16. The compound according to claim 1, selected from

5- [5- (N-propyl-N '-methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole, 5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-methylphenyl) -1H-pyrazole,

5- [5- (N-propyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-fluorophenyl) -1H-pyrazole,

5- [5- (N-isopropyl-N' -methylaminosulfonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- {5- [2- (2-fluorophenyl) ethyl ] -2, 4-dihydroxyphenyl } -1- (2-chlorophenyl) -1H-pyrazole,

5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- (2-chlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-chlorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxy-5-chlorophenyl) -1- (2-fluorophenyl) -1H-pyrazole,

5- (2, 4-dihydroxy-5-bromophenyl) -1- (2-ethylphenyl) -1H-pyrazole,

5- [5- (N-propyl-N-methylaminocarbonyl) -2, 4-dihydroxyphenyl ] -1- {4- [2- (4-methylpiperazin-1-yl) -ethoxy ] phenyl } -1H-pyrazole,

and pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios.

17.A process for the preparation of compounds of formula I according to claims 1 to 16, and pharmaceutically acceptable derivatives, solvates, salts and stereoisomers thereof, characterized in that

a) In which R is¹、R²And R³A compound of the formula II having the meaning indicated in claim 1 and X represents H or methyl

And wherein R⁴、R⁵And R⁶A compound of the formula III having the meaning indicated in claim 1,

subsequently, if desired, converting the resulting compound in which X represents methyl into a compound of the formula I in which X represents H by ether cleavage,

and/or by reacting one or more radicals R in the compounds of the formula I, for example by¹、R²、R³、R⁴And/or R⁵Conversion into one or more radicals R¹、R²、R³、R⁴And/or R⁵：

i) The nitro group is reduced into amino group,

ii) hydrolysis of the ester group to a carboxyl group,

iii) converting the amino group to an alkylated amine by reductive amination,

iv) converting the carboxyl group into a sulfonamidocarbonyl group,

v) converting the acid chloride into an amide,

and/or converting a base or acid of formula I into one of its salts.

18. A medicament comprising at least one compound according to claims 1 to 16 and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or auxiliaries.

19. Use of a compound according to claims 1-16 as well as its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all ratios, for the preparation of a medicament for the treatment and/or prophylaxis of diseases in which the inhibition, regulation and/or modulation of HSP90 plays a role.

20. The use of compounds according to claims 1 to 16 as well as pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, according to claim 19 for the preparation of a medicament for the treatment or prophylaxis of tumor diseases, viral diseases, immunosuppression for transplantation, inflammation-induced diseases, cystic fibrosis, diseases associated with angiogenesis, infectious diseases, autoimmune diseases, ischemia, fibrotic diseases,

is used for promoting the regeneration of nerve,

used for inhibiting cancer, tumor cell growth and tumor metastasis,

is used for protecting normal cells from toxicity caused by chemotherapy,

for the treatment of diseases in which incorrect protein folding or aggregation is a major causative factor.

21. The use of claim 20, wherein the neoplastic disease is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic carcinoma, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary adenocarcinoma, cystadenocarcinoma, myeloid carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, chondrosarcoma, ovarian cancer, neuroblastoma, or a combination thereof, Ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, waldenstrom's macroglobulinemia, and heavy chain disease.

22. The use according to claim 20, wherein the viral pathogen of a viral disease is selected from the group consisting of hepatitis a virus, hepatitis b virus, hepatitis c virus, influenza virus, varicella virus, adenovirus, herpes simplex virus type I (HSV-I), herpes simplex virus type II (HSV-II), rinderpest virus, rhinovirus, echovirus, rotavirus, Respiratory Syncytial Virus (RSV), papilloma virus, papova virus, cytomegalovirus, echinovirus, arbovirus, huntavirus, coxsackie virus, mumps virus, measles virus, rubella virus, polio virus, human immunodeficiency virus type I (HIV-I) and human immunodeficiency virus type II (HIV-II).

23. The use of claim 20, wherein the inflammation-induced disease is rheumatoid arthritis, asthma, multiple sclerosis, type 1 diabetes, lupus erythematosus, psoriasis, and inflammatory bowel disease.

24. The use according to claim 20, wherein the angiogenesis-related diseases are diabetic retinopathy, hemangioma, endometriosis and tumor angiogenesis.

25. The use according to claim 20, wherein the fibrotic disease is scleroderma, polymyositis, systemic lupus erythematosus, cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.

26. The use according to claim 20, wherein the disease in which incorrect protein folding or aggregation is the main causative agent is scrapie, creutzfeldt-jakob disease, huntington's disease or alzheimer's disease.

27. A medicament comprising at least one compound according to claims 1 to 16 and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and at least one further pharmaceutically active compound.

28. A medicine packaging bag (medicine packaging box) which is formed by independently packaging the following substances

(a) An effective amount of a compound according to claims 1-16 and/or pharmaceutically acceptable derivatives, solvates and stereoisomers thereof including mixtures thereof in all ratios,

and

(b) an effective amount of an additional pharmaceutically active compound.

29. Intermediate compounds of formula I-I

Wherein

R¹Represents OCH₃OBzl, OAc, p-methoxybenzyloxy or I,

R²，R³the expression "H" is used to indicate the formula,

R⁴，R⁵，R⁶each independently of the others represents H, Hal, CN, NO₂、A、COOH、COOA、NH₂OH, OA or SO₂NH₂，

X represents CH₃Bzl, Ac or p-methoxybenzyl,

a represents an unbranched or branched alkyl radical having 1 to 6 carbon atoms in which 1 to 5 hydrogen atoms may be replaced by F and/or Cl, or a cycloalkyl radical having 3 to 7 carbon atoms,

and salts thereof.