CZ20004168A3 - New 1,2,5-trisubstituted 1,2-dihydroindazol-3-one with anti-asthmatic, antiallergic, anti-inflammatory, immunonodulatory and neuroprotective effects, process for their preparation and their use as medicaments - Google Patents

Abstract

The invention relates to the preparation of novel 1,2,5-trisubstituted 1,2-dihydro-indazol-3-ones, a process for their preparation and their pharmaceutical use. These compounds have antiasthmatic, anti-allergic, anti-inflammatory, immunomodulatory and neuroprotective effects.

Description

New 1,2,5-trisubstituted 1,2-dihydro _- syndazol-3-ones with antiasthmatic, antiallergic, anti-inflammatory, immunomodulatory and neuroprotective effects, method of their preparation and their use as drugs

Area, techniques

The present invention relates to the preparation of novel indazol-3-ol derivatives and their use as drugs having antiasthmatic, anti-allergic, anti-inflammatory, immunomodulatory and neuroprotective effects.

State of the art

Cyclosporin A (CsA) and FK506 are immunosuppressive natural substances of fungal origin that inhibit ^Ca2 *-dependent signal transduction in some cell types. In T lymphocytes, both compounds inhibit the transcription of many genes. CsA and FK506 both bind with high affinity to soluble receptor proteins, such as cyclophilin (Cyp) or FK506-binding protein (FKBP) (G. Fisher et al., Nature 337 (1989), 476-478; MW Harding et al., Nature 341 (1989), 755-760).

The CsA-Cyp or FK506-FKBP complex binds calcineurin (CN) and inhibits its phosphatase activity. The cytosolic, phosphorylating component of the transcription factor NF-AT has been identified as a cellular target molecule for CN, so that in the absence of CN, the activity of the active transcription complex on the IL-2 promoter cannot be triggered (M.K. Rosen, S.L. Schreiber, Angew. Chem. 104 (1992), 413-430; G. Fisher, Angew. Chem. 106 (1994), 1479-1501).

Allergic and asthmatic diseases are caused by an inflammatory reaction that is controlled by T-lymphocytes and their mediators.

.1

Corticosteroids are still the drug of choice for the treatment of many allergic diseases. CsA and FK506 are also effective in the treatment of bronchial asthma and underlying inflammation, both in animal experiments and in clinical trials.

Despite a large number of attempts to identify new active immunophilin inhibitors, it has not yet been possible to prepare or isolate any structure more active than CsA, FK506, rapamycin or derivatives of these natural substances. The high inhibitory potential of CsA, FK506 and rapamycin is, however, significantly limited by various side effects, in particular renal toxicity and neurotoxicity (N.H. Sigal et al., J. Exp. Med. 173 (1991), 619-6128). The reason for this fact is the non-specific interaction between immunophilin ligands and cell-specific binding proteins. As a result, the known therapeutic effects of these immunosuppressive agents are significantly limited. In addition, the lack of selectivity of these compounds seems to be a problem, especially in long-term therapy.

Substances that inhibit the activity of peptidylprolyl isomerases (PPIs), such as CyP or FKBP, have neuroprotective properties, stimulate neuronal growth and are suitable for the treatment of neurodegenerative diseases (WO 96/40140, US 5696135, WO 97/18828).

Substituted indazole derivatives are known which differ from the compounds of the present invention in the substituents X, Y, Z, R ³ -, R ² and R ³ and in their pharmacodynamic effect.

Baiocchi et al. (Synthesis 1978 (9), 633-648) describes in general the synthesis and properties of 1H-indazol-3-ols.

Schindler et al. (WO 97/34874) describe 1,3,5-trisubstituted indazoles having antiasthmatic, antiallergic, anti-inflammatory and immunomodulatory activity.

EP 0 199 543 describes 1,6-disubstituted

1.2-dihydroindazol-3-ones and their use for pharmaceutical purposes.

WO 94/24109 contains indazole derivatives which are suitable for the treatment of HIV infection.

Ketami et al. (J. Heterocycl. Chem. 7(4), 807-813 (1970)) describes 1,5-disubstituted 1,2-dihydro-indazol-3-ones.

US 3470194 describes the preparation of disubstituted (1,2-dihydro-3-oxyindazol-2-yl)alkanoic acids using polar solvents.

K.W. Auwers (Ber. Dtsch. Chem. Ges. 58: 2081-2088 (1925)) and K.W. Auwers (Justus Liebigs Ann. Chem. 451: 281-307 (1927) describe the preparation of acylindazoles and their migration.

Zoni et al. (II. Farmaco Ed. Sci. 23(5) 490-501 (1968)) and Zoni et al. (Bol. Chim. Farm. 107, 598-605 (1968)) describe the alkylation of 1-substituted 1H-indazol-3-ols.

Evans et al. (Tetrahedron 21, 3351-3361 (1965) describe the synthesis of 1,3-substituted acyl- and tosylindazoles.

Tse et al. (Arch. Pharm. 329(1): 35-40, (1996)) describe the anti-inflammatory properties of N-substituted indazoles.

Anderson et al. (J. chem. Soc. C, 3313-3314 (1971)) describe

1.3-substituted tosylindazoles.

Pallazo et al., (J. Med. Chem. 9, 38-41 (1966)) and

Guyla et al. (Acta Pharm. Hung. 44, 49-57 (1974)) describe

c · ···· synthesis of 2-dimethylaminoalkyl-1-phenylindazol-3-ones.

Klicnar (Coli. Czech. Chem. Comm. 42: 327-337 (1977)) describes acetylindazoles.

Tserng et al. (J. Org. Chem. 38: 3498-3502, (1973)) describe the synthesis of 1,2-disubstituted 1,2-dihydroindazol-3-ones.

Aran et al. (Heterocycles 45: 129-136 (1997)) describe the selective synthesis of 2-substituted indazol-3-ones without N-1 substitution.

Aran et al. (Liebigs Ann. 1996, 683-691), Aran et al. (Liebigs Ann. 1995, 817-824) and Aran et al. (J. Chem. Soc. Perkin Trans. I, 1119-1127 (1993)) describe 1,2-substituted 5-nitroindazol-3-ones and their cytostatic activity.

Bruneau et al. {J. Med. Chem. 34: 1028-1036 (1991)) describe 1- and 2-substituted indazol-3-ones as inhibitors of 5-lipooxygenase.

Wyrick et al. (J. Med. Chem. 27: 768-772 (1984)) describe

1,2-disubstituted indazol-3-ones active in lowering cholesterol levels.

Schmutz et al. (Helv. Chim. Acta 47: 1986-1996 (1964)) describes the alkylation of indazolones.

Yamaguchi et al. (Chem. Pharm. Bull. 43(2), 332-334 (1995)) describe 2-substituted (1-pyridin-3-yl)indazoles and their antiasthmatic effects.

Due to the many adverse effects of known preparations, the lack of curative effect and the still too non-specific therapy, there is a need for compounds suitable for the treatment of asthmatic diseases that would have high efficacy and safety.

The invention is based on the discovery of new compounds inhibiting rotamas and/or inhibiting pulmonary infiltration by eosinophils and also relates to a method for their targeted synthesis.

A completely new class of compounds that surprisingly specifically bind to immunophilins is represented by the compounds of formula I according to the present invention. This class of compounds has a high affinity for immunophilins such as CypB.

The essence of the invention

It has now surprisingly been found that novel indazole derivatives can inhibit the effects of PPIase. Therefore, these compounds are of considerable importance for the preparation of drugs for the treatment of diseases in which PPIase inhibition is beneficial. Such diseases are, for example: peripheral neuropathy, neurodegenerative diseases, stroke, Parkinson's and Alzheimer's disease, traumatic brain injury, multiple sclerosis. It has further been shown that the compounds of the present invention can inhibit the migration of eosinophil granulocytes into tissues, where this migration is characteristic of the late phase of the asthmatic reaction.

The invention relates to novel 1,2,5-trisubstituted 1,2-dihydroindazol-3-ones of the general formula I:

formula I where X, Y, Z, R ¹ , R ² and R ³ have the following meanings:

X can be -SO -, -SO-, -(CH ) -(CH) -O-, -(CH ) -(C=O)-,

2 JO 2 JP 2 Jp

-(CH ) -(C=O)-NH-, -(CH ) -CHOH-, -CHOH-(CH ) -, -(CH ) -CH=CH-,

E> 2 E> 2 jp 2p

-CH=CH-(CH ₂ ) -, where ρ = 1...4;

Y can be -(C=O)-, -(C=O)-NH-, -(C=0)-NH-(CH ) -,

Jp

- (C=0) - (CH ) -, -(CH ) -, -(CH )-0-, -(CH ) -(C=0)-,

JP 2 JO 2 £> 2 jp

-(CH ) -(C=0)-NH-, -(CH ) -(C=0)-NH-(CH ) -, - (CH ) -CHOH-, jp 2 p» 2 Jp 2

-CHOH-(CH.) -(CH } -CH=CH-, -CH=CH-(CH ) where ρ = 1...4;

jp 2 2 jp

Z can be -0-, -O-(CH ) where p = 1...4, -NH-, -NH(C=O)-,

-NH-(C=O)-NH-, -NH-(C=O)-O-, -NH-CH ₂ -(C=O)- and -NH-(C=O)-CH _from -;

R ¹ , R ² and R ³ may be the same or different and have the following meanings: mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles containing 5 to 14 ring atoms, in particular phenyl, naphthyl, anthranyl, fluorenyl; or mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles containing 5 to 15 ring atoms and 1 to 6 heteroatoms, which are preferably N, O and S, in particular triphenyl, pyridinyl, isoxazolyl, benzimidazolyl, benzo[1,3]dioxolyl, pyrimidinyl, quinolyl, quinazolinyl, morpholinyl, pyrrolidinyl, pyrrolyl, benz[1,2,4]oxadiazolyl, benzothiazolyl;

where the carbocycles and heterocycles may be mono- or polysubstituted by groups selected from the following groups:

-C _i -C _g alkyl, -OC _i -C _g alkyl, -OC^-C^cycloalkyl, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles containing 3 to 14 ring atoms, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5 to 15 ring atoms and 1 to 6 heteroatoms, of which N, and S, -F, -Cl, -Br, -I, -OH, -SH, -NO ₂ , -NHC^-C^alkyl, -N(C _x -C ₆ alkyl) ₂ , -NHC _g -C _x4 -aryl, -N(C _g -C _i4 -aryl) ₂ ,

-N(C ₁ -C ₆ alkyl)-(C _s -C _i4 -aryl), -NHCOC _i -C _g alkyl, -NHCOC _g -C _i4 -aryl, -CONHC _i -C _g alkyl, -CONHC _g -C _x4 -aryl, -CONHSO ₂ C _x -C _g alkyl,

-CONHSO C -C -aryl, -CN, -(CO)C-C alkyl, -(CS)C-C alkyl,

-COOH, -COOC -C alkyl, -O-C -C -aryl, -O-(CO)C-C alkyl,

-O-(CO)C _g -C _i4 ~aryl, benzyl, benzyloxy, -SC _x -C _g alkyl,

-S-C-C-aryl, -CF, -(CH)-COOH, where p is 1 to 4,

-(CH ₂ )^-COOC _x -C _g alkyl, where ρ = 1 to 4, -SO ₂ -C _x -C _g alkyl,

-SO C -C -aryl;

6 14 ^J

R ¹ may further be H (but not if X = CH ₂ );

R ³ -z may further be NO ₂ .

The compounds of the present invention are novel, but the following conditions apply to them:

If Z is -NH-(C=0)-, -NH-(C=0)-NH-, -NH-(C=0)-0-,

-NH-(C=O)-CH -, and at the same time R ^x is phenyl, monosubstituted or polysubstituted by groups selected from the following groups: -COOH, COOCi _{-C g} alkyl, - (CHJ ^-COOH, where p = 1-4,

-(CH ) -COOC -C alkyl, where p = 1-4, -CONHC -C alkyl, jp 3_ 6 3_ 6

-CONHC -C -aryl, -CONHSO C -C alkyl, -CONHSO CC -aryl, & 3-4L 2 3- € 2 6 3.4c lH-tetrazol-5-yl, then R ² must not be phenyl, monosubstituted or polysubstituted by CN, halogen, C^-C^alkyl, C^-C^alkyloxy • · · · • · · · · · · · · · · » • · · ·« · * » »

• · · · group, CF ₃ .

If R ³ -Z = NO , then R ^x -X and R ² -Y must not have the following meanings at the same time:

R^-X = benzyl, 4-methoxybenzyl,

R ³ -Y = benzyl, picolyl.

The invention further relates to physiologically tolerable salts of the compounds of formula I.

Pharmacologically acceptable salts are obtained in a conventional manner by neutralization of bases with inorganic or organic acids or neutralization of acids with inorganic or organic bases. Useful inorganic acids are, for example, hydrochloric acid, sulfuric acid, phosphoric acid or hydrobromic acid, organic acids are, for example, carboxylic, sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, maleic acid, fumaric acid, tannin, succinic acid, alginic acid, benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, cinnamic acid, mandelic acid, citric acid, malic acid, salicylic acid, 3-aminosalicylic acid, ascorbic acid, embonic acid, nicotinic acid, isonicotinic acid, oxalic acid, amino acids, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid. Useful inorganic bases are, for example, sodium hydroxide solution, potassium hydroxide solution, ammonia and useful organic bases are, for example, amines, preferably tertiary amines such as trimethylamine, triethylamine, pyridine, • · · » . ;

···· * · « .

• » · » · » ·· «· ···» ··

N,N-dimethylaniline, quinoline, isoquinoline, alpha-picoline, beta-picoline, gamma-picoline, quinaldine or pyrimidine.

In addition, physiologically acceptable salts of the compounds of formula I can be obtained by converting derivatives having tertiary amino groups into the corresponding quaternary ammonium salts using known methods. Quaternizing agents that can be used are, for example, alkyl halides such as methyl iodide, ethyl bromide or n-propyl chloride, but also arylalkyl halides such as benzyl chloride or 2-phenethyl bromide.

Furthermore, the invention of compounds of formula I which contain an asymmetric carbon atom also relates to the D forms, L forms and D,L mixtures and - in the case of more asymmetric carbon atoms - to diastereomeric forms. Those compounds of formula I which contain asymmetric carbon atoms and are obtained as racemic mixtures can be separated into optically active isomers using known techniques, for example with the aid of optically active acids. However, it is also possible to use optically active starting substances from the outset, to obtain the corresponding optically active or diastereomeric compounds.

The invention relates to the use of the compounds of the present invention and their physiologically acceptable salts as:

1. rotamase inhibitors for the preparation of medicaments for the treatment of diseases mediated by this enzyme; and/or

2. inhibitors of the late phase of eosinophilia for the preparation of drugs for the treatment of diseases mediated by these cells.

Such diseases include, for example, peripheral neuropathy, neurodegenerative diseases, stroke, Parkinson's and Alzheimer's diseases, traumatic brain injuries, multiple sclerosis, bronchial asthma, allergic rhinitis, allergic • · ♦ · * ·» «· • · · · · · ♦ · · · · · ···« • · · · ·····« · · ······« conjunctivitis, atopic dermatitis, eczema, allergic vasculitis, eosinophil-mediated inflammations such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome, autoimmune diseases such as rheumatoid arthritis, rheumatoid spondylitis, lupus erythematosus, psoriasis, glomerulonephritis and uveitis, insulin-dependent diabetes mellitus and sepsis.

The compounds of the present invention or their pharmacologically acceptable salts are further useful for the preparation of medicaments for the prevention of rejection reactions after transplantation of cells, tissues or organs.

In the preparation of pharmaceuticals, an effective dose of the compounds of the present invention or their salts is used, in addition to conventional auxiliaries, carriers and additives.

The dose of the active compound varies depending on the route of administration, the age, weight of the patient, the nature and severity of the disease being treated, and similar factors.

The daily dose may be administered in a single dose or divided into multiple doses and is in the range of 0.001-1000 mg.

Possible forms include oral, parenteral, intravenous, transdermal, topical, inhalation and intranasal formulations.

For administration, conventional pharmaceutical compositions in the form of tablets, coated tablets, capsules, dispersible powders, granules, aqueous solutions, aqueous or oily suspensions, syrups, juices or drops can be used.

φ· • 9 ··

Φ · · • ·

Φ « • · «Φ ΦΦΦΦ • φ ♦ · · φ · · «

ΦΦ ·

Solid pharmaceutical forms may contain inert additives and carriers, such as calcium carbonate, calcium phosphate, sodium phosphate, lactose, starch, mannitol, alginates, gelatin, guar gum, magnesium or aluminum stearate, methylcellulose, talc, highly dispersible silicic acids, silicone oil, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar or vegetable or animal fats and oils, high molecular weight solid polymers (such as polyethylene glycol); preparations suitable for oral administration may contain, if appropriate, additional flavoring agents and/or sweeteners.

Liquid dosage forms may be sterilized and/or may optionally contain auxiliary agents such as preservatives, stabilizers, wetting agents, active ingredient penetration enhancers, emulsifiers, bulking agents, solubilizing agents, salts, sugars or sugar alcohols for regulating osmotic pressure or as buffering agents, and/or viscosity-adjusting agents. Auxiliary agents of this type are, for example, tartrate or citrate buffers, ethanol, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts). High molecular weight polymers such as, for example, liquid polyethylene oxide, microcrystalline celluloses, carboxymethyl celluloses, polyvinylpyrrolidones, dextrans or gelatin are useful for viscosity control. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersible silicic acids, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, vegetable and animal fats, solid high molecular weight polymers such as polyethylene glycol.

«

Oil suspensions for parenteral or topical application may be vegetable, synthetic or semi-synthetic oils, such as, for example, esters of fatty acids containing 8 to 22 carbon atoms in the fatty acid chain, for example palmitic, lauric, tridecyl, margaric, stearic, arachidonic, myristic, behenic, pentadecanoic, linolenic, elaidic, brassicic, erucic or oleic acids, which are esterified with mono- to trihydric alcohols containing 1 to 6 carbon atoms, such as, for example, methanol, ethanol, propanol, butanol, pentanol or their isomers, glycol or glycerol. Fatty acid esters of this type are, for example, commercially available Migliols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic/capric acid esters with saturated fatty alcohols, polyoxyethylene glycerol trioleates, ethyl oleate, vodka fatty acid esters such as artificial duck fat, isopropyl cocoate, oleyl oleate, decyl oleate, ethyl lactate, dibutyl phthalate, diisopropyl adipate, polyol fatty acid esters and others. Also suitable are silicone oils of various viscosities or fatty alcohols such as isotridexyl alcohol, 2-octyldodecanol, cetyl stearyl alcohol or oleyl alcohol, fatty acids such as oleic acid. Furthermore, it is possible to use vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil.

Possible solvents, gelling agents and solubilizing agents are water or water-miscible solvents. These include, for example, alcohols such as ethanol or isopropyl alcohol, benzyl alcohol, 2-octyldodecanol, polyethylene glycols, phthalates, adipates, propylene glycol, glycerol, di- or tripropylene glycol, waxes, methylcellulose, cellulose esters, morpholines, dioxane, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, cyclohexanone, etc.

Useful film-forming agents include cellulose ethers that dissolve or swell in both water and organic solvents, such as hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, or soluble starches.

It is also possible to use mixed forms between gel and film forming agents. Here, ionic macromolecules are usually used, such as, for example, sodium carboxymethylcellulose, polyacrylic acid, polymethylacrylic acid and its salts, sodium amylopectin semiglycolate, alginic acid or propylene glycol alginate in the form of sodium salt, gum arabic, xanthan gum, guar gum or carrageenan.

Other excipients that can be used are: glycerol, paraffins of various viscosities, triethanolamine, collagen, allantoin, novantisolic acid.

The compositions may also require the use of surfactants, emulsifiers or wetting agents, such as, for example, sodium lauryl sulfate, fatty alcohol ether sulfates, sodium N-lauryl-S-iminodipropionate, polyethoxyethylated castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (e.g. Tween), cetyl alcohol, lecithin, glycerol monostearate, polyoxyethylene stearate, alkylphenyl polyglycol ethers, cetyltrimethylammonium chloride or the monoethanolamine salt of a mono/dialkyl polyglycol ether of orthophosphoric acid.

The compositions may also require the use of stabilizing agents such as montmorillonites or colloidal silicas which stabilize the emulsion, or agents which prevent the decomposition of the active ingredient, such as antioxidants, for example tocopherols or butylhydroxyanisole, or preservatives such as p-hydroxybenzoic acid esters.

Preparation, filling and sealing of the products is carried out under usual antimicrobial and aseptic conditions.

The dosage of the pharmaceutical composition depends on the age, condition and weight of the patient and on the route of administration. Usually the daily dosage of the active compound is between 0.001 and 25 mg/kg of body weight.

Preparation

According to the present invention, compounds of general formula I can be prepared by the following methods.

Compounds of general formula I, where X = -SO ₂ -, -S0-, are prepared according to the procedure according to scheme 1.

The 1H-indazol-3-yl sulfonates II are reacted in the presence of a base and, if appropriate, in the presence of a diluent to give compounds of the general formula III, where R ¹ , R ³ , X and Z are as defined above.

The 1H-indazol-3-yl sulfonates II or 1-sulfonylindazoles III are reacted, if appropriate, in the presence of a base, in particular sodium hydride, and if appropriate, in the presence of a diluent, in particular dimethyl sulfoxide, with compounds of the following general formulae:

Hal-YR ² , 0=C=N-(CHJ^-R ² , [R ² -{CHJ ^-0=0] ₂ O, where p = 0 to 5, • » ► * · where R ¹ , R ² , R ³ , X, Y and Z are as defined above and Hal is a halogen atom selected from the group consisting of F, Cl, Br or I, to obtain compounds of general formula I, where R ¹ , R ² , R ³ , X, Y and Z are as defined above.

Scheme 1:

Formula II Formula III ►

Compounds of general formula I, where X = -(CH _z ) -{CH _a )^-O-,

-(CH ) -<C=0)-, -{CH) -(C=0)-NH-, -(CH ) -CHOH-, -CHOH-(CH ) -, 2 2 ² jp

-(CH ₂ ) -CH=CH-, -CH=CH-(CH ₂ ), where p = 1-4, is prepared according to Scheme 2.

Compounds of general formula III are reacted, if appropriate, in the presence of a base, in particular sodium hydrides, and if appropriate, in the presence of a diluent, in particular tetrahydrofuran or dimethylsulfoxide, with compounds of the following general formula:

Hal-YR ² , 0=C=N-(CH )-R ² , [R ² -(CH )-C=0] O, where p = 0 to 5, (£> 2 2 ♦ ·

1111 • · where R ³ -, R ² , R ³ , X, Y and Z are as defined above and Hal is a halogen atom selected from the group consisting of F, Cl, Br or I, to obtain compounds of general formula I, where R ^x , R ² , R ³ , X, Y and Z are as defined above.

Scheme 2:

Formula III

Formula I wherein the compound of formula III may also be present as a tautomeric form of the compound of formula IV, according to Scheme 3.

Scheme 3:

Formula III

Formula IV

The compounds of general formula I are novel.

• ·

Examples of embodiments of the invention

The following compounds of the present invention are exemplified.

2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-1-(4-methoxybenzenesulfonyl)-1,2-dihydroindazol-3-one;

2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-1-(4-trifluoromethoxybenzenesulfonyl)-1,2-dihydroindazol-3-one;

2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-1-(4-chlorobenzenesulfonyl)-1,2-dihydroindazol-3-one;

1-(4-fluorobenzenesulfonyl)-2-(2-hydroxy-5-nitro-benzyl)-5-methoxy-1,2-dihydroindazol-3-one;

N-(4-[2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-3-oxo-2,3-dihydroindazole-1-sulfonyl]phenyl)acetamide;

2-(4-fluorobenzyl)-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

2-(4-fluorobenzyl)-5-methoxy-1-(4-chlorobenzenesulfonyl)-1,2-dihydroindazol-3-one;

1-(4-fluorobenzenesulfonyl)-2-(4-fluorobenzyl)-5-methoxy-1,2-dihydroindazol-3-one;

2-(2-fluorobenzyl)-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

1-(4-fluorobenzenesulfonyl)-2-(2-fluorobenzyl)-5-methoxy-1,2-dihydroindazol-3-one;

2-(3-Methoxybenzyl)-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

2-(3-trifluoromethylbenzyl)-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

2-[2-(4-Chlorophenyl)thiazol-4-ylmethyl]-5-methoxy-1-(phenol-4-sulfonyl)-1,2-dihydroindazol-3-one;

···· ·

5-Methoxy-2-(3-phenylallyl)-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

5-Methoxy-2-(3-oxo-3-phenylpropyl)-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

2-[2-(2,6-difluorophenoxy)ethyl]-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

2-[2-(2-bromo-4,6-difluorophenoxy)ethyl]-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

2-[2-(2-bromo-4,6-difluorophenoxy)ethyl]-5-methoxy-1-(4-methoxybenzenesulfonyl)-1,2-dihydroindazol-3-one;

N-(4-{2-[2-(2,4-ioxo-1,4-dihydro-2H-quinazolin-3-yl)ethyl]-5-methoxy-3-oxo-2,3-dihydroindazole-1-sulfonyl}phenyl)acetamide;

2-{3-[4-(3-chlorophenyl)piperazin-1-yl]-propyl}-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

1-(4-chlorobenzenesulfonyl)-2-{3-[4-(3-chlorophenyl)piperazin-1-yl]-propyl}-5-methoxy-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

N-benzyl-2-[5-methoxy-3-oxo-1-(toluene-4-sulfonyl)-1,3-dihydroindazol-2-yl]acetamide;

2-[5-methoxy-3-oxo-1-(toluene-4-sulfonyl)-1,3-dihydroindazol-2-yl]-N-(4-methoxyphenyl)acetamide;

2-(2,6-dichlorobenzoyl)-5-nitro-1-(toluene-4-sulfonyl)-1,2-dihydroindazol-3-one;

1-(3,4-dichlorobenzyl)-2-(2-hydroxy-5-nitrobenzyl)-5-methylthio-1,2-dihydroindazol-3-one;

2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-1-(3-nitrobenzyl)-1,2-dihydroindazol-3-one;

5-Methoxy-1-(3-nitrobenzyl)-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2-fluorophenyl)amide;

5-Methoxy-1-(3-nitrobenzyl)-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2,6-dichlorophenyl)amide;

5-Methoxy-1-(3-nitrobenzyl)-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2-fluoro-6-trifluoromethylphenyl)amide;

• ·

Methyl 3-[2-(2-fluorophenylcarbamoyl)-5-methoxy-3-oxo-2,3-dihydroindazol-1-ylmethyl]benzoate;

1-(4-fluorobenzyl)-5-methoxy-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2,6-dichlorophenyl)amide;

4-nitrobenzyl)-1-(4-fluorobenzyl)-5-methoxy-3-oxo-1,3-dihydroindazole-2-carboxylate;

1-(2,6-difluorobenzyl)-5-methoxy-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2,6-dichlorophenyl)amide;

1-(2-Chloro-6-fluorobenzyl)-5-methoxy-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2,6-dichlorophenyl)amide.

Compounds are characterized by melting point, thin layer chromatography, elemental analysis, NMR spectroscopy, IR and UV-VIS spectroscopy, and optionally mass spectrometry.

Purification by liquid chromatography on a column

In the preparation of the compounds of Examples 1 to 35, 1- and 3-O-substituted 1H-indazoles of general formula V may be formed as by-products.

Formula V

Compounds of the general formula I can usually be separated from compounds of the general formula V by recrystallization. If this procedure is insufficient, chromatographic separation is necessary under the following conditions: stationary phase: conventional silica gel phase, for example Si 60 to 100 A, particle size 5 - 100 mM. Eluent:

• · • · · · methylene chloride/ethyl acetate = 95/5 or methylene chloride/methanol = 95/5. Compounds of general formula I are more polar than compounds of general formula V so that compounds of general formula I are eluted first under the stated chromatographic conditions. This purification method is applicable to all examples 1 to 35.

Example 1: 2-(2-hydroxy-5-nitrobenzyl)-5-methoxy-1-(4-methoxy-benzenesulfonyl)-1,2-dihydroindazol-3-one;

_O2N

ch ₃

5.01 g (15 mmol) of 5-methoxy-1H-indazol-3-yl-4-methoxybenzenesulfonate were dissolved in 70 ml of DMSO and reacted portionwise with 1.5 g (37.5 mmol) of sodium hydride (60%). After stirring for 2 hours, a solution of 2.81 g (15 mmol) was added dropwise.

2-hydroxy-5-nitrobenzyl chloride in 25 ml DMSO and the mixture is stirred at 90-100 °C for 3 hours. After cooling, 400 ml water is added and the mixture is stirred for 3 hours and extracted three times with 400 ml ethyl acetate. The combined organic phases are washed with 100 ml water, dried over sodium sulfate and distilled to dryness in vacuo and the residue is recrystallized from ethanol.

Yield: 3.0 g (41.1% of theoretical yield) mp 215-217 °C ^X3 C-NMR (DMSO-d ₆ ; 300 MHz) :

C=0.

Ir (KBr): v = 1669 cm ^x C=0.

= 46.0 CH_N; 55.8 2xCH ₃ 0; 165.1 >

O· _V • » »· * » • · • · ···· »·· • · 4 • * • » • * · «· ♦ ·<«► ·· *·

The compounds listed in Table 1 are prepared by analogous methods.

Table 1

Formula VI

R = CH 0

a. 3

Example R ^J

R ³ Yield Tt IR (KBr) ^,3 C-NMR <™>' ^c ''cTo ¹ W

4-Tolyl

4-trifluoromethoxyphenyl

4-chlorophenyl

4-fluorophenyl

4-Acetylaminophenyl

4-Tolyl

4-chlorophenyl

212-215 (2-PrOH)

99-103 (EtOH)

212-216 (MeCN)

210-212 (EtOH)

242-244 (EtOH)

151 (MeOH)

179 (EtOH)

1673 46.62

1694 46.81

1690 45.33

1690 46.54

1672; 46.50

1713

1703 48.89

1704 49.81 • ·

with 4-fluoro- phenyl 10 4-Tolyl ^ch X p 11 4-fluoro- phenyl F 12 4-Tolyl O-CHj 13 4-Tolyl O~CFj 14 4-Tolyl with 15 4-Tolyl 16 4-Tolyl xp 17 4-Tolyl F 18 4-Tolyl Br 19 4-Methoxy- phenyl ^CH x,JX Br 20 4-Acetylaminophenyl 0 CH.—-CH, JI . ,\O 21 4-Tolyl •χκ)

28 167-169 (EtOH) 1708 49.53 65 164-167 (2-PrOH) •1712 44.54 16 151-153 (MeCN) 1713 49.36 10 125-127 (MeCN) 1704 47.77 18 110 (EtOH) 1704 49.86 52 192-193 (MeCN) 1703 47.14 58 137-139 (2-PrOH) 1708 46.22 19 140-145 (EtOH) 1690; 1716 41.20 10 151-153 (EtOH) 1718 46.99 7 125-126 (2-PrOH) 1717 46.86 14 76-81 (EtOH) 1711 48.70 15 245-247 (MeCN) 1714 38.22; 44.75 14 157-162 (EtOH) 1704 45.71; 47.78; 52.78; 55.77

·· · 9 » 9» · · • 999 9··· 999

Φ 9999 9999

9 9 9 9 9 9

9 9· 9 9 9 · 9 9999 «9 9

CI 45.92;

22 4-chloro- phenyl -C-U 11 165-168 (MeCN) 1704 47.75; 52.80; 55.80 23 4-Tolyl 0 5 221-223 (EtOH) 1685; 1718 42.27; 50.24 24 4-Tolyl ^CH, ^f TI _CH 6 226-228 (EtOH) 1690; 1704 51.31

Example 25: 2-(2,6-Dichlorobenzoyl)-5-nitro-1-toluene-4-sulfonyl)-1,2-dihydroindazol-3-one

CH ₃

5.0 g (0.015 mol) of (5-nitro-1H-indazol-3-yl)-toluene-4-sulfonate are dissolved in 50 ml of pyridine and the mixture is stirred at 80 °C for 30 minutes with 3.77 g (0.018 mol) of 2,6-dichlorobenzoyl chloride. After cooling, the mixture is mixed with 150 ml of water, treated with 5N HCl and the solid material is filtered off with suction and washed with water. The crude material is purified by preparative HPLC using silica gel Si 60 and methylene chloride/ethyl acetate (99/1) as eluent.

• ·» ·« • * · « » ·

Yield: 2.4 g (32% of theoretical yield)

mp 195-197 °C (EtOAc) ¹³ C-NMR (DMSO-d _s ; 300 MHz): = 20.27 CH 2 ; 159.33 C=O; 162.87

C=0.

Ir (KBr) : v = 1726 cm' ³ - C=0.

Example 26: 1-(3,4-dichlorobenzyl)-2-(2-hydroxy-5-nitrobenzyl)-5-methylthio-1,2-dihydroindazol-3-one, hydrate • 9 9 11 i • * · · · · · · · · · · · · · ·

1 ·

1

3.6 g (11 mmol) of 1-(3,4-dichlorobenzyl)-5-methylthio-1H-indazol-3-ol were dissolved in 100 ml of DMSO and reacted portionwise with 0.34 g (13.2 mmol) of sodium hydride (95%). After stirring for 2 hours, a solution of 2.1 g (11 mmol) was added dropwise.

2-hydroxy-5-nitrobenzyl chloride in 20 ml DMSO and the mixture is stirred at 60 °C for 3 hours. After cooling, 200 ml water is added dropwise, the mixture is stirred for 4 hours and the solid material is filtered off with suction. The precipitate is extracted by stirring with methanol with heating and recrystallized from 2-propanol.

Yield: 1.0 g (18.5% of theoretical yield)

mp 225 °C ^{x 3} C-NMR (DMSO-d ; 300 MHz): = 13.7 CH S; 48.8 2xCHN; €160.0 3 2 c=o.

IR(KBr): ν = 1623 cm ^-1 C=0.

»· · · · · · · · ···· · · * · « · · • · · · · « · • · · · · ·0«· * · · · · · · ···· ··· ·· ···· tt ·

The compounds listed in Table 2 were prepared analogously, using 5-methoxy-1-(3-nitrobenzyl)-1H-indazol-3-ol as the starting material.

Table 2

Formula VII

^R1 = CHO

Example R ^s R ³ Yield Tt IR (KBr) ¹³ C-NMR (% theor.) (°C) !«”*'] (DMSO) c=o n-ch ₂

232 1542 40.51;

(MeCN) 53.44

Example 28: 5-Methoxy-1-(3-nitrobenzyl)-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2-fluorophenyl)amide

0* ♦ 0 · 00 00 • 000 0 · · 0 φ 0«

0 · 0 0 0 0

0«00 ·000

0 · · · · · 0000 000 00 0000 0« 0

1.8 g (0.013 mol) of 2-fluorophenylisocyanate are added to a solution of 3.0 g (0.01 mol) of 5-methoxy-1-(3-nitrobenzyl)-1H-indazol-3-ol in 100 ml of tetrahydrofuran and the mixture is heated at reflux temperature for 4 hours. It is then concentrated to 20 ml and the precipitate formed is filtered off with suction and recrystallized from ethyl acetate.

Yield: 1.1 g (25% of theoretical yield)

mp 149-151 °C ¹³ C-NMR (DMSO-d ; 300 MHz): = 157.22 C=0; 165.15 C=0.

β

Ir (KBr): v = 1628; 1727 cm ^-1 C=O.

The compounds listed in Table 3 were prepared by an analogous procedure.

Table 3

^R1 = CH0

Example ^R2

R Yield Tt IR (KBr) ' ³ C-NMR (% theor.) (°C) {cm') (CDCl3) c=oc=o

F

170-172 1684; 156.77; (EtOAc) 1730 164.88

200-201 1693; 155.21;

(EtOH) 1732 163.16

149-154 1,685; 155.65;

(EtOH) 1721 164.95;

166.48 • tttt • · • tt tttttttt

165 1695; 156.43;

(MeCN) 1736 165.01

156-158 1730 b 157.05;

(MeCN) 164.83

169-171 1692; 159.38; (EtOAc) 1740 168.14

151-153 1687; 156.79; (EtOH) 1737 165.53

In vitro and in vivo experiments were performed to determine the antiasthmatic, antiallergic, anti-inflammatory and/or immunomodulatory activity of the compounds of the present invention. The compounds of formula I of the present invention surprisingly bind to immunophilins and inhibit their peptidyl-prolyl cis-isomerase (PPIase) activity. For the initial screening (10 mmol/l) the inhibition of human cyclophilin B in the PPIase assay was determined.

Assay for the determination of proptidyl-prolyl isomerase (PPIase) activity and inhibition « · · · · · · · • · · · · · · · · • · · · ·

Way:

PPIase activity is assayed using a conventional enzymatic assay (G. Fisher, H. Bang, C. Mech, Biomed. Biochim. Acta 43: 1101-1111; G. Fisher, H. Bang, A. Schellenberger, Biochim. Biophys. Acta 791, (1984), 87-97; D.H. Rich et al., J. Med. Chem.

38: 4164-4170, (1995).

Compounds of formula I according to the present invention are pre-incubated at 4°C for 15 minutes with 10 nmol Cyp B. The enzyme reaction is started after the addition of the test peptide.

Suc-Ala-Ala-Pro-Phe-Nan after addition of chymotrypsin and HEPES buffer. The change in extinction at 390 nm is then recorded and evaluated. The photometrically detected extinction changes are due to two sub-reactions: (a) rapid cleavage of the trans-peptide by chymotrypsin;

(b) non-enzymatic cis-trans isomerization, which is catalyzed by cyclophilins. The respective PPIase activities of the compounds of general formula I according to the present invention are shown in Table 4.

Table 4

Example PPIase Inhibition activities in (%) at 10 μM 1 70 2 50 3 93 4 90 5 67 26 98

Inhibition of late-phase eosinophilia 24 hours after ovalbumin inhalation in actively sensitized guinea pigs • tf · · * · · tf· • · · J tftf · tf «tf • tf tftf tf · · • · · · · · v tf··· tftftf tftf tftftftf tftf

Way:

The inhibition of pulmonary eosinophil infiltration by the test substances was tested in an in vivo test on male Dunkin-Hartley guinea pigs (200-250 g) sensitized to ovalbumin. Sensitization was performed by two intraperitoneal injections of a suspension of 20 µg OVA together with 20 mg of aluminum hydroxide as adjuvant in 0.5 ml of physiological saline per animal, given on two consecutive days. 14 days after the second injection, the animals were given mepyramine maleate (10 mg/kg i.p.) to prevent death from anaphylaxis.

30 minutes later, the animals were exposed for 30 seconds in a plastic box to an aerosol containing OVA (0.5 mg/ml) prepared in a nebulizer using compressed air (19.6 kPa) (allergen challenge). 24 hours after application, the animals were sacrificed with an overdose of ethyl urethane (1.5 g/kg body weight i.p.) and bronchoalveolar lavage (BAL) was performed using 2 x 5 ml of physiological saline. BAL fluid was collected, centrifuged at 300 rpm for 10 minutes, and the cell pellet was resuspended in 1 ml of physiological saline. Eosinophils were stained using the Becton-Dickinson Eosinophil Staining Test Kit (No. 5877) and counted in a Neubauer chamber. 2 control groups (nebulization with physiological saline and nebulization with OVA) were used in each test.

The percentage of inhibition of eosinophilia in the test group treated with the compounds of the present invention was calculated according to the following formula:

(A - C) - (B - C)/(A - C) x 100 = % inhibition

The test substances were administered intraperitoneally or

• · « · · « · • · · · ♦ · · · « ·«·· · · orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethylcellulose, and the application was carried out 2 hours before the application of the allergen. Control groups were treated with a vehicle corresponding to the form of administration of the test substance. The number of animals per control and test groups was 3-10. The results are shown in Table 5:

Table 5:

Ex. Dose (mg) Submission Eosinophils million/animal x + s Inhibition (%) A B C 1 2x30 i.p. -2h/+4h 1.89+0.42 0.51+0.25 0.55+0.12 97

A = Eosinophils in the control group with OVA and vehicle administration;

B = Eosinophils in the group with application of the test substance and OVA;

C = Eosinophils in the control group with application of 0.9% NaCl and vehicle;

x = average values; s = standard deviation;

The compounds of the present invention are therefore suitable for the preparation of medicaments for the treatment of diseases which are associated with the suppression of immunological processes.

Claims (10)

New 1,2,5-trisubstituted 1,2-dihydroindazol-3-ones of formula I wherein X, Y, Z, R ¹ , R ² and R ³ have the following meanings: X can be -SO-, -SO-, - (CH) -, - (CH) -O-, - (CH) - (C = O) -, - (CH) - (C = O) -NH-, - (CH) -CHOH-, -CHOH- (CH) -, - (CH) -CH = CH-, 2 p 2 p 2 £> 2 p -CH = CH- (CH) -, where ρ = 1 ... 4; Y may be - (C = 0) -, - (C = 0) -NH-, - (C = 0) -NH- (CH _{2) p} -, - (C = O) - (CH ₂ ) _p -, - (CH ₃ -, - (CH ₃ ) -O-, - (CH 3) 4 - (O = 0) -, - (CH) - (C = O) -NH-, - (CH) - (C = O) -NH- (CH) -, - (CH) -CHOH-, -CHOH- (CH) -, - ( CH) -CH = CH-, -CH = CH- (CH) -, where ρ = 1 ... 4; 2 p 2 p 2 p Z may be -O-, -O- (CH) -, wherein p = 1 ... 4, -NH-, -NH (C = O) -, 2 p -NH- (C = O) -NH-, -NH- (C = O) -O-, -NH-CH- (C = O) - and -NH- (C = O) -CH-; R ³ -, R ² and R ³ may be the same or different and have the following meanings: mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles containing 5 to 14 ring atoms, namely phenyl, naphthyl, anthranyl, fluorenyl; or mono-, or tricyclic saturated or mono- or polyunsaturated heterocycles containing 5 to 15 ring atoms and 1 to 6 heteroatoms, which are preferably N, O and S, in particular triphenyl; Pyridinyl, isoxazolyl, benzimidazolyl, benzo [1,3] dioxolyl, pyrimidinyl, quinolyl, quinazolinyl, morpholinyl, pyrrolidinyl, pyrrolyl, benz [1, 2,4] oxadiazolyl, benzothiazolyl; wherein the carbocycles and heterocycles may be mono- or polysubstituted with groups selected from the following groups: -C 1 -C ₆ alkyl, -OC ₁ -C ₆ alkyl, -O-C ₃ -C ₇ cycloalkyl, mono-, bi- or tricyclic saturated or mono- or polyunsaturated carbocycles containing 3 to 14 ring atoms, mono-, bi- or tricyclic saturated or mono- or polyunsaturated heterocycles having 5 to 15 ring atoms and 1 to 6 heteroatoms, which are preferably N, O and S, -F, -Cl, -Br, -I, -OH, -SH, -NO ₂ , -NHC ₁ -C ₆ alkyl, -N (C ₁ -C ₆ alkyl) ₂ , -NHC ₆ - C ₁₄ -aryl, -N (C ₆ -C ₁₄ -aryl) ₂ , -N (C ₁ -C ₆ alkyl) - (C ₆ -C ₁₄ -aryl), -NHCOC-L-Cgalkyl, -NHCOC ₈ -C ₁₄ -aryl, -CONHC ₁ -C ₆ alkyl, -CONHC ₆ -C ₁₄ -aryl, -CONHSO ₂ C ₁ -C ₆ alkyl, -CONHSO ₂ C ₆ -C ₁₄ -aryl, -CN, - (CO ₃ C ₆ -C ₆ alkyl, - (CS) C ₁ -C ₆ alkyl, -COOH, -COOC C ₁ -C ₆ alkyl, -O-C 8 -C ₁₄ -aryl, -O-C ₁ -C ₆ -C ₁ -alkyl, -O- (CO) C 8 -C ₁₄ -aryl, benzyl, benzyloxy, -SC ₁ -C ₆ -alkyl, -S-Cg-C ₁₄ -aryl, -CF _3, - (CH ₂₎ p COOH where p is 1-4, - (CH ₂ J-COOC 1 -C 8 alkyl, where ρ = 1 to 4, -SO ₂ -C ₁ -C ₈ alkyl, -SO ₂ -C-C ₄ ^_ ary1; R ¹ may further be H (but not when X = CH ₂ ); R ³ -Z may further be NO ₂ ; with the proviso that compounds of formula I are excluded when Z is -NH- (C = O) -, -NH- (C = O) -NH-, -NH- (C = O) -O-, -NH - (C = O) -CH ₂ -, and at the same time R 1 is phenyl, monosubstituted or polysubstituted with groups selected from the following groups: -COOH, COOC-L-Cg alkyl, - (CH ₂ ) p -COOH, where ρ = 1 to 4, - (CH ₂ ) p -COOC ₁ -C ₆ alkyl, where ρ = 1 to 4, -CONHC ₁ -C ₆ alkyl, · · · · · ·,,,,, · ·· « -CONHC -C-aryl, -CONHSOC-alkyl, -CONHSOC-aryl, 1H-tetrazol-5-yl, then R ² can not be phenyl, monosubstituted or polysubstituted by CN, halogen, C ^ -C ^ alkyl, C ^ C ^ alkyloxy, CF _3; and if. R ³ -Z = NO ₂ , R 1 -X and R ² -Y must not simultaneously have the following meanings: R ^x -X = benzyl, 4-methoxybenzyl, R ² -Y = benzyl, picolyl. 2. Compounds of formula 1 selected from the following group: 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-methoxybenzenesulfonyl) -1,2-dihydroindazol-3-one; 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-trifluoromethoxybenzenesulfonyl) -1,2-dihydroindazol-3-one; 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (4-chlorobenzenesulfonyl) -1,2-dihydroindazol-3-one; 1- (4-fluorobenzenesulfonyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1,2-dihydroindazol-3-one; N- (4- [2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-3-oxo-2,3-dihydroindazole-1-sulfonyl] phenyl) acetamide; 2- (4-fluorobenzyl) -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 2- (4-fluorobenzyl) -5-methoxy-1- (4-chlorobenzenesulfonyl) -1,2-dihydroindazol-3-one; 1- (4-fluorobenzenesulfonyl) -2- (4-fluorobenzyl) -5-methoxy-1,2-dihydroindazol-3-one; 2- (2-fluorobenzyl) -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 1- (4-fluorobenzenesulfonyl) -2- (2-fluorobenzyl) -5-methoxy-1,2-dihydroindazol-3-one; 2- {3-methoxybenzyl) -5-methoxy-1- (toluene-4-sulfonyl) -1,2,4,4,4,4,4,4 4 4 4 4 4 4 4 4 4 4 • 444 444 44 4444 -dihydroindazol-3-one; 2- (3-trifluoromethylbenzyl) -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 2- [2- (4-chlorophenyl) thiazol-4-ylmethyl] -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 5-methoxy-2- (3-phenylallyl) -1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 5-methoxy-2- (3-oxo-3-phenylpropyl) -1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 2- [2- (2,6-difluorophenoxy) ethyl] -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 2- [2- (2-bromo-4,6-difluorophenoxy) ethyl] -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 2- [2- (2-bromo-4,6-difluorophenoxy) ethyl] -5-methoxy-1- (4-methoxybenzenesulfonyl) -1,2-dihydroindazol-3-one; N- (4- {2- [2- (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl) ethyl] -5-methoxy-3-oxo-2,3-dihydroindazole-1 -sulfonyl} phenyl) acetamide; 2- {3- [4- (3-Chloro-phenyl) -piperazin-1-yl] -propyl} -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydro-indazol-3-one; 1- (4-chlorobenzenesulfonyl) -2- {3- [4- (3-chlorophenyl) piperazin-1-yl] propyl} -5-methoxy-1- (toluene-4-sulfonyl) -1,2-dihydroindazole -3-one; N-benzyl-2- [5-methoxy-3-oxo-1- (toluene-4-sulfonyl) -1,3-dihydroindazol-2-yl] acetamide; 2- [5-methoxy-3-oxo-1- (toluene-4-sulfonyl) -1,3-dihydroindazol-2-yl] -N- (4-methoxyphenyl) acetamide; 2- (2,6-dichlorobenzoyl) -5-nitro-1- (toluene-4-sulfonyl) -1,2-dihydroindazol-3-one; 1- (3,4-dichlorobenzyl) -2- (2-hydroxy-5-nitrobenzyl) -5-methylthio-1,2-dihydroindazol-3-one; 2- (2-hydroxy-5-nitrobenzyl) -5-methoxy-1- (3-nitrobenzyl) -1,2-dihydroindazol-3-one; 5-Methoxy-1- (3-nitrobenzyl) 35 (2-fluorophenyl) amide 35 -3-oxo-1,3-dihydroindazole-2-carboxylic acid; 5-methoxy-1- (3-nitrobenzyl) -3-oxo-1,3-dihydroindazole-2-carboxylic acid (2,6-dichlorophenyl) amide; 5-methoxy-1- (3-nitrobenzyl) -3-oxo-1,3-dihydroindazole-2-carboxylic acid (2-fluoro-6-trifluoromethylphenyl) amide; Methyl 3- [2- (2-fluorophenylcarbamoyl) -5-methoxy-3-oxo-2,3-dihydroindazol-1-ylmethyl] benzoate; 1- (4-Fluorobenzyl) -5-methoxy-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2,6-dichlorophenyl) amide; 4-nitrobenzyl) -1- (4-fluorobenzyl) -5-methoxy-3-oxo-1,3-dihydroindazole-2-carboxylate; 1- (2,6-Difluorobenzyl) -5-methoxy-3-oxo-1,3-dihydroindole-2-carboxylic acid (2,6-dichlorophenyl) amide; 1- (2-Chloro-6-fluorobenzyl) -5-methoxy-3-oxo-1,3-dihydroindazole-2-carboxylic acid (2,6-dichlorophenyl) amide. 3. Physiologically acceptable salts of the novel compounds of the formula I according to claim 1 or 2, characterized in that they are prepared by neutralizing bases with inorganic or organic acids or neutralizing acids with inorganic or organic bases or quaternizing tertiary amines to form quaternary ammonium salts. Use of compounds of formula 1 and salts thereof according to any one of claims 1 to 3 as therapeutically active compounds for the manufacture of medicaments for the treatment of PPIase-mediated diseases. Use of compounds of formula 1 and salts thereof according to any one of claims 1 to 3 as therapeutically active compounds for the manufacture of a medicament for the treatment of diseases associated with suppression of immune processes. A process for the preparation of compounds of formula I according to any one of claims 1 to 3, characterized in that it comprises: (A) for X = -SO -SO-, reaction according to scheme 1 such that 1H-indazol-3-yl sulfonates II Formula II is reacted in the presence of a base and optionally in the presence of a diluent, to give compounds of formula III wherein R ³ -, R ³ , X and Z are as defined in claim 1, and by reaction of 1H-indazol-3-yl sulfonates II or 1-sulfonylindazoles III, if appropriate in the presence of a base, in particular sodium hydride, and, if appropriate, in the presence of a diluent, in particular dimethylsulfoxide, with compounds of the general formula Hal-YR ² , O = C = N- (CH ₂ -R ² , [R ² - (CH ₂ ) _p -C = O] ₂ O, where p = 0 to 5, where R ¹ , R ² , R ³ , X, Y and Z are the same as defined in claim 1 and Hal is a halogen atom selected from the group consisting of F, Cl, Br or I to give compounds of formula I wherein R ¹ , R ² , R ³ , X, Y and Z are as defined in claim 1; (b) for X = - (CHJ ^ -, - (CH ₂ ) ~ -O-, - (CHJ ^ - (C = 0) -, 0 · 0 0) · 0 · · • · 0 0 0 0 • 0000 0000 0 0 0 0 0 0 0 0000 000 00 0000 00 0 - (CH) - (C = O) -NH-, - (CH) -CHOH-, -CHOH- (CH) -, - (CH) -CH = CH-, 2 P 2 2 E> 2 -CH = CH- (CH) -, wherein p = 1-4, a reaction according to Scheme 2, wherein the compounds of formula III react, if appropriate, in the presence of a base, in particular sodium hydride, and, if appropriate in the presence of a diluent, in particular tetrahydrofuran or dimethylsulfoxide, with compounds of the general formula Hal-YR ² , O = C = N- (CH) -R ² , [R ² - (CH) -C = O] 0, where p = 0 to 5, wherein R ¹ , R ² , R ³ , X , Y and Z are the same as defined in claim 1 and Hal is a halogen atom selected from the group consisting of F, Cl, Br or I to obtain compounds of formula I wherein R ¹ , R ² , R ³ , X, Y and Z are the same as defined in claim 1; wherein the compound of formula III may also be present in tautomeric form as the compound of formula IV ^X R 'according to Scheme 3. A pharmaceutical composition comprising as active ingredient at least one compound of formula I according to any one of claims 1 to 3 and physiologically acceptable carriers and / or diluents or auxiliary agents. A pharmaceutical composition comprising as active ingredient at least one compound of formula I according to any one of claims 1 to 3 and a suitable carrier. · Tff tff tfff tfff tfff tfff tfff tfff Pharmaceutical composition according to any one of claims 1, 2, 3, 7 and 8, characterized in that it is in the form of a tablet, a coated tablet, a capsule, an aerosol, a powder formulation, a patch, a solution, an ampoule or a suppository. Use of compounds of formula I according to any one of claims 1 to 3 and / or pharmaceutically acceptable salts according to claims 7 and 8 as agents having anti-asthmatic, antiallergic, anti-inflammatory and / or immunomodulatory effects either alone or in combination with each other or in combination with carriers.