CZ20004152A3 - Novel 1,5 and 3-0-substituted 1H-indazoles exhibiting anti-asthmatic, antiallergic, antiphlogistic, immunomodulating and neuroprotective activity, process of their preparation and their use as medicaments - Google Patents

Abstract

The present invention relates to the preparation of new 1,5- and 3-O-substituted EI-indazoles, to a process for their preparation and to their pharmaceutical use. These compounds have anti-asthmatic, anti-allergic, anti-inflammatory, immunomodulatory and neuroprotective effects.

Description

Technical field

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

BACKGROUND OF THE INVENTION

Cyclosporin A (CsA) and FK 506 are immunosuppressive natural substances derived from fungi, which inhibit the Ca ² * -dependent signal transmission pathway in some cell types. In T cells, 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). Both proteins catalyze the isomerization of cis- and trans-amide linkages of rotamate peptides and are also often referred to as immunophilin.

The CsA-Cyp complex or FK506-FKBP binds calcineurin (CN) and inhibits its phosphatase activity. The cytosolic phosphorylation component of NF-AT was determined 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 (MK Rosen, SL Schreiber, Angew. Chem. 104 (1992), 413-430, G. Fisher, Angew, Chem 106 (1994), 1479-1501).

Allergic, asthmatic diseases are based on an inflammatory response that is controlled by T lymphocytes and their mediators. 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. However, the high inhibitory potential of CsA, FK506 and rapamycin is significantly limited by various adverse effects, particularly renal toxicity and neurotoxicity (N.H. Signal et al., J. Exp. Med. 173 (1991), 619-6128). This is due to the non-specific interaction between immunophilin ligands and cell-specific binding proteins. As a result, the known therapeutic effects of these immunosuppressants are significantly reduced. In addition, the lack of selectivity of these compounds appears to be a problem especially in long-term therapy.

Substances that inhibit peptidylprolyl isomerase (PPIas) activity, such as CyP or FKBP, have neuroprotective properties, stimulate neuronal growth and are useful in 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 ¹ , R ² and R ³ and in their pharmacodynamic effect.

Corsi (Boli. Chim. Farm. 111, 566-572 (1972) and Giannangeli (Boli. Chim. Farm. 121: 465-474 (1982) describe synthesis

5-hydroxybendazac and EP-A-0 191 520 discloses the use of [(1-benzyl-5-hydroxy-1H-indazol-3-yl)] acetic acid for the treatment of colds.

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

WO 97/34874 discloses 1,3,5-trisubstituted indazoles having anti-asthmatic, anti-inflammatory and immunomodulatory activity.

WO 96/04266 describes, inter alia, (1H-indazol-3-yloxy) acetamides substituted with basic radicals and their anti-asthmatic, antiallergic, anti-inflammatory and immunomodulatory properties.

Pfannstiel et al. (Ber. Dtsch. Chem. Ges. 75 (9), 1096-1107, (1942)) describes the preparation of nitro-1H-indazol-3-ol.

Ketami et al. (J. Heterocycl. Chem. 7 (4), 807-813 (1970)) discloses the (sic) anti-inflammatory effect of 1,5-disubstituted 3-hydroxy-1H-indazoles.

Hannig et al. (Pharmazie, 30 (11), 706-708) discloses 1-benzylated (indazol-3-yl) acylaminocarboxanilides.

JP 48026760 contains, inter alia, 1-benzyl-1H-indazol-3-yloxyacetamides.

EP-A-0 290 145 contains 1,3,6-trisubstituted indazoles which are leukotriene antagonists.

US 3470194, Pallazo et al., (J. Med. Chem. 9, 38-41 (1966)) and

Guyla et al. (Acta Pharm. Hung. 44, 49-57 (1974)) disclose 1,5-disubstituted (indazol-3-yl) oxy-alkanoic acids and their

anti-inflammatory activity.

Klicnar (Coli. Czech. Chem. Comm. 42: 327-337 (1977)) describes physical data for acylindazoles.

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

EP 0448206 contains 1,3,6-trisubstituted indazoles and their use as herbicides where only -OH or O-alkyl is allowed in the 3-position.

EP 0191520 describes (1-phenylmethyl) -5-hydroxy-1H-indazol-3-yl) oxyacetic acid and its pharmaceutical use.

EP 0199543 discloses indazoles and other heterocycles having acidic substituents in the radical M as leukotriene antagonists.

US 3966761 contains trisubstituted aminoindazoles and discloses their anti-inflammatory and analgesic effects.

US 3318905 discloses 3-dialkylaminoalkyloxyindazoles having analgesic and anti-inflammatory activity.

K.W. Auwers (Ber. Dtsch. Chem. Ges. 58: 2081-2088 (1925)) describes the composition of acylindazoles.

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-ol.

Evans et al. (Tetrahedron 21, 3351-3361 (1965))

the synthesis of 1,3-substituted acyl and tosylindazoles.

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

1,3-substituted tosylindazoles.

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

Because of the many side effects of known formulations, lack of curative effect, and hitherto unspecific therapy, there is a need for compounds useful for the treatment of asthmatic diseases that have high efficacy and safety.

The invention is based on the discovery of novel compounds having the ability to inhibit rotamase and / or inhibit lung infiltration by eosinophils, and also relates to a method for their targeted synthesis.

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

SUMMARY OF THE INVENTION

It has now surprisingly been found that novel indazole derivatives can inhibit the effects of PPIase. Therefore, these compounds are of great importance in the preparation of medicaments for the treatment of diseases in which the inhibition of PPIase is beneficial. Such diseases are, for example: peripheral neuropathy, neurodegenerative diseases, stroke, Parkinson's and Alzheimer's disease, traumatic brain injuries, multiple sclerosis. Furthermore, it has been shown that the compounds of the present invention can inhibit the migration of eosinophils

9,999 granulocytes into tissues, where this migration is characteristic of the late phase asthmatic reaction.

The present invention relates to novel 1,5-s-3-O-substituted 1H-indazoles of formula I:

wherein X, Y, Z, R ^x , R ² and R ³ have the following meanings:

X can be -SO ₂ -, -SO-, - (CH ₂ ) _p -, - (CH ₃ -, - (-) -) - (O = 0) -, - (CH) - (C = O) -NH-, - (CH) -CHOH-, -CHOH- (CH) -, - (CH) -CH = CH-, -CH = CH- (CH) -, where ρ = 1 ... 4 ;

Y can be - (CH) -, - (CH) -O-, - (CH) - (0 = 0) -, p 2 p 2 p

- (CH) - (C = O) -NH-, - (CH) - (C = O) -NH- (CH) - (CH) -CHOH-, p 2p 2p 2p

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

Z may be -O-, -S-, -SO-, -SO ₂ -, -O- (CH ₂ ) -, 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 ₂ -;

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-, 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, phenyl [1,2,4] oxadiazolyl (sic), phenylthiazolyl;

wherein the carbocycles and heterocycles may be mono- or polysubstituted with groups selected from the following groups:

-CC 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 containing 5 to 15 ring atoms and 1 to 6 heteroatoms, which are preferably N, O and S, -F, -Cl, -Br, -I, -OH, -SH, -NO ,,, -NHC _x C _g alkyl, -N (C _x -C ₆ alkyl) _2, -NHC ₆ -C _X4 -aryl, -N (C -C_ _{e-aryl) 2,}

-N (C _x -C ₆ alkyl) - (C ₆ -C -aryl _x4) --NHCOC _x -C _{alkyl, C} -C --NHCOC _{g X4} -aryl, -CONHC _{x C6} alkyl, -C0NHC ₆ - C _X4 -aryl, -C0NHS0 C _x -C _{2 alkyl,} -CONHSO ₂ C ₆ -C _X4 -aryl, -CN, - (CO) _x C -C _alkyl, - (CS) C _x -C _g alkyl , -COOH, -COOC -C _{x alkyl,} -OC ₆ -C _X4 -aryl, -0- (CO) C _x -C ₆ alkyl,

-0- (CO) C ₆ -C _X4-aryl, benzyl, benzyloxy, -SO _x -C _g alkyl, -SC ₆ -C _X4 -aryl, -CF _3, - (CH ^ COOH wherein p is 1 up to 4,

- _(CH2) ^ - C00C -C _{x alkyl,} where ρ = 1 to 4, -S0 ₂ C _x -C _g alkyl,

-SO-C-C-aryl;

it 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:

If Y = - (CH ₂ ) (C = O) -, - (CH 3 - (C = O) -NH-, where p = 1 to 4, R ² must not be pyridine, piperazine, pyrimidine,

Tetrahydropyridine;

When Z is -NH- (C = O) -, -NH- (C = O) -NH-, -NH- (C = O) -O-,

-NH- (C = O) -CH -, and at the same time R ^{1 is} phenyl, monosubstituted or polysubstituted by groups selected from the group consisting of -COOH, COOC _and -C ₆ alkyl, - (CH 3 COOH, where p = 1-4,

- (CH -COOC _{x C6} alkyl, wherein p = 1-4, -CONHC _i -C _e alkyl,

-CONHC -C -aryl, -C0NHS0 C -C alkyl, C -C -aryl -CONHSO, ^J e 14 '2 · 16 "26 14 H-tetrazol-5-yl, then R ² can not be phenyl, monosubstituted or polysubstituted by CN, halogen, C 1 -C ₄ alkyl, C ₁ -C ₄ alkyloxy, CF ₃ .

If R ³ -Z = NO, then R ¹ -X and R ² -Y must not have the following meanings:

R 1 = X = benzyl, 4-methoxybenzyl,

R ² -Y = benzyl, picolyl.

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

The pharmacologically acceptable salts are obtained in a conventional manner by neutralizing bases with inorganic or organic acids or neutralizing 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 acids, sulfonic acids such as acetic acid, tartaric acid, lactic acid, propionic acid, glycolic acid, malonic acid, 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, Ν, Ν-dimethylaniline, quinoline, isoquinoline, alpha-picolinol , beta-picoline, gamma-picoline, quinaldin 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 a known method. Useful quaternizing agents 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.

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

The invention relates to the use of the compounds of the present invention

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

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

Such diseases include, for example, bronchial asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, eczema, allergic vasculitis, eosinophil-mediated inflammation such as eosinophilic fasciitis, eosinophilic pneumonia and PIE syndrome, autoimmune diseases such as rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis , multiple sclerosis, psoriasis, glomerulonephritis and uveitis, insulin dependent diabetes mellitus and sepsis.

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

In the preparation of medicaments, an effective dose of the compounds of the present invention or salts thereof is used in addition to conventional excipients, carriers and additives.

The dose of the active compound will vary depending on the route of administration, the age, weight of the patient, the nature and severity of the disease being treated, and the like.

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

Possible forms are devices for oral, parenteral, intravenous, transdermal, local, inhalation, and intranasal φ · · · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ ·· Submission.

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

Solid pharmaceutical forms may contain inert ingredients 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 silica, 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); compositions suitable for oral administration may contain, if appropriate, additional flavoring agents and / or sweeteners.

The liquid dosage forms may be sterilized and / or optionally may contain auxiliary agents such as preservatives, stabilizing agents, wetting agents, penetration enhancers, emulsifying agents, bulking agents, solubilizing agents, salts, sugars or sugar alcohols for control. 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 non-toxic salts thereof). High molecular weight polymers such as, for example, liquid polyethylene oxide, microcrystalline celluloses, carboxymethylcelluloses, polyvinylpyrrolidones, dextrans or gelatin are useful for controlling viscosity. Solid carriers are

For example, starch, lactose, mannitol, methylcellulose, talc, high dispersible silicic acids, high molecular weight fatty acids (such as stearic acid), gelatin, agar-agar, calcium phosphate, magnesium stearate, vegetable and animal fats, high molecular weight solid polymers such as polyethylene glycol.

The oily suspensions for parenteral or topical administration may be vegetable, synthetic or semisynthetic oils, such as, for example, fatty acid esters of 8 to 22 carbon atoms in the fatty acid chain, for example palmitic, lauric, tridecylic, margaric, stearic, arachidonic, myristic , behene, pentadecane, linolene, elaid, braside, erucic or oily esterified with C 1 -C 6 monohydric alcohols, such as, for example, methanol, ethanol, propanol, butanol, pentanol or isomers thereof, glycol or glycerol. Fatty acid esters of this type are, for example, commercially available Mygliols, isopropyl myristate, isopropyl palmitate, isopropyl stearate, PEG 6-capric acid, caprylic / capric acid esters with saturated fatty alcohols, polyoxyethylene glycerol trioleate, ethyloleate, hydrogen fatty acid esters such as duck artificial fats sebaceous glands, isopropylcocoate, oleyloleate, decyloleate, ethyllactate, dibutylphthalate, diisopropyladipate, fatty acid esters of polyols 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. Further, vegetable oils such as castor oil, almond oil, olive oil, sesame oil, cottonseed oil, peanut oil or soybean oil may be used.

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, 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-forming and film-forming agents. Ionic macromolecules, such as, for example, sodium carboxymethylcellulose, polyacrylic acid, polymethylacrylic acid and its salts, sodium amylopectinsemiglycolate, alginic acid or propylene glycol alginate in the form of sodium salt, acacia, xanthan gum, guar gum, are usually used herein.

Other adjuvants that may be used are: glycerol, paraffins of different viscosities, triethanolamine, collagen, allantoin, novantisoleic acid.

Surfactants, emulsifying agents or wetting agents, such as, for example, sodium lauryl sulfate, fatty alcohol ether sulfates, sodium N-lauryl-Siminodipropionate, polyethoxyethyl castor oil or sorbitan monooleate, sorbitan monostearate, polysorbates (for example Tween), lecithin, glycerol monostearate, 9 9 9 9 9 9 10 11 12 13 14 15 16 17 Polyoxyethylene stearate, alkylphenyl polyglycol ethers, cetyltrimethylammonium chloride or the monoethanolamine salt of the mono / dialkyl polyglycol orthophosphoric ether.

Stabilizing agents, such as montmorillonites or colloidal silicas, which stabilize the emulsion, or agents that inhibit the decomposition of the active ingredient, such as antioxidants, such as tocopherols or butylhydroxyanisole, or preservatives, such as acid esters, may also be required in the compositions p-hydroxybenzoic acid.

The preparation, filling and sealing of the compositions is carried out under conventional antimicrobial and aseptic conditions.

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

Preparation

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

Compounds of formula I wherein X = -SO ₂ -, -SO-, are prepared 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 formula III wherein R ¹ , R ³ , X and Z are as defined above.

1H-indazol-3-yl sulfonates II or 1-sulfonylindazoles 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 dimethylsulfoxide, with compounds of the general formula Hal-YR ² , wherein 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 formula I wherein R ¹ , R ² , R ³ , X, Y and Z are the same as defined above.

Formula II Formula III

Compounds of formula I wherein X = - (CH) -, - (CH) -O-,

30 2 jp

- (CH 3 - (C = O) -, - (CH 3 - - (C = O) -NH-, - (CH 3 - -CHOH-, -CHOH- (CH 3)),

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

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 dimethylsulfoxide, with compounds of the formula Hal-YR ² , where R ¹ , R ² , R ³ , X,

Y and Z are the same as defined above 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 same 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

The compounds of formula I are novel.

• · · · · · · · · · · · · · · · · · · · · 9 ·

999 9999 99

DETAILED DESCRIPTION OF THE INVENTION

The following compounds of the present invention are exemplified.

3- [2- (2-bromo-4,6-difluorophenoxy) ethoxy] -5-methoxy-1- (toluene-4-sulfonyl) -1H-indazole;

5-methoxy-1- (toluene-4-sulfonyl) -3- [5- (3-trifluoromethylphenyl) -1,2,4-oxadiazol-3-ylmethoxy] -1H-indazole;

6- {2- [5-methoxy-1- (toluene-4-sulfonyl) -1H-indazol-3-yloxy] acetyl} -3,4-dihydro-1H-quinolin-2-one;

N- (2,4-difluorophenyl) -2- [5-methoxy-1- (toluene-4-sulfonyl) -1H-indazol-3-yloxy] acetamide;

3- (6-chlorobenzo [1,3] dioxol-5-ylmethoxy) -5-methoxy-1- (3-nitrobenzyl) -1H-indazole;

3- [3- (4-fluorophenyl) propoxy] -5-nitro-1- (3-nitrobenzyl) -1H-indazole;

3- [3- (6-chloro-benzo [1,3] dioxol-5-ylmethoxy) -5-methoxy-indazol-1-ylmethyl] -phenylamine;

1- (4-fluorobenzyl) -5-methoxy-3- [2- (4-nitrophenoxy) ethoxy] -1H-indazole;

3- [2- (2-bromo-4,6-diflurphenoxy) ethoxy] -5-methoxy-1- [2- (4-nitrophenoxy) ethyl] -1H-indazole;

3- [2- (2-bromo-4,6-difluorophenoxy) ethoxy] -1- [3,4-dichlorobenzyl] -5-methylthio-1H-indazole;

1- {1- [2,4-Dichloro-benzyl) -3- [2- (4-nitrophenoxy) -ethoxy] -1H-indazol-5-yl} -3-naphthalen-1-yl-urea.

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

Purification by liquid chromatography on a column ························· ···· ·· ·

In the preparation of the compounds of Examples 1 to 123, 1,2-dihydroindazol-3-ones of general formula V can be formed as by-products.

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

methylene chloride / ethyl acetate = 95/5 or methylene chloride / methanol = 95/5. Compounds of formula (V) are more polar than compounds of formula (I), so that compounds of formula (I) are eluted first under the chromatographic conditions. This purification method is applicable to all Examples 1 to 123.

Example 1: 3- [2- (2-bromo-4,6-difluorophenoxy) ethoxy] -5-methoxy-1- (toluene-4-sulfonyl) -1H-indazole

F • · · · · ·

• · · · · · · · · · · · · · · · · ·

31.8 g (100 mmol) of 5-methoxy-1H-indazol-3-yl-toluene-4-sulfonate are dissolved in 300 ml of DMSO and treated portionwise with 3.54 g (140 mmol) of sodium hydride (95%). . After stirring for 15 minutes, a solution of 28.5 g (105 mmol) of 1- (2-bromo-4,6-difluorophenoxy) -2-chloroethane in 100 mL of DMSO was added dropwise and the mixture was stirred at 90 ° C for 3 hours. After cooling, the mixture is treated with 1.5 liters of water, extracted three times with 400 ml of ethyl acetate, the organic phase is dried over sodium sulphate and distilled to dryness in vacuo and the residue is recrystallized from ethanol.

Yield: 25.1 g (45.3% of theory)

mp 133-134.5 ° C ¹³ C-NMR (DMSO-d; 300 MHz): = 21.3 CH; 55.9 CH O; 69.3 and 72.1, each CH_, O.

The starting materials used to prepare the compounds of Examples 2 to 76 (Tables 1, 2, 3 and 4) were as follows:

5-methoxy-1 H -indazol-3-yl-toluene-4-sulfonate;

5-methoxy-1 H -indazol-3-yl-4-chlorobenzenesulfonate;

5-methoxy-1 H -indazol-3-yl-4-fluorobenzenesulfonate;

5-methoxy-1 H -indazol-3-yl-4-methoxybenzenesulfonate;

5-methoxy-1H-indazol-3-yl-4-trifluoromethoxybenzenesulfonate;

5-methoxy-1H-indazol-3-yl-thiophene-2-sulfonate;

5-methoxy-1 H -indazol-3-yl-4-acetylaminobenzenesulfonate;

5-methoxy-1H-indazol-3-yl-quinoline-8-sulfonate; 5-methoxy-1H-indazol-3-yl-naphthalene-1-sulfonate;

5-methoxy-1 H -indazol-3-yl-2,5-dichlorobenzenesulfonate; 4- (5-methoxy-1 H -indazol-3-yloxysulfonyl) benzoic acid;

5-nitro-1H-indazol-3-yl-toluene-4-sulfonate;

5-nitro-1H-indazol-3-yl-4-methoxy-benzenesulfonate.

The synthesis of the compounds of Examples 2 to 31 is carried out analogously to the procedure of Example 1. The other starting materials used are, respectively, R ³ - and n-substituted phenoxyalkyl bromides or chlorides.

Table 1: 3-Phenoxyalkyloxyindazole-1-sulfonamides

Formula VI

R ¹ = CH ₃ O

Example R ² R ^J n Yield (% theor. ; M.p. (° C) ¹³ C NMR (DMSO-d 6 CH 2 (ppm)) 2 4-Tolyl phenyl 2 37 140 (2-PrOH) 65.22; 68.26 3 4-Tolyl phenylf 3 29 113-115 (2-PrOH) 28.51; 64.24; 66.99 4 4-Tolyl fenyli- 4 22nd 136-137 (2-PrOH) 25.37, -25.60 67.32, -69.75 5 4-Tolyl 2-bromophenyl 2 6 123-125 (MeOH) 64.92, -66.24 6 4-Tolyl 4-chloro- phenyl 2 26 153 (2-PrOH) 64.73 7 4-chloro- phenyl 4-chlorophenyl 2 9 149-154 (MeCN) 66.24, -68.74 8 4-fluoro- - ; phenyl 4-chloro- phenyl 2 29 121-126 (EtOH) 65.48; 67.97 9 4-Methoxyphenyl 4-chloro- (phenyl) 2 37 160-162 (2-PrOH) 66.26 -68.61 10 4-tri- fluor- 4-chloro phenyl 2 22nd 117-120 (MeCN) 66.24, -68.77

methoxyphenyl • ·

21 ·· ·· ♦ · ♦ ♦ • · ·· · ··· tf · 9 · · 9 9 · · «9 9 9 9 9 9 9 · 11 4-Tolyl 2,6-di- chlorine- phenyl 2 34 136- 137.5 (MeCN) 69.24, -71.42 12 4-Tolyl 2,4-dí- fluor- phenyl 2 15 96-100 (EtOAc) 67.87, -68.69 13 4-Tolyl 2,6-difluorophenyl 2 21 101- 102.5 (EtOH) 69.35 14 4-Tolyl 2,4,6-tri-i fluor- phenyl 2 7 1101lll. 5 (EtOH) 69.29, -72.45 and 15 Dec 4-Methoxy. phenyl. 2-bromo-4,6-difluoro- phenyl 2 10 119- 121.5 (EtOAc) 67.64 16 4-chloro- phenyl 2-bromo-4,6-difluorophenyl 2 5 138- 139.5 (EtOH) 69.41 17 4-Tolyl 2,6-dibromo-4-nitrophenyl; 2 16 131 (MeCN) 69.17, -72.17 18 4-Meth- ^OX Y phenyl · 2,6-di- bromo-4- nitro- phenyl 2 14 153 (EtOH) 69.72, -72.73 19 Dec 4-Tolyl 4-Nitro- phenyl ' 2 9 152-156 (2-PrOH) 66.92, -68.40 20 May 4-chloro- phenyl 4-Nitro- phenyl '· 2 16 159-161 (MeCN) 66.91, -68.49 21 4-methoxy- phenyl 4-Nitro- fennel 2 20 174-178 (2-PrOH) 66.96 -68.37 22nd 2-Thio- 3 phenyl 4-Nitro- phenyl 2 35 150-155 (MeOH) 66.93, -69.58 23 4-Tolyl 4-cyan- phenyl 2 19 148-151 (2-PrOH) 65.64, -67.65 24 4-Tolyl 4-carbox- amidophenyl 2 15 175-180 (2-PrOH) 66.03, -68.62

• φ · · · · · «« «« «« «· · · · · · · · ·

The following derivatives were prepared from 5-nitro-1H-indazol-3-yl-toluene-4-sulfonate in an analogous manner:

Formula VI: R ¹ = NO

EXAMPLE ³ < ^tb > Yield < ^tb >< ¹ >

CH ₂ (gpm)

25 4-Tolyl 4-chloro phenyl 2 58 150 (MeCN) 65.05, -68.10 26 4-Tolyl 2,6-di-. chloro, phenyl 2 35 117-125 (n-BuOH) 69.88, -71.21 27 Mar: 4-Tolyl 2,6-difluorophenyl 2 25 120 (n-BuOH) 69.93, -72.07 28 4-Tolyl 2,6-di- bromo-4-nitrophenyl 2 48 159 (n-BuOH) 69.88 29 4-Tolyl 4-Nitro- phenyl 2 20 May 212-216 (MeCN) 65.39, -67.54

By reducing the 5-nitro group using the procedure of Example 87, the following derivatives are prepared:

Formula VI, R ¹ = NH

Example R ² R ² n Yield (% theor.) M.p. (° C) ¹³ C NMR (DMSO-d 6 CH ₂ (ppm)) - 30 4-Tolyl 4-chloro- phenyl 2 86 192.5- 195 (2-PrOH) 66.31 • 31 4-Tolyl 2,6-di- bromo-4- 2 73 169 (2-PrOH) 68.68 / 71.30

nitrophenyl ·

• 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00

Example 32: 5-methoxy-1- (toluene-4-sulfonyl) -3- [5- (3-trifluoromethylphenyl) -1,2,4-oxadiazol-3-ylmethoxy] -1H-indazole

3.06 g (9.5 mmol) of 5-methoxy-1H-indazol-3-yl-toluene-4-sulfonate are dissolved in 50 ml of DMSO and treated portionwise with 0.34 g (14.2 mmol) of sodium hydride. (95%). After stirring for 15 minutes, a solution of 2.5 g (9.5 mmol) of 3-chloromethyl-5- [3- (trifluoromethyl) phenyl] -1,2,4-oxadiazole in 20 mL of DMSO was added dropwise and the mixture was stirred for 15 min. Stir at 60 ° C for 3 hours. After cooling, the mixture is treated with 200 ml of water, stirred for 6 hours and the precipitate is filtered off with suction and recrystallized from ethanol.

Yield: 1.9 g (36.7% of theory)

mp 138-144 ° C ¹³ C-NMR (DMSO-d _e, 300 MHz): 19.0 CH _3; 54.1 CH ₃ O; 60.0 CH ₂ O.

The compounds of Examples 33 to 50 are synthesized in analogy to Example 32.

Table 2: 3-Benzyloxyindazole-1-sulfonamides or heteroanalogs

R ^x = CH ₃ 0

Formula VII

Example R Yield m.p. C NMR (% theor.) (° C) (DMSO-d6)

CH ₂ (ppm)

33 4-Tolyl 4-Benzyloxyphenyl 23 159-161 (MeCN) 70.51; 71.52 34 4-Tolyl 2-methoxy-5-- 15 Dec 132-136 65.67 acetylphenyl (EtOH) 35 4-Tolyl 2-fluoro-6- 21 156-160 61.76 chlorophenyl (2-PrOH) 36 4-chloro-1- 2-fluoro-6- 23 151-155 62.78 phenyl ^c chlorophenyl (EtOH) 37 38 4-fluorophenyl 4-Tolyl 3-trifluoro- ^ methylphenyl- -2-fluorophenyl 10 23 113 (MeOH) 151-152 (2-PrOH) 70.48 65.43 39 4-fluoro-_ phenyl 2-fluoro- phenyl. 18 149-150 (MeCN) 66.39 40 4-fluoro- phenyl 4-chlorophenyl 9 110-114 (EtOH) 69.16 41 4-Tolyl 4-chloro-2- -nitrophenyl 25 85-90 (2-PrOH) 67-74 42 4-Tolyl ^from xx °> 34 198-202 (MeCN) 68.68; 102.66 65.35; 43 4-Tolyl χχ? 19 Dec 183-184 (EtOAc) 65.63; 91.49 of 44 4-Tolyl 10 248-252 (MeCN) 65.25; 65.79; 92.38 of IN/ 64.55; 45 4-fluorophenyl 10 246-250 (MeCN) 65.93; 91.58 of 46 4-Tolyl z ch ₃ 10 168-174 (EtOH) 62.82 47 4-chloro- phenyl Z CH, > - H 14 180-182 (EtOH) 60.92

- H ₃ C-mixed at about 60 ° C for 3 hours. After cooling, the mixture is treated with 200 ml of water, stirred for 6 hours and the precipitate is filtered off with suction and recrystallized from acetonitrile.

Yield: 2.2 g (37.8% of theory)

mp 232-237 ° C ^and - ³ C-NMR (DMSO-d: 300 MHz): = 21.4 CH; 23.2 CH; 28.7 CH;

56.1 CH ₃ O; 69.5 CH 2 O; 189.3 2x C = 0. ¹

The compounds of Examples 52 to 65 were synthesized in analogy to Example 51.

Table 3:

-phenacylindazole-1-sulfonamide

-and

Formula VIII

R ¹ CH = O

Example R ² R ^J Yield (% of theory) M.p. (° C) ¹³ c'nmr (DMSO-CH _Z (ppm): 52 4-Tolyl 4-chloro- phenyl 7 173-180 (MeCN) 70.00 /190.55 53 4-Methoxyphenyl 4-chloro- phenyl 37 183- 183.5 (MeCN) 70.59 / 191.38 54 4-chloro- phenyl 4-chloro-phenyl 21 166-169 (2-PrOH) 72.50 / 192.84 55 4-Tolyl 3,4-di- chlorine- phenyl 9 173-178 (MeCN) 72.65 / 192.52 56 4-chloro-phenyl 3,4-di- chlorine- phenyl 13 175-178 (MeCN) 70.41 / 190.03

·····························

57 4-Acetylamino phenyl · 3,4-sti chlorine- phenyl 4 225-229 (EtOH) 71.51 / 191.47 58 Naftalen- -1-yl 3,4-di- chlorine- phenyl 17 210-212 (MeCN) 70.97 / 190.68 59 Chinolin- · -8-yl 3,4-Di- chloro- phenyl 33 213-218 (MeCN) 71.19 / 191.43 60 4-Tolyl  4-di phenyl: 8 196-200 (MeCN) 73.54 / 194.35 61 4-chlorophenyl 4-diphenyl 44 207-210 (MeCN) 73.04 / 193.65 62 4-Methoxy; fenyli 4-diphenyl 23 198-205 (MeCN) 71.55 / 192.43 63 4-Acetylamino- 4-diphenyl 2 248-249 (n-BuOH) 71.53 / 192.47

fenyT

The following derivatives were prepared from 5-nitro-1H-indazol-3-yl-toluene-4-sulfonate in an analogous manner:

Formula VIII, R ^x = NO ^r 2

Example Ø ² - R Yield (% of theory) M.p. (° C) ¹³ C NMR (DMSO-d 6 CH ₂ (PP®)) · 64 4-Tolyl 4-chloro- phenyl 35 201-207 (MeOH) 72.06 / 191.74

By reducing the 5-nitro group using the procedure of Example 87, the following derivatives are prepared:

Formula VIII, R ¹ = NH 2

Example R ² R ^J Yield (% of theory) M.p. (° C) ¹³ C NMR (DMSO-d 6 CH ₂ (ppm)) 65 4-Tolyl 4-chloro-phenyl 64 193- 195.5 (2-PrOH) 71.28 / 192.18

«« In «4 · · • · · 9 9 8 • 9 9 9 9 9 9 9 9 9 9

889 98 8999 88

Example 66: N- (2,4-Difluorophenyl) -2- [5-methoxy-1- (toluene-4-sulfonyl) -1H-indazol-3-yloxy] acetamide

3.66 g (11.5 mmol) of 5-methoxy-1H-indazol-3-yl-toluene-4-sulfonate are dissolved in 50 ml of DMSO and treated portionwise with 0.41 g (17.2 mmol) of sodium hydrides. (95%). After stirring for 15 minutes, a solution of 2.36 g (11.5 mmol) of alpha-chloro-2,4-difluoroacetanilide in 20 mL of DMSO was added dropwise and the mixture was stirred at 60 ° C for 3 hours. After cooling, the mixture is treated with 200 ml of water, stirred for 6 hours and the precipitate is filtered off with suction and recrystallized from methanol. The recrystallized precipitate is suction filtered (by-product), the filtrate is concentrated to 30 ml and after recrystallization is complete, the material is suction filtered. Yield: 1.0 g (17.8% of theory)

mp 155-159 ° C ¹³ C-NMR (DMSO-d: 300 MHz): = 20.8 CH; 55.7 CH O; 67.2 CH 0;

3 3 2

165.4 C = 0.

IR (KBr): 1706 C-O.

The compounds of Examples 67 to 76 were synthesized in analogy to Example 66.

Table 4: Other 3-substituted indazole-1-sulfonamides

• * 99 · »9 9 9 9

R ¹ = CH O p /

Example ^Λ

Yield m.p. C NMR (% theor.) (° C) (DMSO-d6

CH 2 - (ppm)

67 4-Tolyl ^CH 2 O 16 128-129 70.13 (2-PrOH)

4-Tolyl

4-Tolyl

4-fluorophenyl

4-Tolyl

4-Tolyl

4-Tolyl

4-Tolyl

135-140 72.79

142-144 67.08 (EtOH)

154-157 69.58 MeCN

165-169 69.40 MeOH

177- 67.97

178.5 (EtOH)

196-200 67.79

147-151 65.86 (EtOH)

O · 9 · «• * * * · · · · · · · · · · · · · · · · · ·

4-Tolyl

4-Methoxy, phenyl.

238-241 67.20

216 dec. 66.85

Example 77: 3- (6-chlorobenzo [1,3] dioxol-5-ylmethoxy) -5-methoxy-1- (3-nitrobenzyl) -1H-indazole

4.5 g (15 mmol) of 5-methoxy-1- (3-nitrobenzyl) -1H-indazol-3-ol are dissolved in 100 mL of DMSO and treated portionwise with 0.72 g (18 mmol) of sodium hydrides (60 mmol). %). After stirring for 2 hours, a solution of 3.1 g (15 mmol) of 6-chloropiperonyl chloride in 20 mL of DMSO was added dropwise and the mixture was stirred at 60 ° C for 3 hours. After cooling, 250 ml of water are added dropwise, the mixture is stirred for 4 hours and the solid material is filtered off with suction. The precipitate is first recrystallized from isopropanol, then from ethanol.

Yield: 3.3 g (47.0% of theory)

mp 134-135,5 ° C ^X3-C NMR (DMSO-d _e, 300 MHz):? 51.5 = CH ₂ N; 55.7 CH ₃ O; 67.8 CH _of O;

101.7 OCH ₂ O.

• · · · · · ······· · · ···· · · ·

The synthesis of the compounds of Examples 78 to 85 was carried out analogously to the procedure of Example 77.

Table 5: 1- (3-Nitrobenzyl) -3-alkyloxyindazoles

Example R Yield (% of theory) M.p. (° C) ¹³ C NMR ~ (DMSO-d6 CH2 (ppm)) 78 4-chlorophenoxyethyl 31 118-120 (2-PrOH) 51.46 / 66.68; 67.32 79 4-nitrophenoxyethyl 75 163-166 (acetone); 50.48 / 67.03; 67.10 80 4-carboxaminophenoxy- ethyl 94 159-162 (EtOH) 50.47 / 66.22; 67.28 81 2-bromo-4,6-nitrophenoxy-ethyl; 44 63-73 (2-PrOH) 52.01 / 68.32; 72.80 82 2,6-dibromo-4-nitrophenoxyethyl 18 118-121 (EtOAc) 51.95 / 68.09; 72.59 83 ^ch 2 -H-Cl 55 160-170 (acet- he;) 50.39 / 68.30 84 2,6-dichlorobenzyl 61 139-143 (EtOH) 50.49 / 65.31

• · · * · · • · • »· · • · · · • «· • · • • • • • · ♦ • · · · • • · « • ·

141-144 51.91 / 71.00

Example 86: 3- [3- (4-Fluorophenyl) propoxy] -5-nitro-1- (3-nitrobenzyl) -1H-indazole

5.97 g (19 mmol) of 5-nitro-1- (3-nitrobenzyl) -1H-indazol-3-ol and 4.47 g (29 mmol) of 3- (4-fluorophenyl) propan-1-ol are dissolved in 150 ml of tetrahydrofuran and the mixture was treated with 7.6 g (29 mmol) of triphenylphosphine. A solution of 5.1 g (29 mmol) of diethyl azodicarboxylate in 10 ml of tetrahydrofuran was then added dropwise and the mixture was stirred at 20-25 ° C for 5 hours. The mixture is distilled to dryness in vacuo, the residue is mixed with 50 ml of 1N sodium hydroxide solution for 2 hours and neutralized with 5 ml of 10N hydrochloric acid and the aqueous supernatant is decanted. The oily material obtained is crystallized by mixing with methanol and recrystallized from n-butanol.

Yield: 4.7 g (54.9% of theory)

mp 85-90 ° C ¹³ C-NMR (DMSO-d; 300 MHz): = 30.35 CH; 50.91 CK; 51.15 CH N;

€ 2 2 2

68.95 CH O.

Example 87: 3- [3- (6-chloro-benzo [1,3] dioxol-5-ylmethoxy) -533-9 9 9 9 9 9 9 9 9 9 9

In *. * 0 9 9 9 9 9 9

9 9 9 9 9 9

99999999 9 9,999 9,999

-methoxy-indazol-1-ylmethyl] phenylamine

2.2 g (4.7 mmol) of 3- (6-chlorobenzol [1,3] dioxol-5-ylmethoxy) -1- (3-nitrobenzyl) -4-indazole are dissolved in 500 ml of dioxane, the mixture is reacted with about 1 G of Raney nickel and hydrogenated for 2 hours at 70 ° C, 20 bar. After cooling, the catalyst is filtered off with suction, the filtrate is distilled to dryness in vacuo and the residue is recrystallized from dioxane.

Yield: 1.8 g (87.5% of theory)

mp 153-154 ° C ¹³ C-NMR (DMSO-d; 300 MHz): = 52.6 CH H; 55.7 CH O; 69.7 CHO;

2 3 2

101.7 OCH O.

'2

The synthesis of the compounds of Examples 88 to 90 was carried out analogously to the procedure of Example 87.

Table 6:

1- (3-Aminobenzyl) -3-alkyloxyindazoles o-R

Formula XII

34 • · * · • Φ • * ·· 11 · 9 10 · 1 · Example R Yield (% of theory) M.p. (° C) ¹³ C NMR (DMSO-d 6 CH ₂ (ppm)) 88 2H-Cl 89 227-230 (2-PrOH) 50.99 / 66.63; 67.35 89 ^CHrx ° <B ° NHj 77 176-178 (dioxane) 52.00 / 66.43; 67.33 90 yQ. _o h — ci 40 155-158 (2-PrOH) 50.84 / 70.57

Example. 91: 1- (4-fluorobenzyl) -5-methoxy-3- [2- (4-nitrophenoxy) ethoxy] -1H-indazole

4.1 g (15 mmol) of 1- (4-fluorobenzyl) -5-methoxy-1H-indazol-3-ol are dissolved in 100 ml of DMSO and treated portionwise with 1 g (25 mmol) of sodium hydride (60%). . After stirring for 2 hours, a solution of 3.7 g (15 mmol) of 2- (4-nitrophenoxy) ethyl bromide in 20 mL of DMSO was added dropwise and the mixture was stirred at 80-90 ° C for 3 hours. After cooling, 250 ml of water are added dropwise, the mixture is stirred for 4 hours and the precipitate is filtered off with suction and recrystallized from ethanol.

Yield: 3.1 g (47.2% of theory)

mp 117-120.5 ° C ¹³ C-NMR (DMSO-d ₆ ; 300 MHz): = 50.7 CH_N; 55.4 CH _and O; 67.0 CH _of O;

67.2 CH 0.

The compounds of Examples 92 to 98 were synthesized in analogy to the procedure of Example 91.

• »119 119 1 11

Table 7: 1- (4-fluorobenzyl) -3-alkyloxyindazoles

Formula XIII

Example

Yield Tt ¹³ C NMR (% theor.) (° C) (DMSO-d6)

CH ₂ (ppm)

81.5-83.5 (EtOH) 50.51 / 65 65.99 190-195 (2-PrOH) 50.73 / 66 67.21 64-66 (2-PrOH) 52.22 / 68 72.93

49;

52;

27;

97-98 (EtOH) 52.25 / 60 72-75 (EtOH) 51.96 / 58

135-136.5 (2-PrOH) 52.31 / 68 119-121 (EtOH) 53.79 / 72

• ·

Example 99: 3- [2- (2-bromo-4,6-diflurphenoxy) ethoxy] -5-methoxy-1- [2- (4-nitrophenoxy) ethyl] -1H-indazole # 1 · * 9 ·· · · · ♦ · · · ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦ ♦

2.7 g (8 mmol) of 5-methoxy-1- [2- (4-nitrophenoxy) ethyl] -1H-indazol-3-ol are dissolved in 50 ml of DMSO and reacted in portions with 0.4 g (16 g). , 7 mmol) of sodium hydrides (95%). After stirring for 15 minutes, a solution of 2.17 g (8 mmol) of 1- (2-bromo-4,

Of 6-difluorophenoxy) -2-chloroethane in 20 mL of DMSO and stirred at 60 ° C for 3 hours. After cooling, 200 ml of water are added, the mixture is stirred for 6 hours and the precipitate is filtered off with suction and recrystallized from ethanol.

Yield: 1.7 g (37.6% of theory)

mp 102 ° C ¹³ C-NMR (DMSO-d _s, 300 MHz) = 46.3 CHJX; 54.3 (CH2); 66.6 CH 2 O;

66.9 CH 0; 71,3 CH O.

The compounds of Examples 100 to 111 were synthesized in analogy to Example 99.

Table 8: 1- (4-fluorobenzyl) -3-alkyloxyindazoles

R ² f · f f f f f f ^{2 2 2 2} tu tu tu tu tu tu tu tu tu tu tu ·· · * ···· · · ·

Formula XIV NO

Example

Yield Tt ¹³ C NMR (% theor.) (° C) (DMSO-d 6)

CH ₂ (ppm)

100 ALIGN!

101

102

103

104

105

106

48 110-116 (EtOH) 67.86; 68.55; 68.84 18 157-161 (EtOAc) 65.90; 66.06; 70.53 33 181-184 (MeCN) 68.21; 71.36 29 195-197 (MeCN) 66.91; 70.44 63 153-156 (MeCN) 67.71 50 158-165 (MeCN) 67.78, -70.60 40 167-171 (MeCN) 67.51 55 91-98 (EtOH) 64.69, -66.97

107

• ttt f

9 1 1 1 1 12

9 9 9 1

9, 9, 11, 11, 11 »

108

109

110

CF,

91-96 (EtOH)

144146 (MeCN)

177177.5 (MeCN)

67.87, -69.65

64.50 67.89

63.93; 64.82; 67.04 90.63

Formula XIV, R ² = Cl Example, R ¹ Yield - (% theor.) M.p. (° C) ¹⁵ C NMR t (DMSO-d 6 CH ₂ (ppm)) .111 ^ch ^ _o hQ-c 6 110-116 (EtOH) 66.92; 67.32; 67.60

Example 112: 3- [2- (2-bromo-4,6-diflurphenoxy) ethoxy] -1- [3,4-dichlorobenzyl] -5-methylthio-1H-indazole

3.6 g (11 mmol) of 1- (3,4-dichlorobenzyl) -5-methylthio-1H-indazol-3-ol are dissolved in 100 mL of DMSO and treated portionwise with 0.34 g (13.2 mmol) sodium hydride (95%). After stirring for 2 hours, a solution of 3.0 g (11 mmol) of 1- (2-bromo-4,6-difluorophenoxy) -2-chloroethane in 20 mL of DMSO was added dropwise and the mixture was stirred at 0 ° C. · · »W 9 W W W W W W 9 9 9 9 9 9

999 9999 99 9999 99 999 ° C for 3 hours. After cooling, 200 ml of water are added dropwise, the mixture is extracted three times with 100 ml of ethyl acetate and the combined organic phases are washed with 50 ml of water, dried over sodium sulphate and distilled to dryness in vacuo. The residue is dissolved in 100 ml of chloroform, extracted by vortexing with 100 ml of 1N sodium hydroxide solution and 100 ml of water, the organic phase is dried over sodium sulphate and distilled to dryness and the residue is purified by liquid chromatography (silica gel 60 / 0.2-0). 5 mm, eluent: methylene chloride / methanol = 9: 1).

Yield: 0.3 g (5% of th.)

mp 46-49 ° C ¹³ C-NMR (DMSO-d _e, 300 MHz): 18.4 CH ₃ = S; 51.7 CH ₂ N; 68.3 CH 2 O;

72.7 CH 2 O.

The synthesis of the compounds of Example 113 was performed analogously to the procedure of Example 112.

Table 9: Substituted 1-benzyl-3-alkyloxy-5-methylthioindazoles

STEED

Example R Yield (% of theory) Mp ¹³ C NMR (° C) (DMSO-d ₆ CH ₂ (ppm)); ¹¹³ 74 134-139 51.62 / 71.09 (EtOH)

• 9 9 9 9

9 9 4 9 9 · ♦ «· · t 9 9 9 9 9 9 4

999 9994 44 4444 4 9 94 ·

Example 114: 1- {1- [2,4-Dichlorobenzyl) -3- [2- (4-nitrophenoxy) ethoxy] -1H-indazol-5-yl} -3-naphthalen-1-ylurea

2.9 g (6.1 mmol) of 1- [1- (2,4-dichlorobenzyl) -3-hydroxy-1H-indazol-5-yl] -3-naphthalen-1-ylurea were dissolved in 70 mL of DMSO and It is treated portionwise with 0.22 g (9 mmol) of sodium hydride (95%). After stirring for 10 minutes, a solution of 1.5 g (6.1 mmol) of 2- (4-nitrophenoxy) ethyl bromide in 10 mL of DMSO was added dropwise and the mixture was stirred at 60 ° C for 3 hours. After cooling, 400 ml of water are added, and the mixture is stirred for 3 hours and extracted three times with 400 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate, distilled to dryness in vacuo and the residue is recrystallized from methanol.

Yield: 1.3 g (33.2% of theory)

mp 179-183 ° C ¹³ C-NMR (DMSO-d; 300 MHz): = 48.8 CH N; 67.1 CH O; 67.3 CH 0.

€> 2 2 W

The compounds of Examples 115-123 were synthesized in analogy to Example 114.

Table 10: Substituted 1-benzyl-3-alkyloxyindazol-5-amines

R ² = 3,4-Cl '2 <>

9 9 9 9 9 9 9 9 9999 9999

Example ^R1 r ₃ Yield m.p. (% theor.) (° C) ¹³ C NMR (DMSO-d 6 ClPJppm)

115

y ^CHi yyy c, i9 o

159-168 48.33 / 64.65;

(MeOH) 65.35

116

Η H

Y o

Cl · ^

178-188 48.37 / 65.29;

(MeOH) 65.48

117

CH H CH.

Y o

146-153 50.63 / 71.05 MeOH

118 w ^H CH / O

149-155 50.44 / 71.01 MeOH

119

209-211 50.71 / 71.03 BuOH

Formula XVI, R ² = 2,4-Cl.

r ₃

Example

Yield m.p. (% theor.) (° C)

C NMR (DMSO-d 6 CH ₂ (ppm))

Η H r ~ * u

123

192-196 48.98 / 70.98 (MeCN) 9 · 4 · 4 · 4 · 4 · 4 · 4 4 · 4 ♦ * • 4 4 ·· 4 4 · ♦ 4 ·· 4444 4 · ·· ♦ · 4 · ·· ♦

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

Assay for the determination of prptidyl-prolyl isomerase (PPIase) activity and inhibition

Way:

PPase activity was assayed using a conventional enzyme 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, DH Rich et al., J. Med Chem.

38: 4164-4170 (1995).

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

Suc-Ala-Ala-Pro-Phe-Nan after addition of chymotrypsin and HEPES buffer. The extinction change at 390 nm is then recorded and evaluated. 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 catalysed by cyclophilin. The respective PPIase activities of the compounds of formula I of the present invention are shown in Table 11.

ΦΦ φ

• Φ ΦΦ Φ Φ Φ Φ

Φ Φ • ♦

· Φ • · Φ Φ

Φ »Φ

ΦΦΦΦ ΦΦΦ ΦΦ ΦΦΦΦ

Φ

Φ

Φ

Φ

Table 11

Example Inhibition of PPIase activity in (%) at 10 µM 1 95 7 70 9 90 32 70 41 71 66 40 73 67 84 90 114 100 ALIGN! 116 90 121 100 ALIGN!

Inhibition of late phase eosinophilia 24 hours after ovalbumin inhalation in actively sensitized guinea pigs

Way:

Inhibition of lung infiltration by eosinophils with test substances was tested in an in vivo test in male Dunkin-Hartley guinea pigs (200-250 g) sensitized against ovalbumin. Sensitization was performed by two intraperitoneal injections of a suspension of 20 µg of OVA together with 20 mg of aluminum hydroxide adjuvant in 0.5 ml of saline per animal administered on the following two days. 14 days after the second injection, 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 aerosol box containing OVA (0.5 mg / ml) prepared in a nebulizer using compressed air (19.6 kPa) (allergen exposure). Control animals received nebulized saline. 24 hours after administration, the animals were sacrificed with an overdose of ethylurethane (1.5 g / kg body weight i.p.) and bronchoalveolar lavage (BAL) was administered using 2 x 5 ml saline. The BAL liquid was collected, centrifuged at 300 rpm for 10 minutes and the cell pellet was resuspended in 1 ml saline. Eosinophils were stained using a Becton-Dickinson (# 5877) assay kit for staining eosinophils and counted in a Neubauer chamber. Two control groups (saline nebulization and OVA nebulization) were used in each test.

The percent 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

Test substances were administered intraperitoneally or orally as a suspension in 10% polyethylene glycol 300 and 0.5% 5-hydroxyethylcellulose, and administered 2 hours before allergen administration. Control groups were treated with a vehicle appropriate 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 the following table:

φ φ φ φ φ φ φ · • • φ φ

Table 12

- Ex. Dose [mg / kg] Submission Eosinophils (millions / animal) x ± > with Inhibition; (%) 1 10 i.p.-2h AND 2.11 ± 1.05 (B) 1.23 ± 0.38 C 0.67 ± 0.23 61 30 p.o.-2h 3.49 ± 1.47 1.75 ± 1.86 0.83 + 0.30 65 8 10 i.p.-2h 2.46 + 1.08 1.84 ± 0.94 0.97 ± 0.47 41 32 10. i.p.-2h 1.93 ± 0.75 0.86 ± 0.49 0.66 ± 0.12 85 91 10 i.p.-2h 2.89 ± 1.66 1.16 ± 0.65 0.47 ± 0.24 71 99 10 i.p.-2h 1.93 ± 0.75 1.35 ± 0.67 0.66 + 0.12 46 30 p.o.-2h 1.81 ± 0.23 1.33 + 0.23 0.33 ± 0.08 33 107 10 i.p.-2h 2.46 ± 1.08 1.44 ± 0.92 0.97 + 0.47 68 114 10 i.p.-2h 1.93 ± 0.75 1.19 ± 0.43 0.66 ± 0.12 58

A = Eosinophils in the OVA and vehicle control group;

B = Eosinophils in the test substance and OVA administration group;

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

x = mean 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 suppression of immunological events.

Ί? sl t θ η. t o to · θ η éá. x? o 3c y

Claims (10)

New 1,5- and 3-O-substituted 1H-indazoles 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> 2 ^{2 2} -CH = CH- (CH ₂ ) _p -, where ρ = 1 ... 4; Y may be - (CH) -, - (CH) -O-, - (CH) - (C = O) -, * 2 Jp 2 Jp 2 jp - (CH) - (C = O) -NH-, - (CH) - (C = O) -NH- (CH) -, - (CH) -CHOH, 2 Jp 2 jp 2 3? - = - 3? -CHOH- (CH) -, - (CH) -CH = CH-, -CH = CH- (CH) -, where ρ = 1 ... 4; 2 jp 2 jp 2 p Z may be -O-, -S-, -SO-, -SO ₂ -, -O-C (CH 2) -, 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 ₂ - ; 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-, or tricyclic saturated or mono- or polyunsaturated heterocycles having 5 to 15 ring atoms and 1 to 6 heteroatoms; 0 0 0 Which are preferably N, O and S, in particular triphenyl, pyridinyl, isoxazolyl, benzimidazolyl, benzo [1,3] dioxolyl, pyrimidinyl, quinolyl, quinazolinyl, morpholinyl, pyrrolidinyl, pyrrolyl phenyl [1,2,4] oxadiazolyl, phenylthiazolyl; wherein the carbocycles and heterocycles may be mono- or polysubstituted by 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 having 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-pCgalkyl, -N (C ₁ -C ₆ alkyl) ₂ , -NHC 8 -C ₁₄ -aryl , -N (Cg-C ₁₄ aryl) _2, -N (C ₁ -C ₆ alkyl) - (C ₆ -C ₁₄ aryl), -NHCOC ₁ -C ₆ alkyl, -NHCOCg -C ₁₄ -aryl, -CONHC ₁ -C ₆ alkyl, _C-14 -CONHCg -aryl, -CONHSO ₂ C ₁ -C ₆ alkyl, -CONHSO ₂ C ₆ -C ₁₄ -aryl, -CN, - (CO ₃ -C ₁ -C ₆ alkyl, - (C ₅ -C ₆₎ -C 1 alkyl, -COOH, -COOC ₁ - C ₆ alkyl, -O-C 8 -C ₁₄ -aryl, -O- (CO) C ₁ -C ₆ alkyl, -O- (CO) C 8 -C ₁₄ -aryl, benzyl, benzyloxy, -SC ₁ -C ₆ alkyl , -S-C 8 -C ₁₄ -aryl, -CF ₃ , - (CH ₂ ) p -COOH, where p is 1 to 4, - (CH ₂ ) p -CCOOC ₁ -C 8 alkyl, where ρ = 1 to 4, -SO ₂ -C ₁ -C ₆ alkyl, -SO ₂ C 8 -C ₁₄ -aryl? 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 if Y = - (CH ₂ ) _p - (C = O) -, - (CH ₂ ) _p - (C = O) -NH-, where ρ = 1 to 4 and R ² may be pyridine, piperazine, pyrimidine, tetrahydropyridine; 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 ₁ -C ₆ alkyl, - (CH _{3 p} -COOH, where p = 1 -4, - (CH) -COOC-C alkyl, wherein p = 1-4, -CONHC-alkyl, -CONHC -C -aryl, -CONHSO C -C alkyl, C -C -aryl -CONHSO, lH-tetrazol-5-yl, then R ² can not be phenyl, monosubstituted or polysubstituted by CN, halogen, C ^ -C ^ lkylem C 1 -C 6 alkyloxy, CF ₃ ; if R ³ -Z = NO ₂ , then R ^x -X and R ² -Y must not 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: 3- [2- (2-bromo-4,6-difluorophenoxy) ethoxy] -5-methoxy-1- (toluene-4-sulfonyl) -1H-indazole; 5-methoxy-1- (toluene-4-sulfonyl) -3- [5- (3-trifluoromethylphenyl) -1,2,4-oxadiazol-3-ylmethoxy] -1H-indazole; 6- {2- (5-methoxy-1- (toluene-4-sulfonyl) -1H-indazol-3-yloxy] acetyl} -3,4-dihydro-1H-quinolin-2-one; N- (2,4-difluorophenyl) -2- [5-methoxy-1- (toluene-4-sulfonyl) -1H-indazol-3-yloxy] acetamide; 3- (6-chlorobenzo [1,3] dioxol-5-ylmethoxy) -5-methoxy-1- (3-nitrobenzyl) -1H-indazole; 3- [3- (4-fluorophenyl) propoxy] -5-nitro-1- (3-nitrobenzyl) -1H-indazole; 3- [3- (6-chloro-benzo [1,3] dioxol-5-ylmethoxy) -5-methoxy-indazol-1-ylmethyl] -phenylamine; 1- (4-fluorobenzyl) -5-methoxy-3- [2- (4-nitrophenoxy) ethoxy] -1H-indazole; 3- [2- (2-bromo-4,6-diflurophenoxy) ethoxy] -5-methoxy-1- [2- (449) -nitrophenoxy) ethyl] -ΙΗ-indazole; 3- [2- (2-bromo-4,6-diflurphenoxy) ethoxy] -1- [3,4-dichlorobenzyl] -5-methylthio-1H-indazole; 1- {1- [2,4-Dichlorobenzyl) -3- [2- (4-nitrophenoxy) ethoxy] -1H-indazol-5-yl} -3-naphthalen-1-ylurea. Physiologically acceptable salts of the novel compounds of formula 1 according to claims 1 or 2, characterized in that they are 4 prepared by neutralizing the bases with inorganic or organic acids or by neutralizing the acids with inorganic ^or organic bases or quaternization of tertiary amines to give 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) X = -S0 ₂ "-S0-, the reaction according to Scheme 1, so that the H-indazol-3-yl sulphonates II Formula II In the presence of a base and optionally in the presence of a diluent, they react in the presence of a base to obtain compounds of formula III wherein R ¹ , R ³ , X and Z are the same as defined in claim 1, and reacting the 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, especially dimethylsulfoxide, with compounds of the general formula. of formula Hal-YR ² , 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; (b) for X = - (CH) -, - (CH) - (CH) - (C = O) -, 2 JO 2 jo 2 j? - (CH) - (C = O) -NH-, - (CH) -CH 2 -, -CHOH- (CH) -, - (CH) -CH = CH-, -CH = CH- ( CH) wherein p = 1-4, by reaction according to Scheme 2, wherein the compounds of formula III are reacted, if appropriate, in the presence of a base, in particular sodium hydride, and, if appropriate, in the presence of a diluent, especially dimethylsulfoxide with compounds of the formula Hal-YR ² , 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 as defined in claim 1; wherein the compound of formula III may also be present in tautomeric form as the compound of formula IV 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. 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.